Offering Catalogue

What we do
OFFERING CATALOGUE 2010-2011
What we do
AFGHANISTAN. Basic health concerns like acute respiratory infections and diarrhoeal diseases cause around 40% of childhood deaths.
INTROdUCTION 5
Welcome to NNE Pharmaplans first issue of What we do a catalogue about how we help our customers improve peoples lives around the world. Our reason for being is Engineering for a healthier world. We cannot claim to save lives or cure diseases. We do not produce any medicine, but we put all our engineering and consulting capabilities behind the companies that do our customers. And by supporting our customers, we play our part. Our customers work with us because we are born out of their industry. Over the past 80 years we have matched technical knowledge with industry experience and worked out simple or complex solutions according to our customers needs. We trust you will be inspired and find numerous examples of how we can help address many of the challenges our customers face in everyday working life. Thats what we do! Best regards
Hans Ole Voigt, CEO
Content Content
9 Engineering for a healthier world 12 develop, establish, improve 13 Offering map Part I Segments and offerings 17 Biopharmaceuticals 18 Biotech 26 Sterile & aseptic 37 Vaccines 45 Pharmaceuticals 46 Active pharmaceutical ingredients 52 Oral solid dosage 59 Medical devices 60 Medical devices and drug delivery systems 67 Industrial biotech 74 GMP compliance 84 Sustainability & environment 92 Containment & cleanroom 100 Logistics and facility layout 108 Laboratories 114 Manufacturing information systems 120 Performance and organisation Part II Working with us 130 A healthy decision platform 132 Fast and flexible projects 134 Intelligent revamps 136 Reliable execution 138 Efficient sourcing 140 Pure knowledge 143 144 146 148 NNE Pharmaplan offices Extended content Keyword index, categorised Keyword index, alphabetised
Todays surgical patient faces a number of risks including medical errors, aggressive bacterial infections and after-surgery complications like haemorrhaging and pains.
INTROdUCTION 9
Engineering for a healthier world

With global reach and local knowledge and an emphasis on being close to our customers, NNE Pharmaplan delivers tailored solutions based on the idea of engineering for a healthier world. Through new and innovative products, the pharma and biotech industries make the world a healthier place. At NNE Pharmaplan, we focus on the pharma and biotech industries, and our mission is to contribute to a healthier world through the services we deliver to our customers. When we deliver consultancy or projects, we help bringing products faster to market, decreasing the overall cost of production and ensuring patient safety. We share our customers commitment to improving the lives of patients everywhere. And as the pharmaceutical industry evolves, it constantly develops new products, technologies and business practices. We take pride in staying on top of these issues:
Listening to our customers We aim at understanding our customer at all levels to ensure our overall strategic development matches yours and that our services meet your business drivers and not just our contract. We aim to proactively learn about the process, conditions and user requirements for your individual projects and we listen to your directions and feedback in close, daily dialogue during projects. We are not perfect, but we are always striving to increase our knowledge and awareness. So, if you ever feel that were not living up to these goals, please tell us we will listen. Customer satisfaction We measure customer satisfaction on nearly all projects and we set very ambitious targets. In fact, customer satisfaction is a mandatory KPI in all NNE Pharmaplan units, and its measured and reported on a monthly basis to our Executive Management. Our customer satisfaction measurements include cooperation, delivery and professional quality. Long-term relationships We build customer relationships that go far beyond the individual project. Establishing an on-going dialogue with our customers is more important than winning a new project. We value the small projects that make our customers daily life easier just as much as we like the large greenfield projects. We wish to maintain a strong relationship with the individuals who are working with our solutions and we endeavour to ensure a globally consistent approach no matter where in the world you work with NNE Pharmaplan.
We are dedicated to the industry more than 97 percent of our revenue comes from pharma and biotech companies We are dedicated to our customers more than 80 percent of our turnover is repeat business We are close to our customers globally, locally and often on site We play a major role and are very active in professional societies for the pharmaceutical industry, such as ISPE, PdA, ECA and others Most importantly, we are committed to helping our customers realise successful projects
10 INTROdUCTION
Copenhagen Kalundborg Hillerd Hjrring
Cork Boston San Francisco

(Berwyn)
(Kinsale)
Chartres Lyon Basel Vevey
(Cambridge)
Philadelphia Research Triangle Park

(Morrisville)
Ofces Project references
INTROdUCTION 11
Uppsala Stockholm Turku
(Sollentuna)
Malm
Moscow Frankfurt Marburg Ulm
(Bad Homburg)
Tianjin Shanghai Guangzhou New Delhi Noida Mumbai Bangalore Kuala Lumpur
(Selangor)
12 INTROdUCTION
develop, establish, improve

NNE Pharmaplans expert consultancy and engineering services can help you maintain optimal production processes. The daily life in pharmaceutical production is both interesting and challenging: do you establish the capacity yourselves or buy it? Or do you contract production or development? At what scale do you work? do you invest for the long haul or wish to minimise the immediate spending? What technologies do you deploy? Are there new opportunities that you should consider? In short, how do you implement your business strategy of today or tomorrow? Very few operational facilities stay as they were designed and built. With the operational experience comes the possibility of continuous improvements. New production technologies or product developments open up for further optimisation addressing the different bottlenecks in the production. Mergers, consolidations, expansions, product transfer, contract manufacturing, regulatory actions or new regulations are all examples of changing conditions that require adaptations to new products or processes. The product and the process The focus of all these efforts is to ensure and maintain optimal production processes. NNE Pharmaplan focuses not only on the general engineering processes involved but also on the particular technologies and business conditions of each segment. We know the differences between the various pharma and biotech segments and their products and processes and build our services on broad product and process know-how and experience. Supporting functions Yet, pharmaceutical production is not only about products and processes. The supporting functions have to be in good shape as well. Compliance and sustainability are critical factors requiring special attention, critical utilities, environmental measures, safety, logistics, quality control and information systems. And last, but not least, the organisation and the people are vital. Offering map Our offering map to the right gives an overview of all our fields of expertise process as well as supporting functions. The offering map presents our core offerings. We have dedicated specialists in each field and up to date know-how as well as vast experience to base our solutions on. In the following chapters, we address core challenges in each of these areas and show how NNE Pharmaplan can contribute to the development, establishment and improvement of your product manufacturing.
Offering map
NNE Pharmaplan at a glance

Over 80 years of experience in the pharma and biotech industries More than 25 global locations in Europe, North America and Asia Workforce: More than 1600 Turnover: dKK 1,488 million/EUR 200 million/USd 266 million ISO 9001 certified globally
INTROdUCTION 13
Offerings for all pharma/biotech segments
Biopharmaceuticals
Vaccines
Pharmaceuticals
Medical devices
Industrial biotech
Biotech
Vaccines
Active pharmaceutical ingredients
Medical devices and drug delivery systems
Industrial biotech
Sterile & aseptic
Oral solid dosage
GMP compliance Sustainability & environment Containment & cleanroom Logistics and facility design Laboratories Manufacturing information systems Performance and organisation
... and for the entire manufacturing life cycle Develop Establish Improve
develop an optimal approach to achieve the required production capabilities
design and establish facilities all the way to efficient and compliant service
Augment the efficiency and quality of ongoing operation through optimisation and support
A wealth of specific services to implement our offerings Develop

Strategies Supply chain manufacturing Automation Single use Quality by design Site selection
Establish
Facility projects Programme management ngineering, basic design, detailed E design Architecture Automation Construction management Commissioning Quality Risk management
Improve
Upgrades Compliance gap analysis & assessment ew products and N technologies debottlenecking Automation upgrades ast upgrades with minimal F interruption

Analyses Technology transfer Manufacturing sciences development support design for manufacturing
Solutions Automation and IT solutions Cleanrooms Turnkey facilities Process modules
Operational excellence Process optimisation Output, uptime and cost improvements Lean & Six Sigma Change management eadership and people L development ontinuous improvement C methods
Studies Feasibility analyses Conceptual designs Master plans
Ramp-up Production ramp-up Training Process validation, cleaning validation
Support services Sourcing Cleanroom testing Troubleshooting Revalidation Specialist staff
Highlights
Fast track Cost-effective operation and facilities Turnkey facilities IV, vaccines Multiproduct revamps Personalised drugs and treatment Single-use technology Risk-based approach and quality by design ASTM E2500 verification Automation and IT
Our service philosophy

Passionate and committed to working in your industry We deliver Valuable insight Consistent and fast execution Superior outcomes
Part I Segments and offerings
USA. The number of people with haemophilia in the United States is estimated at 20,000. About 400 babies, mostly males, are born with haemophilia each year.
Biopharmaceuticals 17
Biopharmaceuticals
The immense growth and rapid development in the biopharmaceutical segment pose multifarious challenges. At NNE Pharmaplan, we see a wide array of new and interesting opportunities. With their remarkable therapeutic benefits, biopharmaceuticals have the potential to improve patients lives all over the world. a number of previously incurable diseases can now be cured, or at least treated. the life expectancy and quality of life have improved for patients with diseases like multiple sclerosis, cancer and arthritis. and more and more rare diseases can be addressed with increasingly specialised drugs. Biopharmaceutical activities are on the rise in many pharmaceutical companies in fact biotech and vaccines have been a major driver of the wave of mergers and acquisitions in recent years. and we expect the changes in biopharmaceutical manufacturing to continue. old as well as new large-molecule products are being produced in increased titers and often decreased batch sizes. at NNe pharmaplan, we see the new manufacturing paradigm of combining new single-use biotech technology with proven stainless steel solutions as a challenging and interesting area. actually, new products produced in smaller volumes will ultimately develop into personalised drugs. New, smaller and more flexible multiproduct facilities are becoming popular as adaptability becomes a business plan prerequisite and the significant capital costs of first generation facilities become prohibitive. and personalised medicines that target smaller patient groups are uniting with single-use technology. Biopharmaceuticals and aseptic processing were the roots of our business and have been our core expertise throughout the years.
18 Biotech
Biotech
Cost effective productivity is always a top priority, and whether it requires establishment of new facilities or improvement of existing production, NNE Pharmaplan can deliver the optimum solution. Whether your product is a novel cell or genebased therapy or an established therapeutic protein, the driving forces are competition, flexibility and efficiency: competitive production of mature biotech products including the generic versions, flexibility to use existing capacity for new or modified products, and efficient pilot launch and small-scale production for bringing new products to market. While this optimisation can ensure rapid production for clinical trials and boost production capacity for one or more products, the underlying challenge remains the same: costeffective production is required in order to bring biopharmaceutical therapies to the world. at NNe pharmaplan we are at the forefront of knowledge in this exciting journey and our project and customer portfolios represent global best practices and landmark facilities. We are leading when it comes to fast establishment of new facilities, but we are equally resourceful when your issue is optimising existing facilities. Whether your facility requires de-bottlenecking for a high-titer process, transition from single to multiproduct capability, a global automation strategy for a multivendor skid installation or you simply need to establish a cost-effective operation with novel process technologies, we deliver a competitive edge that provides increased productivity. over the years, NNe pharmaplan has been an integral part of the biologics revolution. From the first insulin treatments to todays breakthrough technologies in gene and cell therapy, tissue engineering and transgenic products, NNe pharmaplan continues to deliver innovative and creative solutions for our customers.
Biotech 19
Groundbreaking plant received the Facility of the Year Award 2005 When Novo Nordisk decided to build a new facility dedicated to the production of haemophilia medicine, the company turned to NNe pharmaplan for its innovative approach to design and engineering. the plant needed to be an integrated facility for mammalian cell fermentation, recovery and purification. Demonstrating global leadership the facility was built as a fast-track project in 18 months using modular engineering including comprehensive parallel construction of independent process modules and off-site testing of each process module. the result was a groundbreaking facility that initiated a modular engineering approach with customised solutions for the life sciences industry. once the facility was complete, it soon became a candidate for the prestigious Facility of the Year award. the award is given to a pharmaceutical manufacturer with a facility project that demonstrates global leadership through cutting-edge engineering, innovative new technology or advanced applications of existing technology.
Powerful example of modern modular engineering and design the candidacy of the Novoseven facility was based on the following features: designed to support the fast-track modular approach met an undefined demand for a life-saving drug by including a modular designed, expandable production area characterised by simplicity and transparency to ensure a safe working environment the facility was chosen among 28 outstanding pharmaceutical facilities from five continents. the nine-member judging panel chose the Novoseven plant as the winner for several reasons: creative design within a super fast-track timeline for project execution, application of modular engineering for greater control and flexibility, and dramatic and pleasing architectural features throughout the facility. the plant is now helping Novo Nordisk lead the way in breakthrough medicines for the treatment of haemophilia, as well as inspiring the construction of similarly innovative facilities.
NNe pharmaplaN services Featured iN this chapter: Getting a high throughput development facility at low cost Building versus buying Delivering high stakes revamp Flexible, fast, modular Get strategic with single-use technologies Next generation biotech facilities Single-use technology catalogue Yield increases create new bottlenecks 200 percent increase through bioprocess optimisation Automated approval of chromatography runs Plasma fractionation Challenges in advanced therapy facilities
20 Biotech
GETTiNG A hiGh ThrouGhPuT DEvEloPmENT FACiliTY AT low CoST

We recently worked with a customer on an initiative to expand development capacity. the customer was having trouble meeting demand when their pipeline began to rapidly expand after they released a series of blockbuster biopharmaceutical drugs. our customer wanted to achieve high throughput development capacity to support a
growing number of products projected to reach the market in the near future. a new development facility was the ideal choice, but the budget was limited, so to get the most out of their funds and organisational capacities, the expansion had to be done in several buildings on the same site. We worked with research, development and production user groups to align process technology across functional areas to seamlessly scale-up the production of material for clini-
cal trials. We used economic considerations, room layouts, workflows and 3d configuration of process suites to support the decision process. single-use technology became a more integral part of the strategy because of its advantages in retrofit scenarios and its reduced demands on area and installations. in the last design iteration, we used a permanent 3d configuration of single-use processing that showed involved user groups how the activities could be accommodated in the retrofitted facility. as the scope progressed more to a single-use technology solution, it became clear how the goal of high throughput development capacity could be realised in facilities that otherwise would not have had sufficient space. the combined effect resulted in a project that progressed much faster, had much more capacity, required less capital investment and made fewer overall interruptions on the production site.
BuilDiNG vErSuS BuYiNG

Bringing a biopharmaceutical product to market requires careful consideration of whether to build or buy manufacturing capacity. the timelines involved in building a facility are still so long that for most biopharmaceutical products it is necessary to start construction before final clinical proof of the therapeutic is available. otherwise, you run the risk of not having sufficient capacity for market entry. on the other hand, the large capital investment may prove premature in case the clinical proof does not materialise. the alternative is to buy capacity at a contract manufacturing organisation (cmo) well in advance of market entry. this ensures capacity at a premium but still defers the larger facility investment. this classic building versus buying decision was at the centre of our concept study for a company with a promising therapeutic protein in clinical phase three development. Based on our reference library of fast-track facility projects, we estimated the realistic construction phase for the building scenario (with a buffer interval) and could then determine what up-front, low-capital investment activities could be in place before clinical
proof was available. Based on these activities and our reference timeline, our customer could compare the building and buying scenarios in order to get an overview of their options. our final, optimised scenario was a hybrid where buying capacity was employed as the first phase strategy in order to build
up sufficient storage to cover the gap in capacity until building production capacity was initiated after clinical proof. in this way our customer obtained a production strategy that relied on a low level of capital investment while still ensuring sufficient and timely capacity for market entry well beyond the launch phase.
Biotech 21
DElivEriNG hiGh STAkES rEvAmP

When one of our customers needed to rapidly transform one of its cell culture facilities from being a single-product facility to a multi-product production facility, they looked to NNe pharmaplan to design, engineer and manage the entire revamp project. this major overhaul affected the site infrastructure, facility expansion and upstream and downstream processes and it involved a team of nearly 100 engineers.
our modular approach was mandatory in this complex project as parallel execution on almost all fronts was necessary to meet the challenge. the approach allowed for decoupling of activities so that inevitable changes had only minimal impact on other areas. as the project progressed, it became clear that the scope was broader than anticipated in the front-end study. additional upgrades were added and our initial capacity gap analysis revealed that the black and clean utility systems would need to have more users and larger capacities than first assumed. the deadline for the start of the facilitys multi-product production was inflexible and the existing production needed to meet output goals before the shutdown for reconstruction. so the clock was ticking from day one. Biotech revamp projects come with the added complexity of sterile manufacturing, cleaning and sterilisation in place (cip, sip) and automation requirements. and the new design also needed to reflect experiences from the existing production translated to the multi-product case. an effective, detailed design phase enabled us to carry out a fast and efficient pit stop phase that lasted less than six months. in this period more than 18,000 welds and over 800 instruments were installed along with the process equipment. With a scope that expanded by 50 percent after start-up and an extremely compressed time schedule, we were able to deliver the project on time and on budget with 550,000 accident-free hours of hard work.
FlExiBlE, FAST, moDulAr

at NNe pharmaplan, two of our key concepts are fast-track and modular engineering. a great example of this is a turnkey facility we built in malaysia. the facility, constructed in prefabricated modules, produces mammalian cell-based therapeutic proteins and monoclonal antibodies. We chose a modular design in order to meet the main requirements from the customer. one of the customers success criteria was high flexibility as the customer wanted to be able to grow according to market and industry demands. another requirement was cGmp-compliance enabling the customer to adhere to strict international standards and provide products and services globally. so we installed and pre-tested the equipment and systems in europe in a controlled environment before shipping them to malaysia. in addition, the customer had a very short timeframe, which NNe pharmaplan met by installing the modular facility on site within six days. since the facility is located in a complex that also houses the company headquarters and laboratories, another advantage of this modular approach was that the construction of the facility caused no major disruptions to the companys other operations. today, the facility is our customers flagship. it became malaysias first Gmp-compliant biotech facility and took our customer to the forefront of the countrys biotech sector.
22 Biotech
% Cost reduction relative to traditional
GET STrATEGiC wiTh SiNGlE-uSE TEChNoloGiES

single-use technology is on track to revolutionise biopharmaceutical production. the advantages are many. investment and variable cost reductions are the most commonly cited benefits, but they represent only one part of a strategically important decision in production technology. our position on single-use versus stainless steel is that a structured and in-depth evaluation of technologies and their implications is necessary, since the drug manufacturer essentially shifts responsibility over to the single-use suppliers. Whether the issue is product quality, operator safety, production capacity or facility design, our experience shows that the scope is always broader than first envisioned and that our structured approach will benefit any implementation.
single-use technology introduces new frontend considerations such as process compatibility, leachables/extractables, film selection, back-up suppliers, waste management and more and the manufacturers Qa system is extended to cover not only raw materials but also production technology. at NNe pharmaplan, our stage gate model approach to the strategic use of single-use technology allows you to capture these critical aspects of this new production paradigm at the right level. and our model will benefit your entire facility and all the business functions involved in your manufacturing operation. We can quickly evaluate cost advantages based on a modular engineering approach. By evaluating various process designs in terms of cost as a function of the percentage of process equipment that is installed as single-use technology we are able to develop trend curves for cost advantages of single-use technology in a typical bioprocess
Project-specific trend curve 40 35 30 25 20 15 10 5 0 0 20 40 60 80 100 % Single-use process modules
scope. You can then use the trend curves to quickly forecast the savings for alternative configurations. this type of fast approach can give you a 360 evaluation of single-use technologys impact on a facility area, hvac, process equipment, utilities and automation costs without getting caught up in the details too early in the process.
NExT GENErATioN BioTECh FACiliTiES

When youre planning to launch new biopharma products, you need to balance risk, cost and time and deal with issues such as:
deciding whether to build a new facility or upgrade an existing one
achieving flexibility for multiple products establishing a layout that guaranties optimal utilisation of the process areas meeting cGmp requirements to be able to produce in the existing facilities introducing single-use technologies to reduce investment cost and simplify installation
For a customer in need of a new greenfield mab facility, we reduced the installation scope drastically based on an operation scheme where the process followed a natural flow in time and movement, solutions prepared just-in-time into single-use bags, rolled across process corridors and parked at bays for through-the-wall transfer to process rooms. the result was a facility design based on lean workflows through optimised locations for solution preparation and storage, minimised transport and staging distances and appropriate segregation between process steps, people and product. in another case, our customers legacy facility needed to be upgraded to support viral clearance claims in downstream processing for introduction of a new product in this case the team used fast 3d models to build design variants and evaluate their consequences for the process suites the models were also used for manufacturing teams to verify the concept. the conceptual design package included production scheduling, room layouts, work flows and only minimal structural changes to the existing facility. We also obtained a reduction in variable costs in the range of 10-20 percent and an optimised buffer preparation and storage work flow.
Biotech 23
SiNGlE-uSE TEChNoloGY CATAloGuE

in a market where new products and new consolidations frequently surface, a structured approach to technology evaluation is necessary to ensure an objective evaluation. at NNe pharmaplan, technology implementation expertise and hands-on experience with process technologies are trademarks of our process group, which has collected information in an evaluation format that rates technologies and companies with respect to technical approach, process experiences and also strategic considerations, such as geographical locations and number of production sites. several of our customers have made strategic single-use technology decisions based on our technology catalogue, and we have audited suppliers and tested the technologies. We maintain excellent supplier relationships in order to get the latest information about new developments. By a series of workshops, we will take you through and evaluate all the technology/supplier combinations. together, well then select the preferred technologies for further testing in a pilot plant scale. From this structured approach, we can prioritise the testing effort so that your pilot plant capacity and resources will be applied in the most optimal manner.
YiElD iNCrEASES CrEATE NEw BoTTlENECkS

You need to fit new high-titer mab processes into an existing facility. But your facility was designed and built for a legacy product that didnt feature these high yields. advances in cell lines, media composition and bioreactor control strategies have resulted in significantly increased upstream yields so now its the downstream processes that are the bottleneck in your mab facility. What do you do? if you have a new business case that covers multiple new processes with a wide range of yields, it might exceed the scope of your facility. it then becomes a challenge to fit a multi-product process into a facility that was built for a single product, without imposing constraints on the facilitys ability to accommodate future, yet unknown processes. the problem is that increased yields will most likely lead to increased buffer consumption, process pool volumes and cycle times. in one large facility project, we worked intensively with a customer who was facing this very challenge. But they also had the added difficulty of a building that was already constructed, meaning that certain limitations on infrastructure and layout were already
present. so we performed a detailed flexibility study based on assumptions about likely process parameters for reference processes and their implications for process operations and support system dimensions. after a series of downstream workshop sessions, we optimised and value engineered the facilitys design and ended up with a
downstream design that could do the job without being too excessive with respect to installation and area demands. our modular engineering approach gave the customer the flexibility to actually go back and reintroduce the legacy process into the facility in combination with the high-titer processes without causing major changes to the layout or support systems.
24 Biotech
200 PErCENT iNCrEASE ThrouGh BioProCESS oPTimiSATioN

When building a greenfield biotech facility, capacity analysis and time scheduling are crucial as the entire facility design relies on them. these steps can also help minimise the impact on your existing production or facility start-up, so they are especially critical when you need to revamp your facility to increase capacity or to accommodate a major process change. as process development usually continues while a new facility is being engineered and built, changes are an inherent feature of biotech facility projects. this complexity comes with the biotech territory and changes in yields, retention times, chromatography capacities or cip procedures can lead to situations where the production target cannot be met or the facility not fully utilised. this situation ultimately results in your facility not being able to support the treatment demand for a serious illness. But quickly setting up a team to provide a well-informed overview of
kg product
Capacity and production need

1800 1600 1400 1000 800 600 400 200 0 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Year Capacity Ferm 1 Line 2 Capacity Ferm 1 Line 1 Capacity Ferm 2 Line 1 kg product 1200 1800 1600 1400 1200 1000 800 600 400 200 0
Capacity and production need
2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Year Large product Medium product Small product
bottlenecks, solutions and consequences can ensure the success of your project. over the past 20 years, we have made over 100 detailed capacity analyses for our customers. today our toolbox includes in-house developed applications as well as Biosolve and superpro/schedulepro, but deep process knowledge and facility understanding are the real core tools. We are constantly improving our toolbox to offer you the best optimising services for: Batch size and dividing in sub-batches
Batch execution including defining cycles at chromatography steps optimised gel load tank sizes Buffer consumption utility consumption cip of equipment
With the right tools, your revamp project can increase capacity by more than 200 percent in your existing building shell. our optimisation projects have produced capital investment savings of up to 29 percent.
AuTomATED APProvAl oF ChromAToGrAPhY ruNS

purification of bioprocess streams by column chromatography is a key step in the manufacturing of many biopharmaceuticals. But this process step is subject to variations that originate in the differences in bed height, resin lifetime, fouling, packing efficiency, etc. at NNe pharmaplan, we have a great deal of experience with high resolution and separation chromatography processes in industrial Gmp settings. apart from design, specification, installation and qualification of equipment, we can also design and implement automation and batch execution systems for purification processes. in a recent project, our customer needed to ensure that column runs were approved in a timely manner and on an unbiased uniform basis in a 24/7, large-scale operation. they wanted to maximise batch throughput and focus their limited operator resources on the most critical tasks. our automation experts saw the potential for introducing an automated approval algorithm that would
make the automation system approve all typical column runs without further action and would only notify the operators in case of exemptions. in this setup, we used historical data to programme the algorithm to recognise atypical runs and only accept chromatography runs that fall into the normal range. the algorithm identifies atypical events by comparing durations of up to 20 segments in the chromatography charts this is actually optical density as a function of flow value, not time, thus making this curve check independent of time. the implementation of the automated approval of chromatography runs has ensured that the customers atypical runs are never introduced to the product pool and that operator time is focused on these atypical runs only. and thats not all. some of the other automated chromatography applications include individual column load calculation based on titer and bed height and calculation of gel performance to determine gel lifetime and regeneration events.
Biotech 25
PlASmA FrACTioNATioN
Blood fractionation companies live in an interesting time: an increased focus on rare diseases, growing demand, and decreased plasma availability, competition with recombinant products, patient safety, and complex regulations are all putting pressure on the blood plasma fractionation segment. manufacturing therapeutic proteins by blood plasma fractionation requires many purification steps and process vessels. this makes capacity expansion prohibitive in terms of cost and space. at NNe pharmaplan, we have gained extensive expertise from working with 70 percent of the leading companies within the blood fractionation industry. as an example, we have supported a major plasma fractionation manufacturer who wanted to double their production capacity by expanding an existing building. our engineers worked with the customer as part of a fully integrated project team to deliver a design that could achieve this goal and meet the companys budget and timeframe. the project team came back with a series of design iterations and investigations that supported how single-use technology and in-line dilution of concentrated buffers could reduce costs in the multi-vessel, multi-purification steps process. inside the facility, we also helped improve working conditions by decreasing manual operations such as vessel cleaning and solutions preparation. By adopting this new production technology strategy, our customer was able to save significantly on the initially projected costs and they also got an improved project timeline.
ChAllENGES iN ADvANCED ThErAPY FACiliTiES

advanced therapies represent an exciting new segment in biopharmaceuticals. as the general trend moves away from blockbuster drugs to more personalised drugs, gene therapy, cell therapy and tissue engineering can be seen as a subset with its own hurdles. its an attractive market, but it also holds a number of challenges. the financial issue is clear: the cost of a product typically increases as volume decreases so these therapies are relatively expensive and governments and
insurance companies are yet to provide clear reimbursement standards. performing clinical trials with a smaller, more specific patient population can be more effective, but its also more difficult to arrange. and manufacturing poses a basic logistical problem the therapy will need to be supplied to a small number of patients that are located globally, so the facility may have to include facilities for administering the therapy too. at NNe pharmaplan, we have worked on a number of projects within the field of advanced therapy so we can help you
overcome some of these obstacles. When one of our customers in south Korea had to set up a new production facility for cell therapy, they asked us for help based on our expertise in process technology for patient-specific cell therapeutics and Gmp compliance. the customer provides cell therapy for the regeneration of damaged heart tissue in the case of chronic or acute heart damage. the autologous cell therapy works by culturing the patients own stem cells in vitro at the production facility and transferring them to the damaged tissue area when a sufficient culture density is reached. through a series of workshops, we delivered a facility design that took into account the customers special requirements for quality and their business case for advanced therapy medicinal products. one of the critical requirements for this kind of facility is to avoid patient-to-patient cross contamination. so we developed a flexible concept that included 10 production suites (class B) in the first project phase and provided the customer the possibility to increase this to 30 production suites in subsequent expansion phases.
26 Sterile & aSeptic
Sterile & aseptic

Aseptic and sterile processing is complex, both in terms of technology and regulatory requirements. We can help you identify the best solution, taking into account all relevant aspects. contamination is a killer and the world of finished drug products is complex and challenging. aseptic handling is essential for the integrity of all pharmaceutical products and devices. aseptic handling also adds a layer of complexity to the pharmaceutical production processes from formulation and preparation until the product is filled in its final container. traditionally this has been done in a conventional cleanroom, but today a number of technologies are available (isolator, raBS (restricted access barrier systems), single-use systems and sterile transfer of materials) to ensure a high sterility assurance level (Sal). in the inspection field, vision system techniques further enable the industry to achieve high productivity and high product quality. Other steps in the process, including labelling and packaging, are also undergoing rapid developments. Fuelled by counterfeit complaints, labelling and traceability requirements are on the rise. and the implementation of efficient logistics systems, including automated guided vehicles (aGV) and automated warehouses, present new challenges for the integrated operation of facilities and the use of technology. at NNe pharmaplan, we have deep insight into aseptic and sterile fill and finish processes. this includes our first-hand experience operating in these environments, extensive knowledge of regulatory developments, practical experience integrating the different technologies and awareness of the industrys most recent developments. We can advise you on the mix of technologies that makes the most sense financially for your company. and we can help you balance your investment costs, operational costs, regulatory requirements and risks.
Sterile & aSeptic 27
Operational excellence in design recognised in 2009, hameln pharmas sterile production plant designed by NNe pharmaplan was awarded the prestigious international iSpe Facility of the Year award in the Operational excellence category. For more than 50 years the German company hameln pharma has been a specialist contract manufacturer of parenteral solutions and suspensions. hameln pharmas activities involve the manufacturing and marketing of liquid pharmaceuticals, primarily for hospitals and intensive medicine. New sterile production plant NNe pharmaplan helped hameln pharma establish the 9,200 m sterile production plant that won the award for operational excellence. Well before the engineering and construction phases, hameln pharma contacted NNe pharmaplan in order to set the qualification concept, conduct
a risk analysis and prepare the validation master plan. NNe pharmaplan was also responsible for reviewing and reworking the conceptual design, the basic design, process engineering and qualification. the award jury highlighted the facilitys lean production concepts, which were implemented throughout the design and construction of this facility. For example, the u-shaped structure of the filling systems reduced traffic in the highest class of cleanroom, increasing the plants productivity. Significantly increased production capacity the innovative, flexible sterile facility was built and put into operation after a project time of only 25 months at hameln pharmas headquarters in hameln, Germany. the facility has increased the companys production capacity significantly and created space for the implementation of innovative technologies.
NNe pharmaplaN SerViceS Featured iN thiS chapter: High-tech aseptic facility helps meet regulations and save costs EU GMP pushes the use of technology Finding the right contract manufacturers Infusion solutions worldwide Optimised formulation delivers capacity increase Complexity in freeze drying Full-scale delivery of freeze drying isolator line Wash and sterilisation an integral part of aseptic operations Campaign filling a more efficient way Packaging challenges Inspection technologies Fighting counterfeit drugs Microdosing a new siliconisation technology Internal logistics and material handling Contamination finding the root cause Single-use in filling operations: the future?
FINdING tHE rIGHt CONtrACt MANUFACtUrErS

investing in your own filling and packaging capacity may be a costly way to produce your final product. in a number of situations, contract manufacturing is a better option. NNe pharmaplan can help customers search for and screen contract manufacturing organisations (cmO), and advise the customer in the selection process. Based on our many years of experience in the pharma and biotech industries, our global presence, our representation in numerous trade associations and a list of customers from all over the world, we have a vast network of industry experts and contacts in the industry. in addition to this, we have a number of reliable database sources to draw on.
HIGH-tECH ASEPtIC FACIlIty HElPS MEEt rEGUlAtIONS ANd SAvE COStS

implementing a modern and efficient aseptic processing facility requires advanced knowledge of the available technologies including their benefits and pitfalls as well as thorough understanding of the regulations that govern the industry. this makes balancing the interpretation of current regulations with new technological developments a key challenge. in a state-of-the-art, large-scale aseptic fill finish project in Japan we provided regulatory and technological know-how to a customer to ensure the right choice of process technology. Because the new fill finish plant will distribute products to the world market, it must comply both with european, uS and Japanese regulations. But the customer had an
additional challenge: they operate in a very competitive market and so the entire project was cost-driven. We helped the customer choose the best available technologies, including selecting restricted access Barriers (raBS) technology over isolators wherever possible. this resulted in significant investment savings. in addition, we designed the air flows to achieve the right air change level in the complicated room setup and used simulation software to create an energy-efficient yet fully compliant hVac installation. Once these decisions had been made, we carried out conceptual, basic and detailed design and were responsible for the overall project management, including infrastructure and process automation. We also managed both the construction and the design qualification. after completion of the facility, we support the customer with start-up and optimisation services.
We conduct each cmO search to find the company that can produce the exact product that you need. many customers will have very specific requirements for the cmO. criteria often include technical or compliance requirements, cultural and language-related considerations or which countries have approved the cmO. Based on these criteria we will present the candidates to you, pointing out their strengths and weaknesses, and making it as easy as possible for you to make the best choice. We are also able to arrange visits and perform audits of the selected cmO to verify that it is in compliance with current Good manufacturing practice. Our auditors come from a background of regulatory authorities such as the iSO and the Fda, and also include people with experience of working in quality and production. after the final cmO selection, we offer to help you with contract negotiation to ensure you get the best possible conditions for collaboration with the cmO.
EU GMP PUSHES tHE USE OF tECHNOlOGy

the eu Gmps new annex i, manufacture of Sterile medicinal products, emphasises in particular the process of freeze drying. the regulations require freeze-dried vials to stay in grade a conditions until final closing giving rise to potential area classifications and operator interventions issues as well as
concerns for the environment, monitoring and vial integrity assurance. all this means that you need to consider your technology carefully: is isolator technology necessary? Will restricted access barriers (raBS) be sufficient? do you need to automate the loading and unloading of freeze dryers? and how will the different solutions affect your investment and operational costs?
INFUSION SOlUtIONS WOrldWIdE

the manufacturing of pharmaceutical forms demands high standards when planning production facilities. even established pharma companies can benefit from an experienced, reliable partner. NNe pharmaplan has completed more than 40 plants for the manufacturing of infusion solutions in more than 30 countries worldwide including technology transfer for standard solutions. Our expertise includes plants for the manufacturing of infusion solutions and filling into various forms of primary packaging such as glass bottles, plastic bags and bottles (blow fill seal technology) ranging from 100 ml to 1000 ml, or pVc and polyolefin bags for irrigation solutions up to 5,000 ml.
We offer our customers extensive knowhow in infusion manufacturing technology, including:

the generation and distribution of water for injection (WFi) Solution preparation and storage manufacturing bottles or bags Filling bottles or bags Sterilisation of the products inspection and packaging
We also provide production manuals (standard operating procedures) and quality control manuals as well as training of staff at a similar plant. and we prepare both standard infusion and plasma expander solutions and parenteral nutrition solutions (including fat emulsions).
Our projects range from semi-manual to high-grade automation and our services from process engineering up to the supply of a complete plant on a turnkey basis.
flexible system with mobile tanks and off-line cip/Sip, where such a system is appropriate. due to the above utilisation rates, companies are often on the lookout for solutions that can improve efficiency to obtain shorter batch change-over time or reduce the cost of goods sold (cOGS). to NNe pharmaplan, the basis of optimisation is flexibility, thorough process understanding and industry-specific experience. We can challenge your production setup, equipment choice and flow in order to achieve a more flexible and efficient production setup. For customers with many different products and batch sizes, we have incorporated flexible systems with mobile tanks that can be taken in and out of the process and cleaned and sterilised away from the process to render the formulation area free for use with other tanks. companies with a narrow product range will often benefit from more integrated systems optimised with a number of tanks that fit the rest of the production line. Such systems can also have integrated computer and/or batch control. at NNe pharmaplan, we have implemented highly automated systems with integrated recipe control, raw material tracking, batch reporting and even integrated data acquisition from different in-process controls like ph, temperature and others.
OPtIMISEd FOrMUlAtION dElIvErS CAPACIty INCrEASE

an integrated and automated formulation area can be the key to high throughput and consistent quality. designing and installing systems that can handle the diverse substances and amounts with accuracy, traceability and without interruptions require specialist knowledge and thorough process understanding to create the correct interfaces to steps further down the line and especially to the utility systems.
the complexity of formulation and filling tanks is partially due to the intricate system of pipes leading materials to and from the tanks and the huge number of valves, connections, sampling points, etc. that are also part of the tank system. consequently, cleaning-in-place (cip) and sterilisation-inplace (Sip) of the tanks specifically important due to the criticality of the formulation process are complicated and very timeconsuming. in fact, the time spent on cip/ Sip renders a machine capacity utilisation rate of only 30-40 percent for most formulation areas. Optimisation options include a more
with variable or unpredictable freezing and drying behaviours. at NNe pharmaplan, we have more than 25 years of experience with freeze drying projects, from small size pilot plants (including liquid nitrogen cooling systems) to largescale production plants with fully automated control of all cycles, including cleaning and Sterilisation in place (cip/Sip) and filter tests. We have a dedicated team focused on recent trends, quality and regulatory issues, and we collaborate with leading suppliers of freeze dryers. Suppliers are evaluated during audits and project cooperation, where quality and expertise are constantly assessed. Our objective is to deliver integrated solutions and know-how in order to find your optimal solution that is sustainable and ensures a fast time to market.
WASH ANd StErIlISAtION AN INtEGrAl PArt OF ASEPtIC OPErAtIONS

For pharmaceutical companies and hospitals involved in sterile and aseptic production, wash and sterilisation is a crucial part of ensuring that products live up to the requirements for high quality and safety. having the right equipment to meet your needs and fit in with your existing process equipment is the cornerstone of any wash and sterilisation process. Wash and sterilisation equipment includes washing machines, autoclaves and closure processing equipment (cpe). as opposed to washing machines and autoclaves, cpe can be used in interaction with isolator filling technology to process caps, rubber stoppers, pitons and glass beads and feed them directly onto the isolator filling lines using aseptic containers without breaking the class a aseptic environment. at NNe pharmaplan, we are experienced in designing and establishing wash and sterilisation in complete pharma plants for active pharmaceutical ingredients (api) and aseptic production. We focus on the correlation between wash and sterilisation and other production processes such as filling, quality assurance and the utility areas, which helps us work out what to consider and who to talk to in order to achieve the best solution possible.
COMPlExIty IN FrEEzE dryING

