Since 1994, when more than 80 children in Haiti died from taking cough syrup containing contaminated glycerin, the supply chain of pharmaceutical starting materials has been identified by both regulators and industry alike as an important aspect of drug safety and security. In today’s globalised world, starting materials are handled by different intermediaries, re-packaged and transported over long distances using many different carriers. Business profit became the priority at the expense of an underestimated risk to patient safety.
In the meantime, standards and regulations have been developed and implemented with the intent to prevent such incidents in the future. The World Health Organisation (WHO) published its Good Trade and Distribution Guidelines in 2003 to provide guidance on how to assure the safety, quality and security in the supply chain of pharmaceutical starting materials. The European Commission followed in 2004 with GMP regulation for active pharmaceutical substances, but it took another seven years before GDP for APIs were introduced into European regulation in the form of the Falsified Medicines Directive (FMD) (2011/62/EC). In the same directive, pharmaceutical excipients will be included in the scope of GMP requirements and further changes within Chapter 5 of the EU GMP Guidelines Part I will explicitly describe requirements for supply-chain security measures within the pharmaceutical industry.
The FMD was drafted primarily to prevent falsified finished dosage forms infiltrating the market. Nevertheless, regulators became aware that falsified and sub-standard pharmaceutical starting materials are part of the risk for the patients and, therefore, incorporated related requirements into the FMD. With this new regulation, Europe will still have different regulation for active substances and excipients. Drug manufacturers have to define the level of GMP to be applied by excipient manufacturers based on a risk assessment, but GDP for excipients will not form an explicit part of this regulation, whereas both GMP and GDP for active substances are required and specified in related GMP and GDP guidelines of the European Commission.
Between the first WHO activity on GDP in 2003 and the FMD in 2011, many similar incidents to the Haitian one have occurred, such as the many deaths from diethylene glycol-contaminated propylene glycol and glycerin in China and Panama. More than 30 deaths occurred in the United States in 2008 from falsified heparin. The necessity for regulators to react was evident, but it took some time for regulations to change and to raise the appropriate level of awareness in Europe.
In the meantime, the International Pharmaceutical Excipients Council Europe (IPEC Europe) together with its sister association IPEC Americas published a GDP guideline for pharmaceutical excipients (1) in 2006 to provide voluntary industry guidance tailored for excipient supply chain together with the related GMP guideline (2). Excipients are comprised by a variety of substances widely used in other non-pharmaceutical applications and handled by many entities with little or no understanding of the risks for drug safety. IPEC, therefore, focused its efforts in the past 10 years in developing this guidance and contributed to its implementation by suppliers and users of excipients. These GDP guidelines are a tool to build appropriate links between all parties in an excipient supply chain and raise the required awareness for patient safety aspects. Furthermore, to address the lack of an official European GDP guideline for excipients, IPEC’s GDP guidelines close that gap and help the industry to apply appropriate GDP principles in excipient supply chain, thus contributing to patient safety in the sense of the FMD.
The latest effort by IPEC was the incorporation of these guidelines into a certifiable standard of GMP and GDP for suppliers of pharmaceutical excipients—EXCiPACT (www.excipact.org). This standard will help contribute to the verification of supply-chain security of pharmaceutical excipients and is in-line with the current paradigm of global pharmaceutical regulation.
1. IPEC, The IPEC Good Distribution Practices Guidelines for Pharmaceutical Excipients (2006), accessed 10 July 2014.
2. IPEC,The Joint IPEC-PQG Good Manufacturing Practices Guidelines for Pharmaceutical Excipient(2006), accesssed 10 July 2014.
About the Author
Frank Milek, PhD, is head of GMP and SHEQ operations, Aug. Hedinger GmbH & Co. KG, and currently chair of IPEC Europe.