Europe: EMA Updates Q&A for MAHs on Nitrosamine Impurities in Medicinal Products

Summary: The European Medicines Agency (EMA) has released the eighth revision of the document entitled “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products”. Key changes are as follows:

• Revision History – New
• Q4: What are the currently identified risk factors for presence of nitrosamines? (UPDATED)
  • N-Nitrosamines can be formed when an amine and nitrosating agent are combined under favourable conditions although other generation pathways are also possible, such as e.g. oxidation and reduction processes from hydrazine-type compounds and N-nitro derivatives.3,4 Root causes for N-nitrosamines in medicinal products identified to date can be grouped as risk factors linked exclusively with the manufacturing process and storage of active substance and/or as risk factors associated with manufacture and storage of the finished product. Moreover, there are risk factors specifically linked to GMP aspects. Currently identified risk factors for N-nitrosamine impurities in medicinal products are listed below, along with some identified in the literature. However, the list is not exhaustive and further root causes may also be applicable – it is up to MAHs to determine if there is a risk with their product:

Risk factors related to the manufacture of the active substance:

1. Use of nitrite salts and esters (e.g. NaNO2, alkyl nitrites), or other nitrosating agents (e.g. nitroso halides, nitrosonium salts, nitrogen oxides, nitro alkanes, halogenated nitro alkanes, Fremy’s salt, nitroso sulfonamides),3,4 in the presence of secondary or tertiary amines within the same or different steps of the manufacturing process. Sources for secondary or tertiary amines can also be starting materials, intermediates, reagents, solvents (e.g. DMF, DMAc and NMP) and catalysts, which contain amine functionality, amine impurities (e.g. quaternary ammonium salts) or which are susceptible to degradation to reveal amines.
2. Nitrite formation by oxidation of hydroxylamine or nitrite release from nitro-aromatic precursors (e.g. by fluoro de-nitration), in the presence of secondary or tertiary amines within the same or different steps of the manufacturing process (see 1).5
3. Use of disinfected water (chlorination, chloro-amination, ozonisation) in the presence secondary or tertiary amines within the same or different steps of the manufacturing process (see 1).6,7,8,9
4. Oxidation of hydrazines, hydrazides and hydrazones by hypochlorite, air, oxygen, ozone and peroxides in the manufacturing process or during storage.4 Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts).
5. Use of contaminated recovered or recycled materials (e.g. solvents, reagents and catalysts).

Risk factors also related to the finished product

1. Reaction of nitrosatable nitrogen functionality in APIs or their impurities/degradants with nitrosating agents present in components of the FP during formulation or storage. A particular risk of formation of nitrosamines should be noted for active substances that contain a nitrosatable amine functional group. Several examples have been reported where the amine functionality was shown to be vulnerable to nitrosation and formation of the corresponding Nnitroso impurity (i.e. NO-API). Secondary amines appear particularly vulnerable to this reaction although some cases with tertiary amines have also been observed. Vulnerable amines could also be formed by degradation (e.g. hydrolysis) during formulation or storage. Nitrites have been identified as impurities in many common excipients.10 MAHs and/or applicants should be aware that N-nitroso API impurities can form at levels exceeding the AI even if nitrite levels in the excipients are very low. The overall nitrite content will also depend on the relative composition in terms of the excipients. As it has been reported that N-nitroso impurities can form from APIs or their impurities/degradants (containing amine functionality or susceptible to degradation to reveal amines) during manufacture of the finished product, as well as during storage, MAHs should give consideration to the stability of the finished product and should ensure that the AI of any N-nitrosamine impurity is not exceeded until the end of shelf life of the FP. For further information, please refer to the assessment report of the CHMP’s Article 5(3) opinion on nitrosamine impurities in human medicinal products.

2. Degradation processes of active substances, including those induced by inherent reactivity (e.g.presence of nitro-alkyl, oxime, or other functionality 3,4) or by the presence of an exogenous nitrosating agent. This could potentially occur during both active substance and finished product manufacturing processes or during storage and could be influenced by crystal structure, crystal habit and storage conditions (temperature, humidity etc.). For more details, refer to page 6 of Referral under Article 31 of Directive 2001/83/EC for ranitidine and published literature.11,12

3. Oxidation of hydrazine or other amine-containing functional groups present in active substances or their impurities/degradants (e.g. from hydrazones and hydrazides), either in active substance manufacturing processes or during storage.4 This root cause has also been observed during manufacture and storage of finished products containing such functional groups. Potential oxidants include oxygen and peroxides (common impurities in some excipients).10

4. Use of certain packaging materials. Relevant nitrosamine contamination has been observed in primary packaging of finished products in blister with lidding foil containing nitrocellulose. During the blister heat-sealing process, nitrogen oxides can be generated thermally from nitrocellulose. Under these conditions, nitrosamines have been shown to form from low molecular weight amines present either in printing ink or in the finished product and to transfer to the product and/or to the cavity via evaporation and condensation.

