Good manufacturing practice (GMP) for pharmaceutical products is well established and incorporated in European Union regulations. And thanks to the International Conference on Harmonization's Q7 guideline, active pharmaceutical ingredients (APIs) also have standard GMPs worldwide. There is still no legal requirement in Europe, however, for GMP or GDP (good distribution practice) compliance regarding pharmaceutical excipients. The lack of regulation in this area is surprising given that most pharmaceutical products contain excipients.
There are still too many examples of recorded deaths due to the use of adulterated or mislabeled pharmaceutical excipients. In 2006, in Panama, for example, nearly 100 people died after taking cough syrup that contained glycerine that had been contaminated with diethylene glycol. The contaminated product was produced in Hengxiang, China, and traveled through several distributors, including one in Barcelona, before entering Panama at the site of the drug manufacturer.
In this case, too many stakeholders involved in the supply chain seemed to simply close their eyes when it came to understanding the way excipients should be managed. This lack of knowledge, control, and traceability is still a major concern, made worse by the fact that many excipients are purchased through agents and brokers on the open (commodity) market.GDPs for excipients
The supply chain of a pharmaceutical excipient starts at the point of manufacture and continues until used by the finished-product manufacturer. Other parties may be involved in the chain as well, including distributors, transporters, warehousing companies, forwarding agents, traders, and brokers. Although some of these parties do not have direct contact with the product (e.g., transporters), those that do (e.g., repackagers, processers, samplers ) require a higher level of control and GDPs.
Because excipients are often produced in different grades and sold for many applications such as for food, cosmetics, and personal care products, they are traditionally handled as either technical or industrial-grade materials. In fact, because excipient usage for pharmaceutical products makes up a small percentage of the total volume of excipients manufactured, not all excipient manufacturers and distributors are aware of, or recognize, the specific requirements of a pharmaceutical product containing an excipient when it comes to quality and functionality. Most quality-management systems are based on the International Organization for Standardization's ISO 9001, which does not incorporate critical GMP and GDP principles such as cross-contamination and change control, guarantee of traceability, comprehensive sampling and testing, hygiene, cleaning, or documentation.
Parties involved with food and feed applications have implemented risk-based quality systems based on principles of hazard analysis and critical control points (HACCP) as described by the World Health Organization (WHO). HACCP principles, however, also do not fully cover excipient GMP and GDP principles.
In January 2004, therefore, the International Pharmaceutical Excipients Council of Europe (IPEC–Europe) began work on a new guide through its GDP Committee, in conjunction with IPEC–Americas and support from the Japanese Pharmaceutical Excipients Council (JPEC) and WHO. Although the guide is based on WHO's good trade and distribution practices for pharmaceutical starting materials (1), the IPEC guide is more specific, focusing on the "how to" for pharmaceutical excipients.
The final guide, IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, was published in early 2006 and provides a custom quality system for the pharmaceutical excipients' supply chain, incorporating GDP principles and reflecting specific processes for excipient distribution (2). Because of the variety of activities involved in the excipient supply chain, a matrix of applicability for various parties and activities is included. Overall, the guide is meant to help ensure full traceability of pharmaceutical excipients and to prevent contamination and cross-contamination in the supply chain.
The IPEC guide chapters cover the following processes: quality management, organization and personnel, premises, warehousing and storage, equipment, documentation, contract activities, repackaging and relabeling, complaints, recalls, returned goods, handling of nonconforming materials, and dispatch and transport. The following section describes these basic GDP recommendations in more detail.