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J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions LLC.
Joseph A. Albanese, director of Analytical Strategy and Compliance at Janssen Research and Development, LLC
Processes, people, and tools are needed to comply with the pharmacopoeia and approved drug product registrations.
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 is presented at the beginning of a series of 12 articles (1–12) published to increase the understanding of this far-reaching and complex situation and to give practical guidance on addressing pharmacopoeia compliance. The articles appear in three online Regulatory Sourcebook eBooks and can be accessed through a dedicated webpage (13) with individual links to each of the 12 articles.
The detailed information in the articles provide important compliance considerations for the bio/pharmaceutical industry, including innovator, generic-drug, virtual, and start-up companies who discover, develop, manufacture, and distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products.
This current article provides an overview and summary of key points from the series—in effect, a narrative table of contents—intended to bring greater awareness to the availability of the articles, which can help provide guidance for this important pharmacopoeia compliance work.
The first article in the series (1) provides the legal and regulatory basis for the fundamental principle of pharmacopoeia compliance in the United States, Europe, Japan, and many other countries, thereby establishing the foundation for subsequent articles in the series. The purpose and content of pharmacopoeias is presented, and it is noted that the pharmacopoeias impact drugs and their ingredients throughout the entire product lifecycle. Additional important points are also introduced: a company must comply with “current” pharmacopoeia requirements, meaning a company must monitor and implement updates published by the pharmacopoeias; and a company must comply with applicable pharmacopoeia requirements and also with their approved drug product registrations, so that a company must address the complexity of these compliance challenges. The information provided in the first article is useful for enabling engagement and discussion among the many stakeholders within a company who are impacted by pharmacopoeia requirements, ensuring a common understanding across the various functions, and helping to avoid the risks associated with non-compliance.
The second article (2) provides a comprehensive, end-to-end framework to help bio/pharmaceutical companies better understand the external and internal challenges that make pharmacopoeia compliance difficult. Among the external challenges are the lack of broad harmonization of pharmacopoeia requirements around the world and the significant number of new and revised requirements that are routinely published. Internal challenges for companies include the lack of broad understanding of the need for and the complexity of remaining compliant. Enhanced awareness provided by the second article can facilitate the establishment and maintenance of collaborative partnerships among internal stakeholders to help address the compliance challenges.
Today, there are as many as 40 pharmacopoeias published around the world. Their history, presented in the third article of the series (3), reveals a common purpose, which is to support the health of the population through consistent standards for medicines. Many, including the United States Pharmacopeia, British Pharmacopoeia, and more recently, the European Pharmacopoeia, were established to harmonize the content and remove inconsistencies between the various pharmacopoeias which then existed. Regional and international initiatives continue even today, with global pharmacopoeia standards being one potentially beneficial outcome. The global and historical perspective is helpful in understanding the complexity and challenges of pharmacopoeia monitoring and compliance.
Building on information in prior articles, the fourth article (4) provides some industry perspective on the benefit of harmonization or convergence of pharmacopoeia standards around the world. When the standards are not aligned, the differences increase the cost and complexity of compliance. The concepts of the “ideal pharmacopoeia” and “compendial globalization” are presented as potential models to help achieve consistent and appropriate quality requirements for medicines worldwide. Concluding the fourth article, readers are asked to imagine a world where there is no need for translation, because the pharmacopoeias are all saying the same thing. Global pharmacopoeia standards would help to support the availability of medicines with consistent quality for patients worldwide.
There are many pathways to achieve harmonization, and several approaches are currently underway. The pharmacopoeias and regulatory agencies around the world, in collaboration with their stakeholders, have been actively and successfully working toward harmonization for quite some time. The fifth article in the series (5) describes what has been achieved in this area so far and what is yet to come. Among the topics covered are the Pharmacopoeial Discussion Group and the International Council for Harmonization (ICH), with particular attention given to the ICH Q3 topic on impurities and Q4B on the interchangeability of selected pharmacopoeia text. Contributions of the World Health Organization are also described, which include their convening of the International Meetings of World Pharmacopoeias and the resulting establishment of Good Pharmacopoeial Practices to encourage harmonization of compendial standards. Also discussed is the successful collaboration between the bio/pharmaceutical industry and the pharmacopoeias to achieve prospective and informal harmonization of new monographs for drug substances and products.
As noted in the first article (1), a company must comply with “current” compendial requirements, which introduces the need to monitor and implement updates published by the pharmacopoeias. The revision processes used by the pharmacopoeias and their associated schedules for publication of proposed and official updates are detailed in the sixth article (6). Designating pharmacopoeias as either “global” or “national”, based on regulatory acceptance, can help give visibility to some of the differences between their processes. This in turn can assist individual companies in focusing their compendial work on those activities that help ensure compliance.
