Monograph Development: Why and When to Participate

iQoncept - Stock.adobe.com

This article is a continuation of the series intended to provide a practical guide to pharmacopoeia compliance for the bio/pharmaceutical industry. The first articles provided details on why pharmacopoeia compliance is necessary (1) and why compliance is difficult to achieve and maintain (2). Subsequent articles provided a historical and global perspective of the pharmacopoeias (3) and described the benefits of global pharmacopoeia standards (4) that may be achieved through ongoing harmonization efforts (5). The process used to revise the pharmacopoeias was described (6) as was the associated surveillance process used by the industry to monitor these revisions (7) to facilitate ongoing compliance with current pharmacopoeia requirements. It was noted that monitoring only the official revisions published by the pharmacopoeias puts a company in a reactive position to achieve compliance with updated requirements. Working further upstream to include surveillance of proposed updates published by the pharmacopoeias provides an opportunity for companies to take a more proactive position by providing comments to potentially influence the new and revised requirements that are proposed.

This article explores another proactive advocacy approach that a bio/pharmaceutical company may take through participation in the development of new and revised monographs in the various pharmacopoeias. Monographs are developed based on the submission of information and materials from a company having regulatory approval for the product, and this submission feeds into the pharmacopoeia revision process (6). The monograph is published by the pharmacopoeia as a proposed update, which in most cases moves forward to become the official standard for the material. Aligning the monograph with approved product registrations makes it easier for a company to achieve compliance with the requirements in the monograph. There is a need to answer practical questions regarding a company’s participation in this monograph development activity, for example:

• Why should a company submit a proposal for a new or revised monograph to the pharmacopoeia?

• What is the appropriate timing-in various situations-for submitting a monograph? How long will it take for the monograph to be completed?

• To which pharmacopoeias should the monograph be submitted?

• Which functional group in the company should submit the monograph? How does the company connect with the pharmacopoeias? Who should follow-up regarding the submission?

• What information is needed for the submission? How should the information be pulled together? What physical materials (e.g., samples, impurities, potential reference standards) are needed to support monograph development?

• Does the company need a procedure for monograph submission? What is the procedure that the pharmacopoeias follow to develop a monograph?

• What can Company A do if a monograph is developed based on a submission from Company B? Can Company A influence the outcome? Does Company A still need to comply?

Value of public standards in the pharmacopoeias

Before considering the factors that impact a company’s decision on whether and how to participate in the development of new and revised monographs, it is helpful to differentiate the various sectors within the broad scope of the bio/pharmaceutical industry. For the purpose of these articles, the term “bio/pharmaceutical” includes innovator, generic-drug, virtual, and start-up companies that discover, develop, manufacture, and/or distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products. In this context, the value of the public quality standards published by the pharmacopoeias around the world can be explored.

The Good Pharmacopoeial Practices (GPhP) guidance published by the World Health Organization states, “A pharmacopoeia’s core mission is to protect public health by creating and making available public standards to help ensure the quality of medicines” (8). The GPhP guidance continues, “Pharmacopoeial monographs provide an important tool for assurance of the quality of marketed pharmaceutical ingredients and products through testing of their quality.” These monographs are generally available for excipients, drug substances, and drug products, providing the tests, analytical procedures, and acceptance criteria that enable assessment of the quality of the material. Taken together with the other requirements contained in the pharmacopoeia, these monographs can help safeguard the health of patients around the world through the availability of public quality standards.

The bio/pharmaceutical industry is focused on delivering quality products to patients. Earlier in this series of articles, the content of the pharmacopoeia was described with consideration of the impact of the pharmacopoeia throughout the lifecycle of a drug product (1). From a practical business perspective, the value and benefit of the pharmacopoeia content to a specific company may vary based on the sector in which the company operates (e.g., innovator, generic-drug company, contract manufacturer) and the specific pharmacopoeia content under discussion.

