“Aseptic Processing”

Presentation and Panel
WCC PDA Dinner Meeting
November 30
, 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
Finish Product
Control &
Aseptic Processing: Essential Elements
 Design
Zoning, Differential Pressure
Relative Humidity
Personnel and Material Flow
 Air Filtration
 Material of Construction
 Sanitization
 Component Preparation/Sterilization
Aseptic Processing: Essential Elements
 Product Formulation
 Filtration
 Filling
 Lyophilization
 Capping
 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
 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

Simple, or not so simple?
 “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 isn’t 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
 “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
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
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
Soybean-Casein Digest
Medium (TSB)
TSB 14 days @ 20-25ºC
FTM 14 days @ 30-35ºC
TSB 7 days @ 20-25ºC
TSB 7 days @ 30-35ºC
Test method Destructive:
Sample contents transferred
Integral container
Sensitivity False positives
Detects high level sterility
No false positives
Detects single vial failure

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