At last - a more level playing field

A new EU directive should help to establish a more level playing field where APIs are concerned. Hilary Ayshford reports.

Around 80% of European medicines are produced using APIs made in premises in China and India that have never been inspected. But all that looks set to change with the entry into force on 31 October 2005 of Directive 2004/27 amending 2001/83, which says that 'only active substances ... manufactured ... to good manufacturing practice' are permitted.It will be the responsibility of a Qualified Person (QP) in each company to ensure that the APIs used conform to GMP standards as defined by ICH Q7A, which lays down detailed guidelines on GMPs for APIs. Compliance must be declared in the Marketing Authorisation Application (MAA) - in other words, it will no longer be allowable to buy the API from a trader without a declaration and supporting data to prove compliance by the API producer.

A GMP certificate from Health Authorities will not be sufficient evidence that the GMP requirements are met, and an audit report less than three years old must be on file and available to the regulators.

In effect, the regulation gives the Competent Authorities (CAs) in the EU the right to inspect the premises of API manufacturers, traders and brokers, including those of non-EU manufacturers.

During inspections at dosage form manufacturers there will be increased focus on incoming APIs, while the use of 'fingerprinting' of APIs by the OMCL Network that links the laboratories of 85 authorities is one of several measures to counteract possible fraud or counterfeiting. Enforcement penalties will include measures such as MA withdrawals and rapid alerts and recalls.

But while he welcomes the new legislation, Guy Villax, chairman of the Pharmaceutical Business Committee of CEFIC's European Fine Chemicals Group, points out that the lack of precedents means that many areas are still in need of clarification.

For example, although the EU authorities 'may carry out unannounced inspections at the premises of manufacturers of active substances used as starting materials', such inspections are less stringent than those carried out by the US FDA and, as things stand, are not compulsory, he told delegates at December's European Fine Chemicals Conference.

There is no provision for random audits - and if there is no random audit there is no deterrence, Villax stressed. Inspections are carried out only when there is a suspicion of non-compliance - and out of 58 inspections carried out, eight led to suspensions of DMFs, all of them in Asia and most held by brokers.

Furthermore, EU inspectors are competent but assume that API producers are all honest, says Villax, just as reviewers assume that the data in a DMF reflects what is done at the plant.

He also has reservations about the format of the GMP certificate, in particular whether it is general or specific. 'The format of the GMP certificate needs harmonisation across Europe, and GMP certificates should be matched (be traceable) to a DMF version that is dated,' he said.

Similarly, it is not clear whether audit reports merely state facts or if they draw conclusions as to whether an API is compliant or not, nor whether a corrective action plan should be included. And because these reports are no longer confidential, this may compromise the constructive nature of a client audit as 'sensitive aspects' may be omitted.

Just as there is no harmonisation of GMP certificates and audit reports, sanctions too are a matter for the member states. 'If there is no enforcement through inspections and sanctions,' says Villax, ' then the legislation isn't worth much.'

ongoing clarification

On the positive side, EMEA is aware of the lack of clarity. It is in discussion with all the major associations on the various issues connected with the obligations of marketing authorisation holders in assuring the active substances they use have been manufactured in accordance with GMP.

EFCG is promoting the third party audit process, with EMEA leading the way and clarifying the process, while industry provides input, auditing resources and competences. It is also issuing a simple guide to buying APIs that meet GMP standards; and carrying out an EU-wide benchmarking exercise to assess member states' readiness to enforce the directives, the results of which will be announced at the EFCG conference 'The Business of Compliance' in April. To avoid an avalanche, Villax says, third party audits need to be acceptable, and MA holders allowed to share audit reports on the same API.

For their part, the next steps for the Health Authorities must be enforcement, enforcement, enforcement.