EDQM Presents 10 Common Deficiencies in New CEP Applications for Chemical Purity

Pharmaceutical manufacturing of active pharmaceutical ingredients (API) is based on following GMP quality guidelines to ensure its chemical purity. Certificates of Suitability (CEP) issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM) represent a critical validation of a substance’s compliance with the European Pharmacopoeia monographs. However, many candidates fail to meet the requirements for this certification.  

In February 2024, EDQM issued a document “Top Ten Deficiencies in New Applications for Certificates of Suitability for Chemical Purity”. This document is meant to assist applicants in structuring their application following the “Content of the Dossier for Chemical Purity and Microbiological Quality of Substances for Pharmaceutical Use” guideline published by the EDQM.

The team behind GMPInsiders has explored and interpreted each deficiency, followed by actionable steps to address these challenges.

Details in Describing the Manufacturing Process of the API (3.2.S.2.2)

EDQM’s first and foremost deficiency in this report is the inadequately detailed or poorly described manufacturing process of the substance, starting from the introduction of raw materials. It encompasses inconsistencies between the information presented in sections S.2.3 (Description of Manufacturing Process and Process Controls) and S.2.4 (Control of Critical Steps and Intermediates) of the application dossier. This particular issue accounts for 12% of all queries raised by assessors, indicating its significance in the application evaluation process.

Key Points to Address the Deficiency

• Synthetic Flow Diagrams: For synthetic and semi-synthetic substances, applicants must provide a comprehensive synthetic flow diagram. This diagram should detail all synthetic intermediates, with non-isolated intermediates indicated within square brackets. Such visual representations play a crucial role in helping assessors understand the synthetic pathway and the sequence of chemical transformations.
• Consistency Across Sections: A critical evaluation is conducted to ensure that the information presented across sections S.2.2 (Manufacturing Process Development), S.2.3, and S.2.4 is consistent and coherent. Applicants must meticulously verify that all raw materials, including those recovered, are accurately listed and described in the relevant sections, ensuring no inclusion of reagents by mistake.
• Detailed Quantifications: The application should specify the quantities of all raw materials utilized and the batch size at each stage of the manufacturing process. Such detail is pivotal for assessors to evaluate the scalability and reproducibility of the manufacturing process.
• Blending Processes: If the manufacturing process involves blending intermediates, the application must explicitly state that this process adheres to the principles outlined in the ICH Q7 guideline. Additionally, it should be clarified that batches undergo comprehensive testing before blending, ensuring uniform quality and purity.

Justification of Specifications Related to Isolated Intermediates and Starting Materials (3.2.S.2.4 and 3.2.S.2.3)

A common stumbling block in new CEP applications is the proposal of inadequate or poorly justified specifications for the control of isolated intermediates and starting materials’ quality. This deficiency encompasses both the lack of appropriate specification limits for specified, unspecified, and total impurities and the inadequate justification for the proposed criteria. It is critical to underscore that this issue pertains to 11% and 7% of all queries related to isolated intermediates and starting materials, respectively, signalling a prevalent challenge for applicants.

Strategic Approaches to Compliance

• Comprehensive Acceptance Criteria: Specifications for starting materials and isolated intermediates must include well-defined acceptance criteria for specified, unspecified, and total impurities. This step is fundamental in mitigating risks to the final substance’s quality. Moreover, these criteria should not be arbitrary but justified with robust scientific reasoning, focusing on the impurities’ fate and carryover.
• Identification and Characterization of Impurities: Major and recurrent impurities must be meticulously identified and/or characterized. Such impurities require individual specification at acceptance criteria that are scientifically justified. The justification process often involves detailed discussions on the fate and carryover of these impurities, potentially necessitating spiking studies to elucidate their behaviour within the manufacturing process.
• Justification for Acceptance Criteria: In cases where the proposed acceptance criteria for unspecified impurities are broader than those for specified impurities, a solid justification is imperative. This ensures that the control strategy for impurities is comprehensive and tailored to the specific risks they pose.
• Addressing Mass Balance Discrepancies: Discrepancies in the mass balance—represented by the sum of the assay and total impurities—must not be overlooked. Applicants are expected to provide clear rationales for any discrepancies observed, detailing the scientific or technical reasons behind them.

Discussing the Risk of Having Potential Mutagenic Impurities in the API (3.2.S.3.2)

Addressing the risk of potential mutagenic impurities in the final substance is a critical aspect of the CEP applications that often present challenges, being the focus of 7.5% of all queries. This complex area requires applicants to deeply analyze the manufacturing process and the potential for mutagenic impurities to emerge at various stages. 

EDQM mandates a thorough discussion in the dossier on this matter, reflecting an understanding of where these impurities might come from and how they can be controlled or eliminated. This includes impurities introduced during manufacturing, those formed during the synthesis of the final substance, and those that could result from degradation.

