Saul Gylys is President, GPCS, LLC. Kalamazoo, MI, sagylys@gmail.com.

Saul Gylys

	US Pharmacopeial Convention (USP) standards have been recognized in the Federal Food, Drug, and Cosmetic (FD&C) Act since it was enacted in 1938. FDA’s Over-the-Counter Drug Monograph System (FDA OTC Monograph System) allows marketing of products that are “generally recognized as safe and effective” (GRASE). Products marketed under this system require compliance to the USP monograph, if one is available. A means to an efficient, organized approach to developing monographs for these products remains elusive. Several options for development have been proposed, and these approaches are discussed in this article (1–5). The authors hope to facilitate further collaboration among all the stakeholders for USP OTC Monograph Modernization with the goal of identifying a satisfactory approach for USP, FDA, and industry.

	FDA’s Over-the-Counter (OTC) Drug Monograph System allows marketing of products that are “generally recognized as safe and effective” (GRASE). The benefit of this system is that finished OTC products that are in the scope of the FDA OTC Monograph System (21 

] part 330) can be marketed without a FDA new drug application (NDA)/abbreviated new drug application (ANDA)/biologics license application (BLA) pre-market approval. The FDA OTC Monograph System includes hundreds of drug substances/ APIs that manufacturers can formulate together in specific doses and dosage forms with different excipients that can result in thousands of different ingredient combinations. According to the Consumer Healthcare Products Association (CHPA), approximately 100,000 drug substance/dosage form/formulation combinations could currently be marketed through the FDA OTC Monograph System (6).

	USP is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed, and consumed worldwide. These standards have been recognized in the FD&C Act since it was first enacted in 1938. Products marketed under the FDA OTC Monograph System require compliance to the USP monograph, if one is available. 

United States Pharmacopeia-National Formulary (USP–NF)

, however, does not contain monographs for many of the products marketed under FDA’s OTC Monograph System. Since its inception in 1820, USP has compiled a few thousand monographs, but a means to an efficient, organized approach to developing monographs for products marketed under the FDA’s OTC Monograph System remains elusive. USP has been updating the OTC product quality standards, which includes the incorporation of impurities testing into existing monographs as well as the introduction of OTC product standards that are not yet established in the compendia. This initiative is referred to as USP OTC Monograph Modernization. To date, this initiative has arguably made slow progress as numerous OTC drug product monographs remain absent from the 

	In situations where a USP product monograph is not available, each manufacturer is responsible for establishing the specifications and quality assurance controls to ensure compliance of their product with current good manufacturing practices (cGMPs). This lack of standardized quality expectations complicates surveillance activities by FDA. Without a public standard, such as an organic impurity analytical method, the enforcement arm of FDA must either develop its own analytical method or contact the product manufacturer to obtain analytical methods and specifications when the need arises for testing of the product.

	There are several challenges to achieving USP OTC monograph modernization. The primary consideration is the sheer scope and number of monographs that need to be addressed to ensure product quality of OTC drug products regulated under the FDA OTC Monograph System, which are uniquely different than those that are subject to pre-market approval through an NDA or ANDA. Due to their GRASE status, the formulation and development timelines are often fast to react to the constant change in consumer tastes and medicinal needs. In addition, OTC products often contain multiple active ingredients within the same formulation. Formulations can be quite complex and innovative due to the variety of dosage forms (i.e., suspensions, rapid release tablets, etc.) and excipients needed (e.g., flavors, dyes, preservatives, etc.). Finally, it is not uncommon for many formulations to exist for the same product type as manufacturers may offer various flavors and colors, or multiple manufacturers (including store brand products) of the same active combination of a particular dosage form may exist. For instance, there may be dozens of different formulations for an acetaminophen suspension product where consumers are presented with a choice for flavors (e.g., berry versus cherry), for one that is dye-free, or for one that is manufactured by a private label company.

