Aseptic Processing

Presentation and Panel

Discussion
WCC PDA Dinner Meeting
November 30
th
, 2006

Jennifer Cheung
Genentech, Inc.
What is Aseptic Processing?
The production of sterile drug products by
bringing together the product, container,
and closure that have been subjected to
different sterilization methods separately,
and assembled them in an extremely high
quality environment by skilled personnel
using the right tools.
Aseptic Processing: Essential Elements
Documentation
Finish Product
Testing
Control &
Verification
Personnel
Process
Equipment
Facility
Aseptic
Processing
Aseptic Processing: Essential Elements
Facility
Design
Zoning, Differential Pressure
Temperature
Relative Humidity
Personnel and Material Flow
Air Filtration
Equipment
Material of Construction
Sanitization
Component Preparation/Sterilization
Aseptic Processing: Essential Elements
Process
Product Formulation
Filtration
Filling
Lyophilization
Capping
Personnel
Gowning Qualification
Aseptic Technique
Control and Verification
Environmental and Personnel Monitoring
Aseptic Filling Simulations (Media Fills)

Aseptic Processing: Essential Elements
Finished Product Testing
Sterility Testing
Particulate Testing
Container Closure Integrity Testing
Other Final Product/Release Testing
Stability Testing
Documentation
Media Fill Records
Production Batch Records
EM Trend Data
Release Testing Batch Records
Investigation
Response to Excursions
Corrective Actions
Sterility Testing
Monitoring of aseptic processing
Compendial requirement
US Pharmacopoeia
European Pharmacopoeia
British Pharmacopoeia
Japanese Pharmacopoeia
Code of Federal Regulations
Test methods became harmonized with the
publication of the BP 2004, Ph Eur 5.1 and USP
28 editions
Sterility Testing Method Overview
Limited number of samples: 4 to 20 containers
per medium for parenteral preparations
Limited volume for analysis: Not less than 1mL
for 1-40mL containers; not less than 20mL for
>40mL containers
2 Media: Soybean-Casein Digest Medium and
Fluid Thioglycollate Medium
2 Temperatures: 22.5 + 2.5 C and 32.5 + 2.5 C
14 days of incubation
Inspect for evidence of microbial growth
(turbidity)

Simple, or not so simple?
Incubation
Incubate for 14 days
14 days? Or 14 x 24 hours?
Why is the maximum incubation for bacteria 3 days in growth promotion
test and 5 days in validation of sterility test? After all, why isnt the
maximum incubation be 14 days?
Method Validation
Should validation of sterility test be repeated at each testing location for
the same product, when testing methodology is the same?
Is revalidation of sterility testing methodology necessary? If so, at
frequency? Every 12 months?
Can bulk material be used as a substitute for final vials in the validation
of sterility test?
How many firms use environmental/process isolates in the validation of
sterility test?


Simple, or not so simple?
Method Monitoring
How many firms perform stasis test (i.e. monitoring the efficacy
of test media at the end of the incubation period)? How often
should stasis test be performed on each product?
Sample/Sampling Plan
Is bulk sterility testing, as required by CFR for biologics, an
absolute requirement for biotech products?
Sampling plan for final product: Beginning, middle, end; or
randomly throughout the entire batch? How to obtain 20
representative samples for a >10000 vials fill?
Qualification of Personnel
How to qualify a sterility tester?
Re-qualification of testers? How often?
Interpretation of Result is Simple
USP
These Pharmacopeial procedures are not by themselves designed to
ensure that a batch of product is sterile or has been sterilized. This is
accomplished primarily by validation of the sterilization process or of the
aseptic processing procedures. When evidence of microbial
contamination of the article is obtained by the appropriate
Pharmacopeial methods, the result so obtained is conclusive evidence
of failure of the article to meet the requirements of the test for sterility,
even if a different result is obtained by an alternative procedure.
FDA Guidance for Industry
A sterility positive result can be viewed as indicative of production or
laboratory problems, and the entire manufacturing process should be
comprehensively investigated since such problems often can extend
beyond a single batch.
To invalidate a positive sterility test is extremely difficult, if not
impossible.
Quality should be built into the product, and testing alone cannot be
relied on to ensure product quality.

Media Fills
Validation of aseptic processing
True parameter for assuring that a
manufacturing process is capable of
producing sterile pharmaceuticals using an
aseptic process.
Media fill program provides evaluation of
multiple systems.

Sterility Test Versus Media Fill
Sterility Test Media Fill
Guidance
Documents
FDA Guidance for Industry
Code of Federal Regulations
Multiple Pharmacopeia
FDA Guidance for Industry
EU Guide to Good
Manufacturing Practice
Revision to Annex 1
Sample size/Lot Maximum 40 All
Media Soybean-Casein Digest
Medium (TSB)
Fluid Thioglycollate Medium
(FTM)
Soybean-Casein Digest
Medium (TSB)
Incubation
conditions
TSB 14 days @ 20-25C
FTM 14 days @ 30-35C
TSB 7 days @ 20-25C
TSB 7 days @ 30-35C
Growth
promotion
Yes
Yes
Test method Destructive:
Sample contents transferred
Non-destructive:
Integral container
Sensitivity False positives
Detects high level sterility
failure
No false positives
Detects single vial failure