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

Joseph A. Albanese

This series of articles continues to take a thorough look at compendial activities that impact the bio/pharmaceutical industry to help ensure compliance with requirements published by the pharmacopoeias. In these articles, the term “bio/pharmaceutical” should be considered in the broadest sense and includes innovator, generic, virtual, and start-up 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. One aspect of the history of the pharmacopoeias should be apparent; there is a long-standing tradition of evaluating existing, divergent drug standards and establishing instead a unified system that supports patient access to medicines with consistent quality. This is true whether the divergent standards existed at the city-level, as were addressed through the creation of the country-specific 

), or if the existing standards were at the state-level, as were addressed through the creation of the 

). This is also true at a regional level, as in the creation of the 

), which established harmonized standards for medicines in Europe where individual country-specific standards had previously existed. And this is true in the initial intention of the 

) to develop a unified pharmacopoeia that could be used around the world.

	In this context, it may be suggested that harmonization is embedded in the development and history of the pharmacopoeias. However, the pharmacopoeias are themselves embedded within the current regulatory and legal framework of the country or region in which they are applicable. The intersection of the pharmacopoeias and regulatory agencies impacts the direction and approaches taken to move toward harmonization at a global level. Pharmacopoeia harmonization provides better support for global regulatory agencies and addresses the global nature of bio/pharmaceutical manufacturing and supply, which ultimately benefits global patients who rely on these medicines to extend and improve their lives. This article provides some industry perspective on the need to harmonize compendial standards, which may be helpful in considering the future direction of pharmacopoeias. These considerations are important because the sheer number of pharmacopoeias and the current lack of broad harmonization add complexity to a company’s processes for compendial monitoring and compliance.

	The history of pharmacopoeias since the earliest times has reflected the goal of creating consistent standards for medicines that are used by those who need them. The process of achieving these consistent standards may be described as standardization, harmonization, or any of a number of other words that have a similar meaning. Before delving into some of the ongoing activities to achieve consistent compendial standards in today’s global environment for medicines, it is prudent to first address potential concerns with the term “harmonization” itself. Recent discussion has suggested that it may be preferable to shift from using the word “harmonization” to instead use “convergence” in the context of pharmacopoeias. There is perhaps some merit in this suggestion, as it might also be perceived as embodying a regulatory dimension of compendial interchangeability, which is essential to the ultimate goal of consistent requirements for medicines. However, it may also be suggested that the terms “harmonization” and “convergence” in fact have similar meanings. One definition of “harmonization” is the “process and/or results of adjusting differences or inconsistencies to bring significant features into agreement” (1). The term “convergence” means “moving toward union or uniformity” (2).

	It should be noted in regard to pharmacopoeias that “harmonization” or “convergence” do not necessarily mean “unison” or “identical”. Although the availability of completely “identical” compendial standards might be a desired goal to overcome the challenges of non-harmonized standards in the pharmacopoeias, it should be recognized that “identical” standards are probably not achievable for a number of practical reasons. Fundamentally, the standards published in the pharmacopoeias must be available in the languages needed by their users, regardless of the country. Compendial standards that are equivalent or interchangeable in a practical or functional way should be the goal. Any level of harmonization is beneficial and moves in the right direction to help provide medicines with consistent quality to patients around the world.

	To further enable the development of consistent standards for medicines, it is proposed to shift the focus away from the process (i.e., harmonization or convergence) and instead emphasize the intended outcome: global pharmacopoeia standards. Details about ongoing activities to achieve global pharmacopoeia standards will be provided later, but first, it is appropriate to ask why this goal is important.

	The need for global pharmacopoeia standards: Making the case

	The challenge of compliance with the separate, often divergent compendial requirements contained in the various pharmacopoeias around the world provides a strong argument to support the need for global pharmacopoeia standards. The benefits seem obvious in having global pharmacopoeia standards to ensure consistent quality of medicines. Manufacturing and supply-chains for the bio/pharmaceutical industry today are global. There is benefit to the industry in having consistent standards with which to comply. There is benefit to regulators who can review drug applications and inspect pharmaceutical facilities anywhere, without the complication of divergent pharmacopoeia standards. Most importantly, the patient population today is global. Ultimately, there is benefit to patients located around the world who can receive medicines with the same quality, evaluated against consistent specifications included in all the pharmacopoeias, regardless of where the product or its ingredients were manufactured.

