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The process used to monitor and participate in pharmacopoeial changes is described.
Editor’s Note: Read related article, Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions.
The process used in the bio/pharmaceutical industry for surveillance of compendial changes (Figure 1) starts with publication of proposed changes by the pharmacopoeias and continues to the publication of official updates. The first steps of the industry surveillance process are the same for proposed and official revisions: monitor pharmacopoeia publications, filter for potential impact, and communicate the changes. Having an effective process for these initial steps is crucial to the ultimate success of complying with pharmacopoeia updates. The subsequent steps involve a deeper look into proposed changes to assess the impact and develop an implementation plan, followed by evaluation of the official changes and execution of the implementation plan. The process also provides opportunities to respond to proposed changes and submit revision requests for official changes, if needed.
Monitor pharmacopoeia publications. The compendial affairs function needs to have access to the publications it intends to monitor (i.e., new editions, supplements, and forum publications). For official editions and supplements to the global pharmacopoeias, this can be done mainly on-line by purchasing the appropriate licenses. For proposals in the global pharmacopoeia forum, access is available through free on-line website postings. Because the global pharmacopoeias are published in English, the compendial affairs function in many multi-national companies can review the table of contents (TOC) in the publications/website postings to identify relevant items. This work may be more difficult for companies where English is not the primary language. Many companies monitor and filter the items in the TOC when each publication is received; alternatively, this may be done on a monthly basis to capture revisions in all publications identified within that time frame.
National pharmacopoeias present challenges for the compendial affairs function due to less regular publication schedules and the fact that revisions may not be available in English. To successfully monitor these pharmacopoeias, the compendial affairs function needs a strong tie to the company’s local responsible group in that country, if available. This local group could reside in the quality, regulatory affairs, or other area, or in a local manufacturing site in that country. With well-defined roles and responsibilities, this local contact group (or in-country partner) monitors the local language pharmacopoeia publication or website to identify new items for review and impact assessment by the company. Once identified, the local group would determine the urgency for a complete and accurate translation into English, based on the time allowed for commenting on proposals or implementation of official changes. The roles and responsibilities are best defined in a cross-functional process with agreement between the partners and should be reviewed periodically to ensure it is working effectively.
Filter for potential impact. Reviewing the TOC in a pharmacopoeia publication represents the first in a series of “filters” through which changes are passed to determine if it applies to a company. To perform this filtering properly, the compendial affairs function must have a way to identify all excipients, APIs (procured or manufactured internally), and drug products across their entire supply chain. Gathering this information can be overwhelming and inefficient, as many business systems are not designed to provide this comprehensive “where-used list”. This information must be combined from several sources within a company, a time-consuming activity that is repeated each time the TOC filtering needs to occur, as the list needs to be current.
This list of materials and products is used to filter the TOC in the pharmacopoeia publication to identify individual monographs of interest to the company. One complicating factor is the nomenclature used by the pharmacopoeias and by a company for materials, with a single material potentially having multiple names. It is important to know how each material is named in a pharmacopoeia publication and how it may be named in your company’s systems (e.g., trade name, chemical name, or some other abbreviated name due to field-size limitations in the enterprise system, such as SAP). See the following examples:
Another complex task is identifying which general chapters in the pharmacopoeias apply to the company. Combined, there are over 2000 general chapters contained in the global and national pharmacopoeias that need to be considered. There is redundancy in several of the chapters across the many pharmacopoeias, but the compendial affairs function needs to identify the respective chapter in each. For example, the harmonized chapter for uniformity of dosage units appears as United States Pharmacopeia (USP) <905>, European Pharmacopoeia (Ph. Eur.) 2.9.40, and Japanese Pharmacopoeia (JP) 6.02, while the non-harmonized chapters for weight/mass variation and content uniformity appear as Ph. Eur. 2.9.5 and 2.9.6, Indian Pharmacopoeia (IP) 2.5.3 and 2.5.4, and Chinese Pharmacopoeia (ChP) 0101 and 0941. It is important to establish this list to filter the TOC for general chapters, so time and resources are only spent on further assessment of those items that impact your company.
The publication of a new general chapter requires a company to determine whether to add this to their TOC filter list. A company must also decide whether to monitor and comment on non-mandatory, informational chapters in the pharmacopoeia (e.g., chapters above <1000> in USP or above 9000 in ChP). There is an additional factor in considering these informational chapters: some of the “non-binding” information may be critical and should possibly be monitored and/or adopted, especially because the chapters may be referenced in other chapters that are mandatory, and regulatory agencies may decide to enforce certain aspects contained within the chapters, even though listed as informational. To minimize the risk of missing a general chapter with potential impact to the company, essentially all new and revised chapters in a pharmacopoeia publication may need further assessment.
