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Must, Shall and Should – the use of these words in GMP

I am often asked what the difference between these words mean in the context of GMP, so in this post I try and explain, using European Union Good Manufacturing Practice (EU GMP) as my point of reference.  However, I think that there are occasions within EU GMP where the incorrect terms have been used in error, as we will see.

The legal bit

There the two main parts to EU GMP, firstly the rules and secondly the guidelines.  For human medicines, the rules can be found in Directive 2003 94 EC.  Here the rules (the laws) for manufacturing sites are found.  As this is a legal document, you would expect to see lots of “musts”.  In-fact, there are none.  It is full of “shalls” with the occasional “should”.  The word “shall” does in-fact mean an expectation, so for “shall” we can also read “must”, which is what you would expect in a legal requirement.

The guidelines

Then there are the nine guidance chapters of GMP.  These are guidelines, and therefore should be full of “shoulds”, as “should” opens up the options for an alternative way of achieving the requirements, which is the way GMP is written.  There are lots of “shoulds” in the nine chapters of GMP, with no “shalls” and a few “musts”.

There are “musts” in the GMP chapters, which at first does not appear to be logical, as how can you have a “must” in a guideline?  Well, you can, and this is generally explained when the guideline is repeating the actual requirement of the law (or article of the Directive) itself.  For example, Article 7 of Directive 2003 94 EC covers Personnel.  Here it states “The duties of the managerial and supervisory staff … responsible for implementing and operating Good Manufacturing Practice, shall be defined in Job Descriptions.  Their hierarchical relationships shall be defined in an Organisation Chart”.

So, you need to have Job Descriptions and you need an Organisation Chart.  In the corresponding Chapter 2 of the Guide the GMP (Personnel) we have a “must”, at clause 2.2 which states “The manufacturer must have an Organisation Chart”.  So this makes sense, as there is a “must” as it is repeating the “shall” from the Directive itself.

However, this logic is not repeated with the requirement for Job Descriptions.  You would expect to also see a “must” here too, but in-fact we get a “should” as it states “people in responsible positions should have specific duties recorded in written Job Descriptions”.  So the use of words is not always right and consistent.

This is likely to be due to general errors that have crept in over time and may be due to words being translated from one language to another incorrectly.  So, I do not think that I have answered the actual initial question correctly, other than you should see “musts” and “shalls” in the Directive and “shoulds” in the guidelines, however, as we have seen, this is not always the case.

If you have any comments on this, please let us know.

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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