Why Pharmacopoeia Compliance Is Difficult–An End-to-End Compendial Framework

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For the bio/pharmaceutical industry, compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable. This article provides a comprehensive, end-to-end framework to help companies who discover, develop, manufacture, and/or distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products, to better understand the external and internal challenges that make pharmacopoeia compliance difficult. Understanding the challenges enables an exploration of the approaches that may be taken to help ensure ongoing compliance with pharmacopoeia requirements.

An end-to-end framework for pharmacopoeia compliance

The critical question that must be asked is: what is necessary for compendial compliance? The answer is provided in an article describing the bio/pharmaceutical industry’s pharmacopoeial surveillance process (1): a company must comply with current pharmacopoeia requirements. This was true when the article was written 15 years ago and is still true today. Ongoing compliance requires timely and effective monitoring of pharmacopoeia publications (including both proposed and official changes) and implementation of these changes in the impacted quality, regulatory, and site/functional area procedures and documents. While this represents the essential compliance perspective, it does not adequately capture the totality of work that is typically required for the compendial affairs function within a given bio/pharmaceutical company. A comprehensive view of these activities can be found through an end-to-end consideration of compendial affairs.

At a high level, the functions performed by individuals in the compendial affairs area typically include strategy, surveillance, and implementation within an overall framework of ongoing compliance with current pharmacopoeia requirements. Early strategy activities are aimed at proactive advocacy to better enable the final objective, which is on-time implementation and compliance within the impacted sites and functional areas that must meet the compendial requirements published by the pharmacopoeias when they become official. Between the strategy and implementation functions are the critical surveillance activities, which include review of new and revised compendial requirements, initially at the proposal stage and subsequently when they become official and enforceable. The work done during compendial surveillance provides an opportunity for advocacy; although in this case, it is in reaction to the proposed revisions. In the authors’ experience, the upstream, proactive advocacy is often more effective than the reactive, downstream advocacy in influencing the outcome of compendial changes. Surveillance also provides the ability to plan for implementation when the pharmacopoeia updates become official, which can be very beneficial to help ensure on-time compliance.

This high-level overview of compendial activities, however, does not convey the significant effort required to establish and maintain compliance with current compendial requirements. A comprehensive, detailed picture of this work is provided in Figure 1. With the ultimate and essential goal being compendial compliance, it is instructive to explore the details looking first at the final stages of the overall process.

Figure 1. Compendial end-to-end process. (Figure courtesy of the authors)

In the authors’ experience, the majority of compendial changes impact central or site testing standards that are used to ensure the quality of pharmaceutical products and their ingredients. Some compendial changes may also impact central or local procedures, including those in functional areas such as packaging, labeling, storage, distribution, and even research and development. These changes resulting from new or revised compendial requirements are usually implemented according to change control procedures established by the company. For quality document updates, revisions typically occur within a global change-management system, which is separate from compendial systems, although each system and process needs to provide visibility to the other to ensure no compliance gaps emerge. Change control should require the compendial revisions to be reviewed by all impacted stakeholders, and in particular those in regulatory/chemistry, manufacturing, and controls (CMC) functions who have visibility to the global registrations for the company’s product portfolio. Compendial changes represent only one type that are typically brought into the change control process, which also includes changes driven by regulatory and manufacturing process updates. Compendial changes often put additional strain on systems and processes that are utilized to implement the necessary revisions on time, given the complex supply and regulatory environment for bio/pharmaceutical companies.

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Upstream from the compliance function are the surveillance activities, which encompass the review of compendial updates at the proposed and official stage. Effective surveillance requires the appropriate processes, people, and tools to enable compliance. As shown in Figure 1, this work is based upon user-centric partnerships and teams to develop and execute implementation plans for ongoing compendial compliance. As mentioned earlier, the surveillance activities also provide an advocacy opportunity to respond and potentially influence the course of compendial revisions.

Further upstream are the strategy activities that help enable compliance through proactive engagement with the pharmacopoeias. This work includes the submission of new and revised monographs and chapters for consideration by the pharmacopoeias, as well as involvement with pharmaceutical industry associations that engage in constructive dialog with the pharmacopoeias. One recent advocacy development that has generated much interest is the elaboration of new compendial monographs and chapters that are prospectively harmonized from the beginning; an initiative that has been enabled by bilateral and multilateral agreements between pharmacopoeias, and supported by monographs that are contributed by bio/pharmaceutical companies. The work of prospective harmonization-which is mutually beneficial to the industry, pharmacopoeias, regulators, and ultimately to global patients-has resulted in the successful development of many new compendial standards that are globally acceptable and applicable and serves as a model for proactive partnership between the industry and pharmacopoeias.

