API Manufacturing Inspections: A Global View

By Patricia Van Arnum - DCAT Editorial Director

April 18, 2018

A newly issued report by the European Medicines Agency details an increase in inspections at active pharmaceutical ingredient (API) facilities as part of greater cooperation between European, US, and Australian regulatory authorities and the World Health Organization to share information on GMP inspections of manufacturers of APIs that are located outside the participating countries.

Over six years, 1,333 inspections were carried out at 458 manufacturing sites of common interest. These sites were located in 18 different countries, most of them in India (49%) and China (36%). With Canada and Japan also joining the international alliance, what are the key goals and deliverables of this API inspection program going forward? DCAT Value Chain Insights takes an inside look.

Increased international cooperation

The European Medicines Agency (EMA) and its European and international partners strengthened their interactions to improve the oversight of active pharmaceutical ingredient (API) manufacturers worldwide as highlighted in the International API inspection program report for 2011-2016, which the EMA published in April 2018.

This international collaboration allows EMA, several European Union national authorities (France, Denmark, Ireland, Italy, and the United Kingdom), the European Directorate for the Quality of Medicines (EDQM), the US Food and Drug Administration (FDA), Australia’s Therapeutic Goods Administration (TGA) Health Canada, the Japanese Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA), and the World Health Organization (WHO) to share information on good manufacturing practice (GMP) inspections of manufacturers of APIs that are located outside the participating countries.

“Nowadays, many pharmaceutical companies outsource the production of APIs to contract manufacturers located all over the world,” said the EMA in an April 12, 2018 statement in commenting on the study. “This has led to an increased need for inspections, to ensure adequate oversight of these facilities. The overall objective of this initiative is to ensure more sites are monitored by making best use of inspection resources worldwide through increased cooperation, mutual reliance between participating regulatory bodies, reducing duplication of inspections and increasing inspection coverage.”

The initiative started with a pilot in 2008-2010, and it became a full program in January 2011. The report gives an overview of the activities carried out by European authorities, the FDA, TGA and WHO between 2011 and 2016. Health Canada and the PMDA only joined at a later stage, therefore the report does not cover information on their activities.

The purpose of the pilot program was to increase mutual confidence between regulators worldwide in the field of inspections and to achieve a better use of international inspectional resources through better communication, better coordination and collaboration on inspections of manufacturing sites of common interest. It was also aimed at facilitating a more risk-based approach to inspection planning. New tools for work sharing and exchange of information were developed and used by the participants to share inspection reports and to organize joint inspections of API manufacturers located outside the participating regions. Increased transparency and visibility of inspections performed by participating authorities allowed a successful collaboration between authorities on sites of common interest and increased the number of inspections performed of value to more than one authority.

The report notes that over six years, 1,333 inspections were carried out at 458 manufacturing sites of common interest. These sites were located in 18 different countries, most of them in India (49%) and China (36%).

During this period, the program has grown both in membership and sites of common interest. The level of information shared between participants has increased, and overall inspection coverage grew, according to the report. “The participating authorities concluded that this program is beneficial and agreed to continue their collaboration,” noted the EMA in its April 2018 statement. “At the same time, a series of proposals were made to further streamline day-to-day operations, such as improvements of the electronic platforms for information exchange, and also regular reviews of the program deliverables.”

The data show that there was an increase in the number of API sites inspected by participating authorities included in the program, and this increase has supported the exchange of information on inspections which in return supported a better GMP oversight for the participating authorities. The report points out that more information was shared by participating authorities, and therefore, the program brought more transparency and efficiency for the planning and realization of GMP inspections. The following expected deliverables were assessed in accordance with the program’s terms of reference: (1) increased transparency and visibility of inspections performed by participating authorities; (2) an overall increase in the number of API sites inspected by participating authorities; (3) a decrease in duplicate inspections; (4) an increase in the number of inspections performed of value to more than one authority; and (5) an assessment of the deliverables by the participating authorities.

Going forward, the participants agreed to determine clear deliverables to be assessed at regular intervals within the program to include: (1) a review of re-inspection frequencies/schemes among participants; (2) explore how to maintain metrics such as number of inspections deferred, number of inspection reports exchanged; (3) increase visibility of the program to industry; promote the approach of this group to other authorities worldwide, and include new participants if there is interest; and (4) promote the need to amend national regulations in order to lift the legal requirements that lead to technically unnecessary duplication of inspections.