J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions LLC.

J. Mark Wiggins

Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable. This fundamental principle of pharmacopoeia compliance has been explored throughout this series of articles intended to bring greater visibility and understanding to the bio/pharmaceutical industry, where compendial processes are not always well understood (1–11). The articles present many facets of the processes, people, and tools needed for a company to comply with the pharmacopoeia as well as their product registrations. The articles reflect the continuing evolution of the pharmacopoeias, their requirements, and the need for harmonization to achieve truly global pharmacopoeia standards.

	This final article in the series has two purposes: to summarize all the considerations that go into a company’s compendial affairs program and to look ahead at topics that will likely result in further evolution in the pharmacopoeias around the world. This look into what is on the horizon is important to help companies prepare for the inevitable changes and ensure the continued supply of quality medicines to patients globally.

 presents a holistic view of the roles, responsibilities, activities, and other considerations of the compendial affairs function, which are necessary to ensure pharmacopoeia compliance across the bio/pharmaceutical industry. This figure captures four major areas that define a company’s strategy and approach to determine its compendial affairs program. A successful program establishes many processes and maintains a series of complex internal and external partnerships to ensure a company can comply. The articles in this series touch on all four areas to provide guidance and clarity to companies struggling to set a strategy or to improve their current processes. They also provide rationale to support a business case to justify the people, processes, and tools necessary to enable compliance. The information can serve as the basis for standard operating procedures (SOPs) or work instructions for compendial affairs activities, regardless of which functional group within the company has the responsibilities.

The series began by providing the legal and regulatory basis that make pharmacopoeia compliance a requirement (1). To meet this obligation, an end-to-end framework was described that conveyed the internal and external difficulties in complying (2). The lack of harmonized standards increases the complexity of compliance (3–5). The decisions made by a company define the strategy and enable the execution of that strategy by the functional area designated with oversight of the compendial affairs responsibilities. The responsible group, represented by the large yellow circle in Figure 1, would ensure all internal stakeholders are connected to the established processes and understand the impact their area has on the overall effort to ensure compliance. Management support across the company is essential for the compendial affairs function. This includes assurance that sufficient resources are available within a central function and from contributing or impacted departments to execute the company’s established processes.

 The critical outcome from the compendial affairs function is compliance (orange bubble in Figure 1). To help achieve this, two articles focused on the details of the pharmacopoeia revision process and the industry surveillance process that enable implementation of compendial changes needed for a company’s compliance (6,7). The compendial affairs function must develop the appropriate tools that allow quick access to project status, ongoing communications, expected next steps, and the generation of metrics usually requested by management to measure success. The compendial affairs function needs management commitment to ensure the accountability of the people throughout the company assigned to execute the processes effectively and efficiently to maintain compliance. Case studies were presented to demonstrate why the compendial affairs function must establish and maintain strong internal partnerships across the company to ensure the established processes run well (10,11).

The significant opportunity for the compendial affairs function is advocacy (green bubble in Figure 1). The decision a company makes on advocacy efforts is an important part of its compendial affairs strategy, determining whether the organization will be proactive or reactive in their interaction with the pharmacopoeia authorities. A company can choose to participate in the development of monographs, comment on draft proposals, and join teams to elaborate or revise general chapters. Alternatively, a company may choose to have no advocacy role and only to implement the updated requirements that appear in official pharmacopoeia publications. This decision has a significant impact on the resources needed for the compendial affairs function and from other impacted areas to support a company’s established compendial processes.

	Advocacy approaches were explored in several articles that focused on monograph development, compendial responses, and external partnerships with bio/pharmaceutical trade organizations. The deep-dive into the advocacy processes highlighted the pros and cons of choosing to participate or not. A list was provided of several external organizations a company can join to enable open discussions and to leverage their responses on issues with broad impact (7). The effectiveness of an organization’s advocacy is a critical part of their compendial success. If a company submits comments on proposals that are adopted by the pharmacopoeia, it may be easier for the company to implement the official revision than it would have been if no comments had been submitted. A roadmap was provided to help a company define its strategy for the important advocacy effort of monograph development: why and when to participate with the pharmacopoeia authorities (8). The operational aspects of who in the company should own monograph submissions, how to participate, and how to achieve harmonized monographs were also explored (9). The details presented in these articles provide the basis for a checklist that a company can utilize if it decides to proactively engage in monograph development.

A company needs to decide which pharmacopoeias are in scope for their compendial affairs program (purple bubble in 

). To assist in this determination, one article presented the history of the pharmacopoeias and how they have evolved over time, especially in the past 200 years (3). A common thread was highlighted, that the formation of a new pharmacopoeia was historically driven by the need for consistent standards that ensured patients received high-quality medicines. The case was made for today’s need for global harmonization of the standards in the pharmacopoeias to benefit global patients (4). The inconsistency of the standards adds extra work and complexity for a company to comply. An aspirational goal of a “world where there is no need for translation” was introduced as the ultimate outcome of any global harmonization activities (4,12). The current state of harmonization activities was discussed, including efforts by the Pharmacopoeial Discussion Group (PDG) and the International Council for Harmonization (ICH), as well as the concept of prospective harmonization, which reflects a partnership between the industry and pharmacopoeias and is supported by the 

 guidance (5,13). Definitions for global and national pharmacopoeias were provided (6) to help an organization define which pharmacopoeias are in scope for their surveillance processes. The breadth of the compendial affairs program is directly related to the decision made by a company of which pharmacopoeias will and will not be reviewed.

. Throughout the articles, the authors referred to the people, processes, and tools needed for the compendial affairs activities. Teamwork within the organization (blue bubble in Figure 1) is the most critical aspect to ensure efficient processes and successful outcomes for a central compendial affairs function. The need for cross-functional support within the company was specified as critical to ensuring the success of a specific process. Without teamwork, advocacy efforts to comment on proposals or to implement an official revision to remain compliant will not happen. It is critical that the company develop an end-to-end perspective to maintain compendial line-of-sight, understanding how the efforts of every part of the organization affect the outcomes that are achieved. The entirety of the compendial processes become almost impossible to sustain without teamwork in an organization.

	In summary, the ultimate objective of these articles was to provide a thorough understanding of compendial challenges and opportunities for those involved in the work, and to help educate others in their company on the importance of the activities. The articles contribute ideas and suggestions to help companies avoid recreating the wheel and assist in developing best practices for bio/pharmaceutical companies to ensure compliance with compendial and regulatory requirements. Meeting these compliance goals enables on-time delivery of high-quality medicines for patients around the world, fulfilling the mission of every health authority and pharmacopoeia, as well as the entire bio/pharmaceutical industry.

	New regulations emerge, existing regulations change, and unexpected problems arise that require all stakeholders to evolve, including the pharmacopoeia. Schwarzwalder and Bishara (14) described this constant evolution, pointing out that a compendial affairs function must look at potential changes that are being evaluated by the pharmacopoeia authorities for implementation in the future. As noted in a previous article in this series (6), there are many reasons that can spur changes to the pharmacopoeia. Some additional examples include:

		Contamination issues, such as glycerin contaminated with diethylene glycol (15), heparin contaminated with oversulfated chondroitin sulfate (16), or nitrosamines found in sartans, a class of drug products used to treat high blood pressure (17). Each incident has led to significant safety concerns, with new tests and controls being added by the pharmacopoeia.

