Chemistry of Active Substances Guideline: EMA Request Feedback
Published Jan 20, 2025
Chemistry of Active Substances Guideline: EMA Request Feedback
Published 20th January 2025
The European Medicines Agency (EMA) has initiated a consultation on the proposed revisions to the guidance on the chemistry of active substances including mainly updates related to nitrosamines.
New Guidance Amendments
The guideline, originally adopted by EMA’s Committee for Medicinal Products for Human Use in 2016, outlines the necessary information for the manufacture and control of chemical active substance used in medicinal products. In 2022, EMA highlighted the need to update the guideline to incorporate recommendations for reducing the risk of nitrosamines and to manage the other potential impurities.
EMA emphasised the need to assess the risk of nitrosamine formation and carry-over during the synthesis of starting materials, particularly when nitrosating agents or secondary and tertiary amines are involved. If a risk is identified, manufacturers should establish appropriate control strategies in the starting material specification or further downstream in the active substance process. Alternatively, they may consider sourcing starting materials from a different manufacturing process.
Risk of Contamination from Nitrosating Agents and Amines
A new section addresses the risk of contamination from nitrosating agents or amines in raw materials, such as reagents, catalysts, and solvents, including water. Manufacturers must evaluate the potential for these contaminants to carry over during preparation, which could lead to nitrosamine formation in the active substance manufacturing process. The EMA expects the API manufacturers to define and justify “adequate acceptance criteria.”
Starting Materials Derived from Fermentation or Extraction
Additionally, a new section on semi-synthetic active substances derived from fermentation or extraction from biological materials has been added. The EMA recommends that companies thoroughly understand and appropriately discuss the impurity profile of such starting materials. For fermented starting materials, manufacturers should consider potential carryover of specific impurities, such as DNA from the fermentation process, in addition to typical impurities.
Starting Materials of Animal or Human Origin
The guideline also introduces a paragraph which outlines the EMA’s preferred approach to starting materials of animal or human origin, requiring manufacturers to provide detailed information on the source, processing, characterisation, and control of all such materials, including safety data for viral or transmissible spongiform encephalopathies.
Specification of the Starting Material of Animal Origin
“The specification of the starting material of animal origin should adhere to the principles set out in the European Pharmacopoeia monographs,” EMA stated, emphasising the need to address the potential presence of foreign matter, microbiological contamination, total ash, heavy metals, environmental pollutants, radioactive contamination, residual solvents, and other relevant impurities.
The EMA is accepting feedback on the draft guideline until 31 January 2025.
| Title of the section | Revisions highlighted | Brief summary |
|---|---|---|
| 4.2.2. Description of Manufacturing Process and Process Controls 3.2.S.2.2 Schematic representation of the manufacturing process | Graphical representations of the synthetic process(es) should be provided, covering the entire process for the active substance and each intermediary process stage/step. These should comprise of reaction schemes that include chemical structures and, molecular formulae and molecular weight of starting materials, intermediates and the active substance, as well as Uncommon or non-standard abbreviations for reagents and solvents should be avoided.S | 1) A clarification has been included to the graphical representations of the synthetic process(es) provided covers the entire process for the active substance and each intermediary process stage/step. 2) The schematic process(es) should comprise of reaction schemes that should now also include molecular weight of starting materials, intermediates and the active substance apart from chemical structures and molecular formulae. 3) Specifics around all reagents (including depletion agents such as nitrites for azides) used in the synthetic process (es) apart from catalysts and solvents used should now be included. 4) Specifics around the way non-isolated intermediates are identified. And clarification on which intermediates are isolated and which ones are non-isolated 5) A block flow diagram that identifies in-process controls, operating conditions, unit operations, weights, yield ranges etc. should preferably also be provided rather than optional in the current effective guidance. 6) Uncommon or non-standard abbreviations for reagents and solvents should be avoided. |
| 4.2.2. Description of Manufacturing Process and Process Controls 3.2.S.2.2 Sequential procedural narrative | A sequential procedural narrative of the manufacturing process should be submitted. | This section has been updated to include additional materials in the description such as depletion agents, recovered materials, gases and materials used for quenching or work-up. Additionally the need to express all reagents and catalysis in molar equivalent relative to the starting material should be summarised. |
