Many of our clients and readers have NDAs, ANDAs, and supplements that are still pending approval due to a “complex regulatory issue” where the FDA has missed its goal date; in some cases, this missed date was many months ago.  There can be several reasons for this type of delay but, as we have blogged about before, one of the most vexing and complex issues before the Agency today is related to nitrosamine impurity issues and, more specifically, Nitrosamine Drug Substance‑Related Impurities or NDSRIs.  Frequently, application and supplement approval delays have reached six months or more.  In some cases, applicants are in the unenviable position of having seen competitor applications approved while their application is stalled and remains pending with the FDA.  This writer recently assisted a client in reaching out to the CDER Ombudsman, Ms. Virginia Behr, regarding a nitrosamine‑related impurity delay that was holding up the approval of an original application.  The reply was not encouraging, but not unexpected either: “The issue is going to take some time to sort out.  There is a large team working very actively on it.   …I think it’s likely going to take months, not days or weeks.”

Sorting out an issue as complex as NDSRIs has generated a lot of buzz and there are some upcoming workshops dedicated to the topic.  The FDA and Health and Environmental Sciences Institute (HESI) have collaborated to host a workshop on May 31st and June 1st on nitrosamine risk assessments and NDSRIs, and are offering a free webcast to interested participants.  Check out this link for more details.  The Center for Research on Complex Generics (CRCG) is also offering a workshop on June 15th on Mitigation Strategies for NDSRIs including Quality and Bioequivalence Considerations for Generics.  The in‑person registration closes soon, but CRCG is also offering a virtual attendance option through its website.  Check out this link for more information on the workshop.  The USP is doing its part to support collaboration and knowledge‑sharing by hosting the Nitrosamines Exchange.  This interactive group discusses methodology, structures to select for QSAR approaches to proposing interim limits, and many other topics.  Check it out here.

The scale of the NDSRI issue continues to be uncovered with new impurities discovered, and this will need to be a development consideration for all new products moving forward.  Currently, the FDA is talking only to applicants with products on the market as NDSRIs are a public health issue for marketed products and, in some cases, the conversations are part of drug mitigation strategies to avoid shortages, but those stuck behind the ropes, still waiting for approval or even feedback on what they can do to help the FDA make an approval decision, aren’t hearing anything.  Complex regulatory issues, no timeline for resolution, check back in a few weeks has been the standard, repeated reply for months.  With so many applications affected and in various stages of the regulatory review and approval process, this issue may be approaching an unprecedented level of complexity for the FDA to unravel, such that it cannot do it alone.  As a colleague blogged about earlier in May here, the FDA has opened a non‑rulemaking docket here to solicit feedback on the NDSRI issue and to gather recommendations on how to collaborate and work toward resolution.

NDSRIs are a grave concern for drug product manufacturers, both branded and generic, and, as reflected in the Ombudsman’s feedback above, the Agency has a large team actively working on it, but this is still likely to take months to resolve.  So, what can you do?  Consider contributing comments to the FDA docket and sharing your brilliant collaboration ideas!  The FDA has worked with other health authorities to share basic information on which products and drug substances might be affected, but the bigger issue with knowledge‑sharing is how to share testing methodologies or testing data across applications and applicants.  The FDA can make some data public, but it is also bound by confidentiality restrictions and can’t publicly disclose an acceptable intake limit, an amended or enhanced AMES method, or a successful study protocol and/or results without the written permission of the applicant that submitted the data.  No one wants to see multiple in-vivo tox studies performed to generate the same data, or worse, get different results and generate more confusion around an acceptable intake limit for an NDSRI (think of all the animals and time that would be wasted!).  To achieve the level of cooperation and collaboration that will likely be needed to resolve NDSRI issues for all applicants, the formation of a public‑private partnership or similar knowledge‑sharing platform may become critical.  How can the FDA facilitate collaboration to generate reliable compound‑specific data on NDSRIs and reduce (or even better, eliminate!) the need for additional and potentially duplicative testing?  Would an extension of the recommended timeline for submission of changes in drug applications, as described in the Nitrosamine Guidance, from its current date of October 1, 2023 to June 1, 2024 allow for additional assessment and enable collaborative efforts among affected applicants?  For applicants waiting for action on their pending applications, this may be the best way to get the Agency moving again and help get applications over the line for approval.  The comment period is currently open through July 3rd.  Offer your thoughts and help move the conversation forward!