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An effective surveillance program for monitoring the activities of pharmacopoeias around the world requires processes, people, and tools from across a company.
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.
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.
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, Figures 1–2). 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-European Pharmacopoeia (Ph. Eur.), British Pharmacopoeia (BP), and United States Pharmacopeia–National Formulary (USP–NF)-would be necessary, along with monitoring several of the important national pharmacopoeias, including the Japanese Pharmacopoeia (JP) and those in China, Russia, and India. For a smaller bio/pharmaceutical company focused on products in clinical development, surveillance of only Ph. Eur. and USP–NF may be sufficient to remain compliant.
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:
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 Table I.
Mid-West Compendial Discussion Group
Western Compendial Discussion Group
* 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,Figure 3).
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.
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.
Advocacy. 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.
Compliance. 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.
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. Sincere appreciation also goes to the compendial affairs group at Merck & Co., Inc. for valuable discussions over many years that helped shape the concepts and processes described in this article.
1. J.M. Wiggins and J.A. Albanese, “Revision Process for Global/National Pharmacopoeias,” BioPharm International Regulatory Sourcebook eBook, 26–Â39 (December 2019).
2. N. A. Schwarzwalder and R. H. Bishara, American Pharmaceutical Review 7 (4), 53-57 (Jul-Aug 2004).
3. J. M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Difficult,” BioPharm International Regulatory Sourcebook eBook, 26-34 (September 2019).
4. J.M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Necessary,” BioPharm International Regulatory Sourcebook eBook, 18–25 (September 2019).