Pharmaceutical companies have spent much time, effort, and money to ensure excipient quality. Whether an excipient travels
through a short and direct, or long and complex supply chain, history has shown that, unfortunately, dangerous, often life-threatening
changes are sometimes made to the excipient along its path. Consider the following examples:
- In 1990, approximately 330 people died in Bangladesh after a paracetamol solution was flavored with glycerin containing diethylene
- In 1996, tragedy struck in Haiti, when a pharmaceutical company bought glycerin it believed was produced in Europe. The glycerin
had been handled by at least seven distributors and was traced back to China. The contaminated glycerin contained a significant
amount of DEG and led to the deaths of 80 children.
As a result of the Haiti incident and a subsequent investigation uncovering the involvement of numerous distributors and brokers,
in 1998, the World Health Organization (WHO) developed the Good Trade and Distribution Practices for Pharmaceutical Starting
Materials (GTDP) guidelines. That same year, the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas)
published a position paper on vendor qualification. IPEC-Americas, along with IPEC–Europe and IPEC–Japan, have since published
numerous guidelines covering such topics as good manufacturing practices (GMPs), good distribution practices (GDPs), the use
of certificates of analysis (COAs), and significant-change notification to help manufacturers protect their excipient supply
In spite of these efforts, supply-chain incidents involving excipients occurred agin in China in 2005 and in Panama in 2006.
As a result of these incidents and drug-importation discussions with the US Food and Drug Administration, IPEC-Americas and
IPEC–Europe released a position paper on proper excipient pedigree in December 2008 (available for free download at
Three basic approaches of tracking chain of custody were explored, including paper trail, barcoding, and radiofrequency identification
(RFID). Because of the complexity of the excipient industry, the authors (including excipient manufacturers, users, and distributors)
deemed that the quickest approach that could be implemented with the least disruption to the supply chain was a verified paper
trail. (It's important to note that FDA reviewed the position paper; the authors considered the agency's comments and for
most the part, included them in the final version).
Although a single program cannot prevent fraud, a pedigree approach—using existing paperwork (or electronic paperwork) to
the greatest extent possible—is a strong deterrent. The IPEC Excipient Pedigree Position Paper is founded on four premises:
- WHO and IPEC GDP guides already recommend documentation that can be used to support a paper-trail
- The 1998 IPEC–Americas position paper on the qualification of excipient vendors places a full obligation on the excipient
user to be aware of the product's complete supply chain
- Distributors consist of all parties involved in trade and distribution, including (re)processors, (re)packagers, transport
and warehousing companies, forwarding agents, brokers, traders, and suppliers other than the original manufacturer
- Excipient makers, users, and distributors must cooperate to make this scheme work.
The excipient manufacturers' role includes manufacturing the excipient according to the IPEC/Product Quality Group GMPs,
as well as following the GDPs for distribution operations performed. Additionally, the position paper states that a manufacturer
is expected to provide documentation to verify it shipped the excipient to a distributor if it used this supply chain.
Finally, if the manufacturer is using a distributor, it is recommended that the manufacturer ensure the distributor is in
compliance with IPEC GDPs and that the distributor takes appropriate measures to prevent cross-contamination. IPEC and the
authors of the position paper believe that verification is best accomplished by auditing the distributor. The paper also recommends
that excipient manufacturers and distributors conduct mock recalls to test the effectiveness of their recall procedures.
The IPEC GDP guide calls for a distributor to provide the user, upon request, with a chain-of-custody record for the excipient.
This record might include bills of lading or air bills with the financial data redacted. The distributor should also provide
a COA for each delivery (a copy of the COA from the original excipient manufacturer is acceptable).