	Compliance with differing quality standards across the many pharmacopoeias has long been a challenge to be addressed by the bio/pharmaceutical industry. The value and benefits of global pharmacopoeia standards to industry and patients have been noted by the different pharmacopoeia organizations. USP has written, “Harmonization reduces manufacturers’ burden of having to perform analytical procedures in different ways, using different acceptance criteria, in order to satisfy pharmacopoeial requirements that vary across regions” (3). The 

 notes the practical consideration of international trade as it relates to the availability of medicines. “Globalisation and expansion in international trade present a growing need to develop global quality standards for medicines” (4). For medicines, the standardized test methods and specifications in the pharmacopoeias must “ensure consistent product quality, regardless of its source … especially in view of the shift of API production from Europe and the [United States] US to India and China” (5). It is also noted that a “harmonized regulatory system, with mutual recognition of assessment/decision-making by licensing authorities and inspectors, including globally harmonized pharmacopoeias, would be beneficial in several ways” (5). Pharmacopoeias can “also play an important role in protecting patients from some of the downsides of globalization, namely adulteration and counterfeiting of medicines,” however the “prevention of drug adulteration or counterfeiting is not achievable by a pharmacopoeia or any other stakeholder alone” (5). Still, it seems evident that global pharmacopoeia standards could help in this objective, providing consistent standards of quality for medicines to support patients around the world, whereas divergent compendial standards only serve to complicate the situation.

	Ideal pharmacopoeia and compendial globalization–an industry perspective

	The bio/pharmaceutical industry has itself been discussing the benefits of “harmonization” in today’s global pharmacopoeia environment. The purpose and role of the pharmacopoeias and the global picture were described in previous articles in this series. There are as many as 40 pharmacopoeias published by authorities around the world. The pharmacopoeias were established and evolved to ensure the quality of medicines and their ingredients for patients in a country or region. Today’s global patient population was not necessarily part of the overall consideration for the pharmacopoeias, especially early in their development. As a result, the standards contained in the various pharmacopoeias were not generally aligned, creating a challenge for the industry to comply with all the applicable requirements. Having struggled with the challenge of differing compendial standards for many years, discussion was initiated between pharmaceutical industry representatives from the Pharmaceutical Research and Manufacturers of America (PhRMA) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) to explore what might be described as the “ideal” pharmacopoeia. The result of these discussions was a position paper, published in 2008, that presents this industry perspective (6). The paper stated that the ideal pharmacopoeia would provide appropriate standardization to facilitate drug registration and support regulatory agencies through a single, global
	compendial standard.

	Considering each of these points in turn, appropriate standardization means the pharmacopoeia would focus on the specific content that provides the greatest value to the bio/pharmaceutical industry for the quality control of drugs. Facilitating drug registration would be achieved by simplifying the preparation (by industry) and assessment (by regulators) of drug applications using reference to a common standard for generally accepted quality parameters for pharmaceutical products and ingredients. Alignment between the pharmacopoeias and regulators is essential, so the ideal pharmacopoeia would include standards that are consistent with the needs and expectations of regulatory authorities. Most importantly, the ideal pharmacopoeia would provide a single compendial standard that could be used worldwide. The industry perspective on the ideal pharmacopoeia provides a model for the future: a long-term goal that could achieve harmonization of compendial standards, further enhancing the role of the pharmacopoeias to support and promote global public health through safe and effective medicines with appropriate quality to benefit patients around the world.

	Another article from industry describes compendial globalization and achieving harmonization through standardized practices and collaboration among the pharmacopoeias and health authorities (7). This article discusses the need for “consistent and appropriate quality requirements for medicines because disharmonized standards do not provide additional value or benefit, but rather increase the cost and complexity of bringing medicines to patients worldwide.” The approach to harmonization described as compendial globalization “provides a basis for the pharmacopoeias to work together in new ways with consistent processes coupled with sharing of information and work.” The three principles that support compendial globalization are:

		Standardized pharmacopoeial practices, which establish a consistent approach for the pharmacopoeias to elaborate compendial standards

		Pharmacopoeial collaboration, which enhances the cooperation among the pharmacopoeias to enable the development, sharing, and adoption of harmonized compendial standards

		Regulatory acceptance, which ensures the participation and agreement by regulatory authorities with the harmonized processes and outcomes in those countries where the pharmacopoeia standards apply.

	The pharmacopoeias and regulators around the world, in collaboration with their stakeholders, have been actively and successfully working toward the goal of harmonization for quite some time. These ongoing harmonization efforts are supported and encouraged by the bio/pharmaceutical industry.

