Professional Documents
Culture Documents
Pharmaceutical Manufacturing
Equipment From a Laboratory
Perspective
Adam W. Grobin
Southern California
Pharmaceutical Discussion Group
Sept. 19, 2013
Disclaimer
Any views or opinions expressed or presented are
solely those of the author and do not necessarily
represent those of any employer past or present.
The
Manufacturing
Floor
Macro Scale
Team Activity
Highly Proceduralized
Specific Roles / Compartmentalization
The Laboratory
1. clean
a : free from dirt or pollution <changed
to clean clothes><clean solar energy>
b : free from contamination or disease <a clean wound>
c : free or RELATIVELY FREE from
radioactivity <a clean atomic explosion>
2. clean
a : UNADULTERATED, PURE <the clean thrill of one's first flight>
b of a precious stone : having no interior flaws visible
c : free from growth that hinders tillage <clean farmland>
utensils, and any other contact surfaces used to manufacture, package, label, or hold
components or dietary supplements
http://articles.philly.com/1989-03-23/business/26126982_1_rohm-haas-bristol-myers-warner-lambert
A recent example
Europe wide recall of HIV drug due to cleaning
related contamination. Reports indicate a MSA
storage tank cleaned with ethanol was not free of
ethanol prior to charging with MSA.
API produced soon after had elevated levels of a
potential GTI (10 x > TTC). Batches made months
later exhibited values as high as 2,300ppm (EMs
TTC = 0.6ppm)
http://www.roche.com/media/media_releases/med-cor-2007-06-06b.htm
Practical Definitions
Cleaning: Removal of residues and contaminants to a
controlled level. The residues and contaminants can be
by cross-contamination from previously
manufactured products in the equipment or from the
cleaning procedure (detergents / sanitizers) or
degradation products resulting from the cleaning
process itself, as well as microorganism*.
Cleaning verification: A quality control process for
determining the effectiveness of a cleaning process
for a specific cleaning event.
Cleaning validation: A methodology used to assure
the effectiveness and consistency of a cleaning
process to remove residues and contaminants
The Approach
For the purpose of calculation, equipment
contamination is assumed to be evenly
distributed throughout the equipment surface
and any contamination quantified will be
considered completely dispersed in the
subsequent product.
Practical Considerations
Assuming a Safety Factor of 0.1% (1/1,000)
No more than 0.1% of the minimum therapeutic
dose of Drug A will be found in the largest daily
dose of Drug B
This is a good start, but how is the limit
calculated?
Method LOQ/LOD
Limit Test vs. Quantitative Assay
50% to 150% ?
80%, 100%, 120% ?
Setting Limits
Product Specific
Bracketing / Cleaning Matrix
Product families: Similar solubility, cleaning
procedure, safety profile. Selecting worst case
Special Consideration:
Allergenic and highly potent materials
e.g. penicillins and cephalosporins
e.g. anovulent steroids, potent steroids and
cytotoxic compounds
Microbiology
Limits for Aseptic Manufacturing equipment can
be justified using a similar carry over argument,
with recognition that the components of the next
product also contribute to the total bioburden
Bioburden NMT 25 cfu per 25 cm2 This level is
readily dealt with by typical SIP processes.
Endotoxin less than 0.25 EU/mL
(surface EU x contact surface area = transferred EU)
Useful Assumptions
Minimum batch size set to minimum capacity
of compounding / mixer for agitation to operate.
Maximum Dose of Next Product 4g/day
(based on some antibiotics). Phase 1 does
escalation protocol
Equipment surface area a few pieces will
provide the majority of the area
Safety Factor: 1/1000 by Phase 3, 1/10000 NCEs
Organizational Interdependencies
The process of developing a suitably sensitive
analytical method, validating, and establishing a
surface recovery factor is time consuming.
Without the required inputs such as equipment
surface area, area to sample swab / rinse, largest
daily dose of next product, smallest batch size of
next product etc., a residue limit isnt established.
A fit for purpose method is not developed without
a target limit / LOQ, LOD in mind.
Multifunctional Endeavor
Toxicology NOAEL, LD50
Clinical / Med Affairs - Posology
Engineering Equipment surface area & material of
construction
Manufacturing Scheduled based on business needs,
execute cleaning, perhaps swabbing
Chemistry Swab preparation, residue analysis, timely
results
Microbiology Sampling, bioburden, endotoxin, advise
on cleaning procedures and equipment storage
Validation Project coordination, protocols
Quality Assurance Quality system oversight
Cleaning Agents
Sampling Methods
Direct Surface Sampling
Swabbing
Viewed as more reliable
Insoluble or dried residues
may be removed by physical
action
When accessible, hardest to
clean areas can be sampled,
indicating a likely maximum
level of the residue
Swab selection
Technique dependent
Rinsing
Non-Specific Methods
Methodology
Considerations
Conductivity
Total organic carbon (TOC)
Visual
pH
Short / no development
Typically faster
My be sensitive to other
considerations (excipients,
cleaning agents)
Greater likelihood of false
positives
May require a specific method
to investigate OOS
Specific Methods
Methodology
Considerations
Time Limits
End of manufacture to start of cleaning ? calendar
days
Start of cleaning to completion of cleaning
Verification sampling
Completion of sampling to initiation of analysis
Unextracted vs extracts & storage (stability/recovery)
The Challenges
Communication, communication, and
communication
Lack of appreciation for necessary prerequisite
information
Useful Tools
Cleaning Validation Master Plan
RACI Chart (Responsible, Accountable, Consulted, Informed)
Overview of the process for involved parties
Clear / executable SOPs
Acknowledgments
My many colleagues in Pharma manufacturing
and R&D
The work of the PDA Technical Committees and
National Regulatory Authorities
Discussion