Joseph A. Albanese, director of Analytical Strategy and Compliance at Janssen Research and Development, LLC

Joseph A. Albanese

Articles

This article presents a case study at the intersection of monograph development and compliance.

A Practical Approach to Pharmacopoeia Compliance

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. 

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

The first article of this series about compendial activities in the bio/pharmaceutical industry stressed that 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 (1). The second article provided an end-to-end compendial framework to aid in understanding many of the challenges with ensuring compliance (2). One significant factor that makes compliance challenging is the multiple pharmacopoeias around the world and the lack of broad harmonization of the requirements and standards they each contain. Subsequent articles explored the history of pharmacopoeias and the current global situation (3), with consideration of the potential benefits of compendial harmonization and a description of current activities to achieve global pharmacopoeia standards (4, 5).

Another challenge is the significant volume of new and revised requirements, which are published by the pharmacopoeias as both proposed and official changes. It is essential for bio/pharmaceutical companies to monitor these periodic updates to ensure ongoing compliance. The surveillance process used by the industry is driven by the revision process and publication schedules of the pharmacopoeias. Designating pharmacopoeias as either “global” or “national” can help give visibility to some of the differences between them, and can, in turn, assist individual companies in focusing their compendial work on those activities that help ensure compliance with pharmacopoeial requirements.

Defining global and national pharmacopoeias

In the second article of this series (2), brief definitions were provided for “national” and “global” pharmacopoeias.

National pharmacopoeias form the legal requirements in their individual countries and are important for ensuring access to medicines for patients in these specific markets.

Global pharmacopoeias form the legal requirements in their country/region and are acceptable to regulatory agencies well beyond the geographical boundaries covered by the pharmacopoeia, ensuring access to medicines for patients at a global level.

It is helpful to consider these designations in more detail (

) are considered global pharmacopoeias, based on their acceptance by regulators around the world. Many other important pharmacopoeias are considered national.

Revision process for global pharmacopoeias

Revision Process for Global/National Pharmacopoeias

In their article (6), Schwarzwalder and Bishara made the critical point, “… pharmacopoeial requirements are not static, and continued compliance demands that companies in this regulated industry be alert to changes.” The article continues, “(a) program for reviewing pharmacopoeial proposals and implementing changes is needed to ensure continued compliance.”

Surveillance activities used by bio/pharmaceutical companies are triggered by the publication of new and revised pharmacopoeial requirements. The publication schedule, in turn, is driven by the pharmacopoeia revision process. The ongoing revision of pharmacopoeias can be initiated in several ways. For example, pharmacopoeia changes can be driven by a significant technology update that requires a general chapter to be revised. Changes could be started to reflect a new International Council for Harmonization (ICH) guidance (e.g., Q3D) with impact to both existing general chapters and to monographs for many materials. Pharmacopoeial updates may be driven by collaborative efforts to achieve harmonization, as with the activities of the Pharmacopoeial Discussion Group (PDG), which is comprised of representatives from the 

). Pharmacopoeial evolution can be sparked by industry with the submission of a new or revised monograph. With so many possible avenues for change, the situation clearly demands that a company have a process for monitoring and staying up to date with the continuous revisions in the pharmacopoeias. But obviously, monitoring is not enough, since impact assessment and change control are needed to enable ongoing compliance with the current requirements. These considerations will be discussed in later articles.

The revision process used by global pharmacopoeias includes internal steps taken by the responsible organization and authorities, and also has steps that connect with external stakeholders (e.g., the bio/pharmaceutical industry and health authorities) that may be impacted by the changes (7, 8). 

 shows the process steps followed to generate a proposal for a new or revised monograph or general chapter, and the subsequent steps to move the proposed update to official status. At the outset, the governing body of the pharmacopoeia-called the Commission for 

-defines its strategic direction and proposed workplan for the duration of the cycle, based on its own governing rules. For 

, this is a three-year cycle, coinciding with the publication of each new edition. The activities of the 

 Commission are reported annually, with a triennial review to provide assurance that they are operating effectively. For 

, the Convention is on a five-year cycle. The Commission or Convention establishes expert groups or committees that further refine the direction, focus areas, and specific workplans, which are used to identify, prioritize, and pursue key issues and gaps in compendial coverage (9). These expert groups are typically comprised of volunteers from industry, academia, healthcare, and government agencies, to ensure that a broad representation of stakeholders contribute to the process. The expert groups review suggestions received for new or revised items as possible updates to the pharmacopoeias. Suggestions for new general chapters or monographs and revisions to existing general chapters or monographs, with appropriate justification for the request, may come from various stakeholders such as industry, academia, healthcare practitioners, and trade organizations, or may come from the pharmacopoeia expert groups or staff themselves. Proposals specifically for harmonized general chapters and excipient monographs may also come as a result of the work of the PDG.

Within the overall context of pharmacopoeia revisions, it is useful to realize that industry can influence this process through active collaboration and communication with the pharmacopoeias to make proposals for new and updated requirements. This influence will be explored in a later article that looks at the monograph submission process. Additionally, having a company’s subject matter experts participate on an expert group is another excellent way to participate and influence the direction of new and revised pharmacopoeial requirements.