	The principles of the ideal pharmacopoeia and compendial globalization reflect industry’s support for and alignment with pharmacopoeia initiatives that move toward harmonization. Industry’s view of an aspirational goal for harmonization to achieve global pharmacopoeia standards was presented at a joint workshop held between the European Directorate for the Quality of Medicines and HealthCare (EDQM/

) in 2016. Invited remarks were provided on behalf of EFPIA, the trade association representing the research-based pharmaceutical industry in Europe, and whose members supply many important medicines that contribute to the health of patients in Europe, China, and around the world. In these remarks (8), it was noted that the pharmacopoeias and industry share a common goal, which is to ensure the availability of medicines for people around the world. The pharmacopoeia’s core mission is protecting public health by creating public standards to help ensure the quality of medicines. The bio/pharmaceutical industry’s mission is to provide medicines that extend and improve the lives of patients around the world, medicines with consistent quality, complying with the applicable regulatory and pharmacopoeia requirements.

	When the standards published by the pharmacopoeias are not aligned, the differences increase the cost and complexity of compliance, potentially hindering the export and import of products between countries and creating uncertainty in the supply of medicines to the patients who need them. There are important initiatives underway to bring more consistency between pharmacopoeia standards, including retrospective and prospective harmonization, the World Health Organization’s (WHO’s) 

(9), and greater collaboration among the pharmacopoeias. Attendees at the joint workshop were asked to imagine consistent standards published by the pharmacopoeias in the languages needed by their stakeholders … to imagine a global pharmaceutical industry that can ensure compliance with these standards, because they contain consistent requirements … and to imagine regulators who can use these globally consistent pharmacopoeia standards to help ensure the quality of medicines.

	Ultimately, attendees were asked to imagine the patients around the world who would be able to receive medicines with consistent quality, wherever the medicines are manufactured. To imagine this world, where there is no need for translation, because the pharmacopoeias are saying the same thing. How do we get there? Pharmacopeias and stakeholders get there through retrospective, prospective, and informal harmonization to achieve global pharmacopoeia standards, through implementation of WHO’s 

, and through ongoing collaboration. Continued progress toward this goal is in the interest of global patients and society as a whole.

	Global pharmacopoeia standards would help to support the availability of medicines with consistent quality for patients around the world. There are many pathways to achieve compendial harmonization, and several approaches are currently underway. Industry’s perspective on the ideal pharmacopoeia and approaches to achieve compendial globalization support these ongoing harmonization activities. Subsequent articles in this series will describe how the industry still faces challenges in complying with compendial standards, whether those standards are harmonized or not

	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.


	3. USP, “Pharmacopeial Discussion Group (PDG),” 

 34 (4), pp. 120-121 (April 2010).
	6. J. M. Wiggins, J. A. Skutnik, J. L. Shimek-Cox, and N. A. Schwarzwalder, 

 32 (11), pp. 122-125 (November 2008).
	7. J. M. Wiggins and H. D. Schneider, Jr., 

36 (4), pp. 94-101 (April 2012).
	8. J. M. Wiggins, “Importance of Pharmacopoeia Standards: Their Added Value for Stakeholders,” Remarks provided on behalf of the European Federation of Pharmaceutical Industries and Associations (EFPIA) at the Workshop “The Chinese and European Pharmacopoeias–The New Editions,” Strasbourg, France, October 17, 2016.
	9. WHO, 

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

Articles

Pharmacopoeia harmonization provides better support for global regulatory agencies and addresses the global nature of bio/pharmaceutical manufacturing and supply.

Global Pharmacopoeia Standards: Why Harmonization is Needed

The pharmacopoeias and regulatory agencies around the world, in collaboration with their stakeholders, have been actively and successfully working toward the goal of compendial harmonization for quite some time. The following takes a closer look at these ongoing efforts to harmonize compendial standards, with perspective that may be helpful in considering the future direction of pharmacopoeias.

	One of the long-standing activities focused on harmonization of compendial requirements is that of the Pharmacopoeial Discussion Group (PDG), which comprises the 

). Each of the participating pharmacopoeias has information on their website regarding PDG (see 

), and the following summary highlights some key aspects of this work.