| 4.2.2. Description of Manufacturing Process and Process Controls 3.2.S.2.2 Recovery | Recovery (e.g. from mother liquors or filtrates) of solvents, reactants, intermediates or the active substance is considered acceptable according to ICH Q7 (Ref 8) or EU GMP Part II. | Recovery materials should now be fully described and included in the reaction scheme and/or block flow diagram. |
| 4.2.2. Description of Manufacturing Process and Process Controls 3.2.S.2.2 Re-working | Reference to reworking Re-working procedures should not be included in the dossier and should be carried out according to ICH Q7 or EU GMP Part II | Inclusion of the reference to EU GMP Part II |
| 4.2.3. Control of Materials 3.2.S.2.3 | All materials used in the manufacture of the active substance (starting materials, solvents, reagents, catalysts, depletion agents, process aids, gases and materials used for quenching and work-up, etc.) should be listed | Addition of materials – depleting agents, gases and materials used for quenching and work-up in the list of raw materials and their intended function. Specification that now includes specific identification and purity limits has been included. Information on the analytical method validation requirements is also now included. |
| 4.2.3. Control of Materials 3.2.S.2.3 Active Substance (AS) Starting Material(s) | The requirements of ICH Q11 (Ref 4) and related Q&A in relation to the selection of starting materials are relevant to all active substances, regardless of the type of development approach. … The marketing authorisation applicant should propose and justify which substance should be considered as the AS starting material (SM), e.g. incorporated as a significant structural fragment into the structure of the active substance. Non-isolated compounds are not considered appropriate to be selected as starting materials. The name and address of the starting material manufacturers should be provided. The addition of manufacturers for the starting materials needs to be approved by a variation according to European legislation. … Starting materials should be substances with defined chemical properties and structures. Structure elucidation of starting materials should be performed using state of the art techniques, except for European pharmacopoeial active substances. Complete specifications should be provided, including limits for impurities. The possibility that any kind of impurity, for example isomeric impurities, or mutagenic impurities (including those from the ‘cohort of concern, Ref 10) present in a starting material may be carried through the synthetic process unchanged or as derivatives should be discussed. Such impurities should, if relevant, be controlled in the starting material by appropriate acceptance criteria with suitably validated methods. Acceptance criteria should be established by the applicant based on evaluation of the fate of impurities present in the starting material, when subjected to the normal processing conditions. Materials of plant origin Starting materials of animal or human origin: Information on the source, processing, characterisation and control of all materials of animal or human origin must be provided, including viral and/or TSE safety data in the relevant part of the dossier. A contaminant/impurity profile should be established and submitted. Information on the scientific name (species) of the animal and animal part used should be specified, as should the solvents, reagents and catalysts used in the process. The specification of the starting material of animal origin should follow the principles set out in the European Pharmacopoeia monographs and the potential presence of foreign matter, microbiological contamination, total ash, heavy metals, environmental pollutants, radioactive contamination, residual solvents, and other relevant impurities should be discussed. Information on the geographical origin and extraction process may be appropriate depending on the subsequent synthetic steps. Relevant viral safety and/or TSE data must be provided if any material of animal or human origin is used during the starting material manufacturing process (e.g. arising from fermentation, enzymes, amino acids, etc.). | - Addition of reference to the related Q&A EMA/CHMP/ICH/809509/2016 and deletion of reference to the requirements for selection and justification of starting materials for the manufacture of chemical active substances EMA/448443/2014 - Addition of a statement regarding the addition of manufacturers for the starting materials needs to be approved by a variation according to European legislation. - The specific requirement on performing the structure elucidation of starting materials using state of the art techniques, except for European pharmacopoeial active substances has been added. - Reference to mutagenic impurities (including those from the ‘cohort of concern’ and a reference to ICH guideline M7 (R2) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk EMA/CHMP/ICH/83812/2013 and the related Q&A EMA/CHMP/ICH/321999/2020) has been included. - Inclusion of evaluation details relating to nitrosamines during the starting materials synthesis has been included. Additionally information on establishing adequate control strategies if nitrosamines are identified. Or exploring the use of other starting material sources using a different manufacturing process. - A separate section specific for starting materials of animal or human origin has been included and details information required such as the source, processing, characterisation and control of all materials of animal or human origin including viral and/or TSE safety data. |
