Regulation of Pharma Excipients in Europe: Implications for Manufacturers and Suppliers

Pharmaceutical manufacturers and their excipient suppliers are facing an uncertain future with the formal introduction of Good Manufacturing Practice (GMP) requirements in the European Union. However, there is still considerable debate about the form these will take as well as opportunities for stakeholders to have their say.

The European Commission says it has a clear mandate to draw up legislation, at least for some high-risk excipients (see Table 1), in the interest of public health. This stems from a series of cases in which excipients have caused in major public health problems as well as from other concerns including the possibility of transmissible spongiform encephalopathy (TSE) contamination in animal derived excipients.

In 2006, 21 people died in Panama after taking a government-made cough syrup containing diethylene glycol that had been mislabeled as glycerol, a widely used excipient. Another 38 people suffered side effects including disorientation and kidney failure. Several countries, including Panama, issued a major recall of toothpaste made in China in 2007 because it contained diethylene glycol that had again been mislabeled as glycerol. While no deaths were reported in this case, previous contamination episodes involving medicines have been far more serious. In 1996, glycerol contaminated with diethylene glycol killed 88 people in Haiti, while in 1990-1992 paracetamol syrup contaminated with diethylene glycol from propylene glycol led to 236 deaths in India and Bangladesh. In 1990, 47 people died in Nigeria after taking cough syrup contaminated with solvents. The complex supply chain in the Panama case, which saw the glycerol/diethylene glycol pass from a supplier in China not registered to supply pharmaceutical-grade products through the hands of several companies and traders before being bought by the Panamanian government. This illustrates the view that, in most cases, problems with excipients have occurred because of a failure in good distribution practice (GDP) rather than GMP. The Commission’s aim is to develop a set of agreed guidelines, incorporating both GMP and GDP, which will harmonize the regulation of excipients. The EC has already completed a major overhaul of pharmaceutical legislation and brought in new GMP standards for active pharmaceutical ingredients (APIs) as part of Directive 2004/27/EC. Critically, this reform has made the extension of GMP requirements to at least some excipients inevitable, as Directive 2004/27/EC states that “this point (GMP for starting materials) shall also be applicable to certain excipients, the list of which as well as the specific conditions of application shall be established by a Directive adopted by the Commission.” The scope of such a Directive is clear and designed to safeguard supply chains in Europe regardless of the source of ingredients. It will apply to both total and partial manufacture or import of starting materials, and the various processes of dividing up, packaging or presentation of the starting materials prior to its incorporation into a medicinal product. This includes repackaging or re-labeling, such as might be carried out by a distributor. A draft Directive entitled “Specific Conditions on the Application of Principles and Guidelines of GMP for Certain Excipients” was drawn up in December 2006. The main topics covered by the Draft can be seen in Table 2.