	Perhaps the biggest technical challenge to USP OTC Monograph Modernization is the need for inclusion of impurities testing in the product monographs. Given the large number of OTC product formulations currently on the market, an attempt to develop a single impurities test method, or even set of methods, to cover all products within an official monograph becomes a daunting, if not impossible, task. Furthermore, the ability to distinguish a formulation excipient peak from a true unspecified impurity peak without intimate knowledge of the formulation and behavior of the formulation over its shelf life is not feasible. This complexity increases when multi-active OTC products are taken into consideration because impurity profile analysis procedures are sensitive to the number, types, and relative concentrations of drug and non-drug- related components in the formulated product. Therefore, it is unclear how surveillance activities by FDA could accurately confirm product compliance without consulting with the product manufacturer. In such cases, the authors suggest that the regulatory authority consult the manufacturer upfront to avoid the time and effort involved in the analysis of a product against a public standard test method, which may or may not be appropriate for the product, only to find the results confounded by the presence of indiscernible chromatographic peaks.

	Because USP relies on industry and FDA support for the development of OTC product standards, alignment on the strategy for USP OTC Monograph Modernization is crucial. In early 2014, a prescription/non-prescription USP stakeholder project team consisting of industry, FDA, and USP representatives was formed that focused on developing strategies for the implementation and modernization of uniform procedures and acceptance criteria for OTC medicines. The CHPA USP Monograph Modernization Team, a subcommittee of the CHPA Product Quality and Manufacturing Committee, further built on the foundation established through the work of the industry/FDA/USP project team and has developed this paper to share considerations from these modernization efforts. This paper summarizes several strategies that have emerged from these teams as the most viable avenues to achieve USP OTC Monograph Modernization in a practical way that not only supports FDA’s desire and USP's mission of modernizing OTC quality standards but also provides acceptable implementation approaches that are pragmatic from an industry compliance perspective. The primary goal of this discussion is to align terminology and promote further discussion on the advancement of USP OTC Monograph Modernization. This paper also aims to provide useful information in understanding the complexity of this issue to those who are new to the OTC industry and that do not have extensive experience with these products. While this paper provides structure for future modernization discussions, its primary focus is on the organization and content of information within the USP monographs and chapters. Implementation of some of these options may require an accompanying pathway of updates to current regulatory guidance or notices that govern the use of a public standard within the FDA OTC Monograph System.

	This paper summarizes six options to create up-to-date drug product compendial “quality” monographs for products marketed under the FDA OTC Monograph System. Table I provides an overview and comparison of these compendial approaches and procedures that have been reviewed and determined to be the most viable options to date. Discussion of each of the options follows detailing their benefits and challenges.

	The implementation of each option described in 

 presents benefits and challenges from both conformance and compliance perspectives. For clarity, a “benefit” refers to an aspect of the described approach that would not deter industry innovation, would support FDA surveillance activities, and would fulfill the USP mission to further ensure the quality and safety of OTC drug products for the consumer.

					Table I. Proposed definitions for approaches to modernization. USP is US Pharmacopeial Convention.

					Multiple well-defined, validated procedures officially published within a substance or product monograph

					• First published=first approved by USP Expert Committee and designated as 

					Procedures within a drug substance or drug product monographs, where only performance characteristics are defined (e.g., base chromatographic conditions, specifications for active ingredients and their impurities and/or select system suitability criteria)

					• Manufacturers are given flexibility to optimize their specific testing parameters as long as performance characteristics are met and methods (sample preparations and analyses) are appropriate for intended use and are validated to current CGMP and USP expectations.

					Published as a general method in its own unique chapter that is referenced by multiple drug product monographs

					Multiple test methods that are developed to cover a wide design space to maximize separation of potential impurities. The test methods are not necessarily optimized or practical for routine quality control use. For example, the Tool Kit methods may include the option of several high-performance liquid chromatography (HPLC) column chemistries each with a long, shallow gradient and the option of a few mobile phase solvent systems.

					•   Only one of the procedures is required to be suitable to demonstrate product compliance and the most suitable procedure is to be determined by the product manufacturer.

					•   Surveillance activities may include analysis of the product against all Tool Kit procedures.

					•   This has the potential to be used within a product monograph or general chapter. 

					Individual product monographs or General Chapter that includes only the required specifications

					•    Manufacturers develop tests and procedures, supported with an appropriate validation, that are optimized for their product and product matrices.

					•     No labeling is required if the product complies with the specification limits.