General chapters. The general chapters in the pharmacopoeias provide a wide range of information, including analytical and biological procedures that are used to test materials and products. It is broadly agreed these general chapters are beneficial for all bio/pharmaceutical companies because they facilitate product development, enabling greater focus on specific attributes that are critical to the quality of a material or product. These procedures, whether a simple test for loss on drying for an excipient, or a microbiological test for a drug substance, or a dissolution test for a tablet formulation, enable routine testing by providing details on how to perform the test and, in some cases, the applicable acceptance criteria. Importantly, the information in pharmacopoeia general chapters is broadly accepted as an appropriate quality standard by regulatory authorities around the world.

Excipients. There is also general agreement across the industry regarding the value and benefit of having specific tests and acceptance criteria contained in monographs for excipients. From the perspective of excipient suppliers, the availability of a monograph provides a quality standard for the material that should be acceptable to multiple customers. For bio/pharmaceutical companies, the benefits include having multiple suppliers that can provide excipients meeting the same core requirements, simplifying the sourcing of these materials, and reducing the burden of laboratory assessments to determine comparability of materials from alternate sources. Excipient monographs also facilitate communication with health authorities regarding excipient quality attributes. Using compendial-grade excipients in drug products aligns with regulatory expectations for review and inspection, simplifying product registrations by allowing reference to the pharmacopoeia monograph as the standard of quality for the material. Referencing the monograph eliminates the need to include specific acceptance criteria, methodology, and validation information for the excipient in the drug product registration.

Drug substances and products. Divergent perspectives begin to emerge across the industry when considering the value and benefit of specific monographs for drug substances and drug products. Monographs for small-molecule drug substances and products have long been established in the pharmacopoeias, and the quality requirements in the monographs apply to both innovator and generic-drug companies alike. These monographs, however, do not typically become available until later in the drug product lifecycle. Indeed, the new drug substances and products must first be discovered and developed by an innovator company, and the applicable monographs follow. The initial quality requirements are approved by health authorities as submitted in new drug applications.

Generic drugs. As with the innovator company, drug substance and product monographs are generally not available for those generic-drug companies that are first to enter the market; product development work is typically well underway before specific monographs are available for the materials. The value of the monographs emerges with the approval of subsequent generic versions, helping to ensure consistent quality, especially as the availability of the product grows across today’s global supply chain. It is here that the ultimate value for patients is realized, with the quality standard in the monographs for the drug substance and product applying to all companies.

Biologics and vaccines. There is, perhaps, even less agreement throughout the industry on the value or benefit of monographs for biological products and vaccines. The pharmacopoeias, and in particular the European Pharmacopoeia (Ph. Eur.), have published monographs for some biologicals since the 1990s, including human insulin, somatropin, interferon, erythropoietin, and vaccines (9). For vaccines, there are typically only a few manufacturers for a specific product, limiting the applicability of the monograph to these companies. Despite this, the public quality standard contained in the vaccine monograph can be beneficial to regulatory agencies and medicine control laboratories involved with batch release of the product. For other, simpler biological products, including peptides and some proteins, the size and structure of the material itself can often be well-characterized by the tests typically listed in a monograph, which would be applicable to multiple manufacturers for these products.

For more complex biotherapeutic products, in particular monoclonal antibodies (mAbs), the greater complexity of the material and the associated challenges in product development and manufacture create potential challenges in the development and application of quality requirements in product-specific monographs, especially as the number of companies working in this area continues to grow. There is concern that specific monographs cannot be considered as minimum requirements for acceptability of “similar” biological products, risking the false assumption of product equivalence. This is in conflict with regulatory guidance and patient safety considerations. Even while the pathways for regulatory approval of biosimilar products continue to evolve around the world, there is ongoing debate regarding the applicability of specific monographs to these complex products. The pharmacopoeias are also considering different approaches to public standards for complex biotherapeutic products, with the Ph. Eur. and Chinese Pharmacopoeia (ChP) developing product-specific monographs, while the British Pharmacopoeia (BP) and the United States Pharmacopeia (USP) are exploring alternate approaches to quality control, including the establishment of performance-based standards (10, 11).

