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 criticised 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 Harmonisation (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) 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 Organisation (WHO). Under the FMD, written confirmation will have to be provided with API shipments from July
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 Organisation (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 authorisation 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 ($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,