The authors discuss a new approach to address globally harmonized compendial standards.
Twenty-first century challenges require 21st century solutions. This fact applies broadly in our current global economy, where many industries are looking beyond traditional, developed markets to the emerging markets. One such industry is healthcare, where medicines are used to extend and improve the quality of life for patients around the world. There is an increased 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. Medicines may be globally sourced across developed and emerging markets, and the supply chain for ingredients and drug products is complicated by the overall lack of consistent, harmonized quality requirements.
The lack of harmonized drug standards is the result of several existing conditions, including national and regional laws, regulatory requirements and expectations, and applicable pharmacopeial (or compendial) requirements. Pharmacopeias with differing standards exist in many of the developed and emerging economies. The purpose of this paper is to initiate discussion on a new approach to address the challenge of achieving globally harmonized compendial standards for pharmaceutical ingredients and dosage forms. The concepts include development of standardized practices and enhanced collaboration among the pharmacopeias, as well as participation and agreement by the regulatory agencies.
One approach to achieving harmonized quality requirements for medicines is the creation of a single, global compendial standard. This was a key consideration in the recently published article describing the "ideal pharmacopeia" (1). But this idea is not new. The original objective in the creation of the International Pharmacopoeia (Ph. Int.) more than 60 years ago under the direction of the World Health Organization (WHO) was the creation of a unified pharmacopeia. The European Pharmacopoeia (Ph. Eur.), first elaborated in 1964, is a more recent example of the successful creation of a single, harmonized, broadly applicable pharmacopeia, where several individual national pharmacopeias previously existed. It is also recognized that the United States Pharmacopeia–National Formulary (USP–NF) and the British Pharmacopoeia (BP) provide compendial standards that are applied well beyond their geographical boundaries.
Other approaches to developing harmonized compendial standards include the efforts by the Pharmacopeial Discussion Group (PDG) and International Conference on Harmonization's (ICH) Q4B guideline (2). These activities, which generally focus on retrospective harmonization of widely used general chapters and excipient monographs in the USP–NF, Ph. Eur., and Japanese Pharmacopoeia (JP), have achieved some success, but are limited in scope and are time-consuming. It is well understood that there are inherent challenges in retrospective harmonization. More recent approaches include the prospective harmonization pilot project, a collaboration between the pharmaceutical industry, Ph. Eur., and USP to achieve harmonized API monographs (3).
Although these approaches have provided some progress toward creating harmonized compendial standards, they have largely been limited in their breadth and depth. In consideration of today's continuing reality of multiple national and regional pharmacopeias, and our need to serve a global patient population, other approaches must be considered to achieve a 21st century solution.
The approach presented here builds upon the success of retrospective and prospective harmonization, along with recent bilateral partnerships among the pharmacopeias, to serve the needs of patients in both developed and emerging markets. The goal of this approach is to provide harmonized, globally applicable quality standards for medicines within the existing framework of multiple national and regional pharmacopeias to the benefit of patients worldwide.
Compendial globalization provides a basis for the pharmacopeias to work together in new ways with consistent processes coupled with sharing of information and work. The concept is illustrated in Figure 1, which depicts a 3-legged stool to emphasize the balance needed among the 3 principles. The stool is set upon the foundation of "Patient Benefit," accomplished through the global availability of medicines with consistent and appropriate quality requirements. The specific objective is depicted by the seat of the stool: the development of globally harmonized compendial standards. Supporting the stool are the 3 legs or principles of compendial globalization:
Figure 1: The three principles of compendial globalization. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
1. Standardized pharmacopeial practices, which set forth consistent and agreed upon philosophy, structure, principles, and practices (both technical and quality) for use by pharmacopeias in the elaboration of compendial standards (monographs and general chapters).
2. Pharmacopeial collaboration, which enhances co-operation among the pharmacopeias to enable development, sharing, and adoption of new and revised harmonized compendial standards.
3. Regulatory acceptance, which ensures participation of and agreement by regulatory authorities with the harmonized processes and outcomes in those countries where the standards apply.