	PDG was formed in 1989 with representatives from the European Directorate for the Quality of Medicines & HealthCare (EDQM/

), the Ministry of Health, Labour, and Welfare (MHLW/

), and the United States Pharmacopeial Convention (USP), with the World Health Organization (WHO) joining as an observer in 2001. During its 30-year history, PDG has met on a regular basis to advance harmonization work in Europe, Japan, and the United States, focusing on selected excipient monographs and general chapters in the pharmacopoeias. To date, harmonization work has been completed on 28 of the 31 general chapters and 46 of the 60 excipient monographs on the current PDG work program. These harmonized compendial standards are an important achievement and reflect the long-term commitment by the PDG partners to establish consistent standards for use in these three major regions of the world. But it can also be argued that the process has taken too long to reach the established goals. Indeed, retrospective harmonization of existing compendial standards is challenging and complex. Recognizing the concern over timely progress, PDG has recently streamlined their work structure, eliminating two stages of the harmonization process (

), with the objective of trying to achieve harmonized outcomes more quickly.

. Pharmacopeial Discussion Group (PDG) revised working procedure: 5-stage approach for harmonization (1). (Figure courtesy of the authors)

					Upon PDG approval to add the revision to the workplan, the coordinating pharmacopoeia (CP) prepares and forwards the Stage 1 draft and supporting data to PDG for pharmacopoeial expert committee review/comment. The CP reviews comments received and, if all three pharmacopoeias agree, the proposed harmonized draft document moves forward for public comment/inquiry.

					The Stage 2 draft and commentary are published in the respective forum of each pharmacopoeia. Each pharmacopoeia analyzes comments received during the public comment/inquiry stage and submits its consolidated comments to the CP for review. If appropriate, the CP prepares a draft harmonized document (Stage 3A) and commentary, which are sent to the other two PDG pharmacopoeias.

					The Stage 3A draft is reviewed and commented on by the other pharmacopoeias. Any remaining differences are resolved, or they are assigned as non-harmonized attributes or local requirements. When agreement is reached, a Stage 3B draft is sent by CP to the other pharmacopoeias for final confirmation and sign-off.

Stage 4: Regional adoption and implementation

					Stage 4 takes place individually according to the procedures established by each pharmacopoeia. The harmonized document is submitted for adoption by the responsible pharmacopoeia organization. Each pharmacopoeia incorporates the harmonized content according to its own procedure and informs each other of the date of implementation, which may vary in the three PDG regions depending on their legal requirements, need of translation, and publication schedules. Each pharmacopoeia indicates the harmonization status according to their policy, with any residual differences indicated by specific symbols (black diamonds indicate non-harmonized attributes, white diamonds indicate local requirements).

					For chapters evaluated by ICH Q4B for regulatory interchangeability, a topic-specific annex is processed for publishing and implementation by each regional authority.

					The PDG pharmacopoeias have agreed not to revise unilaterally any harmonized document after sign-off or after publication. Revisions with appropriate justification will follow the PDG working procedure described above, with revisions of a sign-off document indicated as Revision 1, 2, 3, etc. An expedited procedure may be applied in certain circumstances, resulting in a revision reverting to Stage 3A as opposed to Stage 1.

					Any pharmacopoeia which has identified an error in a sign-off text may submit a request for correction to PDG together with appropriate justification.

	PDG has provided a practical definition of harmonization; a pharmacopoeial monograph or general chapter is harmonized when a pharmaceutical substance or product tested by the document’s harmonized procedure yields the same results and the same accept/reject decision is reached. When full harmonization cannot be achieved through PDG discussions, an approach termed “harmonization by attribute” is pursued, in which some elements of the monograph or general chapter are harmonized, but others are not. This situation occurs when there is lack of full agreement between the PDG partners as to the specific tests, methods, or acceptance criteria needed in the monograph for a particular excipient or the specific details contained in a general chapter. With harmonization by attribute, interchangeability of the compendial requirements is achieved only with respect to the harmonized elements, while compliance with the individual non-harmonized pharmacopoeial requirements in each region is necessary. The PDG pharmacopoeias have agreed not to revise unilaterally any harmonized document after publication, while revisions for appropriate reason may be pursued through discussion among the members of PDG according to their established working procedures.

	The accomplishments and commitment by PDG to achieve consistent pharmacopoeia standards in the 

 are to be recognized and commended. Any amount and degree of harmonization is good and moves in the desired direction of global pharmacopoeia standards. The challenge remains how to expand the harmonization outcomes, recognizing the scope of the PDG activities is somewhat limited. The focus of PDG harmonization is on excipient monographs and general chapters, but their current work program includes only a fraction of the total number of excipient monographs and general chapters in the pharmacopoeias. The PDG activities do not include harmonization of monographs for drug products or APIs. The pharmacopoeias participating in the PDG work represent three major regions of the world, and the standards are accepted in many countries outside the geographical boundaries of these countries and regions, but there are many other important pharmacopoeias and regions that are not part of this harmonization work, so global applicability has not been achieved. And the specific harmonization outcomes are not always fully aligned, as mentioned in the context of harmonization by attribute. All these limitations in the PDG work have led to additional harmonization activities to support and supplement the overall goal of global pharmacopoeia standards.

