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1 December 2005

EU GMP Guide: New Draft for Annex 1 "Sterile Manufacturing" Published

On 11 November, the EU Commission published a revised draft of Annex 1 to the EU-GMP Guide. This annex formulates the additional requirements on the manufacture of sterile medicinal products. Since the latest major revision was conducted in 1996, the document has been revised several times. However, some of the new versions have given rise to misunderstandings.

Annex 1 was under revision since 2003, especially because EN/ISO 14644-1 on cleanroom technology was meant to be included. Now the EMEA has published a draft (Draft Amendment to Annex 1 of the GMP guide for public consultation) for commenting that - apart from the integration of EN/ISO requirements - takes account of further current developments, one of which is the new FDA Guidance for Industry "Sterile Drug Products Produced by Aseptic Processing". 

The changes concern the following topics:

  1. Cleanroom classification
  2. Indication of media fill acceptance criteria
  3. Bioburden monitoring prior to sterilisation
  4. Indication of environmental conditions for freeze-drying vials before final capping

The suggested changes also result in a change in the numbering of the chapters!

Cleanroom Classification

Former chapters 3-6 newly structured as chapters 3-11: After the latest revision, the chapters 3-6, especially the notes on cleanroom classification, were among the most discussed chapters of this annex. Since the text had in part been contradictory or unclear, great parts have now been rephrased.

In one of the next GMP News on this website, we will have a close look at the consequences for the industry. 

It is evident that the text is strongly oriented towards EN/ISO 14644-1 and that the classification should be considered as independent of the environmental monitoring of the process. Another salient point is that many of the passages on cleanroom measurements that were criticised in the last revision have now been taken up.

Indication of Media Fill Acceptance Criteria

Former chapter 42 - now chapter 47: The text of this chapter is nearly unchanged. The following items have been added:

  • The indication of acceptance criteria for media fill. These have been taken over from FDA's Aseptic Guide nearly unchanged.
  • The instruction that, when investigating "gross failures" (whatever this is), the influence on the batches produced since the last successful media fill should be considered.

Bioburden Monitoring Prior to Sterilisation

Former chapter 52 - now chapter 57: The following items have been added:

  • Bioburden monitoring should be conducted for each batch - for products produced by aseptic manufacture and for terminally sterilised products.
  • If overkill procedures are performed on terminally sterilised products, bioburden assay only has to be conducted at suitable intervals.
  • In case of parametric release, bioburden assay should be performed on each batch of product and considered as an in-process test.
  • Where necessary, endotoxin burden should also be measured.
Indication of environmental conditions for freeze-drying vials before final capping

Former chapter 88 - now chapter 93: The following items have been added:

  • Partially stoppered freeze-drying vials should always be stored under grade A conditions before final capping.
  • The text defines that freeze-drying vials are not fully closed until the aluminium cap has been crimped into place.
  • The crimping equipment is mentioned as a source of non-viable particulates. For this reason only the microbiological requirements of Grade A conditions have to be fulfilled.

On the whole, the draft certainly represents a considerable improvement compared to the last version, above all since it takes account of current regulations, like EN ISO 14644 and the FDA Aseptic Guide, also with regard to international harmonisation. 

Our seminar recommendation: On 18 and 19 May 2006, the European Compliance Academy organises the event "Environmental Monitoring - Compliant and Reasonable" in Copenhagen.

Dr Andreas Mangel

Source: Draft Amendment to Annex 1 of the GMP guide for public consultation



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