March 2021
Real CMC Tips and Insights

published 5 Apr 2021

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in March 2021 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

ASMF Version Discrepancies

An ASMF may be submitted by an ASMF holder to support multiple MA or variation applications made by different applicants for different products. Each update to an ASMF, whether required during assessment or initiated by the ASMF holder, results in an updated ASMF version number. Discrepancies in version numbers are among the commonest validation issues, therefore it is crucial to confirm with the ASMF holder - before submitting - that the applicant’s part is the most recent available version and matches the restricted part submitted by the ASMF holder.

The Applicant’s Drug Substance Module

When an ASMF is used to submit information on a drug substance to competent authorities, the applicant must still present a drug substance module as follows: the applicant’s specifications and analytical procedures for the material in 3.2.S.4.1 and 3.2.S.4.2, analytical validation in 3.2.S.4.3 (if the applicant’s analytical procedures are not identical to those validated by the ASMF holder), batch analyses in 3.2.S.4.4, justification of specifications in 3.2.S.4.5 and information about reference standards in 3.2.S.5.

The EDQM Knowledge Database

The free Knowledge Database on the EDQM website is an extremely useful resource. From it you can find out monograph status: if a monograph is available, under elaboration, being revised, harmonised, and interchangeable. The monograph’s revision history tells you what changes happened and when. Certificates of suitability granted for the substance are listed. In many cases, the database also provides specimen chromatograms and lists reference standards (with links to the EDQM reference substances database), chromatography columns and key reagents required for testing.

Revision of Nitrosamine Risk Assessments

You have performed a nitrosamine risk evaluation for your small molecule product and have submitted a ‘No risk identified’ notification to EMA or national competent authorities. However, nitrosamine risk evaluation must continue throughout your product’s lifecycle. Monitor newly identified root causes published by EMA and elsewhere. Consider the potential risk of nitrosamine formation as part of your change control process. Perform periodic re-evaluation.

ICH Training Materials

Everyone in the industry is familiar with ICH guidelines, which provide harmonised guidance on various technical matters. On the other hand, most users of the guidelines are unaware of the extensive training materials that accompany many of the guidelines and are available for free on the website in the form of presentations, supporting documents and videos. As an example, ICH Q9 on Quality Risk Management is supported by a briefing pack with presentations on the various risk management methods and tools.


For previous monthly round-ups, you can follow these links:

February 2021 Real CMC Tips & Insights Round-Up:

January 2021 Real CMC Tips & Insights Round-Up:

December 2020 Real CMC Tips & Insights Round-Up:

November 2020 Real CMC Tips & Insights Round-Up:

October 2020 Real CMC Tips & Insights Round-Up:

September 2020 Real CMC Tips & Insights Round-Up:

August 2020 Real CMC Tips & Insights Round-Up:

July 2020 Real CMC Tips & Insights Round-Up:   

Search Real Regulatory