The request for a new or revised monograph or general chapter is reviewed by the appropriate pharmacopoeia staff and expert group to determine if it should proceed as a proposal for public review and comment. For 

, input is obtained from the pharmacopoeia authorities in each European member country on whether to add the requested update to the workplan. In progressing the work to develop the update, the pharmacopoeia expert group and staff may be assisted by advisory working parties or expert panels with technical knowledge on the particular subject. Additional information may be sought from the original submitter of the request, from other manufacturers, additional interested parties, or from specialists with knowledge in that particular area. Often, laboratory work is performed by the pharmacopoeias, regulatory agencies, industry, or academia to support the proposal by verifying the suitability of analytical procedures and qualifying physical reference standards needed for the proposal.

A draft of the proposal is prepared and published by the pharmacopoeia, usually through an on-line forum for public review and comment by stakeholders. The expert group considers any comments received and determines the appropriate next step in the process, which may be a recommendation to move the proposal forward as an official change, to make further revision to the proposal with possible re-publication in the forum (if changes are significant), or to cancel the proposal. Responsibility for adoption or approval of the proposal to move it to official status is given to the decision-making body of the pharmacopoeia. For 

, the decision is made by the Commission and requires unanimous agreement. For 

, the decision is made by the expert group based on majority vote.

Once adopted, the new or revised monograph or general chapter is published in the next edition or supplement to the pharmacopoeia and becomes official on the date specified for the update. It is at this point that companies must comply with the updated requirements. It is also at this point that a request for further revision to a monograph or chapter-or to any of the official requirements in the pharmacopoeia-may be submitted by a company or other stakeholder, with appropriate justification for the requested revision. This request would start the pharmacopoeia revision cycle over again from the beginning. While these ongoing updates provide an opportunity for advocacy, more importantly they stand as the fundamental reason why a company must monitor pharmacopoeia publications to remain compliant with the current requirements.	 

Publication schedule for global pharmacopoeias

As noted above, the pharmacopoeia revision process includes two stages where information is made available to stakeholders:

Draft proposals for new and revised monographs and general chapters

This information is provided by the pharmacopoeias through two types of publications and online postings:

Proposals are communicated through a pharmacopoeia forum, which provides stakeholders the opportunity to comment on the new or revised item

Official updates to general chapters and monographs are published in new editions and supplements to the pharmacopoeia.

All stakeholders are expected to implement the updated official requirements in the timeframe specified by the pharmacopoeia.

Proposed updates in pharmacopoeia forums.

 The forum publications for global pharmacopoeias, typically available on-line and in English only, contain proposals for new and revised monographs and general chapters that are provided for public review and comment. The forum publications for 

 occur at a set frequency: four times per year for 

). Having visibility to the publication schedule is beneficial to industry for planning the workload and resources needed for the review process. The expectation is the same for each of the pharmacopoeias to their stakeholders: to review those proposals with potential impact and provide any comments, along with scientific rationale and supporting data regarding issues and concerns with the proposal. Comments are typically expected within 90 days from the date the forum is published.

Official updates in pharmacopoeia new editions/supplements.

 New editions and supplements to the pharmacopoeias are published to provide updated official requirements for monographs, general chapters, and other content. These updates become official on a set date, typically six months from the date of publication, although this timeline can be different for national pharmacopoeias. A company needs to be compliant with the new and revised general chapters and monographs by the specified official date. While it is generally allowed that the updated requirements may be implemented early, it must be understood that implementing the requirements late does not meet the regulatory expectation of compliance with “current” pharmacopoeial requirements.

The publication schedules and format (hard copy and/or electronic) for new editions and supplements are unique for each pharmacopoeia (

, published simultaneously in both English and French as official languages, is on a three-year cycle; a new edition is published every three years with two supplements provided later in the first year, followed by three supplements published in each of the second and third year of the cycle (for a total of one new edition and eight supplements during the three-year cycle). The 

 is available in both print/hard copy and on-line formats. In the print version, the supplements are non-cumulative, whereas the supplements are integrated in the electronic version, making it completely cumulative.

 is published yearly in English, available in print and on-line formats. The 

 does not publish supplements during the year for content that is specific to the 

 but does update the on-line publication (not the hard copy version) to reflect the updates made to the 

, as these updates are incorporated into the 

, a new edition is provided yearly in English, with a Spanish edition available for Spanish-speaking pharmaceutical scientists and professionals. The 

 publishes updates to official requirements in two supplements to the new edition every year. The 

43–NF38, which was scheduled for publication in November 2019, will be the last edition available in print/hard copy or on a USB flash drive. Future supplements and editions will not be printed. Starting with the first supplement to 

38, which will be published in February 2020, only the online format will be available, and it will contain all current 

. The pharmacopoeial processes allow for other approaches and timelines for the publication of proposed and official changes. These allowances can be especially important for revisions that need to be put in place quickly, for example, to address safety concerns related to the requirements contained in a general chapter or monograph. The “Guide for the Work of the European Pharmacopoeia” provides for the publication of rapid revisions, as well as corrections of errors in 

 may also publish minor revisions, which are justified and necessary, but not considered controversial and do not, therefore, require prior publication in their forum as a proposal. While perhaps not controversial, these minor revisions often still have impact, and a company may find it challenging to implement the changes quickly, after they are seen for the first time as official updates.