Key Points to Address the Deficiency:

• Comprehensive Discussion on Potential Mutagenic Impurities: Applicants must include a detailed analysis of potential mutagenic impurities in their dossier. This involves identifying impurities that may be introduced during manufacturing, arise from the synthesis of the final substance, or form due to degradation. Listing and classifying these impurities according to ICH M7 guidelines is essential.
• Classification and Control Strategy: Each identified mutagenic impurity must be classified from class 1 to class 5, as per ICH M7. A control strategy aligned with these principles should be proposed, demonstrating a clear plan to mitigate the risk posed by these impurities.
• Determination of the Threshold of Toxicological Concern (TTC): The TTC for each impurity should be calculated in line with ICH M7 guidelines. This calculation should consider the maximum daily dose (MDD) of the drug substance, using sources like the Human Medicine European Public Assessment Report (EPAR) or Martindale. The acceptable intake level must also be determined based on the expected duration of use.
• Justification of Control Measures: For mutagenic impurities, it’s crucial to justify the chosen control measures. ICH M7 option 3 controls require support through appropriate spiking and/or carryover studies. Similarly, option 4 controls demand a demonstration that, given the understanding of the process and its impact on residual impurity levels, the impurity level will always stay below the acceptable limit. This may also necessitate supporting analytical data.

Presentation of Acceptance Criteria for Starting Materials (3.2.S.2.3)

The fifth top deficiency identified in CEP applications relates to the absence or inadequacy of acceptance criteria and analytical methods for raw materials, including recovered materials, used in the manufacture of the final substance. This deficiency, accounting for 7.1% of all queries, underscores the critical need for detailed specifications for all materials involved in the manufacturing process. EDQM emphasizes the importance of ensuring that these specifications are not only provided but are also scientifically justified, particularly when it comes to materials introduced at later stages of manufacturing.

Key Points to Address the Deficiency

• Comprehensive Specifications for Raw Materials: Applicants must provide clear and comprehensive specifications for all raw materials used throughout the manufacturing process. This includes detailed acceptance criteria that cover the quality and purity of these materials to ensure they meet the required standards for the production of the final substance.
• Justification for Acceptance Criteria: Specifications for raw materials, especially those used later in the manufacturing process, should not include broad acceptance criteria without appropriate justification. Applicants need to demonstrate the rationale behind their criteria, particularly focusing on how these materials might affect the impurity profile of the final substance.
• Impact on Impurity Profile: The potential impact of raw materials (including recovered materials) on the impurity profile of the final substance must be thoroughly evaluated. This involves assessing how the quality and purity of these materials could contribute to the overall quality of the final product.
• Adherence to EDQM Requirements: For materials of specific concern, such as those of fish origin or peptones, it’s crucial to comply with specific EDQM requirements. This may involve additional testing or validation to ensure that these materials do not adversely affect the safety or efficacy of the final substance.

Reprocessing and Recovery of Raw Materials (3.2.S.2.2)

The handling of reprocessing and recovery of raw materials within the framework of CEP applications represents another significant challenge, spotlighted as the sixth top deficiency. This particular issue, drawing 6.1% of all inquiries, points to a need for clearer, more detailed explanations regarding the strategies for both reprocessing and recovery of materials during the manufacturing phase. 

EDQM mandates that applicants must not only outline these processes but also provide justifications and specific details according to the EU “Guideline on the Chemistry of Active Substances.”

Key Points to Address the Deficiency

• Detailed Reprocessing Steps: Applicants must offer a comprehensive narrative describing any reprocessing steps involved in the manufacturing process. This includes defining specific triggers that necessitate reprocessing. Simplistic statements that fail to provide depth or reasoning, such as “Reprocessing is a repetition of the approved step X,” are deemed insufficient and inappropriate.
• Clear Recovery Process Description: The application should precisely identify at which stage in the manufacturing process materials are recovered. It should detail how this recovery is conducted and specify where these materials are reintegrated into the process. This clarity ensures that the recovery process is understood and meets regulatory standards for quality and safety.
• Justification for Reprocessing and Recovery: Beyond detailing the steps and triggers for reprocessing and recovery, applicants must justify these actions. This involves explaining why reprocessing or recovery is necessary, how it maintains or improves the quality of the final substance, and any impact it may have on the product’s purity or safety.

Risk Assessment of Nitrosamines (3.2.S.3.2)

The deficiency related to the absence or inadequacy of nitrosamine risk assessment in CEP applications has been identified as a significant concern, accounting for 4% of all questions. Nitrosamines, being potentially carcinogenic, necessitate a rigorous assessment of risk across all stages of pharmaceutical manufacturing. 

EDQM expects applicants to conduct a comprehensive risk assessment following the International Council for Harmonisation (ICH) Q9 and M7 guidelines, along with the European Medicines Agency (EMA) Q&A document on nitrosamines. This includes an evaluation not just of the manufacturing process but also of the materials used within it, such as starting materials, reagents, and solvents, whether new or recovered and considerations around degradation.

