Module 3 - Strategic case studies in practice

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