Since the first publication of Annex 1 (Manufacture of sterile medicinalproducts) 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 havebeen several update proposals. TheGMP news from 1 December 2005 described thesedrafts in detail.
Now the contents of this draft have almost completely been included in the finalversion. On 15 February, the EU Commission published the modified version. Therequirements laid down in this document have to be implemented by the industryby 1 March 2009. For the capping of lyophilised vials, the transition period hasbeen extended to 1 March 2010.
The following changes to the current version have been made:
- The classification of clean rooms and associatedexplanations
- Recommendations with regard to media fills
- Recommendations with regard to bioburden monitoring
- Recommendations with regard to capping for freeze-driedvials
For your information, we have created a comparison between the current versionof the document and the newly published one. You will find it at the end of thisnews 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 the2003 version. Now the permitted limit for 5,0 µm particles in class A (inoperation & at rest) has been raised to 20. Also new are the specifications withregard to portable particle counters and the strong emphasis on monitoring, alsoreferring to an integration of "risk management".
Completely new are the acceptance criteria for media fills, which are nowaligned with the FDA Aseptic Guide. Moreover, the final version now alsoexplicitly requests trouble shooting for contaminations; also in view of thebatches produced since the last media fill.
The bioburden analysis is supposed to be conducted for every batch - producedaseptically or end sterilised. This procedure should also be applied toparametrically released products (is regarded as in process test). Exempted areoverkill methods, for which the bioburden test can be conducted in appropriateintervals. Where necessary, the endotoxin burden needs to be examined as well.
The most severe changes pertain to the capping of lyo vials. For instance, ingrade A conditions, partly closed, freeze-dried vials are supposed to be helduntil 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 1recommends a "separate station" with an appropriate air extraction.
The capping can be realised with sterilised caps or as a process outside theaseptic area. In latter case the vials are supposed to be protected with grade Aair until the final crimping. Vials with missing or misplaced stoppers should berejected before the crimping. Wherever human intervention is involved at thecrimping station, the appropriate technology should be used to minimise thedanger 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 1becomes effective. It is 12 months - with the exception of the implementation ofthe capping of freeze-dried vials. Here the transition period is 24 months -another indication for the severe changes.