On June 7, 2001 the EC announced the
modification of paragraph 42 of Annex 1 ("Supplementary and revised
guidelines for the manufacture of sterile medicinal products").
What does paragraph 42 of
Annex 1 deal with?
It is the paragraph that
defines standards for media fills in aseptic methods.
And what is new about it?
The revised version now
requires the inclusion of various interventions performed routinely in
production of media fills. In addition, worst case situations are also to
be covered within the media fills.
Also new is the definitive
requirement for the initial validation by means of three consecutive runs
per shift as well as the revalidation after significant changes:
The other original
instructions with respect to a revalidation (changes to the equipment
and/or the process) remain unchanged.
The intervals for a
periodic revalidation are now given as: every six months.
contamination" is given as the target of the media fills, in
addition every contamination should be investigated. The acceptance
criterion for the contamination rate of less than 0.1% with a 95%
confidence interval is, however, still valid, despite the "zero
The requirement for the
establishment of alert limits and action limits is also new. These two
terms have been included along with "media fill" in the glossary
of the EC-GMP Guide.
The alert limit is that
limit which informs one at an early stage if the normal conditions have
been deviated from. This deviation then leads to an investigation without
definitive corrective actions necessarily having to be taken.
According to the glossary,
when the action limit is exceeded an immediate search for the error should
be initiated, followed by the initiation of corrective action.
At FDA, too, the topic of
media fill is becoming more and more the focus of inspections. Among other
things, lack of training in aseptic production is meanwhile already the
fifth most frequent topic of warning letters (internal evaluation of the
fiscal year 2000 by Concept Heidelberg, see GMP-News of July 18, 2001).
Where can one now get help
with the topic of media fill?
ISO 13408-1 gives very
detailed criteria for the aseptic production of medicinal products. This
standard contains, inter alia, the information included in the
modifications of paragraph 42. For instance, in this standard you also
find concrete information about interventions which should be simulated
during media fills as well as information about the contents of media fill
records. It also describes alert and action limits on the basis of the
0.1% contamination rate as well as instructions for dealing with failed
ISO 13408-1 is, of course,
also known at FDA.
However, this standard is
already undergoing revision again.
Please click here
if you want to download the new Annex 1.