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Nitrosamines EMEA-H-A5(3)-1490 25 June 2020 EMA/369136/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Procedure under Article 5(3) of Regulation EC (No) 726/2004 Nitrosamine impurities in human medicinal products Procedure number: EMEA/H/A-5(3)/1490 Note: Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ...................................................................................... 2 1. Information on the procedure ............................................................... 7 2. Scientific discussion .............................................................................. 7 2.1. Introduction......................................................................................................... 7 2.2. Quality and safety aspects ..................................................................................... 7 2.2.1. Root causes for presence of N-nitrosamines in medicinal products and measures to mitigate them............................................................................................................. 8 2.2.2. Presence and formation of N-nitrosamines in human medicinal products .................. 9 2.2.3. Confirmed root-causes for the formation of N-nitrosamines in medicinal products with regard to excipients and as contaminants from primary packaging .................................. 21 2.2.4. Discussion on root causes and strategies to mitigate the presence of N-nitrosamines in human medicinal products ...................................................................................... 23 2.3. Consideration for analytical method development to identify and quantify N- nitrosamines in APIs and finished products ................................................................... 25 2.3.1. Analytical Methods ........................................................................................... 25 2.3.2. Sample Preparation Procedures ......................................................................... 26 2.3.3. Potential causes of erroneous analytical results ................................................... 28 2.3.4. Internal Standards ........................................................................................... 29 2.3.5. Advantages of mass spectrometric detection devices............................................ 29 2.3.6. Currently used methods in OMCLs ..................................................................... 29 2.3.7. Sensitivity of the analytical methods .................................................................. 30 2.3.8. Discussion on analytical aspects ........................................................................ 31 2.4. Considerations for calculating risk for exposed patients in case of detection of N- nitrosamines in medicinal product(s) ........................................................................... 31 2.4.1. Background exposure to N-nitrosamines ............................................................. 31 2.4.2. Mutagenicity and carcinogenicity of N-nitrosamines ............................................. 35 2.4.3. N-Nitrosamine carcinogenicity in animals ............................................................ 37 2.4.4. Use of in vitro mutagenicity data for carcinogenicity potency ranking of N- nitrosamines ............................................................................................................ 41 2.4.5. Generic methodology to calculate excess risk for humans ..................................... 43 2.4.6. Literature review of epidemiological studies ........................................................ 44 2.5. Methodology for defining limits for N-nitrosamines ................................................. 48 2.5.1. Limits for individual nitrosamines, for multiple N-nitrosamines and less than lifetime (LTL) approach ......................................................................................................... 48 2.5.2. Limits for nitrosamines without sufficient substance specific data........................... 50 2.5.3. Other risk management approaches ................................................................... 51 2.5.4. Comparison of different options for setting limits ................................................. 52 2.6. Consideration for further studies .......................................................................... 56 2.6.1. Consideration for further non-clinical/clinical studies ............................................ 56 2.6.2. Consideration for further epidemiological studies ................................................. 56 2.7. Relevance for the CHMP opinion on medicinal products containing sartans with a tetrazole ring............................................................................................................ 58 3. Expert consultations ........................................................................... 59 3.1. Ad-hoc expert group ........................................................................................... 59 3.2. BWP consultation ............................................................................................... 64 EMA/369136/2020 Page 2/90 3.3. QWP consultations .............................................................................................. 64 3.3.1. Summary of QWP responses to first CHMP LoQ.................................................... 64 3.3.2. Summary of QWP responses to second CHMP LoQ ............................................... 65 3.4. SWP consultations .............................................................................................. 66 3.4.1. Summary of SWP responses to first CHMP LoQ .................................................... 66 3.4.2. Summary of SWP response to second CHMP LoQ ................................................. 70 3.5. PRAC consultation .............................................................................................. 71 4. Conclusions ........................................................................................ 73 4.1. Root causes for presence of N-nitrosamines ........................................................... 73 4.2. Analytical methods for N-nitrosamines .................................................................. 74 4.3. Setting Limits for N-nitrosamines in human medicinal products ................................ 75 4.3.1. Presence of more than one N-nitrosamine .......................................................... 76 4.3.2. N-nitrosamines with insufficient toxicological data ............................................... 76 4.3.3. Less-than-lifetime (LTL) approach ..................................................................... 76 4.4. Considerations on epidemiological studies ............................................................. 77 5. Recommendations .............................................................................. 77 6. References .......................................................................................... 82 EMA/369136/2020 Page 3/90 List of abbreviations AI Acceptable intake. In the context of this document, an intake level /limit associated with a theoretical excess lifetime cancer risk of 1:100,000 based on considerations in ICH M7(R1) for substances from the “cohort of concern” API Active Pharmaceutical Ingredient AIM Active Ingredient Manufacturer = active substance manufacturer ALARA as low as reasonably achievable ALARP as low as reasonably possible BCNU Bischloroethyl nitrosourea CCNU 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea CHMP Committee for Human Medicinal Products CPDB Carcinogenic potency database CoA Certificate of Analysis CoC Cohort of Concern Compounds CEP Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) CRS Chemical Reference Substance (official standard) DIPNA N,N-diisopropylethyl-N-ethylamine DMF Dimethylformamide DI Direct injection DS Drug substance EDQM European Directorate for the Quality of Medicines EFSA European Food Safety Agency EIPNA Ethylisopropyl-N-nitrosoamine EMA European Medicines Agency ENOCs Endogenously produced N-nitroso compounds EPA Environmental Protection Agency FDA Food and Drug Administration IARC International Agency for Research on Cancer IPC In-process control IR Infrared Spectrometry IU International Units LCDB Lhasa Carcinogenicity Data Base LOD Limit of Detection LTL Less than Lifetime EMA/369136/2020 Page 4/90 LOQ Limit of Quantification MA Marketing Authorisation MAH Marketing Authorisation holder Methyl-CCNU 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea MGMT Methyl-guanine-methyl-transferase MNNG N-Methyl-N´-nitro-N-nitrosoguanidine MS Mass Spectrometry ND Not detected NDBzA N-nitrosodibenzylamine NDEA N-Nitrosodiethylamine NDELA N-Nitrosodiethanolamine NDiBA N-Nitrosodiisobutylamine NDMA N-Nitrosodimethylamine NDPA N-Nitrosodi-n-propylamine NDPhA N-nitrosodiphenylamine NHMTC N-nitroso-2-hydroxymethyl-thiazolidine-4-carboxylic acid NHPRO N-nitrosohydroxyproline NIAN 1-Nitrosoindole-3-acetonitrile NLT Not less than NMEA N-Nitrosomethylethylamine NMNU
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