’s “Rules and Procedures of the Council of Experts” specify processes that can be used to make official revisions to the 

 more quickly than through their standard process (8,11,12). These accelerated processes include the publication of interim revision announcements (IRAs), revision bulletins (RBs), and errata, which are posted on the 

 website on a regular (monthly) schedule. IRAs are first published as proposals in the forum, given a 90-day notice and comment period, then posted as official text on the 

 website and incorporated into the next available official publication. If circumstances require a more rapid publication of official text, a revision bulletin is posted on the 

 website with the official date indicated. Errata are published to correct content in the 

 that does not accurately reflect the intended requirements as approved by the experts, and may address inaccuracies in chemical formulas, mathematical equations relevant to analyses, or inaccurate descriptions of apparatus or materials used in analytical tests. The 

 also publishes compendial notices to inform stakeholders of the changing status of monographs and general chapters, for example, to modify general chapter titles, appendix titles, or references to external resources that may be listed throughout the pharmacopoeia. These processes for accelerated revisions do not always require publication in the forum and allow revisions to become official prior to the next edition or supplement. There is another process for 

 pending monographs to allow development of new or revised monographs for articles awaiting approval by FDA (13). 

 also publishes stimuli articles, which present initial thinking of the experts in their development of new or revised general chapters or other standards and provide additional time for comments from stakeholders. The wide array and frequent use of these other approaches to notify stakeholders of proposed and official updates makes routine (monthly) monitoring of the 

 website an important component of a company’s surveillance process to remain in compliance with current requirements.

Revision process and publication schedule for 

Shifting focus from the global to the national pharmacopoeias, special consideration should be given to 

, because it does not fit as easily into the global or national designations. Because it is primarily required in Japan only, the 

 is a national pharmacopoeia according to the authors’ definitions. The revision process and regular publication schedule for 

, however, more closely align with those of the global pharmacopoeias, making it simpler for a company to include 

 in their surveillance activities. As with the global pharmacopoeias, the 

 revision process includes steps that are internal to the organization and steps that connect with external stakeholders, with communication of proposed and official updates occurring on a regular basis. 

 shows that proposed updates are published four times per year in the 

 forum is published in a hard copy/print version only, although some of the proposed revisions are also posted on the 

 forum is provided in both the Japanese and English languages within the same print copy, but the entire content is not exactly the same in each publication due to delays in translation of some of the proposals. This translation timing may make it difficult for a company to provide a timely response to revisions published in the 

 updates are published in a new edition every five years, with two supplements published during the five-year cycle between editions. Partial revision to official 

 requirements may also be made at any time on the 

 editions and supplements are published in hard copy/print versions, first in Japanese (the official language) and subsequently in English. Free, on-line PDF versions of the official 

 edition and supplements are available on the 

 website, in both Japanese and English, although the English version may not be the most current edition. The English translation may take up to 12 months for completion, but this delay is taken into account in establishing the official date, which is usually set at 18 months after the official publication. Experience has shown, however, that compliance for companies located in Japan is expected sooner. This situation creates the potential for inconsistencies in the procedures and documentation for a multi-national company regarding updated 

 requirements if there are manufacturing sites both inside and outside of Japan. Because of this, some companies may implement new 

 requirements based on the official Japanese version, which provides extra time to complete the necessary change control activities. The benefits for a company to translate from the Japanese to enable implementation of updated 

 requirements and the earlier opportunity to respond to 

 proposals make it important for the compendial affairs group in a company to have a strong connection with their local contact group in Japan, if available. Compliance with compendial requirements in Japan is also made more difficult by the publication (not on a regular schedule) of official compendia other than 

Japan’s Specifications and Standards for Food Additives

Requirements for Antibiotic Products of Japan

Minimum Requirements for Biological Products in Japan

. The health authorities in Japan expect compliance with these additional compendial requirements if standards do not otherwise exist in the official 

Revision process and publication schedule for other national pharmacopoeias

Looking at the revision process and publication schedules for other national pharmacopoeias, it is apparent that there are differences from the global pharmacopoeias and from each other. These differences, in particular the irregular publication schedules and the need for translation, pose challenges for industry surveillance activities and necessitate partnership with a company’s local contact group, if available, in these countries to help with compliance. Differences between the pharmacopoeias have been explored in the International Meetings of World Pharmacopoeias convened by the World Health Organization (14, 15), which have focused on ways to achieve international harmonization among the many pharmacopoeias. One outcome of these discussions has been the publication of 

), which defines approaches and policies in establishing pharmacopoeial standards (16). One key consideration contained in the 

 document is the assurance of an open and transparent process throughout the development and revision of pharmacopoeial standards. This process calls for engaging stakeholders in the process by making workplans available and providing adequate and timely public notification with allowances for commenting. While the revision processes for national pharmacopoeias typically follow similar steps as previously described, there is not always a similar level of transparency as seen with the global pharmacopoeias. National pharmacopoeias do not publish their proposed revisions for public comment at a predetermined time; it typically happens in an ad-hoc fashion. The lack of a regular schedule for notification of proposals contributes to the challenge for industry in monitoring the national pharmacopoeias.

) commission, for example, publishes items for comments on its website when a sufficient number of new and revised monographs and general chapters have progressed through their development process. These proposals are published in Chinese only. Comments on first draft items typically receive a 90-day commenting period, whereas items that are second or subsequent drafts typically get only 30 days for commenting. Many large multi-national companies find it difficult to meet the commenting deadlines for 

 since the proposals must first be translated into English to enable assessment of the potential impact. It is important, therefore, for the compendial affairs function in a company to have a strong connection to the local contact group in China, if available (e.g., regulatory affairs, quality, etc.) to perform the monitoring, identification, and translation of items with potential impact. If needed, the local group can also translate the company’s comments from English to Chinese so a response can be provided back to the pharmacopoeial authority.