		Continuing harmonization efforts between global and national pharmacopoeias.

		Creation of new or revised ICH guidance documents (e.g., Q12 or Q14).

		Implementation of new technology, such as continuous manufacturing.

		New drug product platforms, such as oligonucleotides or gene therapies.

		Development of new or revised regulations by health authorities (e.g., microplastics use in medicinal products) (18).

	In the coming years, it is expected the following issues will result in new requirements in the pharmacopoeia or changes to the approaches currently established, to ensure that quality standards exist for the medicines being manufactured. The evolving standards will impact the bio/pharmaceutical industry and companies need to monitor these “on the horizon items” to try to influence the direction or advocate for change, if needed, and to quickly adapt the established processes in their company’s compendial affairs program to ensure compliance with the updated requirements.

 The use of a “one-size-fits-all” approach for methods has always been challenging for the pharmacopoeia authorities, especially as drug substances and drug product formulations increase in complexity. The pharmacopoeias have used different approaches to solve issues when they arise from this complexity. Even today, there are new approaches being considered, which require the attention of the industry to advocate during the elaboration process or to comment on new draft proposals. The 

) provides for the use of flexible monographs (8,9,19). In this approach, more than one test is listed for the drug substance or drug product. Other global pharmacopoeias use different approaches to solve this issue, while national pharmacopoeias currently have no defined policy or procedure to address the challenge. It is anticipated that the national pharmacopoeias will change in the coming years to address the conflicts caused by more complex drug substances and drug products. For example, a notice was published by the 

) indicating that the proposed monograph for eribulin mesylate, which contains 19 chiral carbons, results in a complex situation for impurities and degradants (20). The proposal requires manufacturers to share their control strategy, based on which starting materials are used, with the 

 Expert Committee to ensure equivalency to the proposed monograph.

	For small-molecule drug products, the flexible approach is used routinely for the dissolution test, which is not only dependent upon the drug substance solubility in a chosen medium, but on the excipients used in the formulation and the manufacturing process. Because each manufacturer uses a unique process and formulation for its drug products, differences in dissolution are not uncommon. The US Pharmacopeial Convention (USP) has solved this by listing all different dissolution tests in a monograph. It is a reasonable solution that provides relief when compliance to an existing standard might not be achieved due to the differences in chemical and physical properties of the drug product formulation. By contrast, surveys are being conducted by the

) Commission to gather stakeholder input in determining whether the dissolution test in drug product monographs should include specific methodology and limits or simply have the test and acceptance criteria listed “as approved by the competent authority” (21,22). The absence of a specific dissolution test in the monograph would require each new manufacturer to develop an appropriate dissolution method and have it approved by the health authority as part of the product registration. The dissolution requirement listed in the general monograph for dosage forms would still be met to provide the proper quality for the drug product without the pharmacopoeia including specific details. The approach allows for the needed flexibility resulting from different drug product formulations from different manufacturers.

	Flexible monographs provide the ability for drug manufacturers to comply with their registration and the pharmacopoeia with the recognition that one approach may not be suitable for all manufacturers. As technology and therapeutic drug products become increasingly more complex, it is necessary for the pharmacopoeias to continue to change. The director of the European Directorate for the Quality of Medicines and HealthCare (EDQM) provided important perspective on the impact of innovation, stating, “By listening attentively to the needs of both regulators and industry and rapidly incorporating new technological advances, pharmacopoeias can ensure that their content remains relevant and state-of-the-art and that their quality standards and methods are not only able to ensure the safety and efficacy of medicines but reflect advances in technology and science. This proactive course is matched by an ability to react swiftly to emerging challenges and with a large degree of flexibility (through alternative methods)” (23).

Complex biotherapeutics: Monographs and general chapters.

 Monograph development for complex biotherapeutics has been a topic of vigorous debate between compendial authorities, regulators, and the innovator and generic bio/pharmaceutical industries for the past several years. Today, there is no single position among all pharmacopoeias and regulators as to the need for product-specific monographs for complex biologics. The European Medicines Agency (EMA) and Official Medicines Control Laboratories (OMCL) have indicated their support for product-specific monographs, noting the benefit of having a single standard to help surveillance testing rather than having to use a specific manufacturer’s methodology. As a result, the EDQM published the first of these product-specific monographs for etanercept and infliximab concentrated solution in the 

using a flexible monograph approach (9). FDA has not expressed similar support for 

monographs for complex biologics (24). In fact, opposition to these monographs is so strong that legislation was introduced to the US Congress stating that biological products would no longer have to comply with 

 standards, including monographs (25). This stark difference in health authority views is a reminder of the important intersection of pharmacopoeias and regulatory agencies and why companies must monitor these situations to remain compliant and to influence both parties through appropriate advocacy.

	Among national pharmacopoeias, industry association surveillance has revealed that the Chinese Pharmacopoeia Commission (CPC) and National Institute for Food and Drug Controls (NIFDC) intend to establish reference standards and monographs for seven monoclonal antibodies drug substances and products (26). These new monographs will likely be included in the 12th edition of the 

), scheduled for publication in 2025. The 

 currently contains one monograph for a monoclonal antibody, nimotuzumab injection, a single-sourced orphan product. The proposed addition of these seven multi-sourced products is an ambitious goal for the CPC. It will be important for companies who manufacture these products to participate in the 

 monograph elaboration process in partnership with CPC and NIFDC. It is not known how the CPC will address the complexity that comes with the analysis of these products from multiple manufacturers, as the “one-size-fits-all” approach will not work and could potentially block manufacturers from the market. Today it is unknown whether other national pharmacopoeias will publish monographs for complex biologic drug products.

	The pharmacopoeias are exploring other approaches for complex biotherapeutics. USP has announced a wide range of approaches that would be applicable to complex biologics, including performance-based standards, product class standards, and general chapters (27). They are actively requesting stakeholders to participate on project teams being established to develop these standards. The 

 Commission is also exploring alternative approaches for complex biologics, notwithstanding their legal obligation to include 

monographs for complex biotherapeutic products in the 

 Commission completed a consultation and announced a plan to develop performance-based standards and product-class-based standards that would provide a foundation for manufacturers to follow, while retaining flexibility for developing a complex biologic (28).

Health authorities are moving toward requiring manufacturers to set clinically relevant specifications (CRS) for the registration of a new drug product. The specifications account for clinical impact of variations in the critical quality attributes (CQAs) and process parameters. This ensures a consistent safety and efficacy profile of commercial product relative to product used in clinical trials. This contrasts with the approach previously used, which incorporates both safety and process capability to establish specifications for a drug product. Both approaches are dependent on the manufacturing process and relevant data generated during product development. Because each company will have its own unique formulation, manufacturing, and product development process, it is not clear how this will impact the establishment of pharmacopoeia monographs. The complexity of developing a single quality standard for drug substances and drug products that will be applicable to all manufacturers with approved CRS in their registrations will certainly be a challenge and require changes in how monographs are established.

