FDA finalized guidance to the industry regarding nitrosamine impurities, “Control of Nitrosamine Impurities in Human Drugs” in Feb 2021. However, the guidance has left the industry with more questions than answers. Post-publication of the final guidance, the FDA and Industry (AAM, PHARMA, CHPA) had a meeting on May 4, 2021, where the pharmaceutical industry representatives presented on how the FDA’s nitrosamine-related decisions have overly impacted the innovators, generics, and over the counter pharmaceutical industry alike. Agency has posted its responses to the industry’s questions on the FDA website. While the document provides information regarding some of the FDA’s current thinking on nitrosamine impurities, there are several topics that need clarification. One of the major questions is related to nitrosamine substance-relate dated impurities (NDSRIs).
The NDSRIs have their origin in the drug substance itself and thus difficult to control without understanding the source of the nitro-sating agent in the route of synthesis of the drug substance and the formulation of the finished product. The other question that has been troubling the industry is the acceptable levels of NDSRIs in their drug products. Agency, in the May 4th, 2021 meeting has expressed that “read across” may be acceptable in setting limits of NDSRIs. However, with nitrosamine-related data being far and few in the literature, this may be challenging.
Although almost 3 years have elapsed since the contamination incident, the FDA and other international regulatory agencies continue to face many challenges. One is that nitrosamines are formed and widely distributed in the environment— found in fresh vegetables, fruits, smoked and grilled meats, and fish; in water; in the air; and formed endogenously.
Therefore, eliminating or minimizing nitrosamines in drugs is problematic. Eliminating or minimizing nitrosamines as impurities in drugs begins with quality control. To date, not all root causes have been identified; new root causes continue to emerge. Factors such as stability, excipients, and storage conditions act nitrosamine formation, hampering mitigation and control efforts.
The Fourth edition of the Nitrosamine Impurities forum scheduled for the 13th-14th of December 2022, in Mumbai will be a one-day conference and one-day workshop model. The forum aims to discuss the recent developments related to nitrosamine impurities, the challenges faced by the pharmaceutical industry, and work towards possible solutions that may lead to a world with lower levels of nitrosamines. The workshop will span over 5 hours with an open discussion and question and answer session.