Globalization of the pharmaceutical industry—and the challenges and opportunities it poses—dominates conversations among manufacturers,
regulators and standard-setting bodies. This month, the American Association of Pharmaceutical Scientists (AAPS) annual meeting,
held in conjunction with the FIP Pharmaceutical Sciences World Congress (PSWC), has as its theme, "Improving Global Health
through Advances in Pharmaceutical Sciences." This speaks to the mission of the United States Pharmacopeial Convention (USP),
which is holding a preconference workshop in New Orleans on "Impurities, Adulteration, and the Changing Role of USP in Global
Anthony DeStefano, PhD
Economically motivated adulteration has emerged as a formidable threat to the pharmaceutical industry—and to the health of
patients worldwide—as global sourcing has become the industry norm and as globalization has increasingly complicated the management
of supply chains. Although adulteration was once thought to be a problem limited to developing countries without adequate
regulatory controls, recent examples have proven this not to be the case. We've seen heparin adulterated with oversulfated
chondroitin sulfate, glycerin adulterated with diethylene glycol, and milk products and pet food adulterated with melamine.
All were tragic incidents that marred the pharmaceutical and food industries. All led to greater interest and public concern
in the way pharmaceutical companies operate in the global environment. And all resulted in changes at USP. These include revisions
made to the specific standards implicated in these episodes of patient harm, but also a re-evaluation of the organization's
approach to documentary and physical standards and what they should contain. The "big picture" modifications to the organization's
standard-setting philosophy are still evolving.
Overall, however, these tragedies have demonstrated not only the importance of standards, but also the essential partnership
among FDA and other regulatory bodies, industry, and pharmacopeias in ensuring drug safety and quality. Even though the public
health crises that resulted from these episodes have largely stabilized, the threat of recurrence is still present—and USP's
work still is in progress. For instance, USP is working on the Stage 3 update to its heparin standards (Stages 1 and 2 were
completed in 2008 and 2009, respectively). The Stage 3 revisions will focus on optimizing identification tests and impurity
test methods. In the area of excipients, USP plans to publish a new monograph for hydrogenated starch hydrolysate—the final
standard in a group related to glycerin that USP updated by adding tests to detect diethylene and ethylene glycol. (Other
important work in the area of excipients includes an effort to revise standards for essential oils that have been or are considered
to be at risk of being adulterated through substitution of low-grade oils.)
Unfortunately, it is impossible for the pharmacopeias to guess what the next quality related threat will be and develop a
test to find it. USP is therefore taking a more practical approach and working to develop better, more specific tests for
assays and impurities. The organization has embarked on a multiyear initiative of monograph modernization in which the organization
has prioritized a long list of monographs to update because they use outdated technology, lack impurity tests, or are otherwise
deficient by modern standards.
Ensuring that USP monographs contain appropriately specific assay and impurity methodology allows the organization to maintain
its focus on providing public standards that will effectively assess and assure the quality of the material of interest rather
than developing tests to find the next adulterant.
Of course, adulteration is not the only contamination issue we grapple with. Globalization of the supply chain increases
the risk of contaminants posing a threat to the quality of pharmaceutical products and ingredients, thus, USP's work in the
area of contamination control continues. One of the most high-profile and far-reaching examples is that of elemental impurities
(i.e., heavy metals). Revision of USP's standards for elemental impurities (currently contained in General Chapter Heavy Metals
<231>, and now proposed in a series of three new chapters) has been in the works for several years. Once official, all drug
products recognized in the USP–National Formulary (NF) will need to meet USP standards, unless an exclusion is allowed in a monograph.
When evaluating the existing elemental impurity standard, USP determined that an overhaul was necessary to address the standard's
lack in range of elements, selectivity, and sensitivity, and to establish permissible daily exposure limits for the elements
of interest in the drug products. The three new USP chapters propose a toxicologically based approach to setting limits for
the elemental impurities in pharmaceutical products and dietary supplements, and instrumental approaches to provide the sensitivity
and selectivity needed to demonstrate compliance with the proposed standards when products are tested.
Understanding that the revision will have a major impact, and require significant work on the part of manufacturers, USP has
involved the pharmaceutical industry in the process through workshops and other forums in addition to its typical public review
Public health is paramount and this work provides an opportunity for USP and industry to jointly and expeditiously advance
standards that will be reasonable to implement and also ensure quality medications. USP is an observer in the International
Conference on Harmonization (ICH) Q3D expert working group, which was formed to establish globally agreed-upon permissible
daily-exposure levels of key elements in pharmaceuticals. USP's initial draft chapter, Elemental Impurities—Limits <232>, served an important role in helping the working group get off to a fast start. USP anticipates advancing chapters for
a final round of comments on elemental impurities in early 2011 in the Pharmacopeial Forum.
Industry and consumer awareness
These initiatives will be addressed at the AAPS/PSWC USP workshop this month. We are seeking as much input as possible into
these issues, which are important to the industry and the pharmacopeia. In fact, USP recently launched a public-awareness
campaign designed to educate consumers, industry, regulators, and others about the importance of quality standards.
The centerpiece of the campaign is an online resource center featuring videos with FDA and USP leaders, as well as other parties
representing practitioner, consumer, and manufacturer's interests. The page is accessible at
More information on USP's workshop at AAPS/PWSC is available at
Anthony DeStefano, PhD, is vice-president, General Chapters, of the US Pharmacopeial Convention (USP).