Analytical quality by design (AQbD) provides the ability to change method parameters within the method’s design space, referred to as the method operable design region (MODR) (29). The intent of AQbD is to develop a robust analytical method that is applicable throughout the lifecycle of the product to provide appropriate regulatory flexibility in the analytical method. The analytical target profile (ATP) defines the parameters that must be met to ensure a robust analytical method. The ATP is designed to capture the quality attributes of a reportable value of a method through determining the level of acceptable variability of the method. A suitably designed and applied ATP can be a measure of assurance that an analytical method is fit for purpose throughout its lifecycle, from development through validation and into a commercial setting. The use of AQbD will widen the approved operating range of an analytical method without compromising the integrity of the data it provides. Design of experiments (DoE) is a part of AQbD, representing the interaction among the input variables that ultimately affect the method response and results. The results from DoE define when results are acceptable and provide the acceptable ranges in which the method can be reliably run without the need for revalidation.

	It remains to be seen how AQbD will be integrated into the pharmacopoeia. Certainly, general chapters will be adapted to provide guidelines on how to properly implement AQbD for a method. Relevant chapters have been updated in the 

 in which flexibility is allowed for an analytical method to be changed without the need for revalidation if an AQbD approach has been implemented. The 

 Commission is exploring an approach to allow AQbD, following their evaluation of how this could be done for a small-molecule drug product (30). The flexibility provided by the AQbD approach can be used in drug substance and drug product monographs. A key question is whether monographs will continue to contain a single method with specific operating parameters and system suitability requirements as they are today, or if they will evolve to present an ATP/MODR that can be applicable to a particular method for the material. This will certainly be an area for bio/pharmaceutical companies to follow and provide comments as needed.

 Many small-molecule bio/pharmaceutical companies are moving toward a continuous manufacturing (CM) platform for production of drug substances and solid oral drug products. The CM platform moves the industry away from the traditional batch or lot manufacturing and takes advantage of the QbD principles for manufacturing. The CM approach necessitates the use of constant monitoring of the materials as they move through the manufacturing process. As a result, “typical” release specifications are not applied in the same way as with batch testing. This change in manufacturing approach is gaining acceptance by global regulators for more products, and the impact to the pharmacopoeia may still be a few years away. The pharmacopoeias will have to evolve to understand how monographs will differentiate between release and shelf-life criteria in a quality standard that is applicable to all manufacturers using different manufacturing approaches. Currently, monographs only list one set of acceptance criteria that apply to both release and shelf-life. Although it is possible to differentiate specifications in a regulatory filing, it will be a future challenge to the pharmacopoeias to accomplish this task. Pharmacopoeias may perhaps use the AQbD approach with an ATP for a given method or some other approach. Certainly, this will be important for all companies interested in CM to follow as the situation unfolds.

	It is interesting to note that USP has developed a week-long interactive training course for technical personnel in industry to gain direct insight and in-depth understanding of CM (31). As the use of CM evolves in the bio/pharmaceutical industry, general chapters related to the CM topic, including process analytical technologies (PAT) and statistical design controls, will be impacted. Still, regulators and pharmacopoeias are not yet in the same place on CM topics, including requirements when changes occur to an approved CM process. This represents another area where collaboration between regulators, pharmacopoeia, and industry could help deliver harmonized standards. It would provide great benefit to the industry to have harmonized general chapters in the pharmacopoeias for CM, because CM helps to lower the cost of manufacturing and ultimately benefits patients.

Multivariate statistical process controls.

 As the concepts of QbD, PAT, and real-time release testing (RTRT) were being introduced in the pharmaceutical industry, concerns were raised whether the pharmacopoeias were trying to develop standards too quickly that would impair rather than enable progress in this area. This largely did not happen. Instead, both the 

 today contain language making it clear that PAT and RTRT are acceptable as alternatives to ensure compliance with compendial requirements. The language of these chapters was crafted by the pharmacopoeias in partnership with industry and other stakeholders.

 published a draft informational chapter, 5.28 Multivariate Statistical Process Controls (MSPC), to provide guidance on good practices and requirements (32). 

is the first pharmacopoeia to publish a general chapter on this topic, which will provide information complementing existing general chapters on chemometrics. The new 

chapter provides guidance on the use of MSPC being applied to CM, PAT, and RTRT (33,34).

 Prompted by the discovery of two probable human carcinogens (N-nitrosamines) in drug products made by different manufacturers, EMA has mandated that companies manufacturing sartan blood pressure medicines review their manufacturing processes to ensure N-nitrosamine impurities are not produced (17). There have been limits imposed on the maximum amount allowed for these products.

	Many governments have required that all drug substances be evaluated for the possible formation of nitrosamines, with screening required if they can be present in the material. Although needed to ensure patient safety, the impact to the industry is significant and could grow with additional controls being implemented by the pharmacopoeias. EDQM has begun revising 

 monographs for the identified drug substances to add controls for N-nitrosamines and published a draft revision to the general monograph 2034 Substances for Pharmaceutical Use (35). The draft revision adds a section requiring a risk assessment of the drug substance manufacturing process to evaluate the theoretical risk of N-nitrosamine impurities formation and, if needed, implement a control strategy to detect and limit these impurities (36). A comprehensive list of actions taken by EDQM can be found on their website (37).

 Impurities can be introduced from the primary packaging systems and materials used in the bio/pharmaceutical industry. USP is revising their general chapter <661> on plastic packaging systems (38) and created two new sub-chapters, <661.1> and <661.2>, that apply, respectively, to the resins used for manufacture of a packaging system and to the packaging systems as a whole. The new chapters become official in May 2020, with the current chapter becoming obsolete in December 2025. This example highlights the value in companies commenting when new drafts are proposed by the pharmacopoeia. The original requirements and timelines proposed by USP were unrealistic for the industry to adopt. After many public meetings where the industry explained the difficulty to comply in the specified timeframe, USP provided this delayed implementation so that companies have five years to transition to the new requirements in 2025. USP has published other chapters applying the same risk management approach to elastomeric components used in packaging and delivery systems, including <382>, <1381>, and <1382>. Additionally, 

 <661.2> and <1382> require a “suitability for use assessment” that could include testing for any packaging system that is at risk, with extractables and leachables among the tests that should be conducted.

	It is reasonable to expect other pharmacopoeias to update their requirements for containers and packaging. For example, based on recent surveillance, the 

 is expected to publish existing national standards for drug packaging containers (materials), commonly referred to as the YBB standards. Additionally, there is an informal working group focused on the creation of a new ICH Q3E guideline for the assessment and control of extractables and leachables for pharmaceuticals and biologics (39). Timing for the development of this ICH guideline is not currently known, nor is the manner in which it could eventually be incorporated into the pharmacopoeias, but industry should continue to monitor developments in this impactful area.

 Rapid microbiological testing is an area where additional harmonization would facilitate expanded use of the technology. New chapters introduced in the pharmacopoeia are beginning to address this topic, but they are not fully harmonized. There are differences in method validation requirements between general chapters in 

 9201 (40). Differences between the chapters, including the number of replicates needed for a validation test and the amount of an organism to be added for recovery in a test, lead to a problematic situation. The result is that multiple validations must be done by the company trying to implement the technology, with little value added to ensuring product quality. Companies utilizing this technology should ensure these topics are included in the compendial monitoring processes to enable possible advocacy and ensure eventual compliance.

