In recent years, USP has revised its monographs for several excipients considered at high risk of contamination with ethylene
and diethylene, providing limits of not more than 0.10% of these two contaminants. Contamination with these substances has
been identified as the culprit in some high-profile incidents and appeared to be the result of failures in Good Distribution
Practices (GDPs). In 2006, for example, at least 100 deaths were attributed to the presence of diethylene glycol in bottles
of cold medicine prepared by the Panamanian government (6). What was believed to be 99.5% pure glycerin was actually counterfeit
and passed through multiple trading companies on three continents. An investigation by the New York Times revealed that in the course of the supply chain, a certificate attesting to the purity of the "glycerin" was altered by eliminating
the name of the manufacturer and previous owner (6). It was also found that the manufacturer was not certified to produce
Purchasers of excipients should expect complete transparency from their suppliers with regard to transportation, storage,
repackaging, and relabeling, and should also audit their supply chains using the GDP Guide for Pharmaceutical Excipients published by the International Pharmaceutical Excipients Council (IPEC) as a basis (7). IPEC recommends that pharmaceutical
manufacturers to audit their excipient manufacturer and all distributors in the supply chain or use the results from a qualified
third-party audit (8). As reinforced by the tragedy in Panama, it is also important for the user—in partnership with the supplier—to
verify the chain of custody of an excipient to ensure the pedigree's accuracy.
In the authors' experience, there is increasing pressure by regulators to perform audits of not only the API manufacturer,
but of the excipient supplier as well. Typically, the marketing authorization holder is expected to qualify their suppliers,
including those that provide excipients. However, the sheer quantity of audits has become a hot topic for discussion. At Merck
Millipore's facility in Germany, the company receives approximately 100 customer audits every year relating to pharmaceutical
raw materials, and an increasing number of these audits relate specifically to excipients. Preparing, organizing, hosting,
and following up on these audits can put a strain on resources, and there is a limit to the number of audits that can be completed.
Because of this, companies usually have to prioritize which audits must be performed.
Recent initiatives, such as those being developed by Excipact, an excipient manufacturing certification scheme developed by
members of several industry organizations, and Rx–360, an international supply-chain consortium formed in 2009 (9, 10), suggest
using third-party organizations to audit excipient suppliers and ensure continued conformance. After a successful audit, Excipact
will issue the supplier a certificate that confirms alignment with GMP and GDP requirements. This certificate will be renewed
as appropriate. Excipact includes representatives from the European Fine Chemical Group (EFCG), IPEC–Europe, IPEC–Americas,
the European Association of Chemical Distributors (FECC), and the Pharmaceutical Quality Group (PQG), a special interest group
of the chartered professional body for quality, the Chartered Quality Institute, who have agreed to work together on the development
of an international certification scheme for excipients suppliers. A similar approach is taken by RX-360, which currently
has more than 50 members and observers. The purpose of the consortium is to "enhance the security of the pharmaceutical supply
chain and to assure the quality and authenticity of the products moving through the supply chain" (10). The consortium is
preparing to launch an audit program that will supply members with reports of APIs, excipients, and other materials used in
final-drug manufacturing. The audits will be performed based on well-accepted guidelines and standards developed by groups
such as IPEC/PQG or the International Conference on Harmonization (ICH) (11–13). Audits conducted through Excipact or Rx–360
will cover general questions related to quality and GMP that will be useful to all excipient and pharmaceutical manufacturers.
Audits of single customers will concentrate on specific drug-product related topics concerning the excipient.
Excipient suppliers are expected to be familiar with a wide range of analytical methods and possess cross-functional knowledge
of chemicals, pharmaceuticals, and packaging materials. In addition, the excipient supplier should demonstrate competency
in global regulatory requirements, and have broad expertise in toxicology, quality control, and method development. Another
important factor in ensuring excipient quality is communication. Communication is imperative, and the drug manufacturer should
be as open as possible with their supplier to convey their requirements. This exchange should include discussion of how the
material will be produced, controlled, and delivered, as well as how changes to the initial specifications will be handled.
Proper documentation is also vital. Many companies provide regulatory documentation with their pharmaceutical raw materials.
Merck Millipore provides password-protected access to information on pharmaceutical raw materials that can be used for qualification,
such as certificates of analyses of three batches, a description of the manufacturing process, and an overview of the cross-validation
of analytical methods. Analytical procedure and stability data are also available in line with ICH requirements. To simplify
the search for information, the documents are structured according to the ICH M4 Common Technical Document (CTD) format (14).
The agreement to assemble all the quality, safety, and efficacy information in the common CTD format has revolutionized the
regulatory review processes and led to harmonized electronic submission that, in turn, has enabled implementation of good
review practices. For industries, it has eliminated the need to reformat the information for submission to the different ICH
regulatory authorities. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and
the strongly recommended format of choice for NDAs submitted to FDA.
When evaluating suppliers, the total cost of excipient acquisition, including the possible risks associated with particular
suppliers, should be considered. Inability to obtain the necessary documentation, lack of supply-chain security, or difficulties
in re-supply are just some of the problems that can lead to significant operational, regulatory, and financial setbacks for
the drug manufacturer. A trusted supplier should provide comprehensive product-related documentation and offer a regulatory
service that helps the manufacturer minimize the risks associated with delivering the required excipient. Established quality
systems and standards are also important to help ensure patient safety.