	A “challenge” is a consideration that may have significant impact on a product’s labeling and/or ability to comply with the USP test methodology and specifications. Challenges are, for example, identified aspects that may create redundant and/or costly laboratory work or those that have potential to delay availability of the product to the consumer.

	It is important to understand the benefits and challenges of each option so that key stakeholders, including USP, FDA, and industry, can work together to drive the USP OTC Monograph Modernization efforts. In each of the subsequent subsections, some of the benefits and challenges of each option are presented.

	The Referee Procedure is the traditional approach of the current USP monograph system where a single test method is defined within the product monograph. OTC products that are required to comply with the USP standard need to comply if tested against the referee procedure testing conditions and specifications throughout the product’s shelf life. Examples of this approach are ubiquitous throughout the USP. For a specific example, refer to the aspirin tablets product monograph assay method, which contains a single test with specification limits to which all products marketed as aspirin tablets under the FDA OTC Monograph system must comply.

	The Referee Procedure is beneficial from a conformance perspective in that it follows the current USP 

) revision and implementation process. Current published examples of this option are common in the 

); therefore, no new infrastructure or revisions to the standard setting process would be required to implement this approach. From a compliance perspective, this option aids FDA in product-specific surveillance activities as a referee procedure would provide one standard against which all impacted products would be regulated.

	This single procedure option is challenging from a conformance perspective due to OTC drug product formulation complexity. It is likely that one procedure will not work for all commercial products. This would force a manufacturer to either establish equivalency, reformulate a product to comply with the USP’s test method, or reluctantly label their product as “Does not meet USP” despite confidence of high product quality through their own developed test methods and cGMP controls. Establishing equivalency is challenging, if not impossible, in cases where executing the compendial method is problematic for a particular product or where the compendial test fails for reasons other than safety, quality, identity, potency, or purity. For example, demonstrating equivalency is not possible in cases where a formulation-specific impurity co-elutes with the API peak for a product tested by the compendial method. Re-formulation of a product simply to meet the compendial test requirements is unrealistic and inhibits innovation.

	From a compliance perspective, if the Referee Procedure is not adequate for testing a manufacturer’s product, the manufacturer may choose to submit their internal method to USP for incorporation into the compendia. However, the current compendial review and approval process can be lengthy and is not satisfactory given the typical market life expectancy of OTC products. In certain instances, the Referee Procedure approach for assay and impurities tests may be adequate, such as for single active ingredient OTC products. For complex formulations (e.g., multi-active products), identifying a suitable referee analytical procedure for assay may or may not present challenges, while implementation for impurity procedures is almost certainly expected to present significant challenges. As discussed in the Introduction, a Referee Procedure should be capable of separating analytes of interest from matrix components (e.g., dyes, flavors, etc.), degradation products, and process impurities that may be present due to different active ingredient sources and synthetic routes. A Referee Procedure capable of achieving this may not be possible for all marketed OTC products that fall under a given USP product monograph.

	USP allows a manufacturer to use an alternate method (a method developed and validated by or for the manufacturer) as a surrogate for a method listed within the USP; yet, the product must still comply, if tested, by the USP listed method. Alternate methods can be employed without submission to the USP. In the current compendial process, implementation of additional methods in the product monograph is necessary when a product cannot be tested by the USP listed method(s). These additional methods should be submitted to the USP for inclusion and thus leads to flexible procedures, which are discussed in the next section.

	A Flexible Procedure approach has also been used within USP OTC monographs to address formulation variations where alternative tests are warranted. This flexibility allows for inclusion of multiple Referee Procedures to account for product formulation variations. The initial test procedure described in the monograph is generally the first procedure to have been approved by the Expert Committee. Subsequent procedures are listed in order of approval by the Expert Committee. Procedures used beyond the first listed require labeling on the product to guide regulatory authorities as to which test will appropriately confirm product compliance.

	An example of this approach can be found in the current 

. For example, the monograph for loratadine orally disintegrating tablets contains two procedures for organic impurities. In this case, the appropriate procedure is chosen based on the formulation matrix of the tablet. A similar approach could be applied to other drug product monographs, where several procedures are included to address formulation variations. As another example, several drug product monographs contain a flexible procedure approach to dissolution testing where multiple tests are included and the manufacturer determines the most appropriate for their product.