The perceived value of specific monographs by a particular company will likely guide the company’s willingness to participate in monograph development. Given the broad range of products across the bio/pharmaceutical industry, it should be noted that the focus of this article is on small-molecule drug substances and drug products and the development of new monographs for these materials. The concepts and approaches, however, may also be applied to the development of monographs-whether new or revised-for the broader industry, including over-the-counter medications, dietary supplements, herbals, traditional medicines, and excipients. The information provided here may also be extrapolated to the development of new and revised general chapters in the pharmacopoeias.

Benefits of proactive engagement to develop monographs

Pharmacopoeias are embedded in the legal and regulatory framework in countries around the world (1, 3). Pharmacopoeias contain monographs for specific drug products and ingredients, which serve as the public standard, providing minimum quality requirements that all manufacturers must meet for the material.

An end-to-end compendial framework was provided in the second article of the series to aid in understanding the range of activities that may be carried out by the compendial affairs function within a company to help ensure pharmacopoeia compliance (2). The upstream strategic activities in the process were termed “proactive compliance” and included participation in the development of new monographs in the pharmacopoeias.

Bringing together the history, the regulatory and legal framework, the need for a company to comply, and the opportunity for proactive engagement with the pharmacopoeias, there is one fundamental consideration to keep in mind: monographs happen. This simple truth conveys the reality that monographs will be developed and published by the pharmacopoeias whether a specific company chooses to participate in the process or not.

Foundational to any company’s compendial process is the strategy it chooses to follow with monograph elaboration. This critical strategy decision affects resourcing of the compendial function, because it can require significant resources to elaborate a monograph. The decision also determines if a company is going to be proactive or reactive in its approach to the development of compendial standards. There are pros and cons for a company to consider with each approach.

Proactive approach. The reasons to proactively participate in monograph elaboration include the ability to influence the outcome of the public standards that are developed. For an innovator company in particular, the submission of monographs is part of a strong advocacy program that brings the company’s knowledge and experience to bear for its product. Proactive participation should result in a monograph that has minimal impact to the innovator company, because the core quality standards contained in the monograph should closely align with the requirements in the approved drug product registrations. The resulting standards in the monograph for a drug substance can be used for multiple product formulations and dual-active products.

Proactive engagement in the monograph development process helps build a strong collaborative relationship with the pharmacopoeia authorities and enables those involved in compendial activities in a company to become acquainted with individual scientists at the pharmacopoeias. This involvement can be beneficial in other compendial activities for the company, including greater effectiveness with responses submitted to other proposed revisions published by the pharmacopoeias.

Another potential benefit of proactive participation is the possibility of establishing a harmonized monograph across multiple pharmacopoeias (see Sidebar). Proactive participation, however, comes with a higher upfront resource cost to prepare the monograph submission and respond to questions during its elaboration. Additionally, the outcome of the monograph is not guaranteed, so there could be impact to the company’s product registrations and quality testing despite collaboration with the pharmacopoeia authorities.

One important benefit of a proactive approach for an innovator company is avoidance of the development of a monograph by a competitor, which can create compliance challenges. There are benefits to an innovator company having the public standard in the pharmacopoeia based on the quality standards in their approved drug product registration, rather than having to comply with monograph requirements developed by another company. Additionally, physical reference standard materials supplied by the innovator company to support the monograph provide similar benefits and potentially simplify the processes for the company, eliminating the need to perform comparison testing with an in-house standard.

