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Chapter 3 of European Union Good Manufacturing Practice (EU GMP) has been updated and came into operation on 1st March 2015.  This post summarises the main changes.  The EU GMP Chapter 3 OLD and EU GMP Chapter 3 NEW versions of the chapter can be found by clicking on these links so you can compare the two for yourself.

The only change to the new chapter is at clause 3.6.  Other than this the rest is exactly the same.  It may initially appear that this is only a minor update, however the clause itself is the largest clause of the whole chapter and concerns what exactly is a “dedicated facility” – something that has not clearly been defined for many years.

In the old version of Chapter 3 it stated this at clause 3.6:

“In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitising materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms).  The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities.  For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.  The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products.”

Note that there is an odd use of the word “must” here.  As I have said in many previous posts, the chapters of EU GMP are guidelines.  Therefore how can the word “must” be used?  Normally GMP uses the word “should” rather than “must”.  I think that in using the word “must” (and this is the only time it is used) they are stressing the importance of the need to go to extreme lengths to avoid cross-contamination in the case of highly potent materials.

Essentially the old clause is calling on the need for “dedicated and self-contained facilities” when it comes to the manufacture of penicillins, biological preparations, antibiotics, hormones and cytotoxic products.  The background to this relates to the amount of harm that could be done to a patient by cross-contamination of tiny amounts of these substances.  For example it is not known, in the case of people being sensitive to penicillin, what quantity of penicillin is actually needed to cause an adverse effect.

Whilst I am sure that nobody will argue against the need for “dedicated and self-contained facilities” when it comes to the manufacture of certain types of medicinal products there is lack of guidance on exactly what a “dedicated” facility or item of equipment is.  For example, a dedicated item of equipment many be used for one product type only.  However, you may make different strengths of that product using the same equipment, so it is not truly dedicated to a single product.  Plus, what is a dedicated and self-contained facility anyway?  Here the range of options are quite wide.  You could be talking about have an item of equipment that is only used to make one type of product, but it is located in a room with other items of equipment used to make difference products.  You could go further than this and perhaps have the item of equipment located in its own room, but there could be other rooms next door with equipment used to make totally different products.  Do you want this room to have its own air conditioning system?  Others might say that the product should not be made in its own room but should be made in its own facility, building or even site.  So once you start to analysis exactly what a “dedicated and self-contained facility” actually is, a great deal of ambiguity certainly is created.

So, it is with much relief that after years of trying to get clarity and agreement on this area Chapter 3 has been updated to hopefully sort this situation out.

In the new version of Chapter 3 it now states this at clause 3.6:

“Cross-contamination should be prevented for all products by appropriate design and operation of manufacturing facilities.  The measures to prevent cross-contamination should be commensurate with the risks.  Quality Risk Management principles should be used to assess and control the risks.  Depending of the level of risk, it may be necessary to dedicate premises and equipment for manufacturing and/or packaging operations to control the risk presented by some medicinal products.  Dedicated facilities are required for manufacturing when a medicinal product presents a risk because:

  1. the risk cannot be adequately controlled by operational and/ or technical measures,
  2. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta lactams) or

iii. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.

Further guidance can be found in Chapter 5 and in Annexes 2, 3, 4, 5 & 6.”

 

So there we have it – much clearer!  Well – perhaps not?  There certainly is more guidance here.  The word “must” has now gone and there is a greater level of detail as to why certain products should be made in dedicated facilities.

Essentially the new clause is asking the manufacturing site to do some form of documented risk assessment when it comes to defining for themselves what a “dedicated facility” actually is.  If they are unable to demonstrate that there is no risk of any adverse effects via cross-contamination then a dedicated facility may be required.  However, there is still no guidance on what a “dedicated facility” actually is.  Is it a dedicated room with a facility making many other products, a dedicated floor in a building, a dedicated building or even a dedicated site?  Whatever measures are taken to avoid cross-contamination sites should ensure that they have addressed the risks and ensure that appropriate measures are in place to avoid problems occurring.

Dominic Parry

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.

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Our 2-day course is updated for Annex 1 changes

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