GMP reagent management: Many unspoken rules?

So inconspicuous and yet so important, especially from today’s perspective: Section 6.19 of Chapter 6 of the EU GMP guidelines once again significantly increased the effort required to carry out analytical tests:

6.19 Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.

Miniature manufacturing instructions

If strictly interpreted, this means that a miniature manufacturing instruction and therefore also a specification should be created for each affected article – and of course all of this should be integrated into the usual document control system. No, this has not yet been an explicit requirement to this extent, even if it was tacitly expected in some inspections.

But that’s not all: in order to determine whether and how often, for example, a reagent itself must be tested analytically, stability data must now be used(!) – in a strictly literal interpretation.

Pharmacopoeia descriptions

There are plenty of unanswered questions: Can pharmacopoeia descriptions (if available) replace written manufacturing instructions for reagents? Do expiry dates or re-test data from reagent suppliers also count as stability data in the broadest sense (and this is still not clear)? If I change the manufacturer of an initial reagent, do I have to document everything via a change control procedure, i.e. is this a ‘significant’ change?

No footnotes, no Q&A document from the EMA – until now. However, the consequence of non-compliance with section 6.19 is clear: in extreme cases, analysis results may be called into question and retesting of already marketed products may be necessary as a follow-up measure. Where results were included in the assessment of critical incidents (e.g. OOS events), a reassessment may also be appropriate.

Our recommendation: The legislator has obviously deliberately made long-standing unspoken requirements much clearer. If your lab has any gaps here, don’t put it off, but make an action plan now to fix it! Definitely better than only reacting when the child has fallen into the (GMP inspection) well…

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Dr. rer. nat. Dietmar Gross

Vita

• COO Experts Institut
• Senior Project Consultant
• Apotheker
• Langjährige internationale Projekttätigkeit in Europa, Nordamerika, Asien, Russland
• Sachkundige Person (D – AMG, AMWHV, CH – HMG, AMBV)
• Breite Compliance Expertise im Commercial (c)GMP- und Development GMP-Bereich (IMP-GMP)
• Langjähriger Third-Party GMP-Auditor (GMP- und Non-GMP)
• GMP/GDP-Trainer seit 2010
• Quality Culture Mediator
• Trained in cross-cultural aspects of communication, contextualization, and cultural anthropology as part of an MA.MIn and DIcs enrollment at Grace College&TS, US.