June 2022
Real CMC Tips and Insights

published 4 Jul 2022

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 June 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

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

ou 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.

Related Substances Specifications

Thresholds for setting impurity limits in finished product specifications are calculated with reference to the maximum daily dose (MDD)  of the drug. The MDD is the maximum approved daily dose in the target countries for the drug substance via the route of administration of interest. (The approach is different for fixed dose combination products, for which thresholds are based on the MDD in the SmPC for the product under evaluation.) The calculated thresholds are the same for all strengths of a product.

Unidentified Impurities in Fixed Dose Combination Products

In fixed dose combination products, it may be difficult to associate unidentified related substances with a particular drug substance. This becomes more complicated when identification thresholds differ for the drug substances in the combination. In that case, specifications for unidentified impurities must be based on the lowest threshold for the drugs in the combination. When the threshold is exceeded, the impurity should be identified and associated with the correct drug substance.




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