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:
- Cleanroom classification
- Indication of media fill acceptance criteria
- Bioburden monitoring prior to sterilisation
- Indication of environmental conditions for freeze-drying vials
before final capping
The suggested changes also result in a change in the numbering of the
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
Indication of environmental conditions for freeze-drying vials before
- Bioburden monitoring should be conducted for each batch - for
products produced by aseptic manufacture and for terminally sterilised
- If overkill procedures are performed on terminally sterilised
products, bioburden assay only has to be conducted at suitable
- 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.
Former chapter 88 - now chapter 93: The following items have been
- 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.