Emerging Standards and Introduction of Adaptable Organic Impurities procedure(s) for Over-the-Counter Drug Products

Emerging Standards and Introduction of Adaptable Organic Impurities procedure(s) for Over-the-Counter Drug Products^a

Donna Seibert^b, Robert Buice^b, Gail Reed^b, Xiaoping Wang^b, Gregory Webster^b, Kylen Whitaker^b, Jingyue Yang^c

Correspondence should be addressed to: Andrea F. Carney, Senior Manager, Small Molecules, US Pharmacopeia, 12601 Twinbrook Parkway; Rockville, MD 20852; email: afc@usp.org

Two USP initiatives are converging, the need to include adaptable methodology in the compendium and the evolution of emerging standards (ES).  This article describes synergies that exist between the availability of emerging standards and new types of methodologies not typically included in compendial monographs.  An innovative Quality by Design (QbD) approach applied to the development of chromatographic methods for Over-the-Counter (OTC) products stands to benefit from the relatively new ES process that facilitates the sharing of supporting data and the collection of feedback from stakeholders on the proposed approach instead of the Pharmacopeial Forum (PF). Emerging standards are not compendial and can therefore provide a more interactive process for content generation and may help facilitate more efficient paths for improvements in organic impurities controls for OTC products.

Initially introduced as a non-binding way to involve stakeholders earlier in the standards generating process, the number of USP emerging standards has grown from two published in 2022 to 12 as of this writing. Momentum for this process has steadily increased and the existing emerging standards comprise a range of content, completeness, and complexity. The ES process can be useful as a starting point for developing standards where all tests are not yet available or only partial information is available to USP.  From an organic impurities' perspective, emerging standards can also be used to flag common degradants that may eventually become specified impurities, and when available, present validated ranges for those degradants for OTC products.   Publication of common degradants would allow drug product manufacturers to weigh in with any available toxicological information that may be useful in ensuring safety in OTC products.  Moreover, the ES process allows flexibility to include information not normally observed in USP monographs (e.g., validation data, forced degradation study results, etc.). This process gives the stakeholders a starting point for analytical methods. It also provides a platform for product manufacturers to share information with USP for future development of monographs.  

The flexible nature of the emerging standard allows introduction and socialization of new ways of presenting analytical information. For example, the Guaifenesin Extended-Release Tablets Emerging Standard published in March 2024 includes method development based on QbD principles; it defines a method operable design region (MODR) and provides method validation data for conditions selected for the final method. 

Flexibility in monograph content has been especially critical when considering products marketed under the FDA OTC Monograph System, which was incorporated into the Code of Federal Regulations in 1972. Products marketed under this system are considered generally safe and effective (GRASE) and do not require pre-approval by the FDA to be marketed. Because many of these products have a long history of use, and no one specific manufacturer holds responsibility for the introduction of a given product into the market, many of these products lack applicable USP compendial content.  Filling the compendial gaps for OTC monograph products has been a consistent focus of the USP Monograph Modernization effort since 2010.

Over time, USP and OTC stakeholders have proposed a number of ways to generate missing monograph content. For organic impurities specifically, significant challenges arise when attempts are made to apply a single referee method to products already in the marketplace, largely because of the wide variety of flavors, colors, and excipients used, and the fast pace of change in formulations for OTC products.  In short proposing a single referee method may not be the best approach to sufficiently support the breadth of marketed formulations, let alone leave room for future innovation in the OTC space.

A consortium of industry scientists from Consumer Healthcare Products Association (CHPA) member companies, USP, and FDA colleagues has been working together to develop adaptable methodology for OTC Monograph products.  Much of the focus over recent years has been centered on a pilot project for Diphenhydramine Oral Solutions.  The approach includes enhanced method development as defined by the ICH Q14 guideline and validation of methods containing ranges of chromatographic parameters. For a fuller description of the development and preliminary validation approach for these methods, please consult the Stimuli Article, “A Novel Approach Using Quality by Design to Develop and Implement Flexible Methods in Non-Application Over-the-Counter Monographs,” published in PF 49(1). 

In brief, multiple methods with distinct selectivity were acquired from participating laboratories, evaluated, and optimized to identify the most suitable conditions to separate proposed common degradants, other related compounds, and common excipients used in Diphenhydramine Oral Solutions.  Predictive chromatographic modeling software was used to generate chromatographic space where resolution between the active pharmaceutical ingredient (API), common degradants, other related compounds, and common excipients remains acceptable. The three evaluated methods were subsequently put through a multi-lab feasibility study to show portability across laboratories when used with two test samples that are representative of, but not identical to, products in the market. All three proposed methods were found suitable for further validation work.   Final methods will include validated ranges for parameters such as mobile phase composition (% organic solvent or modifier), pH, flow rate, temperature, etc. With this adaptable methodology, the end user will need to determine which of the three methods performs most effectively for any specific product and will need to establish the normal operating conditions for the product at hand.

The approach used for these standards goes beyond traditional compendial monograph content and what has been presented in other Emerging Standards to date in multiple ways.

1. Instead of a single method, three distinct sets of chromatographic method conditions are presented.  The end user may screen and select the method that is most suitable for the analytes expected or observed in each product.
2. Instead of fixed chromatographic conditions as in Guaifenesin Extended Release Tablet Emerging Standard, certain method parameters for each method may be adjusted within the method operable design region (MODR) space presented.  This allows end users to further optimize separations and increase the chances that at least one of the methods in the standard is suitable for existing and future products. The presented MODR space is verified and validated to allow this flexibility. 

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—The emerging standards concept being presented in this paper is one manifestation of how this approach could work. USP is seeking comments on the emerging standards concept promoting iterative approaches to development of methods monitoring Organic Impurities for OTCs 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.

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.