	International Council  for Harmonization

	The International Council for Harmonization (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration (2). Since its inception in 1990, ICH has gradually evolved, to respond to the increasingly global face of drug development. ICH’s mission is to achieve greater harmonization worldwide to ensure that safe, effective, and quality medicines are developed and registered in the most resource-efficient manner. Harmonization is achieved through the development of ICH guidelines in four categories-quality, safety, efficacy, and multidisciplinary-through a process of scientific consensus with regulatory and industry experts working side-by-side. Initially, ICH included six members: representatives from the regulatory agencies and industry associations of Europe, Japan, and the US. In continuing to address the larger global situation for medicines, ICH has expanded to include seven additional regulatory members and three additional industry members, as well as more than 30 observers, including WHO.

-the pharmacopoeias that form the PDG-are either members or observers to the ICH process. However, the connection between harmonization activities carried out by PDG and ICH is perhaps not well understood and warrants further discussion. As detailed above, PDG develops harmonized compendial standards for some excipients and general chapters, engaging with their stakeholders, including industry, through established procedures of notification, review, and comment for each of the pharmacopoeias. The scope of harmonization by PDG is limited; the scope of pharmacopoeia harmonization by ICH is even more limited. For ICH, the areas of major focus are the processes for drug development and registration, with industry and regulators as the working partners. In the development of the ICH Q6A and Q6B guidelines for establishing specifications for new drug substances and new drug products, including both chemical and biological products, it was recognized that harmonization of 11 specific compendial test chapters was essential to obtain full utility of the guidelines. In section 2.8 of the ICH Q6A guideline, there is specific reference to the pharmacopoeias and the work of the PDG; it is stated that pharmacopoeial procedures should be used wherever they are appropriate. This intersection of the ICH guidelines and the pharmacopoeia chapters, which were undergoing harmonization by PDG, created a formal connection between the two initiatives, resulting in the ICH Q4 topics (3). On the ICH website, there is a brief note regarding ICH Q4, which can be paraphrased as follows: ICH will trust the PDG process to achieve pharmacopoeia harmonization for the 11 compendial chapters. Perhaps due to the slow pace of the PDG harmonization work, ICH added a follow-on Q4A topic. On the ICH website, the brief note regarding Q4A goes a bit further that that provided for Q4, to state that ICH will receive progress reports from PDG on the pharmacopoeia harmonization work. Unlike other ICH topics, there are no specific guidelines associated with either ICH Q4 or Q4A.

	Q4B working group examines interchangeability

	Recognizing the imperfect outcomes reflected in PDG’s harmonization by attribute, in 2003, industry requested that ICH establish the Q4B Expert Working Group (EWG) to address how regulatory authorities in the ICH regions would recognize the interchangeability of the PDG harmonized pharmacopoeial chapters in the 

 (4). The resulting ICH Q4B guideline, titled “Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions”, was finalized in 2007 and describes a process for the EWG to develop topic-specific annexes with information about the PDG harmonized chapters and their implementation (the Q4B Outcomes) to avoid redundant testing by industry (5). The initial scope for the Q4B EWG was the 11 specific compendial chapters needed to facilitate use of the Q6A and Q6B guidelines, but this was expanded to result in 16 topic-specific annexes. These annexes cover a wide range of pharmacopoeia general chapters, including Residue on Ignition/Sulphated Ash, Disintegration, Dissolution, Uniformity of Dosage Units, Extractable Volume of Parenteral Preparations, Microbiological Examination of Non-Sterile Products, Sterility, and Capillary Electrophoresis. Each of the annexes provides the Q4B Outcome regarding interchangeability of the harmonized compendial test chapters, along with the conditions, considerations, and timelines to assist in the implementation and use of the referenced pharmacopoeial text
	by stakeholders.

