EMA：人用药品亚硝胺评估最终报告-2020年07月.pdf

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. Introduction7 2.2. Quality and safety aspects7 2.2.1. Root causes for presence of N-nitrosamines in medicinal products and measures to mitigate them8 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 packaging21 2.2.4. Discussion on root causes and strategies to mitigate the presence of N-nitrosamines in human medicinal products23 2.3. Consideration for analytical method development to identify and quantify N- nitrosamines in APIs and finished products25 2.3.1. Analytical Methods25 2.3.2. Sample Preparation Procedures 26 2.3.3. Potential causes of erroneous analytical results 28 2.3.4. Internal Standards29 2.3.5. Advantages of mass spectrometric detection devices29 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) 3