Inside EDQM: Active Ingredient Inspection and Certification

According to pharmaceutical legislation in the European Union (EU), any active pharmaceutical ingredient (API) included in a medicinal product to be marketed in the EU must be produced in compliance with good manufacturing practices (GMPs). The holder of the marketing authorization for a medicinal product is responsible for ensuring that this requirement is met. With each marketing authorization application (or subsequent variation relative to the API), a certification of GMP compliance for all APIs used in the product signed by the Qualified Person (QP) of the manufacturer must be submitted. This QP declaration cannot be replaced by a GMP certificate issued by a competent authority.

Susanne Keitel, PhD

However, EU legislation provides the supervisory bodies of the region's member states and those of the European Economic Area (EEA) with the authority to carry out inspections of API manufacturers to verify the declaration submitted by the QP. These inspections are not routine but are selected based on risk in accordance with the recommendations published in the Compilation of Community Procedures on Inspections and Exchange of Information, Rev. 10, as "Guidance on the occasions when it is appropriate for competent authorities to conduct inspections at the premises of manufacturers of active substances used as starting material."

To complement its certification procedure, which constitutes one of three possibilities in the EU to submit quality documentation for API in-licensing procedures, the European Directorate for the Quality of Medicines (EDQM) conducts inspections of API manufacturers and traders that have applied for a Certificate of Suitability (CEP). EDQM is, among others, responsible for the European Pharmacopoeia. The EDQM inspection program is mandated by the European Commission and focuses on ensuring on-site compliance with GMP and the procedures outlined in the applicant's submitted dossier.

Figure 1: Number of inspections performed by EDQM each year (1999-2009). EU is European Union. EEA is European Economic Area.

EDQM is responsible for organizing the API inspections and any follow-up actions, including the implementation of subsequent action regarding CEPs and communication with the concerned authorities. Every year, a program of inspections is scheduled in accordance with the Community Procedures document. The program is circulated to the EU and EEA supervisory authorities for comments and then sent to the Steering Committee of the Certification Procedure for adoption. Inspections of selected companies are conducted based on the final program. Not all manufacturing and distribution sites covered by a CEP or a CEP application are inspected, in accordance with EU legislation.

Covering Asia

EDQM inspections are conducted by a team of GMP inspectors from competent authorities throughout the EU and EEA or from countries with which the EU has an operational mutual recognition agreement (MRA) in the field of GMP and EDQM.

Most inspections are conducted outside of Europe, mainly in India and China, reflecting the distribution and relevance of API production worldwide and the origin of CEP applications handled. For inspections carried out in non-EU/EEA countries, local official inspectors are invited to join the team as observers.

EDQM carries out approximately 30 on-site inspections every year. Information exchanged with other competent authorities brings the number of sites covered to approximately 50 manufacturing sites per year. The outcome of these inspections shows a high level of noncompliance to GMP. For example, in 2009, 35% of the sites inspected were found to be noncompliant. However, it is important to stress that this statistic is not representative of overall compliance by API manufacturers in Asia or worldwide. In contrast, the data indicate that the triggers used to select inspection sites based on risk are effective. The increase in noncompliance over the years further demonstrates the effect of fine-tuning the risk-based selection criteria.

Inspection outcomes

When an inspection outcome is positive, a GMP certificate is granted by the inspector from the competent authority of the EU or EEA to the manufacturer. Additionally, EDQM issues an attestation stating that the company has been inspected and found compliant with GMP and the CEP application dossier.

In the case of major deficiencies or in case of a refusal by the company to be inspected, actions may be taken on the corresponding CEPs or CEP applications (e.g., suspension or cancellation of the CEP, closure of ongoing CEP applications). The inspector issues a statement of noncompliance which is also distributed to the appropriate competent authorities. Suspensions and cancellations of CEPs are reported to all concerned authorities so that action regarding related marketing authorization(s) can be taken. Suspensions and cancellations are published on EDQM's website. A suspension may only be lifted after the company takes satisfactory corrective actions and after a re-inspection confirms the implementation of those actions.

International collaboration

EDQM is involved in the international pilot project coordinated by the European Medicines Agency to exchange information on API inspections with the US Food and Drug Administration and Australia's Therapeutic Goods Administration (TGA). EDQM has also carried out joint inspections with the World Health Organization (WHO) for API manufacturers covered by CEPs which were also within the scope of the WHO prequalification program. The WHO prequalification of medicines is a service provided by WHO to assess the quality, safety, and efficacy of medicinal products to give international procurement agencies the choice of a wide range of quality medicines for bulk purchase for distribution in resource-limited countries.

Susanne Keitel, PhD, is director of the European Directorate for the Quality of Medicines and Healthcare (EDQM) of the Council of Europe in Strasbourg, France. EDQM is also responsible for the European Pharmacopoeia (Ph.Eur.), Susanne.Keitel@edqm.eu.