The quality and safety of the U.S. (and international) drug supply has garnered much attention over the past year. Whether it is quality control problems in popular medications, heists resulting in stolen pharmaceuticals, substandard, adulterated, or counterfeit drugs being sold in developing countries (and even in developed nations), the industry has faced a barrage of negative headlines. Of course, ensuring high quality and safe medications is a complex task, particularly as the industry has grown into a global one. It takes many components, including vigilant regulatory bodies, ethical manufacturers, and ever-evolving standards-setting bodies. The role of the latter tends to be the most unfamiliar to the general public, but also to some who work in the pharmaceutical industry. Yet quality standards remain an essential element of maintaining a well-functioning system—and are becoming even more vital as contamination and adulteration issues increase. Quality standards as set by the U.S. Pharmacopeial Convention (USP) play an important role, and include standards for finished drug products (for both small molecules and biologics), active and inactive pharmaceutical ingredients, and packaging and distribution standards, as well as storage standards, labeling standards, practice standards for pharmacists, nomenclature standards, and others.
The Role of USP
Quality standards for pharmaceuticals have historically been a critical—yet largely behind-the-scenes—component of the safety nets that protect the quality of medicines. In the United States, USP, a private nonprofit organization, develops standards that help ensure the identity, quality, purity, strength, and consistency of finished medicines and their active and inactive ingredients. Pharmaceutical products and their ingredients are required by U.S. law to comply with USP’s standards, or risk being deemed adulterated or misbranded.
In the last several years, we’ve seen a number of instances in which contaminated or adulterated products or ingredients have presented threats to public health. One of the most well-known examples is the adulteration of the blood thinner heparin, which resulted in patient deaths and adverse reactions in the United States and around the world. Responding to these threats, USP revised standards that have been—or are at heightened risk of being—adulterated based on economic motivations. This was the case with heparin, as well as with the excipient glycerin (with specific incidents of adulteration involving cough syrup and toothpaste incorporating the sweetener) and others. USP has also addressed contamination issues, which include revising its standards for elemental impurities (heavy metals).
Focus on Packaging and Distribution
Along with modifying product and ingredient standards, another critical area of focus for USP in the coming years will be that of packaging standards. While consumers, legislators, regulators, and advocacy groups are concerned with lead and other impurities in drug products and other consumer products, there has also been a great deal of attention regarding such components in drug product packaging. We’ve also seen increasing exploration and utilization of new packaging technologies to address counterfeit medications as this problem has grown. Beyond packaging, USP is looking at the distribution of medicines as a whole as supply chains grow increasingly complex, providing new opportunities and avenues for counterfeiters. USP is currently prioritizing its work for its new 2010–2015 cycle (the organization renews its focus every five years following its USP Convention meeting, electing experts to serve on its scientific committees and creating new work plans on standards activities) in these and other areas. We hope to engage the pharmaceutical industry as we consider these modifications, as they will certainly affect domestic and worldwide operations. Some of these changes will be voluntary (guidance chapters), while others will be mandatory for manufacturers marketing products in the United States.
Supply Chain Complexity, Security
Of course, it is not breaking news that supply chains have grown longer and more complex—and are continuing to do so. Recognizing the global nature of today’s pharmaceutical operations and the long, multi-step journey a drug product can travel through the supply chain to the end-user, USP has undertaken a major revision of its guidelines detailing best practices for the storage and transportation of drug products (contained in the USP–NF General Chapter Good Storage and Shipping Practices for Drug Products <1079>). The new approach takes into account global issues that can arise, not only with regard to items such as keeping medicines at their proper temperature during transport, but going far beyond its original contents by discussing the importance of having a systems-wide approach to securing supply chains. It covers topics such as the role of quality agreements to ensure clarity and transparency regarding the responsibilities of each party in the supply chain, along with a host of other issues. USP will be looking to expand on many of the areas in the chapter in much more detail, with possible spinoff chapters on temperature mapping and supply chain security, among other topics. As dangers such as hijacked pharmaceuticals during transportation continue to grow, these chapters can help set forth important guidance.
Exposure Issues—Elemental Impurities and Extractables/Leachables
In addition to revising its elemental impurities standards for drug products and dietary supplements, USP is looking at elemental impurities in packaging materials. Metals are of concern in product packaging, just as they are in finished drug products. When considering limits for metals in packaging materials, this will require a completely different set of specifications and limits (allowable levels). One of the biggest USP efforts in the packaging area will be a new guidance chapter on extractables and leachables. Because packaging containers are not inert, by-products from plastics, glass, and rubber materials could migrate into a drug product. Chemicals used in the manufacturing of packaging components are increasingly controversial—not just in the pharmaceuticals industry but across the board. Indeed, extractables and leachables may alter a medicine and thus impact a patient. Some medicines, such as parenteral products injected directly into a patient, may be particularly vulnerable. USP plans to develop an informational chapter on this topic, but also will likely be incorporating some required updates into its chapters focusing on Elastomeric Closures for Injections <381>, Containers—Plastics <661>, and Containers—Glass <660>. Proposals for these changes, as with all USP standards, will be published in the Pharmacopeial Forum—the vehicle through which USP proposes revisions and new standards and accepts comments on them.
An area of constant innovation is anticounterfeiting technologies in packaging. There are of course significant economic concerns for pharmaceutical manufacturers, and public health concerns for all when medications are tampered with, or when fake medications are produced and packaged under a false name—using a company name and similar packaging to trick patients. What chapters can be developed, and how USP can provide helpful guidance to industry as it considers and incorporates a host of new technologies, is something the organization is looking into as its Packaging, Storage, and Distribution Expert Committee begins its work.
Advancing Public Health through Quality Standards
With the function of standards evolving to meet current threats, USP has embarked on a public awareness campaign to highlight the role that these standards play in securing the U.S. and international drug supply, supplementing other essential efforts of regulators and manufacturers. USP has developed an online resource center containing videos of public health experts articulating the need for standards, as well as a host of other resources explaining how FDA and USP collaborate and showcasing “standards in action.” These materials are available at www.usp.org/aboutUSP/impactVision/valueOfStandards/. We invite all interested parties to visit the site to learn more about our role, and to monitor www.usp.org to stay up-to-date as USP advances work on its packaging, distribution, and product-specific standards.