Iterative Approach to Standards Development and the “Emerging Standards” Concept

USP has always taken an iterative approach to developing standards, continuously evolving its standards from inception to official status to further revision in response to stakeholder input and advances in technology and regulatory science. This paper outlines why iterative approaches are increasingly important and introduces the concept of an “emerging standard”—a standard underdevelopment made available at an earlier stage for stakeholder input and contributions. Emerging standards are intended to improve USP’s official standards elaboration process by increasing transparency and allowing for broader stakeholder participation prior to formal notice and comment through publication in the Pharmacopeial Forum. Two examples of emerging standards are being published with this article to further illustrate the idea (USP Emerging Standards: Methods for the Analysis of Acetaminophen Injection and USP Emerging Standards: Methods for the Analysis of Palbociclib), and USP is seeking feedback on this concept and the evolution of its iterative approach to standards-setting.

Public standards developed by the US Pharmacopeia (USP) play a critical role in assuring the quality of medicines consumed in the US and around the world. These standards define specifications that medicines and their ingredients must meet throughout their life cycle, ensuring the consistency and quality of drugs across manufacturers and regions. By providing a common benchmark for quality, standards also facilitate the development, manufacture, authorization, and post market surveillance of medicines and help increase access to quality medicines. To achieve these benefits, however, it is essential that the quality standards keep pace with the pharmaceutical environment and reflect the needs of its many stakeholders.

In recent years, there have been sweeping and dramatic changes in this environment. The pharmaceutical market has become truly globalized, with manufacturers increasingly operating across multiple countries with highly variable technical and regulatory capabilities. Globalization has resulted in increasing fragmentation and vulnerability in the supply chain, as has become starkly apparent during the COVID-19 pandemic. At the same time, there is a larger pipeline of new medicines in development than anytime in history, with a marked shift towards new and increasingly complex and sophisticated therapies and modalities. Advances in engineering and software technologies, from gene sequencing, process engineering, and analytical technologies to data modeling and analytics are continuing to transform the drug development process and accelerate the introduction of innovative and unique products. The industry also is seeing the increasing adoption of new manufacturing approaches, such as continuous and “on-demand” manufacturing and the use of advanced data and analytical technologies to monitor and measure product quality throughout the manufacturing process. As USP and others have recognized, today’s rapidly evolving and increasingly complex pharmaceutical landscape requires new approaches to the development of quality standards¹.

Within the pharmaceutical regulatory system, establishing quality public standards is the responsibility of pharmacopeias such as USP, working closely with regulators, manufacturers, and other stakeholders. Robust public input and participation in the standards-setting process are critical to make sure standards meet stakeholder needs and effectively respond to public health priorities. Standards development inherently is an iterative process, with proposed standards being revised and finalized based on stakeholder feedback. Even after a standard is established, it is subject to continuous revision based on ongoing stakeholder input as well as advances in science and technology.

Traditionally, the standards-setting process has been very structured and deliberate, including a formal notice and comment period to ensure the opportunity for public input. This formality is important in the final stages of establishing pharmacopeial standards given that such standards may be legally recognized and mandatory in nature. However, this deliberate and formal process may have significant drawbacks when utilized at earlier stages of standards development. It can be extremely time-consuming, especially if there are multiple cycles of notice and comment. And the process is not always well understood by or accessible to all manufacturers, regulators, and other stakeholders, who, as a result, may not participate or take advantage of the opportunities to contribute to a standard.

These issues have been exacerbated by the increasingly global, complex, and constantly evolving pharmaceutical environment.USP must now find ways to engage an increasingly broad and diverse group of stakeholders, stay abreast of an accelerating paceof knowledge creation and accumulation, and respond quickly to rapidly shifting public health priorities. Therefore, more nimble, flexible approaches to standards development and stakeholder engagement are needed.

USP has taken several steps to adapt to this rapidly changing environment and ensure that its standards remain timely and relevant. These include new, more interactive stakeholder engagement mechanisms such as open forums, roundtables, webinars, workshops, advisory groups, and online communities that bring together regulators, industry, and other stakeholders around the world to exchange information on science and standards topics. USP has also created mechanisms for informal, early communication of standards proposals prior to formal publication for public comment to broaden distribution and awareness and encourage greater input from stakeholders.

Through these efforts, USP has increased its engagement and collaboration with manufacturers, regulators, and other stakeholders to provide standards and resources more quickly to meet evolving public health needs. An example of this is USP’s work on nitrosamine impurities, where in response to emerging information about the dangers of some of these impurities, USP worked with stakeholders to rapidly develop a new general chapter and accompanying reference standards to help manufacturers identify and analyze these substances.