	In the past few years, the health authorities in Japan, China, Brazil, Russia, and Korea have begun requiring a company to perform compliance checks for their registration files versus what is actually being performed. This points to the increasing importance of compliance with the national pharmacopoeias in these countries, where gaps will inevitably become evident during this assessment. Before bringing an additional national pharmacopoeia into their monitoring program, a company must first ensure there is “baseline compliance” with the existing requirements in the pharmacopoeia. This baseline compliance will likely require a cross-functional project to identify any gaps with existing requirements before routine monitoring of revisions to the pharmacopoeia can begin. There are several important points to consider (e.g., translations) when trying to consistently monitor national pharmacopoeias (6,7). These considerations also apply when performing gap evaluations for current filings, which must include the national pharmacopoeia requirements.

 China is the largest potential healthcare market in the world based on the size of its population. Recent government reforms and a drive to ensure better healthcare for its people make it a country to focus on in the coming years. It is no longer to be considered an emerging market, but rather, will soon join the United States and Europe among the countries/regions where new drug product registrations will occur first. Though this may be a shocking statement to some, the statement is supported by the rate of regulatory change and the availability of accelerated processes to bring newer therapies to China sooner, instead of several years after approval in other countries. Included in this change is the 

 and its practices. China joined ICH in 2017 (41) and is currently in the process of adopting and implementing several ICH quality guidance documents (42,43), many of which will have major impact on the pharmacopoeia, such as ICH Q3C (residual solvents) and Q3D (elemental impurities). Additionally, with the adoption of ICH M7 and Q3A and B, designation and reporting of impurities in 

	The CPC has also announced its intention to work with the World Health Organization “… to jointly establish a pharmacopoeia exchange mechanism and a multi-national pharmacopoeia comparison information platform to lay the technical foundation for promoting international pharmacopoeia coordination” (44). In the authors’ experience, it is evident the CPC is open to science-based comments from multinational companies and has shown a willingness to adopt new concepts. With the ongoing changes in the regulatory environment, one can envision the 

 will become more important in product registrations for the Asia Pacific region, alongside the 

. Clearly, for any company intending to license and market a drug product in China, compliance to the

 is now mandatory and a strategy on how to achieve and maintain this compliance should be developed.

Brazil joined ICH in November 2016 (45) and implementation of several ICH guidance documents has occurred or is being planned (46). This change will impact general chapters and monograph requirements in the most recently published 6th edition of the 

) and future editions in the coming years. Companies will need to monitor the publication for any changes that impact their company’s products.

 Russia is currently an ICH observer, and with this status, has not yet implemented any of the ICH guidance documents (47). However, the latest XIV edition of the 

) was published in December 2018, and it contains more than 60 revised or new general chapters. The addition of chapters highlights the need for a company to establish monitoring of the 

. The regulation requiring companies to perform gap assessment of their procedures against the Russian normative document includes baseline compliance to the 

 general chapters. Companies must comply with these requirements at the next license renewal for the drug product or by 2022, whichever comes first. Additionally, there is increased activity from the Russian Ministry of Health (MoH) to request the development of new product monographs in the 

. This increased activity from the MoH indicates companies need to keep Russia on their radar to remain compliant.

Efforts to establish new pharmacopoeias in the Eurasian Economic Union (EAEU), which includes Russia, and MESCOUR region, which includes Brazil, were described in a previous article (3). As these new pharmacopoeias come closer to reality in the coming years, it is important for a compendial affairs group to monitor the proposed documents being posted, to comment as appropriate, and to ensure the company has a plan to comply when the requirements are published as official. It is not yet clear if these new publications will replace the existing national pharmacopoeias in their respective countries or if the new regional publications will be harmonized with any of the remaining national pharmacopoeias that may continue to exist.

	This brings to a close the series of articles on pharmacopoeia compliance. It is the authors’ hope that the information presented has been helpful and the ideas for the future will continue, especially efforts aimed at harmonization to achieve global pharmacopoeia standards. There is a continuing need for all stakeholders to work toward the goal of a world where there is “no need for translation”; where the following is achieved:

		Consistent standards published by pharmacopoeias in the languages needed by their stakeholders

		A global pharmaceutical industry that can ensure compliance with these standards, because they contain consistent requirements

		Regulators who can use these globally consistent standards to help ensure the quality of medicines

		No need for translation, because all the pharmacopoeias are saying the same thing.

	The authors put forth a bold challenge to readers: let us make every effort to ensure that the pharmacopoeias reach a state of harmonization that will support the objective of “no need for translation.” If this goal of global pharmacopoeia standards is realized, even if it takes as long as 50 years, then it can be asserted that the pharmacopoeias, regulators, and the bio/pharmaceutical industry have truly done all they can in this important area, working together to further their shared mission of effectively serving patients globally.

	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.

J.M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Necessary,” 

Pharmaceutical Technology Regulatory Sourcebook eBook

“Why Pharmacopoeia Compliance Is Difficult,”

 Pharmaceutical Technology Regulatory Sourcebook eBook

 “A Brief History of Pharmacopoeias: A Global Perspective,” 

“Global Pharmacopoeia Standards: Why Harmonization is Needed,” 

“Harmonization Efforts by Pharmacopoeias and Regulatory Agencies,”

“Revision Process for Global/National Pharmacopoeias,” 

“Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions,” 

“Monograph Development: Why and When to Participate,” 

“Monograph Development: How to Participate; How to Harmonize,” 

“A Practical Approach to Pharmacopoeia Compliance,” 

“A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials,” 

	12.  J.M. Wiggins, “Importance of Pharmacopoeia Standards: Their Added Value for Stakeholders,” Remarks provided on behalf of the European Federation of Pharmaceutical Industries and Associations (EFPIA) at the Workshop “The Chinese and European Pharmacopoeias-The New Editions,” Strasbourg, France, Oct. 17, 2016.

, WHO Expert Committee on Specifications for Pharmaceutical Preparations Fiftieth Report, Technical Report Series No. 996, Annex 1, pp. 67–85 (2016).

	14.  N.A. Schwarzwalder and R.H. Bishara, 

 “Fatalities Associated with Ingestion of Diethylene Glycol-Contaminated Glycerin Used to Manufacture Acetaminophen Syrup–Haiti, November 1995–June 1996,”

	16.  H. Liu, Z. Zhang, and R.J. Linhardt, 

“Sartan Medicines: Companies to Review Manufacturing Processes to Avoid Presence of Nitrosamine Impurities,” 

“ECHA Proposes to Restrict Intentionally Added Microplastics,” 

News Release, ECHA/PR/19/03, Jan. 30, 2019.

“Briefing on Proposed Draft Official Monograph Eribulin Mesilate,”

	21. BP, “Consultation Response: Dissolution Testing in BP Finished Products Monographs for Solid Oral Dosage Forms,” 

Dissolution Test in Individual Monographs on Solid Oral Dosage Forms: Your Feedback Counts!” 