Key Points to Address the Deficiency

• Comprehensive Risk Assessment for Nitrosamines: Applicants must include a detailed risk assessment for the presence of nitrosamines. This assessment should align with the ICH Q9 and M7 guidelines and consider the specific advice provided in the current EMA Q&A document on nitrosamines, including Appendix 1.
• Consideration of All Possible Sources: The risk assessment should thoroughly evaluate potential nitrosamine sources. This includes not only those inherent to the manufacturing process but also those that might be introduced through starting materials, reagents, and solvents, accounting for both new and recovered substances. The assessment should also consider the potential for nitrosamine formation or carryover as a result of product degradation.
• Addressing Formation and Carryover: It’s critical that the risk assessment suitably addresses the potential formation and carryover of nitrosamines within the product. This involves implementing control strategies or adjustments in the manufacturing process to mitigate these risks effectively, based on the insights gathered from the EMA Q&A document.

Lifespan of Related Substances in API (3.2.S.3.2)

The eighth top deficiency highlighted in CEP applications pertains to an inadequate approach toward addressing the origin, fate, and carryover of related substances into the final pharmaceutical substance. This issue, accounting for 4% of all inquiries, underscores a critical gap in ensuring the chemical purity and safety of the final product. 

EDQM has pinpointed a common shortfall in discussions that overly rely on the Pharmacopoeia Europaea (Ph. Eur.) impurities standards without adequate consideration of additional impurities that might be present in the final substance due to various manufacturing stages or degradation processes.

Key Points to Address the Deficiency

• Beyond Ph. Eur. Impurities: Solely relying on the Ph. Eur. impurities for guidance is insufficient. Applicants are expected to expand their discussions to encompass the formation, carryover, and fate of all related substances, including starting materials, intermediates, process-related impurities, and degradants that may not be listed in the Ph. Eur.
• Addressing Additional In-house Impurities: The suitability of the Ph. Eur. monograph to control impurities not listed in the transparency list of the monograph should be evaluated, especially for additional in-house impurities that might be present above the reporting threshold. A comprehensive approach to controlling these impurities in the final substance is essential.
• Supporting Statements with LOD/LOQ: When discussing related substances, any statements indicating that impurities were “not detected” or are “less than the limit of quantification” should be substantiated with the limit of detection (LOD) and limit of quantification (LOQ) for the associated analytical methods. This ensures that such statements are grounded in rigorous analytical assessment.
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Discussion on Residual Solvents (3.2.S.3.2)

The ninth top deficiency involves a lack of comprehensive discussion on residual solvents in CEP applications, accounting for 4% of all questions. This gap highlights a critical aspect of pharmaceutical manufacturing, where the presence of residual solvents must be rigorously evaluated and documented. 

EDQM expects that applicants not only assess these solvents but also substantiate their claims with appropriate analytical data, such as limits of detection (LOD) and quantification (LOQ), and address the origin and potential impact of these substances, including compliance with ICH Q3c Annex 1 requirements.

Key Points to Address the Deficiency

• Substantiation of Claims About Residual Solvents: Any statements made about residual solvents being “not detected” or “less than the limit of quantification” in the final product should be supported with specific method validation performance characteristics (LOD and LOQ values) for the analytical methods used. This ensures that such claims are based on quantifiable, reliable data.
• Clarification of the Origin of Impurities: It’s important to clarify the origin of impurities that are common solvents but may form as by-products of the manufacturing process (e.g., acetic acid, ethanol). Understanding their origin is crucial for implementing effective control strategies to minimize their presence in the final product.
• Discussion on Class 1 Solvents: Applicants are required to specifically address the potential presence of Class 1 solvents, known for their high toxicity and risk to human health (such as Benzene, Carbon tetrachloride, 1,2-Dichloroethane, 1,1-Dichloroethene, and 1,1,1-Trichloroethane). This discussion should include an assessment of these solvents as contaminants of other solvents used in the manufacturing process and demonstrate compliance with ICH Q3C standards.

Identification of Starting Materials (3.2.S.2.3) 

The failure to appropriately identify starting materials, leading to 3.5% of all inquiries, underscores the importance of aligning with ICH Q11 guidelines. The accurate identification and justification of starting materials are critical, especially when these materials contribute significantly to the final substance’s structural composition. Misidentifying such substances can lead to insufficient control measures and impact the final product’s quality and safety.

Key Actions for Addressing Starting Material Identification

• Follow ICH Q11 Guidance: Adhere strictly to the ICH Q11 guidelines and the associated Q&A document for selecting and justifying starting materials. Detailed reasoning for the choice of starting materials should be documented, considering their role and contribution to the final substance.

• Correct Identification of Significant Contributors: Ensure that substances contributing significant structural components to the final product are correctly identified as starting materials, not merely as reagents. This distinction is crucial for applying the appropriate quality controls and regulatory compliance measures.

Final Verdict

EDQM’s document on the top ten deficiencies that were observed during the evaluation of new applications for CEP for chemical purity highlights specific weak spots of CEP applications with an intent to help applicants avoid such issues. Followed by EDQM’s guidelines, policies, FAQs and other helpful documents, applicants are encouraged to ensure they stay informed on general CEP procedures.

Achieving a Certificate of Suitability is a testament to a substance’s compliance with the highest standards of chemical purity. By addressing these common deficiencies, applicants can streamline their certification process, ultimately contributing to the development of safer, more effective pharmaceuticals. This journey, while challenging, is essential for ensuring public health and maintaining trust in the pharmaceutical industry’s commitment to quality.