New Version of Annex 1 to the EC GMP Guide on Sterile Manufacture Published

GMP News
21 February 2008

New Version of Annex 1 to the EC GMP Guide
on Sterile Manufacture Published

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 explanations
  • Recommendations with regard to media fills
  • Recommendations with regard to bioburden monitoring
  • Recommendations with regard to capping for freeze-dried vials

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 news issue.

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.

The new Annex 1 will also be covered in the ECA Education Course Clean Rooms in Barcelona, Spain, from 10-12 June 2008.

Sven Pommeranz
Dr. Robert Eicher
On behalf of the European Compliance Academy (ECA)

Source: New Version of Annex 1 to the EC GMP Guide:

The comparison of the two documents can be found here.

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