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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.
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.
Figure 1 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.
Compendial affairs activities. 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.
Compliance. 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).
Advocacy. 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.
Scope. A company needs to decide which pharmacopoeias are in scope for their compendial affairs program (purple bubble in Figure 1). 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 Good Pharmacopoeial Practices 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.
Teamwork. 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:
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.
Flexible monographs. 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 United States Pharmacopeia (USP) 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 Japanese Pharmacopoeia (JP) 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 JP 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 British Pharmacopoeia (BP) Commission and the European Pharmacopoeia (Ph. Eur.) 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 Ph. Eur. using a flexible monograph approach (9). FDA has not expressed similar support for USP 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 USP 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 Chinese Pharmacopoeia (ChP), scheduled for publication in 2025. The ChP 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 ChP 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 BP Commission is also exploring alternative approaches for complex biologics, notwithstanding their legal obligation to include Ph. Eur. monographs for complex biotherapeutic products in the BP. Recently, the BP 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).
Clinically relevant specifications. 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. 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 USP and Ph. Eur., 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 BP 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.
Continuous manufacturing. 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 Ph. Eur. and USP 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.
The Ph. Eur. published a draft informational chapter, 5.28 Multivariate Statistical Process Controls (MSPC), to provide guidance on good practices and requirements (32). Ph. Eur. is the first pharmacopoeia to publish a general chapter on this topic, which will provide information complementing existing general chapters on chemometrics. The new Ph. Eur. chapter provides guidance on the use of MSPC being applied to CM, PAT, and RTRT (33,34).
N-Nitrosamine contamination. 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 Ph. Eur. 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).
Containers/packaging. 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, USP <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 ChP 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. 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 Ph. Eur. 5.1.6, USP <1223>, and ChP 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. 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 ChP 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 ChP will potentially change.
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 ChP will become more important in product registrations for the Asia Pacific region, alongside the JP. Clearly, for any company intending to license and market a drug product in China, compliance to the ChP is now mandatory and a strategy on how to achieve and maintain this compliance should be developed.
Brazil. 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 Brazilian Pharmacopoeia (FBras) and future editions in the coming years. Companies will need to monitor the publication for any changes that impact their company’s products.
Russia. 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 Russian Pharmacopoeia (SP RF) 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 SP RF. The regulation requiring companies to perform gap assessment of their procedures against the Russian normative document includes baseline compliance to the SP RF 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 SP RF. This increased activity from the MoH indicates companies need to keep Russia on their radar to remain compliant.
New regional pharmacopoeias. 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:
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.
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,” www.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,” www.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 eBook, 26–37 (December 2019).
8. J.M. Wiggins and J.A. Albanese, “Monograph Development: Why and When to Participate,” Pharmaceutical Technology Regulatory Sourcebook eBook, 14-23 (March 2020).
9. J.M. Wiggins and J.A. Albanese, “Monograph Development: How to Participate; How to Harmonize,” www.PharmTech.com (March 2020).
10. J.M. Wiggins and J.A. Albanese, “A Practical Approach to Pharmacopoeia Compliance,” Pharmaceutical Technology Regulatory Sourcebook eBook, 24-32 (March 2020).
11. J.M. Wiggins and J.A. Albanese, “A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials,” www.PharmTech.com(March 2020).
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.
13. WHO, Good Pharmacopoeial Practices, 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, American Pharmaceutical Review, 7 (4) 53–57 (July–August 2004).
16. H. Liu, Z. Zhang, and R.J. Linhardt, Natural Product Reports, 26 (3) 313–321 (March 2009).
17. EMA, “Sartan Medicines: Companies to Review Manufacturing Processes to Avoid Presence of Nitrosamine Impurities,” ema.europa.eu, Press Release, Feb. 1, 2019.
18. ECHA, “ECHA Proposes to Restrict Intentionally Added Microplastics,” echa.europa.eu, News Release, ECHA/PR/19/03, Jan. 30, 2019.
19. USP, “
, April 29, 2016.
20. PMDA, “Briefing on Proposed Draft Official Monograph Eribulin Mesilate,” September 2019, PMDA.go.jp.
21. BP, “Consultation Response: Dissolution Testing in BP Finished Products Monographs for Solid Oral Dosage Forms,” pharmacopoeia.com.
22. EDQM, “Dissolution Test in Individual Monographs on Solid Oral Dosage Forms: Your Feedback Counts!” EDQM.eu, European Pharmacopoeia Public Enquiry, Jan. 17, 2019.
