In the summer of 2009, the European Commission had decided to exclude excipients from the new directive because it believed the costs of implementing excipient-certification standards outweighed the benefits. At the time, the legislation was expected to focus only on production and distribution of finished medicines and active pharmaceutical ingredients (APIs).
In the meantime, the International Pharmaceutical Excipients Council of Europe (IPEC-Europe), in partnership with the European Fine Chemicals Group (EFCG) and other trade associations, began to develop Excipact, a voluntary standard that will enable excipient manufacturers and suppliers to obtain quality certificates for their products. Certification would be based on GMP and GDP standards in existing IPEC guidelines and verified by accredited third-party auditors."Excipients need to be appropriately regulated as they are an integral part of a medicinal product," says Alexandra Brand, chairman of EFCG's Excipact global steering committee and global vice-president for pharmaceutical ingredients at BASF (Ludwigshafen, Germany). "We support workable guidelines of regulatory authorities for excipient GMP and GDP which minimize risks without over-burdening industry."
Excipact's developers would like to see the program expand beyond Europe. IPEC-Americas is therefore working with NSF International, a US standards organization, on a similar standard with the participation of the US Food and Drug Administration. Excipact is expected to be operational next year after a consultation period with various stakeholders.
Members of the European Parliament and the Council of Ministers, the arm of the EU that represents EU member-state governments, now recognize the importance of subjecting excipients to GMPs and GDPs. The parliament's committee on environment, public health, and food safety (ENVI), the lead committee on the counterfeit medicines directive, rejected claims by the European Commission that the safety of excipients in medicines was not a major issue because there have been relatively few incidents of fatalities from toxic nonactive ingredients. "The consequences of the use of falsified excipients are well documented," says Marisa Matias, ENVI rapporteur on the proposed directive. In their explanation to the amendements, ENVI and Matias referred to the Commission's impact assessment of the proposed directive, which provided details of sharp increases in seizures of counterfeit medicines throughout the EU. Matias also argued that excipients, much like APIs, can be falsified, contaminated, or adulterated, thereby leading to patient deaths. Take for example, the contamination of cough syrup when diethylene glycol was substituted for glycerin, leading to deaths of many around the world in the 1990s and in 2006, or the infant formula in China in 2008 that was contaminated with melamine.
The committee also suggested that under the directive, the European Commission, in coordination with the European Medicines Agency, be required to publish guidelines for "specific good manufacturing practices for excipients." The Commission would be advised to take into account existing standards on this topic, including IPEC's GMP guideline and the ISO:9001 standard on quality management systems.
The Council of Ministers did decide late last year that certain excipients "identified on a risk-based approach" should be covered in the directive. In the draft language of the amendments to the directive, excipients are placed on the same level as APIs with respect to GMP and GDP requirements.
"Ideally, we would like to see the Commission adopt Excipact as its guidelines for GMP and GDP for excipients," says Iain Moore, chairman of IPEC-Europe's certificate project committee and products and quality assurance manager at Croda Europe (Snaith, England). Unfortunately, the commission cannot legally adopt trade associations' guidelines as legal EU standards, but they can cite international standards such as those produced by ISO, said Moore.
One option may be for IPEC and other trade associations supporting Excipact to start the lengthy process of persuading ISO to adopt it as one of their standards. The more likely option is for the EU to back indirectly the ideas behind it by approving legislation recognizing the necessity for GMP and GDP standards for excipients. Parliament is expected to debate ENVI's proposed amendments at a plenary session this month.
Sean Milmo is a freelance writer based in Essex, UK.