Freeze drying is one of the most complex processes in pharmaceutical and biotech production, and it poses numerous technological and regulatory challenges to manufacturers. technologically, the process is a challenge because many freeze dried materials are composed of multiple elements
FUll-SCAlE dElIvEry OF FrEEzE dryING ISOlAtOr lINE

at one of our customers facilities, the freeze dryer is connected to an isolator filling line. to keep the vials in the isolator environment, the vials are transported and loaded into the freeze dryer by an automated load system. the automated loading system is able to load the entire freeze dryer shelf by shelf in a controlled environment supervised by a Scada (Supervisory control and data acquisition) system. We worked with the customer to prepare the complete design and functional specifications. after assembly at the vendor site, all functions were tested and the equipment was shipped to the customers site. due to difficult handling and building construction, the equipment was lowered through the roof into the production area. the weight of
the complete installation was more than 30 tonnes. in order to optimise the space in the cleanroom area, all the technical installations and the condenser were placed on the floor below the chamber and maintenance was thus removed from the production area. When the freeze drying cycle is completed, the chamber is automatically emptied by the unloading system that consists of a cart on rails embedded in the floor. the cart can empty an entire vial package ( shelf size) at a time. the vials are moved to a buffer rack to ensure fast unloading. From there they are automatically transported to the capper and then taken to a lower class area. the entire installation was managed, planned and tested by NNe pharmaplan, and we ensured the necessary qualification documentation for all the equipment.
CAMPAIGN FIllING A MOrE EFFICIENt WAy

For many companies, the time it takes to change over between batches is a bottleneck in the production process. most of the time lost between batches is due to cleaning, which is complex and time-consuming. however, you can save time using campaign filling. With campaign filling, you can fill more than one batch between each session of full cleaning/decontamination. and between batches in each campaign, some reduced cleaning can be carried out. the campaign approach represents a significant opportunity to minimise the costs of non-production activities such as cleaning, sterilisation and machine assembly. ultimately, campaign filling can increase the number of batches produced per year, and thus increase your annual production capacity. regulatory requirement although the campaign approach is now becoming common practice in aseptic processes, there is still a lack of clarity about what regulatory authorities accept and expect in terms of validation. Some concepts, however, are frequently discussed in the regulatory guides and can help clarify the expectations of the main regulatory authorities. the Fda guide, Sterile drug products produced by aseptic processing, recommends that Factors associated with the longest permitted run on the processing line that can pose contamination risk are addressed during the media fill programme and, When appropriate, time limits should be established for each phase of aseptic processing, and these limits Should be supported by data. eu Gmp (annex i) similarly states, the interval between the sterilisation and use of components, containers and equipment should be minimised and subject to a timelimit appropriate to the storage conditions. Successful campaign filling implementation in 2006, NNe pharmaplan implemented campaign filling in an isolator for an aseptic manufacturing company. For the six years the facility had been in operation, the isola-
tor filling line had been producing only one batch after each full decontamination of the isolator. the filling line and isolator had been ramped up prior to 2006, which had resulted in several improvements and very stable performance. But a lot of time was still spent on batch change-over. Between every batch, the isolator was decontaminated and the filling system was cleaned and sterilised in place (cip/Sip). each batch change-over took between 24 and 30 hours. Based on this, the customer had three main success criteria for the project: increasing of the Overall equipment efficiency (Oee) of the isolator filling line reducing the cost of Sold Goods (cOSG) using the isolator filling line as an isolator and not as a conventional cleanroom We gathered a few process specialists to carry out the project, which was divided into four phases: 1. the idea phase which clarified the projects objectives and areas for improvement. 2. the analysis phase which included simulating current and future batch change-over with a model built out of lego blocks to help the team visualise the filling line and isolator. this phase also
included a capacity analysis, a description of batch separation activities and a cost/ benefit and risk analysis. 3. the implementation phase in which the campaign period was validated with three times media fill carried out on the last day in the campaign. 4. the evaluation phase. Based on calculations, the process was designed to facilitate seven and a half days of campaigning to comply with the customers goal for a 20 percent increase in capacity, and this goal was reached within six months of operation. accordingly, six months after the implementation new goals were set for production. these involved increasing the campaign filling period from seven and a half to 21 days. this was implemented over the course of the following two months. today, the facility runs the isolator for 21 days without opening it. this has resulted in a total capacity increase of more than 30 percent. Overall, the project was a huge success for the customer. it turned out to be a low-cost project (our consultant hours and a loss of only three days of production for media fill) that yielded a very high increase in capacity, so the payback time was very short. Furthermore, the risk was very low due to full separation (change/sterilisation of wet parts) between batches.
PACkAGING CHAllENGES
the majority of problems on packaging lines are related to poor line clearance, so its important to create a design that mitigates these issues. design considerations for a line layout should include the ability to manage quick change-over, perform line clearance between product batches and clean the line in an easy and controlled manner. at NNe pharmaplan, we have carried out numerous layout studies for both new and existing packaging areas. in preliminary phases, we can support the packaging component development and suggest optimised solutions and setups. By using lean manufacturing concepts in the packaging area, we can further optimise your running production. Because of our many years of experience in the industry, NNe pharmaplan has thorough knowledge of the different packaging machine providers both in terms of technological capabilities and their ability to administer large machinery deliveries. accordingly, we can help you choose the provider and the equipment that will best suit your specific production. We can also help you choose the right packaging material for your production process, packaging line and equipment, or we can adjust your packaging line to tie in with your product and packaging material. Our team will work with you on the specification, installation and qualification of your packaging equipment and processes. NNe pharmaplan also offers a broad range of other engineering and consulting services related to packaging, for example:

labelling and coding on primary, secondary and tertiary packaging materials and carriers
Blister packaging of tablets, vials, devices and protective packaging cartoning in end, and top load flow wrap and pouch packing, wraparound and wallets case packing in shipper boxes or bulk shipments palletising integrated or stand-alone test and verification technology involved in the above mentioned processes internal product handling, buffers, robots and transport systems packaging of high potency drugs
INSPECtION tECHNOlOGIES
in pharma and biotech manufacturing, and particularly in regards to parenterals, inspection is a crucial part of ensuring that finished products respect patient safety and live up to relevant quality and safety requirements. consequently, inspection is subject to increasingly tight regulatory requirements for quality. a precise inspection process is
key to ensuring quality, but it is also critical to ensuring a high throughput. too strict inspection may weed out products that are actually satisfactory and therefore should not be discarded. Such false rejects lead to an output and a turnover that is lower than it could be. NNe pharmaplan has experience within a wide range of products (suspensions, solu-
tions, lyophilised) and containers (cartridges, vials, syringes, ampoules) as well as numerous inspection technologies. Our experience includes fully automated visual inspection machines, table inspections, leak detection (instead of visual inspections for chips and cracks), closure inspections using high voltage, vacuum or headspace analysis, checking of different (device) assemblies, OcV (optical character verification) of label imprints and reading/checking of data matrix codes to prevent counterfeit products. With our many years of inspection technology experience, NNe pharmaplan is familiar with all main suppliers of machinery and can offer advice on which providers to choose. Were also at the forefront when it comes to new inspection technologies, so we can provide you with consulting on traditional as well as innovative solutions.
FIGHtING COUNtErFEIt drUGS

Fake drugs are a cruel reality in the pharma and biotech industries. counterfeit medicines are found everywhere in the world, and are as common in developed countries as they are in developing countries. they also exist on the internet where consumers, in good faith, look for the cheapest price for drugs they might not otherwise be able to afford. counterfeiting pharmaceutical products is a multi-billion dollar industry and, each year, customs officers impound more and more shipments of counterfeit drugs intended for sale on the internet. in fact, the level in 2007 showed an increase of nearly 400 percent compared to 2005/2006. the list of counterfeit drugs is growing: malaria and hiV treatments, heart medicine, anti-depressives, heparin, cough medicine and more. even low-cost generic drugs and devices in the low-earning segment are subject to counterfeit. Bogus products range from random mixtures of harmful toxic substances to inactive, ineffective preparations. they can result in treatment failure, severe disablement, organ failure and even death. Some contain a declared, active ingredient and look so similar to the genuine product that they deceive health professionals as well as patients. But in every case, the source is unknown and its content unreliable. eliminating counterfeit drugs is a considerable public health challenge. Numerous countries already have laws in place to try and put a stop to the production and import of counterfeit drugs, and health authorities, pharmacies, distributors and suppliers of pharmaceuticals are collaborating on anticounterfeit initiatives to control the problem. the victims of counterfeit drugs are, first and foremost, consumers, but also pharma and biotech companies suffer under counterfeiting, which is a huge threat to their business and their trademark. moreover, as the originator of the product, the manufacturer has an obvious role to play in product authentication and supply chain control efforts. the solution is to make authentic products easily verifiable, which also makes it easier to identify fake products. many pharmaceutical companies have added visible security features to their packaging. these include
holograms, embossing, special ink and two-dimensional bar codes. however, these visible features not only provide minimal security, they also require trained personnel to carry out authentication. many companies use barcodes to identify item level packaging because they are familiar with the technology, and because barcodes are inexpensive to print and apply. however, when a barcode is pre-printed as part of a products packaging, it cannot be used to identify counterfeit products because they do not provide item level identification and are susceptible to easy reproduction. more sophisticated technologies have been developed to facilitate security printing and authentication. the common basis for these technologies is to apply a unique identification code to each individual pack, which will be checked by the pharmacist behind the counter before dispensing the product to the customer. if the pharmacists scanner identifies a duplicate code, it will trigger an alarm, and perhaps initiate an investigation into the source of the counterfeit product. automated identifications, or auto ids, are types of identification that machines can read, and they include:
Barcodes two-dimensional codes radio frequency identification (rFid) tags Optical character recognition (Ocr)
each type has a number of sub-types, which all have pros and cons, leaving you with a vast number of options and a difficult decision to make. We can help you choose the technology that best meets your needs. We can also carry out the design and installation to make sure it is fully integrated with your production line. We do all the footwork to help you get started and bring you up-to-speed with a complete solution. as well as an effective measure against counterfeit drugs, modern identification technologies represent a number of other benefits: application to electronic pedigrees, supply chain management, reverse logistics and inventory control assurance that information is read automatically and correctly every time less redundancy as information can be reused in different places less monotonous and lengthy registration work easy track-and-trace of product shipments
MICrOdOSING A NEW SIlICONISAtION tECHNOlOGy

millions of patients all over the world rely on daily self-injections. this not only makes them dependent on high quality medicine, but also on easy-to-use self-injection devices that enable easy, controlled administration. this requires an even friction between the plunger and glass as it moves through the container. the amount of silicone oil on the inside of the pharmaceutical glass is critical. it determines the level of resistance in the container, and thus controls how easy or difficult it is to activate and empty the injection device. the silicone coating ensures efficient emptying of the container and eliminates dosage errors and waste, so improving siliconisation is key to improving the product. recently, a new siliconisation technology called micro-dosing has come into play.
micro-dosing involves spraying silicon on the inside of the glass, but in this case the spray nozzle is led through the entire length of the glass rather than just spraying from the bottom. this makes the layer of silicon on the glass walls more uniform, which creates more even friction on the glass. in addition to more homogenous siliconisation, microdosing also has the benefit of lower process variation, which leads to more consistent product quality and products that are compliant with regulatory requirements. in one of our projects we implemented a siliconisation system based on microdosing. the customer wanted to replace their existing spray siliconisation system for cartridges in order to achieve:

With the concept of Quality by design in mind, NNe pharmaplan helped the customer develop, specify, purchase, install and validate the new siliconisation system. We also trained the customers staff to use the new system. the project resulted in a significant process improvement that included higher Overall equipment effectiveness (Oee), easier maintenance and increased reliability.
more homogenous cartridge siliconisation reduced process variation Fewer adjustable parameters longer holding time in the sterilisation tunnel
Within sterile production, we are experienced in the classification of sterile areas so we can design logistics and transportation systems that respect the room zoning and prevent contamination in the material handling process from one classified area to another. For one of our customers, we designed a new semi-automatic logistics solution for a packaging facility on three levels with production areas on the first and second floors and in the warehouses, and receive and dispatch areas on the ground floor. the design comprises a number of customised solutions such as a narrow-aisle warehouse, vertical conveyors between the ground floor and the second floor, an automatic staging buffer for batch materials and a waste duct system. another customer needed a totally new logistics concept in an existing building. We designed the logistics concept as a process line arrangement, featuring a covered automatic warehouse in the existing warehouse, an automatic store and pick function, automatic de-palletising and palletising, automatic transport to the assembly and packaging lines, aGV transport to the assembly line and a conveyor and lift transport to the packaging lines.
INtErNAl lOGIStICS ANd MAtErIAl HANdlING

the design of internal logistics and material handling is a complex exercise that involves connecting manufacturing processes in a way that ensures the right material is at the right place at the right time. this not only applies to the transport of materials and products to and from the production line but also to the receive and dispatch processes, storage processes and waste handling. at NNe pharmaplan, we have many years of experience in material handling and internal logistics for Gmp environments within the pharma and biotech industries. and we offer a wealth of engineering and consulting services and technical solutions within these fields, including logistics design, warehouse layout, design of conveyers, specification of aGVs and load carriers.
CONtAMINAtION FINdING tHE rOOt CAUSE

every now and then, unexpected problems or events occur in any type of production that result in poor product quality. authorities increasingly hold pharmaceutical and biotech companies responsible for determining and documenting the root causes of such slip-ups in production. While the nature of problems such as sterility failure or contamination is easy to identify, companies often lack the tools and knowhow required to investigate the source of the problem in a structured and effective way. With our vast process knowledge and proven methods, we can offer you valuable support in the investigation of root causes. Our approach is based on so-called root cause analysis (rca). this is a set of problem-solving methods aimed at identifying the root causes of problems or events. rca
is based on the belief that problems are best solved by attempting to correct or eliminate root causes, as opposed to merely addressing the obvious symptoms. rca includes different tools such as the ishikawa method, or the fishbone methods, which is an internationally recognised quality risk management tool for the life science industry (ich Q9). it can be treated as a visual tool that looks at a range of criteria to identify the root cause, including:

has expertise in one or more of these areas. as a result, the root cause investigation is structured and systematic, ensuring all the criteria are explored in depth. Our rca package deal includes workshops to keep you involved throughout the process and to share all methodology and findings so you are equipped to deal with them and get a more thorough understanding of the process and any risks involved. We will work closely with you to develop a prioritised action plan along with a cost estimate for the elimination of the root cause.
Measurement Man Machine
measurement man (human error) machine mother Nature (process environment) material method
Problem
rather than putting one person in charge of investigating all parameters, NNe pharmaplan provides the tools and a strong team of subject matter experts. each team member
Mother Nature
Material
Method
SINGlE-USE IN FIllING OPErAtIONS: tHE FUtUrE?

compared to traditional stainless steel process equipment, single-use equipment significantly reduces the risk of contamination and it also reduces investment, increases flexibility and decreases time to market. many companies within the pharma and biotech industries have been using single-use for years in biotech applications. and if you have a fill-finish production, implementing single-use technology in both existing and new processes can help you realise business benefits and more effective production. Over the years, NNe pharmaplan has designed many single-use systems for filtration, preparation and filling for a wide range of customers in the pharma and biotech industries. in terms of preparation, single-use technology is suitable for batch sizes smaller than 1,000 litres. implementing single-use equipment in the preparation allows the dispensing of powder to be done in a closed system and enables simplified automation. in filtration and filling, single-use equipment facilitates a completely closed system using
bags, plastic hoses and sterile couplings, and it enables filtration and integrity tests in-line. peristaltic filling is required, allowing pumps to be placed outside grade a and providing excellent filling accuracy for small volumes. as with any technology, single-use systems have both advantages and disadvantages. the disadvantages include a higher need for logistics in the handling of bags and other parts, a higher cost per batch and its environmental impact. the many advantages include: maximum flexibility Fast change-over limited cleaning validation (no cip/Sip) No cross-contamination between products lower investment cost Shorter implementation time
the advantages are the reasons we consider single-use technology to be the technology of the future. We have worked on many projects where single-use technology turned out to be the best choice, for example in the construction of a complete biotech facility in biosafety level 2 (BSl2) with fill-finish based on single-use and a conceptual and basic design for single-use formulation and filling.
RUSSIA. After years of decline, the tuberculosis incidence has doubled during the 1990s and Russia is now among the 20 most affected countries in the world.
Vaccines 37
Vaccines
They have revolutionised therapeutic treatment, but to truly eradicate diseases, vaccines must be available and affordable everywhere. Our modular engineering concept is designed to facilitate this. The modern world of pharmaceutical treatments would be unthinkable without vaccines. The good old story of how edward Jenner in 1796 the observation that milk maids typically avoided smallpox because they had been exposed to the milder cowpox is really engineering for a healthier world when its best. it is a well-known truth that prevention is cheaper than treatment, and the whole vaccine business is a living example of what this may mean in real life. in fact, vaccines have helped prevent or even eradicate a number of serious diseases and this is an ongoing trend continuing in our modern world. new and promising vaccines are in development that may remove some of the human races biggest fears in life. Today, the vaccine industry addresses a wealth of diseases, ranging from measles and flu through tropic diseases and paediatric vaccination programmes to cervical cancer, and is the fastest growing segment in the pharmaceutical industry. in africa and yet emerging economies, cancer vaccines or even flu vaccines are often a luxury. short of HiV and malaria, both of which have yet no vaccine, emerging economies mainly require paediatric and similar vaccines. if these vaccines were used consistently, they could help eradicate illnesses like measles from the continent. However, before this can happen, the price of the vaccines must be lowered and they must be available everywhere. at nne Pharmaplan, we develop modular vaccine facilities, which will help facilitate this, by providing a cost-effective alternative to design to order.
38 Vaccines
Vaccines
Bulk vaccine manufacturing is subject to many challenges and rapid development unique to vaccines. Being on top of that development we offer a wide range of services to make sure you will be too. The production of bulk vaccines involves challenges and issues that are not often seen in other pharmaceutical production, such as eggbased processes, containment and biosafety, and downstream processes that are almost exclusive to vaccine production. Vaccine production is more than 100 years old and a well-established technology. However, recent years have seen a dramatic development in production scale and technologies. For instance, flu vaccine production has grown dramatically, further fuelled by the increasing awareness of the need for pandemics preparedness. each year, the WHO defines which flu vaccine must be produced. The product needs to be ready five months later. in emerging and third world countries, access to low-cost vaccines determines millions of lives. in recent years, a number of countries including developing countries are working on ensuring their supply chain through local production an effort supported by the WHO. an additional trend is that non-injectable vaccines (e.g. tablets and inhalers) are emerging as a convenient and efficient way of dealing with some diseases, in particular allergies. another interesting development is the migration of vaccines into other areas: cancer vaccines (therapeutic and hopefully preventive) are one of the primary growth areas in pharma today; biodefence, preparedness to withstand biological terror attacks; and personalised vaccines. nne Pharmaplan has been involved in all of these areas working for a great number of the leading vaccine producers worldwide, and also cooperating with WHO to establish efficient and safe vaccine production. Our team includes leading vaccine experts with many years of industry experience. We can help you establish all the relevant processes and utilities for cost-effective global bulk vaccine manufacturing whether it is for a full facility, an upgrade or an expansion including fast-track projects and multiproduct facilities, process development and scale-up or process troubleshooting. We also develop modular vaccine facilities based on vaccine biotypes.
Vaccines 39
Meeting the need for vaccines in record time Bavarian nordic needed to transform an existing pharmaceutical production building into a clean and qualified new facility for the production of its vaccine against smallpox. The facility had to be ready very fast in order to prove that Bavarian nordic could produce the vaccine for its rFP3 order evaluation for the production of vaccines for emergency use in the us. A fully modernised, validated facility The project included a facility clean up of the previous pharmaceutical production process. all existing interior walls and surfaces in the production areas were demolished and a cleaning validation was performed before the construction of new process and production areas. nne Pharmaplan helped the customer with all phases of the project from early strategy and site selection to full operation and completed the project in just 11 months from basic design to handover. nne Pharmaplan was also responsible for procuring building and environmental permits and production permits for biological agents.
in order to achieve this fast-track project execution, a host of accelerating measures like: single use technology massively parallel project execution intensive teambuilding involving users, engineers and contractors Ensured capacity The result of the project is a state-of-the-art, future-proof facility, which also contains a shell construction area for possible future expansion. With a production capacity increase of a minimum 40 million doses per year, the company has ensured the supply of its current and future vaccines and its ability to meet growing demand. Bavarian nordic is now an important supplier of smallpox vaccines to several governments, most notably the us. and the company has other vaccines in the pipeline, primarily based on the patented mVa-Bn technology. These include a number of vaccine programmes within biodefence, therapeutic cancer vaccines and infectious diseases. With these vaccines, Bavarian nordic could help address some of the worlds most pressing health issues.
nne PHarmaPlan serVices FeaTured in THis cHaPTer: Multiproduct BSL2 vaccine facility Establish multiproduct production Standardised vaccine facilities a new concept Therapeutic vaccines and their promise for the future Egg-based vaccine facilities Handling GMO approvals Biosafety & biosecurity Getting started with manufacturing from idea to operation Lean vaccine production Tech transfer a matter of know-how
40 Vaccines
MuLTiprOducT BSL2 vAccinE fAciLiTy

When a vaccine manufacturer approached us with a tight deadline for establishing a new multiproduct vaccine facility coupled with an equally tight deadline for bringing the first product to market, it was clear that a front-end study focusing on a robust and compliant layout and building functionality was an important part of the solution. We conducted a series of front-end workshops covering GmP, containment/biosafety
and technology concepts to meet regulations for multipurpose production. and we used fast 3d designs early on in the layout process in order to consolidate footprint estimates. nne Pharmaplan assumed responsibility for all project phases all the way from conceptual, basic and detailed design through procurement support, construction and installation management to commissioning supervision and qualification. after qualification, we performed performance qualification and process validation services, working as a PQ/PV project manager/facilitator to ensure the timely completion of stable batches.
a Bsl2 facility (biosafety level 2), the production unit is based on unidirectional flows, separate access to all process rooms from an outside clean corridor and exit via a shared unclean corridor. The equipment concept combines multiuse stainless steel/glass and single-use technology, with single-use technology for bioreactors, media and buffer preparation, downstream processing and intermediate product storage. single use gives the facility a number of advantages:
ESTABLiSH MuLTiprOducT prOducTiOn

in order to reduce downtime in facilities and gain greater flexibility a number of companies that produce vaccines are looking into creating new, or upgrading existing facilities, with multiproduct facilities as an option or requirement. also, as containment buildings are generally high maintenance, requiring complex
systems such as HVac and kill systems, many companies want to improve the usage rate of their multiproduct facilities. and in some cases, the actual details of the production process are still unknown when facility design begins. as a result, companies need flexible multiproduct facilities whether they are new or retrofit. at nne Pharmaplan, we look into the feasibility of retrofitting an existing facility from single to multiproduct, evaluate flows and containment strategies such as unidirectional flows and investigate the possibilities of using flexible equipment strategies such as single-use equipment. This approach is particularly important when looking at upgrading pilot facilities, launch facilities and other similar facilities, but the concepts can be used all the way through the product cycle.
Flexibility for a range of production platforms microbial and cell culture in upstream suites downstream multipurpose suites minimal wash and sterilisation functions media and buffers readymade
several different products can be produced in the facility at any given time. accordingly, the facility meets a host of requirements ensuring that there is no cross-contamination between products; keeping personnel and products in an advancing one-way flow; keeping the production rooms clean; and finally ensuring that there is no contamination of the surroundings. after completion, production progressed very reliably without contamination from day one, and the customer was able to meet their production deadlines.
Vaccines 41
STAndArdiSEd vAccinE fAciLiTiES A nEw cOncEpT

From made to order to made to configure. nne Pharmaplan is investing in preparing modular vaccine facility concepts, designed for vaccine biotypes. modular vaccine facilities gives you the chance to fast-track your project and lower your investment. Having most of the design work already in place means that the only major task in the final design stage is to select or reject individual modules. This modular concept enables you to concentrate your investment in new facilities on in-house clinical data possibly at a lower investment cost and allows you to produce more price-friendly facilities, such as production facilities for vaccines for the third world. Our modular concepts for vaccine facilities are based on facility biotypes for facilities that handle live seed stocks of infectious agents similar to the phenotypic classification principles for bacteria and viruses. Facility biotype integrates biosafety levels for infectious agents, background processing of cleanrooms, process unit operations and architectural modularity, which also gives you the modular flexibility to expand. it also takes into account the inherent conflicts between designing for biocontainment and designing for GmP, producing single or multiple products, and balancing cost with design.
using a full interdisciplinary design, we focus on a number of areas, including: generalising the overall layout for a particular type of process or facility; using flexible and singleuse equipment extensively; and closing the process as much as possible. This ensures fewer high classification cleanrooms and lowers the use of clean utilities like WFi while still giving you the necessary capacity. We fabricate the modules in low-cost countries, and lower the design and layout cost by simply adding or subtracting individual modules and functions enabling us to en-sure you get the right facility at a reasonable price.
Icosahedral/ Naked/ helical/ enveloped complex N I E RNA Family Reo Birna Calici Picorna Ravi Toga Retro Corona Filo Rhabdo Bunya Orthomyxo Paramyxo Arena Parvo Papova Adeno Hepadna Herpes Irino Baculo Pox Strand ds ds (+)ss (+)ss (+)ss (+)ss (+)ss (+)ss (-)ss (-)ss (-)ss (-)ss (-)ss (-)ss ss ds ds ds ds ds ds ds
We also believe that this approach enables you to provide greener and more affordable vaccines.
Genome size (kb) 22-27 7 8 7-8 10 2 3,5-9 16-21 12.7 13-16 13.5-21 13.6 16-20 10-14 5 5-8 36-38 3.2 120-200 150-350 100 130-280 Example rotavirus Infectious bursal disease virus lagovirus poliovirus yellow fever rubella HIV-1 coronavirus ebola virus rabies Hantavirus Influenza A measles Lassa fever Parvo virus H1 JC virus adenovirus hepatitis B herpesvirus ranavirus baculovirus Vaccinia
N I E DNA H C N/E E E
THErApEuTic vAccinES And THEir prOMiSE fOr THE fuTurE

Therapeutic cancer vaccines were put firmly on the map in may 2010 when dendreon corp. successfully obtained approval for its prostate cancer vaccine Provenge, which
extends the lives of men with advanced prostate cancer. We still expect to see more therapeutic vaccines one of the newcomers to the vaccine market but the cancer vaccine market also includes preventive vaccines, such as the HPV vaccine.
Fighting cancer is an important milestone for the vaccine industry and this is shown by the numbers. Global statistics show that the risk of getting cancer before the age of 75 is 18.7 percent, and the five most common types of cancer in men and women are lung, breast, colorectal, stomach and prostate cancer (Globocan 2008 statistics). The perspective of developing cancer vaccines is huge! at nne Pharmaplan, we have worked with a number of companies that deal with cancer therapeutic vaccines, such as Bavarian nordic, ark Therapeutics and Oncos Therapeutics. Our specialised knowledge in both the layout and the operating conditions for small-scale vaccine production helps the start-up companies and our large-scale vaccine and biotech experience has proven useful for the mature producers of preventive cancer vaccines.
42 Vaccines
BiOSAfETy & BiOSEcuriTy

in the world of vaccines, almost all facilities require some degree of containment and specialised inactivation of waste, such as effluents and solid waste. nne Pharmaplan has experience with fitting containment facilities up to Bsl3+/Bsl3ag level into existing buildings or other restricted spaces, and we understand the restraints and specific challenges such projects can pose. We have worked on these projects in many areas of the world and so are also familiar with country-specific regulations governing these types of projects. in addition, we also focus on biosecurity, taking into account the individual country laws and guidelines as well as general guidelines. in europe, these guidelines are based on the united nations security council resolution 1540, stating that materials that could be used to develop weapons of mass destruction in casu biological weapons must be secured against acquisition for nefarious purposes. For both biosafety and biosecurity, we consider more than the design and layout of the facility. We also focus on issues that cannot be addressed in the building or engineering controls, but still need to be integrated into the work routines of people involved. The foundation for all vaccine containment projects is the risk assessment for biosafety and biosecurity and we follow this closely, all the way through to everyday facility use. and of course, we also offer consultancy on both biocontainment and biosecurity independently of each other if required.
EGG-BASEd vAccinE fAciLiTiES

When the sneezing starts, it is usually too late to get this seasons flu shot because every year, the seasonal vaccines are reinvented with that years flu strains, and produced for release just in time for use. The majority of flu shots are still produced in egg-based facilities, which is a trusted but not new technology. Few of the vaccines are produced in cell culture, and even fewer as other types of active agents, such as viruslike particles or other new and emerging techniques. using eggs works well for seasonal vaccines. But for the pandemic situation, when a lot of vaccine is needed in a very short time frame,
the more modern approaches are generally better suited to deliver the necessary doses in the time available. designing egg-based facilities requires skills in egg handling and the specific processing required, such as handling and incubating millions of eggs for flu vaccine production. all this ends up as part of the virus-infected waste and requires special handling in order to produce a safe and easy-to-handle waste stream. We have extensive expertise in this area, gained from numerous large-scale flu projects as well as other egg-based technologies like ceF (chicken embryo fibroblast cells), e.g. Bavarian nordics fast-track manufacturing facility.
HAndLinG GMO ApprOvALS

When looking into the world of new vaccines, you can see that a large number are based on genetically modified organisms (GmOs) of some sort, for example the cell line used for manufacture or the virus. This
means that facilities both research laboratories and full-scale manufacturing lines must meet very specific GmO requirements. With extensive experience in GmO requirements and approvals, we are able to evaluate GmO requirements alongside any other containment-related requirements. We also have extensive experience of approval for GmO projects and production which, as well as facility approval, is also required for working with a GmO agent. We can help you prepare a specific and extensive risk assessment, as well as your procedures for the handling of agents, spills, internal and external transport, waste and other production elements.
Vaccines 43
TEcH TrAnSfEr A MATTEr Of knOw-HOw

most companies know how hard it can be to find the right technology for a specific product, for instance or to transfer technology from site to site or from department to department, for example when taking a product from small-scale laboratory work to pilot-scale development and production. nne Pharmaplan can help. Our team has a strong background in the vaccine and related industries and organisations. and our numerous personal contacts enable us to perform efficient technology and cmO searches (contract manufacturing Organisations). We can also help you perform technology transfers. We make an interdisciplinary team available to you that is specialised in vaccine processes and containment-related issues, including the handling of the inherent conflict between Good manufacturing Practice (GmP) and containment.
GETTinG STArTEd wiTH MAnufAcTurinG frOM idEA TO OpErATiOn

a start-up company manufacturing vaccines may often struggle to find people with a high degree of specialised knowledge. in these cases, nne Pharmaplan can help. Our in-house expertise means you will always have access to the support you need when starting up your facility.
Our capabilities cover all the start-up knowledge you need, from preparing feasibility studies and business cases and selecting a site, to designing a facility concept and preparing it for start-up. and because the actual start-up also requires specialist skills, we offer to help with organisational development and training, writing of standard operating procedures (sOP), qualification and validation, technology transfer and even production. phases to establish the best way for you to benefit from the lean tools and techniques. and on more normal lean projects, where lean is used to optimise existing processes, we can help you by taking the role of change agent. When working as a change agent, we support you by:

LEAn vAccinE prOducTiOn

in general, business cases suggest that companies can increase productivity by around 20-30 percent by implementing lean philosophies, techniques and tools and lean can even help boost employee satisfaction. The lean tool box is generic, but at nne Pharmaplan, we combine lean with an indepth knowledge of handling, process flows, waste flows, GmP/GmO/Bsl requirements and all the other specific issues that affect the nature of vaccine production. This means we can work with you from the early design
simplifying and optimising workflows Value stream mapping Outsourcing support functions implementing automated equipment compression activities creating staged working periods
USA. Cardiovascular diseases cause 40% of all deaths in the United States. This is more than all forms of cancer combined.
phArmAceuticAls 45
pharmaceuticals
Todays pharmaceutical manufacturing is more complicated than ever. We offer a unique mix of local and global experience to help you overcome current and future challenges. the modern history of small molecule pharmaceuticals started in 1899, when Bayer was awarded the patent for Aspirin. since then, an industrial revolution has improved the quality of life for many people by providing access to important treatments of a wide range of diseases. in fact, traditional pharmaceuticals mostly as tablets offer a very convenient and costeffective way of taking medicine, which we simply consider as part of our everyday life. today, many pharmaceutical companies are facing patent expiry of significant products and generic competition is becoming stronger and stronger. the situation is further aggravated both by generic competition and cutting of health care costs in most countries around the world. the pressure for cost-effective production goes hand in hand with a continued or even increased focus on product quality. the pharmaceutical industry is forced to reinvent itself through new quality paradigms, more efficient production and more cost-effective supply chains. the art of manufacturing traditional pharmaceuticals is becoming more multi-faceted, due to the increased diversity of the supply chain of most pharmaceutical companies. new suppliers of raw materials, potential sourcing from contract manufacturers, an increasingly international supply chain, more markets, diversity in batch sizes, different regulations, labelling or traceability requirements are just some examples. the expiry of patents and the rearranged supply chains represent the end of the blockbuster era. innovation-driven pharmaceutical companies are looking into increasingly specialised pharmaceuticals besides their branded generics. We know that many of our customers see the challenge and we offer our help in many areas. As a global company, we follow the trends and opportunities of regulations, bestpractice industry standards and technology through our global network. And more importantly, we offer services locally through our many offices, adapted to your local needs as well as your global challenges.
46 Active phArmAceuticAl ingredients
Active pharmaceutical ingredients

Current trends in active pharmaceutical ingredients (API) show increasing offshoring activities and simultaneous advances in product and technology. We can help you deal with both. the synthesis of chemical substances still accounts for the bulk of active pharmaceutical ingredients. the major blockbuster ingredients are produced by well-established processes, and many of the patents for these products have either expired or will expire in the next few years. this is leading to increased price pressure, an increasing share of generic products and increased focus on cost-effective manufacturing. in industrialised countries, this has led to a decline in the number of Api facilities. But in developing countries, particularly in Asia, the growth has been significant due to the transfer of production, and to the increasing consumption of pharmaceuticals. Besides the massive capacity investments, the boom in the Asian pharma industry presents challenges such as technology transfer, auditing of suppliers and gmp compliance. From a volume perspective, the major trend is to go east. the capacity growth and consequently also the investments in europe and the us are very limited. But new, typically more specialised, pharmaceutical products are still developed. this results in new challenges and opportunities, such as handling of toxic ingredients resulting in high containment requirements, development of radiopharmaceuticals, development of pilot and launch facilities and new applications or formulations of traditional medicine. At nne pharmaplan, we can offer expertise within a number of relevant processes, including synthesis and extraction processes. We also provide specialised knowledge of local conditions and the kind of technology transfer that is necessary for cost-effective global Api bulk manufacturing.
Active phArmAceuticAl ingredients 47
From dietary supplement to prescription medicine cardiovascular diseases claim 17.1 million lives a year worldwide more than any other disease. many of these lives could be saved with a healthier diet, in addition to life-saving therapies such as prescription omega-3 fatty acids. the norwegian company pronova Biopharma is the only producer of a marine-originated omega-3 product to have obtained eu and FdA approval for their prescription drug, which treats elevated levels of triglycerides in humans and secondary prevention of post-myocardial infarction. the product is branded as Omacor in europe and Asia, and lovaza in the us. the classification of Omacor/lovaza as prescription drug presented pronova Biopharma with a number of challenges. First of all, good manufacturing practices (gmp) are much stricter for medicine. secondly, the increase in market demand called for a huge, quick increase in production capacity. nne pharmaplan had the expertise to help the company meet both challenges. the cooperation started in 2006 when nne pharmaplan assisted pronova Biopharma with an expansion and upgrade of pronovas existing facilities in sandefjord, norway. When the sales prognoses for pronova Biopharma called for an urgent expansion of the production capacity to
twice its size, nne pharmaplan was the natural choice to help, and a danish seaport was chosen for the companys first production plant outside norway. the completion of the greenfield production facility in Kalundborg crowns the joint achievements of a long-term supplier-customer relationship. nne pharmaplan was in charge of project execution from site selection through conceptual design, detailed design, construction, commissioning & Qualification, process validation and Automation integration. nne pharmaplan had all the key pharmaceutical engineering disciplines in-house, which ensured a flexible project organisation and fast decisionmaking. the nne pharmaplan project manager shared an office with the pronova project team, and a customer user group gave input to every aspect of design and construction. the other key task of the project manager was to make sure that the five hundred plus employees from nne pharmaplan offices in denmark, germany, china, ireland, sweden and the us were constantly kept up to date on the development and their own roles. the new state-of-the-art plant doubles pronovas existing production with a nominal production capacity of 1,200 tonnes per year. the project was completed within budget and in only 20 months eight weeks ahead of schedule!
nne phArmAplAn services FeAtured in this chApter: Tech transfer: combining state-of-the-art with local practice Securing product quality when offshoring Upgrading Indian API facilities Efficient high-containment API facilities Decontamination of old facilities Master Inline how to improve mixing of liquids Containment in a flexible pilot environment A greener future: the renaissance of synthesis production Automate to optimise: the way to more cost-effective CIP
SECUrIng ProDUCT qUAlITy WhEn oFFShorIng

during the last five years, health authorities and pharmaceutical companies have increased their focus on ensuring the sufficient quality of raw materials and products manufactured in countries with lower quality standards (gmp standards). At the same time, companies are becoming more aware of the potential economic benefits of sourcing from or even offshoring production to these countries. At nne pharmaplan, we have local insight that enables us to support your company with services such as audits, mock inspections and gap analyses of sub-suppliers in many countries, including india and china.
TECh TrAnSFEr: CoMbInIng STATE-oF-ThE-ArT WITh loCAl PrACTICE

in todays global business environment, all large and midsized pharmaceutical companies face a regulatory challenge as many of their products are fully or partly manufactured in developing countries such as india or china. this issue has received a great deal of attention from regulatory authorities due to many cases of severe quality problems in ingredients and semi-manufactured products from developing countries. An example is the heparin crisis in 2007-2008. the issue also receive a lot of attention from local health authorities as well as within the developing countries. the challenges originate in the fact that developing countries have very limited experience with the regulations, production methods and technology in industrialised nations. Accordingly, the transfer of knowledge, methods and quality standards is a challenge for many Western companies that want to work with chinese or indian sub-suppliers. With 10 years of first hand experience in these markets, nne pharmaplan has a broad network of contacts within the health authorities and local pharmaceutical companies in many countries, including china and india. We have worked with many of our customers to transfer this type of know-how (also known as tech transfer) in connection with both construction projects and contract
manufacturing activities. Our experience shows that combining Western and local know-how is the key to ensuring success, so weve made our tech transfer services one of our main focus areas. the tech transfer challenge is especially important for companies with well-known products that have lost or are about to lose their patents. in these cases, there is usually many years of know-how tied to the product, the process and the equipment, and this will need to be documented in order to facilitate tech transfer. more often than not such know-how is undocumented, which makes describing, analysing and documenting the core process knowledge (the cornerstone of a successful tech transfer) difficult. establishing production capacity in another country and within another culture is not easy. it requires in-depth product, process, technology and equipment understanding as well as local business understanding and cultural and regulatory insight. nne pharmaplan helped a customer translate a production technology that was used at a plant in europe into chinese conditions. the fundamental process understanding coupled with local regulatory requirements enabled a technology transfer that could accommodate local conditions and meet the customers international quality standards.
We work together with your internal quality department to conduct audits and quality documentation in order to ensure that subsuppliers or offshoring partners meet all your expectations. Our inspections are conducted by local employees who speak the language and possess thorough knowledge of local and Western quality standards. this has proven a huge asset in ensuring quality standards are met and in collaborating with local companies on issues such as improvement possibilities and best practice sharing. ultimately this also has a positive effect in terms of improving the trustworthiness and competencies of local sub-suppliers. At present, nne pharmaplan has three offices in china (tianjin, guangzhou and shanghai) and three in india (new delhi, mombai and Bangalore). typically, we will conduct audits and inspections using a combination of local and international resources, and we are continuously working on extending these services so that they can eventually be offered from all of our offices around the world.
UPgrADIng InDIAn API FACIlITIES

indian Api companies are showing a growing interest in upgrading their production to reflect modern quality standards as well as increasing competitiveness in both local and global markets. As the indian Api market is characterised by fierce price competition, the financial aspect of such an upgrade project is the main driver for most companies. so rather than demolishing the old production plant and building a new greenfield facility, indian companies generally choose the more economical solution of upgrading their existing facilities. But turning an outmoded production facility into a modern plant that conforms to Western technology standards and international regulations is not simple. At nne pharmaplan, we have carried out a number of facility upgrades and greenfield projects for customers in india. in all of these projects, time and budget have been areas of concern, as competitiveness in the indian market is dependent on the ability to sell the products at a low price. in addition, most indian customers want to increase capacity and flexibility in order to enable higher output and new product manufacturing. the main challenge in upgrading indian Api facilities to meet international authority standards is the fact that they were originally designed without any cleanrooms for prod-
uct handling. All clean areas thus have to be designed and constructed from scratch. due to limited budgets, indian Api companies request that cleanrooms are built within the existing facility rather than as an extension. this is a challenge in itself, as cleanrooms require special hvAc conditions that are easier to implement in a new building. the establishment of a cleanroom is further complicated by the fact that many Api facilities in india are constructed so that all utilities, including the water supply and electricity, are shared by all facility sections. this means that if a utility cut-off is required for any one block in the facility, it will cut off the utilities for all blocks, thus rendering a shutdown of the entire site. in a recent project, we were able to minimise the space used for the critical high-potent areas with critical process steps performed in closed systems or within safety booths.
As the establishment of cleanrooms in an existing facility requires all utilities to be cut off, a full production shutdown is inevitable. With tight time schedules and budgets always being drivers for indian projects, minimising production loss is a key success criteria for all companies. in one such case, our customers success criteria were: minimum loss of production, extension of capacity and FdA compliance. the construction required vacating the block where the clean area was to be established and cutting off all utilities. through careful planning and coordination, nne pharmaplan managed to minimise the production shutdown to only 2-3 days.
EFFICIEnT hIgh-ConTAInMEnT API FACIlITIES