There is another opportunity even further upstream to facilitate compliance, which could be considered the beginning of compendial activities within a company. This opportunity may be described as compendial line-of-sight (C-LOS), which is aimed at developing analytical methods and specifications for drug products and their ingredients that are right-first-time (RFT). At a practical level, this means giving visibility to groups involved in product and method development regarding the expectations and norms of pharmacopoeias, so this understanding can be incorporated at the appropriate stage in the product lifecycle and reflected in the global drug product registrations. For all the potential benefit and simplification that could be achieved through C-LOS, it must also be acknowledged that it has rarely been incorporated in the processes for drug development in bio/pharmaceutical companies, due to limited resources and competing priorities. The goal of C-LOS, however, provides a potentially useful approach to compendial compliance, so consideration of how to move in this direction should still be pursued. Fundamentally, early conversation and collaboration across a variety of functional areas is necessary, with appropriate processes and tools developed to make C-LOS possible and sustainable.

The overall compendial activities have long been carried out by multinational companies for changes published by the global pharmacopoeias, which may be defined as those that are acceptable to regulatory agencies well beyond the geographical boundaries covered by the pharmacopoeia. For example, regulators in many countries around the world accept compliance with the compendial standards published in the European Pharmacopoeia (Ph. Eur.), British Pharmacopoeia (BP), and United States Pharmacopeia–National Formulary (USP–NF). But the end-to-end description of compendial affairs activities is not complete without recognizing the need to also address compendial standards listed in national pharmacopoeias, which form the legal requirements in these individual countries and are important for ensuring access to medicines for patients in these markets. Among the 40 pharmacopoeias published around the world that must be considered in order to ensure compliance are those in Japan, China, India, Brazil, Russia, and Korea.

Given this end-to-end perspective, a company must ensure sufficient resources are available and organized within an appropriate functional area to enable and facilitate the specific work that must be performed by the individuals assigned to carry out these tasks. Cross-functional and cross-divisional processes, partnerships, tools, and training are needed to enable effective execution of the activities that ensure ongoing compendial compliance.

Challenges to pharmacopoeia compliance

The challenges that make pharmacopoeia compliance difficult (Table I) can best be examined through the end-to-end framework detailed previously to help address the impact of the pharmacopoeias. The standards published by pharmacopoeias affect the entire lifecycle of a product, and compendial compliance must be addressed from early development to late-phase clinical trials, continuing to commercial launch and beyond. There are differing regulatory expectations and processes around the world, which contribute to the challenges of pharmacopoeia compliance.

Once a drug product is licensed, a manufacturer must comply with their approved registration and with applicable monographs and associated general chapters, along with other applicable content in the pharmacopoeias. Compliance can be difficult if there are differences between the country-specific registrations and the applicable pharmacopoeias, in terms of the acceptance criteria or analytical approaches used to evaluate the material or product.

Overall

External

Internal

Typically, a company must comply with the tightest limits, whether listed in the pharmacopoeia or included in the product registration, to ensure compliance globally. Additionally, as stated in the pharmacopoeias, compendial requirements apply throughout shelf life for drug products and their ingredients, and these requirements must be incorporated in the company’s stability program. For example, the USP General Notices, Section 3.10 states (2): “The standards in the relevant monograph, general chapter(s), and General Notices apply at all times in the life of the article from production to expiration.” The BP General Notices, Part II state (3): “A formulated preparation must comply throughout its assigned shelf-life (period of validity). The subject of any other monograph must comply throughout its period of use.” Bio/pharmaceutical drug manufacturers and distributors, including innovator, generic, virtual, contract, and start-up companies need a strategy and a process to determine and document how they will ensure compliance with regulatory and pharmacopoeia requirements.

Pharmacopoeias and harmonization. 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. There has been considerable effort by the Pharmacopoeial Discussion Group (PDG)-which includes representation from the USP–NF, Ph. Eur., and the Japanese Pharmacopoeia (JP)-and further supported by the International Council for Harmonization (ICH) Q4B process to harmonize compendial requirements across these pharmacopoeias. This effort has yielded several general chapters and excipient monographs that contain essentially the same requirements. However, this output represents only a small fraction of the entire pharmacopoeia content and the harmonized standards have not been incorporated broadly across the many other pharmacopoeias in the world. Also, this harmonization work does not include monographs for drug substances and products, which are out of scope of both the PDG and ICH Q4B processes, so the pharmacopoeia requirements for the same material can vary greatly. There have been successful efforts to develop prospectively harmonized monographs for drug substances and products between the pharmacopoeias (e.g., USP, Ph. Eur., and BP), but results of this interaction are limited, and the true impact and value remain to be fully realized. Additionally, several important national pharmacopoeias were not included in the harmonization processes, which has created differences in the official general chapters and monograph requirements for excipients, drug substances, and drug products in the respective pharmacopoeial publications. This situation potentially hinders future harmonization efforts for these materials, because it is difficult to change existing standards, making a manufacturer’s compliance to all pharmacopoeias a truly daunting task. It is hoped that the pharmacopoeias around the world, with the support of the industry, continue their harmonization efforts to reduce or eliminate differences between their published standards, to the benefit of the global patient population.

