A thousand different excipients can be used when formulating pharmaceuticals and, as a rough estimate, excipients can comprise
more than 90% of a medicinal product's weight. Excipients are no longer characterized as simple inert additives to the API,
and the need for stringent, quality management of excipients has grown rapidly. In 2010, FDA noted five drug recalls due to
dissolution failures ascribed to excipients (1). In one case, FDA issued an import alert and an advisory to drug and dietary
supplement manufacturers warning of high levels of peroxide in the excipient crospovidone manufactured in China (2). In the
warning, FDA explained that drug manufacturers who used excipients containing high levels of peroxides would observe a loss
of drug potency and the formation of excessive impurities during the product's shelf life.
Lack of regulation
Although pharmaceutical excipients are major components of dosage forms—and potential hazards to patients—there is a lack
of binding regulation. In recent years, however, several industry standards have been developed. In the United States (US),
the recently introduced Drug Safety Enhancement Act includes the following parameters (3):
- Establishment of registration for excipient manufacturers
- Failure to have an effective quality system deems the drug "adulterated"
- Quality systems encompass management responsibility and an internal and independent quality unit
- Risk management and supply-chain management.
According to the Act, inspections of the drug product and API will occur once every two or four years while inspections of
excipient manufacturers "may occur." Further, inspections of foreign sites will occur with the same frequency as inspections
of US manufacturing sites. Meanwhile the European Union has included pharmaceutical excipients in the recent amendment of
Directive 2001/83/EC (4), providing member nations with guidance on how excipients should be regulated in pharmaceutical manufacturing
and throughout the supply chain. Despite these efforts, however, there are no binding regulations for excipients. For example,
although the US Pharmacopeia (USP) recommends industry standards, the adoption of these standards is voluntary for excipient suppliers and drug manufacturers
(5). Matters are also further complicated by the fact that excipient safety requirements can vary between different countries.
The role of suppliers
While the move toward more stringent and harmonized regulations continues to make progress, it is incumbent on suppliers and
manufacturers to jointly take the lead in ensuring excipient quality. This imperative was reinforced by FDA when the regulator
warned about the presence of high peroxide levels in crospovidone, but it should apply to all excipients:
"It is essential that [excipient] users implement robust supplier management programs... Manufacturers should employ sound
risk management principles in establishing appropriate scrutiny and actions to take for a given supplier, including but not
limited to the following:
- Review supplier history, including any relevant information on manufacturing reliability;
- Determine reliability of results reported on Certificates of Analysis;
- Consider information obtained from ongoing communications with suppliers; and
- Determine whether the quality of any finished product has been impacted" (2).
In the current regulatory environment, pharmaceutical manufacturers are under increasing pressure to develop better knowledge
of their excipient supply chain. At the same time, excipient suppliers must also shoulder a significant responsibility for
ensuring quality and mitigating possible risks, which may include excipient variability, trace impurities, the use of an inappropriate
grade of materials, contamination, mix-up across the supply chain, and economically motivated adulteration.