When dealing with the production of highpotent active pharmaceutical ingredients, safety and regulatory compliance are key factors. the challenge is to protect the production staff and the environment and at the same time protect the product from being contaminated. With budget, time and quality considerations in mind, nne pharmaplans expertise in gmp compliance and high-potent technology makes it possible to design and construct Api facilities, in a safe and contained manner that complies with both european and us-FdA gmp requirements.
more and more facilities deal with high containment requirements. it can be a challenge in an existing facility, but modern technology and risk management experience often make it possible to solve the ever-growing containment challenges.
DEConTAMInATIon oF olD FACIlITIES

reusing an existing pharmaceutical facility for a new product is in many cases a tempting alternative to establishing a new facility even if the new product is very different from what is being or has been previously produced in the facility. Apart from the facility itself, many utilities and sometimes cleanrooms can be reused, rendering huge savings for the company. even in cases where the financial savings are minimal, the use of existing facilities can save a significant amount of time in site establishment and permit application. however, before any new product can be introduced into an existing manufacturing facility, it is necessary to decontaminate the facility equipment and systems to prevent cross-contamination between existing products and the new one. depending on the products in question, the requirements for decontaminating an old facility can be very strict, especially in the case of antibiotics and hormones. For piping and production systems, decontamination is used for cleaning and disinfecting equipment prior to a regular cleaning-in-place (cip) process. As such, decontamination is intended to substantiate the following cip that is carried out prior to production start-up.
At nne pharmaplan, we have conducted many decontamination projects and we deliver decontamination as a standard product before handing over systems to a customer. Our contamination programme contains the following basic elements: first, a risk assessment to identify potential contamination risks, sources and consequences. On the basis of the risk assessment, we develop a decontamination plan and subsequently,
we will perform the cleaning/decontamination activities. this is followed by sampling and validation, and lastly a validation of the sampling and test methods to ensure a reliable result. When you work with nne pharmaplan, you will get a decontamination solution that is customised to your specific situation.
MASTEr InlInE hoW To IMProvE MIxIng oF lIqUIDS

the mixing of liquids is traditionally prepared by batch or inline mixing systems. Both systems have disadvantages such as:

space consumption sensitivity to pressure variations non-homogeneous mixing instability
higher than the output, providing numerous advantages. First of all, it will give rise to improved process stability i.e. extremely accurate control of ph (ph up to 0.01) and/or concentration of the substances, uniform products with no local spots with high concentration or ph and improved process stability as ph variation downstream can be equalised upstream. Another advantage is reduced time and cost due to less chemical demand by reduced waste from storage and on-time delivery due to faster, reduced production time. in addition, using master inline will minimise space requirements through reduction of space and equipment, eliminating mixing and storage tanks, continuous buffer preparation with less impact on central mixing facilities and the use of mobile equipment so that plug and play can be manufactured offsite.
slow speed inaccuracy local spots with extreme ph
nne pharmaplan has experience in a new mixer system that we call master inline. the system is a sophisticated version of the inline system. master inline mixes different liquids in a mixing loop with a flow that is five times
x5 Batch Inline Master Inline
ConTAInMEnT In A FlExIblE PIloT EnvIronMEnT

high containment and production flexibility are often considered to be two, mutually exclusive manufacturing objectives that run in opposite directions. Building high containment facilities that can adapt to various product types and processes is therefore a huge challenge and one that requires specialist know-how. this is particularly true when it comes to pilot plants. By its nature, a pilot plant must be flexible enough to accommodate multi-purpose production of a variety of existing products and future, sometimes unknown, products. On the other hand, manufacturing products in high containment surroundings requires fixed processes in order to prevent containment failure and, hence, contamination of the aseptic products. in addition, when a facility handles a wide range of solvents, it also needs to be explosion-proof. Based on nne pharmaplans proven expertise in the high containment field, one of our customers awarded us a turnkey contract to design and construct their pilot plant. the fact that nne pharmaplan carried out the project on a turnkey basis was very beneficial to the customer, as they only needed to deal with one supplier. We were responsible for all project phases and took care of all assignments. As a result, the turnkey model provided a very comfortable solution for the customer.
A grEEnEr FUTUrE: ThE rEnAISSAnCE oF SynThESIS ProDUCTIon

As environment and sustainability have become focus areas in the global corporate world, including within pharma and biotech manufacturing, synthesis production has obtained a somewhat tarnished reputation. As a result, the industry has seen a marked changeover from synthesis production to bioproduction in recent years and with that a significant decrease in the number and size of pharmaceutical synthesis facilities worldwide. nne pharmaplan possesses a great deal of specialist process knowledge and experience within synthesis production as well as clean technologies, involving recycling of solvents, safe waste disposal and energy-efficient manufacturing, and can help synthesis companies build a sustainable production.
in connection with establishing or expanding a synthesis production, we can be a valuable collaboration partner who can supplement your own process expertise and bring new ideas and concepts into play to achieve the best possible solution. nne pharmaplan has a large heath, safety and environment (hse) division, which in close collaboration with you and your equipment suppliers can provide a sustainable solution that supports cost-effective, energysaving and eco-friendly synthesis production.
AUToMATE To oPTIMISE ThE WAy To MorE CoST-EFFECTIvE CIP

companies that rely on manually operated cleaning-in-place (cip) usually spend far too many man-hours controlling and supervising the cleaning process and they are still not guaranteed 100 percent consistency from one cleaning sequence to the next. sometimes manual cip can even result in a significant loss of production time, as production has to be stopped during the cleaning period, which can take weeks. upgrading to fully-automated cip is one of the best solutions to tackle these issues regardless of the manufacturers product and existing cip concept. At nne pharmaplan, we have experience from a wide range of cip-related projects in the pharma and biotech industries. recently, one of our customers needed to optimise production time to increase their annual production capacity at a large pilot plant. the facility was intended for campaign manufacturing of a broad range of diverse products. cleaning between production batches and different product campaigns was therefore crucial and complex.
the cip sequence had to be flexible to ensure thorough cleaning after each product, and it needed to be able to adapt to different process equipment, for example tanks and/or pipes, and to various solvent types and cleaning agents. the manufacturing process was further complicated by the fact that production involved vacuums and the risk of explosion. the cleaning process therefore needed to be customised. nne pharmaplan upgraded the cip sequence to be fully automated. We also challenged the customer on their overall cleaning method and proposed a new one that was more cost-effective. the result was a decrease in cip time from three weeks to two days, a reduced number of utilities required for cleaning and a solvent reduction of 80 percent.
52 Oral SOlid dOSage
Oral solid dosage

Increasing demand and competition for Oral Solid Dosage (OSD) products force manufacturers to optimise productivity and cost-effectiveness. NNE Pharmaplan offers to facilitate. OSd products are the dominant pharmaceutical product form addressing a large range of diseases and a well known as well as comfortable form of medication. The business framework for the pharmaceutical industry has changed in recent years with major influence on the manufacturing and marketing of solid dosage products. expired patents for blockbuster products decrease the market for propriety products and increase the market for generics. The lack of new chemical entities leads to lack of follow-up products. Cost increases in the health care sectors of the western world combined with the spread of drugs to more and more people in less developed countries make prices rise. This situation has given rise to major changes in the production methodology as well as supply chain for solid dosage products. asia has increased its production capacity dramatically servicing both local expanding markets and the rest of the world. Fierce competition between manufacturers has also resulted in flexible multipurpose facilities and more demand for lower unit cost of the products. in the generic drug sector, manufacturers increase production capacity taking over propriety products. The traditional Big Pharma companies are leveraging their experience and know-how to market quality branded generics. Specialised new drugs such as sustained release formulations and combined aPi products as well as optimised variations of existing drugs are introduced to the market to differentiate the supplies of solid dosage forms. High potency products and new oncological products, requiring high operator protection, enter the market. NNe Pharmaplans is deeply involved in the development of both solid dosage technologies and the increased production capacity in europe, the US and not least asia.
Oral SOlid dOSage 53
How to upgrade GMP and maintain full production How can we ensure production runs smoothly while our production facility is revamped? This is the challenge Merz group Services in germany presented to NNe Pharmaplans engineering and construction management. Merz group Services had a production facility for forms of non-sterile dosage, including a wide range of oral products that it needed to make fully gMP compliant and it was imperative that the project did not disrupt production. Merz group Services asked NNe Pharmaplan for support in planning and executing the project and to help maintain production capacity throughout the upgrade so market demand could be met. at NNe Pharmaplan, we believe the basis for smooth project execution is close cooperation.
and, with the facility in operation throughout the project, every team had to act quickly and decisively. We coordinated the production, construction and installation teams to make sure this happened. in case of a sudden rise in demand, the facility would have to be able to meet it without disrupting the upgrade project. NNe Pharmaplan produced several scenarios, each with its own risk assessment. This enabled Merz group Services to make the best decision, without losing sight of their goals. The NNe Pharmaplan project manager explains: Close coordination and good communication with the customer are the key success factors in the project. Thanks to the partnership we have developed, i feel almost like a part of the Merz group Services team.
NNe PHarMaPlaN ServiCeS FeaTUred iN THiS CHaPTer: Cost-efficient OSD facilities Product optimisation and development Multipurpose high containment facilities Low cost production technology transfer Optimising packaging and logistics Radiopharmaceuticals Optimising material and personnel flow Process Analytical Technology (PAT) New trends in manufacturing of OSD
COST-EffICIENT OSD fACILITIES

all of our Oral Solid dosage (OSd) customers ask for new projects designed for the best balance between investment and running costs. in addition, they require the ability to increase capacity and flexibility without disrupting the ongoing production. in order to fulfil those demands we apply many different methodologies such as iT simulation of production evaluation of different technical solutions during design phase leaN design estimation and optimisation of production cost ramp up consultancies For a customer in germany, we started our engineering execution by making process simulations for different production scenarios, taking into account variations in layout, shift models, production time, maintenance time and batch sizes. internal storage and transfer capacities were also taken into account. The result was an OSd production building with vertical material flow that would be
easy to extend if necessary. The buildings central technical areas can be accessed without crossing production areas, so maintenance can be carried out without disrupting production. To realise the new layout, NNe Pharmaplan used a 3 or 4-shift model to achieve a stepwise increase in production capacity, replace old production equipment and install additional equipment in the reserve areas without interrupting production. From a starting capacity of 2.5 billion tablets a year, the production climbed to a massive 12 billion a year.
PRODuCT OPTIMISATION AND DEvELOPMENT

Formulation and solid dosage forms are under constant development addressing issues like toxicity, controlled release and counterfeit.
NNe Pharmaplan is able to support manufacturers in regard to this development. We offer help to find new formulations and dosage forms, for example personalised tablets to increase traceability and sprays or strips with direct printed aPis. in addition, nanotechnology will lead to more secure production processes, helping to prevent
counterfeiting by giving each batch a unique fingerprint. This fingerprint is not just on packaging material, but on or in each individual tablet. Taking such measures can help reduce the economic risk. When the manufacturer and the engineer start developing a new product from laboratory to production, they have the opportunity to combine NNe Pharmaplans knowledge of the latest advances in equipment technology with their own research and create a highly competitive facility for modern dosage forms. NNe Pharmaplan offers a range of solutions for traditional project execution, including standardisation, optimisation lean performance and Six Sigma studies. We also offer solutions that go above and beyond the limitations of standard engineering, helping our customers do more than merely lower the variable and fixed costs. This is where NNe Pharmaplans unique insights into the pharma industry add true value to your new production facilities.
MuLTIPuRPOSE HIGH CONTAINMENT fACILITIES

during the last 10 years, the pharma industry has seen a significant rise in the number of high-potent active pharmaceutical ingredients (aPis) as well as oncological products. The term high potent characterises a substance that produces a marked pharmacological, physiological and/or toxicological effect in the recipient even in small amounts. applied at the correct dosage, such substances are beneficial to the health of a patient. But if released during the manufacturing process, they may have adverse effects on the health of the operators. This means that requirements for good Manufacturing Practice (gMP) as well as Health, Safety and environment (HSe) must be taken into account. and because these are regulated by two different legislative bodies, the requirements do not always coincide, so solutions have to be designed to satisfy the needs of both gMP and HSe. Because the new aPis and oncological products tend to be more hazardous than their precursors, the requirements for protection of operators and the environment have also increased. due to the limited knowledge of new substances characteristics in the development phase many of them will be classified as potentially hazardous for safety reasons. High containment strategies will therefore be a natural part of the pharmaceutical development work and production. and thats not all. applying the latest risk assessment methods to existing aPis could now classify many of them as potentially hazardous. Substances will be classified based on the mass it takes to cause a hazardous level of pharmacological/toxicological activity in the recipient. Such classifications are expressed as the Oel (Occupational exposure level) or the OeB (Occupational exposure Band). The well-known BUCK pyramid is used to express the OeB across five bands, from OeB 1 to OeB 5 where the OeB 5 is the most hazardous one. The trends towards high containment multipurpose production really challenge the containment strategy inside a facility. Having defined all known hazardous information available and the pharmaceutical processes needed, it is important to balance operator friendliness against operator safety, crosscontamination, complexity and operational costs. This way we create the necessary and sufficiently contained equipment solution. The goal is always to avoid personal protection during the process operations and to integrate containment and CiP in the process equipment as far as possible.
LOw COST PRODuCTION TECHNOLOGy TRANSfER

Many pharma companies face the challenge of transferring production equipment, products or knowledge from one facility to another existing or a new facility. You may wish to scale up from a pilot facility to largescale production. You could also have global, geographically differentiated production facilities or want to move production closer to your customers to reduce transportation costs. Other purposes could be to facilitate your contact to local authorities and buyers or to minimise labour and raw material costs. The technical transfer process involves elements such as gMP compliance, regulatory demands and technical know-how. But also the human resources that are not available in the existing production organisation. Thanks to our truly global presence, NNe Pharmaplan can support such transfers by:
Project management and resource allocation, both internal and external Mapping local suppliers of raw materials like filler, binders, lubricants and aPis with the right physical properties Mapping the existing production setup such as granulation principles and tablet technologies Mapping the local suppliers component and product flow to ensure optimum delivery of excipients and other raw materials in terms of logistics Managing the movement of equipment when needed inter-calibrating test equipment establishing training and translations of standard operating procedures Start-up of production and qualification of the transferred process
When expanding your existing businesses or entering new markets, we can also help you organise the know-how providers for your new production facility abroad, based on our global network.
OPTIMISING MATERIAL AND PERSONNEL fLOw

Some Oral Solid dosage (OSd) facilities have grown over many years resulting in inefficient and sometimes non-transparent practices. aging OSd sites may not have fixed flows because each bulk product has to be transferred from one step in production to the next. different methods and handling concepts can be used in parallel. at each production step, bulk material has to be stored in interim storage areas. and every hour, someone has to check the status.
OPTIMISING PACkAGING AND LOGISTICS

We have a proven track record of helping customers develop concepts for their packaging materials and design, packaging process and any related internal and external logistics. Our integrated approach leads to optimal transport and storage units, efficient use of space for logistics and effective warehouse handling. We analyse the economic aspects of a range of solutions to achieve a balance between operational efficiency and initial outlay. Our engineers calculate flows and space for pallets and cross-correlate everything from architecture and building services to gMP compliance. This guarantees you running packaging lines that are cost-efficient and safe.
For instance, NNe Pharmaplan carries out a logistical analysis of a customers existing warehouse. The goal is to optimise internal logistics and prepare a revised layout with a shorter flow and less idle time. as a result, the customer will save space and money. The space that is freed up will be used to create a new process area without the need to build a costly extension. Besides traditional engineering methods, we can also help you combat counterfeiting with modern principles and technologies such as serialised unique 2d coding. This enables seamless traceability from primary packaging to a coded pallet, so that each product can be quickly identified and verified at every stage of the packaging and logistics chain.
during a facilitys lifecycle there has to be an adaption of capacity, technology and organisation. This easily ends up in a wild combination of criss-cross flows after a series of compromises in design, layout and procedure. in reality, there is often a lot of room for improvement. a typical NNe Pharmaplan gMP-upgrade project wont just tackle the HvaC and revamp the existing premises; it will also include changes to material and personnel flow. For example, establishing a clear gowning and locker policy eliminates crosscontamination, raises the compliance and reduces the need to use precious storage space in the production area. all proposed changes have to be compliant with regulations and technologies.
RADIOPHARMACEuTICALS
One of the most important considerations is the protection of operators and the environment against radioactive contamination. due to the radioactivity of the radionuclides, operators have no direct
contact with, or access to the production environment. all handling procedures are carried out using manipulators or automated systems in hot cells. The operator is protected from radioactive contamination by lead shielding, including lead glass windows. at NNe Pharmaplan, we take particular care to make sure all of the production lines technical components and solutions are reliable. its an essential requirement to make sure maintenance can be carried out easily and safely. One way to achieve this is to place electrical installations where there is no radioactivity. another way is to design simple, robust components for the radioactive atmosphere that are easy to maintain and replace using manipulators. The risk of radioactive leakage from the hot cells is eliminated with negative air pressure and a double-redundancy air handling system.
Products in the radiopharmaceutical niche include capsules to treat thyroid diseases, tumour-seeking sterile injectables and tiny medical devices which can be injected directly into malignant tumours. Since 2002, we have been involved in several projects that use radioactivity to detect and treat specific medical conditions with alpha and gamma radiating isotopes. designing production lines for the production of radiopharmaceuticals requires special know-how. Most production lines are designed from scratch based on the particular requirements of the radionuclides they will handle. NNe Pharmaplans experience and know-how can be used to produce radiopharmaceuticals such as: Sterile radioactive drugs radioactive medical devices radioactive drugs for oral dosage
PROCESS ANALyTICAL TECHNOLOGy (PAT)

Process analytical Technology is a powerful tool for developing Oral Solid dosage (OSd) products. Commonly applied during product formulation and the development of the manufacturing process, it is also useful in commercial manufacturing for monitoring or controlling process and product-critical quality attributes such as identity, appearance, assay, content uniformity (CU), purity and dissolution. in development, PaT tools are used to gain knowledge of a process quickly and systematically. These tools include: design of experiment (doe) a planning tool that proposes as few experiments as possible to design the process, identify critical process parameters and the ranges they can operate within to deliver the right product Process analysers, including both simple, unvaried process sensors such as temperature and moisture, and more advanced process analysers such as near infrared (Nir), infrared, raman and focused beam reflectance measurements Multivariate data analysis used to analyse data from the various probes, resulting in a process track, measurements of inprocess material characteristics or measurements of product quality attributes acting as a consulting partner to the pharma industry, NNe Pharmaplan has a wealth of practical experience in PaT from design of experiments, multivariate data analyses and the identification and implementation of online process analysers. designing a robust
OSd process upfront will ensure you a fast return on investment (rOi) on your installations. at NNe Pharmaplan, we act as your practical partner who identifies the approach that will lead to cost reductions from laboratory to patient. For instance, we consult a global key account with regard to secondary process automation. That is the key issue for minimising costly and unpredictable r&d functions. in most cases, dedicated PaT applications are implemented in manufacturing, controlling process parameters or material attributes. involved in several PaT applications, we have experience of using Nir to identify raw materials in the dispensing area, to control the blending or granulation end-point, to measure assay, CU and dissolution after compression or to control the moisture level in a fluidbed granulation process through automated adjustment of the inlet air temperature.
NEw TRENDS IN MANufACTuRING Of OSD

To meet the increasing competition on the market and the trends towards more potent drugs and multi-purpose generic production, it is important to focus on:
Process equipment suitable for different production methodologies and batch sizes Process equipment with shorter changeover time between different products as well as effective and sufficient cleaning processes integrated in the equipment Contained process equipment for personal protection, avoiding cross-contamination Operational excellence including lean and effective supply chain management Sustained release formulation to differentiate against the competitors line extension products to increase the life cycle of the aPi Combination products for better therapeutic effects Smart and safe packaging devices to ensure the best handling and use of the OSd product
investments in these areas together with benchmarking will lead to more cost-efficient production and lower unit costs. Many OSd manufacturers realise the difficulty of improving their business platform on their own and therefore use consultants. Contracting with us to investigate and define the opportunities for increasing your operational excellences will inspire your organisation to move forward in the right direction.
58DR CONGO. Millions of people aresysteMs Medical devices and drug delivery injured and infected through unsafe injections every year. WHO, UNICEF and UNFPA have a joint policy to use auto-disabled syringes when administering vaccines.
Medical devices 59
Medical devices
Medical devices have a wide range of applications, but it requires expert knowledge to develop and improve them. NNE Pharmaplan can assist you with all issues every step of the way. Medical devices play a huge role in many different healthcare settings. they are crucial in patient treatment and diagnostics, and they cover a wide range of instruments from prostheses to drug delivery pumps. although medical devices are immensely diverse, they still require some common areas of expertise. For example, risk assessment is needed when improving the design of products and equipment; world class production and troubleshooting skills are critical in the development process; efficient workflows demand production layouts with different classification areas; and medical device production needs to be validated for cost-effective gMP compliance. Medical devices cover single-use products such as catheters, cannulae and iv bags as well as infusion and transfusion sets. Other examples are medical dialysers, syringes, injection systems and inhalers, electro-medicine equipment such as diagnostic and monitoring instruments, as well as intra-wound care products and stent implants for ostomy care. growth and development characterise the industry short product life cycles with continuous improvements based on new science, technology and materials. at nne Pharmaplan, we are dedicated to supporting all aspects of the medical device industry, from the development phase all the way to the establishment and improvement of production facilities. and we know how to incorporate data driven decisions in product development to achieve consistent, cost-effective results.
60 Medical devices and drug delivery systeMs
Medical devices and drug delivery systems

Bringing medical devices from concept to market with fast, reliable and innovative solutions is one of NNE Pharmaplans special competencies and fields of experience. With our global presence and roots in the pharma and biotech industries, nne Pharmaplan understands what it takes to complete a successful medical device programme, from product conception to the design and manufacturing process and all the way until the device is ready for market launch. nne Pharmaplan has been the in-house engineering and consulting partner of novo nordisk since the early medical device days. Over the years, weve evolved along with the device market as the business went from vials and syringes to pulmonary devices and the newest generation of world-class injection devices and needles. today we support novo nordisk on three continents. nne Pharmaplan has more than 75 engineers within medical device production know-how. We cover a wide range of competency profiles with specialists from a variety of technologies. Our knowledge is based on our experiences with many different industries, companies and cultures. We have a long history of working closely together with our customers r&d organisations and we provide a wide range of services to this highly diversified medical device segment.
Medical devices and drug delivery systeMs 61
Syringe design that makes a difference unsafe injection practices are a huge problem in developing countries. syringes are often used multiple times, contributing to the spread of diseases such as aids and hepatitis B, and causing more than one million early deaths each year. unfortunately, creating an affordable solution has been a real challenge. the World health Organization (WhO) knew that auto-disabled syringes would slow the spread of blood borne infectious diseases in developing countries. so to put their plan into action, the WhO turned to nne Pharmaplan for expert design and production support. Our engineers developed an innovative auto-disabled syringe with a one-way valve that makes the syringe impossible to reuse immediately after the liquid begins to leave the needle.
Our innovative syringe design is now used by uniceF. to produce the syringe, nne Pharmaplan teamed up with our customer MedecO from the united arab emirates. But the project required more than just production design and implementation; apart from the transfer of nne Pharmaplan syringe knowledge it required a turnkey project to design and build a new facility in abu dhabi. Production started in 2003 and the year after MedecO began delivering the first shipments of auto-disabled syringes to uniceF. a great example of a drug delivery device that directly enhances a treatments effectiveness, the auto-disabled syringes proved highly effective. uniceF continues to place orders, and the production facility was expanded in 2006 and 2007 to include additional production lines.
nne PharMaPlan services Featured in this chaPter: Product functionality testing in R&D Establishing semi-automated and high-speed production lines Revamping existing production lines Medical device validation The troubleshooting process and its impact Specification and establishment of pilot equipment Global transfer of technology and equipment Risk assessment of products and production Assessing medical device CMO environment Equipment supplier recommendation Design platforms and flexible production layouts Streamlining global production set-up Data-driven product development
Business opportunity
Feasibility and proposal
Device planning
Design and concept verification
Development engineering prototypes
Detailed design verification
Product validation and pilot production
Launch (scale-up)
REvAMPiNG ExiSTiNG PRODuCTiON liNES

6
PRODuCT fuNCTiONAliTy TESTiNG iN R&D

at nne Pharmaplan, we provide services in all phases of medical device and drug delivery projects. When it comes to testing the functionality of a product prototype, customers often ask us to help them set up their r&d tests in the various development phases so they can achieve a production-like environment faster. We provide test set-ups, test equipment and testing of works-like and made-like models. We establish product and process tolerance
chains and proactively use the relationship between functional requirements and design parameters. By manufacturing parts with different measurements and using them for prototypes, we are able to optimally test tolerance limits. the relation between design and process parameters enable us to identify critical sources for validation. Our goal is to help you dramatically increase the speed and predictability in your r&d iterations. and we do this by providing datadriven decision support based on design for six sigma (dFss) and design of experiments (doe).
after acquiring another company or introducing a new medical device to your portfolio, you might need to revamp some of your existing production facilities and manufacturing equipment. this process, however, is often more complicated than you might expect as revamping or reconfiguring existing production setups involves several cross-functional disciplines. there are many things to consider. do you have written procedures for all your organisational processes? do you have documented specifications and procedures on the existing equipment? are these updated? introducing new product components and new plastic materials to a fully-automated injection-moulding facility calls for new injection moulding machines with higher capacity and new piping. you will also need to reconfigure a wide range of systems such as cooling water, printers and the automation and it setups. and new recipes are required to bring each of the manufacturing steps together from feeding of the raw material to injection moulding of plastic parts, decoration of parts, subassembly, packaging and storing the new product, and finally registering the product in the erP system with an electronic batch release according to Part 11. at nne Pharmaplan, we look at the overall production flow along with the detailed requirements for the specific process in order to implement a layout that is easier to validate according to gMP. We provide a huge variety of cross-disciplinary competencies to achieve an optimal flow in your revamped facility.
Our expertise covers all phases of the production setup, including the entire production building layout, space requirements, logistics and component flow, equipment specifications and the selection of qualified suppliers. We also work closely with suppliers when ordering the equipment for the production assembly line. We combine our pharma and process knowledge with our experience in executing projects. We interview customers and use their lessons learned in our user requirements specifications and in our production equipment specification for the subcontractors. at nne Pharmaplan, we also undertake to order all equipment and perform the necessary tests to ensure that the equipment and the entire assembly line are constructed as required. using the latest validation guidelines, we can provide all final testing such as Factory and site acceptance tests (Fat & sat) and installation, Operational and Performance Qualification (iQ, OQ & PQ). you and your employees will need to become familiar with your new equipment, so we train production employees to support you and we help you perform proper maintenance of all your production equipment. not only is this structured approach to production efficient; it also gives you stateof-the-art technology and enables you to rapidly ramp-up your production.
ESTABliShiNG SEMi-AuTOMATED AND hiGh-SPEED PRODuCTiON liNES

you might have a drug/device combination product with various regulatory requirements. your challenge could also be establish a production layout with different classification areas without damaging your workflow or to install the right number of airlocks for personnel and material handling. Or perhaps you need to design and control the different pressure ratios between the filling line area and the assembly line to obtain the required quality level. Whatever your needs, nne Pharmaplan has the experience to build a semi-automated or high-speed production line that suits you, both in a global context and for multipurpose sites.
MEDiCAl DEviCE vAliDATiON

validating medical devices to ensure theyre cost-efficient and in gMP compliance starts in the early phases of development. the process begins with a risk analysis of the product and the production equipment, and this forms the basis for the validation master plans for all of the production equipment. nne Pharmaplan offers device validation by optimal use of 820 gMP: Process valida-
tion is required for processes where the results cannot be fully verified by subsequent inspection and test. the risk-based approach is used together with 820 gMP. We provide an overview of whats really needed and we offer advice on how to avoid typical pitfalls such as excessive validation due to inadequate risk assessment or excessive performance validation and inadequate validation of inline process control.
SPECifiCATiON AND ESTABliShMENT Of PilOT EquiPMENT

as a medical device manufacturer, you need to be able to transfer knowledge from your r&d area to your production area as quickly as possible in order to address major impacts on your production investments. at nne Pharmaplan, we use our experience from running production lines and testing products in development to support our customers when they need to specify and establish pilot equipment. Pilot equipment is typically used for small-scale production, including clinical trials and pilot launches. But its also used to determine component robustness in high-speed production. this is useful in processes such as moulding, joining, decoration and assembly. using pilot equipment, product functionality can be verified in a production-like environment. Pilot equipment is also used to investigate production and quality set-ups. can the product be tested and verified? if not, we provide alternative component designs to make it work. nne Pharmaplan has a long tradition of working closely with our customers r&d organisations. By using tools such as design for Manufacturing (dFM), Failure Mode, effects, and criticality analysis (FMeca), design of experiments (doe), value chain analysis and cost Modelling we bring r&d and production together. Our focus is always specifying product quality, highlighting critical product functions and production processes, and providing a cost landscape. in fact, we have reduced investment costs for our customers while at the same time increasing their final production equipment output by up to 30 percent. establishing pilot equipment is a major achievement its your first production setup.
Bring focus on production back to early stages of product development
Production considerations (EUR, allocated)
Is process output verifiable
Yes
Is verification sufficient and cost-effective
Yes
Verify and control the process
No
No
Validate
Redesign product and/or process
Process validation decision tree
ThE TROuBlEShOOTiNG PROCESS AND iTS iMPACT

When developing a new generation of a point-of-care device, one of our customers unfortunately detected some quality issues just before launch and turned to nne Pharmaplan for help. First, we reviewed the design of the subassembly and the related manufacturing processes and identified insufficient repeatability of part quality as the root cause. We then assessed the process setup and the customers suppliers. the customer carried out several optimisations that resulted in small improvements, but the part quality was still not adequate to launch the product. the moulding yield of one of the parts was unacceptable, so we
reviewed the part design based on our material and process knowledge. the conclusion was that the current component material design was not suitable for the products requirements in terms of reliable product measurements and wear. to meet these requirements, the tooling and process setup needed adjustments. We suggested a redesign of the part and the injection moulding tool. the customer asked nne Pharmaplan to further investigate tools and machinery, and we identified and implemented optimisations to the part design and tool layout. We then met with the supplier and gave input to design of experiments (doe). Based on these improvements, the customer achieved the necessary quality level and a 30 percent improvement in the moulding process yield.
Focus on production
Impact on production investment
Project execution [time]
GlOBAl TRANSfER Of TEChNOlOGy AND EquiPMENT

at some point, your company will probably face the challenge of transferring production equipment and knowledge to a new facility. Perhaps youll need to scale-up production from a pilot or launch facility to a large-scale, global production facility. Or maybe youll want to move production closer to your customer in order to reduce transportation costs and facilitate contact with local authorities and buyers. Or maybe the move will be to minimise labour and raw material costs.
at nne Pharmaplan, we use our global presence to support these transfers through a range of services. One includes mapping the cost-and-supply situation in different locations to calculate the net Present value of various options; another service maps the existing production setup in terms of production parameters, operating procedures, equipment and installation. We also offer mapping of the component and product flow in terms of logistics. and we are able to manage the relocation of equipment including importing used equipment. in addition we offer to help with inter-calibrating test equipment, training and translating of sOPs (standard Operating Procedures).
Project management
CMO knowledge
CMO
Customer
Equipment supplier
Drug supplier
Component supplier
ASSESSiNG MEDiCAl DEviCE CMO ENviRONMENTS

its important to establish a successful cooperation with a contract manufacturer that extends from product development to market launch and nne Pharmaplan can help. One of our customers was looking for a contract manufacturer of medical devices. they asked us for an assessment of how to control the industrialisation phase when outsourcing to a contract manufacturer. Our customer needed the right level of production equipment investments and a setup of sufficient quality, so the assessment needed to cover an optimised, reliable project plan in order to minimise the projects risk.
RiSk ASSESSMENT Of PRODuCTS AND PRODuCTiON

is there a connection between your critical medical devices functional specifications and your critical manufacturing processes? does your production setup lack transparency? have you identified the right level of inline process control in your production process? the right level of inline process control is the key to increasing your yield and the quality of your medical device. too few process controls can result in increased double work, while too many process controls can result in high validation costs. if your production process requires many process controls, it might be possible to improve the design of your components. the more you know about
your product and your production process, the more predictable your project will be. at nne Pharmaplan, we are used to the industrys tight deadlines, so we will work closely with you to achieve maximum predictability with our risk assessment tools, such as Fta (Fault tree analysis) and FMeca (Failure Mode, effects and criticality analysis) and our expertise gained from a wide range of projects.
We worked closely together with our customer and the potential contract manufacturers to assess the adequacy of the production setup, process design and quality setup. Our goal was to ensure a sufficient quality level and provide documentation for global launch, production equipment investment, product costs and a project execution plan. during the process, we also offered recommendations for alternatives to the customers organisational setup in their engineering and development departments. and when the agreement with the selected contract manufacturer was signed, the customer hired nne Pharmaplan to follow up on the contract manufacturers activities and deliverables.
EquiPMENT SuPPliER RECOMMENDATiON

achieving a low total cost of ownership for your production equipment takes partnering with world-class suppliers. at nne Pharmaplan, we use a work and equipment breakdown structure to identify the right equipment and the right suppliers for your particular production line. We identify suppliers locally and globally and maintain a global suppliers list, which is our centralised database of supplier information. We evaluate suppliers starting out with an initial meeting with the customer, followed by some days at the suppliers site, and finally we come back with our full report and recommendations. We are also able to perform the qualification of each suppliers equipment, a task that is often underestimated due to its required level of documentation in gMP-regulated areas. We have the experience both when it comes to the establishment of a new production line and revamping of an existing one, undertaking equipment specification and support of production equipment such as injection moulding, laser printers, vision inspection equipment, decoration, assembly, packaging and sterilisation.
STREAMliNiNG GlOBAl PRODuCTiON SET-uP

With globalisation on the rise, nne Pharmaplan has more and more customers asking us for support in adjusting or developing procedures and specifications to fit a global agenda. When you are in the process of going global, you might have multiple production facilities for the same medical device each with different batch data. and disparate production setups of moulding machines, assembly equipment, in-line processing or quality control (Qc) test equipment could result in uneven product quality, leading to regulatory issues. so when youre ready to roll-out a complex global strategy, nne Pharmaplan is here to help. We can streamline your corporate production setup to make your product portfolio less complex. and when you use the same Qc tests and methods in all your production facilities, youll be able to easily compare test results across sites. We can also help you standardise your equipment, terminology, tools and methodologies across sites, which is a crucial part of becoming more efficient and benefitting from global experience and knowledge sharing.
DESiGN PlATfORMS AND flExiBlE PRODuCTiON lAyOuTS