	When applying such an approach to a drug product monograph, the manufacturer is required to label the product to indicate which test (or procedure), if any beyond the first listed, is used for compliance.

	The Flexible Procedure is beneficial from a conformance perspective because it offers method options to industry based upon formulation characteristics. The first test method will ideally be able to evaluate a variety of commercial OTC finished drug products with additional test methods added as needed. This approach follows the current USP comment and implementation process; therefore, no new infrastructure would be required. From a compliance perspective, this approach would allow some flexibility, which supports both industry innovation as well as the desire to periodically reformulate products to provide variety to the market place and maintain consumer interest, such as through the introduction of new product flavors.

	This approach is challenging from a conformance perspective because, despite the inclusion of multiple acceptable procedures, it is likely that the methods within a flexible procedure will not be appropriate for all currently marketed OTC drug products. Many of the submitted test procedures are optimized for formulations from an individual manufacturer and were not intended for broad application to multiple formulation platforms. Manufacturers would need to evaluate all procedures within the monograph and establish compliance to one of them. This multi-procedure evaluation would need to be repeated each time a formulation is updated by a manufacturer. If none of the procedures are found to be suitable, the manufacturer would need to follow the lengthy submission process to add a new procedure to the monograph. Additionally, there may be instances where a manufacturer will be required to make a small or subtle change to a compendial test procedure within their laboratory to enhance the method efficiency for their product. Questions then arise as to how many test procedures should be included in a flexible procedure monograph and when is a test procedure deemed different enough that it should be included in the monograph as a truly alternative method to cover formulation variations.

	A Flexible Procedure adds complexity to product labeling, creates an unnecessary burden to the industry, competes with critical information required on the label, and can increase the opportunity for errors and mislabeling. The label denotation of the test method used for compliance is not meaningful, and is potentially confusing, to consumers. For example, manufacturer A may use the first published test method (Test 1) and, therefore, does not require additional labeling. Manufacturer B may use the second published test method and, therefore, must label the product as complying with Test 2. This labeling difference may create a disadvantage for manufacturer B, despite the products being of equal or comparable safety, quality, identity, potency, and purity. Also, the additional label information may detract from the visibility of dosing instructions and safety information. This is of special concern for multi-active products where several assay, dissolution, and impurity methods may be used. The label may also be affected each time a formulation change is made. For example, a product whose label is required to state: “Use Assay, Procedure 2, Use Dissolution, Procedure 3, Use Organic Impurities, Procedure 2” is simply not practical and takes up valuable label space. Finally, with multiple methods available to manufacturers for compliance, this approach may also add complexity to FDA surveillance activities.

Option three: Performance-based procedures

	A Performance-Based Procedure is an approach that only defines certain key testing performance characteristics and the associated required specifications. For example, the analytical procedure might only define system suitability requirements such as resolution or precision parameters. The manufacturer then has flexibility to develop their own specific testing method that is optimized for their product formulation as long as the performance characteristics are met and the method is supported with an appropriate validation. An example of this approach in the current 

 is the <233> Elemental Impurities–Procedures chapter, in which performance-based criteria are incorporated into a General Chapter. The main differentiator of a Performance-Based Procedure from an Alternative Procedure defined in 

 General Notices 6.30 is that the specific testing conditions developed by a manufacturer are not required to be submitted to USP for inclusion in the monograph.

	The Performance-Based Procedure option is beneficial from a conformance perspective because it does not confine manufacturers to a specific testing method or set of methods. Because the current 

 contains examples, no new infrastructure or standard setting processes would be required to implement this option. From a compliance perspective, this option is beneficial because standardization of key quality attributes, such as specificity or sensitivity, could be achieved to ensure the safety, quality, identity, potency, and purity of the product to the consumer.

	The Performance-Based Procedure option is challenging from a conformance perspective because a longer evaluation and comment period may be required for industry, USP, and FDA to reach consensus on acceptable procedural attributes, test requirement specifics, and expectations for appropriate justification for different procedures. This option would require an extended implementation period between publication and enforcement to allow manufacturers appropriate time in which to develop and validate methods. For compliance, inconsistencies in interpretation of the performance characteristics may occur that could result in confusion at the manufacturer and FDA surveillance laboratories. Finally, surveillance efforts would require FDA to seek specific methods from each manufacturer.