State Pharmacopoeia of the Russian Federation

), proposed updates are not available on a regular schedule, and when they appear, they are in Russian only, with a comparatively short timeframe to submit comments. The company’s local contact group in Russia can help monitor and translate the items with potential impact.

), proposals for new and revised requirements are also posted on the commission’s website on an ad hoc basis. Even though they are published in English, the irregular publication schedule for these items again makes it helpful to have a connection with the local contact group in India to assist in monitoring the website. The commenting period allowed for IP proposals also seems to be irregular and often quite short compared to the global pharmacopoeias, which makes it difficult to respond to the proposals. For many of the other national pharmacopoeias, there may be even less transparency in their public notification and commenting processes.

For national pharmacopoeias, the governing commission’s workplan typically coincides with the publication cycle. The publication schedules for official updates (15) also reveal differences between the national pharmacopoeias (

), with translation from the local language being another complicating factor for compliance. A new edition of 

 containing official updates is published every five years in the Chinese language. The 

 commission provides an English translation, but for the 2015 edition, there was a significant delay in the availability of the English version, which made it difficult for multi-national companies to comply with the updated requirements. For the 

 2020 edition, there are indications that the English translation will be available more quickly after the Chinese version, which will be helpful in the implementation activities for industry.

 is also targeted every five years, but the actual publication has not strictly adhered to this intended schedule. These official updates to the 

 are provided on the commission website in Russian only; an English translation is not available. The challenges with publication schedules and translations again make it critical to the success of a company’s compendial vigilance program to have a strong connection with their local contact group to provide access to speedy translations of proposed and official items for assessment. The urgency for receiving the translation can be reduced as some pharmacopoeias (e.g., 

) allow a delayed implementation timing due to the lack of the information in English. However, this is not the case with all national pharmacopoeias (e.g., 

) where a very short time may be provided for compliance with the updated requirements following publication in the local language. In the case where implementation follows a short timeline, connection with the company’s local regulatory group (or other identified function) to provide the translation is critical to ensure on-time compliance. Additional information about the pharmacopoeias in India, Korea, and Brazil is provided in 

The revision processes used by the pharmacopoeias, and their associated schedules for publication of proposed and official updates reveal some similarities, but also many differences between global and national pharmacopoeias. Pharmacopoeial revision activities are inextricably bound to the surveillance activities carried out by the bio/pharmaceutical industry. The next article in this series will take a closer look at the industry processes to monitor the significant volume of changes published in the pharmacopoeias and to remain compliant with the current requirements.

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.

Why Pharmacopoeia Compliance Is Necessary

Pharmaceutical Technology Regulatory Sourcebook eBook

, 28–34 (September 2019).
	2. J.M. Wiggins and J.A. Albanese, “

Why Pharmacopoeia Compliance Is Difficult

, 36–42  (September 2019).
	3. J. M. Wiggins and J. A. Albanese, “

A Brief History of Pharmacopoeias: A Global Perspective

 (September 2019).
	4. J.M. Wiggins and J.A. Albanese, “

Global Pharmacopoeia Standards: Why Harmonization is Needed

, 43–47 (September 2019).
	5. J. M. Wiggins and J. A. Albanese, “

Harmonization Efforts by Pharmacopoeias and Regulatory Agencies

 (September 2019).6. N. A. Schwarzwalder and R. H. Bishara, 

 7 (4), 53-57 (July-Aug 2004).
	7. EDQM, “

 Monograph and Reference Standard Development Process, 

-Transitioning from the Print/Flash Drive Format to the 

International Meetings of World Pharmacopoeias

,” World Health Organization (WHO) Working Document QAS/12.512/Rev.1 (March 2013).
	16. WHO, “

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

The revision process and the resulting publication of proposed and official updates for pharmacopoeias around the world are described.

Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement for drug companies seeking to market products in that region. The multiple pharmacopoeias around the world are frequently revised and expanded, presenting challenges for bio/pharmaceutical companies that must monitor this activity.

This article examines the revision process of global and national pharmacopoeias, the publication schedules, and describes differences between the procedures of the various authorities.

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

Pharmaceutical Technology’s December 2019 Regulatory Sourcebook

eBook: Regulatory Sourcebook, December 2019
December 2019
Pages: 17–25

When referring to this article, please cite it as J.M. Wiggins and J.A. Albanese, “Revision Process for Global/National Pharmacopoeias," 

Pharmaceutical Technology Regulatory Sourcebook eBook

This article describes the revision process and the resulting publication of proposed and official updates for pharmacopoeias around the world.

Revision Process for Global/National Pharmacopoeias (eBook)

The pharmacopoeial revision process and the resulting publication of proposed and official updates were described in a previous article in this series (1). To maintain ongoing compliance with current pharmacopoeia requirements as expected by regulators around the world, it is essential for bio/pharmaceutical companies to be aware of these periodic updates, so they can determine the potential impact and implement appropriate changes to their quality and regulatory documentation, as well as impacted processes and procedures. This article details the surveillance activities carried out by industry to monitor pharmacopoeia revisions so that companies can establish effective, efficient, sustainable, scalable, and successful processes to address these compliance challenges.

	Compendial affairs organization, roles, and responsibilities

	At a high level, effective surveillance is comprised of processes, people, and tools. These factors were described in an article written 15 years ago (2), and what is, perhaps, remarkable is that the issues and challenges have not substantially changed since then. Before delving into the details anew, it is helpful to look at one particular group that carries out key steps in the overall process.