Reactive approach. On the other hand, the case against active participation in monograph development is that fewer resources are needed upfront during the elaboration process. No work is required to pull together the information needed for submission of the monograph. During the time when there is no monograph, each company having regulatory approval must comply with its own active registrations, meaning no work is needed to demonstrate equivalence or implement new methodologies from the monograph. A company can still comment when the proposal of the monograph is first published, providing specific feedback on items of concern. This approach, which is more reactive, requires higher resource commitment once the draft monograph is published, with rapid evaluation needed for any new methods it may contain. It can be difficult for a company to significantly influence the draft publication given the work already invested by the pharmacopoeial scientists. Once published as an official monograph, this reactive approach potentially makes compliance more difficult for the company.

In the authors’ experience, there is a benefit in proactive participation in the monograph development process. However, neither approach is right or wrong; it simply comes down to a company’s decision. The consequences can best be summed up as “pay me now or pay me later”. Either approach, whether proactive participation or a reactive position, will require periods of resource-intensive effort. Either approach can have an impact on the outcome of the final monograph, determining how much laboratory work or how many filing updates may be needed to remain compliant.

It is useful for a company to determine its “typical” approach to monograph development, while understanding that it is not a one-size-fits-all outcome. There are scenarios where it may not be advisable for a company to participate in monograph development for a particular product, depending on scientific, regulatory, or business drivers. For example, if a product is expected to have a short lifetime in the market with limited utility to patients because there are better treatments in development, then a company may choose not to work on monograph elaboration for that material. Additionally, for older compounds (more than 25–30 years), if a monograph does not already exist, the benefit of creating one may not justify the resource cost needed to complete the elaboration process.

Ultimately, it is important for a company to decide whether and how they will participate in monograph development. This choice will shape how the compendial affairs function is staffed and empowered for the company. The compendial affairs function should communicate the risks and benefits of a proactive or reactive approach to monograph development to management and critical internal stakeholders. It is common to have to educate the product support team-product director, regulatory support, quality-as to the reasons why monograph elaboration is needed. It is a daunting task to get approval for each new monograph submission, with the scientific data required to support the elaboration activities. It is best to embed the monograph strategy into established compendial processes, so it becomes a “routine” activity that requires limited internal approvals to proceed.

Consideration of appropriate timing for monograph submission

The GPhP guidance states that pharmacopoeial standards should be available for drug products and their active ingredients at an appropriate time to support and benefit patients through the availability of medicines with consistent quality (8). The critical question within this statement is what is an “appropriate time”. If a company decides to participate in the development of a new monograph, they must ask when they will start the process. The appropriate timing will typically vary for each company, for each situation, or even for each product in a company’s portfolio. As with the prior question of whether a company should participate in monograph development, exploring the subsequent question of when to participate reveals there is not necessarily a consistent, single answer. Focusing on the question of timing, two perspectives should be considered: that of the pharmacopoeia and that of the industry.

Pharmacopoeia timing. The process to develop a new monograph in the pharmacopoeia typically takes two to three years. Figure 1 shows the preferred timing for new monograph development from the viewpoint of various pharmacopoeias, reflecting several considerations. Typically, the Ph. Eur. and USP monographs are the earliest to be elaborated, with the preferred Ph. Eur. timing stated as five years post-approval to take advantage of its P4 procedure (12), in which the necessary specifications and supporting information are provided by a single company, usually the innovator, having regulatory approval for the product in Europe. This timing also corresponds with the European Medicines Agency regulatory guidance concerning mandatory renewal of a marketing authorization within five years of its granting in Europe (13). Under the P4 procedure, the Ph. Eur. Commission works to ensure that monographs are available a few years before the patent expiry date, thus making it possible for regulators to assess dossiers on generic drugs based on existing monographs in the pharmacopoeia (14). If the monograph submission is too late to follow the P4 process, the Ph. Eur. monograph is developed (or revised) using the P1 process (15), in which multiple companies with approval for the drug product in Europe may participate in developing the tests, analytical procedures, and acceptance criteria that will make up the public standard. Due to the participation of multiple companies, the development of the Ph. Eur. monograph by the P1 procedure is often more difficult for the pharmacopoeia. It may also be more difficult for individual companies to comply with the final monograph because it may contain requirements from multiple sources.