	The General Chapter option defines testing methods and, occasionally, specification limits in a general chapter that can be applied across multiple product monographs. An example of this option is the <227> 4-Aminophenol chapter that is referenced in most of the acetaminophen-containing drug product compendial monographs to define the testing method and specification for this key acetaminophen degradation product. The General Chapter option has broad applicability in that it may incorporate one of the previously defined procedures (referee, flexible, performance-based) and be referenced by multiple drug product monographs to provide consistency across a class of drug products. In cases for which the General Chapter option includes a flexible procedure, with multiple testing methods for compliance, product labeling may be required.

	The General Chapter option is beneficial from a conformance perspective because it follows the current USP comment and implementation process. Examples of a General Chapter already exist in the 

; therefore, no new infrastructure or revision to the standard setting process would be required. This option reduces complexity in some regard because the publication of the test method(s) occurs in a single, referenced chapter as opposed to individually in each product monograph. Additionally, manufacturers would have fewer test methods to evaluate and/or run for quality control (QC) release when marketing similar products that reference the same general chapter. From a compliance perspective, this approach would aid FDA in surveillance activities because a general chapter would contain sufficient information to execute analysis of the product, can apply across many products, and may reduce the overall number of procedures needed for regulation.

	This option is challenging from a conformance perspective because it limits the ability to optimize methodology for a particular product or dosage form without potentially impacting other products that reference the same general chapter. Due to the complexity of currently marketed OTC product formulations and the number of products that may be impacted by a General Chapter Procedure approach, a longer public comment period to evaluate the General Chapter methods, as well as extended timelines for industry implementation, may be necessary. Addition of the appropriate references to individual monographs will also be required each time a new general chapter is developed and incorporated into the compendia. Although a General Chapter option may attempt to be broad in application across a drug product class, there is no guarantee that the included method(s) will be appropriate to demonstrate compliance for all marketed products, which could negatively impact product labeling.

	The Tool Kit is a novel approach to provide a base of testing procedures that cover a wide design space. The procedures included in the Tool Kit would be developed such that a range of testing parameters are included to allow for optimal coverage of product formulation variations. For example, a high-performance liquid chromatography (HPLC) Tool Kit approach may include chromatographic conditions that use a variety of column chemistries coupled with a variety of gradient conditions to optimize the resolution between potential matrix interferences, active ingredients, process impurities, and/or specified impurities. As these testing parameters are meant to apply to a variety of different formulations, they may not be optimized for use in a routine QC environment. The product manufacturer will be responsible for determining the best suited Tool Kit conditions for their product. Surveillance activities would analyze a given product against all of the Tool Kit methods to ensure compliance against, at minimum, one of the Tool Kit procedures. Because surveillance activities would evaluate all of the Tool Kit methods on a product, product labeling would not be a requirement. Manufacturers may choose their own alternate methods for routine use.

	This option differs from the General Chapter option discussed in the previous section because the Tool Kit incorporates multiple, non-optimized, chromatographic conditions and does not impact labeling. The General Chapter option would be applied across multiple monographs, whereas the Tool Kit approach may be specific to a quality test of an individual monograph. The Tool Kit is one of the more recent OTC Monograph Modernization strategies that has been proposed and is still in an early concept stage. It is included in this paper for benefit of discussion and further refinement.

	This option is a new concept for which there are no current examples. However, there are several benefits to this approach from a conformance perspective. This option would contain generic methods with a variety of separation capabilities, could potentially be used across a broad range of commercial products, and would allow flexibility for industry from a monograph testing standpoint.

	An advantage to this option from a compliance standpoint may be that there would be no impact to product labeling. It is proposed that products may not be required to label as to which Tool Kit method is used to confirm product compliance.

	This option is challenging from a conformance perspective because the generic conditions to be included in the Tool Kit must be determined and thoroughly evaluated for applicability to the products currently on the market. Additionally, this approach may not work for all commercially marketed products and thus would require the same outcomes as discussed above (e.g., reformulation) or submission of new chromatographic conditions to the Tool Kit with, for example, alternative starting points and/or column selection.