Many medical devices and medical device facilities require a flexible design to meet the demand for multiple applications. to cope with this challenge, nne Pharmaplan works with design platform concepts that optimise production layouts according to your unique requirements. this might mean a high-speed production with inline printing flexibility, or a low-scale production facility with a variety of semi-automated or manual subassembly stations. We take logistics into consideration in our production line layouts by preparing them for future device modifications or for the addition of new variants, for example by replacing one station with another. also, individual stations can be designed for flexibility, such as an infusion line where you can change the size of the bags or a laser printing station where you simply change the software programme to handle new components.
DATA-DRivEN PRODuCT DEvElOPMENT

todays production environment is measured by key performance indicators (KPis) such as yield, downtime, scrap and cO2 emissions. top management demands predictability also in product development projects. in fact, this KPi production mindset is on the rise in the product development environment. decision makers want to know about, for example, the number of project milestones met according to agreed specifications within a given timeframe. they also want to know how many development projects end in a product launch, or how many of these products have improved customer complaint rates. the list goes on.
at nne Pharmaplan, we have the competencies to implement data-driven decisions in product development in order to support the development of sound, simple and cost-effective concepts all while showing top management an increase in reliability. We do this by using tools like design for Manufacturing (dFM), product risk assessment (Fta & FMeca), design for six sigma and design of experiments (doe).
Traditional
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the traditional test method is to vary one factor at a time. however, this timeconsuming, costly process results in many separate experiments and a lack of valuable information. using doe, we can vary all factors simultaneously to arrive at the optimal design. We also work closely with design houses when your process requires specific research or product development competencies.
Response
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Time
Screening
70
Time
+ +
20
+
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66 IndustrIal BIotech KIRIBATI. The entire nation, located roughly 4,000 km southwest of Hawaii, could end up completely underwater if global warming worries are realised.
IndustrIal BIotech 67
Industrial biotech
Industrial biotech is an area of innovation and rapid development. The revolutionary technologies it generates, e.g. biofuel, have a huge impact on global change and overall world health. saying the world is rapidly changing isnt a revolutionary statement. But the way industrial biotech contributes to global change is indeed revolutionary. In fact, its hard to imagine a future where our lives arent deeply affected by industrial biotech. the innovative products and technologies that come out of the industrial biotech segment contribute significantly and positively to global progress and to our everyday lives. heavily polluting chemicals are replaced by much more environment friendly biotech products with enzymes as a prime example. Industrial biotech is also known as white biotech (with agricultural being green, and pharmaceuticals red) and has been called the third Wave of Biotech. after thousands of years of agriculture (first wave) and the last century of pharmaceutical development (second wave), biotechnology has entered into all aspects of industrial processing, moving the world away from industry based on petrochemicals. one of the most revolutionary technologies is biofuel fuel derived from biomass that contains 80 percent renewable materials. Biofuels such as bioethanol and biodiesel offer vast savings of carbon dioxide emissions compared with petrol, and thus contributes significantly to improving our environment. Biotechnology is constantly spreading into new fields of application. emerging technologies create products from renewable sources using biotech methods, such as biopolymers from lactic acid, direct fermentation of biodiesel, and biosource for bulk chemicals (e.g. succinic acid) that normally originate from petrochemical sources. Industrial biotechnology widely replaces existing materials, products and production methods with a hard competitive pressure on the unit cost, very unlike the patented pharmaceuticals where time to market is the primary driver. thus, the industrys biggest challenge is to steer innovation in a direction that produces practical results while dealing with the reality of low margins, new processes and co2 neutral production.
68 IndustrIal BIotech
Industrial biotech
At NNE Pharmaplan we have applied our biotechnology know-how to the benefit of the environment for many years and executed a variety of projects with diverse processes and technologies. nne Pharmaplan supports all phases of industrial biotech production and process development, focusing on cost-efficiency and co2 conscious processes by minimising waste while maximising productive output and earnings. our biotech background, understanding of global production issues and process knowledge make us a key partner. We designed and built the first large-scale bioreactors back in the sixties and have installed more than 200 bioreactor trains, with the associated downstream processes. on top of this we have designed a multitude of other industrial biotech facilities ranging from biofuel to extraction facilities and into the food and dairy industries. In this context we have developed a deep knowledge of the involved unit operations from fermentation, separation processes, purification and chemical modification to dry processes. and we have developed a multitude of highly automated production systems with recipe control, advanced fermentation control, automated batch transfers and cleaning in Place (cIP). on top we provide planning and reporting software to document the process and enable optimisation across your global facilities. When establishing biotech facilities we keep a watchful eye on cost-efficiency, both in operations and investment. We have successfully built low-cost facilities in asia that are equivalent in quality and efficiency to facilities in europe or the us.
Building the worlds first biofuel demonstration plant In todays global arena, where global warming and environmental concerns are on top of the agenda, industrial biotech companies play a significant role. the innovative products and technologies that come out of the industrial biotech segment contribute significantly and positively to global change and to the lives of all of us. one of the most revolutionary technologies is biofuel: fuel derived from biomass and containing 80 percent renewable materials. Biofuels such as bioethanol and biodiesel offer vast savings of carbon dioxide emissions compared with petrol and thus contribute significantly to improving our environment. BioGasol is a combined biotechnology and engineering company in the renewable energy field and a spinout from the technical university of denmark (dtu). the companys pilot plants have produced second generation bioethanol since the foundation in 2006. BioGasol decided to build a demonstration facility on the island of Bornholm that would scale up their bioethanol production. the integrated BornBiofuel plant is designed to demonstrate BioGasols proprietary enabling technologies within pre-treatment and c5 (Pentose) fermentation on an industrial scale as well as feedstock flexibility. this means the plant will be able to convert agricultural residues such as wheat and barley straw, energy crops, garden waste and grass from roadsides.
Making the difference While BioGasol had the required project execution knowledge to execute the project themselves, the amount of work involved in the project exceeded their capacity. furthermore, being a start-up company, BioGasol required a project execution methodology and framework in order to undertake such a complex project with a budget of approx. eur 35 million. so they needed an engineering partner to fill in their resource gaps and ensure control of the project execution. our biotechnological background and biofuel project experience made nne Pharmaplan an excellent match for the project. BioGasol hoped to draw on our extensive process and project planning knowledge also outside the pharmaceutical segment and they knew our proven ability to adjust processes to individual customer needs and provide tailored solutions would benefit their new facility. We acted as consultants within project management, procurement and special engineering tasks that required our unique know-how and specialist knowledge. BioGasol also used us as process consultants within hydrolysis, fermentation and distillation, mass balance calculations, heat/cooling integration and cIP concepts. When finished, the process concept will allow the plant to be energy self-sufficient as the heat and power in the plant can be integrated with an external energy system. and all process water will be re-used in the plant, thus minimising waste as well as water consumption.
nne PharmaPlan servIces featured In thIs chaPter: Global delivery of low-cost facilities Emerging trends in industrial biotech Efficiency through simulation and model-based design Establishing a new greenfield industrial biotech plant
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EMErGING TrENds IN INdusTrIAl BIoTEch

as the petrochemical supply chain becomes increasingly strained (with rising cost of raw materials) and the world moves towards a more co2 conscious economy and behaviour, the ability to deliver co2 neutral products based on renewable sources will be come a parameter for remaining competitive. In this context, the future of industrial biotech depends on the effective implementation of the biorefinery concept the ultimate concept in industrial biotechnology. a biorefinery is a facility that produces a wide range of products based on renewable biomass feedstock. the aim is to utilise the feedstock by maximising the productive output from the feedstock constituents, thereby minimising waste while maximising productive output and earnings. In the future, process development and plant design will be targeted at accepting a range of lingo-cellulosic raw materials grown specifically for this purpose. these yield a range of low, intermediate and high value products in separate streams, for example:

GloBAl dElIvEry of low-cosT fAcIlITIEs

Keeping costs down is always a priority for life science companies embarking on any type of project. of course, your companys own financial gain is a concern, but minimising the project cost also benefits the consumers. an effective way to keep project costs down is to buy the needed resources in low-cost regions, for example by offshoring to china or India. however, differences in language and culture can be obstacles to an effective project execution, and most companies prefer to work with an engineering partner who understands the market in which the company operates. With offices in 25 locations around the world, nne Pharmaplan has both the local knowledge and the global reach to offer a project team that is tailored to your companys individual needs and requirements. and weve also executed numerous projects based on offshoring. the last five years have seen an increased demand for enzymes in the bioethanol industry. so in order to meet this demand, novozymes, the market leader for technical enzymes, decided to build a greenfield enzyme factory in nebraska, usa. the company asked us to oversee the ePcm (engineering, Procurement, and construction management) contract for this project and we are managing it from our us office. our nne Pharmaplan team is comprised of chinese, danish and american colleagues working together in our largest ever offshoring setup.
Project execution is unique. We carry out the engineering and construction of the process equipment in china at the same time as were completing the civil constructions and other building work in the us, where the site is being prepared for receiving the equipment from china. the reason we are doing the design work, most of the procurement and the construction in china is that we can achieve an acceptable level of quality at a lower cost for all personnel groups. all the detailed design is done at our offices in china by local engineers in close cooperation with colleagues from the us. the us engineers will review the final design to ensure that the documents can be stamped and sealed according to us laws, standards and regulations. all major items are procured from china, both local products and equipment delivered by international companies. Process equipment is constructed by companies that we have worked with before on domestic projects. We also oversee the construction phase, using local or expatriated specialists or a third party supplier. the projects key words are transportation and logistics. approximately 45,000 m3 will be shipped from two locations in china. most of the equipment will be transported on barges up the mississippi and missouri rivers to Blair, while the rest will be shipped in standard containers. this process will ensure that novozymes gets a complete production facility delivered at a lower cost than if it was designed and constructed locally. the project has already reached some important milestones, and the plant should be ready for operation right on schedule in the second quarter of 2012.
heat and power fuel Bulk chemicals fine chemicals
this mode of operation is comparable to the petrochemical refineries of today where crude oil is processed into a range of products (from tar to polymers) while producing side streams of heat and power. the challenge for the industry is to indentify and develop processes that utilise the full potential of the feedstock into value streams. merely producing a single product while discarding the rest as waste for incineration or landfill will not be sufficient in the next generation of operation where energy and raw materials will be priced at a premium. In order to achieve this, you must take a holistic engineering approach where product and process development is supported by the accurate forecast of future markets and production cost scenarios. and partnering with nne Pharmaplan will help you achieve exactly this approach.
EffIcIENcy ThrouGh sIMulATIoN ANd ModEl-BAsEd dEsIGN

Within industrial biotech, profit margins are much more dependent on the direct manufacturing cost and the optimal use of raw materials and energy than in the pharmaceutical industry. and the refinement and sale of by-products are often key contributors when you want to obtain a competitive operation. the best way to ensure an efficient operation is in the early design stage even before you create your first specification document. By examining the projected material flows, consequences of energy integration alternatives and purity profiles of (by)products in combination with information on variations in raw material prices and the expected market value of products, we can work with you to build a robust business case and provide the basis for accurate and efficient process and facility design. accurate prediction of future plant performance and consumption data requires either vast amounts of experimental data or the ability to do simulations. a combination of both allows extrapolation based on known values. at nne Pharmaplan, we have the expertise to build simulation models aimed at supporting business decisions and exploration of design alternatives. When experimental physical data is lacking, we can have our experts synthesise best guesses based on the latest research in the area and in close collaboration with leading researchers in the field. By linking our decisions to data that is traceable to analytical models and experiments, you get a model-based design that has the ability to express the consequences of design alternatives in terms of business metrics. so your plant and operation design is targeted at achieving a competitive and robust business.
EsTABlIshING A NEw GrEENfIEld INdusTrIAl BIoTEch PlANT

Building an industrial biotech plant requires a strong focus on cost and time. Its a huge investment, and the selling point for the end product even with government subsidies is always cost driven. Building an industrial biotech plant is a complex project that requires a thorough investigation of the mass and energy balance for the total process. You also need to consider heat/cooling integration, tank sizes, purification, cleaning and waste han-
dling. the size of the buildings and tank farms are also important, as is the issue of connecting all the different modules with pipes. also, youll need to think about how the facility should be controlled and automated. at nne Pharmaplan, we have 80 years of experience within the pharma and biotech industries, so we have extensive industry knowledge and specialist know-how of pharma and biotech processes. We have executed and assisted many companies in a wide range of projects that concern the establishment of industrial biotech facilities.
We are currently assisting one of our customers in a dKK 200 million fast-track project to build a new greenfield production plant. the customer operates in a very competitive biotech area, so the main drivers for the project are product quality, reliable plant operation and cost reduction. When completed, the plant will be the largest full-scale plant in the world with its specific technology. this poses a challenge in regard to the technology and the design of the process equipment, because the building and its systems must be tailored to the rather special process equipment requirements. In cooperation with the equipment supplier we delivered a multidisciplinary effort that involved specialists from areas such as civil engineering, building systems, health, safety and environment (hse), process, mechanical, electrical, instrumentation, space management and utilities. the design project team consisted of 30-40 people from nne Pharmaplan, the main equipment supplier and the customers own organisation. We will continue to assist the customer with project management during the projects execution phase, handling suppliers and advising the customer in a number of disciplines.
JAPAN. 13,726 persons were diagnosed with Non-Hodgkins lymphoma in 2006. The same year 8,580 died of this type of cancer.
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GMP compliance
GMP compliance has been subject to so much development and reform that it may be difficult to find your way in todays jungle of regulations. NNE Pharmaplan can guide you on your way to full compliance. GMP regulations intend to ensure that products meet adequate quality requirements but as a result that many pharmaceutical manufacturing processes have become very inefficient with low utilisation rates. This leads to higher costs, inefficient operations and almost no process improvements. as a consequence, the manufacturers find very little room for innovation, research and development. The regulatory authorities have recognised the need for reform. in future, much more emphasis will be placed on quality management principles based on product and process know-how and quality risk management, for which europe, USa and Japan are heading a harmonised approach through the international conference of Harmonization (icH) guidelines. a key document for implementation of the new paradigms is the new aSTM e2500 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and equipment. aSTM e2500 delivers a more streamlined way of qualification. it literally replaces the old document-intensive installation and operational qualification (iQ and oQ) with a much leaner verification performed by subject matter experts according to a combination of best product and process know-how and risk management tools. nne Pharmaplan has been a leading player in the international development of the new guidelines and practices, and we are in the forefront with both consulting to the industry and the practical implementation.
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Supplier surveillance ensures safe, high-quality medicine Medicines can cause unwanted and lifethreatening side effects. one reason for this is that the pharmaceutical companies depend on an increasingly globally dispersed supply chain, including companies operating under very different conditions in low-cost countries. For a pharmaceutical company it is a challenge to know what to look out for, and this makes detecting potential danger signs difficult. Pharmaceutical companies who get a large portion of their aPi from suppliers located far away often face quality issues with their final product. a company turned to nne Pharmaplan to set up high-quality supplier surveillance in china, due to our strong local presence and experience in the chinese market combined with specialist knowledge of GMP/GDP (Good Manufacturing and Good Distribution Practice).
We started by putting together an international project team, including local staff from our chinese office, to create a dedicated single-pointof-contact to an aPi expert. We worked with the customer to perform a joint audit of the aPi supplier, and we also carry out regular control visits both scheduled and unannounced to ensure that the supplier maintains the quality agreement at all times. We also took reference samples from the aPi manufacturer and compared with the samples of the material received from the supplier. We believe that pharmaceutical companies can go a long way towards eliminating contamination issues by screening and monitoring their suppliers more thoroughly. as the supplier surveillance project manager commented, Regular tests and control visits keep the supplier above suspicion. But the basic notion is that you should always be suspicious and seek evidence. This should help stem contamination and quality deterioration in pharmaceutical products.
nne PHaRMaPlan SeRViceS FeaTUReD in THiS cHaPTeR: Quality by Design (QbD) NNE Pharmaplan seven steps to QbD based validation The ASTM E2500 paradigm how much money can you save? Getting ready for audits Taking charge of SOPs to become more efficient Managing compliance GAPs Informed approach to designing quality systems Training and the human brain Future-proof with paperless validation Electronic registration and electronic signatures Compliance across the globe Quality risk management and assessment IT systems for quality and compliance (GAMP5) Sterilisation validation Cleaning validation Fast process validation increases utilisation Setting up failure to achieve success Method validation Process validation according to the new guidelines
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QuAlITy by DESIGN (QbD)

Quality by Design (QbD) is a relatively new trend in the pharmaceutical industry, but it has been common practice in most other industries for decades. naturally, as a manufacturer you aim for high efficiency and minimal rejects. This can be achieved by building quality into your products and processes applying a rigorous scientific and risk-based approach throughout the product lifecycle, i.e. right from development through manufacturing to discontinuation. QbD principles link very well to Six Sigma principles and combined they can be used for your existing processes to improve process robustness, reduce process variability, waste and rejects. Taking an analytical approach to production processes and focusing on variance will give you extensive process understanding. This is priceless when registering applications with authorities and dealing with unexpected production deviations.
Identify critical quality attributes
Identify critical process parameters and material attributes
Control strategy
SOP
PAT
PAT PAT
PAT
PAT
SOP
Regulatory authorities are also increasingly acrisk knowledging the value of QbD. an enhanced Changes to operating procedures process understanding and the opportunity at nne Pharmaplan, we offer a number of for real-time release testing will ensure not services related to QbD including: QbD implementation road maps 5. Improved 1. increased process robustness but also that Understanding 3. 4. Product 2. Assessment only Product & process overview overview matrix assessment process & product of critical attributes critical Quality attributes (cQa) and criti understanding and parameters products with the right quality are delivered to the market faster. cal Process Parameters (cPP) identification Specification Product list and family Experimentation Prior knowledge Summary report of critical quality Risk based Data mining Historical data Prior knowledge Design spaces and control strategies inattributes (CQA) prioritisation & analysis
Process flow diagram Critical process parameter (CPP) matrix scoring Process flow diagram Validation data Forward data Fundamental knowledge Unknowns Historical data Validation data Fundamental knowledge Unknowns Use of scientific expertise
in an attempt to force more process understanding into the medical industry, authorities in western countries have started requesting extensive information about product quality attributes, production proc esses and related process parameters (Optional) Process development in connection with product registration Process improvements and approval. based on science and
cluding PaT, real-time release testing and process control Help with registration in line the new QbD principles QbD principles in new facility projects Process validation based on FDas draft guideline introduction of QbD for existing processes establishing and adjusting quality systems that take QbD into account QbD gap analyses and mock inspections. 7. Continuing 6. Validation plan Training process verification & execution implement quality risk management through the entire productTrending continuous lifecycle. Scientific and
risk-based validation improvement
NNE PhArMAPlANS SEvEN STEPS TO QbD bASED vAlIDATION

Quality by Design (QbD) is intended for implementation during drug development, but the principles behind it are applicable and valuable in a number of other contexts. For
QbD principles. our methodology uses the science and quality risk management principles described in icH Q8-10 and the draft guidance from FDa on Process Validation. in-process testing forand our seven-step approach will guide you control at nne Pharmaplan, we can help youData-driven use of through the process, ensuring you focus on set up control and sampling the areas that influence patient risk most. a process validation programme based on example, a science and risk-based approach to process validation can ensure the(Optional) process Control strategy is aligned with future regulatory guidelines development and help keeping patient risk top of mind.increased Use of
(Optional) Process development
1. Product and process overview
2. Assessment of critical attributes and parameters
3. Understanding overview matrix
4. Product assessment
5. Improved process and product understanding
6. Validation plan and execution
7. Continuing process verification
(Optional) Control strategy development
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ThE ASTM E2500 PArADIGM hOw MuCh MONEy CAN yOu SAvE?
Many pharmaceutical companies have realised that todays standard practices of commissioning and qualification (c&Q) are expensive, time-consuming and bring too little quality for money. Taking a science and risk-based approach may be the answer for many companies removing the paper piles of installation and operational qualification (iQ/oQ), and replacing them with a more efficient and modern approach, harvesting the benefits of risk management and know-how of subject matter experts (SMes). The aSTM e2500 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and equipment was approved in 2007. it is applicable worldwide and in line with the new paradigm from international conference of Harmonization (icH) that is the basis of the icH Q8, Q9 and Q10 guidelines on pharmaceutical development, quality risk management and quality systems. The vision of these concepts was expressed in the 2004 US FDa whitepaper on cGMPs for the 21 century, with the aim of fostering innovation and advance in the science of the pharmaceutical industry. The icH Q8/9/10 concepts led to the concept of Quality by Design and the science and risk-based approach to the pharmaceutical product life cycle model. The aSTM e2500 standard builds on these concepts and draws on several tools, including Quality Risk Management, SMes, Good engineering Practices and vendor involvement to ensure that the level of effort, formality and documentation of the quality risk assessment process is commensurate with the level of risk to the patient. The core concept of aSTM e2500 is described by the term verification, deliberately replacing the terms commissioning, qualification and validation to signify an intentional departure from past practices. Verification is defined as a systematic approach to verify that manufacturing systems, acting singly or in combination, are fit for intended use, have been properly installed, and are operating correct. The main focus of the verification effort is on critical aspects of the manufacturing system, that is the functions, features, etc. necessary for the manufactur-
Product knowledge Product knowledge Requirements Regulatory requirements Company quality reqs.
Good Engineering Practice

Specification and design Verfication Acceptance and release Operation and continous improvement
Risk management Design review Change management
ing process and systems to ensure consistent product quality and patient safety. Some of the disadvantages of traditional c&Q include lack of process scalability/flexibility, inconsistency between component impact assessments and product quality and too much focus on test activities rather than on risk mitigations. in essence, traditional c&Q can be extremely complicated and involve numerous and often unnecessary documents, steps and reviews. By applying the principles of aSTM e2500, you can benefit from a more flexible validation approach, better use of expertise, extensive process knowledge and lean documentation. The standard aims to eliminate todays repetitive testing and to involve subject matter experts (individuals with specific expertise and responsibility in a particular area or field such as the quality unit, engineering, automation, development and operations) to determine test principles and approve protocols and test results.
as such, the aTSM e2500 guide represents a move away from paper quality and rigid documentation practices, and brings a lot of advantages and business benefits:

Faster project execution Focus on patient safety Significant reduction of documentation enhanced process understanding Saving of time and resources Higher production yield (oee) improved quality at lower costs better use of expertise compliance with health authorities expectations to risk-based approach
The standard can be applied for both conventional and QbD-developed products. The key to successful verification of a facility project is a clear quality risk management approach. For new pharmaceutical products developed by Quality by Design principles, verification is largely done as part of product development and registration. But for existing products, it has to be deduced from other sources, including the available process development documentation, process validation packages and manufacturing history. in short, the aSTM e2500 breaks with current methodologies for c&Q by the implementation of a scientific approach, risk management and by re-thinking the way regulatory requirements are verified. The focus on risk to the patient and the flexible verification approach with active involvement of vendors can save resources without increasing the compliance risk.
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MANAGING COMPlIANCE GAPs

Using the Gap analysis Program (GaP) approach, nne Pharmaplan helps customers get an overview of their GMP compliance gaps and subsequently links those gaps to specific quality requirements and regulations. as a result, it is much easier for you to focus your compliance efforts and for your company to prioritise and plan how to achieve compliance. Performing a gap analysis can give you benefits in a number of situations, including when you are dealing with changes made in the regulatory environment (e.g. going from food supplements to pharmaceuticals), preparing for a GMP audit, entering new markets with new GMP requirements and/ or making changes to existing procedures.

GETTING rEADy FOr AuDITS

With our extensive knowledge of current Good Manufacturing Practice (cGMP) guidelines, the drug regulations issued by the FDa, icH, WHo, Pic and eU, and all relevant industry standards we help you succeed with all audits carried out by relevant agencies, accredited bodies or customers. our mock-up inspections ensure you discover and solve any problems before your official audit, and we also offer all the relevant training and implementation assistance you need. our tailored audit services include: Mock-up inspections and audits before regulatory authority inspections GMP audits of contract Manufacturing organisations audits as part of your self-inspection programme
audits of suppliers, component suppliers, equipment or services Various audit training services (such as how to prepare for audits and dos and donts) audit follow-up services
our global reach means that we have skilled auditors all with local knowledge and language skills in offices around the world. and because your needs determine the nature of the auditor or audit teams we set up, our trained auditors include former agency inspectors, iSo auditors and key people with experience in quality and production. We can also cover a broad variety of product types including pharmaceuticals, medical devices, combinational products, biologics, advanced therapies, pharmaceutical excipients, foods and active pharmaceutical ingredients.
a GMP compliance gap analysis gives you an activity plan, as well as an estimation of the resources you need to carry the plan out. and, by working with us, you also benefit from our knowledge of this area, which should help you implement a quality mindset in your organisation.
TAkING ChArGE OF SOPs TO bECOME MOrE EFFICIENT

Pharmaceutical production involves a vast number of Standard operation Procedures (SoPs) to ensure consistency. But as the number of SoPs grows, it can be increasingly difficult to maintain uniformity and organise them so they are easy to understand and follow. at nne Pharmaplan, we can provide experienced people who will help you optimise
and get greater benefit from your SoPs. With experience of rewriting all types of SoPs in a clear and straightforward style, we help you prevent any ambiguities and potential misunderstandings. and we look closely at your specific workflow and suggest changes if appropriate to eliminate any unnecessary SoPs. The result will be greater efficiency throughout your organisation.
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INFOrMED APPrOACh TO DESIGNING QuAlITy SySTEMS

Many companies face one of three main problems with their quality systems. The quality system documents, but does not improve quality The quality system is used as a strict control of production, rather than as a tool to improve quality and business. Production staff only views the quality system as a barrier to improvements This problem is not fixed by simply redesigning the quality system. nne Pharmaplan can help by teaching your staff, helping them work as a unit and understand the importance of Good Manufacturing Practice (GMP). We can also modify your change control and deviation systems, so your production staff benefit from it. The quality system is not used This is often because there is no link between the vision and mission of the company and the production unit. often, the strategic and operational level is in place, but the tactical level is missing. We can help you facilitate the process as you write the procedures required to fill the tactical gap and finally by training your employees in the new procedures.
Continual improvement of the quality management system
Management responsibility
Customers Customers Resource management Measurement, analysis and improvement Satisfaction
Requirements
Input
Product realisation
Product
Output
The quality system does not cover GMP compliance in this case, you need to take your quality system from non-GMP to GMP compliance. We start by reviewing your existing setup and identifying improvement activities through GMP audits and interviews, process mapping and quality risk assessment work-
shops. We then help you develop a redesigned quality system, which could include designing a future governance programme that takes into account governance bodies, participants, agendas and templates. We can even assist with the implementation by coaching your staff and offering advice on how to run your governance system.
TrAINING AND ThE huMAN brAIN

Habits really are difficult to break. and so the key to good training is not breaking habits, instead it is all about replacing them. But for an operator who is used to doing manual work all day, sitting behind a desk for GMP training can be a strain. So at nne Pharmaplan, we take a creative and inspirational approach, in order to educate your staff in a way that they remember and put into practice correctly first time. We offer a wide range of courses, from general courses in GMP, GaMP5 (Good (automated) Manufacturing Practice) and risk assessment to customised training that is tailored to your individual way of doing things. We use a variety of training methods, from standard classroom teaching to hands-
on training, and tailor our courses to suit the attendees, whether they are experienced GMP staff or suppliers who struggle to understand why GMP is so important to your company. Here are just some of the specialised areas our training courses cover:
Risk assessment aseptic behaviour Process analytical Technology equipment verification based on e2500 Quality by Design
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FuTurE-PrOOF wITh PAPErlESS vAlIDATION

Studies have shown that in most corporate environments, knowledge workers spend up to 40 percent of their time trying to find paper documents. The time spent searching for and retrieving documents costs companies vast amounts of money every year not to mention the cost of paper itself. new software tools that facilitate electronic registration and storage of all validation documents allow you to track and manage your complete project validation lifecycle from handling requirements and validating test plans to test execution in one online environment. The result? Validation documentation produced faster and more efficiently. at nne Pharmaplan, we have extensive experience with this new paperless technology and have worked with numerous customers in the pharma and biotech industries to configure, operate and control their validation work.
Release management
Test planning
Requirements management
Customization Electronic signature Import/export Analysis & reporting Word and Excel add-in Risk-based testing
Test execution
Defect registration
We can help you incorporate your validation documentation into the online tool at once, or use a stepwise integration approach that imports the validation documentation as you optimise and revalidate your processes. in either case, all your validation requirements, test phases, test information, test execution, error reports and changes can be approved and saved electronically giving you full traceability and eliminating your reliance on paper. Your
staff can then access and operate documents from anywhere in the world within 24 hours. We can help you design your paperless architecture, taking into account your companys organisational structure and processes. and once the validation data has been accumulated, you will be equipped with a substantial reference library that is quick and easy to access and navigate.
ElECTrONIC rEGISTrATION AND ElECTrONIC SIGNATurES

electronic registrations and electronic signatures can be extremely beneficial to many different production and business processes. But while authorities allow the use of electronic registrations and signatures, they also presuppose that your system complies with various requirements, such as the FDas 21 cFR Part 11 the code of Federal Regulations issued by the US Food and Drug administration. nne Pharmaplan can help you deal with the extent of these requirements in both new and existing systems. We have been involved in implementing electronic records and electronic signatures since they were first launched, and this gives us extensive knowledge of how they can be applied in many different system platforms. This means we are ideally placed to help you interpret the requirements and identify the extent that they need to be applied in your specific systems. as a result, we can ensure you implement electronic registrations and signatures efficiently and tailored to your specific needs, without a high investment in validating your systems.
COMPlIANCE ACrOSS ThE GlObE

as pharmaceutical and biotech companies become increasingly global, it can be difficult to put together talented and qualified international project teams. With a global network of talent and infrastructure, nne Pharmaplan can assemble teams fast to provide customers with unmatched value. one of our customers was expanding in latin america and needed a team with the right technical background and prior experience of the processes involved. With experience on similar projects in France and china, we were able to help the customer overcome a scheduling issue that would otherwise have created a business-critical setback for the project. The scheduling problems were further increased by communication issues the customers company languages were english, French and Spanish and they also had to coordinate with a sister facility in china, several time zones away. We quickly gathered a global team, led by a US project manager and including people from France, Switzerland and china who had prior experience with the specific customer.
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Initiate risk management process
IT SySTEMS FOr QuAlITy AND COMPlIANCE (GAMP5)

in the pharmaceutical industry, iT systems need to meet a variety of quality standards in order to comply with the expectations of official authorities. and, at the moment, official authorities are developing a number of changes which will mean companies will need to take a more flexible approach to Good Manufacturing Practice (GMP) compliance in the future. For many iT system owners, it can be challenging to document that all relevant iT systems are GMP ready. and so, you need to have all your relevant change documentation ready for regulatory audits. Many new iT systems or system updates must be in compliance with new GMP guidelines, as outlined in the science and risk-based approach described in the aSTM e2500-07 standard. Therefore, supplier documentation constitutes a considerable amount of the validation documentation that has to be sent to regulatory bodies and the amount of documentation needs to be evaluated in correlation with the level of risk for the patient and the product.
Risk assessment
Risk identification
nne Pharmaplan worked on writing and interpreting the Good automation Manufacturing Practice (GaMP) guidelines since they were first created. Today, GaMP is a natural part of how we approach any automation solution. We can help you evaluate your iT systems and implement any necessary changes or order to achieve smoother maintenance and a higher degree of flexibility when applying new GMP applications. our services in this area include:

Risk analysis
Risk evaluation Risk management tools
Risk control
unacceptable
Risk reduction
Risk acceptance
Risk communication
acceptable
Risk communication
Risk review
Risk acceptance
Output/result of the risk management process
Review events
QuAlITy rISk MANAGEMENT AND ASSESSMENT

The release of the icH Q9 guideline Quality Risk Management was one of the catalysts triggering the QbD paradigm shift in the pharmaceutical industry. nne Pharmaplan can implement Quality Risk Management and address risk at all points in your organisation and also offer to train your staff. one example is to identify critical quality attributes and process parameters for product development. another example is facility verification and manufacturing process validation as defined in the aSTM e2500 standard. We have prepared a structured approach to facilitate risk assessment: Use well-known tools, such as Hazard analysis critical control Point (HaccP) and Failure Mode, effects, and criticality analysis (FMeca) Gather the right team (R&D, specialists, production, process, pilot and quality assurance) Define high and low risks and when to take action create a risk overview to be used for scoring Define acceptable risks and how to minimise unacceptable risks Make an action list Update your risk assessment using the results of your actions
GaMP4 to GaMP5 migration Risk assessment Gap analysis in relation to required compliance Supplier quality assessment (audit) Selecting and approving the leverage level of supplier documentation Providing Subject Matter experts (SMes) for automation Managing your lifecycle approach
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STErIlISATION vAlIDATION
The mandatory annual revalidation of the sterilisation process is a time-consuming task for companies that produce sterile products. not only does it require a number of working hours that could be easily spent somewhere else, but production must also be temporarily stopped during the revalidation period. Thanks to experience gained from a variety of sterilisation validation projects, we can revalidate your sterile process quickly, smooth-
ly and independently so that you have more time to focus on other issues. our full package solution will ensure you experience the minimum disruption and use as few resources as possible on the project. The key to our revalidation success is experience: our revalidation teams have clearly defined roles for your project with clear definitions of who does what for optimum efficiency. and we take charge of all practicalities from calibration requisition to running tests so all you have to do is provide approved bioindicators and items for autoclaving, and then sign the validation documentation. our expertise means customers return to us time and again. For example, in 2010 we will validate an autoclave for a major pharmaceutical company for the seventh time. our familiarity with the customers equipment and procedures, as well as our vast process knowledge and dedicated team, means that the revalidation will be completed much quicker and more smoothly than if the customer was to do it alone.
FAST PrOCESS vAlIDATION INCrEASES uTIlISATION

When validating processes, companies that maintain contact with the organisation that actually installed the equipment or implemented the processes can shorten the startup time, increasing capacity utilisation from 0 to 90 percent in just a few months and thus saving valuable time. When establishing a new facility for chemical biopharmaceutical production, one of our customers a major healthcare organisation introduced a process that they had not validated before. The customer was knowledgeable in the process itself, but they asked nne Pharmaplan to provide the validation know-how they lacked. We worked closely with the customer to create the setup for validation and the preceding qualification. We began by identifying the critical parameters for the qualification and validation, basing our work on the customers own process knowledge. We then qualified the process by running three batches designed to challenge the parameter limits. Then, while validating the manufacturing process, we introduced three new test batches, this time under normal production conditions. as well as project managing the entire process, we also provided documentation, and assisted with tests and reporting of the validation results. Using a combination of the customers thorough process knowledge and nne Pharmaplans validation expertise ensured the customer was able to quickly supply high quality products from its new facility.
ClEANING vAlIDATION
cleaning validation is still a top-ten issue in GMP observations from FDa. But it takes Time, action, concentration/chemistry and Temperature (TacT) to perform cleaning correctly. More specifically, cleaning validation requires an understanding of the following: Maximum allowable carry over (Maco) from the investigated product to the next product STDprevious = Standard Therapeutic Dose of the investigated product in the same dosage form as STDnext STDnext = Standard Therapeutic Dose for the next product MBS = Minimum Batch Size for the next product (where Maco can end up) SF = Safety Factor (varies with the route of administration but also with the patient population) Regardless of your level of knowledge, nne Pharmaplan can provide the resources and know-how you need to upgrade your cleaning process so you are in compliance
with the current validation guidelines Pic/S Pi006-3. We deliver cleaning validation services to all types of production within the pharma and biotech industries. our services cover the entire cleaning validation spectrum, from establishing cleaning validation protocols and various cleaning validation documentation to setting up cleaning validation strategies including product bracketing concepts and establishing acceptance criteria. We can also help you perform tests and train your staff in cleaning validation and sampling techniques. Work with nne Pharmaplan, and you avoid warning letters from the FDa that could look like this: Your firm failed to have cleaning validation studies for all the products you manufacture with the shared manufacturing equipment used to manufacture drug products and household cleaning agents and other industrial products. also, the cleaning Validation Master Protocol does not include a scientific rationale for the products selected, sampling sites, equipment used, and acceptance criteria established.
GMP coMPliance 83
SETTING uP FAIlurE TO AChIEvE SuCCESS

all pharma and biotech companies regularly have to validate or revalidate productionrelated processes, whether this is in preparation for an audit, in connection with the introduction of a new product, or due to unexpected changes in product output. Regardless of the situation, process validation can be a time-consuming exercise, which might not always result in an optimised process. Why not? The main reason is that most of the companys process knowledge is held by a few
experts who have a very intuitive, but not necessarily operational, understanding. Design of experiments (Doe) is an effective tool to ensure this process knowledge becomes both more evident and operational. Doe is a structured approach to identifying the factors in a process that contribute to particular effects and it involves designing a set of ten to twenty experiments that together will systematically test all the process factors. When the results are analysed, the data can help you identify the factors that most influence your processes and those that do not indicating which process parameters are crucial and which are not.
This enables you to avoid validating every process. instead, you can focus on validating the particular process window and so save both time and money. and as well as helping you identify optimal conditions, Doe techniques help you improve the efficiency and the effectiveness of your trials, ultimately leading to higher product quality during routine production. at nne Pharmaplan, we provide Doe consulting services for the validation and optimisation of production processes, and we always focus on increasing your process understanding, so you can validate more effectively.
PrOCESS vAlIDATION ACCOrDING TO ThE NEw GuIDElINES

Pharmaceutical manufacturing companies regularly have to validate or revalidate their manufacturing processes whether they are modifying existing products, equipment and processes or installing new equipment, or introducing new products or processes. and success in validation or revalidation can only be achieved with a thorough knowledge of the process itself. at the end of 2008, FDa published a draft process validation guidance. and in early 2010, eMa announced that they will update the process validation in europe as well, in accordance with the icH Q8, Q9 and Q10 principles, 2 and make it a lifecycle approach based on science and risk principles. The new concept can be applied to both new and existing products. For existing products nne Pharmaplan have developed the Seven Steps model (page 76) and for new products process validation is linked to the QbD approach, focusing on what is critical to the patient by identifying cQas and cPPs and demonstrating the manufacturing process is controlled to always deliver the right cQas. nne Pharmaplan is involved in training FDa inspectors in the new process validation concept.
METhOD vAlIDATION
When performing analytical method validation, you might find yourself in one of two situations. in either case, nne Pharmaplan can help by providing the required expertise and people you need. you lack knowledge and experience in evaluating, assessing and validating analytical methods We can act as consultants, transferring the knowledge you need to perform method validation now and in the future. our expertise includes: how to implement current icH guidelines (icH Q2 The international conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use); how to qualify equipment in accordance with analytical instrument Qualification (aiQ) USP <1058>;
and how to qualify equipment in accordance with current eP (fundamental for performing method validation according to icH Q2). We can also help you establish what equipment you need and write the validation protocols. you have the necessary knowledge but lack the resources to carry out the validation We can provide you with the qualified people you need to carry out the validation. our experts can give you extra value by challenging your current practise in order to improve your regulatory compliance (in accordance with the latest regulations and trends) and improve the efficacy of your ongoing qualification and validation efforts. We can even handle the method validation project independently, so you have more time to focus on other tasks.
84 SuStainability & environment
Sustainability & environment

Although a potential cost, the increased demand for sustainability also brings opportunities that can positively affect your cost and image. NNE Pharmaplan delivers solutions that balance all relevant aspects. Focus on sustainability and the environment, including energy and climate as well as health and safety, is growing around the world. this escalating demand for sustainable action is driven by a number of factors, from rising energy prices and scarce resources to increasing regulatory requirements and a general focus on climate. in order to achieve a healthy business in the long-term, companies must take a sustainable business approach that meets opportunities and manages risks connected to business economics, the environment and social developments. there are several challenges involved in achieving long-term shareholder value, but also many opportunities to save money by reducing consumption (cost drivers) or developing a profile of sustainability (value drivers). it is no longer a matter of simply meeting legal requirements and conditions, but also of taking Health, Safety & environment (HSe) into a new context making it a central strategic value that is integrated into all parts of the organisation and has a broader perspective of sustainability. Some investigations show a connection between positive financial results and sustainability that is integrated into a companys overall business strategies. the best-known indexes of companies quoted on the stock exchange related to sustainability are probably the Dow Jones Sustainability index and the FtSe4Good index. one of the latest sustainable design paradigms is Cradle to Cradle. this framework looks to create products that are essentially waste free. other paradigms, such as eco-effectiveness, water and carbon footprints and Cleantech, also take a new perspective to reduce emissions, overheads and operating costs. and in work place design, it is important to create an inspiring and healthy working environment. all this falls under corporate social responsibility (CSr). nne Pharmaplan offers virtually all the consultancy services that you need within sustainability and environment and we can considerably improve your environmental footprint, energy consumption and impact on the climate and HSe.
SuStainability & environment 85
HSE management in action our customers in the pharmaceutical and biotech industries often have ambitious HSe requirements. through the application of oHSaS 18001 and iSo 14001 standards, we have developed an HSe management concept that can help you meet your HSe goals with cost-effective and efficient systems. once we have agreed on the projects HSe goals with you, we outline the procedures for turning these goals into action. and a dedicated nne Pharmaplan HSe manager will be responsible for all aspects of the project, from concept to validation. Building an Omega-3 production facility omega-3 is used in the treatment of elevated levels of triglycerides and the prevention of post-myocardial infarction and when Pronova bioPharma wanted to build a new greenfield omega-3 production facility, they asked nne Pharmaplan to help. right at the start of the project, Pronova committed to implementing HSe standards that were much above regulatory requirements,
as well as the standards of their existing facility in Sandefjord, norway. their goals were clear:
Zero operational injuries, with a strong focus on safety during construction incorporation of working environment considerations into plant design implementation of environmentally conscious design Compliance with HSe policies Controlled use of natural resources
applying sustainable design principles to the facility meant we had to bring in new technology: an odour control plant to minimise gaseous emissions: a proactive noise and acoustics abatement system in the production areas; and heat exchange systems to reduce the facilitys water and energy consumption. and, when the facility was handed-over, we documented that the HSe initiatives comply with all the requirements specified at the start of the project, including regulatory requirements. to date, we have carried out HSe management in more than 200 large, medium and small projects of varying complexity and scope. and we can bring this expertise to your next project.
nne PHarmaPlan ServiCeS FeatureD in tHiS CHaPter: Sustainable business strategies Climate management and carbon footprint Energy-efficient process design Realising energy savings and process optimisation Cost reduction using CleanTech Certified green facilities Reducing lifecycle impact during R&D Risk assessment: safety of people and the environment Regulatory fast-track processing Innovative noise abatement Wastewater treatment and handling of GMO waste High potent API: occupational exposure limit Designing proactive working environments
SuSTAINABlE BuSINESS STRATEGIES

in order to be socially responsible, a companys business strategy and business activities must take into account concern for human rights, social conditions, corruption and the environment and climate. Doing so can give the company many advantages. For example, it helps improve the companys image, brand and reputation, and offers consistency in risk and supplier management as well as financial investments. nne Pharmaplan is a member of the un Global Compact and we advise companies on CSr issues and iSo management systems. We always tailor our advice to your company and our process consultants can customise your systems and help you set appropriate ambition levels. our goal is to help you achieve the most value from your CSr work and iSo management, so you can continually improve over the years. For example, we recently worked with a vaccine company to prepare its first CSr report as an appendix to its financial accounts. We created the report through weekly brainstorms, debates and meetings, and structured it by using the Sustainability reporting Framework provided by the un Global Compact and Global reporting initiatives (Gri). as a global company, this enabled the customer to work with CSr in accordance with internationally recognised principles and guidelines and the report was attested by the companys accountant. at nne Pharmaplan, our process consultants work with customers to strengthen their CSr work by implementing certified iSo management systems for environment, quality, working environment and energy. these management systems offer a systematic and documented way to continually improve your working environment, reduce consumption and associated costs and build a stronger brand.
Scope 2 - indirect
SF4
CO2
Scope 2 - indirect
CH4
Scope 2 - direct
N 2O
HFCs
Scope 3 - indirect
PFCs
Purchased electricity for own use
Companyowned vehicles
Production of purchased materials
Contractorowned vehicles Waste disposal
Fuel combustion
Employee travel
Product use
ClIMATE MANAGEMENT AND CARBON fOOTPRINT