Figure 2 depicts the filtering process used in monitoring pharmacopoeia revisions. A typical year may see the publication of 3000 or more total items that are new or revised in the global pharmacopoeias, which must be filtered. Using the lists of materials, products, and general chapters described previously, the compendial affairs function filters the TOC for each publication to identify items that may impact the company. For large multi-national companies, the initial TOC filter may identify approximately 500 items with potential impact. These constitute the set of items each year that may require change control when the items become official. Following the TOC filter, the compendial affairs group or another specified function in the company then carries out a deeper dive to further filter the identified items and determine if they have major impact to the company. Pharmacopoeia updates with the greatest potential impact include the following:
This determination of major impact can be accomplished in several ways, but it is often true that input from multiple groups is required, because of the potentially broad impact of pharmacopoeia updates. A company may have the subject matter expert (SME) for the topic (general chapter) or material (monograph) review the change. In some cases, a specified group of company SMEs may review all changes and assess the potential impact. For the company mentioned in the main article that held the Kaizen event, the improved procedure created a new team, called the “central triage team”, to meet on a regular (bi-weekly) basis and assess each individual compendial change published during that time period to determine those with the greatest potential impact. As suggested by the name, this team is comprised of representatives from central functions within the company, including: compendial affairs; quality control/assurance; external quality assurance; regulatory/chemistry, manufacturing, and controls; bio/analytical sciences; microbiology; and stability. For a large multi-national company, as many as 100 new or revised items per year may be identified in pharmacopoeia updates with potentially major impact. Whichever way the surveillance process is designed, this triage step to assess major impact is important because it will allow more resources to focus on these changes, reflecting the complexity and urgency needed. The remaining items identified-400 in this example (Figure 2)-will fall to the minor or no impact category and require further assessment to determine if they can be closed with minimal additional input from the business.
For national pharmacopoeias, as mentioned earlier, it is important to have a connection with the local contact group in that country. After the publication of a new edition or supplement (i.e., official changes), or forum (i.e., draft proposals for comments), the local group would perform the TOC filtering of items based on the drug products registered and distributed in that country. The list of affected materials or general chapters could be smaller than the global lists for the entire company. If there are products or formulations specific to that market, any unique excipient, API, or drug product monograph needs to be identified and added to the local filtering list. The determination of major impact for these items in the national pharmacopoeias can be accomplished by the local contact group or via the process established for items found in the global pharmacopoeia publications.
Communicate the changes. Once the specific materials and general chapters of interest to a company have been identified, an in-depth assessment is needed for the specific changes, with tasks assigned to the appropriate SME or business function. The notification of pharmacopoeia updates to a company’s impacted stakeholders may be provided individually, with each change sent to the specific SMEs for assessment, or as a compilation of all the changes identified in a particular pharmacopoeia publication or over an established time period. Some companies use both approaches-individual notification and a consolidated list-to ensure visibility and awareness for a wide range of stakeholders, and to increase the chances that all functional areas have an opportunity to consider the potential impact of the changes.
A key part of this communication is determining who in the company needs to receive the information, as well as what tool is used for notification and monitoring the tasks. The compendial affairs function needs to establish the list of SMEs to review/assess each new and revised item found during the filtering step of the process. This is not an easy task, because SMEs reside in multiple functions across a company (e.g., quality, regulatory, analytical, research and development, supply chain, packaging development, labeling, logistics for distribution, and external manufacturing). Once established, the list of SMEs needs to be maintained with updates to reflect turnover in personnel and changes in responsibilities for these areas. Maintaining the engagement and commitment of the SMEs is also challenging, but crucial to the success of the surveillance process. When the compendial affairs function requests assessment of pharmacopoeia updates by SMEs from the business units, a common response is, “it’s not my job,” among others that were touched upon in the second article of this series (1). Given the span of control where SMEs reside across the company, the understanding, commitment, and support by executive leadership and functional area management across the company is important in ensuring routine SME participation in this surveillance process to ensure compliance. The ongoing effort to keep all stakeholders involved and up to date with ever-changing pharmacopoeial requirements is quite a task and should not be underestimated in resource planning for the compendial affairs group.
Proposed changes: Evaluate, develop a response, and plan for implementation. Typically, for global pharmacopoeias as well as many of the national pharmacopoeias, new and revised requirements are first published as proposals, with an opportunity for public review and comment prior to becoming official. At the pharmacopoeia proposal stage in the industry surveillance process, two important actions are undertaken, usually in parallel, for items with potential impact to the company: develop a response to the proposal and plan for implementation of the changes (Figure 1). Submitting comments to pharmacopoeia proposals requires a company decision to pursue this proactive approach to the overall process. There are clear benefits in doing so, but the trade-off is the resources needed by the company to perform this work. Not every revision proposed by the pharmacopoeia requires a response; indeed, the vast majority do not. The assessment step in the surveillance process helps to identify the changes where a response may be beneficial. For these proposed changes, developing appropriate comments can require significant time and effort. This is particularly true, for example, when laboratory work is needed to evaluate a proposed change to an analytical method, or when data-mining of release and stability information is required to determine whether a company can comply with a proposed tightening of an impurity limit.