23. S. Keitel, “The Pharmacopeia in the 21st Century,” PDA.org, PDA Letter, April 2019.
24. S. Kozlowski, “Ensuring That Standardization Does Not Impede Biological Product Innovation,” FDA.gov, CDER Conversations, June 12, 2019.
25. Congress, “A Bill to Lower Health Care Costs,” 116th Congress, 1st session, S. 1895, Section 207, Biological Product Innovation, July 8, 2019, Congress.gov.
26. “Questionnaire on materials collection for the development of monoclonal antibody national standard and mAb pharmacopoeia monograph drafting related issues,” Surveillance and translation provided by the R&D-Based Pharmaceutical Association Committee (RDPAC) of the China Association of Enterprises with Foreign Investment (CAEFI), April 2019.
27. J. Venema, “Ensuring Quality of Medicines: Role of USP Standards,” Presentation at the 2nd PDA Europe Pharmacopoeia Conference: International Developments in the Pharmacopoeial Landscape, Geneva, Switzerland, May 16–17, 2019.
28. MHRA, “Consultation Response: Strategy for Pharmacopoeial Public Quality Standards for Biological Medicines,” Updated September 16, 2019, gov.uk.
29. R. Peraman, K. Bhadraya, and Y.P. Reddy, “Analytical Quality by Design: A Tool for Regulatory Flexibility and Robust Analytics,” Int. J. Anal. Chem., Feb. 2, 2015, hindawi.com.
30. J. Pound, “Analytical QbD and the Pharmacopoeia,” Presentation at the 2nd PDA Europe Pharmacopoeia Conference: International Developments in the Pharmacopoeial Landscape, Geneva, Switzerland, May 16–17, 2019.
31. USP, “Introduction to Continuous Manufacturing: Pharmaceutical Industry,” USP Education–Training Details, USPharmacopeia.csod.com.
32. EDQM, General Chapter: 5.28 Multivariate Statistical Process Control (MSPC), Ph. Eur., Pharmeuropa, 31.3 (July 2019).
33. EDQM, “Ph. Eur. Commission Consults Stakeholders on the General Chapter on Multivariate Statistical Process Control (MSPC) (5.28),” July 4, 2019, EDQM.eu, www.edqm.eu/en/news/ph-eur-commission-consults-stakeholders-general-chapter-multivariate-statistical-process
34. ECA Academy, “New Ph. Eur. Chapter on Statistical Process Control (SPC) Planned,” gmp-compliance.org, GMP News, Sep. 18, 2019.
35. EDQM, General Monograph 2034 Substances for Pharmaceutical Use, Ph. Eur., Pharmeuropa, 32.1 (January 2020).
36. EDQM, “Detection of N-nitrosamine Impurities: The Ph. Eur. Launches a Public Consultation on the Revised General Monograph Substances for Pharmaceutical Use (2034),” Dec. 13, 2019, EDQM.eu
38. USP, General Chapter <661> Plastic Packaging Systems and Their Materials of Construction, Pharmacopeial Forum, 45(2) (March–April 2019).
39. ICH, Quality Guidelines, ICH.org.
40. M.J. Miller, “The Regulatory Acceptance of Rapid Microbiological Methods,” European Pharmaceutical Review, June 29, 2017, europeanpharmaceuticalreview.com.
41. FDA News, “China Joins ICH as Full Regulatory Member, Pledges to Implement Guidelines,” June 22, 2017, fdanews.com.
42. NMPA, “Announcement of the State Food and Drug Administration on the Application of the Guiding Principles of the 11 International Coordinating Committee for the Registration of Human Drugs, including Q2 (R1): Demonstration of Analytical Methods: Text and Methodology (No. 7 of 2020),” Jan. 10, 2020, NMPA.gov.cn.
43. NMPA, “Announcement of the State Food and Drug Administration on Recommending the Application of the Four Guiding Principles of the International Human Drug Registration Technical Coordination Committee, including Q8 (R2): Drug Research and Development (No. 6 of 2020),” Jan. 10, 2020, NMPA.gov.cn.
44. Chinese Pharmacopoeia Commission, “Compendium of the Chinese Pharmacopoeia 2020 Edition,” Jan. 30, 2018, ChP.org.cn.
45. K. Huynh-Ba and A.B. Sassi, “ANVISA: An Introduction to a New Regulatory Agency with Many Challenges,” AAPS Open, Vol. 4, Article 9 (Dec. 12, 2018).
46. A. L. Lopes da Silva, “The Brazilian Pharmacopoeia,” Presentation at the PDA Compendial Joint Industry Group Meeting, Bethesda, MD, USA, July 25, 2019.
47. ICH, “Members & Observers,” ICH.org.