Since the first publication of Annex 1 (Manufacture of sterile medicinal
products) together with the GMP Guide it has already been revised three times -
in 1996, 2001 and in 2003. The 2003 version is still valid, although there have
been several update proposals. The
GMP news from 1 December 2005 described these
drafts in detail.
Now the contents of this draft have almost completely been included in the final
version. On 15 February, the EU Commission published the modified version. The
requirements laid down in this document have to be implemented by the industry
by 1 March 2009. For the capping of lyophilised vials, the transition period has
been extended to 1 March 2010.
The following changes to the current version have been made:
- The classification of clean rooms and associated
- Recommendations with regard to media fills
- Recommendations with regard to bioburden monitoring
- Recommendations with regard to capping for freeze-dried
For your information, we have created a comparison between the current version
of the document and the newly published one. You will find it at the end of this
The classification of clean rooms now shows a strong reference to the ISO 14644
- in this respect the particle concentration has changed in comparison with the
2003 version. Now the permitted limit for 5,0 µm particles in class A (in
operation & at rest) has been raised to 20. Also new are the specifications with
regard to portable particle counters and the strong emphasis on monitoring, also
referring to an integration of "risk management".
Completely new are the acceptance criteria for media fills, which are now
aligned with the FDA Aseptic Guide. Moreover, the final version now also
explicitly requests trouble shooting for contaminations; also in view of the
batches produced since the last media fill.
The bioburden analysis is supposed to be conducted for every batch - produced
aseptically or end sterilised. This procedure should also be applied to
parametrically released products (is regarded as in process test). Exempted are
overkill methods, for which the bioburden test can be conducted in appropriate
intervals. Where necessary, the endotoxin burden needs to be examined as well.
The most severe changes pertain to the capping of lyo vials. For instance, in
grade A conditions, partly closed, freeze-dried vials are supposed to be held
until final closing. The closing of the vials is only final with the crimping.
Because the crimping is known to be a source of particles, the new Annex 1
recommends a "separate station" with an appropriate air extraction.
The capping can be realised with sterilised caps or as a process outside the
aseptic area. In latter case the vials are supposed to be protected with grade A
air until the final crimping. Vials with missing or misplaced stoppers should be
rejected before the crimping. Wherever human intervention is involved at the
crimping station, the appropriate technology should be used to minimise the
danger of microbial contamination. In this respect the annex mentions
"restricted access barriers" and isolators.
Specifically striking is the long transition period until the new Annex 1
becomes effective. It is 12 months - with the exception of the implementation of
the capping of freeze-dried vials. Here the transition period is 24 months -
another indication for the severe changes.