AAPS 2003

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December 8 - 10, 2003 Crystal City, Virginia
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Post-Approval Changes of Aseptic Operations
FDA/EU Guidance

• Bryan S. Riley, Ph.D.
• FDA/CDER/OPS

Future Direction in Aseptic Processing Crystal
City, Virginia
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EU Guidance

• Guideline on the Categorisation of Extension
  Applications (EA) versus Variations Applications
  (V), Oct 2003
• Guideline on the Dossier Requirements for Type IA
  and Type B Notifications, July 2003
• pharmacos.eudra.org/F2/eudralex/vol-2/home.htm

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EU Guidance

• EMEA Post-Authorization Guidance
• Human Medicinal Product
• www.emea.eu.int/htms/human/ postguidance/index.ht
  m
• Variation Regulations (EC)
• No 1084/2003
• No 1085/2003
• pharmacos.eudra.org/F2/pharmacos/
• docs.htmnews

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FDA Guidance

• Changes to an Approved NDA or ANDA (1999)
• Submission of Documentation for Sterilization
  Process Validation in Applications for Human and
  Veterinary Drug Products (1994)
• www.fda.gov/cder/guidance/index.htm

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Sterility Assurance

• Cannot Be Determined by End-Product Testing
  (sterility test)
• Process Validation is Vital

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FDAMA 1997

• Sec.116 Manufacturing Changes for Drugs
• Major (Substantial), Moderate, Minor (Minimal)
• potential to adversely affect the identity,
  strength, quality, purity, or potency of the drug
  as they may relate to the safety or effectiveness
  of the drug.

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Risk-Based

• Assessment of the effect of a change to an
  aseptic process
• Major
• Moderate
• Minor

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Reporting Categories

• Prior Approval - Major
• CBE-0/30 - Moderate
• Annual Report - Minor

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Post-Approval Changes

• Must Validate
• SEC. 506A (b) a drug made with a manufacturing
  change (whether a major manufacturing change or
  otherwise) may be distributed only if, before
  distribution of the drug as so made, the holder
  involved validates the effects of the change on
  the identity, strength, ...

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Guidance I

• Changes to An Approved NDA or ANDA

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Categories of Changes

• Components and Composition
• Manufacturing Sites
• Manufacturing Process
• Specifications
• Package
• Labeling
• Miscellaneous Changes
• Multiple Related Changes

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Changes

• Listed by Category
• Major/Moderate/Minor Changes
• Reporting Categories
• Numerous Examples of Sterile Products
• Data Requirements ????
• Assessment of the Effects of the Change
• Conformance to Specifications
• Additional Testing

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Examples

• Changes to Aseptic Processes
• Major
• New or Refurbished Site
• Addition, deletion, or substitution of steps in
  an aseptic processing operation

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Examples

• Changes to Aseptic Processes
• Moderate
• Changes to Filtration Parameters (including flow
  rate, pressure, time or volume)
• Minor
• A change in contract sterilization site for
  packaging components when the process is not
  materially different ..

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Guidance II

• Submission of Documentation for Sterilization
  Process Validation in Applications for Human and
  Veterinary Drug Products (1994)

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Sterilization Process Validation

• Documenting Sterilization Process Validation
• The efficacy of a given sterilization process
  for a specific drug product is evaluated on the
  basis of a series of protocols and scientific
  experiments designed to demonstrate that the
  sterilization process and associated control
  procedures can reproducibly deliver a sterile
  product.

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Table of Contents

• I. Introduction
• II. Information for Terminal Moist Heat
  Sterilization Processes
• III. Other Terminal Sterilization Processes
• IV. Information for Aseptic Fill Manufacturing
  Processes Which Should be Included in Drug
  Applications
• V. Maintenance of Microbiological Control and
  Quality Stability Considerations
• VI. Additional Information

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Aseptic Processing

• IV. Information for Aseptic Fill
  Manufacturing Processes Which Should be
  Included in Drug Applications

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Aseptic Fill Information

• Building and Facilities
• Overall Manufacturing Operation
• Sterilization and Depyrogenation of Containers,
  Closures and Components
• Procedures and Specifications for Media Fills
• Actions Concerning Product When Media Fills Fail

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Aseptic Fill Information

• Microbiological Monitoring of the Environment
• Container Closure and Package Integrity
• Sterility Testing Methods
• Bacterial Endotoxins Test and Method

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Aseptic Fill

• D. Procedures and Specifications for Media Fills
• The procedures and specifications used for media
  fills, and summaries of the results for
  validation using the same container-closure
  system and filling process that is to be used for
  the product should be described. The
  microbiological testing method(s) used should be
  described. Any procedural differences between the
  media fill and the production process should be
  indicated. A summary of recent media fill
  results, including failures, should be provided.
  .

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Aseptic Fill

• Filling Room
• Container Closure Type and Size
• Volume and Type of Medium
• Number of Units Filled, Incubated, Positive
• Incubation Parameters
• Date
• Simulations
• Environmental Monitoring
• Process Parameters (Production vs. Media Fills)

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Changes to an Aseptic Process

• Post-Approval Changes
• Subset of Data
• Examples
• New Manufacturing Facility
• New Stopper Autoclave

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Summary

• Guidance Available for Reporting Categories
• Guidance Available for Data Requirements
• Some Judgement Still Required
• Contact FDA

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Thank You

• Bryan S. Riley, Ph.D.