EMA/CHMP Concept paper on the revision of the guideline on the chemistry of active substances

Guidance, Documents, Resources
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In Jul-2022 a draft concept paper (IDRAC 350718) was released for comments by the EMA, raising theneed to review and update the 2016 final guideline (IDRAC 235975) to include further recommendationson prevention, risk mitigation and control of N-nitrosamines, other CoC impurities and also other potent toxins.

The draft concept paper is open for comments with deadline of 31-Oct-2022

The following aspects will be taken into account for the revision of the guideline on the chemistry of active substances to further define the requirements in regulatory submissions, with reference to the EMA/CMDh questions-and-answers document on N-nitrosamines and the LLE report:

  • Guidance on appropriate process development in order to mitigate as much as possible the potential presence of N-nitrosamines or other CoCcompounds as well as of other potent toxins (if applicable). The selected manufacturing process should be justified accordingly.

  • Guidance on the need to provide clear information on all the materials used in the process (including raw materials, starting materials, and intermediates) in relation to their function in the corresponding manufacturing step, their applied quantities, and their potential contaminants, and their overall quality.

  • Guidance on the required discussion regarding the presence or formation of N-nitrosamines or other CoCcompounds as well as of other potent toxins. Clarify the new systematic approach suggested by ICH M7 on mutagenic impurities.

  • Guidance on the use of recycled materials.

  • Guidance on specific control options for N-nitrosamines or other CoCcompounds as well as for other potent toxins, including possible control points and acceptance criteria.

  • Guidance on the need to consider formation of nitrosamines or other CoCcompounds as well 50asofother potent toxins during storage

IDRAC_350718_29-Jul-2022_EMA_CHMP_600383_2022_ Draft Concept Paper on the Revision of the Guideline .pdf (113.1 KB)

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Hi, @Naiffer_Host.

Thank for sharing the information. I found the article of this topic.

https://www.raps.org/news-and-articles/news-articles/2022/7/ema-to-address-nitrosamine-impurities-in-upcoming

  • The revised guideline addresses topics such as process development strategies to mitigate the presence of N-nitrosamines or other impurities; the need to provide clear information on the use of raw materials, starting materials and intermediates in relation to their function in manufacturing steps, and their potential contamination risks; required discussions regarding the presence or formation of nitrosamines; the use of recycled materials; specific control options for nitrosamines; the need to consider nitrosamine impurities or other compounds and potential toxins arising during storage.

And I share the original guideline. It will be more practical in the future.
guideline-chemistry-active-substances_en.pdf (203.6 KB)

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A new concept paper and draft guidance are available on EMA.

Draft guideline on the chemistry of active substances - Revision 1

Concept paper on the revision of the guideline on the chemistry of active substances - Revision 1

Draft guideline includes as follows;

4.2.3. Control of Materials 3.2.S.2.3
Active Substance (AS) Starting Material(s)
Risk of formation and carry-over of nitrosamines during the starting materials synthesis should be evaluated (e.g., use of nitrosating agents, secondary or tertiary amines, etc.). If a risk is identified, adequate control strategies (in the specification of the starting material or further downstream in the active substance process) should be established, or other starting material sources using a different manufacturing process may be explored.

Solvents, Reagents and other materials
Materials used in the final stages of the active substance synthesis may require greater control (i.e. tighter specifications) than those used in earlier stages. Possible contamination of raw materials (e.g., reagents, catalysts and solvents including water /disinfected water, processing aids) with nitrosating agents (e. g. NaNO2) or amines, which may be carried over from steps used to prepare them, should be considered, as the presence of those contaminants could cause nitrosamine formation in the active substance process. Adequate acceptance criteria should be defined and justified.
Recovered materials should be controlled by their own specifications with special emphasis on the possibility of contamination with impurities (e.g. nitrosamines) during recovery processes and their accumulation in case of repeated recovery.

4.2.6. Manufacturing Process Development 3.2.S.2.6
In particular, efforts to minimise the risk of nitrosamine formation in the process should be guided by the Q&A document, in which the risk factors are listed, together with the measures for risk mitigation and principles of control strategies. If the use of nitrosating agents is unavoidable within the synthetic process, then combination with nitrosatable compounds under conditions amenable to nitrosamine formation should be mitigated. If potential for formation of nitrosamines is unavoidable, a control strategy at an appropriate control point should be implemented and justified based on adequate process knowledge using a suitable analytical procedure where needed.

4.3.2. Impurities 3.2.S.3.2
Regarding nitrosamine impurities, reference is made to the identified risk factors.
For nitrosamines, the LOQ should be minimum at or sufficiently below the toxicologically required limit, taking into account the purpose of testing (e.g., routine testing, justifying skip testing or omission of specification). A summary should be given on the nature and levels of the actual impurities detected in the batch samples of the material. Justification should be provided for selecting the limits based on safety and toxicity data, as well as on the methods used for the control of impurities (see 3.2.S.4.4.). For qualification of impurities, refer to 3.2.S.4.5.

4.4.3. Validation of Analytical Procedures 3.2.S.4.3
For nitrosamines, additional requirements are stated in the nitrosamine Q&A.

4.4.5. Justification of Specification 3.2.S.4.5
Regarding nitrosamine impurities, exceptions from routine testing may be possible, if the root cause is demonstrated to be well-understood and the requirements outlined in are fulfilled.

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I welcome the move from EMA to include specific consideration for API manufacturers under the guidance.

“Risk of formation and carry-over of nitrosamines during the starting materials synthesis should be evaluated (e.g., use of nitrosating agents, secondary or tertiary amines, etc.) (Ref 11). If a risk is identified, adequate control strategies (in the specification of the starting material or further downstream in the active substance process) should be established, or other starting material sources using a different manufacturing process may be explored.”

“If a mutagenic impurity is liable to be present in the substance, then the control strategy should be demonstrated to be in compliance with control options outlined in ICH M7 and the related Q&A, and the risk of presence of compounds of the “cohort of concern” (according to ICH M7) or other potent toxins should also be discussed. Regarding nitrosamine impurities, reference is made to the identified risk factors”

How will this be received by manufacturers ???

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What an update!!! It is great it is at last highlighted that LOQ should be minimum at or sufficiently below the toxicologically required limit, taking into account the purpose of testing

thank you Yosukemino

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