Pharmaceutical Technology - March 2021

Pharmaceutical Technology - Regulatory Sourcebook - March 2021

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34 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m As shown in Figure 1, if the 2° amine-derived nitrosamine contains hydrogens on the alpha carbon of the amine, it can undergo activation (oxidation) in vivo, which sets off a series of reactions resulting in the formation of an alkyl or aryl diazonium. These are very reactive alkylating agents and proposed to be the chemical entity for genotoxicity. Compounds such as N-nitrosodiisopropylamine (NDIPA) and N-nitrosoethylisopropylamine (NEIPA) are currently and conservatively assumed to have carcinogenic potency equivalent to that of NDEA even though carcinogenicity data show significantly lower carcinogenic potency due to the steric hinderance at the alpha position of the amine preventing the formation of the mutagenic metabolite (dia- zonium, Figure 1) (24–25). Second, well-precedented LTL concepts from ICH M7(R1) are currently and conservatively stated not to be appropriate for NAs (5–6, 26). However, dose-time relationships have been established for NAs, and example compounds were used to develop the ICH M7(R1) framework (17–18, 24, 27– 28). These data can be used to better inform the appropri- ateness of LTL concepts for NAs. For example, model com- pounds are being used to validate the LTL concepts for NAs. Third, regulatory guidance documents mention the use of read-across/structure-activity analyses (SAR) to develop AIs for NA impurities when no carcinogenicity data are available. Data are being pulled together to provide addi- tional guidance on the structural relationship for NAs and carcinogenic potency (29–32). Ongoing research and collaboration The ability to mobilize experts in different aspects of drug development and manufacturing to address the challenge presented by NAs is the result of years of pre-competitive collaboration among IQ member companies. Over the past 10 years, IQ members have developed compliant structures and created a community of scientists and quality experts committed to advancing innovation to develop new tech- nologies and respond to new challenges. As more is learned about NAs, whether about the likelihood of their formation, or new safety findings, the Consortium's ability to quickly engage with a broad range of experts—on a precompetitive basis—promises to provide industry with valuable infor- mation that can be applied to protect patient safety and product quality. References 1. ICH, M7(1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 4 version (2017). 2. R. Kroes, et al., Food Chem Toxicol 42 (1) 65–83 (2004). 3. FDA, Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs (2020). Quality Collaboration Figure 1. Formation N-nitrosamines from secondary amines and mechanism for mutagenesis (8, 33). FIGURE COURTESY OF THE AUTHORS.

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