The surveillance process used by the industry is driven by the revision process and publication schedules of the pharmacopoeias. The seventh article in the series (7) takes a detailed look at industry processes to monitor the significant volume of changes published and to achieve on-time compliance with updated requirements. Monitoring the pharmacopoeia updates provides an opportunity to respond to proposed changes and provide input that may potentially impact the decision on whether and how the updates proceed. Practical guidance is presented in the context of a compendial affairs organization within a bio/pharmaceutical company. There is also an exploration of the additional people and tools necessary to establish effective, efficient, sustainable, scalable, and successful processes for addressing the challenges of pharmacopoeia compliance.
As noted above, responding to proposed updates in the pharmacopoeias provides an opportunity for a company to potentially influence the outcome. There is an opportunity for even more proactive advocacy through a company’s participation in the process to develop new and revised monographs. The eighth article of the series (8) presents many considerations to aid a company in determining whether or not to submit a monograph proposal. Additional considerations are provided on the most appropriate timing for a submission, from the perspective of both the pharmacopoeia and the company. The potential for achieving harmonized monographs is also discussed. The article makes it clear that the answers to these questions on monograph development may not be the same for all companies, or products in the portfolio.
Having explored in the eighth article (8) the considerations of whether and when a company should submit a monograph, once decided, there are additional practical points to consider. These include how to navigate the process of working with a pharmacopoeia and how to approach prospective or informal harmonization of the monograph through collaboration with multiple pharmacopoeias. These additional points are described in the ninth article (9), which also includes detailed considerations of which groups in a company should have the responsibility to submit the monograph and what specific information and materials are necessary to support monograph development. Taken together, the eighth and ninth articles provide a comprehensive set of tools to enable a company to understand and successfully execute the monograph development process.
Compliance with pharmacopoeia requirements that are applicable in a particular country, and also with product registrations as approved in countries around the world, is a significant challenge for bio/pharmaceutical companies. Effectively addressing differences between the pharmacopoeia and approved registrations can be complex. The tenth article of the series (10) tackles the specific compliance challenge that occurs when a new monograph is published in the pharmacopoeias for a drug substance or drug product in the company’s portfolio. Possible options are provided to deal with differences in limits and methods between the monograph and the previously approved registration. This practical guidance can help a company align on the best overall compliance strategy for a given situation.
The tenth article (10) dealt with externally based compliance challenges, driven by decisions made by the pharmacopoeias during the monograph development process. There are other compliance challenges that are internally based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. One such example can be found with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment. This case study is explored in the eleventh article (11), with principles and strategies provided to help companies ensure compliance with applicable pharmacopoeia and regulatory requirements.
The final article of the series (12) attempts to summarize and pull all the various threads of the individual articles together into one consolidated picture of pharmacopoeia compliance. A holistic view is provided for the roles, responsibilities, activities, and other considerations, which are necessary to ensure compliance across the bio/pharmaceutical industry. The article continues with a look ahead at topics that will likely result in further evolution in the pharmacopoeias around the world. Some of the future trends explored are: new approaches to specifications, including those for complex biotherapeutics; the use of analytical quality by design and continuous manufacturing; concerns with impurities, such as N-Nitrosamine contamination; and the growing importance of national pharmacopoeias from around the world, for example those in China, Russia, and Brazil. This look into what is on the horizon can help companies prepare for the inevitable changes in the pharmacopoeias and ensure the continued supply of quality medicines to patients globally.
The need for pharmacopoeia compliance and the challenge of achieving it are explored in detail throughout the series of articles, which are intended to bring greater visibility and understanding of this fundamental principle to the bio/pharmaceutical industry. The articles present many facets of the processes, people, and tools necessary for a company to comply with the pharmacopoeia as well as their approved drug product registrations. The articles reflect the continuing evolution of the pharmacopoeias, their requirements, and the need for harmonization to achieve truly global standards.
Along with the understanding and assistance provided to those who perform the work, the articles have the additional goal of helping to ensure the continued availability of medicines with consistent quality. Meeting the necessary compliance requirements for these medicines ensures meeting the needs of patients around the world, regardless of where the patients live, where the medicines are manufactured, or which pharmacopoeias may apply.
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. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions LLC. Joseph A. Albanese is the director of Analytical Strategy and Compliance at Janssen Research and Development, LLC.
Vol. 44, No. 9
When referring to this article, please cite it as J.M. Wiggins and J.A. Albanese, “Pharmacopoeia Compliance:A Practical Guide,” Pharmaceutical Technology 44 (9) 2020.