Ensuring API Quality—The EDQM Perspective

Pharmaceutical Technology Europe spoke with representatives from the European Directorate for the Quality of Medicines & Healthcare (EDQM), responsible for both the European Pharmacopoeia (Ph. Eur.) and the Certificate of Suitability to the monographs of the Ph. Eur. (CEP) procedure, about API quality from their perspective.

PTE: How crucial is it for pharma manufacturers to ensure the safety of APIs?

EDQM: It is crucial that pharmaceutical companies select APIs of appropriate quality. In the [European Union], the marketing authorization holder/applicant is by law fully responsible for the quality of the API they use, since low-quality and/or ineffective APIs put the patients at risk.

PTE: What are the steps an API manufacturer must take to ensure quality throughout the development and manufacture of an API?

EDQM: The requirements are well described in the international guidelines (ICH [International Council for Harmonisation]) that API manufacturers shall follow, in particular, ICH Q11 Development and Manufacture of Drug Substances and ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients.

ICH Q11 comprises crucial requirements related to manufacturing process development, description of manufacturing processes and process controls, approaches to developing a control strategy, critical quality attributes, [and] quality risk management.

API manufacturers [must] develop an appropriate manufacturing process for their APIs. During this step, knowledge about the API (e.g., its by-products and degradation products) is gained and an appropriate control strategy can be put in place for the next steps. An understanding of the manufacturing steps leading to the formation of impurities enables the implementation of appropriate steps and analytical controls to ensure that the API complies with the expected quality requirements.

Last but not least, API manufacturers have to work according to good manufacturing practice (GMP), as described in EU GMP Part II, which is equivalent to ICH Q7 (i.e., an appropriate quality management system).

PTE: What are the steps sponsors should take to ensure the quality of APIs sourced from a supplier used in final products?

EDQM: APIs used in the manufacture of medicinal products should meet quality standards, in particular pharmacopoeial requirements. In the countries which are party to the European Pharmacopoeia Convention, the legally binding quality standard is the European Pharmacopoeia. If a monograph competent in the European Pharmacopoeia covers the API, the manufacturer of this API and the medicinal products produced using this API shall meet its quality standards. In cases where a specification contained in a monograph (of the European Pharmacopoeia or in another pharmacopoeia) is insufficient to ensure the quality of the substance, the regulatory authorities may request additional specifications from the marketing authorization holder.

PTE: ICH’s Q7A GMPs for APIs touches on all aspects of API production from facilities to equipment to materials management. Of all the areas the guidance covers, is there one particular aspect of API manufacturing that is more crucial for ensuring API quality?

EDQM: The ICH Q7 guideline (Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients) is intended to provide guidance for the manufacturing of APIs under an appropriate quality management system (QMS). This guideline has been introduced in the EU legislation as GMP Part II. The QMS should encompass the organizational structure, procedures, processes, and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. The QMS for APIs needs to be in place for all of these aspects—and if even a single aspect is neglected, the efficacy of the QMS based on ICH Q7 and the quality of the APIs are at risk.

PTE: What methods are available for testing the effectiveness and safety of APIs?

EDQM: Clinical and non-clinical studies are performed on APIs during the development phases of a medicinal product to establish their efficacy and safety. Data thus gained are part of the submission for a marketing authorization and are reviewed by the respective regulatory authorities. If these studies show a negative balance for benefit-risk, the medicinal product will not obtain a marketing authorization—and will not be marketed.

Medicinal products that have obtained a marketing authorization are monitored for their quality, safety, and efficacy over their whole lifecycle. This system is in place to detect any issues that may negatively impact the benefit-risk balance. There are mandatory requirements for pharmacovigilance, with which marketing authorization holders must comply in order to monitor the safety of authorized medicinal products and detect any change to their risk-benefit balance. In case of a quality issue with APIs, the manufacturers must take appropriate action to address the issue, under the supervision of authorities (e.g., withdraw batches from the market).

PTE: Have regulators and industry resolved the nitrosamine problem or is it continuing? What steps can be taken to ensure a similar situation does not occur in the future?

EDQM: Regulators and industry are still acting to resolve the issue and the knowledge regarding their formation in APIs and in medicinal products continues to evolve. Nitrosamines in blood pressure medications are no longer a concern, since all measures to mitigate these impurities have been taken. However, nitrosamines may be found at very low levels in other medicinal products. Regulators have created international task forces (Nitrosamines Implementation Oversight Group, Nitrosamines International Strategic Group), elaborated regulatory guidance, and are sharing emerging information with each other in order to harmonize the actions to be taken.