	Regarding compliance, several significant challenges with the Tool Kit approach have been discussed to date. The first is the added complexity for industry and FDA to determine which method is appropriate for product compliance testing. For surveillance, FDA will be required to run all Tool Kit methods against a product unless additional information (e.g., formulation characteristics, presence of a specific inactive ingredient, etc.) is included in the Tool Kit procedure to direct FDA to the applicable method depending on formulation characteristics. Second, the Tool Kit may require investment in chromatographic screening systems by FDA, for surveillance, and by industry, for compliance confirmation.

	Under a Specification-Only option, the monograph will only define the required specifications (e.g., specified, unspecified, and total impurities) to which the product is required to comply. Specific analytical test method conditions are not included in the product monograph. A Specification-Only option would allow manufacturers the flexibility to develop their own test methods, supported with appropriate validation, that are optimized for their product formulation(s) to demonstrate compliance to the required quality and safety limits set forth in the public standard. This option has been discussed mainly regarding impurities testing. However, it is believed that, in certain cases, it could also be applied to other quality attributes, such as assay.

	The flexibility for manufacturers to develop their own testing methods would foster market innovation and improve efficiency through the continuous improvement of testing methods to confirm product quality and safety. Manufacturers will have a reduced burden to demonstrate equivalency to a public standard method. For compliance, FDA has authority to request the methods and supporting validation for surveillance, investigation, or routine auditing. This could also improve FDA efficiency in confirming product compliance by reducing the need for the FDA laboratory to independently develop testing methods.

	Without a defined referee test procedure, manufacturers will be required to develop and validate their own testing method. Therefore, conformance with this option will be most felt by organizations, especially smaller companies and contract laboratories, who do not have sufficient laboratory resources and, thus, rely on USP to provide validated testing methods. To allow for the time needed to develop and validate methods, appropriate implementation would need to be considered to ensure that the publication of limits for many products does not occur all at once. APIs should be prioritized and limits released on a schedule so that companies have time to develop methods in a systematic way. For compliance, the main challenge is the lack of a standard procedure to use for surveillance and investigation activities and the necessity to request methodology and validation from the manufacturer prior to commencing with these activities.

	Current systems for developing compendial standards for OTC drug products under the FDA OTC Monograph System are not efficient for addressing the many unique challenges presented by this regulatory framework. The analytical procedures must be capable of meeting specificity and sensitivity requirements for multi-active products, impurities, and functional excipients. The compendial procedures must also consider the anticipated frequent reformulation and innovation on the part of manufacturers and allow for needed flexibility to address the ever-changing needs of the consumer.

	The options discussed in this paper provide several means of updating 

 and list the benefits and challenges of each. This communication provides an opening for further discussion on ways to modernize the compendial monographs. The authors understand that the options presented require careful consideration and encourage all interested parties and stakeholders to submit comments to author John Punzi in response to this article. CHPA is committed to facilitating further discussion and considering all viewpoints on these matters.

	1.     A. Potts, PhD, et al., Stimuli to the Revision Process: “Medicines Marketed under the Food and Drug Administration Over-the-Counter Drug Monograph System,”

	2.     K. Russo, PhD, et al., Stimuli to the Revision Process: “USP Monographs in Support of FDA's OTC Monograph System: Modernization Opportunities,” 

	3.     Impurities in Drug Substances and Drug Products Expert Panel, Stimuli to the Revision Process: “Modernization of Organic Impurities Testing in USP Drug Substance and Drug Product Monographs,” 

	4.     D. Fay, PhD, et al., Responses to Stimuli Article: “Medicines Marketed Under the Food and Drug Administration Over-the-Counter Drug Monograph System Regulations: Strategy for Developing Compendial Quality Standards,” 

	5.     USP, USP Proposed General Test 321, Drug Product Assay Tests-Organic Chemical Medicines, 

FAQs About the Regulation of OTC Medicines

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The authors hope to facilitate further collaboration among all the stakeholders for USP OTC Monograph Modernization with the goal of identifying a satisfactory approach for USP, FDA, and industry.