Articles

This article summarizes all the considerations that go into a company’s compendial affairs program and to look ahead at topics that will likely result in further evolution in the pharmacopoeias around the world. This look into what is on the horizon is important to help companies prepare for the inevitable changes and ensure the continued supply of quality medicines to patients globally.

Pharmacopoeia Compliance: Putting It All Together: What Is on the Horizon

Previous articles in this series detailed the monograph development process, which is accomplished through partnership between the bio/pharmaceutical industry and the pharmacopoeias (1,2). Rationale was provided to help companies decide whether they will participate in the process as a potential advocacy opportunity for the company through monograph development for their drug substances and products. In a broader context, however, the overall series of articles is intended to address the challenges for the industry to comply with pharmacopoeial requirements. This article returns to this important topic with a case study at the intersection of monograph development and compliance.

	The drug product lifecycle described in the first article of this series (3) provides context that is helpful for considering compliance challenges. A company initially discovers a new drug substance and develops it into a drug product, performing clinical studies to ensure it is safe and effective. During development, the company establishes standards of quality that are considered appropriate for the drug substance and product. When all the necessary drug development information is available, it is submitted to regulatory agencies to gain marketing approval for the product in countries around the world. During the regulatory review process, differences can emerge in the quality requirements that are approved for the product, based on determinations made by the health authorities in individual countries. These differences are often minor, but may also be quite significant, creating challenges for compliance in all countries where the product is approved.

	An extreme, but not uncommon, example can be imagined for a drug product that contains a genotoxic impurity. Differing views by different regulators as to the appropriate control for this impurity can lead to more than 20 different country-specific limits for the impurity. The company can then test and release the drug product to the individual limits that are approved in each country. A more common approach, however, is to apply the tightest approved limit to enable worldwide release of the product. Even with this global approach, individual certificates of analysis are required to reflect the approved limits in individual countries. Continuing several years further in the product lifecycle, the pharmacopoeias eventually develop monographs for the drug substance and product, which can introduce additional differences in testing requirements.

	Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable (3). The situation is even more complex because a company must comply with the pharmacopoeial requirements that are applicable in a particular country, and also with their product registrations as approved in countries around the world. There are many challenges that make pharmacopoeia compliance difficult, including the need to address differences between the pharmacopoeia and approved registrations (4).

	There are reasons why a company might choose to proactively submit information to the pharmacopoeias to enable monograph elaboration, but different companies may make different decisions (1). One option is for the company not to participate in the process, due in part to the difficulty in resolving differences that may emerge in the pharmacopoeia monograph; the later the monograph is developed, the longer the company can defer addressing the differences. These differences in the monograph, compared to the requirements contained in the product registrations, occur even though the monograph is usually based on specifications that are approved by regulatory authorities, as stated in the 

) guidance (5). Differences between the monograph requirements and the registrations must be resolved so the company remains in compliance. There is some flexibility in how the company complies, with a range of options to resolve the differences, but in this flexibility, there is also complexity.

	Another choice a company might make is to participate in monograph development, but to submit the necessary information when multiple companies are involved in the process. This may be considered an intermediate approach, based on the timing for the submission, which still may result in compliance challenges if the monograph differs from the company’s approved registrations (1).

	At the other end of the range of choices is proactive participation early enough that the company is the only one involved in the initial elaboration of the monograph, reflecting their position as the only company with regulatory approval at that time. One of the benefits of this approach is the possibility of developing a monograph that is harmonized across multiple pharmacopoeias. Even when a company chooses to participate, there will likely be differences between the resulting monograph and the approved registrations. These differences may be understood in the transition from a “private” standard applicable to that company alone, to the “public” standard contained in the monograph. Knowing why the differences emerge, however, does not make it any easier to address them and ensure ongoing compliance.

	In the example provided here, the impact of the publication of a new monograph in the pharmacopoeia is explored, based on the experience of one of the authors (6). Although the perspective is that of an innovator company, the information helps explain the compliance challenges experienced by all companies across the broader bio/pharmaceutical industry. The impact of a new monograph depends, to some degree, on the answer to the following question: which came first-the pharmacopoeia monograph or the regulatory approval? For an innovator company, the approval comes first, typically by many years, and the resulting impact of the monograph is due to differences between the newly published monograph and registrations that have been approved for many years. It is important to note that the differences are in the specifications-the tests, methods, and acceptance criteria-for the drug substance and product that are the subject of the monograph. The drug substance or product do not typically change after the monograph is published, rather the quality filter, or lens, through which the material is evaluated has been changed. If differences in the monograph are significant enough, the challenge of complying with the requirements published in the pharmacopoeia may become so difficult that the company may be forced to take the product off the market. This is clearly not in the best interest of patients who may rely on the medicine.

	If the monograph in the pharmacopoeia is supposed to reflect the requirements in the approved registration, why should there be any differences? The answer lies in the practical basis of converting the approved registration, which is used by a single company, to the public standard in the monograph that will be used by all companies who manufacture and market that drug substance and product. In the authors’ experience, 80% or more of the compliance challenges are related to differences in the control of impurities. According to the International Council for Harmonization (ICH) Q3A (7) and Q3B (8) guidance documents, an organic impurity in a drug substance or product is either specified, meaning it is individually listed and limited with a specific acceptance criterion, or unspecified, meaning it is limited instead by a general acceptance criterion. For the innovator company who developed and validated the analytical procedure used to control impurities in a drug substance, a specified impurity may be identified by a relative retention time (RRT) in the chromatogram, based on standardization of the column and equipment used across the company. The use of RRT to identify the specified impurity becomes problematic when the method is incorporated into the monograph, since equipment and column standardization are no longer guaranteed. Any analyst who has run a chromatographic procedure recognizes the differences that may be observed, for example, when using different C-18 columns, as allowed in monograph methods.

	To address this challenge in identifying a specified impurity, the pharmacopoeias often require that a reference standard be available that enables unequivocal confirmation that an observed peak corresponds to the specified impurity. In many instances, the company that developed the chromatographic procedure does not have a sample of the specified impurity to provide to the pharmacopoeia to establish the reference standard. Also, the company may not have a “dirty batch” of the drug substance that would include the specified impurity and enable identification for the corresponding chromatographic peak. In this situation, taking into account the current process-capability and stability data, the pharmacopoeia may determine that the specified impurity must instead become an unspecified impurity, potentially resulting in a significant tightening of the limit compared to the approved registration. A related challenge that applies to the drug product is determining whether an impurity peak observed in the chromatogram for the product corresponds to a degradation product or is instead, a process impurity from the drug substance. This issue makes it difficult for the monograph to reflect the principle in ICH Q3B that only degradation products need to be controlled in the drug product, and not drug substance process impurities. Another significant difference and compliance challenge can result if the company has developed two different methods for assay and impurities in the drug product, or different methods for different product formulations or strengths, whereas the pharmacopoeia determines that a single method may be used for impurities and assay across the entire product line.