	Although identified by a variety of names, in many companies there is a group or function known as compendial affairs. The activities carried out by the compendial affairs group were described using the end-to-end framework in the second article of this series (3). The compendial affairs responsibilities include surveillance of the pharmacopoeial revision process, which may include publications for both proposed and official updates; advocacy, through responses to proposed changes; and compliance, through involvement in change control to enable implementation of official updates within the company. Another potential advocacy role for compendial affairs is through the submission of new or revised monographs to provide quality standards in the pharmacopoeias for a company’s drug products and ingredients. This activity may also involve coordination within the company and with the pharmacopoeias to provide samples and standards to support monograph elaboration. Direct engagement with the pharmacopoeias and participation in industry trade association activities provide other avenues for advocacy and sharing of best practices and perspectives on compendial issues. In this role, the individuals in compendial affairs also serve as the single point of contact (SPOC) in interactions with the pharmacopoeias. Finally, the compendial affairs group should serve as the internal support for the entire company, providing knowledge and experience in all things related to the pharmacopoeia.

	Considering the numerous responsibilities listed above, each company’s approach to resourcing the compendial affairs function can be very different. Benchmarking of the bio/pharmaceutical industry revealed that some major multi-national companies have three to five full-time employees in a compendial affairs role. The more common approach, however, is that a single individual or a couple of individuals with part-time responsibility comprise the compendial affairs functions. Of course, the fewer the resources available in a company’s compendial affairs function, the more challenging it becomes to consistently carry out all the responsibilities necessary to ensure ongoing compliance. One company utilizes an outsourcing model for monitoring pharmacopoeia revisions, establishing a SPOC in the company to manage the surveillance process that is carried out by external contractors. This approach can reduce the cost of using internal resources for that part of the effort, which is considered largely administrative. The external team can execute the review and filtering process and then assign the identified items with potential impact to a company’s internal groups for complete assessment.

	Another consideration is where within a company the compendial affairs function should reside (1). Key to this organizational decision is realizing that many functional areas in a company may be impacted by pharmacopoeial requirements. In one sense, it can be argued that compendial affairs could fit anywhere within a company, while the practical reality is that this function does not seem to fit well anywhere. Benchmarking has shown compendial affairs to be organized within the quality, regulatory, or research and development functions, or even at a corporate level due to the broad impact. There is no right or wrong organizational approach, but the key consideration is that compendial affairs functions are critical to ongoing compliance. The individuals or group assigned these responsibilities need to have management support across the company to effectively address the impact of pharmacopoeia revisions, ensuring the necessary tasks are assigned the appropriate priority.

	Industry surveillance process: Purpose and scope

	Perhaps the most important of the compendial affairs responsibilities is surveillance of pharmacopoeial revisions. A detailed description of the industry surveillance process is provided in a related article. The purpose of this surveillance is to identify, communicate, and enable assessment of the potential impact resulting from updates to pharmacopoeial requirements within a company in order to plan and execute implementation and help ensure ongoing compliance (see related article, 

). This activity also provides an opportunity to influence the compendial requirements through comments submitted in response to proposed revisions. The number of individual compendial changes to be reviewed for potential impact to a company is staggering: more than 3000 new or revised monographs and general chapters per year in the global pharmacopoeias alone. This number increases as a company scales up to bring additional national pharmacopoeias into the process. Considering this large volume of work, the crucial decisions to be made are which pharmacopoeias and which part of the revision process a company will monitor. These decisions on the scope of compendial affairs activities may differ for different companies.

	The first decision-which pharmacopoeias to monitor-is dependent on where the company’s products are registered and distributed. For a large multi-national company with globally distributed products, surveillance of the global pharmacopoeias-

)-would be necessary, along with monitoring several of the important national pharmacopoeias, including the 

) and those in China, Russia, and India. For a smaller bio/pharmaceutical company focused on products in clinical development, surveillance of only 

	The second decision-whether to follow proposed and/or official revisions-depends on several factors such as company resources, commitment to advocacy, and conscious choices to be proactive or reactive to achieve compliance. Some companies only follow official revisions to reduce the burden of the compendial process. Monitoring and implementing only pharmacopoeia changes that are official is the minimum a company must do to comply with current requirements. Following both proposed and official changes allows a company the opportunity to be more proactive, potentially influencing the outcome of a proposal through advocacy. Either approach is acceptable and will allow a company to comply; however, following only official items drives the company to be more reactive, potentially making them ill-prepared when implementing the changes that occur.

	The challenges of monitoring proposed and official revisions published by global and national pharmacopoeias can make it difficult to achieve on-time compliance with updated requirements. This situation is further complicated by complex global supply chains in the bio/pharmaceutical industry, including multiple manufacturing sites, external manufacturing sites, and excipient/component suppliers that may be impacted by updated pharmacopoeia requirements. Based on the experience of one of the authors, to address these challenges, a large multi-national company assembled the compendial affairs group and a wide range of impacted stakeholders in an international, cross-divisional, multi-site, multi-day Kaizen event with the specific aim of mapping the existing process for compendial review and implementation to identify possible improvements. This enabled the company to develop a new process for pharmacopoeia surveillance that emphasized monitoring pharmacopoeia revisions starting at the proposal stage, stressed the importance of a comprehensive tracking tool, and created new cross-functional teams to assist in the impact assessment for the company. The enhanced process was more effective, efficient, and sustainable in helping to ensure ongoing compliance with new and revised pharmacopoeial requirements.