Figure 1. Monograph timing considerations for pharmacopoeias. IP is Indian Pharmacopoeia. Ph.Eur. is European Pharmacopoeia. USP is United States Pharmacopeia. BP is British Pharmacopoeia. JP is Japanese Pharmacopoeia. ChP is Chinese Pharmacopoeia. KP is Korean Pharmacopoeia. (Figure courtesy of the authors)

For USP, the preferred timing for monograph submission is seven to eight years prior to generic drug entry to the market (16), which generally aligns with the preferred Ph. Eur. monograph timing of five years post-approval. An additional consideration for monograph development timing is the possibility of establishing “prospectively harmonized” or “informally harmonized” monographs in collaboration with both the Ph. Eur. and USP authorities. Details regarding development of harmonized monographs is provided in the Sidebar. In practice, many companies delay monograph submission beyond this time horizon, choosing instead to consider the appropriate timing as three to five years prior to patent expiration. Variability in the patent situation for a particular company, country, or product makes the actual date of submission using this approach more difficult to establish. Additionally, this delay in submission makes it more difficult to pursue a monograph that is harmonized.

A corollary consideration of monograph development is whether the submission should be first for the drug substance (shown as API in Figure 1), followed later-perhaps several years later-for the drug product, or whether the information should be provided to support monograph development of the drug substance and product at the same time. The situation regarding multiple product strengths, different dosage forms, and combination products also enters into the decision-making process. Based on experience with the prospective and informal harmonization of monographs, along with other practical considerations, there are potential benefits in establishing the drug substance and product monographs at the same time. One of these benefits is standardizing the analytical procedures across the monographs for the drug substance and drug product portfolio, particularly tests for the determination of assay and impurities, in setting consistent pubic standards for quality of the product family. This standardization of methodology also carries the potential risk of making it more difficult for a company to apply the monograph methods if they are not aligned with its approved product registrations.

The publication of monographs for small-molecule drug products in the Ph. Eur. is a fairly recent development, with the first such monograph adopted in 2015 (17). By contrast, the BP has long included monographs for small-molecule drug products, in addition to all the other content of the Ph. Eur. that is required for pharmacopoeia compliance in the United Kingdom. In the absence of an applicable Ph. Eur. monograph, compliance with BP drug product monographs is often the expectation of regulatory agencies throughout Europe and in many other countries around the world. For several practical and regulatory reasons, the BP drug product monograph, however, cannot usually be established until after the Ph. Eur. monograph has been developed for the drug substance. The pursuit of harmonized monographs has enabled concurrent development of Ph. Eur. drug substance monographs and the associated BP drug product monographs. Alternatively, the product monograph may be established in the Ph. Eur. rather than the BP, with the Ph. Eur. product monograph then published also in the BP. These considerations enter the determination of when and where to submit the monographs for drug substances and their associated products.

Turning to the other pharmacopoeias shown in Figure 1, the key take-away is that the appropriate time for monograph development is not consistently or precisely defined, but typically would occur after the USP, Ph. Eur., and BP monographs have been established, possibly by several years. For the Indian Pharmacopoeia (IP), there appears to be a correlation between the approval of two to three companies in India and the development of a monograph, although this is not entirely clear in the authors’ experience. There seems to be a good deal of variability in the IP monograph timing, and in some cases, the IP monograph may be developed before the USP, Ph. Eur., or BP monographs. For pharmacopoeias in other countries, including the Japanese Pharmacopoeia (JP), Korean Pharmacopoeia (KP), and ChP, there also seems to be some correlation with approval of several companies for a particular drug product and the elaboration of a monograph. While this timing for IP, JP, ChP, and KP activity seems to decrease the possibility of developing harmonized monographs across several pharmacopoeias-monographs that could truly serve as global pharmacopoeia standards-there is clear interest and commitment by the pharmacopoeia authorities to collaborate with each other and with the industry to establish consistent public quality standards.