	The conditions included in the Q4B annexes address point-by-point the residual differences between the 

 texts following the completion of the PDG harmonization activities, thereby enabling the use of any of the referenced pharmacopoeia chapters as interchangeable in the ICH regions. The need to include conditions is based on the degree to which the harmonized chapters in each of the three pharmacopoeias differ from one another. For example, in the Q4B annex for the Dissolution test chapters, which contain several non-harmonized attributes, the ICH topic-specific annex contains eight conditions that must be addressed in a product registration in order for the compendial chapters to be considered interchangeable. By contrast, the ICH Q4B annex on Capillary Electrophoresis declares that each of the referenced compendial chapters in 

P are interchangeable without any conditions, a situation made possible because the compendial chapter on Capillary Electrophoresis was developed through “prospective harmonization” of the PDG pharmacopoeias. “Interchangeable” is defined in the Q4B guideline to mean that any of the official texts from 

 can be substituted one for the other (appropriately referenced) for purposes of the pharmaceutical registration/approval process with the understanding that an analyst using any of the interchangeable methods will reach the same accept/reject decision irrespective of which PDG pharmacopoeia is used.

	In 2010, after finalizing the 16 annexes, ICH disbanded the Q4B EWG as it was concluded that essentially all chapters within its scope were completed. In the Q4B guideline (5), it was recognized that subsequent changes to the harmonized compendial chapters might occur, which could impact the annexes. The guideline states that ICH should be notified of any future revisions to chapters that had been assessed by the Q4B EWG. In 2018, PDG proposed that they assume responsibility for carrying out any necessary assessment and revision of Q4B annexes as a result of changes made to the harmonized chapters (6). This proposal was accepted by ICH, continuing the important collaboration and intersection between the ICH and PDG harmonization initiatives and among the representatives of the regulatory agencies, industry, and pharmacopoeias.

	The ICH Q4/4A/4B topics are not the only connection between ICH and the pharmacopoeias; the Q3 topics on impurities represent another area where the harmonization activities overlap. Most recently, the development of the ICH Q3D guideline on control of elemental impurities in drug products was completed. This guideline addressed a long-standing issue associated with the pharmacopoeia test for heavy metals in pharmaceutical products and ingredients, while expanding on regulatory guidance from Europe that established limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical substances or drug products. With the publication of the Q3D guideline, the PDG began the process of adopting the new requirements, while moving to eliminate the historical chapters on heavy metals, which employed wet-chemical techniques that were non-specific limit tests to control some metal impurities. While the transition from heavy metals to elemental impurities through the pharmacopoeias and ICH Q3D improves the control of inorganic impurities in drug products, the situation has posed a challenge for industry. How can non-ICH countries be moved toward adopting the ICH guideline, given that the old heavy metals test is being eliminated from several pharmacopoeias? The picture is complicated by the uncertain acceptance of the harmonized requirements by other regulatory agencies and pharmacopoeias around the world; not everyone is moving at the same pace for implementation.

	The Q3C topic on residual solvents represents a similar connection between ICH guidelines and the related pharmacopoeia general chapters for control of these impurities. The Q3A and Q3B guidelines, which establish threshold limits for organic impurities in new drug substances and products also represent an area of overlap with the pharmacopoeias, which control impurities through specific requirements in monographs for drug products and ingredients. The 

 in particular has taken a pro-active approach in adopting the concepts of the ICH Q3A/B guidelines, with general chapters and monographs that help ensure control of identified and unidentified impurities and set limits for both specified and unspecified impurities. Each of the ICH Q3A/B/C/D guidelines has strengthened the connection between the regulatory agencies and pharmacopoeias in the ICH regions, to the benefit of industry through consistent quality standards, and ultimately to patients through consistent quality products.

	With the successful interaction between ICH and PDG, it may be asked whether ICH could be leveraged to expand compendial harmonization to achieve global pharmacopoeia standards and regulatory acceptance, further facilitating the development and registration of drug products around the world. It does not appear, however, that the current ICH work program could pursue this opportunity, being filled with other important and beneficial topics to support the overall goal of medicine availability for patients around the world. In terms of scope, the current connection between ICH and PDG through Q4B only addresses 16 chapters out of 300 or more chapters contained in the pharmacopoeias and none of the monographs for excipients, drug substances or products. While there are 40 published pharmacopoeias, PDG consists only of the 

. Efforts to expand the participating pharmacopoeias in PDG have been discussed but not pursued because it is recognized that retrospective harmonization between the current three pharmacopeias is already difficult.

