Nitrosamines – Expensive Witch Hunt or Very Broad Safety Concern?

I have recently touched upon the subject of nitrosamines in drug products as part of a blog on Extraneous Peaks (here).  The concern about nitrosamines in drug products continues to grow, and it will be a significant challenge for the regulators and pharmaceutical industry to establish meaningful policies and procedures to ensure there are no safety concerns for marketed products.  On September 19, 2019 the European Medicines Agency (EMA) issued a request for marketing authorization holders “·· to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicinal products containing chemically synthesised APIs” (here).  The EMA recommends a 3-step process:  Step 1). Risk Assessment of medicinal products containing chemically synthesised APIs, Step 2). Confirmatory Testing where warranted, and Step 3). Changes to Marketing Authorizations if required to address the any identified risks.  The timing for Step 1 is within 6 months of the publication of the notification, for Step 2 is “as soon as possible”, with Step 3 to be completed within 3 years of the publication of the notification.  This all seems like a monumental task even in the light of the highlighted safety concerns and is especially aggressive timing considering the scope.

The FDA (U.S. Food and Drug Administration) has been approaching the topic by helping the drug industry to establish meaningful limits and testing procedures.  The FDA has updated the interim limits (here) and has provided test methods for quantification of nitrosamine impurities for Angiotensin II Receptor Blockers (here) and ranitidine drug products (here).  The FDA has also challenged the nitrosamine testing data being generated by laboratories using other methods (here).  The FDA is interacting with the EMA, Health Canada, and other regulators on the topic (here).

The potential sources of nitrosamine impurities in drug products are not yet completely understood, nor is the scope of drug products that may be impacted.  Further, the controls that will be required to ensure nitrosamine impurities are not present above acceptance levels will take time and significant resources to develop.  It will be important that good science is used to understand the scope and the impact before setting broad policy even in the light of such a significant concern.  Extra testing will likely be justified and unfortunately be reflected in the cost of manufacturing.  The challenge will be “How much testing is necessary?” to assure safe drug products.

For further information and assistance on the topic of Nitrosamines in Drug Products, please contact either Ron George, Ph.D. at r.george@lachmanconsultants.com or Mary Oates, Ph.D. at m.oates@lachmanconsultants.com.