Customers, employees, and the press and public increasingly expect companies to account for their climate impact, including Co2 emissions. When you publish your environmental accounting, it sends the signal that you take your responsibility for creating a better climate seriously, and demonstrates transparency and credibility within your company. at the same time, your environmental accounts show how your operations affect the climate, and this information helps you decide where to focus on reducing your climate impact and how to save money. mapping of climate gas emissions is often referred to as a companys carbon footprint.
at nne Pharmaplan, we not only map our own global carbon footprint, but we also help our customers to map the climate gas emissions of their activities and processes. We then use this map to analyse your options for reducing emissions, and work out an action plan for future reduction initiatives. this is used to create a strategy for managing climate gas emissions, known as carbon management. We recently helped a biotech company calculate its carbon footprint as part of the CSr report on its facilities in Denmark and Germany. We prepared the carbon footprint according to Scope 1 and 2 of the Greenhouse Gas Protocol, which includes Co2 emissions from the consumption of fuels, electricity, cooling plant leakages and processes.
ENERGy-EffICIENT PROCESS DESIGN

When planning and designing a new factory or production facility, you can realise substantial savings and reduce emissions by taking future energy consumption into account. it is considerably cheaper and easier to implement energy-efficient solutions right from the start, instead of after commissioning. as well as reducing your future energy expenses and greenhouse gas emissions, this approach can also reduce your initial investment. in fact, you can expect to save up to 30 percent on specific processes or equipment, and around 10-15 percent in total on your future energy expenses. energy-efficient design is especially relevant if your processes are validated and performed according to GmP requirements, because alternations are expensive when revalidation is needed.
at nne Pharmaplan, we have extensive experience of incorporating energy efficiency into our designs, either as an integral part of engineering and execution of investment projects, or as individual services.
REAlISING ENERGy SAvINGS AND PROCESS OPTIMISATION

an energy saving project is beneficial for the environment and saves energy and operation costs. When executed with process understanding it often goes hand in hand with a process optimisation that will increase yields and free up capacity in existing equipment. energy saving projects are often performed as energy audits on entire facilities or selected units, processes or equipment and at nne Pharmaplan, we have performed energy audits for companies in a number of sectors, including the pharma and biotech industries. our experience shows that an energy audit can reduce energy costs by at least 15 percent in almost all facilities. We begin by identifying the major energy streams and consumers in your facility, unit, process or equipment. then, we establish a baseline for current energy consumption. once this is complete, we propose alterations, quantify success criteria and calculate pay-back periods. in the next stage, we challenge energy-related parameters, such as temperature set points, to help you identify possible energy savings. by involving our process experts, the result is often not only less energy consumption, but also fewer raw materials, less usage of CiP/SiP,
less downtime or higher throughput. We prepare a catalogue of possible energy saving options and calculate the investment cost and pay-back periods for each option. options are often technical, for example, installing new equipment. However, significant savings can usually also be found by adapting behaviour, such as establishing a new way to perform certain processes. We then work with you to choose the most profitable projects to implement. after implementation, your facilitys energy consumption should be documented by measuring your new energy consumption levels and the results can then be used to help further increase energy efficiency in the future.
Scoping Assessment of current performance Screening energy need and consumptions Data generation + benchmarking Identification of saving potential Interviews Next steps
our energy optimisation projects usually focus on individual components in a facility (such as fans, compressors or pumps) or entire systems Heating, ventilation and air Conditioning (HvaC), cooling, steam or Cleaning in Place (CiP) systems, for example). but, because recovering waste heat is often very useful, we also look into the exchange and utilisation of internal energy streams (process integration). Whatever approach we take, we have the latest knowledge in-house, and are experienced in the main distribution frame between Good manufacturing Practice (GmP) and energy.
Detailed analysis
Design and specification
Implementation
Agree on focus area Identify stakeholders Proposal Kick-off meeting
Process and utility technology People & management

Next steps
Identify possible solutions Tendering Selection of solution Selection of suppliers
Project management Performance and measurements Follow-up
Project scope
Saving potential
Catalogue of solutions
Detailed design and tender Solutions implemented
COST REDuCTION uSING ClEANTECH

Pharma and biotech companies continuously strive to optimise and upgrade their processes and utility facilities in order to increase production capacity. and nne Pharmaplan can help, by supplying knowledge of sustainable design and process integration that ensure your cleaner technology and best available techniques (bat) are evaluated as part of your optimisation project. Producing purified water for the pharma and biotech industries requires several treatment stages in order to meet the quality specified for preparing solvents, Cleaning in Place (CiP) or Water for injection (WFi). as a result, a significant amount of water is lost during the different treatment stages.
We worked with a pharmaceutical company who wanted to reduce their water consumption. initially, we prepared a number of cleaner technology scenarios that included an analysis of the environmental impact of the technology, as well as economic calculations of potential operational savings and
Optimisation of energy and water Recycl. af TO-reject
pay-back time. in the end, the customer chose to introduce a reversed osmosis (ro) plant that reduced both water consumption and the amount of wastewater. the ro plant saved 15,300 m3 of raw water, reduced the amount of wastewater by 15,300 m3 a year and delivered a return on investment within one year.
158 m3/d cf. PDS (158x7x45)
52,244mG/y
Softener
3348 mG/y
58,895mG/y
71,389 mG/y
RO
17,847 mG/y 25%
53,542 mG/y
ED
500 mG/y 3042 mG/y 1%
50,000 mG/y
Delivery
364 mG/y
Distribution, process Distribution, CIP

1362 mG/y
? (PSv)
19,500 mG/y
12,493 mG/y
70%
Reject RO
5364 mG/y 30%
52 m3/d cf. JoSh (62x7x46)
The amount of water from storage tanks to drain is based on the assumption that each tank will be sanitised once per week and that each tank then will be drained from 75% to 10%.
CERTIfIED GREEN fACIlITIES

Sustainable facility design is a hot topic around the world. For many companies, it is a way to improve their green image and reduce the impact their operations have on the environment and it is a key concept when establishing a new facility. When designing sustainable facilities, the architectural form, mass and materials all need to be carefully selected. and one way to measure success is to document the level of green design in your facility through a standard such as leadership in energy and environmental Design (leeD). leeD is the most common standard outside europe and your facility should be documented against leeD throughout the project phases. leeDs main focus areas are:

Sustainable design with focus on low-energy building When working for a process industry customer, our Conceptual Design brief focused on sustainable solutions for the laboratories, workshops and other support buildings. our solution, to reduce the facilitys carbon footprint and energy costs, included:

High-efficient insulation low energy consuming ventilation (demand driven) Heat recovery from server rooms active solar heating for hot water Soil heating optimum placement of glass facades to reduce cooling needs during summer Green roof (sedum)
Optimise energy performance We suggested optimising energy performance by striving towards the highest energy class. the buildings facades will be highly insulated, and the building placed to ensure it gains maximum benefit from solar heat in winter and intelligent solar shading in the summer. and because the building will be located in a continental climate, we recommended using glass on the facades and roof with a very low u-value or triple layers to reduce energy loss. Onsite renewable energy We suggested using groundwater or district cooling. another option is a biomass boiler as an alternative to conventional natural gas furnace Combined Heat and Power (CHP). as for ventilation, free cooling is a must. this can be achieved by improving the design of the cooling baffles, and possibly also by using the lower night temperatures. Access by public transport this customer plans to introduce a company bus to transport employees to and from the facility. Development density and community connectivity We considered site access, via public roads and railways, when selecting the final site. Reduced water use We suggested to consider the supply of drinking and cooling water, electricity and gas thoroughly in order to further optimise the facilitys leeD score and will also map additional ways to reduce water consumption during the basic design phase.
Site selection and site development recycled content of materials alternative transportation/ low-emitting-fuel vehicles energy efficient building enhanced commissioning Good indoor air quality Documentation throughout the project phases
nne Pharmaplan also provided other sustainable solutions for the facility, such as using rainwater to flush toilets, controlling storm water by means of constructed wetlands, planting trees in the green areas around the facility, creating better cycle paths and using local materials with a low carbon footprint. Sustainable design with focus on lEED Gold When a customer asked us to design a new pharmaceutical facility for tablet production, one of their aims was to reach leeD Gold certification. We looked carefully at the sustainable solutions available, and found that the following areas gave the highest leeD point score:
as well as the focus areas above, leeD also focuses on energy-efficient building performance and introducing innovative designs and green solutions in this area can help ensure your facility achieves a high score according to leeD or similar standards like breeam (building research establishment environmental assessment method), which is mostly used in uK/europe.
Solar heating system integrated on roof
Sedum roof (green roof)
Needs-based/demand- Recycling of excess heat from server room driven ventilation
Thermo-active wall element (Selection of) eco-friendly materials Daylight admission to reduce the need for artificial lighting Energy efficient glass faades
Passive solar energy Solar shading Thermo-active floor / thermo-floor
Effective insulation
Energy-efficient lighting No toxic (Needs-based/demand-driven) emission from interior
Terrestrial heat
Reuse of rainwater
REDuCING lIfECyClE IMPACT DuRING R&D

once a pharmaceutical product has been approved by the authorities, it is very difficult to change the production steps, the excipients or the cleaning methods. therefore, it is extremely important to look into the impact that production will have on the environment and peoples health and safety at an early stage in the product development, as this enables you to decide if the impact is acceptable in view of the entire product lifecycle. the impact of your production might be minor in the laboratory, but when scaled up to full production capacity, it could become very large indeed. by taking a systematic approach, we can help you develop more sustainable products that have less impact on the environment, health and safety throughout their entire lifecycle. this can be achieved by: optimising your use of resources (materials, water and energy) Developing and applying sustainable processes reducing exposure, emissions and wastes at nne Pharmaplan, we can perform all the necessary analyses that will help you reduce the impact on your products lifecycle: Step 1: Initial screening very early in the product development stage, you can focus on the substances to be used
in your production, paying special attention to chemicals that have a potentially high impact on wastewater, exposure and air emission. High-attention substances can be appointed as such by your company, or defined as undesired internationally or nationally, or considered undesired due to the precautionary principle or future expected reductions/bans if it is not possible to substitute the hazard chemicals, we suggest ways to reduce the risks, for example through degradation/ inactivation, removing chemicals at source, and finding ways to avoid exposure and emissions. Step 2: SWOT analysis a SWot analysis might help you identify the impact that different production processes could have with focus on materials, substances and processes, for example by looking at the degradability testing of a specific substance, as well as the energy consumption.
Materials / Substances Strength Not classified as toxic Not classified as carcinogenic Not classified as mutagenic Use of critical substances Can be disposed for recycling Can be disposed to incineration with energy recovery Test of biodegradability Under suspicion for endocrine disrupting effect
Step 3: Materials, energy, chemicals and other impacts (MECO) When product development has reached a later stage, you should consider a more thorough analysis. We can prepare a flow diagram that shows each process step, focusing on the product yield, as well as energy, water and chemical consumption. this analysis can demonstrate whether a higher yield is possible and often challenges your assumed temperature levels and water consumption. then, a more thorough analysis of the input and output from each process step will enable you to focus on the impact of the materials and substances used, the impact of energy and water consumption and other impacts, related to health and safety, for example. by estimating the major inputs, we enable you to assess the possibility of reducing the impact of your production by introducing mitigation measures or alternative solutions.
Technology / process Low water consumption Low waste production No emissions to working environment High energy consumption High CO2 emission Installing wastewater treatment Reduction of emissions to air by new filter technology Higher yield New restrictions in environmental legislation coming up (limiting values for emissions)
Weakness Opportunities
Threats
RISk ASSESSMENT: SAfETy Of PEOPlE AND THE ENvIRONMENT

most of our pharma and biotech customers have to consider three main events that could potentially cause significant harm or damage to people and the environment. these are fire, explosion or the release of dangerous substances. at nne Pharmaplan, we can help you gain an overview of the risks faced by people and the environment by assessing all the potentially dangerous situations at your facility in a systematic way. our risk assessments focus on the safety of people and the environment, using a team of specialists in environment and authority processing, as well as mechanical and electrical processes. examples of how our risk assessment adds value to our customers are:
Complying with regulations based on the Seveso Directive if you are obliged to comply with regulations based on the Seveso Directive for hazardous chemicals, we offer qualified consultancy on how to obtain compliance in a smooth and cost-effective way.
Risk assessment approach 1 2 3 4 5 6
Emergency plans We begin by assessing your current safety situation and then recommend how you can handle different risk situations. using these recommendations, you can select the most effective and cost-efficient solution.
Identify the hazards and risks (Can an explosion occur? Can hazardous substances be relesed?) Probability Identify who will be affected and how (e.g. maintenance personnel, operating personnel, civillians) Evaluate the risk (Will an explosion cause deaths or severe injuries?) Characterise the risk by using a severity/probability matrix Define mitigation measurea (e.g. keep hazardous units apart, gas detectors (alarms), sprinklers etc.) Review and update
High 1 Medium 2 Low 3
Low 1
Medium 2 Severity
High 3
REGulATORy fAST-TRACk PROCESSING

When establishing a new greenfield pharmaceutical or biotech production plant, you need to obtain a wide range of approvals, which can comprise environmental impact assessment (eia), environmental approvals, wastewater permit, Gmo, biosafety, atmospheres explosibles (ateX) and fire and safety. Getting all the permits in place at the right time is essential in order to meet a fast-track plan for a timely project implementation and the key is to maintain a clear overview of legal requirements, and keep in close contact with the authorities. However, this is not always easy, as complex regulatory processes often involve almost all professional competencies as well as a number of external parties. nne Pharmaplan can help you maintain an overview, and ensure your facility is completed on time. For example, for one of our customers, getting its product to market quickly was crucial to investors. So the customer decided to fast-track the building
of a new pharmaceutical production plant in Denmark. We succeeded in reducing the time schedule on the eia from 12-18 months to 8 months. all regulatory work was implemented during project execution and continual dialogue with the authorities made a fast-track process possible. We were also responsible for obtaining environmental approval, wastewater permits and Gmo and biosafety approvals on behalf of the customer. in China, we carried out an eia process for a new biotech production facility for a customer, preparing all the necessary analyses, reports and documentation before it was presented to the customer by a specially licensed company. as the eia process in China is long and the authorities needed to approve each project phase before the customer could move onto the next our work began before the actual project design started, and continued until the final construction. and thanks to a tightly controlled time schedule, the customer obtained all necessary approvals and licenses in due time.
WASTEWATER TREATMENT AND HANDlING Of GMO WASTE

many companies face the challenge of handling wastewater and Gmo waste from their production during normal operation, and especially when expanding their facilitys production capacity. Major and minor facilities nne Pharmaplan designed and constructed one of europes largest plants for treating pharmaceutical wastewater and the plant has been upgraded several times to meet increased demand. today, the facility consists of several treatment stages, including inactivation of waste containing Gmo, wastewater treatment (including pre-treatment, biological treatment and subsequent polishing) and sludge treatment and dewatering. the plant treats 4,000m3 of waste containing Gmo and wastewater containing up to 120 tons of organic material (CoD) a day, the equivalent of the waste produced by 750,000 people. but we can also design on a smaller scale. For example, we designed a neutralising facility for the optical industry that treats just 35m3 of wastewater a day. the facility consists of a tank with dosage of acid and a base for neutralising wastewater. Recycling of water from the industry our goal is to develop holistic solutions that provide you with sustainable solutions so we focus on the process modules that minimise water consumption, generate the least amount of wastewater and give you the best opportunities to recycle water internally.
Occupational noise occupational noise needs to be maintained at levels that comply with national regulations and do not cause health problems for employees. nne Pharmaplan worked with a biotech company to mitigate noise in the working environment in all the companys production facilities. based on a mapping of the noise problems, we developed noise abatement measures that will have the highest noisereducing effect with lowest investment. our solutions for the customer include:

INNOvATIvE NOISE ABATEMENT

Environmental noise environmental noise caused by production facilities can sometimes result in complaints from neighbours and non-compliance with the companys environmental permit. We use advanced computer simulation as a mapping support tool and certified noise measurements to develop solutions that mitigate environmental noise in your facility. and we design your noise abatement solution using up-to-date knowledge of the latest noise abatement technologies.
individually designed noise enclosures acoustic room absorption which complies with hygiene requirements vibration and structure-borne noise elimination
of course, these solutions meet the necessarily high product quality, cleaning and maintenance standards. For example, we developed a new hinge to mount acoustic panels that makes cleaning and replacing the panels easier for the customer.
OEL > 1 - 10 mg/m3 > 0.1 - 1 mg/m

3
Band 1 2 3 4
Toxicity Skin/eye irritants Harmful, irritants Toxic,corrosive skin sensitiser Very toxic, harmful to reproduction, may cause cancer Carcinogenic
Requirement Good manufacturing practises Good manufacturing practises with local exhaust ventilation Essentially no open handling / ventilate enclosures Virtually no open handling / containment systems No open handling / closed systems required
the hazard of the actual aPis must be assessed at the very start. this requires health impact data for the aPi, for both acute and chronically adverse effects:

> 0.01 - 0.1 mg/m3 > 0.001 - 0.01 mg/m3
< 0.001 mg/m3
acute toxicity (human) irritancy allergenic effects Chronic effects (carcinogenic, reproduction toxicity, mutagenic, etc.) noael/loel (no observable adverse effect level/lowest observed effect level)
HIGH POTENT API: OCCuPATIONAl ExPOSuRE lIMIT

the health and safety aspects of highly potent active pharmaceutical ingredients (aPis) must be considered before designing a production facility. this requires conducting a risk assessment of all aspects of each production step, analysing the risk of both operational and accidental exposures. the definition varies, but a high potent aPi is generally defined as: a pharmacologically active ingredient or intermediate with biological activity at
approximately 150 g/kg of body weight or below in humans (therapeutic daily dose 10 mg) an aPi or intermediate with an occupational exposure limit (oel) 10 g/m of air as an 8-hour time-weighted average a pharmacologically active ingredient or intermediate with high selectivity (i.e. the ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses a novel compound of unknown potency and toxicity
Health impact data is usually available from animal tests and therefore safety factors must be used to estimate the human health impact. if this data is not available in the product development stage, the desired pharmacological effect can be used for an initial estimate. an occupational exposure limit (oel) is derived from the adverse health impact data. the oel is used in the risk assessment to define the strategy required to reduce exposures. at nne Pharmaplan, we perform the risk assessment in a similar way to a biosafety level (bSl) risk assessment, taking an overall step by step approach.
DESIGNING PROACTIvE WORkING ENvIRONMENTS

Defining the ambitions for the health and safety level at an early stage in a project is important to ensure the facility has a good working climate. it is very difficult to make physical changes to a facility once it has been approved by the FDa or other approving authorities. at nne Pharmaplan, we can operate at three different levels, depending on your requirements: at the inspiring and healing level, which is the highest level and will take your facility far beyond the demands of legislation to provide an inspiring environment for employees. the improved level takes your facility one step further than6 required by the legislation and finally, the acceptable level which fulfils all legislative requirements. Despite the different levels, the methodology remains the same and is based on three key design principles: identifying local health and safety legislative requirements
Thermal comfort needs-based/demand-driven ventilation Eco-labelled and/or indoor climate labelled acoustical as well as wall and ceiling materials No toxic emission from interior Daylight admission to reduce the need for artificial lighting
Sun shading and view from office work stations
Supplemental artificial lighting in accordance with legislative requirements
identifying your health and safety requirements Defining the desired level and specification for parameters (e.g. noise, thermal comfort, ergonomics, acoustic climate, air quality and daylight)
in the subsequent design phases, we use different tools to analyse the health and safety impact of your facility, and to set specific requirements. these tools can include a program to simulate the thermal comfort, lighting, etc. or an acoustic simulation tool. We also use risk assessments, and eco-labelled and indoor-climate-labelled products.
Healing architecture Healing architectural measures help you reach levels beyond legislative requirements. as a design concept, healing architecture represents the vision of how the architecture will affect human welfare and so helps enhance or promote a healing process. often used in the hospital sector, healing architecture takes daylight quality, room ambience, colours, sounds/noise and private spaces into account to support a physically and psychologically healing atmosphere.
92 Containment & Cleanroom
Containment & cleanroom

Contrary to conventional cleanroom design, establishing a containment environment is a complex task that relies on a fine balance between various requirements. We can help you achieve the perfect one. Cleanroom and containment environments are a prerequisite for the research, development and manufacture of sterile and/or hazardous pharmaceutical products. more and more companies need cleanroom environments that are also capable of containment. the GmP cleanroom philosophy aims to protect the product by producing it in a controlled and clean environment keeping dirty effects outside. However, containment has the opposite purpose: to protect employees and the surroundings from hazardous products and materials. this contradiction affects the design process and risk assessments, and the design solution has to comply with both GmP and other requirements at the same time. With experience in both disciplines, nne Pharmaplan is a reliable partner to help you make the right choices when designing these dual-purpose facilities and our risk-based approach and profound knowledge ensure the project is trouble-free, despite its complexity. the optimal containment and cleanroom environment presumes an understanding of the process going on in the cleanrooms. For example, the use of closed processes, restricted access protective measures or isolator technologies might allow you to reduce your reliance on highly classified cleanroom conditions. in this way, you can reduce your initial cleanroom investment costs, cut HVaC running costs, and save space with fewer airlocks and procedures for change of clothes. Based on our experience from hundreds of cleanroom projects with many different applications, nne Pharmaplan can help you assess your existing installations and define an optimal strategy for new ones balancing process, quality and regulatory requirements with efficient operations and investments.
Containment & Cleanroom 93
Designing a hospital cleanroom for 24/7 operation in a pharmaceutical production facility a shutdown of cleanroom operation often means loss of a batch and loss of money for the company; but another batch can be produced, and the end user/patient will still get the product in time although perhaps with a slight delay and without comprise on quality. However, in the hospital world where treatment is often acute, sensitivity to cleanroom shutdown is extremely high. Individual cellular based cancer treatment in a project for the norwegian radium Hospitals Cell & Gene therapy (GCt) department, the focus was directly on the patient and not commercial. the CGt department produces unique treatments for each individual cancer patient and, because it uses the patients own cells to produce the therapy, there is only one chance to get the treatment right. an unplanned cleanroom shutdown could compromise the blood product and, in the worst
case, could cost a patients life and this gave the project a life and death importance. redoing the batch as is done in many pharmaceutical companies is simply not an option for the CGt department. so nne Pharmaplan designed a cleanroom solution that runs without interruption 24 hours a day, 7 days a week. About the Norwegian Radium Hospital and its Cell & Gene Therapy department the norwegian radium Hospital, belonging to the oslo university Hospital, is norways dedicated centre for cancer treatment, and today the hospital is one of the leading cancer research and treatment centre in northern europe. the Cell & Gene therapy (CGt) department harvests and prepares stem cells for blood and bone marrow for all patients receiving bone marrow transplants at the oslo university Hospital. its responsibilities include also translational and clinical research on cellular based cancer vaccines that are tested in patients with malignant melanoma, glioblastoma, prostate cancer, lymphomas and ovarian cancer.
nne PHarmaPlan serViCes Featured in tHis CHaPter: GMP versus containment the right balance Completing a biosafety risk assessment Reducing cleanroom cost through new production technologies Cleanroom laboratories for R&D cancer treatment High containment animal facility design Turnkey modular cleanroom solutions for pilot-scale production Airlock design that supports hygiene procedures NNE Pharmaplan CleanPlus: our cleanroom concept Electromagnetic interlock: the CleanLock PLC Upgrading an existing cleanroom environment Reducing energy costs in your controlled environments Cleanroom testing and certification the proven and painless way Making cleanrooms operator-friendly Go clean: the structured way to make cleanrooms operational
GMP vERsUs CoNTAINMENT THE RIGHT bALANCE

When both Good manufacturing Practice (GmP) and containment are needed, the task is to protect the product, the employees and environment, all at the same time. a lot of synergies can be achieved when combining GmP and containment requirements. these include simple-to-clean design, minimal contaminations, large air change rates and written policies and procedures to provide clean facilities and remove containment. But there are also a number of conflicts to be dealt with. GmP requires positive pressure while containment often requires negative pressure. also, while the optimal GmP flow is from dirty to clean, the containment flow must be from clean (uncontaminated) to dirty (contaminated). so how can conflicts between GmP and containment/ biosafety be solved?
Compromises must be found when both GmP and biosafety are required. the final layout may contain extra positive or negative pressurised zones and this is often solved through airlock design. the flow of both personnel and materials must take both GmP and biosafety into account, as should the facilitys doors (door swings, type of doors). also, both GmP and containment zones should include their own rooms for cleaning equipment. as for kill systems (handling of waste, decontamination of waste water, solid waste, gowning etc.) these should be engineered to live up to both guidelines, even if compromises are made based on the projects risk assessment. GMP and containment: when to consider both? For pharmaceutical manufacturers, such as vaccine producers, hospitals with patient care facilities and isolation rooms for patients, test laboratories and animal research facilities both GmP and containment can be relevant to take into account.
Biosafety
To create a safe environment for workers/to prevent escape of infectious agents to the environment
GMP
To ensure that the product is safe for the end user
Protect the employees
Protect the product
Which guideline takes precedence if both GMP and bsL are relevant? any decisions on which to use should be made in connection with a thorough risk assessment and very often you need to analyse technical solutions from both guidelines. often, the result is a layout and design that combines both approaches.

at low biosafety risk (Bsl-1 / Bsl-2) GmP normally takes precedence at high biosafety risk (Bsl-2, Bsl-3 or Bsl-4) containment should take precedence
CoMPLETING A bIosAfETy RIsk AssEssMENT

Biological agents are live organisms that may cause adverse effects in both humans and nature. Before starting a new production, pilot plant or lab it is important to test the characteristics of the biological agents that will be used in order to identify the optimal design and the optimal containment level. this test is performed as a risk assessment, and also focuses on compliance with legal requirements. all risk assessments are based on two issues: hazard and exposure.
the biological agent has specific characteristics that define the hazard level, while exposure may vary depending on a number of actors, including process activity and equipment type (centrifuges, for example). and if the biological agent is airborne, aerosol formation can be a major risk. the overall risk is defined as: Risk = Hazard x Exposure We suggest a step-by-step based approach for the risk assessment: 1. identify the micro-organism, cell culture or virus by looking into risk class, the infectious dose, the environmental risk
(life-time, biological stability, airborne, etc.), epidemic potential and any allergenic effects 2. analyse exposure and infection routes including inhalation, ingestion and direct contact. the exposure level in each step depends on the actual activity and the amount of biological agent present; the lower the hazard, the lower the overall risk and so the lower the required containment level. as well as exposure in the workplace, exposures can also occur through:

Examples of biological agents and the associated risk class biological agent seasonal influenza Pandemic influenza (H1n1) Pandemic influenza (H5n1) ross river West nile Chikungunya virus bsL risk class Bsl 2 Bsl 3 Bsl 3 Bsl 3 Bsl 3 Bsl 3 Exposure routes Via inhalation and mucous membranes (eyes, nose, etc.) and injuries Via bloodstream (incidents with needles) and via inhalation and mucous membranes
accidental releases electrical or other supply system failures Fire explosions leakages during transport leakage during waste movement leakage due to traffic accidents naturally occurring incidents, such as earthquakes, flooding, hurricanes
Bioterrorism and biosecurity (including nGo actions) must be taken into account as well and safe access procedures, including fencing and access control, should be considered.
REDUCING CLEANRooM CosT THRoUGH NEW PRoDUCTIoN TECHNoLoGIEs

Creating a high class cleanroom environment can prove more expensive than a more common production facility. and because of airlocks and HVaC supply and maintenance requirements, class a, B and C environments also require considerably more space than normal facilities. the answer may be to introduce new production and process technologies, such as isolators and restricted area Barrier systems (raBs). these can enable you to downgrade the room to a lower class and possibly even reduce your space requirements so you can reduce your initial investment as well as your running costs. also, using single-use equipment, such as tubes and bags instead of pipes and tanks, removes many of the limitations of cleanroom design. this can give you a more
flexible setup, and reduce the costs of any future rebuilds. as specialist in new technologies and single use, nne Pharmaplan can help you perform feasibility studies, risk assessments and cost benefit analyses so you can fully research all the possibilities and reach a solution thats safe, flexible and cost efficient.
HIGH CoNTAINMENT ANIMAL fACILITy DEsIGN

risk and security issues dictate that most large-animal high containment research facilities are built in hard-to-get-to locations. and because of the necessarily stringent biosafety operating and maintenance issues, few builders know how to construct the facilities successfully. large-animal high containment facilities are challenging not only to designers and contractors, but also for the research organisation or company. to reach the right facility design solution, the right interdisciplinary project members and other relevant parties must be involved from the very start. nne Pharmaplan will ensure that you get an innovative planning process followed by a highly dedicated interdisciplinary design phase and focused construction resulting in a safe and secure facility. some design parameters require special attention during design and follow-up. epoxy on floors and walls will ensure smooth and easily cleanable surfaces that are resistant to chemicals and pressure washing. the utility and equipment design should optimise operational capacity and yet minimise maintenance costs for airlocks, autoclaves, boilers, HePa filters, kill oven, flow and heat meters. and procedures should be established for regular check of pipes and drains gaskets as well as the tightness of link seals where pipes and cables penetrate walls and slabs.
CLEANRooM LAboRAToRIEs foR R&D CANCER TREATMENT

sentoClone, a swedish life-science research company founded in 2004, provides cancer immunotherapy and recently succeed in developing a new cancer treatment method. Based on the activation and utilisation of the patients own immune systems, the new treatment method uses the bodys own lymphocytes to fight cancer. sentoClone turned to nne Pharmaplan to help establish a cleanroom laboratory to support its research and development of cancer science and cell therapy. the facility had to be installed on the fourth floor of an existing historical building. this proved a challenge, as the customer was not allowed to make any visible changes to the buildings facade or install an elevator. We began by performing detailed front-end planning and design with prefabricated CleanPlus modules. and we then removed a faade module in order to get the building materials and process equipment into the building. the materials were brought in by crane, and there was little room for error the large fluorescence-activated cell sorter (FaCs), for example, slotted through the gap
in the faade with only 50mm of free space on either side to manoeuvre it into place. With nne Pharmaplan in control of the turnkey project from conceptual design to gowning procedures and validation the result was a state-of-the-art facility that meets all regulatory requirements and supports the production of an epoch-making new cancer treatment.
TURNkEy MoDULAR CLEANRooM soLUTIoNs foR PILoT-sCALE PRoDUCTIoN

as pharma and biotech companies move from r&d to the first clinical trials or pilotscale production, they often need fast-track facility design and project execution. this enables them to produce and market a new drug while meeting corporate time-to-market objectives. For small research companies used to flexible working procedures and with scarce resources, the regulated world of Good manufacturing Practice (GmP) is a very new experience and creating all the necessary documentation can put the organisation under stress.
in an industry where saving time can also mean saving lives, building a cGmP Containerised Cleanroom modular Production unit in a shorter time period might be a valuable solution. Containerised Cleanroom modules enable you to reduce construction time by around 30 per cent compared to traditional concrete constructions. and, using an integrated design for the container structure, the cleanroom installation and utilities, can provide a turnkey design solution that makes it possible to quickly go plug and play. at nne Pharmaplan, we can help you define the level of cGmP or Bsl (Biosafety level) you require, and specify the production environment you need. We also execute feasibility studies that can prove useful when investigating if your production could be done at a Contract manufacturing organisation (Cmo) or if you would benefit from a new laboratory facility. Flexible and modifiable cleanroom solutions and laboratory layouts prepare the ground for future expansion. and, at the same time, the investment cost can be split into different execution phases, making the task of raising venture capital from either investors or public funding much easier. We also construct fully equipped and qualified cleanroom units off-site. these are then transported to site for final installation and testing, including commissioning of the cleanrooms, HVaC and interlock systems. the modular system used for both the container structure and the interior cleanroom system makes this solution very flexible. it can be rebuilt for other purposes, upgraded and expanded and even moved to another location. our cleanroom modules, such as CleanPlus, can be installed as cleanroom panels and built into a movable container solution, or integrated as a plug-and-play unit inside an existing facility.
AIRLoCk DEsIGN THAT sUPPoRTs HyGIENE PRoCEDUREs

the right cloth-change and hygiene procedures are essential to obtaining a controlled environment as well as a clean and qualified pharmaceutical product. the design of personnel airlocks is based on gowning procedures. at nne Pharmaplan, we plan and try out our airlock design with the end users. our focus is to ensure that design follows functionality and supports required procedures and behaviours.
the gowning zoning overview is one of the puzzles of preparing the layout and designing the airlocks and it needs to be considered from the start. We begin by discussing gowning procedures with you, covering all elements of the procedure, from entering the facility to going though the gowning regime for each classification zone. the personnel flow is then illustrated in a general layout, and the gowning zoning and airlock designs are illustrated in room drawings that describe procedures, equipment and inventory. We may also create a 1:1 mock-up to try out procedures. this can be used as a guiding tool for the process, supporting decision-making in detailed interior design solutions, including the exact location of equipment and furniture. We know from experience that creating an extended detailed design based on a scale 1:1 mock-up with the possibility of testing flow, area requirements and procedures can considerably reduce production errors caused by human-exposed decontamination.
NNE PHARMAPLAN CLEANPLUs: oUR CLEANRooM CoNCEPT

nne Pharmaplans modular cleanroom concept, CleanPlus, offers proven quality and includes different types of modular cleanroom systems. developed by our swedish office, CleanPlus has been used for 15 years (>35,000 m).
it helps you achieve state-of-the-art facilities with focus on hygienic design and easy maintenance, and is ideal for special containment needs, such as the Biosafety level (Bsl). using CleanPlus, we can help you meet regulatory requirements by designing, installing and validating your cleanrooms according to your needs.
CleanPlus cleanroom system A 1 Walkable celling 2 double panel walls 3 self rising clean room doors 4 Flush mounted windows 5 suitable for alle types of flooring 6 PlC based Cleanlock interlock of doors 7 lighting serviceable from inside/above 8 tailored pass-through solutions 9 integrated air extraction 10 on site intergrated electrical installation 11 Flexible sealing of vibrating pipes 12 easy cleaning work benches 13 rails for extra protection
ELECTRoMAGNETIC INTERLoCk: THE CLEANLoCk PLC

Cleanlock PlC is a hygienic, reliable, maintenance-free system for interlocking airlock doors. a very versatile system, Cleanlock enables you to adapt the functions, including interlock times, etc. to your specific needs. You can also use external systems to monitor and control connected doors through the PlC.
UPGRADING AN ExIsTING CLEANRooM ENvIRoNMENT

implementing new production technologies and process optimisation in existing production facilities can also require revamping the cleanroom environment. and using predesigned and even pre-fabricated cleanroom modules and inventory can help minimise on-site building activities during construction. many manufacturers still use a more traditional cleanroom approach, building up the cleanroom environment with plasterboard and painted surfaces. this can make rebuilding activities more complicated, and even risky, in terms of reconstruction. one way to establish flexibility and easily changeable room design is to use cleanroom wall and ceiling systems with integrated installations for building and process utilities. For example, when rebuilding a sterilewash grade B area during a short shutdown period for one customer, we used a pre-designed and fabricated stainless steel wall with integrated wash basins and utility installations. the wall was brought to the building site just in time for installation, and was mounted, sealed and equipped within one week of construction. this enabled
the customer to meet all milestones, and quickly execute the qualification of room conditions and utility supply. at nne Pharmaplan, we specialise in designing and developing cleanroom inventory and small equipment as standard fabricated products for fast-track execution or as custom-made solutions suitable for rebuilding existing sterile environments. this includes a standard design solution for fast-track facility revamping that uses pre-designed and proven furniture for airlocks (e.g. easily cleanable benches that support procedures, shoe shelves, and production room equipment such as pass-through cupboards with integrated interlocks). and to ensure you experience a short shutdown time and easy ramp up, we take an interdisciplinary turnkey approach, especially when performing revamps. energy savings up to 55-60 percent can be achieved if all mentioned measures are implemented. Possible change of humidity requirements should be given special attention. Furthermore, the following measures may achieve savings of up to 10-15 percent: using recirculation instead of heat exchangers minimising pressure losses in HVaC systems using only energy optimised fans and motors initial investment, costs are quickly earned back through reduced operating costs and environmental considerations. How much can you save? Following measures can be applied for both new and existing HVaC systems:

REDUCING ENERGy CosTs IN yoUR CoNTRoLLED ENvIRoNMENTs

on average, HVaC systems consume between 1,500 and 2,500 kWh/m2 of energy in electricity, heating, cooling, humidifying and dehumidifying. For a pharma or biotech facility, this can account for up to 50 percent of the overall energy consumption. as a result, the energy efficient design of HVaC systems is an essential part of reducing energy consumption, as well as associated energy costs and Co2 emissions. at nne Pharmaplan, we design new HVaC systems for low-cost energy consumption. We also analyse old systems, looking for possible energy reductions and capacity optimisation. although this may take an
energy consumption can also be reduced by downgrading classified areas from nice to have to need to have, and you should consider if class a and B environments can be reduced through alternative process technologies, such as isolators and raBs (restricted area Barrier systems).
lowering temperature, humidity and air change rate requirements minimising air change rates in periods of downtime stopping or reducing speed of udF (unidirectional air Flow) modules in periods of downtime utilising different set points for indoor conditions (summer and winter) utilising different set points for indoor conditions (in operation and at rest)
MAkING CLEANRooMs oPERAToR-fRIENDLy