	While ICH has continued to expand its membership in the past several years, there are still questions about how the newly joined countries will adopt the ICH guidelines, including the Q4B annexes. At a workshop held in Beijing in the fall of 2018, this specific challenge for China was discussed among key stakeholders: regulators, industry, and the pharmacopoeia (7). The unique challenges for the Q4B topic, with its guideline detailing the process for determining compendial chapter interchangeability and the 16 associated topic-specific annexes, were detailed, and the question posed: how should the regulators and pharmacopoeia in China adopt compendial standards that were harmonized without any input from China? Several examples were presented with assessment of differences and scientific rationale that challenged some of the content contained in the PDG harmonized chapters, including particulate contamination, dissolution, microbiological, and sterility testing. The meeting in China serves as a reminder of the difficulties in achieving harmonized compendial standards and expanding their adoption once available. Still, there are additional activities being pursued, aimed at facilitating the development and use of global pharmacopoeia standards.

) supports the needs of developing countries by providing quality standards for medicines that are listed in the WHO Model List of Essential Medicines. What else is WHO doing to enable compendial harmonization? As an observer to the harmonization work of both ICH and PDG, WHO is uniquely positioned to leverage the outcomes of that work and bring advantage by expanding its reach throughout the world. Over the past several years, WHO has adapted the test chapters that were harmonized by PDG and evaluated by the ICH Q4B EWG and included them in 

, providing broader visibility to these harmonized standards in developing countries.

	The WHO has taken a leadership role through additional initiatives, continuing the collaboration with and among national and regional pharmacopoeia commissions, which was essential to the development of the first edition of Ph. Int. Beginning in 2012, WHO convened the International Meetings of World Pharmacopoeias (IMWP), recognizing that in an increasingly globalized world, international pharmaceutical standards are increasingly important to safeguard quality and improve access to medicines (8). Representatives from pharmacopoeias from 23 countries came together at the first IMWP and committed to working further toward harmonization and strengthening WHO’s role in developing global standards for the production and testing of medicines. This unprecedented commitment by WHO and the pharmacopoeias to work together to strengthen international standards has continued through additional IMWP meetings, which have occurred on a regular basis since 2012. The most recent IMWP, the 10th such meeting, was hosted by WHO in Geneva in March 2019, with representation of national and regional pharmacopoeial authorities, including those in Brazil, China, Europe, India, Indonesia, Japan, Russia, and the US. One concrete step toward strengthened cooperation has been the development of a rapid alert system to exchange information and take urgent action during health emergencies. The connection between ICH and PDG also continues to strengthen. At the March 2019 PDG videoconference, a discussion took place on how information on the progress made by PDG should be shared amongst the PDG member pharmacopoeias and other pharmacopoeias participating in the IMWP. These discussions will continue at the next face-to-face PDG meeting, hosted by JP in October 2019 in Tokyo, which will also celebrate the 30th anniversary of PDG (9).

	There are additional contributions from WHO. The initiative to reopen discussion on international harmonization of quality control specifications on a global scale began back in 2002, during meetings held at the 10th International Conference of Drug Regulatory Authorities (ICDRA), “Pharmacopoeial Specifications–Need for a Worldwide Approach?”, in Hong Kong. This led to further discussions among regulators at subsequent ICDRA meetings and at other international events during the following years, including discussions with and among the pharmacopoeias on this topic.

	The main suggestion emerging from all these events was the development of good pharmacopoeial practices (GPhP) to encourage harmonization, facilitated by the WHO Expert Committee on Specifications for Pharmaceutical Preparations, and benefiting from its well-established international standard-setting processes and procedures. The important work of preparing the GPhPs began with the first IMWP meeting and continued through later meetings, with formation of an initial drafting group comprising pharmacopoeia representatives from Argentina, Brazil, Europe, India, Japan, Mexico, the Russian Federation, Ukraine, the UK, and US (10). As a truly global initiative, the entire process was open to all pharmacopeias. With focus and persistence by WHO and the participating pharmacopoeias, and with input provided by stakeholders who reviewed early drafts, the 

	The GPhPs define approaches and policies, along with technical guidance for the development of monographs for APIs and finished pharmaceutical preparations. The guidance is intended to facilitate collaboration and possible work-sharing among the pharmacopoeias, with the ultimate goal of harmonization of compendial standards. Additional GPhP chapters were completed in 2018 to address the development of monographs for compounded preparations and herbal medicines (12, 13). An essential element contributing to the completion of the 

 guidance documents was the collaborative environment that was engendered among the pharmacopoeias and WHO through the IMWP meetings. This engagement has also contributed to other compendial harmonization initiatives, including bilateral and multilateral agreements, memoranda of understanding (MoUs), regional activities between the various pharmacopoeias, and collaboration to support the development of global pharmacopoeia standards.

