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The principle directive for human Good Manufacturing Practice is Directive 2003 94 EC.  This is a legal requirement that must be incorporated into National Law by European Union Member States.  The Directive must be followed by pharmaceutical manufacturing sites holding a Manufacturing Authorisation.  The Directive has a series of Articles within it.  The first few are administrative covering Scope (Article 1) and Definitions (Article 2).  The next three articles are important for establishing the principles of GMP.

Article 3 covers Inspection.  This means that a site with a manufacturing authorisation will be inspected to EU GMP.

Article 4 covers Conformity with GMP.  This makes it a legal requirement that the site works to EU GMP.

Article 5 covers Compliance with Marketing Authorisation This makes it a legal requirement that products are made according to their licence.

The remaining articles are the principle articles of GMP.  These are listed below.  They normally are short sentences of requirements.  Their requirements are law.

Article 6 covers Quality Assurance

Article 7 covers Personnel

Article 8 covers Premises & Equipment

Article 9 covers Documentation

Article 10 covers Production

Article 11 covers Quality Control

Article 12 covers Contracting out

Article 13 covers Complaints, recall and emergency unblinding (during clinical trials)

Article 14 covers Self Inspection (internal audit)

Article 15 covers Labelling of Investigational Medicinal Products

All of these Articles (which are MUSTS) then link to corresponding Chapters in the Guide to GMP.  Here pages of guidance is provided on how the articles can be achieved.  You will see that Article 6 is the same title as Chapter 1, Article 7 the same as Chapter 2 and so on.  The only exception is Article 15, which has no Chapter (but does have an Annex 13)

Chapter 1 covers Quality Assurance

Chapter 2 covers Personnel

Chapter 3 covers Premises & Equipment

Chapter 4 covers Documentation

Chapter 5 covers Production

Chapter 6 covers Quality Control

Chapter 7 covers Contracting out

Chapter 8 covers Complaints & recall

Chapter 9 covers Self Inspection (internal audit)

After the 9 Chapters comes a series of Annexes – additional GMP requirements for certain types of products and situations.  These are listed below.  Organisations work to these as relevant.

Annex 1. Sterile manufacturing.

Annex 2. Biological products

Annex 3. Radiopharmaceuticals

Annex 4. Veterinary medicinal products

Annex 5. Immunological veterinary products

Annex 6. Medicinal gases

Annex 7. Herbal medicinal products

Annex 8. Sampling of starting materials

Annex 9. Liquids, creams & ointments

Annex 10. Metered dose inhalers

Annex 11. Computerised systems

Annex 12. Use of ionizing radiation

Annex 13. Investigational medicinal products

Annex 14. Products derived from human blood

Annex 15.Qualification & validation

Annex 16.Certification by a Qualified Person

Annex 17. Parametric release

Annex 19. Reference samples

Annex 20. Quality Risk Management

Annex 21. Quality Management (due in 2012)

Hopefully this explains how GMP works.  One final quote is from the Introduction to GMP stated below.  This reminds readers that GMP is a guide and there are options to do things differently.

“It is recognised that there are acceptable methods, other than those described in the Guide, which are capable of achieving the principles of Quality Assurance.  The guide is not intended to place any restraint upon the development of any new concepts or technologies which have been validated and which provide a level of Quality Assurance at least equivalent to those set out in this guide”

Not a lot of people appear to be aware of the above comment!  Did you know this?  Want any further help or information?  Please get in touch or make a comment.

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NOTE – UPDATE 28th March 2012.  Also see later blog article on New Structure to EU GMP.

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 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.

Training courses on Annex 1

There are a number of half-day workshops organised to take you through the changes in more detail and to look at how they relate to your organisation.

Our 2-day course is updated for Annex 1 changes

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