For the first action, when a response is needed, the compendial affairs function works with SMEs and impacted stakeholders to evaluate the change and prepare scientifically based comments to submit to the pharmacopoeia authority. In most companies, the compendial affairs function is responsible for this advocacy, aimed at influencing decisions about the official content that will be published in the pharmacopoeias. The compendial affairs advocacy may be associated with a company’s larger regulatory intelligence activities. Effective advocacy requires the compendial affairs function to clearly define what is needed from the SME assessment of a change and in what manner the information is provided back to the compendial affairs group (e.g., comments, suggestions, data). The compendial affairs function must let the SME know when the assessment is due, typically at least 14 days before the response is due to the pharmacopoeia. This allows the compendial affairs function to work through and follow up on internal comments received. It is important that SMEs understand that sound scientific rationale and data (where appropriate) are required to support a request for change to a proposed general chapter or monograph. It is not enough for a scientist to disagree with a statement or requirement without offering the reason for the objection, a suggestion for a change in the statement or requirement, and the appropriate rationale for the suggestion. To enable effective and appropriate commenting, it is recommended that the compendial affairs function develop a training program to help their SMEs in this work. Without this training, the compendial affairs group may spend significant time rewriting or interpreting the comments from SMEs prior to sending them to the pharmacopoeia authority. One possible outcome of the rewrite is that the original intent of the SME comments could be lost. After these internal comments have been received, potentially from multiple stakeholders, the compendial affairs function then shapes the information into a consistent, coherent, and hopefully compelling response that is provided to the pharmacopoeia agency before the established comment deadline. For commenting to the national pharmacopoeias, the connection to a company’s local contact group is essential so comments can be translated into the local language prior to submission. For countries such as China, where turn-around times for review and commenting can be short, this process and expected roles must be well-defined ahead of time to maximize the chances for the company to be successful in their advocacy.
At this stage in the surveillance process, a company has usually filtered and determined which proposed changes may have the greatest potential impact. These major changes often benefit from the effort required by a company to develop and submit comments in response to the proposal. For the remaining items identified with potential impact, an assessment serves to look further into the details of the change to determine whether there is minor impact or no impact to the company. It may be surprising, but true, that this deep dive into details is needed to make this final determination of impact. As illustrated in Figure 2, the remaining 400 items each year are assessed and filtered to find about 100 with minor impact, and the remaining 300 items with no impact. A simple example of a proposal with no impact is a change to a detail in an analytical procedure, when it is found on further assessment that the specific detail is not listed in testing standards or product registrations for the company. Another example is a change proposed by USP to the monograph for a pharmaceutical ingredient, when it is found upon assessment by the manufacturing site that the associated product is only marketed in Europe. It is helpful to also have confirmation from the regulatory group that USP requirements are not listed in the product registrations for that ingredient. It is worth noting that input from multiple functional areas across the company helps to increase the effectiveness of this deep dive to determine the impact of proposed pharmacopoeia revisions; one group usually does not have all the necessary information.
What has been achieved by the process at this stage? A company has been able to take a total of 3000 changes published per year by the global pharmacopoeias, and through a series of filters and further assessment, determine that only about 200 of these truly have impact. The effort needed to identify the revisions with impact is neither quick nor easy, but it is beneficial as it enables the company to then focus on the 100 major changes and the 100 minor changes to determine next steps to maintain ongoing compliance. For major changes, which typically have broad impact across the company, the impact assessment benefits from a “targeted compliance team,” ensuring input from all potentially impacted areas regarding the specific, targeted pharmacopoeial revision. This team is comprised of representatives from appropriate functional areas, including the supply-chain function and impacted manufacturing/stability sites, since no single group can identify the impact of a major change to every area in a company. The targeted compliance team has the responsibility to provide input on the proposed change to help in the development of a possible response to the pharmacopoeia, and equally important, to develop the company’s implementation plan for the specific compendial update being evaluated. Any lab work and data mining performed to support the company’s response to the pharmacopoeia is also valuable in the second action at this stage-determining the implementation plan for the proposed change. Each proposed revision with major impact to the company will affect different stakeholders to different degrees, and it may be questioned who has the decision rights for such a team. The answer is that decisions about the implementation plan must be made in the best interest of the company overall, with input from each area weighed in the determination, and the ultimate benefit to patients firmly in mind. For minor changes, a cross-functional team may not be required to develop the implementation plan, but a similar decision process can be used to determine how best to proceed.
