Thursday, May 21, 2009

How do you establish a reference standard for release of your first GMP lot?

There are some different approaches depending on situation, but here is one general approach that many people use:

* Preclinical material that was used to support IND-enabling tox studies is characterized and used as an interim reference standard. This doesn't have to be manufactured by GMP; could even be research grade material. Characterization tests should be performed and include methods to determine content, primary structure, bioactivity, tentative release tests, etc. Important to have a good handle on content from this standard (i.e., for a protein drug you might look at total protein content by elemental analysis.) Potency units could be defined here as well.
* Use this interim reference standard as a comparator to release your initial GMP material.
* Use material from the first GMP campaign to create a primary reference standard. Again, this material will need to be subjected to a panel of characterization tests in addition to the release tests (typically at least or more in-depth than the characterization done on initial reference standard).
* The primary reference standard supercedes the interim reference standard after it is created and qualified. This typically happens during or immediately after the first GMP campaign.

From an assay validation standpoint, you will always have to start with some initial standard (typically, the interim reference standard, which is all you may have available before GMP manufacture), and you can get into some circularity with accuracy (i.e., assaying the standard against itself). So for your initial standard and assay validation you rely somewhat on orthogonal methods of analysis. Also, as per ICH Q2, accuracy can be inferred from precision, linearity and specificity.

By Lori Nixon, RMC Pharmaceutical Solutions, Inc.

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