	As noted earlier, the industry’s surveillance of pharmacopoeia revisions is comprised of processes, people, and tools. Throughout the detailed description of the process (see related article), the key players have been identified, and what emerges is the broad network that is required to accomplish this work. It is helpful to focus briefly on the people involved in an effective surveillance process, as follows:

		Internal stakeholders/subject matter experts (SMEs)/teams

		Local contact group/In-country partners

		Company leadership/functional area management

	The critical role played by the compendial affairs group in the overall process was presented earlier. The internal stakeholders, working individually as SMEs or as part of a team, and those functional areas that are impacted by specific pharmacopoeia revisions are also necessary in the process. These resources reside over the entire company, as identified earlier in the detailed description of the surveillance process. These SMEs must clearly understand their role in the compendial process, whether it be technical assessment or driving the implementation of a change across the company. Without clearly defined roles and responsibilities, items may not be properly assessed or implemented. The engagement of internal SMEs and impacted stakeholders is critical to the effectiveness and sustainability of the compendial affairs process. Additionally, to effectively manage changes in the national pharmacopoeias, engagement with the local contact group or in-country partner is vital, due to the challenges of irregular revision schedules and the potential need for translation. To be truly successful in the overall effort, the entire process and all the people involved need the support of company leadership and functional area management, who must be aware of the time commitment needed to properly assess a revision, develop appropriate comments, or drive implementation of the change that potentially affects multiple sites, products, and registrations. This time commitment is not trivial and adequate resources need to be available to ensure ongoing compliance with pharmacopoeial requirements.

	All the groups mentioned are internal to a company, but the discussion of people that support the surveillance process is not complete without consideration of a key external connection: pharmaceutical industry associations. These associations may be found in many countries and regions around the world and a list of some key industry groups that monitor the pharmacopoeias are included in 

New Jersey Pharmaceutical					Quality Control Association

					Mid-West Compendial Discussion Group

Pharmaceutical Research and					Manufacturers of America

Association of the					British Pharmaceutical Industry

European Federation of Pharmaceutical					Industries and Associations

Japan Pharmaceutical Manufacturers Association

R&D-Based Pharmaceutical					Association Committee

International Federation of Pharmaceutical Manufacturers & Associations

International Generic and Biosimilar					Medicines Association

International Pharmaceutical					Excipients Council

					*  The IPEC Federation is a global organization consisting of IPEC Americas, IPEC China, IPEC Europe, IPEC Japan, and IPEC India.

	The value gained by a company through connecting with the compendial interest or discussion groups in these industry associations should not be underestimated. It should be noted that these groups do not talk about pharmacopoeia changes that impact only one or a few companies, such as specific monographs for drug products or ingredients. Rather, the focus of their discussion is on changes that have broader impact to the entire industry, as seen with general chapters, which are used by many companies. Key benefits of engaging with industry groups include recognizing you are not in this alone; that it is helpful having many eyes look at the information; and there is power in numbers.

	Participating in these groups as part of the compendial process increases a company’s ability to identify all changes with potential impact and to be more successful in the resulting advocacy efforts. During the proposal stage, through discussions in the industry associations, it is often found that the compendial affairs function in one company has identified a potentially major revision, when other companies may not yet have made that determination. This heightened awareness enables greater assurance that a major change is not missed, and the resulting discussion can focus on how the change may impact the broader industry. If the particular industry group charter allows, and the proposed change warrants, comments can be sent to the pharmacopoeia authorities by the association, representing the input of many companies to bring added weight to any concerns identified. Again, these comments need to be scientifically based and supported by data where appropriate.

	Being connected to industry trade organizations is invaluable in these situations because the organization represents companies that have similar opinions. For high-impact changes, such as elemental impurities, it is important to have this connection to trade organizations to help consolidate the industry point of view. Leveraging this critical mass through comments to proposals can influence the final outcome of the official revision. Investing time to participate in these organizations is a simple yet effective way to leverage the power and influence they have when engaging with the pharmacopoeias. For their part, the pharmacopoeia authorities have demonstrated their willingness to engage with industry to discuss issues that are identified.

	The final piece of the industry surveillance process is focused on the tools that help the compendial activities run smoothly and enable the people to remain actively engaged. This piece of the puzzle is as crucial as the process and people in ensuring a compliant system. Investing in appropriate tools allows for comprehensive tracking, ease of communication, implementation of revisions, and generation of metrics on the effectiveness of the process.

	The most important tool for a compendial affairs program is the one to track the pharmacopoeia changes identified with impact to the company and the current status of these items. The tracking can be done using various tools, from a simple spreadsheet/database or a SharePoint (Microsoft) team site with simple functionality to a specially configured out-of-the-box quality solution or a customized in-house system specifically designed for tracking. Each of these options have been used by a number of companies and are viable solutions to enable proper tracking of the compendial process. As a company works to establish a compendial affairs program, an approach of “crawl, walk, run” can be applied. At the beginning, the process may use a simple spreadsheet to track items of interest. As the program matures and the processes become more defined, a database or a SharePoint team site may be appropriate. The latter offers an opportunity to add automatic notifications and due-date reminders for assessment tasks. It also allows for export of the data to enable metrics (monthly, quarterly, or annually) to be generated. If configured properly, the application will allow for the connection of proposal items and official items to help aid the assessment and change control processes needed for compliance.

