BE of racemic drugs (EMA’s practice) [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2012-01-13 16:02  – Posting: # 7928
Views: 4,547

Dear Scorp!

» A BE study of racemic drug was conducted for EU submission and the bioequivalence was concluded based on the measurement of racemic drug. In the study enantiomers were not measured. The BE study was approved by the several EU regulatory authority. Now one of the EU regulatory body has asked to justify why enantiomers were not measured and why BE was concluded on racemic compound???

When was the study planned (=protocol submitted) and submitted to regulatory authorities? The current GL came into effect on 1 August 2010. Some regulators might assess the study according to the previous NfG (2010), which had more relaxed requirements:

[…] bioequivalence studies supporting applications for essentially similar medicinal products containing chiral active substances should be based upon enantiomeric bio-analytical methods unless (1) both products contain the same stable single enantiomer; (2) both products contain the racemate and both enantiomers show linear pharmacokinetics.

Some European regulatory authorities (f.i. Austria’s) assess all studies submitted after 1 August 2010 according to the current GL – regardless the date they have been performed.

» Please help in getting out of this situation.

Sorry, I can’t do that. If you cannot exclude the conditions required for an achiral assay stated in the GL, the term “unknown” will hit you.

BTW, assessors are a strange bunch. Last year we submitted a study on a single enantiomer IR product with a chiral assay in order to (exploratory) assess potential in vivo interconversion. Both PK and PD of the enantiomers are known to be different. The enantiomeric purity of the generic’s API (99.9%) was much better than the reference’s (95.5%). BE easy: 96.84–101.54% (AUCt), 98.86–112.09% (Cmax). Were asked by a (large!) European authority to perform a sensitivity analysis on the sum of both enantiomers…

Helmut Schütz

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