Falsified Medicines Directive Takes Shape in Europe

The European Union (EU) approved the Falsified Medicines Directive (FMD) last year in an attempt to tackle the growing problem of counterfeit medicines. In addition to combating the trade in fake pharmaceuticals, another prime objective of the legislation is to deal with the increasing amounts of substandard pharmaceutical ingredients entering the EU under the guise of unverified compliance with cGMP standards. Currently, 70% of the EU's APIs are imported according to the European Fine Chemicals Group (EFCG).

Sean Milmo

There has been a lengthy debate about the contents of the directive in the European Parliament and the Council of Ministers, and it has become apparent that the implementation of the directive could be as difficult as its approval. Differences over some of the final details of the legislation could mean that it will not come into full operation for at least a few years because there are still disagreements over how the GMP standards on APIs should be embodied in the directive.

FMD is scheduled to come into effect this month, Jan. 2013; however, the European Commission (EC), the Brussels-based EU executive, is still in the early stages of deciding on the legal status of GMP guidelines in relation to the legislation. Some EU member states are also being slow in incorporating the directive into national legislation. For example, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) was scheduled to complete, only by Nov. 19, 2012, a consultation exercise with stakeholders on how to transpose the FMD into national law. "We are working hard to make sure deadlines are met," says an MRHA official. Furthermore, groups like European producers of APIs, whose grievances about low-quality imports have helped trigger the drafting of the directive, are still complaining that the FMD is not tough enough on GMP standards for non-EU APIs.

The primary intention behind the directive is to establish a secure pharmaceutical supply chain with rules stipulating quality requirements extending from starting materials to the distribution and packaging of medicines. European manufacturers of generic medicines have, however, warned that the legislation's aim to cover both counterfeit and substandard products could push up the cost of low-priced, off-patent pharmaceuticals at a time when European governments with austerity budgets are trying to reduce healthcare costs. Because of the range of the FMD, the EC has been given the power to draw up "delegated acts" or additions to the legislation that do not have to be approved by EU legislature, but have to be adopted by member countries without any changes. These extra details cover areas such as Internet marketing and security features on medicines packaging, on which the EC has been issuing drafts in the form of concept papers for consultation.

A key area to be covered by a delegated act is GMP rules on active ingredients. A concept paper on proposals on principles and guidelines on GMP for active substances has completed its consultation process. At the moment, the drawing up of a delegated act on the guidelines is being handled by an expert group, in which all member states are represented. "The delegated act will be adopted and published by the Commission in 2013," an EC spokesperson said.

The paper's main suggestion is that a 2003 directive that gave legal backing to GMP guidelines on finished medicinal products should be extended to cover the EU GMP guidelines on active substances. "This approach would bring coherence in terms of the regulatory setting for both medicinal products and active substances," the EC said. "The principles and guidelines for GMP would (as a result) be the same during the manufacturing of active substances as well as medicinal products."

There are, nonetheless, parts of the 2003 legislation that would not apply to the GMP guidelines on active substances; for example, marketing authorization for the manufacturing of pharmaceuticals and responsibility for ensuring adherence to GMP standards being allocated to a specific "qualified person" within a drug company.

The EC has proposed that the active substance guidelines would not only apply to APIs, but also to starting materials with an obligation placed on API manufacturers to ascertain that these materials are sourced from premises claimed by the supplier. In addition, the EC suggested that the delegated act on the guidelines would have to be transposed into national legislation within six months of publication so that it can be enforced within nine months.

Several groups within the pharmaceutical industry have criticized the EC proposals. Some are particularly concerned that by bringing together the two sets of guidelines, the Q7 standards for API GMP drawn up by the International Conference on Harmonization (ICH) will be undermined. ICH Q7 provides a basis for international agreement on GMP standards on active ingredients.

The European Federation of Pharmaceutical Industries and Associations (EFPIA), which represents Europe's research-based drug companies, said that bringing the two guidelines together would make interpretation of GMP both ambiguous and complicated. Instead, EFPIA suggested placing the active substances guidelines in a separate section in the 2003 directive or putting these guidelines into a new directive. EFPIA stated that the obligation on API manufacturers to verify the source of starting materials was unenforceable, while the European Generic Manufacturers Association (EGA) thought that it was beyond the scope of the existing EU guidelines for active substance GMP.

Several groups involved in the consultation warned that adapting to the new framework would require a period of more than nine months after publication, particularly for API producers outside the EU. Some suggested that this period between publication and enforcement should be as long as two years, which could result in the FMD not being fully implemented until 2015.

Another controversial aspect of the legislation is the need for imports of active substances into the EU to be accompanied by written confirmation from a national regulatory authority that the plant manufacturing the API complies with GMP standards equivalent to those in the EU. Proposals on this subject were brought forth by the EC in a public consultation. According to the EC, "equivalence" to EU standards is defined as adherence to ICH Q7 and the active substances GMP standards of the World Health Organization (WHO). Under the FMD, written confirmation will have to be provided with API shipments from July next year.

However, the EC is also planning to operate a two-tier system under which some countries will be exempted from having to provide written confirmation on the grounds that their GMP regulatory and monitoring standards are equivalent to those in the EU. To date, Switzerland, Israel, Singapore, Brazil, and Australia have requested to be assessed for exemption. Earlier this year, it was widely reported in the media that India and China, which together account for approximately 80% of API imports into the EU, considered lodging a complaint with the World Trade Organization (WTO) that the written confirmation requirement was an unfair barrier to trade. India seemed to be backtracking in September when the country's Pharmaceutical Export Promotion Council (Pharmexcil) announced that the Indian government would be shortly setting up a competent authority to certify the quality of API exports to Europe.

In a comment on the EC's concept paper on GMP guidelines for active substance, the China State Food and Drug Administration (SFDA) said that APIs should be given the same manufacturing authorization as the production of medicines. Furthermore, the SFDA said that the EU should launch its own compulsory GMP inspections for active substances so that it can issue its own GMP compliance documents.

SFDA's line on GMP is similar to that being pursued by the EFCG. EFCG has been recently reiterating its stance that the only sustainable solution to the EU's problems with substandard imports of active substances is the mandatory inspection by EU regulatory authorities of non-EU active substance plants or by those whose competence is acknowledged through mutual recognition agreements (MRAs). "The implementation of mandatory inspections, via an MRA approach, is a relatively small price to pay to guarantee that the quality of APIs meets the EU standard," said Gian Mario Baccalini, chairman of the EFCG pharmaceutical business committee, in a recent group press conference in Madrid.

EGA estimates the extra costs of a strict regime for vetting GMP standards for imported APIs to be as much as €1 billion (US$1.27 billion). Coupled with possible shortages of active substances if Asian producers cease their exports to Europe, this factor could decide the outcome of the current discussion about the final implementation of the FMD.

Sean Milmo is a freelance writer based in Essex, UK, seanmilmo@btconnect.com.