	Other tools critical to the success of compendial surveillance were mentioned in the filtering stage of the detailed process (see related article): the lists of drug products and related materials, including pharmacopoeia general chapters used by a company. The challenges of trying to pull all the necessary information on materials used, where they are used, and if they are still active are significant. Rarely is a single system available to accomplish this; rather, it requires the aggregation of information from multiple systems throughout the company. Requests may need to go to the various business systems across a company with the resulting information combined into one list by the compendial affairs function to ensure all materials are captured for the filtering process. This is a time-consuming and people-intensive process step, but it may be the only approach to ensure all materials are captured for a company, in the absence of a single, integrated business system. Another important determination is which general chapters need to be assessed by a company. Investing the time to develop a grid of “similar” chapters across the pharmacopoeias and which general chapters are used by the company will ensure a robust filter and reduce the number of items that require further assessment. Typically, a spreadsheet can be used to establish this matrix of general chapters across pharmacopoeias, with an indicator if the chapter is applicable to the company. The list requires periodic follow up to add new general chapters and remove others that have been made obsolete.

	Communication tools are also important for a successful surveillance program, to provide the findings of the ongoing pharmacopoeia filtering process throughout the company and enable assessment for potential impact. This includes communication of individual items and an overview report sent at a regular frequency (per publication, monthly, or quarterly). Microsoft Word programs and Microsoft Excel spreadsheets are the typical tools used for such reports. The compendial affairs function needs to keep up-to-date lists of SMEs and other stakeholders for email distribution of necessary reports or task assignments. Having a dedicated email box for the compendial affairs function is also a recommended best practice for communication. This alleviates individuals in the company from having to know a specific person in the compendial affairs role and allows for people changing their roles and responsibilities. Most people can remember a well-named email address (e.g., Compendialsupport @ company.com) more easily than a specific individual’s name. This generic email address allows all members of the compendial function to monitor requests and questions that may be sent to them from any group in the company.

	If a company’s compendial affairs function submits responses to pharmacopoeia proposals, then a process for this needs to be defined. Typically, responses are submitted on company letterhead and sent via email to the pharmacopoeia authority or a specific scientific liaison in the pharmacopoeia organization. The file is usually submitted in portable document format (PDF) with electronic signature to maintain the integrity of the file, which also serves as the official record of the company’s position on the particular issue. Some pharmacopoeias have online platforms that allow comments to be directly uploaded to that site. It is expected that other pharmacopoeias will follow suit in the coming years. Also, it is recommended that the tracking system, mentioned before, be configured so that submitted comments can be tracked to enable follow-up as needed. This also allows a determination of whether the comments and suggested changes submitted by a company were taken into account in the official version for implementation. This also provides the compendial affairs function with the ability to generate metrics on the company’s efforts to influence the pharmacopoeia authorities.

	The last essential tool for a compendial affairs program is a global change control system. Items that are published as official by the pharmacopoeias typically have a six-month window for implementation from the time of publication. It is important that all appropriate functional areas within a company assess the impact and determine the implementation steps for the site or global function. Key to the change process is a regulatory impact assessment to determine if any product registrations need to be updated. A simple change in a monograph could still result in updates to registrations in several countries, determined by a company’s filing strategies. To have an effective change control process that drives on-time implementation of a pharmacopoeia change, each site or global function must understand their role and execute it promptly. Also, a responsible person or group needs to be identified that will drive the change control from start to finish. This is a difficult job for multi-site, multi-product changes, or changes that impact multiple registrations. It is important for the responsible person to begin this process shortly after the proposal has been reviewed. If a company begins the implementation process when an item is reviewed at the proposal stage, it will have done most of the assessment and planning before the item becomes official, when there is only six months to complete the implementation (see related article, 

	Taken together, the tools supporting the compendial processes can potentially identify emerging trends for each of the pharmacopoeias. The trends are identified by reviewing items in the compendial tracking and change control systems and can then be molded to reflect changes that should be made to existing development and commercial product support processes helping to ensure compendial line-of-sight (CLOS) for the company.

	Measuring success: Advocacy and compliance

	Management will often request a report of metrics regarding on-time completion of items for commenting and for implementation. Having described the details of the industry surveillance process, including the people and tools that are necessary, it is appropriate to ask how to measure success for this work. As it turns out, this can be somewhat difficult to do. Pharmacopoeia revisions take place over protracted periods of time. It typically takes a minimum of 18 months from proposal to official, and often much longer-up to several years for some major changes-for the pharmacopoeial revision process to be completed. Because of this, many changes remain open for a long time and the compendial affairs function may have hundreds of items that have not reached the final step in the process. In the end, however, success can be examined from the standpoint of advocacy and compliance.

. In monitoring pharmacopoeia revisions, a management decision is required on whether the company will be proactive through advocacy efforts or strictly reactive in compliance. Advocacy is aimed at influencing the decisions of the pharmacopoeia authorities to impact the official content published in new editions and supplements. In advocating for changes to revisions that have been proposed by the pharmacopoeia, there are very few quick wins. For people who have been involved in this work, it is often the case that advocacy does not consistently achieve its intended goal. Rarely are all comments submitted by a company accepted by the pharmacopoeia, to be reflected in the official requirements. A reasonable goal is to nudge the proposal in a meaningful way, hopefully influencing the major issues that have been identified, while accepting that minor issues may go unresolved. For their part, the pharmacopoeias must consider all comments received from stakeholders, who may have perspectives that are diverse and even contradictory. The pharmacopoeia authority balances this information to determine how best to proceed.

