Regulatory Update | Mitigating Potentially Mutagenic Impurities

Advice for Handling Potentially Mutagenic Impurities in Regulatory Submissions

BY Philip Crooker, J.D., Vice President,Technical, Parexel - 10.2.19 -

The presence of various nitrosamine-related impurities in the angiotensin II receptor blocker (ARB) class of drugs and now ranitidine has been the subject of numerous pieces in the popular and trade press.  

The European Medicines Agency (EMA) has also urged manufacturers of pioglitazone to test their products and check their processes for the presence of nitrosamine-related impurities.

The issue of managing the acceptable risk level of the presence of potentially mutagenic impurities in drugs is not new and a significant body of work has been developed over the past decade or so on this topic.  The current Step 4 version of the internationally harmonized guidance, ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk was published in March 2017.

The peer-reviewed literature also contains several excellent sources for handling potentially mutagenic impurities in regulatory applications (for example).  Regarding the more recent proliferation of nitrosamine-related impurities, there have been two recent peer-reviewed articles that include a summary of the root cause and regulatory guidance (see and

One of the most recent sources of information regarding how to most effectively handle reporting the presence of potentially mutagenic impurities in regulatory applications comes from the U.S. Food and Drug Administration (FDA) in its “General Advice” (GA) letter sent to applicants with an approved or pending application for an ARB drug product as well as holders of Drug Master Files (DMF).

The EMA has also published its Article 31 assessment report for ARB drug products.  The quality section of the report primarily contains recommendations for how a manufacturer could make changes to its process chemistry to mitigate the presence or remove nitrosamine-related impurities rather than how to present data and information in regulatory submissions.  The discussion here will be based on the “General Advice” letter from FDA but the general principles can be applied to globally harmonized regulatory applications.

Applicants can consider the points FDA raised in the GA letter to more generally assist them in how to effectively report information regarding the origin, control and fate of potentially mutagenic impurities in regulatory applications.  These recommendations include:

  • Batch utilization tables for batches of active pharmaceutical ingredient (API) that were used in formulating drug products and drug product batches.  The data should be derived from all batches that were manufactured by the commercial manufacturing processes for the API and drug products and that are within the proposed or labeled re-test or shelf-life dates.  Applicants can link these tables to demonstrate to the health authorities the pattern of the origin and fate of the impurities from API to the finished drug product.
  • Full testing on receipt data – not just recording data from the API supplier’s certificate of analysis (COA) - taken from representative batches of API that are being used to formulate the drug product.  Typically this routine CGMP information would be kept on file at a manufacturing facility and made available during an inspection.
  • Verification and certification that the API suppliers being used by the drug product manufacturer routinely provide API that meets the permissible regulatory thresholds for potentially mutagenic impurities.
  • Disclosure of any re-work or re-processing of batches that are determined to contain potentially mutagenic impurities above the permissible regulatory threshold.
  • Continue routine release testing of all batches of API for the potential mutagenic impurities of concern until or unless the manufacturer can demonstrate that the process is not a risk for producing these impurities.  This would indicate that a release specification will need to be in place indefinitely for these impurities and that a skip-lot or sunset testing scheme will not be acceptable.
  • Batch data to demonstrate that API starting materials and raw materials used in the API manufacturing process contain no detectable levels of the impurities of concern or that the levels can be purged so that the API contains no detectable levels of the impurities.
  • Include the necessary information to fully identify any contract facility that is being used to recover materials used in the manufacturing processes for ARB production – API and drug products.

There is also a cautionary note to share when examining the GA letter.  In the letter, FDA notes that the internationally harmonized guidance ICH M7 recommends that known mutagenic carcinogens be controlled at or below the acceptable cancer risk level.

Because the FDA believes that it is feasible to limit the nitrosamine-related impurities by taking reasonable steps to eliminate or prevent their presence in drugs, FDA has determined that there is no acceptable specification for these impurities in either the API or drug product despite the acknowledged recommendations in the guidance.  

This is a powerful reminder that guidance documents are not final agency actions, have no legally binding effect on persons or entities outside the federal government and may be modified in the government’s discretion.  It’s a position that regulated industry could see again in similar circumstances.


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