	Other differences may emerge in the monograph, which seem to be less impactful than that experienced with impurities. However, the steps necessary for a company to address these differences in their quality documents and regulatory filings can still pose significant challenges. An example is the addition of a new identity test in the monograph, such as infrared (IR), to complement a chromatographic identity test for the drug substance to ensure that all stakeholders who use the monograph can demonstrate unequivocal identification of the active ingredient. Another example is the widening of an assay limit for the drug substance to reflect appropriate analytical variability. Other examples include modifications to the chromatographic procedure, perhaps adding an isocratic hold at the start of the run to address dwell volume, which will also impact peak retention times, or the addition of new requirements to ensure acceptable system suitability for the method, such as peak resolution. As will be shown later, these changes range from minor to major impact when exploring the options of how to resolve the differences and ensure compliance with the monograph and the registration. The differences will likely impact quality documents and testing performed in the laboratory, with duplicate testing of the same quality attribute as the worst-case outcome to comply with the registration and the monograph. Depending on the company’s compliance strategy, the differences may also impact product registrations, requiring updates or variations in countries around the world.

	Some requirements in the monograph may be very difficult to meet (e.g., tighter impurity limits). If the monograph has already been published as official, another possible approach to resolve differences is communication with the pharmacopoeia to request revision of the monograph to better align with the registration. However, the pharmacopoeia revision process can be slow and is not always successful in achieving the requested changes. The probability of successful revision is also reduced if the company did not provide comments and concerns to the pharmacopoeia when the monograph was first proposed. This points, once again, to the benefit of proactive surveillance of pharmacopoeia updates with an appropriate response at the proposal stage (9). Not only does this provide the company an opportunity to possibly influence the requirements before the monograph becomes official, but it also enables internal discussion to plan for implementation of the requirements in the new monograph, when it does become official.

	This situation, emphasizing the challenge of resolving differences between a new monograph in the pharmacopoeia for a drug substance or product and the information included in product registrations approved by regulatory agencies around the world can best be understood through an illustration that follows the product lifecycle. 

represents the situation for an innovator company before the monograph elaboration process has been initiated. The smaller arrows represent regulatory approvals received in various countries. Currently, the regulatory submission and approval often occurs first in the United States and Europe (covering 30 countries, when following the “centralized procedure” of assessment by the European Medicines Agency [EMA]). At this point in the product lifecycle, the approved registrations in the US and Europe are generally aligned, although there may be differences based on decisions by the regulators for one of the applications, such as revising an impurity limit from “not more than 0.1%” to “not more than 0.10%”, which tightens the limit based on generally accepted rounding rules for scientific data. The next submission might go to the Japanese health authority, with approval granted with some additional changes. The additional differences may be minor, such as the requirement to use six injections rather than five to establish the percent relative standard deviation (%RSD) for a chromatographic procedure. The arrow for Japan in 

 is intended to show that some divergence is starting to emerge in the approved registrations. The next approval might come in China, again with the possibility of some differences compared to the approvals in the US and Europe. The drug applications continue, going next to a country designated as “Most of World #1” (“MOW #1”) and continuing to “MOW #10” and “MOW #150”. The arrows for these countries are intended to convey that the approved registrations in 150 or more countries are generally aligned, despite some differences. This is represented overall by the larger arrow, indicating at this point that the methods and limits in the quality standard (QS) may be used by the company to test the product and ensure compliance with the product registrations approved in 150 or more countries. Also at this point, the registrations and QS follow the typical process for updates and renewals to reflect subsequent regulatory requirements and manufacturing or analytical changes for the material.

 summarizes the situation for the US, Europe, and MOW #150 countries, with the fundamental direction emphasizing the global alignment and necessary compliance with approved product registrations. This figure, however, extends the product lifecycle to include the point of monograph elaboration. In the prospective harmonization pilot project referenced in a previous article (1), the 

) monographs were developed at the same time, and a harmonized outcome was achieved through the collaborative process. Many of the requirements in the harmonized monographs were aligned with the product registrations. However, the monographs also contained some differences from the registrations that were significant enough to make compliance with the new requirements difficult. This is indicated by the small red and blue arrows in 

, which are pointing in a slightly different direction than the aqua registration arrow. Among the differences were significant changes to the chromatographic procedure used for assay and impurities, as well as tightening of impurity controls, changing a previously specified impurity to an unspecified impurity with a new limit of 0.10%, because there was no practical way to identify that impurity peak in the chromatogram. The impact of these changes goes well beyond the US and Europe, because regulators in many countries around the world look at the 

 monographs as quality standards that must be met for medicines in these countries. The monograph situation in the figure becomes more complicated as other pharmacopoeias, such as those in Japan (

), subsequently develop their own requirements, which may differ from the 

 monograph, if not harmonized. Ultimately, there may be as many as 40 different pharmacopoeias that contain monographs applicable to the drug substance or product (10). The overall picture for pharmacopoeias is represented by the large purple arrow, which is not fully aligned with the large aqua arrow for product registrations.

	At the point when the pharmacopoeia monograph has been published as official, companies must comply with the new requirements contained therein, in addition to complying with their approved registrations. The question is how a company can resolve differences and ensure alignment with both the monograph requirements and the registrations. The answer is that this is done through modifications to testing procedures and limits in the quality standard and/or updates to the product registrations. It must be recognized that implementing these changes can have significant impact on available resources, either performing additional testing or submitting updates to 150 or more registrations around the world.

	It is incorrect for a company to assume they do not need to comply with the monograph just because they have a separate regulatory approval (4). Regulatory agencies around the world expect compliance with the requirements in the pharmacopoeia, including new monographs, that are applicable in their country. This is well understood, for example, in Europe and in Japan where it is known that compliance with the new monograph is required. It is not as well understood, but equally true (3), that FDA requires compliance with the 

 monograph as mandated in the Federal Food, Drug, and Cosmetic Act. The challenge becomes how to resolve differences between the monograph and product registrations.

	In some cases, the monograph may include differences in acceptance criteria for certain tests when compared to the approved registration. The practical basis for these differences was discussed above. The monograph limits may be either tighter or wider, and the available options to ensure compliance are either to adopt or not to adopt the different limits in the monograph. However, the choice is not quite as flexible as suggested by this statement. Recalling that a company must comply with the approved registration and the monograph, if the monograph limit is tighter than that listed in the registration, then the tighter limit must be applied going forward to ensure compliance with the monograph. It is possible that a company may have difficulty meeting the tighter limit, which may necessitate communication with the pharmacopoeia regarding possible revision to the monograph, or discussion with the regulatory agencies about possible approaches to ensure the product will continue to be available for patients.

	If the monograph limit is wider (e.g., the assay limit has been widened to reflect analytical variability), then a company can choose to apply the wider limit, but this requires updates to registrations with regulatory approval needed in 150 or more countries to allow the use of the wider criteria, even though this is listed in the pharmacopoeia. Different limits will be required in different countries if some of the regulators do not approve the registration updates. Alternatively, the company may choose not to apply the wider limits, which may seem somewhat counterintuitive. Maintaining the tighter limits as approved in the registration, however, rather than switching to the wider monograph limits means no updates would be needed to the registrations. Meeting the filed limits, which are tighter, obviously ensures compliance with the wider limits in the monograph. This approach requires no work by the company’s regulatory group, but it could have major impact to other groups, including quality and supply. One situation showing the impact of maintaining the tighter limits is a source of supply change, shifting from internal manufacture of the drug substance to an external partner, or from one external partner to another. The company must now insist that the contract manufacturer meet the tighter limits in the registration, rather than the wider limits in the monograph (which would be suitable for all other customers). This results-at best-in higher cost paid by the company for the material or-at worst-the inability for the company to obtain material meeting the tighter limits, with the obvious impact on supply of the medicine.

