Outsourcing Resources

Successfully Outsourcing Formulation Development

Considerations for Emerging Biopharmaceutical Companies
Shabbir T. Anik* and Colin M. Minchom

O
Shabbir T. Anik, PhD, is vice-president of scientific affairs and global PDS operations, Patheon, Inc., 2100 Syntex Court, Mississauga, ON, Canada L5N 7K9, tel. 650.962.8406, sanik@patheon.com. Colin M. Minchom, PhD, is group director of PDS operations, Toronto region operations at Patheon, Inc.
*To whom all correspondence should be addressed.

ne of the first hurdles biopharmaceutical companies face when developing a new drug product is testing the hypothesis that the molecule will ameliorate the disease state for which it is being targeted. After being tested for safety in humans, the molecule must undergo a proofof-concept study that may provide positive signs that the substance will perform as expected. The decision whether to commit significant resources to full clinical development will be made on the basis of the outcome of this first efficacy study. Because many molecules (greater than 80%) fail during the early stages of clinical testing, it is imperative that biotechnology companies commence human testing as quickly and as inexpensively as possible. The reason to fail fast is to enable a companys resources to be targeted at a backup or alternative molecule(s) that will improve the probability of a successful outcome.
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PATHEON

The timely selection of a formulation to establish clinical proof-of-concept is a critical element in the development programs of biotechnology companies. Because most emerging companies outsource their formulation development activities, they must carefully evaluate the contract organization that will conduct the work. This article will discuss attributes to look for in a CPOs formulation development department and will explore how the use of a fully integrated supplier may accelerate the drug development process.

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Biopharmaceutical companies usually face significant time pressures to initiate clinical trials. Under these circumstances, the selection of the right formulation for a proof-of-concept study is critical for several reasons. First, formulations influence the performance of a molecule in vivo and can affect the outcome of clinical trials. In addition, formulations that are difficult to manufacture can delay the start and/or continuation of clinical trials. Finally, unstable formulations can disrupt clinical trials once they are in progress. Most emerging companies outsource their formulation development activities. Therefore, it is essential that a contract product development organization (CPO) performing these activities has the expertise and ability to develop fast-into-human formulations to allow the client to undertake proof-of-concept studies. Furthermore, once proof-of-concept has been established, a CPO must be able to rapidly advance the drug development program through to Phase II and III studies. To do so, the experience of a CPOs scientific staff is of critical importance, as is the suitability of a CPOs facilities. edge of a broad range of dosage forms. Their experience should allow them to understand the formulation requirements at various stages of development. Experience in commercialization of formulations is critical. q The CPOs scientific staff should be prepared to provide its client with a formulation development strategy that includes pros and cons in support of proof-of-concept and the ultimate development program. q In addition to these technical abilities, the CPOs scientific team must have a client-service orientation, meaning that it should be focused on meeting the needs of its clients. The CPO must recognize its limitations and be willing to decline the project if it does not have the required experience.

Built for speed and safety

Similarly, the following important criteria must be considered when evaluating a CPOs facilities: q Formulation development facilities should be engineered for the safe handling and disposal of new chemical entities (NCEs) whose safety profile is not fully defined. A CPO should have a history of handling high potency or unknownhazard molecules. The facilities should be constructed with appropriate air-handling and material-handling systems for such compounds. To ensure safety, separate areas for handling both high- and low-potency compounds should be available. Such facilities allow formulation development to

The CPO organization

When evaluating a CPOs scientific team, a number of important organizational attributes should be considered, including the following: q Members of the CPOs scientific team should have 1015 years of experience in formulation development and possess knowl-

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begin early in the drug development process when safety data for the NCEs are not yet available. q Small-scale equipment ranging from benchtop (gram scale) to 15 kg is essential. Quantities of drug substance are usually in short supply during preclinical and Phase I dosage form development. Small-scale equipment allows a CPO to make the best use of limited resources and provides the flexibility to investigate more formulations early on. q The equipment should be scalable to that used in the pilot plant and in commercial operations. Once proof-of-concept is established, it is imperative that the early development work

is scalable to enable the manufacture of supplies for larger clinical studies. Development work performed at gram scale does not provide the wherewithal to supply clinical studies. Rather, it provides the information necessary to develop a scalable formulation as long as the end use of the development work is considered during the development process. When little or no thought is given to transfer or scale up, or when the equipment to be used for clinical supply is not known, the timeline for supply of clinical materials is lengthened. However, when scalable equipment is available, seamless transfer from development to clinical supply is achieved. q One way to quickly develop fast-into-human formulations is through the use of non-GMP areas for investigative development. Non-GMP development can be more rapid and flexible. Information from such work is fully acceptable as supportive data for a regulatory submission. It must be stressed that although GMP rules are not strictly followed in a non-GMP facility, the principles of good laboratory and documentation practices must be applied to such development work or there is risk of failure during transfer to clinical trial manufacture.

PATHEON

Working with an integrated supplier

Although a tactical approach to outsourcing has served some biopharmaceutical companies in the past, the hard and soft costs associated with the transfer of the project among third-

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party providers often proves this approach to be more costly. In addition, the total project time is lengthened as each party is brought to speed. Fortunately, integrated contract service providers have come of age. Several outsourcing organizations now exist that provide many if not all the services required to take an NCE through to commercialization. They also possess the necessary critical mass and a strong financial position. Decades of downsizing by big pharma has resulted in many excellent scientists now being employed in the outsourcing sector, and many service providers operate world-class facilities formerly operated by big pharma. An integrated supplier can provide a seamless transfer through the drug product development process to commercialization. The reduction in technical transfers means a shortened development time. For example, in moving from formulation development to scale-up, three months can be added to a development program if a company changes service providers at that juncture. The transfer of analytical methods from a third party alone can add four to eight weeks time to a program. These transfers also translate to increased costs, particularly if feasibility or process development work must be repeated because of equipment changes. With an integrated supplier, the probability of success in ensuring the scalability of the manufacturing process is significantly improved. This provides for improved manufacturability and therefore fewer quality problems in the long run. The likelihood of successfully completing a preapproval inspection also increases. Regulatory authorities like to see a rationale for the formulation and a development report that includes process development and scale-up with all the associated analytical results. Having all this information available at one site with the same personnel to explain the entire development program is a significant advantage. In the end, fewer players results in cleaner paperwork and a simpler audit trail for the inspector to follow.

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From proof-of-concept through to commercialization

To meet their development objectives, biopharmaceutical companies must partner with CPOs that have the appropriate resources to allow them to rapidly and inexpensively generate and select the right formulation for proof-of-concept. Once this milestone has been achieved successfully, the emphasis shifts to developing an efficacious, scalable formulation to provide additional clinical supplies and, ultimately, a commercial product. The degree to which biopharmaceutical companies will be successful in outsourcing their formulation development programs will depend on their ability to identify those service providers who are positioned to provide a rapid evaluation of NCEs and then can accelerate the process through to commercialization. PT

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