Quality Risk Assessment

New Draft Annex 1 – PIC/S and EU finally arrives

Finally, nearly 3 years after it was announced, the New Annex 1 for Good Manufacturing Practice (GMP) has been released in draft form. The EU and PIC/S Annex 1 has long been the GMP bible for manufacturers of sterile medicines, but with more than 10 years now passed since its previous revision, it is fair to say an update is long overdue.

When the update was announced in a January 2015 Concept Paper, we were told that there were several pressing reasons that revision was necessary:

  • The global acceptance and implementation of ICH Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System), which are not reflected in the 2007 revision.
  • Advances in sterile manufacturing technology which are not adequately addressed by the 2007 revision
  • Historical ambiguity and inaccuracies in the 2007 revision that need correction or clarification
  • Acknowledgement that Annex 1 has use beyond sterile manufacturing and that the scope and/or title require modification to reflect this.

These all sound like good reasons, but we were also told in the concept paper to expect a public draft in October 2015 and acceptance by PIC/S and EMA in mid-2016 – the concept paper was far from prophetic! Keeping that in mind, what have we been delivered after 35 months?

New Annex 1 (PIC/S and EU) – not a revision, a rewrite

The working group rapporteur, Andrew Hopkins has alluded to this many times in different presentations over the last 18 months, but the evidence is compelling. This is Annex 1, but not as you know it!

  • No fewer than 269 total clauses (compared with 127 in the 2007 version), without consideration to the many sub-clauses, nor the expanded introduction and scope
  • Well over 100 new clauses that have no direct link to an existing clause
  • At least 14 clauses from the previous revision that are not present in any form in the update
  • At least 70 clauses from the previous revision that have been updated in a way that is likely to have at least some impact on some manufacturers
  • Only around 40 clauses that are effectively unchanged from the original 127.


A new focus – Quality Risk Management!

It was touted as a key driver for the change, and the concept of risk management is embedded in the new document like never before:

  • 92 instances of the word “risk”, up from 20 in the previous version, taking the total work count all parts and annexes to about to 600,
  • 15 separate references to QRM and at least one further to “risk management”.
  • Specific emphasis on the place of QRM within the document scope.


A few potential game-changers

The concept paper stated that no adverse impact was foreseen for industry, with respect to either resources or costs. I doubt many believed this statement but, in fairness, there are few, if any changes that are not part of current industry best practices.

A sample of changes I see creating the most discussion for their significance include:

  • The clear expectation for a formal, holistic contamination control strategy. The expectation appears to be for a formal document or dossier which reflects the site-wide strategy for minimising contamination control with respect to sterile manufacturing.
  • Potentially additional requirements for cleanroom classification (beyond ISO requirements) in critical areas
  • The potential intent to mandate HEPA/ULPA filtration in all classified areas (including Grade D). This wording is ambiguous and will no doubt be debated in the consultation period.
  • Significant enhancements to expectations for visual inspection


Lots of new detail

The update contains substantial additional detail on virtually every topic in the 2007 version, hence we’ve ended up with more than twice the number of clauses. In addition to those noted above as potential game-changers, compliance personnel can look forward to new levels of detail on such subjects as:

  • Missing stoppers
  • Cleanroom clothing type and management (compulsory eye wear in A/B, and yes, disposable socks!)
  • Moist heat sterilisation
  • Trending of environmental monitoring results
  • Isolators
  • BFS (both rotary and shuttle)
  • Airflow visualisation
  • Aseptic process simulations (media fills)
  • Lyophilisation
  • Sterility testing … and more!


Some new topics

Of course, with over 100 new clauses, there would have to be new topics. These include:

  • Single use technologies
  • Aseptic operator qualification
  • Application of Quality Risk Management to various topics
  • Cleaning validation for cleanroom surfaces
  • Process water systems
  • Critical utilities
  • Closed manufacturing systems


Some issues remain

Despite the promise to clear up ambiguity and inaccuracies from previous version, in my opinion, some remain

  • The requirement to link bioburden limits to filter efficiency, which if interpreted literally would often lead to limits that would make an inspector gasp in horror.
  • The statement relating to the final stage of airlocks remains unchanged, despite having been a topic of major confusion for years.
  • There continues to be some confusion around the differences between Grade A conditions, and Grade A air supply, which may have been further complicated by the addition of another term, Grade A environment. The definition of Grade A air in the glossary does not fully alleviate the ambiguity.


And maybe some new issues created?

There is obviously a period of public consultation, and no doubt the more obvious issues are either typographical. or will be resolved with appropriate counter argument. However, some of the potential issues include:

  • The requirement that a sample is taken from the worst-case location of a process water system each time the system is used for manufacturing is highly problematic, and hopefully unintentionally misleading. Given that some systems may be used 100s or even 1000s of times a day, that’s going to be an awful lot of water analysis!
  • While not really a significant issue, the definition of single use systems is not very helpful and could be improved by speaking to either of the peak industry bodies who have spent so much time on the topic.
  • There are several minor typographical and language issues which hopefully will be resolved during the consultation period. Some have impact on meaning of the text, while others are just a bit annoying and unnecessary – for example – actions might be described as “preventative”, unless the guidance is specifically talking about CAPA, in which case, they are “preventive”.


Final thoughts

The revised or new Annex 1 is, as promised, a comprehensive rewrite of the previous version, with a focus on application of QRM and PQS to sterile manufacture. There is some excellent new information on a wide range of technologies not previously adequately covered, and several ambiguities and inaccuracies from the 2007 version have been addressed.

Of course, with all new publications, especially drafts, there are points of contention, and the public consultation may be able to address many of these.

Links to the new PIC/S Annex 1 and the draft EU Annex 1.

How we plan to help

PharmOut will be following this blog in days to come with a comprehensive white paper, gap analysis tool and example of a contamination control strategy. We will be looking at all the significant changes, as well as some of the less significant in considerable detail.

In addition, we will offer the first Australian new Annex 1 training in Melbourne 1st February, 2018 and in Sydney on 31st January, 2018, of course we continue to offer our GMP training in PIC/S version 13.

Initial Blog (this post)

Draft Annex 1 – Part 1

Draft Annex 1 – Part 2

Draft Annex 1 – Part 3

Draft Annex 1 – Part 4

Draft Annex 1 – Part 5

Draft Annex 1 – Part 6

Draft Annex 1 – Part 7

Draft Annex 1 – Part 8