Updates and impacts: Understanding the EMA’s revised guideline on active substances

From stricter controls on Starting Materials to enhanced impurity risk management, Lisa breaks down the potential impacts and what they could mean for manufacturers, regulatory professionals, and patients.

Background

The European Medicines Agency (EMA) has proposed significant updates to its guideline on the chemistry of active substances (EMA/454576/2016).

These changes are outlined in a draft guideline (EMA/321776/2024) that is currently under consultation until January 31, 2025 (EMA - CHMP, 2024). The revised directions provide detailed requirements for the manufacture and control of active substances in medicinal products.

The main driver behind this revision is the need to address recommendations contained in the EMA report “Lessons Learnt from Presence of N-nitrosamine Impurities in Sartan Medicines” (EMA, 2020).

These updates aim to minimize risks associated with N-nitrosamines and other potent toxins while preparing for future challenges related to unexpected impurities (EMA - CHMP, 2022). The revisions are relevant to compounds within the “cohort of concern” (Section 4.4.5) and broader regulatory considerations for controlling genotoxic impurities.

Pharmaceutical companies and regulatory professionals must prepare for the impacts on manufacturing, quality control, and regulatory submissions that these proposed updates could have if adopted without change.

While large parts of the draft guideline remain unchanged from the current version, the EMA has added further detail to multiple sections with a specific focus on nitrosamine impurities as well as Starting Materials of human or animal origin (EMA - CHMP, 2024).

Below is a summary of the major updates and their implications for the pharmaceutical industry.

Updates summary

Section 4.2.2: Description of manufacturing process and process controls (3.2.S.2.2)

The revised draft mandates a more comprehensive description of manufacturing processes, emphasizing steps that impact the quality of the active substance or intermediates. Key features include:

Detailed schematic representations: Manufacturers must now include depletion agents like nitrites for azides in block flow diagrams, specifying in-process controls, operating conditions, weights, and yield ranges (EMA - CHMP, 2024). It also advises against using non-standard abbreviations for reagents and solvents to ensure clarity.

Clear documentation of materials: All materials, including depletion agents, recovered materials, and gases and materials used for quenching or work-up must be disclosed in the sequential procedural narrative with their quantities disclosed and attributed to the corresponding step or sub-step.

For each manufacturing step, the quantities of all reagents and catalysts must now be expressed in molar equivalents relative to the starting material/intermediate (EMA - CHMP, 2024).

Focus on recovery processes: While the recovery of solvents and reactants remains permitted, the draft emphasizes that where they are introduced in the process should be indicated within the reaction scheme, process description, and/or block flow diagram.

The draft outlines how the overall risk assessment must now include a discussion regarding impurities. It recommends using recovered materials only in the same process and preferably in the same step, avoiding their use in the final manufacturing step unless justified.

Section 4.2.3: Control of Materials (3.2.S.2.3)

The draft introduces stringent requirements for material quality and purity, with a specific focus on:

Active Substance Starting Materials: Manufacturers must perform structure elucidation (except for European Pharmacopoeial substances) and obtain EMA approval for new Starting Material manufacturers (EMA - CHMP, 2024).

The risk of Impurities, particularly N-nitrosamines, which could be formed and carried over during the synthesis of the Starting Materials, must be evaluated with appropriate control strategies. Alternative sources should be explored if risks are identified.

Starting Materials of human or animal origin: This is one of the biggest proposed changes and guides how manufacturers must provide information including viral and/or transmissible spongiform encephalopathies (TSE) safety data on the source, processing, characterization, and control of all materials of animal or human origin.

The draft includes a requirement that a contaminant/impurity profile should be submitted, and the specification of the Starting Material of animal origin should follow the principles set out in the European Pharmacopoeia monographs.

In addition, the EMA adds that 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.

Starting Material of herbal origin: The draft guideline expands the list of potential contaminants, including aflatoxins and pyrrolizidine alkaloids, while emphasizing the production of the herbal drug and the subsequent extraction and purification processes.

The contaminant profile must now include the number of chemical steps between the Starting Material and the semi-synthetic active substance (EMA - CHMP, 2024).

Semi-synthetic active substances: The draft places importance on the understanding and discussion of the impurity profile of fermented or extracted Starting Materials for semi-synthetic active substances. This extends to the possibility of carryover of specific impurities from the fermentation process (e.g., DNA, proteins.) to the final substance (EMA - CHMP, 2024).

Solvents, reagents, and other materials: The draft reflects the increased regulatory focus on potential carcinogenic impurities once again by emphasizing the potential for nitrosamine contamination of raw materials that could be carried over from the steps used to prepare them.

Specific requirements for the control of enzymes and peptone, including their origin and potential impurities, are also detailed in the draft.

Furthermore, emphasis is placed on controlling the grade of water used during the manufacture of active substances based on a risk-based approach, considering the stage of use, subsequent processing steps, and the nature of the final product (EMA - CHMP, 2024).

The draft also provides new requirements for controlling recovered materials, focusing on contamination risks during recovery processes and impurity accumulation, again emphasizing nitrosamines.