| 4.2.3. Control of Materials 3.2.S.2.3 Starting materials of herbal origin | Information on the source, processing, characterisation and control of starting materials of plant origin must be provided to ascertain suitability. A contaminant profile should be established and submitted taking into consideration the number of chemical steps between the starting material and the semisynthetic active substance. Information on the scientific name (genus, species, variety and author Information on the geographical origin, site of collection or cultivation, harvesting, and post-harvest treatments ( | Starting materials of herbal origin has now been moved to a separate sub-heading. The Ph. Eur. Monograph on herbal drugs has now been included. |
| 4.2.3. Control of Materials 3.2.S.2.3 Semi-synthetic active substances | For semi-synthetic active substances (where a starting material is obtained from fermentation (Ref 13) or by extraction from biological material), the impurity profile of the fermented or extracted starting material should be sufficiently understood and appropriately discussed. Regarding fermented starting materials, in addition to the discussion on typical impurities, the possible carryover of specific impurities from the fermentation process (e.g. DNA, proteins etc.) to the final substance should be discussed. | A separate sub section on the semi-synthetic active substances has now been included. |
| 4.2.3. Control of Materials 3.2.S.2.3 Solvents, Reagents and other materials | Specifications for all materials (solvents, reagents, catalysts, depletion agents, processing aids etc.) used in synthesis should be submitted. 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 For enzymes used in the process, the origin (recombinant, animal or herbal origin) should be indicated and the possibility of specific impurities from the reaction to the final substance should be discussed. Peptone is considered a critical raw material, whose origin (animal or vegetal) and source (supplier name and address) should be specified. In addition, for any material of animal or human origin, TSE and viral safety aspects should be addressed. The grade of water used during the manufacture of active substances will depend on the stage at which it is used, the subsequent processing steps and the nature of the final product, according to a risk based approach to be applied as part of an overall control strategy (Ref 16). 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 | Information on the depletion agents and possible contamination of raw materials with nitrosating agents or amines should now be provided. The enzymes used in the process and the origin, grade of water used and the information on the control of recovered materials are also required to be included. |
| 4.2.4. Control of Critical Steps and Intermediates 3.2.S.2.4 Intermediates | - Information on the quality and control of intermediates isolated during the process should be provided. Identity of isolated intermediates should be confirmed by appropriate state-of-the-art techniques, except for European pharmacopoeial substances. If non-compendial methods are used to control the intermediate, they should be suitably validated. If an intermediate in the proposed synthesis of the active substance is itself an active substance covered by a monograph of the European Pharmacopoeia (Ph. Eur.) covered by a valid CEP, then the CEP can be submitted as an alternative to submitting its process description. Documentation on the additional chemical transformation steps from the intermediate to the active substance should be provided in 3.2.S.2.2. The manufacturers involved in the process covered by the CEP should be listed in module 3.2.S.2.1 and the QP declaration (Ref 17). See also (Ref 18, section 3.3). …. If an intermediate in the proposed synthesis of the active substance is itself an active substance already included in a finished product authorised in the EU and documented in an accepted workshared (WS) ASMF or | - Updated to include the requirements of confirming the Identity of isolated intermediates appropriate state-of-the-art techniques, - Clarification on the data requirement for analytical methods validation has also been provided. - Reference to ‘Questions and Answers on how to use a CEP in the context of a Marketing Authorisation Application or a Marketing Authorisation Variation EMA/CHMP/CVMP/QWP/5/2024’ has been provided - Reference to ‘Active Substance Master File (ASMF) worksharing procedure CMDh_308_2013_Rev.4_2024_05’ has been included. |
| 4.2.5. Process Validation and/or Evaluation 3.2.S.2.5 | Reference to ‘EU GMP Part II: Basic Requirements for Active Substances used as Starting Materials’ has been included | Reference to ‘EU GMP Part II: has been included |
