Report from Europe

The European Union is making changes to its good manufacturing practice (GMP) guidelines at a pace that is threatening to move the region out of sync with global GMP rules, in particular with the US and Japan. The objective of the changes, put forward by the European Commission, the executive body of the Brussels-based EU, is to help pharmaceutical manufacturers reinforce quality controls over their suppliers, particularly in the area of active pharmaceutical ingredients (APIs).

The alterations to the EU GMP code (Directives 91/356/EEC, as amended by Directive 2003/94/EC and 91/412/EEC) were originally drafted to support the 2003 EU legislation on GMP for medicinal products and are considered binding on industry. They are largely based on the more recent quality guidelines adopted by the International Conference on Harmonization (ICH).

Although the ICH guidelines are meant to harmonize practices between the primary member regions (the European Union, Japan, and United States), the European Commission and its regulatory authority, the European Medicines Agency, have been acting ahead of their ICH partners. For example, the Commission recently finalized amendments to its quality risk management of APIs guideline that incorporated principles introduced in the ICH Q9 Quality Risk Management. The US and Japan, even though they have published ICH Q9 as a guidance for industry, have not gone as far as updating binding legislation (e.g., the Code of Federal Regulations sections that apply to drug manufacturing) to date.

In November, the Commission and EMA proposed changes to a chapter in the EU GMP Guide on contract manufacturing to broaden the guideline's coverage of outsourcing activities. The potential changes correspond to language in the ICH Q10 Pharmaceutical Quality System guideline that was adopted by the three ICH regions in June 2008. The alterations make clear the drug manufacturer's responsibilities for ensuring that quality control systems are in place throughout the supply chain and that suppliers are competent in GMP.

The Commission also put forward in November suggestions for changes to rules on starting materials which are, at the moment, not covered by any ICH guidelines (ICH Q11, which is still in Step 2 of the harmonization process, may address this topic in part). The suggestions stipulate that all aspects of the production and control of starting materials be documented, that purchasing staff should have a "thorough knowledge of suppliers," and that the suppliers themselves be periodically audited. These modifications, like others proposed by the Commission during the past few months, are now undergoing a consultation period with industry stakeholders.

"Experience has shown that some manufacturers do not adequately qualify their suppliers, do not have good knowledge of the supply chain or fail to control it properly," says an EMA spokesperson. "Regulators perceive an increasing risk in this area and as the heparin incident illustrates, failures can have disastrous consequences."

Because the ICH guidelines cover individual aspects of pharmaceutical manufacture, there is no uniform single ICH guideline for GMP for finished products, according to EMA. That said, "....there is pre-existing broad equivalence in requirements," says the EMA spokesperson. "We are in regular contact with our US and Japanese colleagues under different frameworks and do not believe that the changes proposed are inconsistent with existing or planned requirements of those international partners."

Nonetheless, the divergences are beginning to concern manufacturers of medicines and APIs. "In general, we always advocate that requirements should be harmonized between geographic areas as much as possible," says Chris Oldenhof, president of the Active Pharmaceutical Ingredients Committee (APIC), a branch of the European Chemical Industry Council.

API producers in Europe are also worried that the scope of the alterations on starting materials could be too broad to be effective. "If the required changes are to apply further upstream to include raw and starting materials throughout the synthesis chain then they will not be realistic," says Oldenhof, who is also manager of external regulatory affairs at DSM (Heerlen, The Netherlands). "It is well-known that unrealistic requirements usually lead to widespread noncompliance and even fraud."

The European Commission has declined to amend the EU guideline to allow for mandatory GMP inspections by regulatory agencies of API plants, which has been a long-established demand of European API producers. "Without adequate plant inspections, levels of compliance will always be quite low," says Oldenhof. "This is the main weakness of the proposals."

For APIC and the European Fine Chemicals Group, which also represents API producers, the Commission's suggested changes are welcome overall because they tighten up existing GMP controls in an area in which it is notoriously difficult to enforce regulations.

Sean Milmo is a freelance writer based in Essex, UK.