Industry timing. The other timing perspective to consider for monograph development is that of an individual company, and this, in turn, may vary based on whether the company is in the innovator or generic sector of the industry (Figure 2). After an innovator company (Manufacturer 1 in Figure 2) receives regulatory approval for a new drug application containing a new chemical entity, there is a period of patent protection and marketing exclusivity during which the innovator is the single source for the product. During this time period, generic-drug companies begin to develop similar versions of the drug substance and product, in terms of pharmaceutical and therapeutic equivalence. One goal is to become the first company (Manufacturer 2 in Figure 2) to market a generic version of the product, realizing all the business benefits that accompany this position. Once the first generic version has been approved, which may occur perhaps 10–15 years after the innovator’s approval, followed by the approval of other generic versions, potentially from many other companies around the world, the product situation changes to reflect this multi-source availability.

Figure 2. Monograph timing considerations for industry. (Figure courtesy of the authors)

At some point during the product’s lifecycle, the possible development of a monograph emerges, at which point the need and value of this specific public standard is weighed against the existing regulatory approval for the product. The monograph will contain the specifications-tests, analytical procedures, and acceptance criteria-that help ensure the identity, strength, quality, and purity of the drug substance and product. It becomes necessary for all companies with regulatory approval to comply with the requirements established in the monographs for the drug substance and product. Additionally, as stated in the GPhP guidance, “Specifications that limit market access by, for example, favoring one manufacturer to the exclusion of others should be avoided” (8). This statement is intended to maintain focus on the benefit to patients worldwide in having public standards that support access to medicines from innovator and generic-drug companies with consistent and appropriate quality.

The earliest opportunity for monograph submission belongs to the innovator company having the initial regulatory approval, during the period of patent protection and marketing exclusivity. Once the decision has been made whether to submit the necessary information for monograph development, consideration then turns to when to submit the information. Many product-specific points are important in this consideration, including ongoing manufacturing and analytical changes that may impact the applicable specifications, as well as the timing for potential entry of generic competition.

As suggested in Figure 2, there is potential benefit to the innovator company in having the monograph established to reflect the quality standard that has been approved by the health authorities for the single-source product. This quality standard must then be met by all subsequent generic-drug companies that wish to market the product, providing benefit to patients through medicines with consistent quality. However, if the innovator company delays its monograph submission, or chooses not to submit at all, then any of the approved generic-drug companies have the opportunity to submit the monograph.

Because monograph development by the pharmacopoeias generally takes about two to three years after the initial submission, more companies may begin work to develop generic versions of the product. When the draft monograph is published by the pharmacopoeia for public review, there will be more companies that may provide comments on the proposed specifications, potentially impacting the final monograph in the pharmacopoeia. Once the monograph is official in the pharmacopoeia, there is the ongoing possibility of subsequent changes to the monograph to reflect specifications approved by regulators as more generic-drug companies are authorized to market the product. The compliance challenges for any given company are commensurate with the degree of difference between the monograph and its own approved product specifications, so the practical goal should be to collaborate to align the pharmacopoeia requirements with the approved registration.

In broad terms, three time periods may be identified for a company as they determine when to submit a monograph: the earliest is zero to five years post-approval, the latest is three to five years prior to patent expiration (or loss of marketing exclusivity) or even later, and the third is the period of time between these two (see Table I). In the authors’ experience, from the perspective of innovator companies, the first of these-zero to five years post-approval-is generally too early. Among the reasons for this conclusion are the limited value of a public standard for a single-source product, with limited available data about the product, and ongoing process and analytical changes typical in the first few years of the lifecycle, as additional experience is gained with the manufactured product. There is also concern about potential loss of intellectual property, especially in countries where there is less patent protection. Experience has shown, however, that this threat is not significant in the larger picture, because many generic-drug companies already have products in development from an early stage, with information available in the literature and through reverse-engineering approaches. Another consideration for early submission is the need to provide reference standard materials to support monograph development, with available inventory potentially limited early in the product’s lifecycle.