| 4.2.6. Manufacturing Process Development 3.2.S.2.6 | The information provided should include detailed descriptions of the individual elements of the control strategy plus, when appropriate, a summary of the overall active substance control strategy as detailed in ICH Q11 (for example in tabular or in a diagrammatic format). The justification for the selected process and its parameters, where necessary should be presented in tabular format for each manufacturing step and for each sub-step in telescoped processes with non-isolated intermediate(s). The rationale should include a discussion on the presence of potentially mutagenic impurities, particularly ‘cohort of concern’ compounds, and other potent toxins originating from intermediates and intentionally introduced materials. The impact of the use of reagents and depletion agents (particularly in molar excess) on the active substance impurity profile should be considered. The selected process should also be justified by discussing the potential for formation of by-products and side products of toxicological relevance considering critical compound combinations. 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. | New paragraphs detailing information to include regarding the manufacturing process selection, in particular its impact on the presence and formation of potential mutagenic impurities and nitrosamine impurities has been included. Description of the effort made to minimise the risk of formation of nitrosamine compounds and, if unavoidable the controls put in place will now be expected in this section |
| 4.3.2. Impurities 3.2.S.3.2 | Information on impurities and their carry-over should be provided. This includes related substances, residual solvents, elemental impurities, reagents and those derived from reagents. The related substances considered as potential impurities arising from the synthesis and degradation products should be discussed and described briefly including an indication of their origin. … To adequately detect and quantify impurities, the applied analytical method should be suitably sensitive. 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). | Additional details on the required information on the potential mutagenic impurities (including compounds of the “cohort of concern”) have been added. Information on the control of nitrosamine impurities is also included. |
| 4.4.1. Specification 3.2.S.4.1 | Addition of the below reference - ICH guideline M7 (R2) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk EMA/CHMP/ICH/83812/2013 and the related Q&A EMA/CHMP/ICH/321999/2020. | Addition of the below reference - ICH guideline M7 (R2) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk EMA/CHMP/ICH/83812/2013 and the related Q&A EMA/CHMP/ICH/321999/2020. |
| 4.4.3. Validation of Analytical Procedures 3.2.S.4.3 | Analytical validation data, including experimental results for the analytical procedures used for the control of the active substance, should be provided unless methods of the respective drug substance monograph in Ph. Eur. are referred to and the tests of the monograph have been demonstrated suitable to control the substance. Validation of analytical tests concerning the active substance should be performed according to the requirements of the current Guidelines. For nitrosamines, additional requirements are stated in the nitrosamine Q&A | Addition of reference to ‘Q&A EMA/409815/2020 (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’) for additional requirements of the analytical methods for nitrosamines. |
| 4.4.5. Justification of Specification 3.2.S.4.5 | - The specification should be based on results from The requirements of the general monograph of the European Pharmacopoeia Substances for Pharmaceutical Use (2034) should be met, where applicable. For existing active substances, the respective monograph of Ph. Eur. or, in default of this, the respective monograph of the pharmacopoeia of an EU Member State should be the basis of the active substance specification. Supplementation by additional tests, (e.g., impurity tests) might be necessary. For existing active substances not covered by Ph. Eur. or a pharmacopoeia of an EU member state, impurity levels above the ICH Q3A qualification thresholds are subject to - If a risk of presence of compounds of the “cohort of concern” (according to ICH M7) or other potent toxins has been identified, then appropriate control of these impurities should also be discussed. 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 (Ref 11) are fulfilled. | Information on the discussion of the control of identified potential compounds from the “cohort of concern” (according to ICH M7) or other potent toxins impurities has been included. |
| 4.7.1. Stability Summary and Conclusions 3.2.S.7.1 | The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions (light stress, higher temperature, etc.), as well as conclusions with respect to storage conditions and retest date or expiry date as appropriate. For stability-indicating parameters, compliance with the established specification limits should be verified during stability studies and this should include any “cohort of concern” compounds or other highly potent toxins which may potentially form or increase during storage. | Information on the potential mutagenic impurities that forms or increases during storage has been included. |
Summary
Although the new draft guideline was published in July, this article is aimed to remind that the public consultation is still open until 31 Jan 2025. This blog details the updates to the guidance which will assist our regulatory colleagues to understand the sections being updated. While most sections of the guideline remain unchanged and retain their original titles, EMA has added new text in multiple sections to provide guidance on minimizing nitrosamine impurities and other potential mutagenic impurities.
Public consultation to provide comments has started on 25 July 2024 until 31 January 2025. Comments are required to be provided using the EUSurvey form.
DLRC’s team of regulatory experts can advise on current guidance on the active substance and author and/or review the documents for regulatory submissions. Contact DLRC via hello@dlrcgroup.com to maximise the potential of your products and company.
