Validating Purity: Problems in Meeting the EMA Reference Standard

Q: I’ve got a question about validating purity according to Section 7 of the EMA Guidelines for Method Validation (effective February 2012). In the Reference Standards section for Ligand Binding Assays (, the guideline says, “Macromolecules are heterogeneous and their potency and immunoreactivity may vary. The reference material should be well characterised and documented (e.g. certificate of analysis and origin). The purest reference standard available at the time should be procured” (emphasis mine).
That seems like a big sentence to put into a compliance document. It would seem analysis could be performed to justify using something of slightly lower purity, no? What are your thoughts on this?

A: The document you reference is a guideline document – so it’s just that: a guideline. However, we agree with the document that for validating purity, you should get the purest reference standard possible. Actually, any reference standard should be as accurate and pure as you can get, regardless of whether it’s stated in a guideline or not. But you’re right that it’s unusual for a guideline document to make such a “state-of-the-art” recommendation.
Here’s our advice to you: make sure you characterize any reference standard you use and have good justification for its use, especially if it’s not as pure as you would like for a reference standard. If variation exists in the purity of the reference standards you get, over time you should overlap the procurement of the standard and perform comparative analysis to achieve as much uniformity as possible.

Answered by Martin Browning, EduQuest President and Co-Founder, and Jan Olson, Vice President of Regulatory and Quality Services (both co-instructors for EduQuest’s FDA Auditing of Computerized Systems and Part 11/Annex 11 training class).


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