GMP Calibration – understand both EU and USA GMP requirements
Around a pharmaceutical manufacturing site there will be many measuring devices that require GMP calibration. GMP requires the calibration of such devices, with similar requirements in both EU and USA GMP, as can be seen below:
EU GMP (Chapter 3.41)
“Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.”
USA GMP (21CFR211.68)
“Equipment … shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.”
Calibration is a very important part of any organisation’s Quality System, yet its coverage in both EU and USA GMP is somewhat limited to the two clauses above. These two requirements do raise a number of questions that GMP does not answer. For example, in EU GMP, what is an “appropriate method” for calibration? In both EU and USA GMP what does “routinely calibrated” and “defined intervals” actually mean? Every month, every 6 months, every year, every 10 years?
One standard you could look at to get a more detailed series of requirements for calibration is ISO 9001. Its requirements are summarised below.
- Be calibrated or verified, or both, at specified intervals, or prior to use, against measurement standards traceable to international or national measurement standards
- Be adjusted or re-adjusted as necessary
- Have identification in order to determine its calibration status
- Be safeguarded from adjustments that would invalidate the measurement result
- Be protected from damage and deterioration during handling, maintenance and storage
- In addition, the organization shall assess and record the validity of the previous measuring results when the equipment is found not to conform to requirements
- The organization shall take appropriate action on the equipment and any product affected
As you can see you get a lot more of an idea of what can be an “appropriate method” for calibration here. Much more depth about using calibration method traceable to national standards, adjusting the gauge if needed, considering the impact of batches affected if found out of calibration, appropriate identification and the need to protect from adjustment.
None of these standards answer the question of when should you calibrate a gauge. Here we need to apply some common sense:
Firstly, establish if the gauge needs to be calibrated in the first place. Is it providing you with GMP/ quality related information that is essential for product quality or is it simply giving you “information only”. If it is for “information only” then it may not need calibrating. Examples of these are gauges on water systems that are simply indicating that the water is flowing at a certain speed. Quality critical data is recorded by other calibrated gauges at other locations.
Secondly, if the gauge does need calibrating then the frequency needs to be based on a number of factors. These can include:
- Manufacturer’s recommendations
- The frequency of calibration of identical or similar items of equipment
- The importance/ impact of the result, especially if it goes out of calibration
- The frequency of use of the item
- The extent that it is stressed during its use (i.e. is it used at the extreme limits of its designed range)
- The history of results
Once a calibration frequency is established it does not need to be “set-in-stone”. You could initially, for example, calibrate a gauge every 6 months for its first few years of use. After several years you could look at the data and consider extending that calibration frequency. You should also consider if the usage of the gauge has changed in this period, as this could affect any decision to change frequency (to less or more frequent).
Finally, ensure that your calibration activities are suitably recorded. These activities are often outsourced to specialist firms, so do check that they are providing you with calibration certificates that are suitable and will stand-up to regulatory inspection.
I hope you find this article of interest. Please feel free to comment or pass on to others.
THIS ARTICLE WAS FIRST PUBLISHED IN 2012 AND WAS UPDATED IN NOVEMBER 2022.
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.
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