GMP Annex 1 – sterile manufacture
In January PIC/S and the GMP/GDP Inspectors Working Group (on behalf of the EMA) agreed on a concept paper regarding the long awaited update to Annex 1, the primary GMP guidance on sterile manufacturing for Europe and PIC/S member countries.
The current version of Annex 1 dates from 2007, although in Australia, it has been in use since the adoption of PIC/S GMP Guide PE 009-8 in 2009. The 2007 version has its roots in earlier editions and has a lot in common with the original 1996 version of Annex 1.
In recent years it has become evident that Annex 1 hasn’t kept pace with regulatory and technological advancements, and the time has come not just for another partial revision, but for a complete review and update of the Annex.
What’s driving the Change?
The PIC/S and GMP/GDP IWG concept paper lists several reasons for the need to revise the Annex:
- The length of time since the last full update (the original Annex 1 was released 19 years ago)
- Advancements in technologies used in the manufacture of sterile medicinal products. No specific technologies are mentioned, but it can be assumed that technologies such as Restricted Access Barrier Systems (RABS), disposable processing equipment and Process Analytical Technology (PAT) may be drivers for the change.
- ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) are now ubiquitous in GMP guidance since the last update. The current Annex 1 was not written with the approaches in these documents (particularly Q9) in mind.
- There are also some historical ambiguities. Some examples, in my opinion, include Grade D in-operation monitoring, averaging microbial monitoring results and the interpretation of the phrase “at least” when applied to environmental gradings.
- There are also historical inaccuracies. The most notable is the direct contradiction between clause 34 and clause 116 regarding the transfer of partially stoppered vials.
- The use of Annex 1 as guidance for cleanroom classification by manufacturers of various non-sterile medicinal products.
- Recent updates to Ph.Eur. regarding methods of production of Water for Injection, which now allows methods other than distillation. This change would bring the Annex in line with the USP.
It is probably reasonable to assume that the desire to continue to harmonise WHO, US FDA and European thinking is also behind the proposed changes.
What are the proposed changes?
Unsurprisingly, we can expect most of the changes to be aligned closely with the reasons for the change. While the concept paper does not provide any significant detail on the proposed changes, it is explained within the paper that the revised Annex 1 will:
- “Clarify to what extent Q9 and Q10 should be followed in the design and implementation of facilities, equipment and processes for the manufacture of sterile medicinal products”
- “Clarify (non-sterile manufacturing) areas of applicability utilising quality risk management principles.”
- “Embrace the use of new technologies to prevent detrimental impact on product and also to encourage the introduction of new technologies that are not currently covered.”
- “Correct the inaccuracies and offer more detail to remove ambiguity and to give clearer interpretation of GMP expectations.”
Also, the suggestion is made that that the revised Annex 1 guideline should or may be updated to:
- Consider the revision to the Ph.Eur. monograph on methods other than distillation for the production of water for injection
- Take into account related changes in other GMP chapters and annexes as well as in other regulatory documents.
- Broaden the scope and title of the guideline to encompass (non-sterile manufacturing) references.
It is fair to say that this list of likely review items covers most of the core issues associated with the current version of Annex 1. One issue which is likely to be addressed, despite not being specifically mentioned in the concept paper, is the impending update to ISO 14644. The revision of the ISO standard is likely to be completed well in advance of the new Annex 1 implementation. Potential updates to the airborne particle concentration limits for cleanroom and clean air devices classification in clause 4 will be highly anticipated by observers.
What impact might the proposed changes have on industry?
Any change to a regulatory guidance gives causes for some anxiety among manufacturers. The last “partial” update to Annex 1 in 2007 was viewed as highly significant, and was seen as requiring both capital and operational cost increases.
The term “complete review” associated with this update will no doubt generate a great deal of interest and concern around these changes. While it is currently impossible to determine the depth of regulatory or financial impact that the update may cause, the concept paper at least provides these comforting words:
“No adverse impact on industry with respect to either resources or costs is foreseen …”.
The paper also includes some cautionary words about the possible need to improve or modify equipment and processes over time to ensure that the statement above doesn’t come back to haunt the writers.
What is the implementation timeframe?
A draft Annex 1 is currently in circulation among the interested parties (EMA and PIC/S regulators). This draft will go through multiple cycles of review and comment over the next few months before its intended public release in June 2016.
Because of Australia’s unique approach to adopting updates to the PIC/S GMP Guide, it is possible that final adoption will come sometime later. It should be noted, however, that the last update to the GMP Guide in Australia was driven largely by the last Annex 1 update, it would not be surprising if this update has the same effect.
PharmOut is hosting an update GMP and Validation Forum on July 11-12 that will discuss the Annex 1 and ISO 14644 in more depth.