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32 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m Quality Collaboration ment of the AIs (6). N-Nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) AIs are based on extrapola- tion from the TD 50 . The data set for NDMA and NDEA in- clude very robust carcinogenicity studies (15 dose groups per compound with 4080 total rats for both compounds) (17–18), in-vivo dose-response mutagenicity studies (19), and mecha- nistic dose-response initiation studies (20–21). These studies allow for more robust modeling of the dose-response curve, al- lowing for significantly higher limits than the traditional TD 50 approach (22–23). Table I. Summary of regulatory guidances for N-nitrosamines for different topic areas. Topic European Medicines Agency (EMA/409815/2020 Updated Jan. 29, 2021) FDA (Updated Feb. 24, 2021) SwissMedic (Updated Sept. 11, 2020) Health Canada (Updated Dec. 15, 2020) Risk assessment scope All marketed drug substances and drug products All marketed drug substances and drug products All marketed drug substances and drug products All marketed drug substances and drug products Exceptions Advanced cancer ICH S9 should be controlled to ICH Q3A(R2)/Q3B(R2) thresholds None mentioned None mentioned None Mentioned Biologicals In scope No information In scope In scope Deadline for Step 1 – Risk evaluation Chemically synthesized: March 31, 2021 Biologicals: July 1, 2021 March 31, 2021 Chemically synthesized: March 31, 2021 Biologicals: July 1, 2021 Chemically synthesized: March 31, 2021 Biologicals: Nov. 30, 2021 Deadline for Step 2 – Confirmatory testing Chemically synthesized: Sept. 26, 2022 Biologicals: July 1, 2023 October 1, 2023 Chemically synthesized: Oct. 1, 2022 Biologicals: July 1, 2023 Chemically synthesized: Oct. 1, 2022 Biologicals: Nov. 30, 2023 Submission of marketing application Risk evaluation and confirmatory testing (if performed) submitted Risk evaluation and confirmatory testing (if performed) submitted. Pending NDAs must also perform risk assessments and provide risks to agency when available. No information Risk evaluation and confirmatory testing (if performed) submitted Analytical requirements LoQ ≤ AI routine control LoQ ≤ 30% of AI skip testing LoQ ≤ 10% of AI omission of specification LoQ ≤ 0.03 ppm or based on dose for high doses LoQ ≤ 0.03 ppm Quantitative method required, LoQ less than the most potent AI of all NAs. ≥30% of the AI may require a specification Nitrosamine-specific AIs NDMA, NDEA, NIPEA, NDIPA, NMBA, MeNP, NDBA, NMPA NDMA, NDEA, NMBA, NMPA, NIPEA, NDIPA NDMA, NDEA, NMBA, NIPEA, NDIPA NDMA, NDEA, NMBA, NIPEA, NDIPA, MeNP, NDBA Generating AI for nitrosamine with chemical-specific data TD 50 from carcinogenicity data TD 50 from carcinogenicity data TD 50 from carcinogenicity data TD 50 from carcinogenicity dataa Nitrosamine AI without chemical-specific data AI – 18 ng/day or SAR/read-across Surrogate can be used with scientific justification No information Determine if nitrosamine would have potency similar to NDEA or NDMA LTL AIs Control to chronic AI. Higher LTL limits will be considered with consul- tation No mention, but cites ICH M7 principles which has guidance for LTL exposures of mutagenic carcinogens No mention, but cites ICH M7 principles which has guidance for LTL exposures of mutagenic carcinogens Control to chronic AI. Higher LTL limits as described in ICH M7 will be considered with consultation. Limits for multiple nitrosamines Total risk level should not exceed 10 -5 Total should not exceed 26.5 ng/day No information Control total cumulative exposure to lowest AI of all NAs ICH is International Council for Harmonisation; MAA is marketing authorization application; NDA is new drug application; LoQ is limit of quantitation; AI is acceptable intake; LTL is AIs developed for less than lifetime (LTL) exposures; SAR is structure activity relationship; NA is N-nitrosamine NDMA is N-Nitrosodimethylamine [62-75-9] NDIPA is N-Nitrosodiisopropylamine [601-77-4] NDEA is N-Nitrosodiethylamine [55-18-5] NMBA is 4-[Methyl)(nitroso)amino]butanoic acid [61555-55-4] MeNP is 1-Methyl-4-nitrosopiperazine [16339-07-4] NDBA is N-Nitrosodibutylamine [924-16-3] NMPA is N-Nitrosomethylphenylamine [614-00-6] NIPEA is N-Nitrosoethylisopropylamine [16339-04-1]