5. Reaction of amines leaching from quaternary ammonium anion exchange resins (e.g. used for purification steps) with nitrosating agents present in the liquid phase. A recent example of this was in the production of water for injections where residual chloramine used to disinfect incoming water reacted with dimethylamine leaching from the anion exchange resin used in the demineralisation step to form NDMA. In addition, disinfection procedures such as e.g.chlorination, chloro-amination and ozonisation can lead to significant N-nitrosamine generation as by-products in case vulnerable amines are present.6,7,8,9 Given the source of contamination, risk is related to the concentration of the reactive agent(s) and thus to the volume of water in or used to dilute a particular product. The same risks could be associated with active substances or finished products manufactured using water purified using similar resins.

Risk factors related to GMP aspects

(&…) 3. Lessons learnt from presence of N-nitrosamine impurities in sartan medicines EMA/526934/2019.

1. Org. Process Res. Dev. 2020, 24 (9), 1558–1585

2. Chem. Rev. 2016, 116, 422−518

3. Crit. Rev. in Environ. Sci. 2017, 47, (24), 2448-2489

4. J. Pharm. Biomed., 2019, 164, 536-549

• 8. How should confirmatory tests be conducted by MAHs and manufacturers? (UPDATED)
  • For the purpose of confirmatory testing as part of step 2 of the call for review to MAHs, testing should generally be carried out on the FP. Testing of the API, its intermediates, starting materials, solvents, reagents, excipients or any other raw materials for nitrosamines, amines, nitrites or other compounds with potential to generate nitrosamines is also recommended, if the risk assessment indicates that they are a potential source of nitrosamine impurities in the FP. In such cases, the results of testing API, intermediates or other relevant materials may be used to support root cause investigations and the development of a justified control strategy for nitrosamine impurities. However, some root causes may only be linked to the API manufacturing process (see Q&A 4). In these cases, testing of the API or intermediates upstream of the active substance could be used as a surrogate for testing the finished product, provided that the risk assessment performed on the FP concluded no additional risk factors for formation of nitrosamine impurities in the finished product (see Q&A 4, risk factors related to the finished product). If testing is carried out on an intermediate, then there should also be no risk factors associated with subsequent steps in the API manufacturing process or the finished product. The confirmatory testing strategy is the responsibility of the MAH and should be justified based on the risk assessment for the finished product and documented in the MAH’s pharmaceutical quality system. It should be clearly justified why testing of the active substance or intermediate is appropriate and why further risk of nitrosamine formation in the finished product or subsequent API manufacturing steps can be excluded. If nitrosamines are detected, then an appropriate control strategy should be implemented in the dossier. In any case, if the control point of nitrosamines is not in the finished product, the responsibility for quality lies with the MAH.
• 13: Which changes would be required for Marketing Authorisations?
  • The application for a variation should contain information on amendments to the marketing authorisation – i.e. in module 3 (3.2.S and 3.2.P), the active substance master files (ASMF) or the Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) that is necessary to control nitrosamine impurities in the active substance and/or FP. Variations should be submitted according to the existing variations classification guideline: EUR-Lex - 52013XC0802(04) - EN – EURLex (europa.eu)
• Q15: When should a test for nitrosamines be included in the MA dossier? (UPDATED)
  • If the root cause has been identified in the finished product manufacturing process or storage, or nitrosamines have been detected in the finished product, but the actual source of contamination remains unclear, routine testing of the finished product is required by default.
  • (…) Only if the amount of nitrosamine present is consistently below 10% of the acceptable limit based on AI in the API or in the finished product, then a test for the nitrosamine could be omitted from the specification. Only if levels of a single nitrosamine are consistently below 30% of the acceptable limit based on AI in the API or the finished product, skip-testing according to the ICH Q6A definition could be acceptable.

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