	Addressing differences in methods–“MARK” principle

	As noted previously, there is some flexibility in how a company chooses to comply with the monograph and registrations. However, in considering differences in analytical methods, the range of options is limited and includes the following: Merge, Add, Replace, or Keep. These choices can be denoted as the “MARK” principle (

), and the decision of which to apply will depend on the specific situation and the level of risk a company is willing to take. The most appropriate option often becomes clear when considering how significant the analytical method differences are. This is detailed below, with an indication of the potential impact to the analytical procedures and to the product registrations.

 The “merge” approach to compliance involves incorporating or merging any additional requirements from the monograph into the testing already performed by the company per the approved registration. This approach is generally applicable to minor method differences, such as additional system suitability criteria listed in the monograph beyond what is currently done. The additional criteria for a chromatographic procedure may include peak symmetry, resolution, or tightening of the %RSD for multiple injections. It would be difficult to defend a decision not to include these additional criteria since they are intended to demonstrate that the method is suitable to provide a valid result. If the laboratory can meet the additional system suitability criteria, they may be simply merged into the existing analytical procedure used for quality testing. If the criteria cannot be met, then discussion with the pharmacopoeia may be necessary for guidance on how to comply with the criteria, or to consider a change to the criteria in the monograph method to reflect the laboratory’s experience. No update to the procedure in the product registration is necessary with the “merge” option because the company is still complying with the requirements already approved by the regulators, and doing even more by complying with the additional criteria in the monograph.

 In elaborating the new monograph, the pharmacopoeia may introduce an entirely new test and analytical procedure to ensure appropriate quality for the material. The new method may also be added to ensure consistency with the testing typically requested in the pharmacopoeia technical guides for monograph content. A simple example of this is the addition of a new test in the monograph to ensure the identity of the drug substance. For the innovator company, identification for the material can often be assured through manufacturing process controls, so the approved registration may include only the chromatographic retention time for the main peak to identify the drug substance. When the quality standard in the monograph is developed to apply to materials from other manufacturers, with possible testing by second or third parties, additional assurance of identity may be needed. The additional test may include an IR identification or confirmation of the counterion in a drug substance that is a salt. The appropriate option in this situation is likely to “add” the new test to the quality standard, increasing the workload in the laboratory. Again, no update to product registrations is necessary because the current testing still ensures compliance with what is approved; there is now additional testing beyond the registration and no compliance gap. An alternate decision in this scenario is for the company not to add the new monograph method, given the process controls for the material. There should be technical justification to document that the material “will pass if tested”. In this risk-based approach, the company would not necessarily need to file this justification, but it should be available on inspection if regulators ask how the company ensures compliance with the additional test in the monograph.

 Some monographs may introduce a procedure that is significantly different than what is included in the approved registration. A challenging example of this is a chromatographic procedure for assay and impurities that is significantly different than what is registered. This situation may arise for several reasons, including the preference by the pharmacopoeias to specify a single method for assay and impurities in all monographs covering the drug substance and the entire product line. At the time of monograph elaboration, this preference makes sense to standardize the test method in the public standard across the product portfolio. Considering the earlier stages in the product lifecycle, however, this approach is typically not reflected in a company’s approved registrations, because the development of the drug substance, followed by the initial formulation of the drug product, and the subsequent introduction of other strengths and dosage forms occur over several years.

	In this case, the company’s compliance choices are either to “replace” the test method currently approved in the registration with the monograph method or to “keep” the approved method instead of the monograph method. Either of these choices requires a laboratory demonstration of equivalency between the currently approved method and the new monograph method to ensure compliance with both. This equivalency data can be used to justify the company’s decision, either upon submitting an update to the product registration or upon inspection of the manufacturing and testing facilities by regulators. The equivalency evaluation requires allocation of laboratory resources, creating challenges due to competing priorities. However, this one-time activity to document the equivalency outcome can help minimize the impact to the company for ongoing, routine testing. On the other hand, if the methods cannot be demonstrated to be equivalent, then a company might instead have to default to the “add” option, running both test procedures to ensure compliance with the registration and monograph. Alternatively, data showing the methods do not give equivalent results may be provided to the pharmacopoeia with a request to revise the procedure accordingly.

	Compared to the somewhat limited impact to the testing laboratory, the choice to “replace” an approved method has the opposite impact on product registrations. Switching from a test method that has already been approved by regulatory agencies requires updates to the product registrations to justify the switch from the currently approved method to the monograph method. This can have a significant impact on the resources in the company’s regulatory/chemistry, manufacturing, and controls (CMC) functions.

	For one large, multi-national company that was involved in the prospective harmonization pilot project, the decision to replace the approved method with the monograph method required the submission of registration updates and variations in more than 150 countries (6). Indeed, the company made the decision to adopt the harmonized monograph in its entirety-the tests, methods, and acceptance criteria-replacing the detailed information previously included in the registrations. Not only was this time-consuming on the front end, the registration updates began a process that took several years to complete, with different timelines for review and approval in different countries. As the regulators in some countries began to approve the registration update, the review process in many other countries had not yet been completed.

	This created a compliance issue in the interim, with the adoption of the monograph approved in some impacted countries, but not yet in others. How can a company comply with both the monograph and existing registrations during this transitional period? One option is to perform testing using both methods until all approvals are received, with obvious impact on the laboratory. Another option is to continue to use the currently approved methods until a fixed implementation date or until approvals are received in key markets, then switching over to the monograph methods, while still waiting for approval in the remaining markets. This approach carries some risk in ensuring compliance with both methods, but relieves the laboratory from having to perform duplicate testing in the interim. The compliance risk can be mitigated by the documented equivalency between the two methods, mentioned earlier. Another compliance risk can emerge if the regulators in one country reject the updated registration, forcing the company to continue duplicate testing to ensure global compliance and release of the product to all countries.

	Given the range and nuance of compliance challenges associated with the “replace” option, it is clearly important that all impacted stakeholders across the company, including analytical, quality, and regulatory, work together to develop and align on the strategy and then execute the implementation plan for adopting the monograph, while ensuring compliance with product registrations. As noted previously, despite the challenges, one benefit of the “replace” option is that the company can remove many of the details of the analytical methods from the registration to refer instead to compliance with the monograph. This simplifies the information detailed in the registration and enables the company to more easily implement subsequent revisions to the monograph, which ensures ongoing compliance with “current pharmacopoeia requirements”, as expected by regulatory agencies around the world (3).