Working in a cleanroom environment is a challenge. Both physical and mental aspects influence the experience and the related behaviours of operators and maintenance staff. Cleanrooms often suffer from a lack of daylight and view of the outside world. in addition, easy-clean surfaces can mean hard materials and this results in a bad acoustic environment. Cleanroom routines can also be stifling. decontamination precautions require operators and maintenance staff to pass through several extended cloth change procedures. the operators often work in isolated rooms without interaction with colleagues. this lack of communication can result in the operator having a limited understanding of the overall process. the answer is to design a high quality cleanroom environment that takes into account the necessary functionality and the production flow and provides the operator with an aesthetic and work-friendly environment which promotes personal wellbeing. With
the right cleanroom design, you will benefit from improved employee satisfaction, higher product quality and production capacity, and you will meet all necessary regulatory approvals. We take the following into consideration in our cleanroom designs: space for flow instead of storage inspiring and motivating atmosphere Communication and idea exchange Corporate visual identity (CVi) teamwork and collaboration easy and logical procedures, such as cloth changes Glass walls in between each room if possible acoustic regulation in cleanroom panels daylight and view to the outside world
CLEANRooM TEsTING AND CERTIfICATIoN THE PRovEN AND PAINLEss WAy

in order to achieve the expected particle classification grade in cleanrooms, the ventilation parameters must be controlled, including air exchange, room pressure differences, recovery time, HePa/ulPa air filtration, airflow velocity and airflow patterns. regulatory authorities expect these parameters to be periodically certified and validated according to standard methods and regulations. When certifying parameters in a cleanroom, we can help you perform the following tests:

Go CLEAN: THE sTRUCTURED WAy To MAkE CLEANRooMs oPERATIoNAL

turning a complex cleanroom construction site into an operational environment can be big challenge, especially if its performed in phases with construction and cleanrooms operating in parallel. at nne Pharmaplan, we work with go-clean strategies to facilitate the stepwise startup of large facilities. the go-clean strategy enables us to make critical sections operational while construction is still ongoing in
other parts of the facility. thus, it serves as the basis of a prioritised start-up sequence as defined by our customer. ultimately, our go-clean strategy ensures that your facility observes good engineering practice (GeP) and cGmP, complies with the basis of design (Bod) and meets your expectations and needs. in addition, the go-clean strategy gives you a record of the process to substantiate the facilitys due diligence, compliance and robustness. For example, when helping establish a major facility in France, we developed a go-clean strategy and plan for the entire facility that included setting-up the physical demarcations between different clean levels. We also provided duty rosters and entry passes, and trained employees. We laid out a complete visual plan for the site, defining gowning requirements, access, cleaning level and personal protective equipment (PPe). as part of the project, we trained more than 300 employees in standard operation procedures and guidelines for various clean levels.
airflow velocity and volumes in the cleanroom measurement and analysis of room pressure differential HePa/ulPa filter leaks test non-viable airborne particulate counts for room classification airflow pattern test/smoke visualisation & video recording test of unidirectional flow units test of production equipment, isolators, clean benches, biosafety cabinets etc. training in cleanroom technology, working techniques and maintenance
at nne Pharmaplan, we focus on reducing production shutdown. as well as calibrated equipment, we have a large number of trained technicians and engineers certified by the national environmental Balancing Bureau and Cleanroom testing and Certification Board (neBB and CtCB).
100 Logistics and faciLity design
Logistics and facility design

In order for a facility to work effectively, the design must support all processes, interfaces and flows. Working with us will provide you with a complete and futureproof solution. Logistics and facility design services affect all processes in a facility, including the manufacturing and business processes. a well-designed facility ensures coherent processes, storage, material flows, utilities and personnel workplaces, and this in turn ensures optimal cooperation between the different business units and processes in the facility. all processes in a facility need raw materials, information and utilities. Likewise, all processes are likely to require product dispatch, waste removal and the recording of process information. also, most processes must be easily accessible for personnel. all these needs create a multitude of interfaces within a facility. a key challenge in facility design is to define which of these interfaces are key and which are not. a prerequisite for designing a well-functioning facility is to know the scope of these key interfaces. they can be material flows, utility flows, personnel flows or information flows. together with the required storage, process and utility capacities, an integrated flow analysis governs the required dimensions of the facility, including the storage areas, transport corridors, general corridors, automated transport systems, piping and personnel facilities. at nne Pharmaplan, our specialists are at the forefront of new treatments and regulatory requirements, and so are our solutions. our roots in the pharmaceutical industry ensure that our logistics analysts, architects and building engineers are capable of revamping or designing facilities that work efficiently, are prepared for the world of tomorrow, and brand our customer in the right way in everything from process architecture to facility design.
Logistics and faciLity design 101
Balancing drivers to create the perfect site When one of our customers contacted us for an evaluation, they needed to find out if their existing facility was suitable for the companys new production needs, including a cgmP compliance assessment. it turned out that the existing premises did not meet the customers requirements and so we began a relocation study that included site selection along with a site master plan. the customer has a large product range, so we analysed the operational conditions in order to plan material handling procedures that would ensure superior logistical performance and an efficient supply chain. this required a deep understanding of the link between the different logistical factors, processes and the premises in order to establish the right facility. all of the
customers activities were gathered in one place, and the opportunity to strengthen their corporate image through architecture was an added value. from the very beginning and all the way through the various project phases to handover, our facility design was based on the business and design drivers agreed with the customer. Layout and building typologies were discussed to find the optimum process and premises combination. in all areas of the facility, we focused on the working environment and sustainability. in the end, the customer got a long-term solution and a well-functioning building for their activities. it looks great both inside out and vice versa with a view of a beautiful landscape and an inspiring work environment.
nne PharmaPLan services featured in this chaPter: From business plan to facility plan capacity and flow analysis Site master planning getting it right today and tomorrow Site selection; weighing the pros and cons Right place, right time, right cost supply chain analysis Keeping it cool cold chain robustness GMP strategies setting your facility up for success Building condition analysis your facilitys health check Revamping new use for existing buildings Material handling a focus area worth your attention Facility design addressing climate change Creating your site atlas Customised layout typology Biosphere your future facility?
FRoM BuSIneSS Plan to FaCIlIty Plan CaPaCIty and FloW analySIS

When you want to achieve an optimal facility design that will serve market demands for many years to come, we can help. our integrated approach takes its starting point in capacity and flow analyses where we estimate your future and existing facility requirements. in a typical project, production forecasts are used to analyse the needs for process equipment and storage. But the nne Pharmaplan approach also analyses the material and personnel flows. We use common Lean principles, but we do so in the context of the special requirements of the pharmaceutical industry, ensuring efficient solutions without
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SIte SeleCtIon WeIGhInG the PRoS and ConS

When selecting the site for a new facility, a variety of issues need to be taken into account. your final site choice depends highly on a subjective evaluation of priorities, but it is still important that your fact-finding and assessment processes are both transparent and systematic. our methods are based on four key elements to be fully examined and quantified: suitability factors like: company image attractiveness to employees Local gmP business environment safety, including the risk from neighbouring plants dependence on landlord or neighbours soft factors like: countrys business climate cultural differences Quality of workforce Workforce flexibility Language skills infrastructure overall risks
Cost NPV 10
compromising product quality or gmP compliance. your facility will need to accommodate changing market demands, new product launches and product upgrades, and our integrated approach accommodate your business requirements by translating these factors into facility specifications.
4 Parameters Index 0 -10, 10 is best Radar graph Best site ~ largest area
10 Time
10
SIte MaSteR PlannInG GettInG It RIGht today and toMoRRoW

should you revamp your existing facility or invest in a new building? its a question with no simple answer, but site master planning might be the solution. a good site master plan contains an analysis of many different parameters, allowing for future-proof planning and the most cost-effective solutions. With a site master plan, you get an overview of future development activities, so you can be flexible in process changes and room utilisation. it also helps you compare the investment setup with other sites. maybe you have a pharma and biotech production site that has developed over many years by way of facility expansions, revamping projects and new facilities. and maybe the result is a confusing, impractical site. if this is the case, or if you want to avoid this situation, a site master plan could be the answer. a site master plan will give you an overall strategy for the future
physical development of your site, whether its existing, brand new, a greenfield, revamp, expansion, purchase or rental. site master planning involves: site strategy: vision and values, investment in the future, production types 8 Physical issues: infrastructure, flows, stepwise execution, common utilities transportation, parking social issues: common activities, canteen, sports sustainability issues: green policy, waste, noise authorities: regional planning, building lines, limitations, plot ratio at nne Pharmaplan, we work with you to define your business and design drivers think of our architects, process engineers and logistics people as the enzymes in your holistic planning process. We turn your ideas and our inspiration into feasible solutions that you can present at board level.
Suitability
Soft factors
10
time factors like: time from start of conceptual design to operation Best practice for permits realistic detailed design and construction time cost net Present value (nPv) calculations like: investment estimates manufacturing cost analysis tax and depreciations in the fact-finding process, we use the knowledge and experience in our local office, as well as publically available databases, industry standards, site visits and information from relevant local authorities. We then present our findings to you, ensuring that all relevant issues and stakeholders have been fully taken into account.
RIGht PlaCe, RIGht tIMe, RIGht CoSt SuPPly ChaIn analySIS

a facility and/or the manufacturing process it houses should always be designed according to its supply chain. so when you are in the process of designing a new facility or restructuring an existing facility, supply chain considerations should always be addressed in order to clarify how the facility/process relates to its existing and future customers and suppliers. at nne Pharmaplan, we can prepare a supply chain analysis that ensures that all your preconditions are in place and approved by the decision makers. and our supply chain analysis will identify key interfaces to consider in your facility design.
one of our customers asked us to identify the benefits of centralising the sterilisation units at 11 hospitals into one large facility. We combined our supply chain, decontamination technology and engineering knowledge to develop a feasibility study and a business case based on analyses of:
the future flow transportation costs equipment supply Layout Quality health, safety and environment cost of construction cost of production and potential savings
the result was a business case that the customer relied on with great confidence because it gave them a 360-degree view of the challenges and how to deal with them from a supply chain and an engineering perspective. We always kept in mind the customers focus on a high-quality decontamination process that was also business-effective. thats what the patients will benefit from as well.
KeePInG It Cool Cold ChaIn RoBuStneSS

in 2005, 40 percent of the pharmaceuticals sold worldwide were temperature sensitive. and 100 percent of biopharmaceuticals are sensitive to temperature. the rapidly growing biopharmaceutical segment (17 percent in 2005 versus a 7-10 percent growth in traditional pharma) is increasing the need for cold chain robustness in the industry. ultimately, the manufacturer is responsible for the cold chain, but accountability is shared across the supply chain from the procurement of raw materials, to administration to the patient. this mutual accountability calls for increased overview, management and control of environmental factors across the supply chain. at nne Pharmaplan, we help you ensure the robustness of your cold chain. By surveying your supply chain just as a regulatory inspector would, we can identify and address gaps in the control and monitoring, ensuring
the many process steps and physical sites involved are well coordinated. good cold chain management is about keeping products cold when possible and monitoring and recording whenever its not possible, for example during processing or air transfer. We help you create and maintain the overview of the time out of refrigeration (tor) across your supply chain. this can involve several sites, countries and sub-suppliers and requires stringent traceability and coordination. in our analysis, we look specifically for gaps in the tracking of tor, which typically occur when responsi-
bility is transferred between business units or business partners. furthermore, we use our process experience to identify undetected exposure to heat or cold that could damage your product during the manufacturing process. We have the necessary experience to establish an overview of your cold chain, fix gaps and ensure you have full control over any environmental exposure your sensitive products may encounter during production and distribution.
Level
C = Corporate S = Site F = Facility
GMP strategy GMP focused building analysis - Existing conditions (as built)
Related
CVI (Corporate Visual identity) Site atlas Maintenance manual
Check lists (requirements)
Gowning procedures Facility personnel Flow overview Facility change Rooms/airlocks overview Gowning procedures Gowning zoning overview
Staff training Illustration (animation/video)
Layout documentation
Design guide (classified areas)
Requirement traceability method Traceability procedure Commissioning templates
O=URS (overall URS) Facility category based Product category based
Rationale
Material specification Colour coding strategy
Classification plans
clear gowning procedures, and a room setup that optimised the framework for achieving good em (environmental monitoring) results and conditions. very often its people that generate most particles. But changing procedures, reorganising the airlocks and tightening-up the cleanroom inventory design enabled us to minimise rebuilding costs and reduce the shutdown time. this kept the customers production losses to a minimum. in situations such as these, our objective is always to ensure uniform guidelines and layout and design solutions at the facility, regional or corporate level. We work with you to establish a set of guidelines that emphasise your quality concept and serve as a basis for future revamping or greenfield projects. the guidelines will give your organisation a level of coherence that communicates your everything-under-control image, which is important when working with health authorities. at the same time, the guidelines will strengthen awareness among your staff in terms of their behaviour in the facilities (classification zoning identification). once you have a set of effective guidelines, you will be able to improve requirement traceability (re-use method) and to ease the quality assurance work.
Flow plans
Finish standards (quality level)
Qualification templates SOPs (standard operating procedures)
System aspect
Finishes & construction
GMP StRateGIeS SettInG youR FaCIlIty uP FoR SuCCeSS

in recent years, there has been a great deal of focus on cgmP conditions in existing facilities, often in relation to upcoming inspections. a customer asked nne Pharmaplan to evaluate the suitability of their existing building premises in relation to their existing production and their forecasted new production. We prepared a gmP strategy that included guidelines, gowning procedures and documentation traceability, starting
with a gmP sanity overview, a gap analysis and a regulatory check. We evaluated the functionality of their existing facility and analysed their handling operations and the flow of the layout/premises. finally, we proposed changes based on the customers required standard so-called will do solutions. throughout this process it was essential to consider both the aseptic and the working environments. this meant developing a layout with clear and logical flow patterns,
BuIldInG CondItIon analySIS youR FaCIlItyS health CheCK

how is your company doing? sometimes it helps to have a set of fresh eyes look at your existing buildings and premises. at nne Pharmaplan, we can take a look to see if they can accommodate production increases and if changes need to be made to related support functions. in other words, we can provide a building condition analysis. sometimes drawings and other facility documents are not up to date or missing. so to do a proper analysis, we will do a site visit and assess the state of your buildings a technical brief. if drawings do not exist, we will document the results of the visit with 2d drawings, providing an as built status on paper as a useful starting point. We will also assess the suitability of your building for the intended purpose and list the opportunities and constraints the
utilisation possibilities. the result could be a proposal for revamp, as the most costeffective solution. in any case, by providing
a thorough analysis as the basis for identifying the optimal solutions, we can help you make the right decisions and plan ahead.
new fumigation airlock 4 1 existing formulation area removed new sterile change room area new W&s area a a Qualified as cold room new cold buffer storage Qc storage moved new airlock area 2 C 6 9 6 exist. filling removed area reserved for new filling available for machine exist. filling removed B 7 1 4 3 2 5 10 10 9 10 new group B corridor connection new storage areas groups c and B new storage areas groups c and B
B C
new inspection to replace existing in Building 2
note: numbers 1 and letters a can be implemented independently of each other
RevaMPInG neW uSe FoR exIStInG BuIldInGS

a company wanted to establish a new pilot plant in their existing building structure in a limited space (a black box area) and in a very short time frame. the architectural concept was based on an open structure with clear layouts, flows and procedures. another requirement was that the on-going production could continue and all construction needed to happen without touching the roofing or interfering with the main structure of the building. finally, all new installations had to be coordinated with the existing ones. the area required for the process exceeded the available space. nne Pharmaplan made a thorough design of the space in a 3d model and got the extra space we needed by establishing the communication areas in the broad main corridors. the pilot plant was designed as the last of three glass boxes inside a larger one, with limited space for the layout. all components entered the building via the dismantled glass faade, including the large steel constructions. it was a bit like building a ship in a bottle. the assignment required tight teamwork and involved all disciplines in a ping-pong match between process engineers, architects and
other team members. to ensure minimal shutdown time and a minimum loss of production time, the planning was very strict, with all things prepared in advance and an execution time schedule coordinated down to the minute. our detailed 3d model was our visual tool for design and communication. detailed planning and high technical skills were needed to solve all design issues in this limited space. in our planning, we also considered
the qualification time of equipment and running production, with the architectural considerations as the unifying principle in the entire process. Just as the customer wished, we stuck to the original architectural concept of a glass box inside a larger glass box, and we were able to help the customer achieve their goal of increased capacity in an inspiring environment and with focus on projecting the right company image.
MateRIal handlInG a FoCuS aRea WoRth youR attentIon

a manufacturing process is only efficient when it has an adequate supply of raw materials and when the output is removed at a steady pace. so to ensure your process operates at its designed rate, we can help you develop a facility design that incorporates the right material handling concepts. material handling is an even bigger challenge in pharmaceutical production than in conventional industries. for example, changeover between zones of different iso classes, transfers in and out of sterile zones, decontamination of load carriers and so on must all comply with good manufacturing Practice (gmP). While strictly complying with gmP, these material handling processes should be efficient in order to not become bottlenecks in the operation of your facility. another important aspect of your material handling is product traceability, which is quite a challenge
in a multifunctional facility with many different process interfaces and interactions with human personnel. When dealing with sensitive products, such as biopharmaceuticals, the material handling concepts must also take into account environmental monitoring and tracking of holding times and storage times to ensure a compliant, effective production. if your facility is designed for high-volume output, we incorporate the latest technologies in automated material handling to ensure steady delivery of raw materials and pick-up of finished goods. material handling equipment such as automated guided vehicles, stocker cranes, conveyors and radio frequency (rfid) tags, are elements we use in designing a facility where all material flows are steady, streamlined and reliable. By taking automation to the next level, we can help you minimise the strenuous and costly manual handling of materials and at the same time use the technology to effectively ensure gmP compliance.
sometimes our analysis shows that certain productions are better off being controlled and handled by human operators, rather than a complex automated system. this might be the case if you have a low-volume production. at nne Pharmaplan, we are dedicated to developing a material handling concept that suits your specific needs and our multifunctional approach ensures that there is always a clear link between the material handling, the production processes and the facility design.
FaCIlIty deSIGn addReSSInG ClIMate ChanGe

how can a facility layout save energy? in a recent project, our overall baseline scope was to create a facility similar to an existing one almost an exact copy. But our customer wanted to challenge the old solution. so we suggested an approach based on sustainability concerns and a change to the layout that would result in a more compact and economical building structure. this implementation created a more practical layout in terms of reduced exterior surface, lower construction height, less volume and less hvac energy consumption. the layout became more precise. We kept in close dialogue with the customer to ensure greater clarity regarding functional areas and a better flow. the new layout merged two buildings and created a central indoor corridor that separated the two buildings. this reduced physical distances and increased visual communication. it also markedly reduced the volume and surface area of the building. finally, we dramatically increased the possibility of incorporating energyefficient building solutions. the positioning and disposition of buildings has an impact on the sustainability of solutions. typical parameters for consideration are sun orientation, wind direction, available building materials and other local factors. With our holistic and long-term solutions, we design high quality buildings that have minimal environmental impact. at the same time, we strive to create a branding asset that demonstrates your companys values within energy efficiency and sustainable solutions.
state-of-the-art industrial facilities as an effective marketing tool. at nne Pharmaplan, we work together with you to define your goals, focus areas, design drivers and overall brand. We start with sketches and illustrations to give you an idea of what your new building or facility could look like. this approach combines the architectural ideas with the structures functional conditions.
CReatInG youR SIte atlaS

a site atlas gives you a view from above, so you can see your company from a new perspective. it helps you identify your companys challenges and opportunities, and it gives you some ideas for improvements at all levels; its like a vitamin injection for your organisation. the result could be an alignment of standards, promoting a gmP culture, providing facilities and premises for visitors and customers, a showroom for your companys ethics and code of conduct, or other initiatives that support your companys identity. the site atlas could involve e.g. site master planning and building condition analysis. it could also cover your companys corporate visual identity (cvi) or design manual. this is a catalogue with guidelines for choice of materials, a colour coding strategy/philosophy, guidelines for using symbols and graphics in
signage and other materials, guidelines for the design of inventory and furniture and the use of artwork in your buildings. the benefits will be: global recognition; brand consistency; and uniform company guidelines, philosophies, strategies, design, and architecture all of which support your company spirit. moreover, we offer workplace design. a truly effective workplace design must be developed around the user requirements and tailored to support your organisations business objectives and way of working. But it also needs to reflect the company culture. renewing your working facilities gives you a unique opportunity to integrate and revitalise your companys values, brand and identity. its an opportunity to build for the future your visual identity through architecture a building is more than just a building. through design and architecture you can show the world exactly who you are as a pharma and/or biotech company. it helps you use your
our designs are always customised. and we focus on genius loci a respect for local building traditions and trends. We then incorporate this with your companys values and your immediate surroundings, for example mountain or seaside scenery. and we dont stop there. We provide you with an integrated design solution that takes artwork and greenery into account when arriving at the final architectural concept. in every aspect of the process, we make sure your companys image, profile and identity are always top of mind.
CuStoMISed layout tyPoloGy

Layout typology is a critical choice when youre working on the master plan or layout for a new facility. the most suitable layout typology depends on your specific process or production method. rating and prioritising the design drivers for these will lead you to the right choice of typology. other areas to consider are: is it a single or multi-storey facility; what are the distances between functionalities; what is the area need versus the faade area; are multiple production areas required or just one; do you have dedicated or shared support areas; what are the requirements for flexibility; and what are the risk and cost parameters related to each type of typology? the building design and arrangement will guide the entire process, transforming complexities into logistic simplicities and complex processes into simple solutions. We focus on each process/production step as one functional unit that integrates areas/ rooms, equipment and handling operations. We then combine these elements into a layout that takes into account the overall flow and classification issues, always keeping in mind the link between the process and the premises process architecture. at nne Pharmaplan, we arrange or facilitate customer/user workshops in order to prioritise and rate parameters, establish your design drivers and layout criteria, and analyse the environmental impact and sustainability factors. We initiate a risk assessment and challenge your requirements. We then establish which facility design would best suit your requirements. and finally, we investigate which site would be most appropriate for you. our goal is to translate your process architecture into facility design, so we help you connect design and process requirements to build valuable and user-friendly environments.
BIoSPheRe: youR FutuRe FaCIlIty?

taking a holistic approach and integrating sustainable technology, social environments and economy factors and focusing on engineering and design to cost you could end up with a living facility with modular pharma production units, all customised for your specific needs and supplied with pre-fabricated, standardised support units such as airlocks, receive/dispatch facilities, storage and utilities. imagine using Lean concepts and optimised flow patterns to combine and stack the units to suit your process and operational needs. and that everything is covered with a weather screen made from local materials to suit local needs showing a respect for the environment and reducing transportation costs and energy consumption. your facility could have a distribution square between the process-specific parts, enabling Lean production principles such as short distances and multi-functional areas. the use of pass-through zones between preparation and production or storage and production makes it possible to pull and not push. We dream of designing your facility as an organism thats transparent, where suitable, to let in as much daylight as possible and thats customised to the site, wherever in the world it may be.
inside the facility, you will sense the entire facility, with its inner process parts as the heart of the organism that generates a positive company spirit. glass walls around the distribution square make it possible to follow the production from the office and canteen area, which is outside the production area but still inside the weather screen.
With offices, canteen and other similar functions scattered across the site placed inside the weather screen and connected by squares, balconies, terraces and hanging gardens, we could make your facility a living, breathing and environmentally aware structure.
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laboratories
Laboratories are key to the development and control of pharmaceutical products. Regulatory compliance and functionality are key to laboratory design and for that, NNE Pharmaplan is a key partner. research in the pharma and biotech industries is under significant pressure. r&D costs and timelines are increasing, resulting in reduced competitiveness. at the same time, the world continues to demand a steady and effective supply of new products and research results. one way to obtain the desired output at the right cost is to improve laboratory efficiency. NNe Pharmaplan offers a number of services to achieve this, ranging from implementing lean techniques and re-organising existing facilities to programming and designing new facilities that support the needs of a rapidly changing business. laboratories are key for pharma and biotech companies, from basic research, through drug development to the final quality control of production batches. basic research conducted at universities, hospitals and private companies leads to improved existing pharmaceuticals and the development of new products that treat or cure critical diseases and so this basic research improves the quality of life for people worldwide. recent years have proven that the best and most innovative research results come from cooperation between different research areas, working in interdisciplinary and creative environments that can attract and maintain the best international researchers. Drug development and quality control require laboratories that are in compliance with GXP (Good Practice) and bsl (bio safety level), and have a carefully planned and functional design. at NNe Pharmaplan, we have worked with a wide range of private companies and universities to create the positive and innovative framework they need.
laboratories 109
Building R&D facilities that are something special Developments in the field of drugs, vaccines and diagnostics have resulted in significant advances in the prevention, diagnosis and treatment of diseases. these advances are the result of continuous research, which is fundamental for improving public health all over the world. research institutions rely on competent people to provide high-level research output and quality. With the ambition of attracting international top researchers and other staff categories, the university of copenhagen asked NNe Pharmaplan to plan, design and construct new laboratory and research facilities. the reputation of the faculty of health sciences as a leading centre within a large number of research areas including metabolic diseases, diabetes, cancer and international health is highly dependent on an inspiring and active research community, in which access to state-of-the-art facilities and technologies is key. A future-proof facility the plan was to establish the new sophisticated center for Protein research in an existing building from 1971, while implementing all known
new laboratory design trends in the new facility. to get the desired flexibility, all the internal fitting of the building were removed and a new layout was established, with separate wet and dry zones. the dry zones were designed with utility and layout, which provided the necessary flexibility for the years to come. When the university started planning its research at the new centre, it only employed a few researchers, so we did more than help the university design and construct the facility. to facilitate the start-up, we submitted and obtained authority approvals for the use of genetically modified organisms (Gmo) and helped prepare the applications for approval of the actual research projects. We also provided a laboratory manager to handle the initial procurement of equipment and establish service agreements with suppliers until the newly established management could hire a suitable candidate. our involvement in the new center for Protein research provided the university with a leading-edge research facility, and ensured a smooth start-up process with a limited number of employees involved, allowing the researchers to devote their time to fulfilling the universitys ambition of world class research.
NNe PharmaPlaN services featureD iN this chaPter: Facilitating creativity in lab design Minimising investment risk laboratory planning Organisational development of laboratory departments Generic laboratories reduce the project cost Animal facilities built on bioethical principles Flexibility and changeability as design drivers Regulatory approvals for GMO laboratories Reducing power consumption in laboratories Maintaining compliance with reduced energy consumption Laboratory automation: lead times and quality Increased efficiency in laboratories Integration and optimisation through laboratory IT
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FAcILITATING cREATIvITy IN LAB DEsIGN

modern research is a social activity that brings together scientists, researchers and laboratory technicians and it requires an environment that allows for informal meetings, facilitates creativity and creates interdisciplinary synergy. modern research is no longer just a matter of creating the ideal laboratory. today, it requires creating an entire facility with laboratory space, support space and social space that provides an integrated and natural symbiosis. at NNe Pharmaplan, we focus on establishing complete facilities to match our customers needs and cultural background, as we firmly believe this is the catalyst of innovative research and new products for a healthier world. for a customer in the us, we turned an existing office building with typical cubicles and
ORGANIsATIONAL DEvELOPMENT OF LABORATORy DEPARTMENTs

as the nature of laboratory work changes, the traditional laboratory organisation needs to keep up. old organisations are a result of autonomous organic growth. this means that often they do not match the organisations strategy or target its actual needs. NNe Pharmaplan approaches this problem by addressing the functional requirements of each department to ensure that the new functional programme, the organisation and personnel resources match the organisations requirements. When planning a major refurbishment or a new greenfield facility, we find that reviewing the organisational setup and the laboratory workflow often reveals inefficiencies or bottlenecks and these can usually be avoided or eliminated if they are taken into account in the initial project phases. for example, subdividing central quality control laboratories can vastly improve an organisations efficiency. Working with one customer, we divided the central Qc laboratory into support, sourcing and release laboratories to improve efficiency and ensure dedicated people with the right skills and mindsets were stationed at all functions. another example is establishing core laboratory facilities to support the research units.
limited green light into a vibrant scientific environment with open-plan laboratories, light office areas, as well as a science square where the different researchers and project managers could meet, exchange ideas and facilitate creative thinking. this design approach enabled the customer to attract international top researchers and highly qualified new employees to its new facility.
3m
3m
3m
Discovery
Research cell bank Cell development
Expression
USP lab DSP lab
7,5 m
2,5 m
Containment lab
Solution prep
5m
Proposal # 1 Phase 3 Level A
GMP pilot
GMP pilot plant QC lab
GMP cell bank
MINIMIsING INvEsTMENT RIsk LABORATORy PLANNING

the optimum programming and planning require identifying conditions and assumptions, customer needs, requirements and goals and creating consistency between needs, requirements and concepts. experience shows that the initial programming and planning phases impact 80 percent of the total investment, which underlines the importance of a properly managed and controlled project start-up to minimise the investment risk.
our programming and planning typically involves the analysis of: functional relations: adjacencies, possibilities of shared functions and outsourcing resources: calculation of required capacity (staffing/area/equipment) area needs: development of room programmes modularisation: planning modules for functional areas this work results in building concepts, layout concepts and cost estimates that give you a solid basis for making decisions. and this ensures that you do not just get the right project, but also that the project is implemented in the right way.
Research unit #1
Core lab B
Core lab A
Research unit #2
Core lab C
Research unit #1 Research unit #2 Research unit #3
Research unit #3
Core lab D
Research unit #4
Sourcing QC lab Central QC lab

Plant 1 QC lab Plant 2 QC lab Plant 3 QC lab
Support QC lab
laboratories 111
FLExIBILITy AND chANGEABILITy As DEsIGN DRIvERs

the focus on efficiency in research and development, combined with the volatility in todays research, requires facilities designed for significant functional change whether it is from laboratory to support area or from laboratory to caf and meeting room. flexible and changeable facilities do more than support changes in research or equipment they also require fewer rebuilds, and the resulting increased facility utilisation reduces maintenance and operational costs.
GENERIc LABORATORIEs REDucE ThE PROjEcT cOsT

todays research is constantly developing and requires uniform laboratories that can support multiple functions. the time when laboratories were specially designed for the individual researcher is over. rapid changes in research, methodology and equipment require a generic laboratory layout that can absorb major changes in function. We find that 10-15 percent of a traditional r&D laboratory facility changes substantially between initial idea and programming to final inauguration. this can increase the total project cost and cause delays and in the worst cases can postpone
regulatory authority approval for the entire facility. at NNe Pharmaplan, generic laboratory layout solutions are the basis for our project execution. this approach helps produce facilities that can absorb future changes in functionality without major changes or reconstructions. our generic approach also helps optimise design time thanks to less end-user involvement during the design process. end-user involvement is concentrated in a number of focused workshops or meetings instead of being scattered throughout the entire design period. finally, the generic approach can help reduce installation complexity, cost and construction time.
We believe that the demand for flexibility and changeability will be one of the most important trends in state-of-the-art laboratory design. at the same time, increased efficiency and reduced development cycles are also becoming more and more important. in close cooperation with our customers, we have created effective and innovative research facilities that benefit pharmaceutical and biotechnology research, and patients, around the world. one of the main challenges is to ensure the right balance between supporting current work processes and providing the flexibility required for supporting substantial changes in future research equipment or methods. functionality is one of the main drivers of our approach, and it is of utmost importance that primary structures and main routing principles support a total paradigm shift in laboratory function. one method to ensure a high level of flexibility is to separate dry and wet zones, centralise core lab functions and ensure flexibility in size of the research unit.
for example, when designing a new animal research facility for one of our customers, our challenge was threefold: to fulfil stakeholder expectations with regard to animal welfare, to upgrade working conditions, and to ensure optimal flow in the facility.
ANIMAL FAcILITIEs BuILT ON BIOEThIcAL PRINcIPLEs

more and more companies request a high focus on bioethics, including animal and employee welfare, when designing animal facilities. We often work in close cooperation with our customers and other stakeholders such as animal rights organisations and top level corporate social responsibility (csr) officers to establish cutting-edge research facilities that fulfil the highest ethical standards for animal research.
in our design approach, we challenged the traditional vivarium design. instead, we placed the vivarium at ground level, allowing green light into all procedure rooms. to reduce animal stress, the entire vivarium was designed with double corridors in a suite layout that linked one procedure room to two-four animal rooms. and to improve the working conditions, we designed and developed a new animal caging system, with an automated watering system and a new filter system, to prevent allergen exposure.
112 laboratories
depth knowledge of regulatory requirements such as the eu council Directive 98/81/ec and current international guidelines right from the start when the initial strategies and plans are made. at NNe Pharmaplan, we have extensive knowledge of regulatory requirements and the associated approval systems regarding research, animal facilities and plants. our vast expertise includes experience in getting approvals for laboratory space to be used for Gmo work and preparing application material for actual laboratory research projects. this means that while the construction of the laboratory is being finalised, and the scientists are possibly located elsewhere in the world, we can help you put together the information and submit the paperwork required for authority approval of research facilities and projects. as a result, our customers have more time to do what they do best research.
REGuLATORy APPROvALs FOR GMO LABORATORIEs

the world of research and development is moving towards a new reality, in which work with potent substances and genetically modified organisms (Gmo) is becoming the rule rather than the exception. When making a laboratory ready to use for Gmo projects, it is crucial that you have in-
Water 5%
Miscellaneous 23%
Cooling 4%
Heating 38%
Power 57% Lab equipment 16% HVAC 46%
MAINTAINING cOMPLIANcE wITh REDucED ENERGy cONsuMPTION

effective ventilation in the laboratory is of utmost importance for employee and product safety. reduced energy consumption in laboratory facilities often results in less air volume and air flow in fume hoods and the general laboratory exhaust and so laboratory testing is extremely important. testing ensures the right safety level, and helps ensure the facility complies with international and european norms and guidelines. the test results can also be used to document compliance and underline employee safety. at NNe Pharmaplan, we ensure effective ventilation in laboratory and animal facilities, and guarantee that the air quality fulfils authority requirements as specified in eN 14175 and iso 14644. We are highly skilled in performing quality and functional tests for fume hoods, safety cabinets, laf benches, pressure differences and particle measurements and we understand the importance of a well-documented test.
Light and IT 11% Total energy consumption Consumption split power
REDucING POwER cONsuMPTION IN LABORATORIEs

international focus on sustainability, combined with a general demand for reduced laboratory operating costs, requires a new approach to the design and renovation of laboratory facilities. Due to special requirements for primarily heating, ventilation, air conditioning (hvac) and temperature control, the consumption of a typical laboratory building is approximately eight times more per square meter than an ordinary office building.
at NNe Pharmaplan, we work actively to reduce the power consumption in laboratory facilities without compromising safety. We work with customers to establish guidelines for using fume hoods and optimising energy consumption in laboratories, with the ultimate goal of ensuring more research for the same funding. Demand-driven hvac systems have a significant impact on energy consumption in laboratories. also, audiovisual alarms can be a cost-efficient and easy way to change employee behaviour and lead to less energy use.
laboratories 113
LABORATORy AuTOMATION: LEAD TIMEs AND quALITy

ever increasing requirements to quality and efficiency can often be met by intelligent laboratory automation solutions.
our goal is to help make your laboratory more efficient without compromising quality. this includes designing and implementing automation solutions in the lab environment. for example, for a biotech customer we have developed systems that automated pre-analytical sample preparation. as a result, the customer reduced their analytical lead time by 42 percent, and scaled down their sample preparation process, saving valuable reagents and lowering the environmental impact of operations. When applicable, we can customise standard instruments to suit specific needs, and even tailor complete systems for customers who have non-standard business requirements.
Enterprise systems SAP MRP MRP
LIMS
Database server (UNIX) Jaguar: SAP, MRP interface Business objects server Jaguar: web based user interface server
Report printing LIMS interface
LIMS
Chromatography control client
LIMS interface web service
AnEx
Oracle database Backend web service Frontend
Instrument control client
ASAP control client
INcREAsED EFFIcIENcy IN LABORATORIEs

Why should you implement lean philosophies in an existing laboratory environment, or when programming and planning new laboratory facilities? it can be difficult for quality control (Qc) labs to cope with variances in tests, inefficient workflows and a high number of re-analyses. and this leads to long lead times, delivery delays, low equipment capacity utilisation and high workload for the employees. the answer is to implement lean philosophies. When addressing lean in laboratories we focus on: simplifying and optimising workflows mapping value streams outsourcing support functions
implementing automated equipment compressing activities Planning (cyclic plan, visual planning, kanban) organisation layout
INTEGRATION AND OPTIMIsATION ThROuGh LABORATORy IT

the pharma and biotech industries are required to document all aspects of their business to consumers and regulatory authorities. as automation and it become integral parts of modern laboratory facilities, more organisations want to embrace electronic information management and this evolution supports lean business processes. at NNe Pharmaplan, we have vast experience of providing effective paperless laboratory solutions to the pharma and biotech industries. our projects have ranged from global enterprise lims implementations to small interfaces that connect instruments to local Pcs. for example, we helped one customer consolidate several local systems into a single centralised solution that serves all its production sites worldwide, and integrates r&D, production and quality control functions. as a result, the customer eliminated slow paper-based processes and the risk of transcription errors and has now enforced uniform procedures throughout the organisation. in addition, because all analytical data is made available on a single platform, the solution provides the customer with complete data transparency.
and our projects have resulted in some significant improvements for customers: improved analysis flow 40% efficiency gain (fte) 50% lead time reduction increased quality (right-first-time) 50% reduction of reprocessing/ reanalyses improved service level to customers 98% on-time delivery of analysis reports
Bacteriology Goods reception Substrates lab Airlock Serology Virology Virologi Washing up Waste
Sample receipt Sample preparation Sample receipt
Purification Electrophoresis Polymerase Chain Reaction (PCR) Histology Microscopy
Sample handling
Airlock
Sample shipment
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Manufacturing information systems