	Most of the initiatives described thus far have focused on harmonization of compendial standards already listed in the various pharmacopoeias, to resolve differences between the existing standards-so-called “retrospective harmonization”. This is difficult, as evidenced by the efforts of the PDG pharmacopoeias to harmonize existing general chapters and excipient monographs resulting in harmonization by attribute. It is also reflected in the discussion on how China might adopt the topic-specific ICH Q4B outcomes, an issue that other countries will also face as they join in the membership of ICH. The underlying question for retrospective harmonization is why a pharmacopoeia should change from a standard that has been developed and used to control the quality of medicines in that particular country, and to adopt a different compendial standard that was “not invented here.” Even with the effective collaboration achieved through the IMWP meetings, much time has been devoted to discussing harmonization of existing standards in the
	 various pharmacopoeias.

	The GPhP guidance documents shift the focus away from retrospective harmonization to facilitate an approach for the development of new monographs that do not yet exist, which may be widely adopted by the pharmacopoeias. The benefit of this approach-so-called “prospective harmonization”-was mentioned for the PDG harmonized chapter that was developed for Capillary Electrophoresis, which did not require any conditions regarding interchangeability in the ICH Q4B annex because there were no residual differences for this standard in the 

. This chapter, along with several others used to characterize biotechnology-derived articles, was harmonized from the beginning through the PDG partnership.

	Another example of prospective harmonization has been the development of new monographs for drug products and drug substances. This initiative has been undertaken through a collaboration between the bio/pharmaceutical industry and the pharmacopoeias, in particular 

, with visibility provided to other pharmacopoeias, including those in Japan, China, Korea, and India. This effort, which has resulted in the successful completion of several new, prospectively harmonized monographs for small-molecule drug substances and products, has evolved to an “informal harmonization” process between
	the participants

	Global pharmacopoeia standards would help to support the availability of medicines with consistent quality for patients around the world. There are many pathways to achieve compendial harmonization and several approaches are currently underway, including the important work by PDG and WHO. Compendial harmonization is also taking place at the intersection of the pharmacopoeias and ICH activities. The IMWP meetings have fostered greater collaboration among the pharmacopoeias of the world and resulted in the GPhP guidance documents to help in the development of new standards that are harmonized. Industry supports these ongoing harmonization activities.

Pharmacopeia Discussion Group (PDG) Working Procedures

ICH Q4B Expert Working Group, Presentation on Q4B

Q4B Guideline: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions

, 14-15 November 2018, Charlotte, NC, USA, 

Adoption of the ICH Q4 Pharmacopoeial Test Method Workshop was held in Beijing

” with presentations from the workshop, wp.chp.org.cn.
	8. WHO, “

International Meetings of World Pharmacopoeias

 videoconference meeting, April 25, 2019, Strasbourg, France, Press Release, EDQM.eu.
	10. Pharmaceutical Technology Editors, “

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

Good Pharmacopoeial Practices: Chapter on Monographs for Compounded Preparations

, WHO Expert Committee on Specifications for Pharmaceutical Preparations Fifty-Second Report, Technical Report Series No. 1010, Annex 6, pp. 235-239 (2018).
	13. WHO, 

Good Pharmacopoeial Practices: Chapter on Monographs on Herbal Medicines

, WHO Expert Committee on Specifications for Pharmaceutical Preparations Fifty-Second Report, Technical Report Series No. 1010, Annex 7, pp. 241-248 (2018).

The authors take a closer look at these ongoing efforts to harmonize compendial standards, with perspective that may be helpful in considering the future direction of pharmacopoeias.

Harmonization Efforts by Pharmacopoeias and Regulatory Agencies

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 

. 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.

	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.

	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 

, 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 

United States Pharmacopeia–National Formulary

). 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.

	The challenges that make pharmacopoeia compliance difficult (

) 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.

	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 

 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 

 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.

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 

)-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., 

), 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.

 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 

 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.

 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 

, 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.

 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?”

	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.

 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.

	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.

	1. N. A. Schwarzwalder and R. H. Bishara, 

7 (4), pp. 53-57 (Jul-Aug 2004).
	2. USP, General Notices and Requirements, pp. 3-12, 

(2018) (published by The United States Pharmacopeial Convention, 2017).
	3. BP, 

, 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).

This article provides an end-to-end compendial framework to understand why compliance with pharmacopoeia standards is challenging.

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

Global Pharmacopoeia Standards: Why Harmonization is Needed (PDF)

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

This article provides the legal and regulatory basis for pharmacopoeia compliance and illustrates pharmacopoeia impact throughout the drug product lifecycle.