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					December 8 - 10, 2003
Crystal City, Virginia
 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
            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.htm
   Variation Regulations (EC)
    No 1084/2003
    No 1085/2003
      pharmacos.eudra.org/F2/pharmacos/
      docs.htm#news
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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
      Approval - Major
 Prior
 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
     Subsetof 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.



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