 The other option, with a significantly different method in the monograph compared to the approved registration, is to “keep” the currently approved method instead of switching to the monograph method. There may be a strong preference for a company to continue using an analytical procedure that has been used for many years to ensure the quality and stability of the drug substance and product. Again, the equivalency of the approved method and the monograph method must be demonstrated. The General Notices in most pharmacopoeias allow the use of alternative methods that are equivalent or better than those in the monograph. Because of this, for most countries, there would be no need to update the product registration if the decision has been made to keep using the currently approved method instead of the monograph method. The demonstration of equivalency would be shown upon facility inspection, if requested, as evidence of compliance with the monograph requirements.

	However, if the new or significantly different method is listed specifically in a monograph of the

, then submission of a variation is required in European countries that are members of the EMA or signatories to the 

 convention. The reason for this is the specific language in the 

 General Notices (11) that states an alternative method may be used instead of one in the 

, provided the alternative method ensures compliance with the monograph and the use of the alternative method has gained the “agreement of the competent authority,” meaning approval by the European regulatory agencies. In the authors’ experience, no other pharmacopoeia or regulatory agencies mandate this prior-approval before the alternative method can be used to replace a method in the pharmacopoeia. In the case of the publication of a new 

 monograph, where a monograph did not previously exist, this regulatory approval for a company to continue using the previously approved method in Europe rather than a method in the new 

 monograph is necessary, even though the company had previously received approval for their method in Europe. In essence, the currently approved method is now considered an alternative method to that in the 

	For the drug substance, there is another way to ensure European regulatory agreement to use methods other than those listed in the corresponding

 monograph. The procedure for “Certification of Suitability to the Monographs of the European Pharmacopoeia” (CEP), described on the European Directorate for the Quality of Medicines and HealthCare (EDQM) website (12), provides for a centralized assessment of applications describing the manufacture and quality control of drug substances to facilitate and simplify exchanges between regulators and industry to ensure compliance with the 

 and therefore with the requirements of the relevant EU legislation. The procedure complements and bridges the 

 monograph and the submission of a marketing authorization dossier for a drug product. Also as noted on the EDQM website, CEPs are recognized by the signatory parties of the 

 Convention and are also recognized by many other countries around the world, including Canada, Australia, New Zealand, Tunisia, and Morocco.

	Compliance with compendial standards is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable and is essential to ensure continued availability of medicines to patients. However, compliance is complicated when there are differences between compendial requirements and approved drug product registrations. Challenges may arise in the elaboration of monographs by the pharmacopoeia, when differences emerge in the tests, methods, and acceptance criteria-ranging from minor to significant-between the monographs and registrations.

	These differences must be addressed to ensure ongoing compliance. Options include the addition of more quality testing or updates to product registrations to bridge any gaps. For method differences, the choices are limited, as expressed in the “MARK” principle: Merge, Add, Replace, or Keep. To achieve compliance decisions that meet both regulatory and compendial requirements, dialogue is needed between impacted stakeholders in a company, including quality, regulatory, compendial affairs, and many others. Aligning on an implementation strategy and maintaining communication throughout the execution of the plan are essential to achieve the best compliance outcome for the company.

Monograph Development: Why and When to Participate,” 

Why Pharmacopoeia Compliance Is Necessary,” 

Pharmaceutical Technology Regulatory Sourcebook eBoo

Why Pharmacopoeia Compliance Is Difficult,” 

	6. J. M. Wiggins, “Adventures in Compliance: Converging on Global Regulatory and Compendial Standards for Drug Substances and Products,” Presentation at the 1st PDA Europe Pharmacopoeia Conference: Convergence, Harmonization and the Future Direction of Pharmacopoeias, Vienna, Austria (May 29–30, 2018).

“Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions,” Pharmaceutical Technology Regulatory Sourcebook eBook,

“A Brief History of Pharmacopoeias: A Global Perspective,” www.PharmTech.com

	11. EDQM, General Notices, Section 1.1 General Statements-Alternative Methods, 

“Certification of Suitability-About the Procedure-Mission & Organisation,”

This series is intended to address the challenges for the industry to comply with pharmacopoeial requirements. This article returns to this important topic with a case study at the intersection of monograph development and compliance.

A Practical Approach to Pharmacopoeia Compliance

	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.

	This article is part of a series that will be published in 2019–2020. 

Pharmaceutical Technology’s March 2020 Regulatory Sourcebook


	eBook: Regulatory Sourcebook, March 2020
	March 2020
	Pages: 14–23

	When referring to this article, please cite it as J.M. Wiggins and J.A. Albanese, “Monograph Development: Why and When to Participate," 

Pharmaceutical Technology Regulatory Sourcebook eBook

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.

Monograph Development: Why and When to Participate (eBook)

	One reason given for proactive participation and earlier submission of a monograph was the possibility of prospective or informal harmonization across multiple pharmacopoeias. It is instructive to take a closer look at this harmonization process. Some practical aspects of following the process to develop harmonized monographs are discussed in the companion article, which can be accessed by

	Historically, the development of a new monograph began with the submission of information by a company to one pharmacopoeia. This information would include specifications (e.g., the list of tests, reference to analytical procedures, and acceptance criteria), as well as select details contained in product development reports, method validations, and drug product registrations. Typical timing for the initiation of the monograph elaboration was driven by requests from the global pharmacopoeias, resulting in submissions going first to either the 

). Later, perhaps several years later, the same information would be provided by the company to the other pharmacopoeia, which had not been part of the original submission. Even later, the information would potentially be provided to additional pharmacopoeias, including the 

). One practical outcome of this sequential approach to monograph development was that the resulting standards would often differ, sometimes in significant ways, regarding methods and limits that were listed in the monographs of the different pharmacopoeias.

	Recognizing the compliance challenges resulting from divergent standards contained in the various pharmacopoeia monographs for a particular material or product, the industry partnered with the pharmacopoeial authorities in a pilot project to develop “prospectively harmonized” monographs in the 

 The approach taken was to submit the necessary information and materials (samples and reference standards) to both 

at the same time, with collaboration among the participants throughout the monograph elaboration process. The industry perspective on the details of this prospective harmonization approach was provided in an article published in the 

 as an interested observer to this new approach for monograph development, the industry article was also translated into Japanese and published in the 

 forum (3). The work was also shared with the authorities of other pharmacopoeias, including 

), through individual discussions and presentations at the Global Summit of the Pharmacopoeias (4).

	The outcome of the initial pilot project was the publication of four new monographs for drug substances that were prospectively harmonized in the 

 However, the conclusions published in a press release from the pharmacopoeias pointed to the difficulty posed by the coordination of the monograph development work between the pharmacopoeias using the formalized process that had been established (5). They determined that achieving pharmacopoeia harmonization remained an important goal, and both organizations were fully committed to continue collaboration on prospectively harmonized monographs, but this would be done using an “informal harmonization” approach.

	Further development of harmonized monographs for drug products was undertaken by companies in collaboration with 

. The first monographs achieved by this informal harmonization approach were published in 

 in 2012 (6). Subsequent collaboration has resulted in the development of dozens of new monographs for drug substances and products that are harmonized between 

, with submissions for individual monographs coming from several different companies. Some of these harmonized monographs have also been adopted by other pharmacopoeias, including 