Table I: Considerations for appropriate timing of monograph development.

For an innovator company, the last of these time periods-three to five years prior to patent expiration or even later, potentially extending after patents have expired and marketing exclusivity has lapsed-may be considered too late, for several reasons. These include likely generic drug entry with submission of information and reference standard materials from multiple sources; increased effort and reduced success in influencing the outcome, resulting in greater likelihood of the need to adopt different methods and limits from what is contained in product registrations as a result of comments received during monograph development; and complexities due to different impurity profiles, formulations, and degradation pathways for multi-source products. As mentioned previously, there is one potential benefit in later submission of a new monograph, which is the delayed deployment of resources for monograph development. However, the subsequent process to evaluate and address monograph requirements, including additional laboratory effort needed to investigate proposed methods and limits-which are likely based on information from another company-poses potentially greater demands on available resources within a company.

The US Pharmacopeial Convention (USP) has recognized that some manufacturers may not wish to submit a monograph until a product approaches multi-source status, although its policy is to first seek to work exclusively with an approved manufacturer (typically the relevant patent holder) until approximately five years prior to potential generic entry (18). If the manufacturer remains unwilling or unable to provide the necessary information, USP may work with another manufacturer willing to sponsor a submission or begin monograph development internally. This timeframe is intended to give due regard to applicable intellectual property and patent considerations, while advancing its public policy goal of ensuring that a monograph is available for review and approval of follow-on or multi-source versions of the product. There is an additional downside associated specifically with USP monograph development; the potential impact on product labeling that may result from the USP flexible monograph approach, if a company’s methods or acceptance criteria are not listed as “Test 1” in the monograph (19).

This means that in practical terms, the time between five years post-approval to five years pre-patent expiry may be “just right” for establishing monographs for drug substances and products. This timeframe represents a fairly broad range that must be further refined for a specific product situation, but there are several benefits to targeting this period for monograph development. These include input from a single source, simplifying the process for the pharmacopoeias, resulting in the innovator company criteria being included in the monograph. The monograph would not block market entry of other companies, following existing legal and regulatory systems, but would establish the quality standard that all subsequent companies must meet to gain approval for the product. Additionally, the USP flexible monograph approach will not impact the innovator’s labeling because its methods will be designated as “Test 1” when subsequent revisions are introduced in the monograph to reflect products from other companies. The information provided by the innovator company in the monograph submission reflects greater process and analytical experience with the product, reducing the likelihood of revisions due to additional product knowledge and any associated regulatory updates. The reference standards provided by the innovator company to the pharmacopoeias in support of the monograph tests will become the official compendial reference standard, eliminating the work required to demonstrate comparability of the in-house standard against the compendial standard.

Perhaps one of the most significant benefits for an innovator company in submitting a monograph when theirs is the only approved product is the opportunity to pursue prospective or informal harmonization in establishing the monograph across multiple pharmacopoeias (see Sidebar). In the final analysis, a company’s decision of whether and when to submit monographs for drug substances and products is critical to helping ensure compliance with the requirements contained in the monographs. A company can leverage the knowledge gained during the monograph elaboration process, including anticipated changes to test methods and limits, to plan for implementation of the official requirements.

Additional considerations for monograph development

Having explored the considerations of whether and when a company should submit a monograph to the pharmacopoeias, once decided, there are additional considerations, including who within a company should have responsibility for the submission and what information is necessary to support the development of the monograph. There are also practical considerations regarding how to navigate the submission process with the pharmacopoeias and how to approach prospective or informal harmonization of the monograph. These additional points are detailed in a companion article (20), which can be accessed by visitingPharmTech.com.

