Dear All,
EMA has updated Q&A docs to provide the additional risk factors for the presence of nitrosamines (like GMP aspects, finished product) and allowing the API or intermediates testing as a surrogate for testing of the finished product if the root cause is only linked to the API manufacturing process.
Please consider the additional risk factors as suggested by the Agency during your NIRA preparation.
Happy Reading!
Thanks & regards,
Sumit
Nitrosamine Imp -Q&A-Mar-22.pdf (469.0 KB)
Hi, @sumitkumarjain
Thank you for sharing the helpful information. I want to add some comments. The update is the following four chapters.
Revision History
Revision history with a summary of changes is newly included.
Q4. What are the currently identified risk factors for presence of nitrosamines?
15 Route causes are divided into three types such as risk factors related to the manufacture of the API, FP, and risk factors from GMP. Lots of examples, references, and detailed explanations are added to make the cases with high-risk clear. And the formation of NDSRI is described in FP part. This chapter is notable.
Q8. How should confirmatory tests be conducted by MAHs and manufacturers?
Testing should be generally carried out on FP. Testing of the API, its intermediates, starting materials, solvents, reagents, excipients, or any other raw materials for nitrosamines are also available, but It should be clearly justified why testing of those compounds is appropriate and why further risk of nitrosamine formation in the finished product or subsequent API manufacturing steps can be excluded.
Q15. When should a test for nitrosamines be included in the MA dossier?
It is the requirement of the MA dossier. When the actual source of contamination remains unclear, routine testing of the finished product is required by default. And control options 1 to 3 (not 4) stated in ICH M7(R1) guideline are available to demonstrate that the nitrosamine will not be present above the AI in the FP.
I’m very interested in Q4.
Adding additional detail to @Yosukemino reply. Updates from 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 Ver.8
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
Risk factors related to the manufacture of the active substance:
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.
4-Oxidation of hydrazines, hydrazides and hydrazones by hypochlorite, air, oxygen, ozone and
peroxides in the manufacturing process or during storage.
6-Use of contaminated starting materials and intermediates supplied by vendors who use
processes or raw materials which may contain residual nitrosamines or nitrosating agents.
Risk factors also related to the finished product:
8-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. 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
9-Degradation processes of active substances, including those induced by inherent reactivity (e.g. presence of nitro-alkyl, oxime, or other functionality3,4) 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.).
10-. 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. This root cause has also been observed
during the manufacture and storage of finished products containing such functional groups.
Potential oxidants include oxygen and peroxides (common impurities in some excipients).
12-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
-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
-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
-(Removed) Even if the control point for the nitrosamine is not at finished product level, a limit
has to be included in the finished product specification and batches should comply if tested