Other examples are the tools that USP was able to quickly develop with stakeholder contributions and input to help combat theCOVID-19 crisis. These include analytical tools to help detect substandard and falsified vaccines and medicines, as well as best practice guides on vaccine handling and storage. Working with the FDA and others, USP also rapidly provided updated standards and guidelines for compounders and manufacturers to help address shortages of alcohol-based hand sanitizers.

These experiences have demonstrated the value of supplementing the traditional formal compendial process with more agile and innovative approaches that increase stakeholder participation and facilitate the development of new quality standards and resources. With widespread adoption of technology globally, and online scientific forums and communities becoming more prevalent, USP is working to expand these approaches and allow for more collaborative, dynamic development of standards not only in response to public health crises, but to more proactively and continuously anticipate and address stakeholder and public health needs.

As part of these efforts, USP is proposing to take a more iterative approach to standards development, where an emerging standard — a standard still under development — would be shared through USP’s website to build stakeholder communities and stimulate early discussion and contribution. Input received at these early stages would be incorporated into subsequent versions of the standard as it evolves into a final, official standard.

This approach would provide greater visibility into the development process while giving stakeholders an opportunity to shape standards from an early stage. For example, USP could include the validation and other scientific data on which an emerging standard is based, giving stakeholders the ability to understand and respond to this data. Emerging standards could also be accompanied by the release of reference materials, to help stakeholders evaluate and contribute to a potential standard. The transparent nature of this approach would allow stakeholders to better understand, react to, and plan for implementation of an emerging standard, providing greater predictability and certainty for both manufacturers and regulators.

The accompanying partial monographs for Acetaminophen Injection and Palbociclib are examples of emerging standards that could be developed through this more iterative approach. These currently contain information regarding identity, assay, and organic impurities, but do not yet have all of the tests and methods needed for an official monograph. By making these emerging standards available at this stage, USP could obtain early stakeholder feedback and contributions that would expedite completion of these standards and allow them to be established as compendial standards.

Similarly, USP has been working on additional nitrosamine impurity detection methods and is now considering making these available informally on its website. These methods could eventually be incorporated into the general chapter through the compendial process, but for now could be provided simply as a resource for manufacturers and others and as a way of gathering early stakeholder feedback.

This approach is analogous to the informal, digital prepublication of scientific articles, which has become increasingly prevalent in the scientific community. Researchers have realized that prepublication allows them to get their work into the public domain more quickly and provides a greater opportunity for collaboration and input than that which is encountered in the formal peer review and publication process. Its value has been seen especially during the COVID-19 pandemic, given the need to quickly advance relevant scientific research and knowledge to address this public health crisis. Similarly, there may be value to providing an emerging standard as a resource to manufacturers and regulators, consistent with risk-based approaches being adopted throughout the pharmaceutical industry.

This approach and the emerging standards concept could be utilized to update existing standards as well as develop new ones, allowing standards to continuously evolve based on the evolving scientific and regulatory landscape. It could be used not only forUSP’s standards for medicine, but also for the quality standards it establishes for other products, such as dietary supplementsand food ingredients. Ultimately, this approach would allow stakeholders to play a more substantial, ongoing role in standardsdevelopment and result in more timely, relevant public standards that reflect the broader scientific and regulatory community andmeet evolving public health needs.

Given the legal weight pharmacopeial standards often carry, it is important to be clear about the role and purpose of this iterative approach and its relationship to the traditional compendial process. This approach would not replace the formal compendial process — rather, it would provide a way of getting to that process sooner, with a more robust proposal that reflects wider public input and can be finalized more quickly. While the emerging standards provided to stakeholders may be a useful resource and have value even in their preliminary form, they would not be considered official standards. They would be informational but could not be relied upon in regulatory filings and would not be part of the official compendium. Rather, as described above, they would be provided to stimulate scientific dialogue regarding appropriate quality attributes and analytical methods for a product or ingredient and to facilitate the development of an official standard.

Quality standards play a key role in helping to maintain a stable, affordable, and accessible supply of safe and effective medicines while also facilitating the development of new therapies. Given the challenges of creating these standards in today’s rapidly changing pharmaceutical environment, it is incumbent on USP and other pharmacopeias to continue pursuing new and innovative ways of developing standards that will reflect and take advantage of advances in science and technology and more effectively involve its broad and diverse stakeholders in the development process.

USP believes an important step in this direction is a more iterative approach to the development of standards, supported by an integrated stakeholder engagement model that exists throughout the life cycle of a standard — from initial scientific concepts to full maturity to reenvisioning that standard as science and the regulatory environment evolve. The emerging standards concept presented in this paper is one manifestation of how this approach could work. USP is seeking comments on the emerging standards concept and how best to advance its iterative approaches and looks forward to sharing additional information on its efforts to more continuously and effectively collaborate with stakeholders to develop standards and help assure the quality of medicines.