	Another aspect of advocacy is how a company reacts when comments are not accepted by the pharmacopoeia authority. The company can contact the appropriate scientific liaison at the pharmacopoeia to ensure the comments were clear and understood. Having established connections with the scientific staff in the pharmacopoeias can facilitate these discussions. Any unresolved issues that appear in the official revision can be the basis for the company to request a new revision to the general chapter or monograph, providing additional rationale or scientific data to support the requested change.

	The advocacy part of the compendial process can be very rewarding when comments are accepted by the pharmacopoeia authorities. It can be equally frustrating when sound scientific rationale may not be accepted, leaving a potential compliance gap for the company. It can be difficult to explain to company scientists and management that the comments were not accepted, and that procedures and documentation may need to be changed to reflect the official requirements. Another frustrating and challenging aspect of the compendial process may be encountered as a result of differing timelines followed by the pharmacopoeias to make harmonized requirements official, as has been seen with the updated chapters on residual solvents and elemental impurities to align with the corresponding International Council for Harmonization (ICH) guidelines. Still, advocacy is a critical part of the compendial process and can result in an official revision that is easier to implement than it would have been if comments had not been submitted.

. The ultimate goal of the industry surveillance process for monitoring pharmacopoeia revisions is to maintain ongoing compliance with current requirements, as expected by regulatory agencies around the world. The success of a company’s process can be measured by on-time implementation of official pharmacopoeia revisions.

	Implementing compendial updates is made more difficult by the large number of revisions that must be addressed, and the assessments needed by many SMEs and functional areas in the company. There are likely instances where a proposed or official revision that impacts the company may not have been identified, or the impact of the change has not been fully assessed by all stakeholders. Even if identified and assessed appropriately, there are times when the change control process is delayed, awaiting key decisions on implementation, as well as assessments by impacted areas, including manufacturing sites and regulatory affairs. Updates to product registrations and gaining approval from regulatory agencies around the world may take a long time due to the complexity of the work. In these situations, a manufacturing site may have to perform duplicate testing, using the old pharmacopoeia requirements and the new ones, managing appropriate compliance in the interim until everything is realigned.

	These situations are often noted by leadership as failures in the process, and while this may be a valid perspective, it does not reflect the majority of cases where these “misses” did not happen. Ideally, management expectations of the process will reflect this reality. In the authors’ experience, one measure of success for the compendial affairs function is “flying under the radar”, going unnoticed by management because everything is proceeding as expected and no compliance gaps emerge. All this success, however, may be forgotten when a potential compliance gap is found. At this point, the success of the process relates to how quickly and how well the company’s stakeholders can come together and address the gap. Sufficient resources are needed for these implementation activities, potentially including method comparability studies, to reach a suitable outcome in a short time while other routine work is also maintained by the functional areas. Learning from these situations can lead to continuous improvement in the surveillance process to minimize the likelihood of another such occurrence in the future.

	Details of the bio/pharmaceutical industry surveillance process have been provided to help address the compliance challenges resulting from pharmacopoeia revisions. The goal for an individual company is to establish an effective, efficient, sustainable, scalable, and successful process to accomplish the work. It is the people and tools that contribute to the effectiveness, efficiency, and sustainability of the process, and the benefits of advocacy activities are clear. The process can evolve over time, with more people and new tools added as resources are made available, which can also support the scalability of the process to add more pharmacopoeias or products to the overall monitoring. Consideration of all these details determines the ultimate success of the process.

	Recalling the fundamental principle stated in the first article of this series (4), compliance with official requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable. However, there is flexibility in how a company complies, and this will be explored in later articles. A future article will describe another advocacy opportunity: collaboration with the pharmacopoeias for the submission and development of monographs.

An effective surveillance program for monitoring the activities of pharmacopoeias around the world requires processes, people, and tools from across a company.

Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions

	Further discussion of global and national pharmacopoeias is useful in providing context for this series of articles. Differences are revealed between the pharmacopoeias designated as global, compared with those designated as national. These differences impact the surveillance and other processes used by the bio/pharmaceutical industry to ensure compliance with pharmacopoeia requirements. The definition for a national pharmacopoeia is straightforward and the understanding is facilitated by the historical context provided earlier in this series. The national pharmacopoeias were developed to support the health of the population in that country through consistent standards for medicines. The national pharmacopoeias in Japan, China, India, Brazil, Russia, and Korea are among those published around the world that must be considered for compliance in these specific countries.

	The definition for a global pharmacopoeia may not be as readily apparent and warrants further explanation. There are no specific literature or compendial references for the designation of a global pharmacopoeia. Rather, the definition is proposed by the authors, based on many years of practical experience dealing with the challenges of surveillance and compliance with pharmacopoeial requirements. Simply put, the designation as a global pharmacopoeia is based on the acceptance of the pharmacopoeia by regulators at a global level. In particular, the compendial standards published in the 

) are accepted by regulators in many countries around the world to help support global access to medicines. Confirmation is provided in 

 for more than 70 specific countries, based upon a regulatory intelligence database query.

			Table I. Regulatory acceptance of “global pharmacopoeias” in countries around the world.			

An understanding of global and national pharmacopoeias is crucial to understanding change processes and access to different markets.