Analysis of the Changes Concerning Process Simulation in FDA's New Aseptic Processing Guide

GMP News No. 487

GMP News
26 October 2004

Analysis of the Changes Concerning Process Simulation in FDA's New Aseptic Processing Guide

Without any doubt, aseptic production is one of the most critical processes in the pharmaceutical environment. For many years, FDA's "Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing" was the leading regulatory document; however, many parts of it were not up to date any more.

After publishing its concept for specifying requirements on aseptic processing in a series of documents for commenting in the past years (1998 - Document not for implementation; 2002 - concept paper; 2003 - draft guidance), the FDA published the final version of the guidance on 29 September 2004. 

The new guidance will certainly represent the most important regulatory interpretation of the requirements on aseptic processing in the coming years.

On the basis of the GMP News of 8 September 2003 dealing with the preliminary concept paper and the draft document, this article is dedicated to the most important changes of the final version compared to the draft version from the example of the requirements on media fill.

In general, one can say that no structural changes have been made compared to the draft. Apart from two exceptions, the final version's table of contents is identical with that of the draft (X. Laboratory Controls, A. Environmental Monitoring Item 3. Disinfection Efficacy instead of Sanitization Efficacy / XI. Sterility Testing – items A: Choice of Methods; B: Media; C: Personnel were summarised as A: Microbiological Laboratory Controls).

However, comprehensive changes have been made to the wording. It is obvious that the numerous industry comments have been taken into account. Another striking fact is that many of the statements begin with "We (the FDA) recommend to ..." instead of the strict wording of the draft.

In the following we will show you a selection of important changes from the example of "Chapter IX. Validation of Aseptic Processing and Sterilization, Part A. Process Simulation".

  • Study Design
  • The rationales for simulated conditions and activities should be defined. Media fills should not be used to justify practices that involve an unnecessary contamination risk.

  • Frequency and Number of Runs
  • Among the specified changes that should be covered by media fills, the text now also lists extended shutdown.

  • Duration of Runs
  • The statement "should adequately mimic worst-case operating conditions" has been replaced by "the duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions".

    Regarding lyophilisation, it should be ensured that the medium remains in an aerobic state in order to avoid potential growth inhibition.

  • Line Speed
  • The text does not refer to "single worst-case line speed" any more, but just to "single line speed".

  • Environmental Conditions
  • The text now says that "stressful conditions" do not include artificially created environmental extremes, e.g. reconfiguration of HVAC systems.

  • Media
  • USP indicator microorganisms are just one example for microbes to be used for growth promotion tests. It is the task of the laboratory to determine whether these microorganisms mimic the environment adequately. Isolates from environmental monitoring or from sterility testing can be used for the growth promotion test.

  • Incubation and Examination of Media-Filled Units
  • Staff members who examine the media-filled units for contamination are not required to have experience in microbiological techniques, but in inspecting the media-filled units. If the QC personnel does not inspect the units themselves, there should at least be QC unit oversight. Any suspect unit should be brought to the immediate attention of the QC microbiologist.

  • Interpretation of Test Results
  • The process simulation run should be observed by the QC unit. If less than 5,000 units are examined, no contaminated unit at all may be detected. The text now includes the sentence "one contaminated unit is considered cause for revalidation, following an investigation". 

    The latest requirements on media fills resulting from the FDA guidance will be presented at the FDA event Process Simulation / Media Fills in Barcelona Spain, 16-17 November 2004

    Further current interpretations of the new Aseptic Guidance will be dealt with at the European Aseptic Conference 2004, Barcelona, Spain, 18-19 November 2004, and at the GMP Education Course Current GMP Requirements on the Use of Bioindicators, Vienna, Austria, 16-17 February.

    Dr Andreas Mangel

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