It is important to understand that proposed changes must not be implemented, because they are not yet official. Though it may seem premature to begin planning for implementation at this stage, doing so increases the likelihood that the changes can be put in place by a company in the relatively short time between the subsequent publication and designated official date for the pharmacopoeia revisions. This is shown in Figure 3, which represents a typical timeline for a proposed revision to become official. Time zero is set as the publication of the proposal, with three months allowed by the pharmacopoeia for public review and comment. Once the comment deadline ends, the pharmacopoeia organization continues their process, leading to publication of the official change in a new edition or supplement. The minimum time taken by the pharmacopoeia to accomplish this is about nine months, although it often takes longer. Once the update is published in the new edition or supplement, six months is usually allowed for its implementation. Starting to develop the implementation plan at the proposal stage provides a minimum of 18 months to accomplish this important work and help maintain ongoing compliance, a full year longer than the six months available after the updates are published in the new edition or supplement. This extra time can be invaluable in making the necessary updates to a company’s procedures, documentation, and product registrations, especially for those changes that have been identified to have major impact.
The impact assessment for proposed pharmacopoeia updates enables effective planning for implementation if/when they become official. Most revisions proposed by the pharmacopoeia move forward from proposal to official without significant change from what was initially proposed. In the authors’ experience, 90% or more of proposed changes move forward 90% of the time with no major change to the proposal. If there are significant changes, as sometimes seen with proposals for new or significantly updated general chapters, the pharmacopoeia will typically publish another draft for review and comment before becoming official. Given this situation, the sooner a company can assess the impact of a pharmacopoeia revision (i.e., at the proposal stage), the better they are able to plan for a smooth implementation of the change, especially given the challenges associated with official change control processes in many companies. This evaluation also enables the submission of comments to the pharmacopoeia, when necessary, advocating in regard to changes that may be unacceptable or unachievable for the company.
Official changes: Evaluate and proceed with implementation. The pharmacopoeia process to introduce new and revised monographs and general chapters continues from the proposal stage to the subsequent publication of updated requirements that become official through new editions and supplements. The publication of these updated requirements triggers the final phase of the industry surveillance process. The specific steps performed by a company at this official stage are essentially the same as described for the proposal stage: monitor the publications, filter for impact, communicate, and evaluate the changes. The ultimate goal, however, shifts to focus on implementation. If the revision was previously evaluated at the proposal stage, a re-evaluation is performed by SMEs or responsible groups to identify changes that may have been introduced from the proposal to the official publication. Any changes from proposal to official are taken into account to adjust the implementation plan that was developed at the proposal stage; changes from proposal to official are also documented in the change control process to properly implement the official revision. The work then progresses to execution of the implementation plan, thereby providing compliance with the updated official pharmacopoeial requirements. If the pharmacopoeia revision was not previously evaluated when it was proposed, this is the first time a company will identify the update, and all the steps of the impact assessment detailed earlier in the process must be accomplished in the six-month timeframe typically allowed between publication of the new edition or supplement and the official date. The evaluation must now focus on what has changed from the previous official requirements, including how these are reflected in the company’s documentation, to the newly updated official requirements. Failure to accomplish all this activity on time, including any laboratory evaluation or data-mining, culminating in the completion of change control, results in a potential compliance gap for the company, which may be revealed upon inspection by regulatory agencies.
A change control process is challenging at best but is a critical part of the compendial process to ensure compliance with current pharmacopoeia requirements. The change control process ensures input from impacted stakeholders, including the quality and regulatory groups, which is especially important when the change will impact multiple sites, multiple products, and potentially hundreds of product registrations around the world. The timing necessary to submit registration updates and receive any needed approvals from the health authorities, potentially over a time horizon of many years, must be considered and managed properly during this interim period.
Although the functional organization and details of the overall surveillance process may vary from one company to the next, there are common elements among the approaches that are effective: having multiple SMEs assist in the assessment; starting at the proposal stage; providing responses to the pharmacopoeia; and planning for implementation of updated requirements. Even in the best compendial affairs programs, there are occasions when a company may have difficulty complying with some of the specific, updated official pharmacopoeial requirements. To address this situation, the last step of the industry process, when needed, is for a company to submit a request for revision to the pharmacopoeia authority, advocating for further revision of the general chapter or monograph that was just made official. This request may not be received favorably by the pharmacopoeia if the company did not provide any comments when the revision was first proposed. Similar considerations as those for developing a company’s response to a proposal also inform the development of a request for revision to an official update, complete with scientific rationale and data needed to support the requested change. This input from a company starts the entire pharmacopoeia revision process from the top, which again triggers the industry surveillance process. As noted before, pharmacopoeias continually evolve and given all the different viewpoints of the impacted stakeholders in a company, one can begin to get an appreciation of the challenges and complexity faced by all.
1. J. M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Difficult,” Pharmaceutical Technology Regulatory Sourcebook eBook, 36-42 (September 2019).