In the early part of the last decade Active Pharmaceutical Ingredients (API) GMP was introduced and was added as Annex 18 of EU GMP. This was really a mistake as the Annexes add to the 9 Chapters of GMP where necessary. API GMP (formerly Annex 18) is a stand-alone GMP guide for manufacturers of APIs and was not an Annex in the traditional sense. As a result API GMP was removed from conventional GMP about 5 years ago and added to a new Part 2, where it now sits next to GMP rather than part of GMP. From this point GMP now had 2 parts – Part 1 containing conventional GMP for finished products (the Chapters and Annexes) and Part 2 containing API GMP on its own.
In the last 6 months a new Part 3 has been introduced. This is entitled “GMP related documents” and includes the following sections. The sections cover guidelines that support and compliment GMP. Click on the documents to open.
The Site Master File section covers explanatory notes on the preparation of a Site Master File.
The section on Q9 Quality Risk Management means that what was for some time Annex 20 on Risk Management has been moved out of conventional GMP (Part 1) and put into the new Part 3.
The section on Q10 Note for Guidance on Pharmaceutical Quality System means that the long-awaited guidance on pharmaceutical quality systems, which was expected to go into Part 1 as Annex 21, now also sits in Part 3.
The final section on MRA Batch Certificate gives guidance on the acceptance of finished products from one EU country to another.
UPDATE 30th March 2012
A good question has been raised by Yves asking if the Annexes are applicable to Part 2 (API GMP).
The annexes were originally written for finished product GMP (Part 1) and many were written with finished products in mind, such Liquids, Creams and Ointments (Annex 9) and Metered Dose Inhalers (Annex 10). I have spoken to the UK Regulatory Authority (MHRA) and they have told me that for API GMP (Part 2) you should use the Annexes where relevant and appropriate, such as Annex 15 on Validation and Qualification.
I hope this clarifies.
Annex 1 has finally arrived, 25th Aug 2022 saw the publication of Annex 1. Normally, updates to GMP chapters and Annexes have a 6-month lead time for implementation. In the case of the new Annex 1, the lead time is 12 months, except for clause 8.123 relating to lyophilization which has 24 months lead time.
Annex 1 was first issued in 1971 as the only annex in the first ever UK guide to Good Manufacturing Practice. Since then, there have been several updates but not full revisions. In 2012 there was a proposal to revise Annex 1 with a re-proposal in 2014 by the UK’s MHRA. At the time, a full rewrite was considered unlikely and instead the intention was to provide a document that would confirm regulatory expectation and as such, not place any new requirements or costs on the pharmaceutical industry.
While this principle, is still upheld, it was clear from the first draft for public comment of December 2017, that a rewrite was being undertaken. The first draft created around 6200 comments coming from regulatory organizations, such as the pharmaceutical cooperation scheme, regulatory bodies outside of the EU, support organizations such as the Parenteral Drug Association, the Parenteral and Healthcare Sciences Society, the Pharmaceutical Microbiology Interest group as well as representatives from the manufacturers within the pharmaceutical industry to name just a few. Rarely do updates require a second public consultation but in the case of the annex 1 update a second draft was issued in March 2020 although this was a more targeted review in terms of the sections and clauses that comment was being sought for.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
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Eudralex = The rules governing medicinal products in the European Union
Volume 4 – GMP Human & Veterinary – represents THE European GMP for medicinal products.
The annexes apply, as appropriate, equally to Part I and Part II (not only to Part I). Part II is part of the GMP (and not outside/beside the GMP).
Part III contents a collection of supporting (not binding) documents but recognized by regulators as an acceptable way of thinking, in particular to Quality Risk Management (Q9) and to Pharmaceutical Quality Management System (Q10).
Hi – not sure about this, i.e the annexes are applicable to API GMP. Will check out and get back to you. Dominic
Hi Yves,
Thanks for you comments. I have checked this out and updated the blog. Regards, Dominic
UPDATE 30th March 2012
A good question has been raised by Yves asking if the Annexes are applicable to Part 2 (API GMP).
The annexes were originally written for finished product GMP (Part 1) and many were written with finished products in mind, such Liquids, Creams and Ointments (Annex 9) and Metered Dose Inhalers (Annex 10). I have spoken to the UK Regulatory Authority (MHRA) and they have told me that for API GMP (Part 2) you should use the Annexes where relevant and appropriate, such as Annex 15 on Validation and Qualification.
Hi Dominic,
I appreciate your open-mind.
My “knowledge” about this particular topic relies on discussions I had with regulators early 2006 (just after the move from Annex 18 to Part II).
As we can observe, this point is still causing troubles by API manufacturers and especially for the auditors in charge of API. Many companies are still refusing to apply as appropriate the annexes to their manufacturing processes.
Hi Yves, I thought this might happen. I am not sure that this is fully understood. Dominic
Thanks, I’ve seen your blog before during my, all of the ex-pats are linked together, which is really cool. Thanks for the mention and I put your link up here too.