Section 4.2.4: Control of critical steps and intermediates (3.2.S.2.4)

The draft emphasizes the need for more detailed quality control for intermediates, including the need for validation data if the test is critical to the active substance’s control strategy.

For intermediates in active substance synthesis which are described in a monograph of the European Pharmacopoeia and covered by a valid Certification of Suitability (CEP), the draft allows for the submission of a CEP as an alternative to submitting the process description (EMA - CHMP, 2024).

The draft also includes information on how the addition chemical transformation steps from the intermediate to the active substance and the manufacturers involved in the process should be included in 3.2.S.2.

Section 4.2.6: Manufacturing process development (3.2.S.2.6)

The draft outlines extensive updates regarding Manufacturing Process Development and places greater emphasis on understanding the control strategy.

It now explicitly requires a summary of the overall active substance control strategy as detailed in ICH Q11 (EMA-CHMP, ICH, 2012), which can be presented in a tabular or diagrammatic format (EMA - CHMP, 2024).

The draft also requires justification for the selected process and its parameters, presented in tabular format for each manufacturing step and sub-step in telescoped processes with non-isolated intermediates.

Considerations include the presence of potentially mutagenic impurities, the impact of the use of reagents and depletion agents on the active substance impurity profile, and justification of the selected process (EMA - CHMP, 2024).

Again, there is a strong emphasis placed on minimizing the risk of nitrosamine formation in the manufacturing process, guided by the Q&A document on nitrosamines which lists the risk factors as well as the measures for risk mitigation and principles of control strategies (EMA, 2024).

Section 4.3.2: Impurities (3.2.S.3.2)

The guideline provides enhanced clarity on the risk of mutagenic impurities and the control strategy must demonstrate compliance with ICH M7 and the related Q&A, and the risk of the presence of compounds of the “cohort of concern” should be discussed (EMA-CHMP, ICH, 2023).

Suitably sensitive analytical methods should be applied to adequately detect and quantify impurities, with a particular focus on nitrosamines (EMA - CHMP, 2024).

Section 4.4.5: Justification of specification (3.2.S.4.5)

The updated guideline introduces the concept of the “cohort of concern.” This includes highly potent mutagenic carcinogens such as N-nitroso compounds (EMA-CHMP, ICH, 2023). Manufacturers must establish robust control measures if these compounds are present.

Implications for the pharmaceutical industry

Benefits:

• Enhanced product quality and safety: The updated guideline strengthens impurity control and quality assurance, ensuring safer pharmaceutical products.

• Encouragement of innovation: Flexibility in adopting advanced manufacturing technologies could offer competitive advantages to early adopters.

Challenges:

• Increased costs: Compliance may require investments in advanced analytical techniques, equipment, and training, posing a challenge for smaller companies.

• Extended timelines: Adapting to the new requirements could initially slow drug development and market entry.

Conclusions

The proposed updates to the EMA guideline on the chemistry of active substances reflect the growing regulatory emphasis on impurity control, especially for nitrosamines.

While implementation may require significant investment and adaptation, the long-term benefits include improved product quality, patient safety, and reduced regulatory hurdles.

Furthermore, the draft introduces an entirely new section describing the EMA’s preferred approach to the sourcing, handling, and documentation of Starting Materials of human or animal origin, aimed at enhancing traceability and safety standards.

The initial implementation of the guidance may prove to be resource-intensive and costly.

However, the long-term benefits of improved product quality and patient safety and the reduced regulatory hurdles could well outweigh the costs.

By improving quality control and risk management, the proposed updates will help reduce the incidence of product recalls and quality-related issues.

The draft could also reduce the likelihood of regulatory delays and rejections, meaning companies can bring their products to market with reduced resources and time.

These updates are indicative of the evolving regulatory environment and underscore the importance of the evolution of regulatory guidelines

Manufacturers should begin preparing now by evaluating their processes, updating control strategies, and investing in advanced analytical methods. These efforts will not only ensure compliance but also strengthen the overall integrity of active substances throughout pharmaceutical supply chains.

Lisa Donaldson is a Regulatory Executive at G&L Healthcare Advisors.

References

EMA - CHMP, 2022. Concept paper on the revision of the guideline on the chemistry of active substances EMA/CHMP/600383/2022, Amsterdam: EMA.

EMA - CHMP, 2024. (Draft) Guideline on the chemistry of active substances EMA/321776/2024, Amsterdam: EMA.

EMA, 2020. Lessons learnt from the presence of N-nitrosamine impurities in sartan medicines EMA/526934/2019, Amsterdam: EMA.

EMA, 2024. 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 EMA/409815/2020 Rev.21, Amsterdam: EMA.

EMA-CHMP, ICH, 2012. ICH guideline Q11 on development and manufacture of drug substance (chemical entities and biotechnological/biological entities) EMA/CHMP/ICH/425213/2011, Amsterdam: EMA.

EMA-CHMP, ICH, 2023. ICH M7 (R2) Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk EMA/CHMP/ICH/83812/2013, Amsterdam: EMA.