Updated and new requirements. Another challenge is the significant volume of new and revised compendial requirements, including both proposed and official changes, that are published by pharmacopoeias around the world. Indeed, the number of individual compendial changes to monographs and general chapters can be staggering. In 2016, there were more than 3000 new or revised monographs and general chapters published in USP–NF, Ph. Eur., and BP alone, requiring review by bio/pharmaceutical manufacturers for potential impact. The following year saw a 20% increase in the number of individual compendial changes that were published by the pharmacopoeias. These individual changes needed to be filtered so a company could further evaluate only those that were pertinent to them. Experience has shown that it is typical to identify as many as 500 new and revised items per year that require further assessment by internal subject matter experts (SMEs) to determine whether the specific compendial update requires action by the company, including change control to quality documents and procedures, as well as potential updates to product registrations. Some companies have indicated the number of changes with potential impact to them is even higher, and the necessary change control and regulatory updates are both costly and time-consuming.

Physical reference standards. The monographs and general chapters published as documentary standards in the pharmacopoeias often include requirements to use physical reference standards to perform certain test procedures. Pharmacopoeias make these reference standards available for purchase and call for their use in the testing for excipients, drug substances, and drug products, impacting makers and users of these materials. There are also reference standards that may be required in compendial tests for specific impurities. The use of reference standards may be included in the tests for biological products, which raises potential issues due to the complex nature of these products. In all these cases, the appropriate use of compendial reference standards for pharmacopoeial testing represents another challenge to compliance throughout a product’s lifecycle. Companies must decide whether reference standards will be maintained by a central group or at many individual manufacturing and testing sites around the world. The material used by the pharmacopoeias to establish these compendial reference standards may have been provided by an innovator or generic-drug company, which may enter into compliance considerations. The USP, Ph. Eur., BP, JP, and other pharmacopoeias may each offer their own separate reference standard, with different assay or purity values assigned, which are to be used for testing according to their own monographs and general chapters, further increasing the complexity of compliance with the multiple pharmacopoeias.

Consideration must be given by a company as to how they will manage the expectations around these compendial reference standards, including whether and how to qualify any “in-house” primary or secondary reference standards against the official compendial reference standards to ensure compliance with the applicable testing procedures in the pharmacopoeias. The regulatory expectations regarding reference standard qualification was included in a presentation in 2011 (4), which pointed to the Compliance Program Guidance Manual for US FDA Staff–Drug Manufacturing Inspections, 7356.002. The following is noted in this manual, Part III–Inspectional, Section C–System Inspection Coverage, Laboratory Control System: “For each of the following, the firm should have written and approved procedures and documentation resulting therefrom … reference standards; source, purity and assay, and tests to establish equivalency to current official reference standards as appropriate” (5). The same 2011 presentation provided an example of the enforcement of this requirement, listing an FDA 483 observation given to a firm because they did not compare or qualify their working standard against the official USP reference standard.

Internal stakeholders. In addition to the challenges described previously, which are largely driven by external factors, there are several internal challenges that make pharmacopoeia compliance difficult to establish and maintain. There may be a lack of understanding within a bio/pharmaceutical company regarding the need for, the complexity of, and the challenges to compendial compliance, which may result in insufficient focus and resources allocated to this critical work. Even if there is understanding, there is often insufficient value attached to the work needed to achieve compendial compliance, resulting in potential de-prioritization of compendial activities when challenged with competing priorities. The need for and value of effective compendial processes to ensure compliance should now be clear, as should be the need to have appropriate tools for tracking and communicating new and revised pharmacopoeia requirements for impact assessment.

Establishing collaborative partnerships with internal stakeholders, who are essential in the compendial review process can be difficult, especially in large companies with a multitude of functional areas and manufacturing sites that may be impacted by compendial revisions. Maintaining these partnerships is complicated by potential transition and turnover of personnel involved in the work. There may be a lack of awareness of or disregard for the pharmacopoeia requirements and discrepancies may emerge from the absence of a C-LOS perspective during product and analytical development. There is often a lack of understanding by internal stakeholders as to their role in the assessment of compendial revisions, and many may have the perspective of “not my job” when asked to provide input to the impact of compendial changes.