Manufacturing information systems can increase efficiency and secure high quality production. With ourlong experience in the field, NNE Pharmaplan will ensure you get the best solution. Manufacturing information systems provide a window to the process. through this window, you can increase your understanding of the process and use this to improve quality control and create a more efficient flow of information around your production facilities and laboratories. in the last few years, there has been a steady increase in the use of high-end automation systems, including batch and recipe controls, historians, electronic batch records, electronic documents and laboratory information systems. in order for these systems to work efficiently in the pharmaceutical industry, they need to be adapted to support the industrys production and business processes. they also have to be developed and implemented in compliance with gMP typically under the good automation Manufacturing Practice (gaMP) guideline. nne Pharmaplan has a long track record of implementing advanced it solutions in regulatory controlled pharmaceutical and biotech environments. Weve helped customers implement numerous systems, from simple barcode tracking solutions to complete paperless production facilities. our process, automation and compliance specialists cooperate, using their process and gMP understanding to ensure that the systems fit the exact needs of our customers. But we also have another key skill: knowing when not to automate or introduce new systems. over-complex automation can hamper efficiency and may ultimately escalate the very problems it was intended to solve. So we help you develop the right level of automation, taking a flexible long-term strategic approach that enables you to harvest the technology developments also in the future.
Manufacturing inforMation SySteMS 115
Combining large-scale automation and rapid delivery nne Pharmaplans automation specialists created a modular design to facilitate the fast-track establishment of the worlds largest insulin aPi facility. When the insulin Bulk Plant (iBP) was handed over to the healthcare company novo nordisk in 2003, nne Pharmaplan had built the worlds largest insulin production facility in the record time of 24 months. We had also implemented a modular MeS system on top of the largest SattLine application in the biopharmaceutical industry in 12 months only to pave the way for the successful fast-track execution of this 32,000 greenfield project. With 80 controllers, 100 workstations and 25,000 io points and operating more than 300 units with more than 500 recipes and 600,000 parameters, the facility now has a fully automated production line and batch reporting system. Such a massive automation solution on a fast-track schedule required a modular design that allowed for the standardisation and reuse of design specifications, code modules, tests and validation protocols.
We identified a modular MeS system that could handle the complex processes and allow us to create functions for handling of master recipes, material definition, material control, equipment modelling, batch execution and reporting. We then created complete sets of modular building blocks for both the process control system and the MeS system and qualified these building blocks through comprehensive tests before applying them in the project. An extended MES system ensures flexible batch documentation iBPs automation system ensures that production is carried out in accordance with the procedures for processing, quality control and cleaning. Processing and quality data is used for generating a batch report for each processing area. Due to the huge amounts of data a traditional process control system could not handle recipes and reports as part of the process control system. We therefore lifted the recipe management into the MeS system, a data-driven solution that defines recipes and reports as data which the user can easily change as needed. that provides great flexibility in terms of future changes and also reduces the need for subsequent revalidation.
nne PharMaPLan ServiceS featureD in thiS chaPter: Enterprise manufacturing intelligence a performance overview Increased capacity with the right automation & IT strategy Use in-process control to obtain a higher quality level Complying with new anti-counterfeit regulations Streamlining production reporting Increase competitiveness with laboratory automation S88 & S95 minimise risk by using standards Smooth implementation of MES
INCrEASEd CAPACITy WITh ThE rIghT AUToMATIoN & IT STrATEgy

a lot of pharmaceutical companies spend a great deal of time focusing on documentation of execution, and fail to dedicate enough time to determine how to optimise production and increase capacity. nne Pharmaplan can help by developing an automation & it strategy that coordinates all the individual pharmaceutical business process activities, ensuring they all aim towards a shared vision of optimisation. the automation & it strategy will take you through your companys processes and systems step by step and ends in a strategy and framework for your future projects and investments. in short, we help you create a common vision for your future automation & it.
four steps to develop an automation & IT strategy: Step 1 Target definition understand the current situation in relation to processes, systems, people and investments and set the targets for the future
ENTErPrISE MANUfACTUrINg INTEllIgENCE A PErforMANCE ovErvIEW

Many pharmaceutical production facilities struggle with various systems, routines and manual operations. Keeping an overview is time-consuming and paperwork heavy. consequently, more and more pharmaceutical companies are on the outlook for a system that can create an integrated production overview an enterprise Manufacturing intelligence (eMi) system enabling:
experience tells us that focus on oee values can increase the efficiency of any plant. for example, the oee value helps you make improvements, enabling you to answer questions such as: is it possible to gain more capacity from existing equipment? Do we need to buy new equipment? Would it be beneficial to change work routines? Which work routines cause the biggest loss? using eMi with one of our customers, we managed to design a new packaging line with an extremely short changeover time by integrating batch reporting in SaP/PP-Pi, using vision system and reporting oee performance data. and because the line continues to collect efficiency data, its performance can be optimised on an ongoing basis.
Step 2 Business and manufacturing process analysis use the current business and manufacturing processes as a basis to identify future needs, system requirements and information flow
Step 3 System framework Design system architecture and standards, allowing for stepwise implementation
visualisation and comparison of equipment efficiency overall equipment efficiency (oee) Statistic process control KPi dashboard showing cogS number (cost of goods sold)
Step 4 Strategic project planning identify, describe and prioritise the projects that need to be completed in order to reach the targets defined in Step 1
USE IN-ProCESS CoNTrol To oBTAIN A hIghEr qUAlITy lEvEl

today, many pharmaceutical producers collect production data that is used only for quality assurance, documentation and regulatory approvals. But they could use this data for so much more. By using in-process control technology, such as Process analytical technology (Pat), you can use your data to measure quality while the product is actually being produced. this data helps you better understand your processes, leading to more innovative and efficient processes and higher quality output. these benefits have been proven to result in a high financial return for companies investing in in-process control data collection. our Pat services cover Pat consulting, data analysis, regulatory and quality advice and training. our goal is to use Pat services to significantly improve your bottom line. over the last three years, we have completed more than 30 projects in europe, asia and the uS all with very impressive results. We combine our Pat expertise with knowledge of QbD
tial issues with the fDa, eMea and other worldwide regulatory bodies. We also assist you with making Pat chemistry manufacturing control submissions (cMc Q8, Q9, and Q10) or simply changing controls under current guidelines. We offer to train your staff in-house in Pat techniques and technologies, and we also run general Pat courses that your staff can attend. reducing product release times from 48 hours to less than 2 Working with one customer, we implemented a clear QbD/Pat strategy to enable the organisation to implement Pat effectively across all its functions. and the results were impressive:
and Six Sigma and apply it to improve your development and manufacturing processes, technology and tools. our advanced data analysis experts help you utilise the power of Pat, so you can perform a variety of tasks, from simple data visualisation to advanced multivariate data analysis and multivariate statistical process control (MSPc). Pat brings with it a new quality paradigm. and we can help you discuss these poten-
the release time of products dropped from 48 hours to less than 2 hours implementing statistical process control (SPc) reduced scrap from 1.2 percent to 0.01 percent a Pat raw material identifier increased the amount of samples one person could identify, from 12 a day to over 300 the overall return of investment for the Pat project was less than 18 months
CoMPlyINg WITh NEW ANTICoUNTErfEIT rEgUlATIoNS

Will you be ready to serialise and track your pharmaceutical products when a new regulation is introduced in the near future? according to the World health organisation (Who), fake drugs account for 7-15 percent of all the medicines circulating in developed countries and this rises to 25 percent in developing countries. as a result of these findings, new global regulatory requirements designed to combat counterfeiting will soon be introduced primarily aimed at codification, serialisation (internal and external tracking) and e-Pedigree (external tracking). Will you be ready? it technology and infrastructure will play an important role in meeting these challenges. a successful company will need to establish an it strategy that includes end-point it target architecture and stepwise migration towards a future it landscape that can sup-
port anti-counterfeiting measures. once the strategy is in place, all relevant it investments will need to be scrutinised (gate model) with respect to complying with the anti-counterfeit strategy. if this is not done, companies face the risk of making expensive investment mistakes in the wrong and inadequate it solutions. nne Pharmaplan can help you to plan well ahead, enabling you to comply with the rules as they come into force and to implement sufficiently flexible and scalable solutions using our extensive knowledge of the production processes and technologies involved in anti-counterfeit solutions, such as packaging, labelling/printing, vision/inspection, automation, MeS systems, erP systems and logistic systems. We are already working with a number of customers in this field and are in close contact with the organisations involved in anti-counterfeiting legislation, such as the uS food and Drug administration (fDa), the european federation of Pharmaceutical industries and associations (efPia) and the Danish association of the Pharmaceutical industry (Lif). this puts us in a strong position to help you prepare for the future.
STrEAMlININg ProdUCTIoN rEPorTINg

It can be done without electronic systems Paper-based batch records consist of many process step descriptions from signatures and data entry points to log book entries and all are written down manually. each paper batch record may include more than 300 steps, 500 signatures, approximately 1,500 data entry points and more than 50 log book entries making it a timeconsuming and high-risk operation, with plenty of opportunity for human error. and this operation is performed many times in production facilities around the globe. in fact, a factory that produces around 5,000 batches a year uses 200,000 pieces of paper, requiring up to four million signatures and resulting in bottlenecks, errors and a significant paper archive. Streamlining the paper flow for reporting requires insight in the production process, the critical quality parameters and the regulatory requirements. a customer in germany was struggling with immense amounts of paper reports and time/consuming work processes in relation to their product release. this caused delay of product releases, inventory build-up and high operational cost.
OEE
100 80 60 40 20 0
Yield for ZX1855 Material 1 50% Material 2 13% Material 3 12% Material 4 25%
Percent
Machine A
Machine B Batch ZX1855

15 12 9 6 3 0 10 20 30 40 50 60
Percent
Hours
the solution was a data management strategy, streamlining the production reporting initially at a paper/based level creating a uniform batch reporting standard, and in the second stage by implementing a complete electronic Production record System. founded on a risk-based approach, the solution provides the customer with a Lean batch release approach, significantly reducing the manual workload and risk of errors. But electronic systems can streamline the process even further going fully electronic with the batch reports can bring huge benefits. you will get a com-
plete electronic Production record System (ePrS). and your deviation handling and KPi data collection and calculation (e.g. overall equipment efficiency oee) will become automated. thus your production release will take place with review by exception in a fully paperless process, eliminating the need for equipment log books. a prerequisite for successful paperless reporting is a Lean and well-structured reporting flow. Just automating a suboptimal reporting scheme may create huge amounts of useless data that require additional control and maintenance to ensure consistency.
best laboratory automation system for your needs. and you can benefit from:

Lead time reduced by up to 45% up to 20% fewer staff up to 65% fewer errors 100% more volume with the same resources Sampling and analysis time reduced by up to 50% 100% paperless laboratory solutions 100% remotely accessible laboratory data
INCrEASE CoMPETITIvENESS WITh lABorATory AUToMATIoN

nne Pharmaplan has successfully implemented 15 laboratory automation solutions in pharma and biotech manufacturing facilities
around the world helping eliminate the inefficiency caused by manual operations and errors. as a global company with deep understanding of industrial processes, automation and it systems, we can help you select the
When the sampling is done for the laboratory, the production is stopped until the results are known. But with a reduction of the sampling and analysis time by 50 percent the benefit is clear. Says the Laboratory Director
S88 & S95 MINIMISE rISk By USINg STANdArdS

Pharmaceutical production facilities consist of many process flows, business systems, hardware and equipment all imposing tough requirements on the automation systems. at the same time the requirements for quality, documentation and flexibility are high. at nne Pharmaplan, we use a proven modularisation and integration approach based on the engineering Standards S88 and S95 enabling us to help you meet future fast-to-market demands and minimise your risks when designing and implementing automated process plants. the S88 standard provides a consistent set of standards and terminology for batch control, and defines the physical model, procedures and recipes. the S95 standard consists of models and terminology that can be used to determine which information has to be exchanged between sales, finance and logistics systems and production, maintenance and quality systems. We helped develop these standards and have worked with them for many years. and we use this experience to give you a solid and logical structure for your production facility and interface with surrounding systems and help you reduce risk with:

ERP
MES SCADA/PCS
Instruments
SMooTh IMPlEMENTATIoN of MES

after years of hesitation, the pharmaceutical industry is slowly embracing Manufacturing execution Systems (MeS) as an important way to gain business benefits. MeS software guides your operators through the manufacturing process while automatically collecting all relevant information and generating electronic Batch records (eBr). in an industry traditionally burdened with paperwork, MeS can relieve your paper levels and improve compliance. recently, MeS has also been implemented alongside operational excellence programmes in an attempt to use MeS as a data source for optimisation analysis. however, deploying MeS in an existing organisation often raises a number of challenges some technical and many organisational. Based on practical experience from MeS projects in the pharmaceutical industry, nne Pharmaplan can give you advice before you implement MeS. We can guide you through all the necessary steps, from initial business analysis to supporting you with daily operation. and use practical real-life examples to help ensure you make the best decisions from the start. We have expertise with all aspect of MeS: We can help you conduct your MeS business analysis, specify your requirements and select the best platform and implementation partner. We can advice you on how to implement, validate and deploy a MeS system in your existing organisation, including applying
change management to the entire organisation. and we know how to organise support and maintenance for your MeS system during operation. Designing MeS to support Lean principles We are working with a global pharmaceutical company to implement a global manufacturing execution solution that gives the customer a standardised system that harmonises processes across all their sites, creates a dynamic workforce and supports their Lean operation. using automated batch releases to get things right first time, the system will increase production efficiency through improved lead times and minimised unit cost. Scalable to business needs, the system will also enable the customer to increase production volumes and releases by exception. finally, by implementing a global system, the customer should achieve global transparency and best practice sharing through extended production analyses. Project characteristics: Large project high complexity integration with many different systems harmonisation/alignment of many different business processes
fast-to-implement maintenance and expansion projects Large investments complex solutions Difficult validation
Work with nne Pharmaplan on your next project and benefit from lower lifecycle costs, a clear project overview and greater flexibility in terms of maintenance and changeover.
nne Pharmaplan deliverables: a global overview and status of production progress Security of supply and operational support 24/7 high product quality at right time to patients
120 Performance and organisation
Performance and organisation

Cost-effective production is a must to survive in the highly competitive pharma market. Evolution calls for operational excellence, and NNE Pharmaplan can help you get to the next level. Patents running out and generics gaining market share, increased pharmaceutical production in low-cost industries, and increased pressure to supply more affordable drugs in both industrialised and developing countries have led to increased focus on cost efficiency. on top of this, regulatory authorities, headed by the Us food and drug administration fda, have realised that rigid documentation and approval requirements can sometimes stand in the way of optimisation, both in terms of cost and quality. at the same time, there is quite a gap between average and top performance facilities. also, the pharma industry is by no means a first mover when it comes to operational excellence (opex), so there is a lot to gain. Just think about the cost pressure and business changes that the automotive industry went through starting with toyota and the Lean methodology. the same thing could be said of the semiconductor industry, which started with motorola and six sigma. in these industries the transformation started decades ago and we are just now getting started. if you look at the mega trends influencing the industry you will see that most of them indicate that, broadly speaking, there will be pressure on efficiency for the next many years. even though our industry is behind when it comes to operational excellence, most companies have now passed through the tool age. they know about tools such as Lean and six sigma and they have trained staff. tools are great to have, and they create a common language. But now you have to take things to the next level, and that means identifying your main challenges and pragmatically applying the right tools to solve them.
Performance and organisation 121
An interdisciplinary effort solves the most complex strategic challenges When a company faces production problems whether they are quality issues or a lack of throughput the underlying issues are often multifaceted. the root cause might be technical problems, procedural or organisational issues, quality controls or inadequate specifications. and in many cases, multiple causes overlap or impede one another. When you end up in a situation where your entire operation is jeopardised and you have problems delivering to your customers, the complexity and time pressures can be overwhelming. of course, not every complex problem demands a complex solution. But in the face of complexity, your best approach is to analyse the situation with several sets of intelligent eyes. a creative team working towards a common goal is the best way to reach the best possible solution. When one of our customers won a major strategic order, they were faced with the challenge
of increasing production by 75 percent in just nine months. further complicating matters, their production was also facing severe quality problems and it was unclear whether or not the final product was suitable for release. Within two weeks, our customer and nne Pharmaplan put together a team of interdisciplinary consultants with backgrounds in:

Lean design of experiments (doe) automation vaccines maintenance Quality and validation gmP
together with the customer, we were able to produce a coherent plan for how to meet the production targets within the allotted time frame. one positive surprise for everyone was that the production could be doubled using the existing equipment. this was a huge relief for the entire team.
nne PharmaPLan services featUred in this chaPter: Value Stream Mapping (VSM) enhances your master plan and investment DOPEX design for operational excellence Practical and proven Lean and Six Sigma approach Get the most out of your technology with change management Establishing an operational organisation from scratch Demystifying Design of Experiments (DoE) Improving clinical trial efficiency Fewer mice and better vaccines with Design of Experiment (DoE)
01. 02. 03. 04. 05. 06. 07.
De ne mission and working principles Stabilise equipment De ne procedures & responsibilities Establish training system Install performance management and continuous improvement Establish people processes Communicate and manage key objectives and milestones
PrACtICAL AND PrOVEN LEAN AND SIX SIGMA APPrOACh

consultants have always been good at packaging, branding and marketing their services. one of the most recent trends in our industry is Lean and six sigma. anyone who has attended an operational excellence conference has witnessed endless discussions about where Lean stops and six sigma begins (and vice versa), and about the difference between the two philosophies and the different approaches within the schools. at nne Pharmaplan, we understand that academic discussions are not what you need. instead, you need to have a clear picture of your challenges and fast knowledge transfer to your organisation from consultants who are focused on implementing the right tools to solve your organisations challenges. When one of our customers yields were too low, we analysed the underlying reasons and developed a programme to help upgrade the customers basic statistical knowledge. We then trained the customers team in a number of Lean and six sigma tools but we never forgot that the customers first priority was to solve the yield problem and not to get a degree in Lean or six sigma. the programme was a big success, and it actually qualified the team for a six sigma green Belt. now they are considering going for the Black Belt they just need to tell us which problem they want to solve next.
VALuE StrEAM MAPPING (VSM) ENhANCES yOur MAStEr PLAN AND INVEStMENt
even if your facility has plenty of storage capacity, incorporating efficiency tools like Lean can bring the overall equipment efficiency (oee) up substantially. By using value stream mapping to focus on your facilitys current flow and capacity, we can alter the need for new buildings and equipment and thereby lower your level of investment.
think ahead and ramp up early an important part of doPeX (design for operational excellence) is getting an early start when planning how you will ramp up your new facility as quickly as possible. the earlier you start to organise and involve your organisation that is responsible for manufacturing in the facility, the better chance youll get a full return on your investment. the best technology in the best facility is not worth much if the manufacturing organisation is unmotivated, unorganised and lacking adequate knowledge. ies) between the average and the top-10 performance facilities. one of our customers bought a facility in france that needed a major overhaul in order to be competitive. the basic challenge for the customer was to increase the facilitys capacity by 50 percent over five years. the improvements needed to be done in the most efficient way possible, so we created a master plan for the site that focused on upgrading and integrating the following areas:

DOPEX DESIGN FOr OPErAtIONAL EXCELLENCE

major production facility changes whether its a move to a new location, a greenfield project or a major revamp offer you a unique opportunity to set up your operation in a new and more efficient way. the potential for efficiency is illustrated by the gap (16 percent according to university studComparing the average facility with the top 10 group Cost savings potential
100% EUR 40 m overall costs Other costs Labour Property, plant and equipment Cost of material 16% 25% 15% 16% 16% 17% 11% 40% Top10%
technology Building Quality Process support overall facility organisation
44% Average plant
By developing a clear master plan, we ensured a coherent, achievable solution for the facility.
GEt thE MOSt Out OF yOur tEChNOLOGy INVEStMENt wIth ChANGE MANAGEMENt
some consulting companies focus on technology and others focus on people and their behaviour. at nne Pharmaplan, we create value by using an integrated approach to focus on both. When one of our customers was implementing a major automation project (Pas|X), we worked with them to develop a change management strategy that would ensure the customer got full value out of the project. the plan took into account how change spreads through an organisation, so it established the following: 1. 2. 3. 4. 5. awareness desire Knowledge ability reinforcement
Define organisation Define roles and responsibilities
Develop business processes
Specify competency requirements
Select and assign people to roles
Train people
Run organisation
Standard operating procedures
EStAbLIShING AN OPErAtIONAL OrGANISAtION FrOM SCrAtCh

Building the organisation to run a facility is just as important as establishing the facility itself. Without a good organisation, good operating procedures and good training any facility can fail to reach the objectives in terms of quality and efficiency. there are a vast number of providers on the market who offer pharma and biotech companies a variety of more or less standardised training courses. although they might be both relevant and educative, they often do not take into account the specific processes of the company. at nne Pharmaplan, we take great pride in delivering customised training programmes that are tailored to the individual facility, taking into account your business strategy, internal organisation, production processes and other relevant aspects. in connection with the establishment of a new aseptic filling plant in Brazil, the customer had a clear success criterion regarding training of both new and existing employees. the facility is designed for fast ramp-up and continuous filling operation and is based on better practises and well known and proven technologies. it is also in compliance with fda regulations. more than 500 new employees were required in order to run the new facility. the majority of the new employees came from outside the pharmaceutical industry, which gave rise to a huge demand for professional training. also, existing employees needed to adopt new skills as changes were made to their existing job requirements.
We developed an in-depth training programme and plan based on a preceding definition of roles and responsibilities, specification of competence requirements and mapping of individual employee competences. the training programme contained individual, team, area and general training and covered topics such as:

together, we created a tangible change management plan that focused on engaging the entire organisation. the business challenge that the Pas|X project needed to address was symbolised by a furious dragon. the dragon was developed by the change agents/front runners in the project, and the goal was to change the dragons mood as the project progressed. this was an integral part of the front runners team building effort and it was a focal point when discussing the projects challenges and risks. the dragon helped communicate the progress, and it supported more traditional change elements to ensure the full business value.
Correlation of change management effectiveness to meeting project objectives
100% 90% Percent respondets that met or exceeded project objectives 80% 70% 60% 50% 40% 30% 20% 10% 0% Poor (N=111) Fair (N=259) Good (n0313) Excellent (n=65) 16% 51% 80% 95%
Production planning and scheduling formulation, filling and packaging operation calibration and maintenance of equipment Quality control in manufacturing and laboratories documentation and quality assurance Warehouse management and logistics
We also delivered conceptual design, basic design, detailed design, commissioning and qualification. thus, the customer got a training solution which was perfectly in sync with the project objectives and conditions.
Overall effectiveness of change management programme

Prosci. From Proscis 2009 Best Practices Change Management benchmarking report
DEMyStIFyING DESIGN OF EXPErIMENtS (DOE)

all pharma, biotech and medical device companies regularly encounter situations where they need to increase their level of process understanding in order to obtain business benefits. this might be, for example, in connection with process revalidation or optimisation. all companies have process understanding, but its not always operational. in other words, it only resides with select experienced engineers that have a rather intuitive approach to that knowledge. in this situation, its difficult to share the knowledge with the whole organisation, especially the operators on the shop floor.
Traditional
Time
70 60
our doe approach aims to increase the level of process understanding and make it operational. doe identifies which factors affect the output quality of the process in question, helping you achieve the best possible product quality and the greatest patient benefits. When you make process understanding operational, it becomes easier to document and future compliance is ensured. Less work for better results the key to minimising validation and optimisation costs is to conduct as few experiments as possible, and that is exactly where doe trumps traditional optimisation methods. benefits Using the doe approach to optimise your processes will:

formed under controlled conditions. typically, we use the following step-by-step approach: 1. identify the testing objective 2. define what is to be measured 3. identify the factors to be controlled during the experiment 4. identify relevant levels for the factors 5. design the test plan for each factor selected in step 3 6. design the trials 7. Perform the trials 8. analyse the results and determine which factors influenced the output 9. implement the new factor settings to achieve the test objective the results of doe-based trials can help identify the factors that most influence the output, and those that do not. they can also show you important details such as the existence of interactions and synergies between factors. in other words, the doe approach will identify the presence of interactions between any two factors, something that one-at-a-time methods always miss. doe makes it possible to identify the optimal settings of factors that will ensure your process achieves the best possible performance and output. higher quality in more areas the doe approach is a valuable tool throughout the pharma, biotech and medical device segments. at nne Pharmaplan, we have used doe in connection with, for example, animal trials, product and process development, up-scaling from pilot to full production scale, and optimisation during production including elimination of scrap. as a method of designing robustness trials, the doe method is compatible with fda demands. While they go beyond the current minimum requirements of a simplistic installation, operational and performance qualification (iQ, oQ, PQ), the doe advantages are clear when you need to demonstrate that a product or process meets its specification and will continue to work reliably. doe can help you achieve compliance with regulatory requirements and obtain business benefits all while serving the interests of patients by ensuring optimum product quality.
Traditional
Time
70 60
50 40 30 50 40 70
+ +
20
Traditional
Time
+
10 % Yield
Screening
Time
Screening
Time
+ + + + + + + + + + + + + + Temp + + + + + + + + Temp + +
60 30 50 20 40 10 % Yield 30 20 10 % Yield 70 60 50 40 70 60 30 50 70 60 50 40 30 40 30 20 10 20 10
Temp
increase the level of operational process understanding identify which factors have the greatest impact on performance and output identify how factors interact reduce time and costs identify optimal process settings identify the best control strategy to keep your process optimised optimise performance and output ensure compliance with regulatory regulations add value to Pat and Qbd implementation (Quality by design and Process analytical technology)
Screening
Time
Temp
Response
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20 10
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Response
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50 40 30 50 70 60 50 40 30 20 10 40 30 20 10 20 10
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a typical approach to optimisation is the one-at-a-time approach where each factor is varied. While one factor is being tested, the others are kept at their nominal or standard values. the number of trials is several times the number of factors. this usually results in a huge number of trials, and interactions are never found (i.e. when the effect of one factor depends on the settings of another) as the effect of each factor is measured in isolation. at nne Pharmaplan, our doe approach involves designing a set of approximately 16 experiments in which all relevant factors are varied systematically. compared to traditional experiments, this can cut the number of trials in half and potentially reduce them to one-tenth. When we build a design, we carefully select a small number of experiments to be per-
Temp
Temp
Temp
IMPrOVING CLINICAL trIAL EFFICIENCy

many of the tools used for optimising traditional production systems can be successfully applied to other business areas as well. infact, our industry spends a great deal of time and resources on non-production or administrative activities. and these processes are usually less efficient. in a period of three years, one of our customers needed to increase the amount of patients in its clinical trials by a factor of 2.5. But they had to do this without increasing the amount of resources by the same factor. We held a series of workshops with the customer to identify a number of initiatives that would improve global efficiencies within clinical trials. We were given the responsibility for one of these initiatives, and so we led an international group of practitioners through a project that included several workshops, data analysis and gxP expertise. the final outcome of the project included the following solutions aimed at improving monitoring efficiency:
changing key standard operating procedures (soP) on monitoring procedures to allow for more flexibility Better use of information in it systems for decision making introduction of remote monitoring reduction of requirements for source data verification (sdv)
FEwEr MICE AND bEttEr VACCINES wIth DESIGN OF EXPErIMENt (DOE)

each year, our industry spends billions on r&d. Both patients and companies benefit from getting efficient drugs to market as quickly and cheaply as possible. one of the phases where doe can help make this possible is during the trials. one of our customers asked us for help to: minimise the number of mice used for vaccine testing identify the adequate dose level Propose a new formulation of the vaccine to be tested in humans
an overview of which factors determine your output. in this case, one of the areas we looked into was the link between dose level and immune response. after one consultant worked for just two weeks on the project, the results were astonishing:

all in all, we helped the customer achieve its target growth in monitoring visits while using only 88 percent of the resources originally expected. We provided the solutions to the problem and the customer provided the decision-making power to make it a success.
all of the above would benefit patients, the business and the mice. We believed the right approach was to conduct a series of design of experiments. doe is basically a statistical method that enables you to set up your experiments in a way that quickly gives you
the amount of mice could be reduced by a factor of 50 the most significant factors for the vaccine were the number of immunisations, the adjuvant type and load (aluminium phosphate at a low dose and a low number of immunisations), and the route of administration (intra-muscular) a new and better formulation and Quality target Product Profile (QttP) were developed for the next set of clinical trials
With just a bit of effort and the right tool, the customer was able to achieve their goals.
Part ii Working with us
INDONESIA. Japanese encephalitis affects thousands of people each year causing death or disability. Especially among children.
Working With us 129
Working with us
NNE Pharmaplan combines expertise with passion to create results. When our experience and service philosophy form a synthesis, our customers gain a competitive advantage. Most people recognise that success does not come from professional expertise alone. in fact, expertise only provides the raw materials for value; its the way we interact with our customers that facilitates results. our service philosophy tells you how we strive to deliver real value that will improve your business results. We are passionate and committed to working in your industry. With a history of more than 80 years and 99 percent of our activities in your industry we have deep and exceptional insights, and live and die with the success of pharma and biotech. our investment in the industry and desire to transform knowledge into results are what fuel our passion. We strive to gain and demonstrate valuable insight. We are genuinely interested in your industry. When we work with you, we make our many years of insight available to you and we meet you with an honest desire to deal with your specific issues. We provide consistent and fast execution. We know the importance of fast and reliable delivery of services and projects be it greenfield or revamps. And as you will see, we hold strong methods and impressive results in this respect. We are focused on superior outcomes. We always live up to our commitments. But we are not satisfied until you have reached your ultimate goal, whether this is an efficiently operating facility, a problem solved or a decision made.
nnE PhArMAPlAn sErvicEs fEAturEd in this chAPtEr, illustrAting our sErvicE PhilosoPhy: A healthy decision platform Fast and flexible projects Intelligent revamps Reliable execution Efficient sourcing Pure knowledge
130 Working With us
A healthy decision platform

investing in production or development capacity is a critical activity in any company. the return on investment has a long lasting effect on your companys balance sheet and the resulting physical assets may very well either lock the development for years or open up for future possibilities. it is important to adequately map and evaluate the drivers behind an upgrade (product change requirements, regulatory, tech transfer, etc.). And it is equally important to identify the benefits, risks and constraints of the different solutions. nnE Pharmaplan can go directly for a conceptual design identifying technical solutions and investment needs. But just as often we are involved in the broader picture, defining the business case for an investment or even assessing whether the investment is at all necessary. Based on our business understanding, process know-how and regulatory expertise, we can help improving your decision basis in many ways:

Evaluation of outsourcing options site selection site master plans risk analysis and reduction Environmental considerations gMP facility strategies (conventional cleanroom, rABs, isolator, etc.) Process technology selection (continuous/batch, single use technology etc.) investment prospects
Production strategies feasibility studies, including net Present value (nPv) calculations
WoRkINg WIth you to dEvEloP thE solutIoNs
Cost of capital 24%
Raw materials 10%
thINkINg out oF thE box

When you have an experienced and creative team look at the different options, solutions may very well emerge that you hadnt thought of. this way nnE Pharmaplan has

At nnE Pharmaplan, we offer to drive your working process, but we always involve you if and when you desire. our typical execution strategy setup includes a number of Depreciation workshops with dedicated resources from 10% your organisation. Prior to the workshops, we usually prepare preliminary results to be discussed and elaborated on. this gives you the opportunity to be very closely involved in Other expenses the analysis and evaluation process, and we 17% will adjust our flexible working methodology to suit your needs.
API 12% Transport of finished goods 1% Wages 20%
4,500 4,000 3,500 3,000 Million pieces 2,500 2,000 1,500 1,000 500 0 2002 2003 2004 2005 2006 2007 2008
Upside
helped customers identify optimisation potential instead of investments phased revamps to reduce impact on production and postpone investment performed innovative reconfiguration of existing equipment, enabling more capacity to be squeezed in used far less investment-heavy technologies such as single-use identified the right product mix to match the financial framework
Downside
2009
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CoNCEPtuAl dEsIgN (Cd)

A conceptual design in its simplest form serves the purpose of ensuring that your investment decisions are based on a clear picture of the associated cost. At the same time, the conceptual design should include a thorough analysis of all viable alternatives and ensure that key stakeholders have a good overview of the upcoming project.
100 80 60 40 20 0
Studies and conceptual design
A good conceptual design covers this ground and provides the decision-makers with a sound platform for decisions. to achieve this, you need a cross-disciplinary approach, a thorough understanding of the relevant processes and business conditions, an extensive knowledge of proven solutions and new technologies available, and a creative mindset. All of this is combined in nnE Pharmaplans trained conceptual design teams. our methodology is based on in-depth process understanding, which means that we include utilities, it and automation, quality and validation assurance (QvA) and building know-how in the process perspective. Modular engineering is often key to executing fast-track projects, especially APi and biotech projects. these modules are defined in the cd phase.
% of total project investment
Realised project investment Project progress [time]
Project completion
Committed investment
the cd is documented extensively, based on graphical tools and presentations which can be used in management presentations.
vIsCoN INtERACtIvE 3d lAyouts

viscon is a powerful, easy-to-use 3d application for project scoping in the conceptual design phase: 3d presentations of facilities in a few hours interactive layout development or verification sessions All major process equipment in 3d, including laboratory furniture A library of the common unit operation modules scalable modular engineering models Automatic calculation of areas around the modules
used throughout our organisation, viscon can easily incorporate additional elements and be used without prior cAd knowledge
(ensuring a steep learning curve). the files can also be used later in the project for 3d visualisation.
132 Working With us
fast and flexible projects

fast project execution is often a strategic asset to pharma and biotech companies: new products get to market fast investments can be delayed, improving cash flow decisions can be delayed until after successful clinical trials increased ability to adapt to market demands the removal of compliance issues From 33 months to 12 months! At nnE Pharmaplan, we address the need for fast project completion through an aggressive approach to fast-track work. our goal is to execute any project within 12 months from project approval after basic design to finalising the operational qualification (oQ). And we now complete projects within 12-20 months on a regular basis.
Front end Design, construction and qualification 33 24 Time 18 15 12 PC/PV
bREAkINg thE sPEEd lImIts AgAIN ANd AgAIN

in the traffic, fast is not a virtue. in pharmaceutical engineering we believe it is. Bringing new drugs fast to market benefits the patients. it also helps innovative companies gain a stronger market position and thus fuels development. And fast projects reduce the risk of wrong investments by bringing the decision and the implementation closer in the time. nnE Pharmaplan has pushed the limits many times: completing a Eur 300 million biotech facility in 24 months including a 50% scope
change that was integrated halfway into the project was only possible because of our consistently modular engineering approach, allowing for rearrangement and duplication of the process modules in the middle of the project. completing a Eur 120 million biotech purification facility in 14 months or 20 months including PQ and Pv on budget and five months ahead of schedule was based on innovative modular engineering, offsite constructed process modules and meticulous planning. completing a Eur 50 million vaccine facility in just 11 months required intense teambuilding, optimal user-engineer cooperation and a tremendously dedicated organisation.
squeezing a Eur 60 million revamp into a running biotech facility, which on paper appeared fully built-up, was enabled by creative rearrangements and tight planning and completed in less than 12 months, requiring only three shutdowns totalling five weeks. We do not achieve these results with a magic bullet no single concept or technology is behind. it is rather a matter of focus and dedication, thorough understanding of the process and the gMP requirements, a holistic and cross-disciplinary approach, availability of sufficient talent and experience, and last but not least of a trustful cooperation between nnE Pharmaplan and our customers.
500 450 Million Euro (adjusted to 2009) 400 350 300 250 200 150 100 50 0 12
Project duration from detailed engineering until OQ
thE FAstEst tRACk

fast track is a phrase that is used, and frequently misused, when referring to pharmaceutical facilities. A pharmaceutical company recently analysed projects that had been labelled fast track. they established that the definition of duration was aligned to start of detailed design to end of operational qualification (oQ). the analysis showed (not surprisingly) a correlation between project size and duration. however, as you can see in the graph, three projects were executed markedly faster than others of similar size three nnE Pharmaplan projects.
18 NNE Pharmaplan
24
30
36
42 Months
Working With us 133
Modular commission Building

Process modules Process modules Distribution modules
thE FAst-tRACk ChECklIst

A question of management Maintain strict control of suppliers use high-performance teams they get things done fast use short communication lines people are more efficient when they know what to do the foundation for a fast-track project complete your cd up front think modular, think constructability use a win-win team structure trust, sharing and innovation are key words tools Modular engineering this gives you the ability to implement scope changes without delaying 3d models an indispensable fast-track tool, fast-track automation, structured in modules (s88) remember the ground rules Module integrity from concept to handover construct the installations off-site front-load your commissioning and qualification
Install
Traditional Building Equipment
modulAR dEsIgN FlExIblE ANd FAst

nnE Pharmaplan uses a modular design methodology as our standard. the facility design is broken down into logical modules that fit the process. Each module design is as self-contained as possible, including automation systems, installations etc. Each module is documented consistently in one package from concept to validation. the modules can (but need not) be constructed and tested separately, and separately from the building itself too, supporting reuse and flexibility (it is easy to add a module). this gives the final facility an inherently logical structure that fits to the process and simplifies operations.
modulAR CAN bE ChANgE-FRIENdly

Establishing the right capacity in the right time is crucial, and one way to achieve this is to use a modular approach. this approach enables multiple parallel activities, giving the project additional flexibility and making project changes more feasible because the effect of a change can be isolated and controlled. one prime example is a Eur 300 million project we have executed. nine months after the project started, the customer changed the scope, asking for the production lines (which were initially scheduled to be finished last) to be finished first. And we still had to keep within the original 24-month schedule. using our modular approach, we were able to efficiently copy and reprioritise the equipment delivery while still maintaining the final layout.
oFF-sItE Is FAstER ANd sAFER

construction off-site or at site that is a location close to the site reduces the number of construction personnel on site, enabling faster construction and integration, and much higher safety. We have many years of experience in using a modular approach that separates the design and management in a project and thus completes massive parallel construction work and the final integration of modules and tested modules fast.
350 300
Manpower
250 200 150 100 50 0 1 2 3 4 5 6 7 8 9 10
Months
134 Working With us
intelligent revamps
you may have many reasons for expanding or improving your production setup: capacity increase, saving energy or production time, improving quality and compliance, tech transfer or introduction of new products. And often solutions are just as plentiful: you can build new capacity. you can improve existing facilities. you can move or outsource production. or you can optimise the existing operations. in our experience many investments can be avoided or postponed by a thorough analysis of the needs and the possible solutions. nnE Pharmaplan has years of experience analysing upgrade needs and defining the revamp scope and sequence of future shutdowns. in order to optimise shutdowns it may be best to execute a revamping project in two or three phases in order to be able to supply the market during a production shut-down if the products durability is short or if cold storage capacity is small, for example. When planning shutdowns its worthwhile to look at all the facilitys needs making sure that the shutdown period caused by a major revamp is efficiently utilised for maintenance activities, tests or maybe other minor projects. When developing a long-term strategy, we take into account how long it usually takes operators to re-start production after a shutdown and how long maintenance and compliance tasks take.
utIlIty gAP ANAlysIs ANd sChEdulINg

one of the most important issues during the front-end engineering phases of a revamping project is to identify whether the utility capacity of the existing plant can match the rebuilt plant. the answer is to begin your plant expansion with a thorough a gap analysis to identify the installed capacity and calculate your precise needs after the expansion. the capacity calculation should be based on the production schedules before and after rebuilding, detailed hour by hour registration of the actual consumption and stock potentially identifying necessary rescheduling to avoid peaks and the estimated needs after revamping.
AN AutomAtIoN solutIoN IN just thREE WEEks

during a three-week shutdown period, nnE Pharmaplan implemented automation solutions that made it possible to transform a one-product production line into a multipurpose line.
the project included transforming one of the facilitys two production lines from a one-product line into a two-product line, as well as optimising the manufacturing capacity of both lines. the reconstruction work on the shared systems (automation backbone, utilities and raw material solvent) was to be carried out during the summer holidays, giving us only three weeks to complete it. We got the order just four months before the shutdown period began. Automation, process and mechanical engineers worked closely with our customer in order to plan the project and the shutdown in detail, ensuring that all disciplines had sufficient time for their activities. We created a software version of the operational facility with its new scope to make sure the automation software was free from errors and to accomplish a smooth start-up on day one after the shutdown.
buIld, REvAmP oR oPtImIsE?