Conclusion

The value of monographs is in the publicly available quality standards they provide for drug substances and products, and the benefits for a company to actively participate in the monograph development process are clear, with considerations for the optimal timing for a specific monograph submission. The next article returns to the challenges of pharmacopoeia compliance through an illustration of the difficulty with monograph requirements, which may differ from approved product registrations, even when a company is proactive in the development process.

Acknowledgment

The authors gratefully acknowledge the contribution of Susan J. Schniepp for her technical review and helpful suggestions during the preparation of this series of articles.

References

1. J.M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Necessary,” Pharmaceutical Technology Regulatory Sourcebook eBook 28–34 (September 2019).

2. J.M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Difficult,” Pharmaceutical Technology Regulatory Sourcebook eBook 36–42 (September 2019).

3. J. M. Wiggins and J. A. Albanese, “A Brief History of Pharmacopoeias: A Global Perspective,” PharmTech.com, September 2019.

4. J.M. Wiggins and J.A. Albanese, “Global Pharmacopoeia Standards: Why Harmonization is Needed,” Pharmaceutical Technology Regulatory Sourcebook eBook 43–47 (September 2019).

5. J. M. Wiggins and J. A. Albanese, “Harmonization Efforts by Pharmacopoeias and Regulatory Agencies,” PharmTech.com, September 2019.

6. J.M. Wiggins and J.A. Albanese, “Revision Process for Global/National Pharmacopoeias,” Pharmaceutical Technology Regulatory Sourcebook eBook 17-25 (December 2019).

7. J.M. Wiggins and J.A. Albanese, “Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions,” Pharmaceutical Technology Regulatory Sourcebook eBook26-37 (December 2019).

8. WHO, “Good Pharmacopoeial Practices,” in WHO Expert Committee on Specifications for Pharmaceutical Preparations Fiftieth Report, Technical Report Series No. 996, Annex 1, 67-85 (2016).

9. E. Charton, “The Role of European Pharmacopoeia Monographs in Setting Quality Standards for Biotherapeutic Products,” Presentation at the European Pharmacopoeia Conference: Tackling Future Challenges of the Quality of Medicines, Tallinn, Estonia, (Sept. 27–28, 2016).

10. Medicines and Healthcare Products Regulatory Agency, “Strategy for Pharmacopoeial Public Quality Standards for Biological Medicines”, gov.uk (2019).

11. F. Atouf, “Latest Updates from USP on Standards for Biologics/Cell and Gene Therapy,” Presentation at Pharmacopeial Interest Group Meeting, 2019 PDA/FDA Joint Regulatory Conference, (Washington, DC, Sept. 16-18, 2019).

12. EDQM, “Elaborate a Monograph–Procedure 4” EDQM.eu (2013).

13. EMA, “European Medicines Agency Post-Authorisation Procedural Advice for Users of the Centralised Procedure” (Dec. 20, 2019).

14. EDQM, The Ph. Eur. Work Programme: Elaboration & Revision, EDQM.eu.

15. EDQM, “Elaborate or Revise a Monograph–Procedure 1” (2013), EDQM.eu.

16. USP, “Prospective Harmonization: A Donor Model to Common Testing Requirements,” Advanced Briefing Materials for USP Prescription/Non-Prescription Stakeholder Forum (Oct. 21, 2014).

17. EDQM, “The European Pharmacopoeia Commission Enters A New Era! Adoption of the first monograph on a finished product containing a chemically defined active substance,” Press Release, April 14, 2015.

18. USP, USP Guideline for Submitting Requests for Revision to USP–NF: General Information for All Submissions (USP, 2016).

19. USP, USP Guideline for Submitting Requests for Revision to USP–NF: Submission Guideline for Chemical Medicines (USP, 2016).

20. J.M. Wiggins and J.A. Albanese, “Monograph Development: How to Participate; How to Harmonize,” PharmTech.com (March 2020).