Taken together, compliance with the pharmacopoeias is usually not well understood in a company, so it can be difficult gaining buy in from SMEs and their managers to perform impact assessments. Deadlines for commenting on proposals and implementing changes that are becoming official are often not well understood. The requests for review, assessment, and implementation of compendial requirements may not receive the proper priority or urgency needed to ensure compliance. It is not uncommon to hear stakeholders remark:

• “Why do we need to comply? We are the innovator company.”

• “Why do we need to comply? We have our approved registration.”

• “It’s not my job. Check with another department to ensure we comply.”

• “Are you serious? This applies to stability testing also?”

• “I am in R&D. Why is this applicable to me?”

• “Is this really necessary?”

Management engagement and support are essential to remove the roadblocks resulting from lack of understanding. Clarity must be provided to highlight the need for compliance and to ensure the appropriate importance and urgency are given to meet deadlines imposed by the pharmacopoeias. It is important to enlist both regulatory and quality departments to aid in the effort to gain support from the overall organization.

Another area that creates confusion for companies is that many consider pharmacopoeia publications only as quality standards that are focused on analytical, physical, and microbiological test methodologies and their associated acceptance criteria for materials. However, as noted previously, there are several general chapters related to packaging, storage, distribution, labeling, and quality systems that require assessment by appropriate SMEs in an organization. It can be a challenge to engage and gain buy-in from the departments that support these other functional areas as well. Additionally, companies that manufacture combination products must deal with general chapters related to medical devices that are being published by
many pharmacopoeias.

Change control. It is instructive to return to the issue of change control and on-time implementation as they relate to pharmacopoeia compliance. One of the most difficult issues with maintaining compliance is the use of change control to implement new and revised items in the pharmacopoeias that will become official on a specified date. Compendial revisions can be complex, and the short time available from the publication of new and revised official changes to the date when companies must comply with the updated requirements is often not sufficient to fully and effectively implement the changes. Examples of complex changes are the ICH Q3C and Q3D guidance on residual solvents and elemental impurities, with the associated updates to the relevant general chapters in the pharmacopoeias.

For bio/pharmaceutical companies, it is expected that these changes are communicated and properly assessed by internal stakeholders in the impacted organizations before they are implemented. For a company that may manufacture the material at multiple locations with different registrations in countries around the world for that product, implementing changes that result from new and revised monographs for a drug substance or product can grind the processes to a halt. It is important to recognize this issue and to ensure management understands the need to use change control, as well as the amount of time that may be necessary to receive the proper assessments from all stakeholders.

Typically, several meetings with multiple departments (e.g., regulatory affairs, quality, analytical technical support, stability) are needed to clarify all potential impact and to ensure this is properly documented in the change control. After the change control is approved, there is a need to have someone responsible to ensure the actions are completed by the official date. However, the ability to meet the official date can be compromised if updates to multiple national filings are required, causing implementation for a specific market to extend past the official date indicated by the pharmacopoeia. This difficulty with on-time compliance then becomes a regulatory and quality inspection risk. A company’s strategy should be documented in the change control indicating how the material will be released during this change transition (e.g., duplicate testing until country approvals are received, or release after notification to the appropriate health authority). It is critical that the quality control, quality assurance, and regulatory groups are aware of and agree with the strategy.

Conclusion

In previous articles in this series, the basis for compendial compliance expectations was provided, along with a comprehensive, end-to-end framework to better understand the external and internal challenges faced by the bio/pharmaceutical industry in trying to meet pharmacopoeia requirements. The next articles in the series will explore the history of the many pharmacopoeias around the world and the need for harmonization, to establish consistent, global pharmacopoeia standards. Subsequent articles will address the creation of effective compendial processes, including that for review of pharmacopoeia updates, to help the industry meet health authority expectations to comply with pharmacopoeia requirements, and deliver quality medicines that extend and improve the lives of patients worldwide.

Acknowledgment

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.

References

1. N. A. Schwarzwalder and R. H. Bishara, American Pharmaceutical Review 7 (4), pp. 53-57 (Jul-Aug 2004).
2. USP, General Notices and Requirements, pp. 3-12, USP 41-NF 36 (2018) (published by The United States Pharmacopeial Convention, 2017).
3. BP, British Pharmacopoeia, General Notices, Part II, pp. I-4 - I-19 (published by The Stationery Office on behalf of the Medicines and Healthcare Products Regulatory Agency (MHRA), 2017).
4. M. Borer, “Pharmaceutical Reference Standards: Overview and Role in Global Harmonization,” Presentation at 3rd DIA China Annual Meeting, Beijing, China (May 16-18, 2011).
5. FDA, Drug Manufacturing Inspections, Compliance Program Guidance Manual–Drugs (CDER), Chapter 56: Drug Quality Assurance, Program No. 7356.002 (Implementation Date October 31, 2017).