Roger L. Williams
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Given events of the past several years, the quality of medicines and their ingredients are foremost in the minds of many pharmaceutical
company executives. With increasing globalization and longer and more complicated manufacturing supply chains, the quality
and safety of our medicines is at much higher risk today than it was a decade ago.
One telling item: A recent survey of industry executives by Pricewaterhouse- Coopers and analyst firm Axendia focusing on
the pharmaceutical supply chain found that half of the respondents said the biggest area of risk is raw materials sourced
outside the United States. A stunning 61 percent said contaminated or nonconforming raw materials will be the top threat over
the next five years.
Contamination has always posed a challenge, but this danger is escalating in today's environment. Another significant area
of concern is economically motivated adulteration of medicines and ingredients—intentional tampering in which higher-cost
pharmaceutical ingredients are replaced with lower-cost ones. This was was clearly illustrated in the case of adulterated
heparin in 2007-2008, an episode in which my organization, the US Pharmacopeial Convention (USP), was intimately involved.
The heparin adulteration demonstrated the key role of quality standards for medicines and their ingredients. But while underscoring
the need for quality standards, it also pointed to the need for up-to-date public standards that better take into account
modern threats that were not a consideration at the time they were originally developed by USP. The tests, procedures, and
acceptance criteria in USP's standards for a medicine and its ingredients are designed to control what should or could potentially
be there, such as impurities resulting from the manufacturing process or degradation of the drug substance in the drug product.
But even the best public testing standards are at a disadvantage when it comes to identifying and measuring unknown contaminants
that might be added deliberately. And the potential number of such contaminants is effectively infinite. Thus the safety net
offered by a public standard has to be combined with other safety nets such as Good Manufacturing Practices (GMPs) and good
supply system oversight and management. All of these are the work not only of USP but also of regulatory bodies such as FDA
and ethical manufacturers and the supplier/distributor industries. The need for concerted action between these parties is
of greater importance than it has ever been in order to combat bad actors intent on counterfeiting and intentional contamination.
Modernization of Standards
USP is a nearly 200-year-old nonprofit standards-setting organization. Our standards for finished pharmaceuticals and ingredients,
published in the United States Pharmacopeia–National Formulary (USP–NF) compendia, designate the identity, quality, purity,
and strength of these articles. They are recognized in law in the United States (all drugs with a USP monograph must conform
to the USP specifications), and are enforceable by FDA. They are also widely used throughout the world. During the heparin
tragedy, the role of standards in the pharmaceutical supply chain—and the importance of up-to-date standards—were on full
display.
However, even before this episode, USP was well aware of the unique role that its standards play, and the need to better focus
on the modernization of all of our standards. This is recognized and supported by FDA as well. This past spring, FDA Commissioner
Margaret Hamburg addressed USP at its Convention meeting, held once every five years. She noted that updating monographs is
one of the most pressing tasks before FDA and USP. Getting to the ultimate goal of being proactive rather than reactive, Hamburg
noted, "would allow us not only to respond to public health crises that may arise, but also to establish standards that would
help us prevent them from happening at all ... USP standards are an invaluable tool to FDA in assuring compliance with our
regulatory standards and protecting the public from adulterated drugs."
While it has long been USP practice to always consider its more than 4,000 standards to be in a constant state of revision
(any party may propose a revision at any time, as our standards are public), the organization recognizes that prioritization
is essential. To this end, USP recently embarked on a formal monograph modernization initiative in which it analyzed data
on patient use of the medicines (indicating public health impact), as well as the level of use of monographs by the pharmaceutical
industry (indicating manufacturer reliance on these standards), resulting in a list of 200 small molecule monographs and 96
excipient monographs that USP is giving priority to. The standards identified in this list are considered in need of updating
for reasons that potentially bear on the ultimate quality of a drug or ingredient, such as use of outdated technology, existence
of safety/environmental concerns, or missing procedures for key aspects such as impurities, among others.
With this effort, we are mindful of the impact standards revisions can have on the pharmaceutical industry. For instance,
in incorporating more current technology into our standards, these technologies will need to be applied broadly by companies
of varying sizes and resources around the world. However, public health will always be the ultimate determining factor. Our
goal is to create more meaningful standards that better serve regulators, manufacturers, and patients.
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