A new update to EU GMP Chapter 6 on Quality Control has been issued and came into operation on 1st October 2014. Here is a summary of the main changes from the previous version Chapter 6 Quality Control OLD. A copy of the new version can be found by clicking on the link: Chapter 6 Quality Control NEW.
The new chapter has a slightly stronger microbiological feel and there is a totally new section on the transfer of testing methods from one laboratory to another. These are also a number of other changes, all of which are highlighted below.
No change from the previous version.
General (6.1 – 6.4):
No change from the previous version.
Good Quality Control Laboratory Practice (6.5 – 6.6):
A new requirement not to move laboratory equipment between high risk areas to avoid accidental cross-contamination. What a high risk area actually is is not defined!
There is also a requirement for the microbiological laboratory to be arranged to minimise cross-contamination (I guess cross-contamination of micro-organisms). This will probably be seen as a mixed blessing by Microbiologists. On the one hand they get their first mention in European Union GMP (EU GMP). On the other hand it suggests that, as is often the case, they are shut away in their own area, away from the rest of their Quality Control colleagues!
There is also a mistake that has gone un-noticed. Clause 6.6 cross-refers to “Chapter 7 – Contract Analysis”. This is an inaccurate reference to a now renamed chapter which is in fact called “Chapter 7 – Outsourced Activities”. This error doesn’t really matter – but it does show us that the Regulators are human and can make mistakes too!
On a final note whilst we are on this section, do note that Quality Control (QC) labs work to Good Quality Control Laboratory Practice (GQCLP) – the name of this section of the chapter. GQCLP is sometimes shortened to Good Control Laboratory Practice (GCLP). QC labs DO NOT work to Good Laboratory Practice (GLP). This is confusing, but in Europe GLP (Good Laboratory Practice) is concerned with toxicological studies on animals.
Documentation (6.7 – 6.10):
There is a new clause added here that you will be amazed was absent before. Clause 6.7 (iv) requires a procedure for dealing with investigating Out Of Specification (OOS) and Out Of Trend (OOT) results. Whilst I guess that every QC Lab on the planet already has such procedures, there was not, until now, a requirement to have such procedures. In fact the words Out Of Specification and Out Of Trend were not mentioned in EU GMP at all! Clause 6.9 also requires the OOS or OOT procedure to be followed when investigating such occurrences.
They have also removed the specific requirement to keep QC related documentation and records for at least 5 years after Qualified Person certification (in effect batch release) or 1 year after expiry date. Instead the reader is simply cross-referred to EU GMP Chapter 4 (Documentation), where it states the same thing.
Sampling (6.11 – 6.14):
There is the first mention of a “sampling plan” at clause 6.12. Previously the chapter simply stated that “samples should be representative of the batch”. Now GMP required a specific “plan”, but there is no mention of what this plan should be based on. Organisations are likely to base the plan on risk. There is still no mention in GMP of the infamous ROOT N +1 sampling plan or any cross-reference to ISO 2859 (Sampling procedures for inspection by attributes). Both of these are commonly used in practice.
There is also a requirement (clause 6.13) to “manage and store samples correctly”. There is though no specific mention of a sample storage area, cupboard or cabinet (which are commonly used). However, the requirement for a location to store samples can be found in EU GMP Chapter 3 (clause 3.27).
Testing (6.15 – 6.25):
The first clause (6.15) covers the new requirement to ensure that if a test method has been validated elsewhere (such as by another organisation) then the current method used must still valid.
There is also a more stronger use of the word “trending” at clause 6.16. Many labs do trend analytical results, but until now GMP simply stated that “for some kinds of data … it is recommended that records are kept in a manner permitting trend evaluation”. This is not exactly a command is it? Now we have the wording “results of parameters identified as … critical should be trended”. Much more direct now I think you will agree.
There is no change to the list of items to be recorded by analysts in labs books or result sheets (clause 6.17) except that clause 6.17 (ix), which is new, now requires that the equipment used should also be recorded. I suspect that most organisations will simply record “critical” equipment used (such as what HPLC was used) and not every single item of equipment (such as a test-tube holder, Bunsen burner, microscope, etc.).
The requirements of clause 6.19 are not essentially new. These cover the use and control of reagents, solutions and reference samples. There is an additional sentence added through at the end of the clause, requiring that the controls used with such items should be commensurate with their use and available stability data. In other words – take care with such items, especially those which will really affect your results if they deteriorate.
There is also a new clause (6.20) covering the use of reference samples, stating that it is preferred if official compendial materials are used. These are, of course, more expensive to use than working standard, which labs may well produce for daily analysis.
Clause 6.21 also adds a bit of a microbiological feel to the whole chapter. I can only guess that in all previous updates of this chapter they forgot to ask the Microbiologist for input, as the wording suggest that the only laboratory of interest is the analytical one. In this clause the words “culture media” have been added with regard to the control of laboratory reagents and standards. Also, there is a need to record the date of opening of a reagent, standard or media. This would apply if the laboratory purchases a pre-prepared item rather than making it themselves.
The Microbiologist really must have been listened to in the wording of this new version of Chapter 6. New clauses 6.23 and 6.24 cover the use of preparation and use of culture media and the disposal of micro-organisms. However, when it comes to disposal of micro-organisms there is no mention of autoclaving or incineration!
On-going stability programme (6.26 – 6.36):
No change from the previous version.
Technical transfer of testing methods (6.37 – 6.41):
This is all new. Five lengthy clauses added here. As the name suggests these clauses cover the transfer of test methods from one lab to another. In essence, the new lab must ensure and document that their test method is equivalent to the previous one. If not, steps will need to be taken to fill any gaps.
This brings me to the end of this chapter. There are a number of changes, but as with other chapter updates, these changes are generally done anyway as best practice or common sense.
I would have thought that there would have been something added about the use of Laboratory Information Management Systems (LIMS). Many labs have these to record results, yet they are still not mentioned in GMP. Perhaps, at a minimum, there is scope to add a requirement to double check the transfer of results from a lab book or result sheet onto a computer system. Maybe this is one for the next update?
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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 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
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