Regulation - The active pharmaceutical ingredients (APIs) industry operates in a complex regulatory framework that is currently going through a process of profound change. API manufacturers as well as manufacturing authorization holders are facing new global challenges regarding GMP and regulatory compliance. One of the major challenges is that compliance levels established at the various API sites worldwide may differ considerably. These topics will be on the agenda of the 12th European Conference on APIs in Venice, Italy, on Nov. 18 - 20.

Rogue APIs - not manufactured under compliant conditions and/or not even by the supposed manufacturer - raise substantial safety concerns regarding the medicinal products that contain them. Also the ongoing suspensions of CEPs for APIs manufactured in Asia show the urgent need for increased oversight. In order to prevent rogue APIs, either as such or already included within final dosage forms, from passing the European borders and from reaching European patients, cooperation between all stakeholders is required. The establishment of an effective system to enforce GMP and Regulatory compliance of API manufacture and trade are urgently needed in order to prevent future calamities, which could be even larger in magnitude than the recent heparin affair.

Enforcement Activities

The two most prominent regulatory authorities in the western world are today still using different approaches to oversee the quality of APIs. While in Europe the manufacturer of the medicinal product - and on his behalf the Qualified Person - needs to assure API-GMP and Regulatory compliance the U.S. FDA rely on their own inspections of the API manufacturers' sites. Both systems are currently trying to cope with the rapid globalization of API manufacture. More evidence is continually accumulating that the inroad of rogue APIs into the European market may be quite large. The current legislative initiatives on both sides of the Atlantic are both aiming to reinforce the systems and to establish oversight that will adequately protect the patients against potentially harmful and - as illustrated by the recent heparin affair - possibly even deadly APIs.

New Guidance Document: ICH Q11

The International Conference on Harmonization is currently working on ICH Q11: Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities). The requirements on the information about the manufacturing process of APIs to be included in the dossier for a marketing authorization differ from one region to another and confront the drug manufacturer with the problem of having to create several versions of the CTD sections S 2.2 - S 2.6 when applying for a marketing authorization. The answer to the question which data on API production a registration authority expects and in how much detail they should be described in the dossier is either not clear or differs between countries. In addition, divergent requirements on APIs manufactured by chemical synthesis and biotechnological methods are the cause for further unnecessary complexity. This leads to a harmonization gap, which is intended to be filled by ICH Q11. The advantages of such a harmonization of requirements are obvious: Saving time and resources when first submitting a dossier and, of course, when submitting an application in case of post-approval changes or variations.

Pilot Project

As an initial effort to improve international sharing of information and to facilitate more risk based approaches to inspection planning, a group of regulators (EU & EDQM, Australia and the U.S.) established a pilot program for joint inspections and coordination of inspection planning. This was based on the system currently operating in the EU where the EMEA outlines a yearly plan for centralized inspections and invites all Member States to contribute to this based on their own inspection plans. Each regulator identifies a contact point specifically for inspection planning purposes. Regulators outline the inspections they have carried out during the last 24 - 36 months, and their preliminary inspection plans for the next 18 months. They provide this information to all other regulators involved in the pilot according to an agreed template. Following review of this information it is planned to identify sites that could be inspected by one of the inspectorates and to provide outcomes (e.g. inspection reports) to other interested inspectorates.

New Variations Regulations
and Guidelines

Ever since Variations Regulations were implemented in the EU there have been frantic discussions going on between regulators and industry on how to improve these in order to make the regulations reasonable and workable. For the dedicated API industry, who are not entitled to file their own variations but depend upon their customers - the marketing authorization holders - to do so, the regulations often acted as a barrier blocking almost all possible improvements in their operations.
But revised, "better" regulations and guidelines have been developed and are subsequently being implemented. It is expected that unnecessarily high regulatory barriers to improvements will herewith be lowered significantly. Similar objectives are being pursued in the U.S. through the FDAs 21st Century Quality initiatives.

Open to Discussion

The leading international forum for discussions on these and further important new developments in the API industry is the APIC/CEFIC Conference. The 12th European GMP Conference will be held in Venice, Italy, from Nov. 18 - 20, 2009. Speakers from FDA, European Commission, EMEA, EDQM, national Authorities and from Industry and Trade have already confirmed their participation. More than 250 delegates are expected for this major event.