one of our customers identified several midsize and large equipment renewal projects that could help expand production capacity and asked us to analyse the situation to provide an overview of capacities, failure statistics and productivity issues. in order to ensure the customer could reach their desired
capacity increase, we recommended them to postpone installing new equipment (such as an additional lyophiliser), and instead optimise the working processes and only complete minor repair works. By demonstrating the significant production improvement potential, we helped the customer save investments and establish a better solution with a safer project execution plan.
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thE AbC oF REvAmP PlANNINg
this approach helps ensure that all revamping projects run like clockwork.
strategy Map rebuilding and upgrading requirements Balance the shutdown duration with the loss of production capacity Evaluate the strategy: one or more shutdowns? Assess if the shutdown can be used for other activities? Map gMP compliance, utilities etc. define the functional scope of the individual revamp project
Planning and on-site preparation Perform a thorough study of the existing facility use laser scanning in order to establish a 3d model, if relevant Prepare the revamp design potentially in 3d Maximise off-site preparation work to shorten the shutdown Prepare a schedule (hour-by-hour) including retesting and approvals confirm all practical conditions, including cleaning and draining of utility systems carry out all possible pre-works receive and check all goods one week in advance, inform all contractors about safety regulations, plans and schedules
Closing down for shutdown cleaning and cleaning in Place (ciP) calibration and testing of equipment, utilities and hvAc storage and protection of production equipment controlled shutdown of hvAc and utility systems factory to go from restricted area to controlled initial demolition works commenced
Construction works factory in red mode and out of service Execution of rebuilding activities new process installations installed Existing facilities rebuilt Process upgrades and renovations the revamp project team runs the plant throughout the shutdown period
Commissioning, mechanical completion and qualification cleaning Pre-tests commissioning calibration and testing of equipment, utilities and hvAc Mechanical completion installation qualification operational qualification user training
PQ/Pv and back in service re-installation and testing of production equipment start-up and testing of hvAc and utility systems closing all shutdown-associated QA activities cleaning qualification and room classification back in place cleaning of production facilities as the facility is returned to restricted area (e.g. blue or green)
136 Working With us
reliable execution
good qualifications, good intentions and even good contracts are of little value if we do not deliver the agreed quality or meet your schedule. for nnE Pharmaplan this means:
our deliveries must always meet the agreed specifications safety must have priority our project communication must be open and transparent We must ensure that projects are on track and if not, take appropriate actions
Behind this commitment stands the dedication of more than 1500 nnE Pharmaplan employees focused on serving your industry.
PRojECt oRgANIsAtIoN ANd govERNANCE

successful projects depend on the team. in nP we focus both on the individual through recruiting and development, and on the team: leadership, communication, cooperation and organisational efficiency kick-off meetings that ensure mutual understanding of roles and targets Project organisational reviews and employee surveys Project evaluation that helps ensure better projects in the future it is also important to have governance mechanisms in place to deal with problems if they come up. We always appoint a top-level manager to back up the project manager should issues arise that stretch beyond the mandate.
EvIdENCE
A lloyds audit revealed that nnE Pharmaplans biggest project in 2009 (a Eur 200 million pharmaceutical facility, completed in 19 months) was ranked among the best in the world. the audit concluded that the project:

2005:
Was very impressive, showing convincing control throughout the entire process demonstrated exceptional performance and used effective and efficient tools showed massive dedication to mitigating risks of all kinds, including risks related to finance, quality, the environment and safety and health took adequate corrective or preventive actions when needed
2008:
2008: this statement is just one in a long line of recognitions including three facilities designed by nnE Pharmaplan that have been awarded the prestigious facility of the year title by isPE:
Working With us 137
globAl kNoWlEdgE shARINg

When you need support from nnE Pharmaplan, you want it locally and easily accessible but still with access to our globally available wealth of know-how and talent. All nnE Pharmaplan, employees are interconnected through a shared knowledge platform on our intranet. Every day sees an intense traffic of knowledge sharing, requests for information, good ideas and advice on the easily accessible ourbook communication platform. More static or encyclopaedic knowledge is accessible in our common store, ourwiki, which includes nnE Pharmaplans project execution model:
Conceptual Design Basic Design Detailed Design Constructions Commissioning & Qualication Handover and operation support
ouR modEl
reliable project execution requires a clear and consistent structure and this is even more essential when the project is executed in various offices in various countries and continents. our aim is to give you the exact same service from beginning to end of a project, no matter where in the world you are based. We do this through a web-based project execution model that ensures we work consistently with well-proven methods worldwide. it also ensures that all our employees have access to our current best practices, and are flexible enough to adapt to yours.
PRojECt CoNtRol: thE FouNdAtIoN FoR suCCEssFul PRojECt ExECutIoN

nnE Pharmaplans project controlling function uses a well proven and flexible toolbox, which contains all the knowledge we have gained from years of experience in the field. the box includes tools for resource estimation and follow-up, procurement, change order management, risk management and earned value management.
the AbC of scheduling in many large projects, we use a three-level scheduling approach: A. the main milestone schedule includes the key interaction points with the customer and is unchangeable (in principle) B. Package schedules ensure the different parts of the project are implemented as needed, including specific recovery action plans c. individual activity schedules are used to measure progress and include measurable tangible results (documents, hours, pipes and floor space, etc.)
Earned value management (Evm) EvM combines the conventional parameters of schedule performance with cost performance. And it answers the essential question: what did you get for your money? EvM is based upon the concept that: All project activities earn value as work progresses the Earned value (Ev), actual cost and planned costs can be compared in order to monitor and predict budget and schedule performance Physical progress is measured in money, so schedule performance and cost performance can be analysed in the same terms
138 Working With us
Efficient sourcing
in the pharmaceutical and biotech industries, non-core spending is significant but largely undermanaged. in fact, 15-20 percent of most company revenue goes to non-core purchases. Procurement is a high-impact activity that can enhance your companys performance and significantly improve your bottom line and risk profile. however, maximising the value of procurement, and ensuring savings opportunities is not simple. it requires expertise across a wide range of buying categories and thousands of suppliers all over the world. Whether you are looking for support across the entire procurement value chain or in specific areas, we offer proven solutions that feature:

Extensive market insight, supplier information and tools Attractive trade and framework agreements with suppliers and contractors lifecycle contract management compliance with hsE and gxP regulations and standards
Experienced and dedicated category, technical and legal specialists
furthermore, our expertise and global infrastructure can help you fulfil both project-based and outsourcing solutions.
souRCINg FRom CostComPEtItIvE CouNtRIEs

sourcing equipment from low-cost countries can be profitable, but risky. Because of nnE Pharmaplans presence in Asia, we are able to source equipment from local suppliers and take advantage of lower costs without compromising technical requirements, regulatory compliance or hsE standards. one of our customers needed to pack a medical device in blister and carton, along with a folded leaflet. the cartons should to be stacked two-by-five and bundled before being manually packed in a box for shipment. to fulfil the customers technical and quality requirements, nnE Pharmaplan found a chinese over-wrapper equipment supplier that could produce 24 bundles a minute.
the benefits were: A cost saving of 90 percent compared to other suppliers delivery time reduced by four months fewer process bottlenecks
PRoCuREmENt IN PRojECts
our procurement power and list of 8000 prequalified global suppliers can facilitate your projects whether executed by nnE Pharmaplan or not. for example, we have worked with a biopharmaceutical company to manage the procurement of a six-piece filling and closing machine for disposable syringe filling lines. the lines were to be installed at three different facilities over a two-year period. due to our extensive market knowledge, we were able to increase competition and we achieved:

in another project, when working on the implementation of an industrial biotech plant in the us, we chose to design and build process modules at two locations in china and then ship the 45,000m of equipment modules to the us. in spite of additional transport and logistic costs we will achieve: Equipment module costs reduced by about 25 percent compared to local us procurement costs A quality level that fulfils us legislation requirements (nnE Pharmaplan employees in china supervised the supplier to ensure an acceptable quality level)
cost savings of 23 percent delivery time reduced by two months service contract costs 15 percent down
Working With us 139
outsouRCINg solutIoNs
if you are looking to redirect your resources to your core activities, rapidly acquire a
world-class non-core procurement operation, or reduce operating costs, nnE Pharmaplan can manage your source-to-pay activities. some examples of these activities could be:
faced with a lack of resources and competencies within capital equipment, construction services, maintenance and repair, a biopharmaceutical company entered a service level agreement with nnE Pharmaplan in order to:
strategic sourcing Analyse spending and develop a sourcing strategy issue requests for quotations and information
Procurement operation
Accounts payable Match invoices with orders and receipts Provide detailed expenditure reports
create and manage online item catalogues Manage supplier and contract databases track supplier performance
Achieve additional savings by focusing internal resources on strategic materials and services take advantage of group trade agreements and shared supplier management costs by using strategic sourcing for selected non-core categories save 10-15 percent on outsourcing costs shift from direct staff costs to indirect staff costs for procurement operations and accounts payable Access a global procurement infrastructure and achieve a lean organisation
RAW mAtERIAls ANd sPARE PARts

nnE Pharmaplan can supply raw materials, spare parts and operational consumables to you after completion of your facility, offering the following benefits:

one-source channel Qualified and certified raw materials competitive prices due to our wellestablished procurement channels technical support in the form of maintenance, repairs and service replacement equipment staff training optimised shipments by consolidating materials from different suppliers Warehousing in the event of emergency shipments highly qualified engineering know-how on demand
tuRNkEy solutIoNs EvERythINg FRom A sINglE souRCE

When planning a facility, it is important to find a partner who can hand over a facility that meets your goals in terms of time, cost and quality. nnE Pharmaplans experience ensures that your expectations are met. We offer the complete package for a pharmaceutical or biotechnological production facility, including the feasibility study, engineering, construction, production start-up and staff training. in most cases, our support begins
with the selection of process technologies and continues after project handover. nnE Pharmaplan has built more than 150 turnkey production facilities all over the world. We have delivered a multitude of iv solution, APi, biotech and medical device facilities. some of the facilities were delivered completely modularised and pre- tested. And we have worked with several of our customers for more than 30 years a testament of our customers confidence and satisfaction.
140 Working With us
Pure knowledge
At nnE Pharmaplan, we take the understanding of our customers business and processes seriously. our staff combines more than 10,000 years of collective experience in the pharma and biotech industries. this includes a large number of experts with backgrounds in production or development as well as in all the technology fields related to engineering. We also feature the highest number of isPE certified industry Professionals (ciPs) compared to any customer or competitor within the life science industry. We make our expertise available to our customers projects and ongoing operation as stand-alone consultancy or as project partner.
NNE PhARmAPlAN AN ACtIvE PlAyER IN thE PhARmA ANd bIotECh CommuNIty

to help spread industry knowledge, we regularly conduct workshops, seminars, training courses and conferences, and we
contribute papers and speeches to the international pharma and biotech community. our work has been recognised in multiple contexts including: 2008 IsPE Company of the year nnE Pharmaplan was named company
of the year in 2008. We were a member of the isPE board, chaired the commissioning and Qualification baseline guide and participated in numerous committees that contributed to the development of significant concepts and guidelines, such as gAMP and Quality by design.
that the most significant difference we had made for him was in fact to remove all those yellow Post-it notes that had been bugging him for months. nnE Pharmaplan offers our experts as consultants who address the topics described in this catalogue with a pragmatic approach. our consultants work together across disciplines acting as the glue between our many disciplines and offerings, but based on your day-to-day issues. our many consultants and specialists combine management consulting, business consulting and operational consulting into services that are tailored to your needs. Just to mention a few examples, we help implementing lean and six sigma programs including training, goal-setting and follow-up. We help with data collection, analysis and directions on debottlenecking of existing facilities. We help streamline, troubleshoot, benchmark, innovate, re-think, facilitate or challenge your organisation as if we were part of your organisation. And very often we simply support your staff when there is just too much to do during a workload peak. We have done this in many different positions, for many different companies and with many different approaches.
CoNsultINg PuttINg PuRE kNoWlEdgE INto WoRk

Working in a pharma or biotech company is so exciting because you write a little bit of history every day. Being part of an industry that makes a real difference for so many people around the world is an
interesting challenge sometimes a little too challenging. this is where consulting services can make a difference. you are definitely the experts in your own business, but input and advice from the outside can bring new inspiration and help you overcome your daily challenges. one of our customers once told us
Working With us 141
NNE PhARmAPlAN ACAdEmy

the nnE Pharmaplan Academy runs an internal training programme to keep our employees up to speed with the latest procedures and best practices. our basic training for new employees includes training in our quality management
system, familiarisation with our strategies and perspectives, and a course on the pharma and biotech industries in general. We also offer a series of training courses that deal with specialised tools and methods and introduce employees to individual customer technologies and business sectors.
Date: Aug. 24 Speaker: BRSQ Seats: 15/20 Date: Aug. 25 Speaker: PLJE Seats: 15/20 Date: Aug. 25 Speaker: FRHA Seats: 15/20 Date: Aug. 26 Speaker: MDAE Seats: 15/20 Date: Aug. 26 Speaker: LPOU Seats: 15/20
Conceptual design purpose and methods
Tags i Categories Add me
CustomER WoRkshoPs
nnE Pharmaplan frequently meets with individual customers in order to share experiences and discuss new trends. our goal is to learn about your needs and requirements, and hopefully to contribute with inspiration. Examples of workshops we offer: A three-hour one-to-one workshop with a senior nnE Pharmaplan project manager to discuss project execution issues A two-hour workshop to discuss the facility status and exchange technology developments one year after project completion A half-day session introducing Quality by design, regulatory trends and practical applications for up to 50 internal stakeholders A full-day session discussing trends in modern biotechnology, including the application of single-use technology
Maintenance support
S88 batch control introduction
PAS-X basic training
Pharma focus 5: business processes and procedures
Date: Aug. 30 Speaker: AKRB Seats: 15/20 Date: Aug. 31 Speaker: MNRP Seats: 15/20 Date: Aug. 31 Speaker: CHUB Seats: 15/20 Date: Sep. 1 Speaker: NCA Seats: 15/20 Date: Sep. 1 Speaker: ALIE Seats: 15/20 Date: Sep. 2 Speaker: LVSP Seats: 15/20
Lean basic
Drafting and understanding contracts
GAMP5 Level I (2 hours)
ERP system integration Novo Nordisk case story (SAP)
Single-use in fill & finish
Learning from project evaluation
142 IntroductIon
nnE PharmaPlan offIcEs 143
nnE Pharmaplan offices

Europe Denmark nnE Pharmaplan head office Vandtrnsvej 108-110 2860 sborg Phone: +45 4444 7777 fax: +45 4444 3777 nnE Pharmaplan Brennum Park 25KP 3400 hillerd Phone: +45 4444 7777 nnE Pharmaplan hallas alle 4400 Kalundborg Phone: +45 4444 7777 nnE Pharmaplan stenager all 4 9800 hjrring Phone: +45 4444 7777 Finland nnE Pharmaplan tykistnkatu 4 B: 305 20520 turku Phone: +358 40 5079 711 France nnE Pharmaplan 9, rue Edmond Poillot 28 000 chartres Phone: +33 2 37 88 79 50 fax: +33 2 37 30 75 28 nnE Pharmaplan Immeuble solarIs - 3 me tage 210 avenue Jean Jaurs 69 007 lyon Phone: +33 2 37 88 79 50 fax: +33 4 37 70 84 98 Germany nnE Pharmaplan siemensstr. 21 61352 Bad homburg Phone: +49 6172 8502 100 fax: +49 6172 8502 501 nnE Pharmaplan Werksgelnde der Behring Werke / hauptwerk Gebude h6, 4. stock Emil-von-Behring str. 76 35041 marburg Phone: +49 6421 1867 940 nnE Pharmaplan magirus-deutz-strae 12 89077 ulm Phone: +49 7314 0321 252 fax: +49 7314 0321 253 Ireland nnE Pharmaplan c/o life science consultants unit 8a, Kinsale commercial Park Kinsale, co. cork. Business Partner Kieran coughlan Phone: +353 21 477 7329 Russia nnE Pharmaplan of. 405, bld.1, 57, dubininskaya str. 115054 moscow Phone: +7 499 270 0999 fax: +7 499 270 3399 Sweden nnE Pharmaplan Box 498, 191 49 sollentuna Visiting address: hammarbacken 12 Phone: +46 8 59 49 60 00 fax: +46 8 59 49 60 99 nnE Pharmaplan rapsgatan 7, hus 13:2 753 20 uppsala Phone: +46 8 59 49 60 00 nnE Pharmaplan World trade center Jungmansgatan 12 211 19 malm Phone: +46 8 59 49 60 00 Switzerland nnE Pharmaplan altkircherstrasse 8 4054 Basel Phone: +41 61 307 9670 fax: +41 61 307 9680 nnE Pharmaplan avenue de Gilamont, 52 1800 Vevey Phone: +41 21 926 9700 North America United States nnE Pharmaplan Perimeter Park onE, 3005 carrington mill Blvd., suite 380 morrisville, nc 27560 Phone: +1 866 810 4073 fax: +1 919 763 1801 nnE Pharmaplan 222 third st suite 2230 cambridge, ma 02141 Phone: +1 866 810 4073 fax: +1 508 484 4973 nnE Pharmaplan 1055 Westlakes dr. Berwyn, Pa 19312 Phone: +1 866 810 4073 fax: +1 610 727 4360 nnE Pharmaplan 150 Executive Park Blvd. san francisco, ca 94134 Phone: +1 866 810 4073 fax: +1 415 656 1399 Asia China nnE Pharmaplan 17f, JinWan mansion no. 358 nanjing road tianjin 300100 Phone: +86 22 2750 1730 fax: +86 22 2750 1745 nnE Pharmaplan room 1001, tower a, center Plaza no. 161 lin he West road Guangzhou 510620 Phone: +86 20 3833 9386 nnE Pharmaplan room 405, man Po International Business center no. 660 Xin hua road shanghai 200052 Phone: +86 21 6282 6077 fax: +86 21 6282 7194 India nnE Pharmaplan a2/118, safdarjung Enclave new delhi - 110029 Phone: +91 11 26197251 / 52 fax: +91 11 26197253 / 26169248 nnE Pharmaplan B-15, sector 2 noida - 201301 Phone: +91 120 4775100, fax: +91 120 4775200, 4775300 nnE Pharmaplan #14, achiah shetty layout 1st cross, rajamahal Vilas rmV Extension, sadashivnagar Bangalore - 560080 Phone: +91 80 23614415, 23617234 / 35 fax: +91 80 23617240 nnE Pharmaplan 703-704, sagar tech Plaza, a-Wing, andheri Kurla road, sakinaka, andheri (East) mumbai - 400072 Phone: +91 22 4064 7000 fax: +91 4064 7099 Malaysia nnE Pharmaplan 16, Jalan 51a/225 46100 Petaling Jaya, selangor Phone: +60 3 7862 3000 fax: +60 3 7862 3001 Email contact to all offices: contact@nnepharmaplan.com
144 EXtEndEd contEnt
Extended content
9 Engineering for a healthier world 12 Develop, establish, improve 15 PART I SEGMENTS AND OFFERINGS 17 Biopharmaceuticals 18 28 28 28 29 29 30 30 30 31 32 32 33 34 34 35 35 26 28 28 28 29 29 30 30 30 31 32 32 33 34 34 35 35 Biotech high-tech aseptic facility helps meet regulations and save costs Eu GmP pushes the use of technology finding the right contract manufacturers Infusion solutions worldwide optimised formulation delivers capacity increase complexity in freeze drying full-scale delivery of freeze drying isolator line Wash and sterilisation an integral part of aseptic operations campaign filling a more efficient way Packaging challenges Inspection technologies fighting counterfeit drugs microdosing a new siliconisation technology Internal logistics and material handling contamination finding the root cause single-use in filling operations: the future? Sterile & aseptic high-tech aseptic facility helps meet regulations and save costs Eu GmP pushes the use of technology finding the right contract manufacturers Infusion solutions worldwide optimised formulation delivers capacity increase complexity in freeze drying full-scale delivery of freeze drying isolator line Wash and sterilisation an integral part of aseptic operations campaign filling a more efficient way Packaging challenges Inspection technologies fighting counterfeit drugs microdosing a new siliconisation technology Internal logistics and material handling contamination finding the root cause single-use in filling operations: the future? 49 50 50 51 51 51 52 54 54 55 55 56 56 56 57 57 Efficient high-containment aPI facilities decontamination of old facilities master Inline how to improve mixing of liquids containment in a flexible pilot environment a greener future: the renaissance of synthesis production automate to optimise the way to more cost-effective cIP Oral solid dosage cost-efficient osd facilities Product optimisation and development multipurpose high containment facilities low cost production technology transfer optimising packaging and logistics radiopharmaceuticals optimising material and personnel flow Process analytical technology (Pat) new trends in manufacturing of osd
59 Medical devices 60 62 62 62 63 63 63 64 64 64 65 65 65 65 Medical devices and drug delivery systems Product functionality testing in r&d Establishing semi-automated and high-speed production lines revamping existing production lines medical device validation the troubleshooting process and its impact specification and establishment of pilot equipment Global transfer of technology and equipment risk assessment of products and production assessing medical device cmo environment Equipment supplier recommendation design platforms and flexible production layouts streamlining global production set-up data-driven product development
67 Industrial biotech 68 70 70 71 71 74 76 76 77 78 78 78 79 79 80 80 80 81 81 82 82 82 83 83 83 Industrial biotech Global delivery of low-cost facilities Emerging trends in industrial biotech Efficiency through simulation and model-based design Establishing a new greenfield industrial biotech plant GMP Compliance Quality by design (Qbd) nnE Pharmaplan seven steps to Qbd based validation the astm E2500 paradigm how much money can you save? Getting ready for audits taking charge of soPs to become more efficient managing compliance GaPs Informed approach to designing quality systems training and the human brain future-proof with paperless validation Electronic registration and electronic signatures compliance across the globe Quality risk management and assessment It systems for quality and compliance (GamP5) sterilisation validation cleaning validation fast process validation increases utilisation setting up failure to achieve success method validation Process validation according to the new guidelines
37 Vaccines 38 40 40 41 41 42 42 42 43 43 43 Vaccines multiproduct Bsl2 vaccine facility Establish multiproduct production standardised vaccine facilities a new concept therapeutic vaccines and their promise for the future Egg-based vaccine facilities handling Gmo approvals Biosafety & biosecurity Getting started with manufacturing from idea to operation lean vaccine production tech transfer a matter of know-how
45 Pharmaceuticals 46 48 48 49 Active pharmaceutical ingredients tech transfer: combining state-of-the-art with local practice securing product quality when offshoring upgrading Indian aPI facilities
EXtEndEd contEnt 145
84 86 86 86 87 87 88 89 89 90 90 90 91 91 92 94 94 95 95 95 96 96 97 97 98 98 99 99 99
Sustainability & environment sustainable business strategies climate management and carbon footprint Energy-efficient process design realising energy savings and process optimisation cost reduction using cleantech certified green facilities reducing lifecycle impact during r&d risk assessment: safety of people and the environment regulatory fast-track processing Innovative noise abatement Wastewater treatment and handling of Gmo waste high potent aPI: occupational exposure limit designing proactive working environments Containment & cleanroom GmP versus containment the right balance completing a biosafety risk assessment reducing cleanroom cost through new production technologies cleanroom laboratories for r&d cancer treatment high containment animal facility design turnkey modular cleanroom solutions for pilot-scale production airlock design that supports hygiene procedures nnE Pharmaplan cleanPlus: our cleanroom concept Electromagnetic interlock: the cleanlock Plc upgrading an existing cleanroom environment reducing energy costs in your controlled environments cleanroom testing and certification the proven and painless way making cleanrooms operator-friendly Go clean: the structured way to make cleanrooms operationall
117 117 118 118 119 119
use in-process control to obtain a higher quality level complying with new anti-counterfeit regulations streamlining production reporting Increase competitiveness with laboratory automation s88 & s95 minimise risk by using standards smooth implementation of mEs
120 Performance and organisation 122 Value stream mapping (Vsm) enhances your master plan and investment 122 doPEX design for operational excellence 122 Practical and proven lean and six sigma approach 123 Get the most out of your technology with change management 123 Establishing an operational organisation from scratch 124 demystifying design of Experiments (doE) 125 Improving clinical trial efficiency 125 fewer mice and better vaccines with design of Experiment (doE) 127 PART II WORKING WITH US 128 Working with us 130 130 130 131 131 132 132 132 133 133 133 133 134 134 134 134 135 136 136 136 137 137 137 138 138 138 139 139 139 A healthy decision platform thinking out of the box Working with you to develop the solutions conceptual design (cd) Viscon interactive 3d layouts Fast and flexible projects Breaking the speed limits again and again the fastest track modular design flexible and fast modular can be change-friendly the fast-track checklist off-site is faster and safer Intelligent revamps utility gap analysis and scheduling an automation solution in just three weeks Build, revamp or optimise the aBc of revamp planning Reliable execution Project organisation and governance Evidence Global knowledge sharing our model Project control: the foundation for successful project execution Efficient sourcing Procurement in projects sourcing from cost-competitive countries outsourcing solutions turnkey solutions everything from a single source raw materials and spare parts
100 Logistics and facility design 102 from business plan to facility plan capacity and flow analysis 102 site master planning getting it right today and tomorrow 102 site selection weighing the pros and cons 103 right place, right time, right cost supply chain analysis 103 Keeping it cool cold chain robustness 104 GmP strategies setting your facility up for success 104 Building condition analysis your facilitys health check 105 revamping new use for existing buildings 105 material handling a focus area worth your attention 106 facility design addressing climate change 106 creating your site atlas 107 customised layout typology 107 Biosphere: your future facility? 108 110 110 110 111 111 111 112 112 112 113 113 113 Laboratories facilitating creativity in lab design minimising investment risk laboratory planning organisational development of laboratory departments Generic laboratories reduce the project cost animal facilities built on bioethical principles flexibility and changeability as design drivers regulatory approvals for Gmo laboratories reducing power consumption in laboratories maintaining compliance with reduced energy consumption laboratory automation: lead times and quality Increased efficiency in laboratories Integration and optimisation through laboratory It
140 Pure knowledge 140 nnE Pharmaplan an active player in the pharma and biotech community 140 consulting putting pure knowledge into work 141 customer workshops 141 nnE Pharmaplan academy 143 NNE Pharmaplan offices 144 Extended content 146 Keyword index, categorised 148 Keyword index, alphabetised
114 Manufacturing information systems 116 Enterprise manufacturing intelligence a performance overview 116 Increased capacity with the right automation & It strategy
146 KEyWord IndEX
Keyword index, categorised

Diseases cancer 17, 37, 38, 39, 41, 93, 94, 95 cardiovascular diseases 25, 44, 47 haemophilia 12, 19, 25 Infectious diseases 39, 41, 42, 61 smallpox 39 Pharma/biotech roducts Biofuel 67, 68, 69, 70 Blood products 19, 25, 93 drug delivery devices 61 Enzymes 67, 69, 70 fish oil 47, 85 flu vaccines 39, 42 high potency pharmaceuticals 32, 49, 52, 55, 70, 71 Infusion (IV) solutions 29, 139 monoclonal antibodies 20, 21, 22, 23 Personalised medicine 25, 54, 93, 95 radiopharmaceuticals 56 therapeutic vaccines 41 treatments 25, 93, 95 Facility types animal facilities 94, 95, 111, 112 contract manufacturing organisations (cmo) 20, 22, 27, 28, 43, 78 hospitals 25, 91, 93, 94, 95, 103 launch facilities 20, 40, 42, 65 multiproduct facilities 20, 21, 22, 27, 40, 51, 55, 70 Pilot facilities 3, 51, 63, 96 r&d and Qc laboratories 62, 63, 93, 95, 109, 111, 118 Process types cell culture 20, 21, 22, 23 clean utilities 134 cleaning in place (cIP)/sterilisation in place (sIP) 21, 29, 30, 35, 50, 51, 82, 87 device assembly 62 downstream 23, 24, 71 Egg-based processes 39, 42 filling 31, 35 formulation 28, 29, 54, 57 freeze drying 30 Injection moulding 63 Inspection 32 logistics 34, 54, 56, 101, 105 microbial fermentation 70, 71 oral solid dosage (osd) 53, 54, 55, 56, 57 Packaging 32, 56 synthesis 49, 51 Warehouse 56, 91, 105 Technologies and solutions analytical methods, quality control (Qc) 83 automation & It 24, 29, 30, 32, 51, 81, 115, 119, 134 cleanPlus 96, 97 cleanrooms 25, 28, 93, 94, 95, 96, 97, 98 containment 35, 56, 82, 94, 96 counterfeit prevention 33, 54, 117 high-titer processes 20, 22, 23 Isolator, raBs 28, 95 laboratory automation 113, 118 mEs & production information 116, 118, 119 Pat 57, 76, 112, 117, 124 single-use 22, 23, 35, 39, 40 Global trends carbon footprint and green technologies 51, 69, 70, 86, 87 Energy reduction 86, 87, 98, 112 Globalisation 64, 65, 70, 75, 137, 138 offshoring 48, 55, 64, 70 Working environment 90, 91, 94, 99 Regulatory requirements Biosafety 29, 38, 40, 41, 42, 94 Biosecurity 38, 42, 94 decontamination 50 Environmental permitting 90 Eu GmP 28, 48, 78, 112 fda GmP 28, 49, 76, 78, 80, 82, 83, 117 Genetically manipulated organisms (Gmo) 42, 90 medical device GmP 63 occupational Exposure level/Band (oEl/oEB) 55, 91 Quality concepts and activities astm 2500 76, 77, 79, 81 audits 28, 48, 75, 78 cleaning and process validation 82, 83 IQ, oQ, verification 77, 80 Quality by design (Qbd) 76, 77, 83 risk assessment 63, 64, 65, 76, 79, 89, 94 standard operating Procedures (soP) 29, 43, 55, 64, 74, 78, 79, 104, 123, 12 Develop product supply approach clinical trials 125 conceptual design 23, 110, 130, 131 feasibility studies 22, 130 manufacturing science 65, 124 manufacturing supply chain 65, 103, 139 output, uptime, cost improvement 27, 31, 43, 57, 71, 87, 105, 113, 122 Product development 54, 61, 62, 63, 65, 89, 93 Product launch forecasting, 20, 102 site selection and master planning 102, 130 start-up companies 25, 41, 43, 69 tech transfer 20, 43, 48, 54, 55, 64, 65
KEyWord IndEX 147
Establish production capacity architecture 19, 104, 105, 106, 107 commissioning 40, 133, 135 construction management 19, 40, 133, 135 Engineering, design 133, 135, 137 facility cost reduction 22, 28, 41, 56, 70, 71, 95 facility of the year 19, 21, 27, 136 fast-track 19, 21, 39, 41, 47, 132, 133 layout, people and material flow 22, 40, 41, 56, 96 low-cost sourcing 41, 70, 138 modular engineering 19, 21, 41, 47, 70, 96, 97, 133 ourmodel 137 Prefabricated process modules 19, 21, 47, 70 Project execution 135, 136, 137 ramp-up 40, 135 safety 19, 21, 49, 85, 133, 135, 136 technology selection 23, 33, 34, 35, 43 training 79, 123, 141 turnkey 21, 41, 51, 96, 139 Vendor assessment 30, 32, 65 Improve production capacity cleanroom testing 99 compliance gap analysis 78, 104, 134 continuous improvement 76, 122 debottlenecking 23 design of experiments (doE) 57, 62, 63, 65, 83, 124 leadership and people development 79, 123, 141 Process optimisation 28, 34, 50, 54, 57, 63, 71 revalidation 78, 82 revamp 21, 24, 40, 54, 56, 62, 98, 105, 134, 135 simulation 54, 71, 87, 90 six sigma 76, 117 sourcing 138, 139 specialist staff 9, 140 troubleshooting 35, 63 upgrade to multiproduct 21, 54, 135
148 KEyWord IndEX
Keyword index, alphabetised

A analytical methods 83 animal facilities 94, 95, 111, 112 architecture 19, 104, 105, 106, 107 astm 2500 76, 77, 79, 81 audits 28, 48, 75, 78 automation & It 24, 29, 30, 32, 51, 81, 115, 119, 134 B Biofuel 67, 68, 69, 70 Biosafety 29, 38, 40, 41, 42, 94 Biosecurity 38, 42, 94 Blood products 19, 25, 93 C cancer 17, 37, 38, 39, 41, 93, 94, 95 carbon footprint and green technologies 51, 69, 70, 86, 87 cardiovascular diseases 25, 44, 47 cell culture 20, 21, 22, 23 clean utilities 134 cleaning in place (cIP) 21, 29, 30, 35, 50, 51, 82, 87 cleaning validation 82, 83 cleanPlus 96, 97 cleanroom testing 99 cleanrooms 25, 28, 93, 94, 95, 96, 97, 98 clinical trials 125 commissioning 40, 133, 135 compliance gap analysis 78, 104, 134 conceptual design 23, 110, 130, 131 construction management 19, 40, 133, 135 containment 35, 56, 82, 94, 96 continuous improvement 76, 122 contract manufacturing organisations (cmo) 20, 22, 27, 28, 43, 78 counterfeit prevention 33, 54, 117 D debottlenecking 23 decontamination 50 design of experiments (doE) 57, 62, 63, 65, 83, 124 device assembly 62 downstream 23, 24, 71 drug delivery devices 61 E Egg-based processes 39, 42 Energy reduction 86, 87, 98, 112 Engineering, design 133, 135, 137 Environmental permitting 90 Enzymes 67, 69, 70 Eu GmP 28, 48, 78, 112 F facility cost reduction 22, 28, 41, 56, 70, 71, 95 facility of the year 19, 21, 27, 136 fast-track 19, 21, 39, 41, 47, 132, 133 fda GmP 28, 49, 76, 78, 80, 82, 83, 117 feasibility studies 22, 130 filling 31, 35 fish oil 47, 85 flu vaccines 39, 42 formulation 28, 29, 54, 57 freeze drying 30 G Genetically manipulated organisms (Gmo) 42, 90 Globalisation 64, 65, 70, 75, 137, 138 H haemophilia 12, 19, 25 high potency pharmaceuticals 32, 49, 52, 55, 70, 71 high-titer processes 20, 22, 23 hospitals 25, 91, 93, 94, 95, 103 I Infectious diseases 39, 41, 42, 61 Infusion (IV) solutions 29, 139 Injection moulding 63 Inspection 32 IQ, oQ, verification 77, 80 Isolator, raBs 28, 95 L laboratory automation 113, 118 launch facilities 20, 40, 42, 65 layout, people and material flow 22, 40, 41, 56, 96 leadership and people development 79, 123, 141 logistics 34, 54, 56, 101, 105 low-cost sourcing 41, 70, 138 M manufacturing science 65, 124 manufacturing supply chain 65, 103, 139 medical device GmP 63 mEs & production information 116, 118, 119 microbial fermentation 70, 71 modular engineering 19, 21, 41, 47, 70, 96, 97, 133 monoclonal antibodies 20, 21, 22, 23 multiproduct facilities 20, 21, 22, 27, 40, 51, 55, 70 O occupational Exposure level/Band (oEl/oEB) 55, 91 offshoring 48, 55, 64, 70 oral solid dosage (osd) 53, 54, 55, 56, 57 ourmodel 137 output, uptime, cost improvement 27, 31, 43, 57, 71, 87, 105, 113, 12 P Packaging 32, 56 Pat 57, 76, 112, 117, 124
KEyWord IndEX 149
Personalised medicine 25, 54, 93, 95 Pilot facilities 3, 51, 63, 96 Prefabricated process modules 19, 21, 47, 70 Process optimisation 28, 34, 50, 54, 57, 63, 71 Process validation 82, 83 Product development 54, 61, 62, 63, 65, 89, 93 Product launch forecasting, 20, 102 Project execution 135, 136, 137 Q Quality by design (Qbd) 76, 77, 83 Quality control (Qc) 83 R r&d and Qc laboratories 62, 63, 93, 95, 109, 111, 118 radiopharmaceuticals 56 ramp-up 40, 135 revalidation 78, 82 revamp 21, 24, 40, 54, 56, 62, 98, 105, 134, 135 risk assessment 63, 64, 65, 76, 79, 89, 9 S safety 19, 21, 49, 85, 133, 135, 136 simulation 54, 71, 87, 90 single-use 22, 23, 35, 39, 40 site selection and master planning 102, 130 six sigma 76, 117 smallpox 39 sourcing 138, 139 specialist staff 9, 140 standard operating Procedures (soP) 29, 43, 55, 64, 74, 78, 79, 104, 123, 125 start-up companies 25, 41, 43, 69 sterilisation in place (sIP) 21, 29, 30, 35, 50, 51, 82, 87 synthesis 49, 51 T tech transfer 20, 43, 48, 54, 55, 64, 65 technology selection 23, 33, 34, 35, 43 therapeutic vaccines 41 training 79, 123, 141 treatments 25, 93, 95 troubleshooting 35, 63 turnkey 21, 41, 51, 96, 139 U upgrade to multiproduct 21, 54, 135 V Vendor assessment 30, 32, 65 W Warehouse 56, 91, 105 Working environment 90, 91, 94, 99
What we do is published once a year Circulation 5000 Concept & design nnE Pharmaplan a/s Text nnE Pharmaplan a/s Photo digital studio, Getty Images, istockphoto and nnE Pharmaplan a/s Print Kls Grafisk hus a/s Head office nnE Pharmaplan Vandtrnsvej 108-110 2860 sborg denmark Phone: +45 4444 7777 fax: +45 4444 3777 Website nnepharmaplan.com reproduction is permitted only with reference to the source

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What we do

OFFERING CATALOGUE 2010-2011

Hans Ole Voigt, CEO

Engineering for a healthier world

Copenhagen Kalundborg Hillerd Hjrring

Cork Boston San Francisco

Chartres Lyon Basel Vevey

Philadelphia Research Triangle Park

Ofces Project references

Uppsala Stockholm Turku

Moscow Frankfurt Marburg Ulm

develop, establish, improve

NNE Pharmaplan at a glance

Offerings for all pharma/biotech segments

Active pharmaceutical ingredients

Medical devices and drug delivery systems

Sterile & aseptic

Oral solid dosage

develop an optimal approach to achieve the required production capabilities

A wealth of specific services to implement our offerings Develop

Solutions Automation and IT solutions Cleanrooms Turnkey facilities Process modules

Studies Feasibility analyses Conceptual designs Master plans

Ramp-up Production ramp-up Training Process validation, cleaning validation

Support services Sourcing Cleanroom testing Troubleshooting Revalidation Specialist staff

Our service philosophy

Part I Segments and offerings

GETTiNG A hiGh ThrouGhPuT DEvEloPmENT FACiliTY AT low CoST

BuilDiNG vErSuS BuYiNG

DElivEriNG hiGh STAkES rEvAmP

FlExiBlE, FAST, moDulAr

% Cost reduction relative to traditional

GET STrATEGiC wiTh SiNGlE-uSE TEChNoloGiES

Project-specific trend curve 40 35 30 25 20 15 10 5 0 0 20 40 60 80 100 % Single-use process modules

NExT GENErATioN BioTECh FACiliTiES

deciding whether to build a new facility or upgrade an existing one

SiNGlE-uSE TEChNoloGY CATAloGuE

YiElD iNCrEASES CrEATE NEw BoTTlENECkS

200 PErCENT iNCrEASE ThrouGh BioProCESS oPTimiSATioN

Capacity and production need

Capacity and production need

AuTomATED APProvAl oF ChromAToGrAPhY ruNS

ChAllENGES iN ADvANCED ThErAPY FACiliTiES

26 Sterile & aSeptic

Sterile & aseptic

Sterile & aSeptic 27

28 Sterile & aSeptic

FINdING tHE rIGHt CONtrACt MANUFACtUrErS

HIGH-tECH ASEPtIC FACIlIty HElPS MEEt rEGUlAtIONS ANd SAvE COStS

EU GMP PUSHES tHE USE OF tECHNOlOGy

Sterile & aSeptic 29

INFUSION SOlUtIONS WOrldWIdE

We offer our customers extensive knowhow in infusion manufacturing technology, including:

OPtIMISEd FOrMUlAtION dElIvErS CAPACIty INCrEASE

30 Sterile & aSeptic

WASH ANd StErIlISAtION AN INtEGrAl PArt OF ASEPtIC OPErAtIONS

COMPlExIty IN FrEEzE dryING

FUll-SCAlE dElIvEry OF FrEEzE dryING ISOlAtOr lINE

Sterile & aSeptic 31

CAMPAIGN FIllING A MOrE EFFICIENt WAy

32 Sterile & aSeptic

Sterile & aSeptic 33

FIGHtING COUNtErFEIt drUGS

34 Sterile & aSeptic