Aseptic Processing

Presentation and Panel Discussion

WCC PDA Dinner Meeting November 30th, 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

Facility Documentation Equipment

Aseptic Finish Product Processing

Testing

Process

Control & Verification

Personnel

Aseptic Processing: Essential Elements

Facility

Design
Zoning, Differential Pressure Temperature Relative Humidity Personnel and Material Flow

Air Filtration Material of Construction Sanitization Component Preparation/Sterilization

Equipment

Aseptic Processing: Essential Elements

Process

Product Formulation Filtration Filling Lyophilization Capping

Gowning Qualification Aseptic Technique Environmental and Personnel Monitoring Aseptic Filling Simulations (Media Fills)

Personnel

Control and Verification

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

Documentation

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?
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? How to qualify a sterility tester? Re-qualification of testers? How often?

Sample/Sampling Plan

Qualification of Personnel

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. 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.

FDA Guidance for Industry

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
Guidance Documents FDA Guidance for Industry Code of Federal Regulations Multiple Pharmacopeia

Media Fill
FDA Guidance for Industry EU Guide to Good Manufacturing Practice Revision to Annex 1

Sample size/Lot
Media

Maximum 40
Soybean-Casein Digest Medium (TSB) Fluid Thioglycollate Medium (FTM) TSB 14 days @ 20-25C FTM 14 days @ 30-35C
Yes

All
Soybean-Casein Digest Medium (TSB)

Incubation conditions Growth promotion Test method Sensitivity

TSB 7 days @ 20-25C TSB 7 days @ 30-35C Yes Non-destructive: Integral container No false positives Detects single vial failure

Destructive: Sample contents transferred False positives Detects high level sterility failure