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Document not for implementation; 2002 - concept paper; 2003 - draft
guidance), the FDA published the final version of the guidance on 29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conditions" has been replaced by "the duration of the media fill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".
