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

GMP News No. 487

26 October 2004

Analysis of the ChangesConcerning Process Simulationin FDA's New Aseptic Processing Guide

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

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specifying requirements on aseptic processing in a seriesof documents for commenting in the past years (1998 -Document not for implementation; 2002 - concept paper; 2003 - draftguidance), the FDA published the final version of the guidance on 29September 2004. 

The new guidance will certainly represent the most important regulatoryinterpretation of the requirements on aseptic processing in the comingyears.

On the basis of the GMPNews of 8 September 2003 dealing with the preliminary concept paperand the draft document, this article is dedicated to the most importantchanges of the final version compared to the draft version from theexample of the requirements on media fill.

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

However, comprehensive changes have been made to the wording. It isobvious 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 fromthe example of "Chapter IX. Validation of Aseptic Processing andSterilization, Part A. Process Simulation".

  • Study Design

The rationales for simulated conditions and activities should bedefined. Media fills should not be used to justify practices that involvean unnecessary contamination risk.

  • Frequency and Number of Runs

Among the specified changes that should be covered by media fills, thetext now also lists extended shutdown.

  • Duration of Runs

The statement "should adequately mimic worst-case operatingconditions" has been replaced by "the duration of the media fillrun should be determined by the time it takes to incorporate manipulationsand interventions".

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

  • Line Speed

The text does not refer to "single worst-case line speed" anymore, but just to "single line speed".

  • Environmental Conditions

The text now says that "stressful conditions" do not includeartificially created environmental extremes, e.g.reconfiguration of HVAC systems.

  • Media

USP indicator microorganisms are just one example for microbes to beused for growth promotion tests. It is the task of the laboratory to determinewhether these microorganisms mimic the environment adequately. Isolatesfrom environmental monitoring or from sterility testing can be used forthe growth promotion test.

  • Incubation and Examination of Media-Filled Units

Staff members who examine the media-filled units for contamination arenot required to have experience in microbiological techniques, but ininspecting the media-filled units. If the QC personnel does not inspectthe units themselves, there should at least be QC unit oversight. Anysuspect unit should be brought to the immediate attention of the QCmicrobiologist.

  • Interpretation of Test Results

The process simulation run should be observed by the QC unit. If lessthan 5,000 units are examined, no contaminated unit at all may bedetected. The text now includes the sentence "one contaminated unit is considered cause for revalidation,following an investigation". 

Dr Andreas Mangel

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