Thank you for sharing information, @Naiffer_Host. I haven’t read all of the literature yet, but I’ll share some past FDA comments as additional information.
16. Can FDA confirm that the control strategy for a nitrosamine can utilize the same principles outlined in ICH M7 for mutagenic impurities, and the same associated four control strategy options?
a. Does FDA agree that Option 3 should be an appropriate control strategy, per ICH M7. If not, does FDA have a perspective on specific alternatives?
If levels in the API are above LOQ and less than AI, FDA recommends a control in the specification of the API. However, adequate justification for an Option 3 approach (e.g., an upstream or in-process control coupled with fate and purge studies that demonstrate the level consistently remains well below the AI may be possible.
b. If a nitrosamine is known to be present in a manufacturing process, is an ICH M7 Option 4 control strategy an acceptable mitigation? Or is a control strategy that includes an analytical test automatically required?
If a nitrosamine is above LOQ in the API then an Option 4 control strategy may not be appropriate. Option 4 requires complete understanding of process parameters, including fate and purge studies, as well confidence that there is negligible risk that the impurity will be present above AI. ICH M7 suggests that this approach may be used for inherently unstable impurities, which does not describe nitrosamines. For application products, Option 4 will be considered on a case-by-case basis if proposed in an application or Drug Master File (DMF). However, ICH M7 principles, with appropriate supporting data and justification, including option 3 and 4, are applicable. Given existing uncertainties regarding nitrosamine impurities and their presence in drugs, for APIs with an impurity detected above the LOQ or at-risk APIs, testing of each batch on release should be conducted. Alternate approaches (e.g., upstream test of an intermediate) should be supported by sufficient process understanding and evidence of adequate statistical control and, for application products, should be submitted to FDA in a supplement prior to implementation. Any drug product batch found to contain levels of nitrosamine impurities at or above the recommended AI should not be released by the drug product manufacturer for distribution. Manufacturers should contact the Agency if a recall is initiated. Under section 501 of the FD&C Act, a drug that is not manufactured, processed, packed, or held in conformity with CGMP to ensure that the drug meets certain quality and purity standards is considered adulterated. FDA may exercise regulatory discretion when warranted to prevent or mitigate a shortage of a drug.
17. Calculated purge factors in API synthesis are an important tool for assessing the presence and/or formation of nitrosamines. However, FDA’s guidance suggests testing all lots of API using at-risk materials in the route of synthesis. What is FDA’s position on the use of calculated purge factors to discharge the risk of nitrosamine presence?
As noted in the response to question #16 above, calculated purge studies that demonstrate the absence of nitrosamines, if suitably justified by the use of experimental data along with process understanding, may be appropriate in controlling nitrosamines.