Standardized pharmacopeial practices
The first principle of compendial globalization is the establishment of a consistent set of acceptable practices to be used by individual pharmacopeias in the elaboration of new and revised compendial standards (see Table I). Having a common philosophy, structure, principles, and practices (both technical and quality) that are agreed upon by the pharmacopeias and impacted stakeholders will ensure the development of appropriate compendial standards for pharmaceutical ingredients and dosage forms. Standardized practices would provide compendial standards that could be harmonized and made globally applicable to ensure appropriate quality for medicines used by patients worldwide. Additionally, regulatory agencies will have assurance that compendial standards are interchangeable because they would be developed using the standardized pharmacopeial practices. It is worth noting that global standards have been achieved and broadly accepted in other industries (e.g., aviation and communication) through the efforts of international and national standards-setting organizations.
Table I: Considerations for standardized pharmacopeial practices.
Many of the individual components that would make up the standardized practices may already be in place for individual pharmacopeias, but have not been considered with a view towards consistent and comprehensive application across all of the pharmacopeias. The key impacted stakeholders (pharmacopeias, regulators, and industry) must collaborate to bring these components together and establish the details of the standardized practices. Collaboration between the pharmacopeias to establish the standardized practices can be extended to the development of harmonized compendial requirements.
The second principle of compendial globalization is pharmacopeial collaboration (see Table II). This principle builds upon the standardized pharmacopeial practices, so that compendial standards developed by one pharmacopeia may then be adopted by other pharmacopeias to provide globally harmonized standards. Pharmacopeial collaboration will enable the coordination and sharing of information and best practices among pharmacopeias with improved effectiveness and efficiency in resource utilization for the pharmacopeias and other impacted stakeholders. As a practical beneficiary of the harmonized outcomes, the pharmaceutical industry plays an important role in this collaboration by facilitating the exchange of information during the development of compendial standards.
Table II: Considerations for pharmacopeial collaboration.
Pharmacopeial collaboration should draw from other approaches to pharmaceutical globalization, such as the Pharmaceutical Inspection Cooperation Scheme (PIC/S), which provides opportunities for sharing of resources and information among regulatory agencies. Pharmacopeial collaboration can build upon existing partnerships and establish new processes to include development, implementation, maintenance, and sharing of compendial standards. The underlying basis for successful pharmacopeial collaboration is the development and consistent application of standardized practices by the pharmacopeias, as previously discussed. The key to success is the regulatory acceptance of the work performed via these standardized practices and collaboration.
The third principle of compendial globalization is not focused on the pharmacopeias, but rather on the regulatory agencies. Compendial globalization can only succeed if the regulators are willing to accept the outcomes based upon the standardized pharmacopeial practices and pharmacopeial collaboration. Having harmonized compendial processes and interchangeable standards will aid in the regulators' efforts to ensure the quality of medicines, in light of the challenges created by the increasingly complex global supply chain.
Acceptance of compendial globalization by the regulatory agencies will be facilitated by their participation in the development of the underlying principles of standardized pharmacopeial practices and pharmacopeial collaboration. The existing framework for regulatory review and comment on compendial standards (monographs and general chapters) provides further assurance of appropriate quality for drug products and ingredients. It is envisioned that harmonized and interchangeable compendial standards could help to harmonize compendial information in regulatory submissions, reducing the number of postapproval changes submitted by industry, thereby removing the need for this additional review and approval by health authorities. Regulatory acceptance of the outcomes of compendial globalization will also provide a baseline for the regulatory expectations for compendial testing that are reviewed during inspections. These aspects will ultimately provide consistent quality medicines for global patients without an additional regulatory burden.
Benefits of compendial globalization
The ultimate beneficiaries of compendial globalization are patients worldwide through the increased availability of affordable medicines with appropriate, consistent, and globally applicable quality standards. This benefit is achieved through the harmonized compendial requirements which facilitate drug development, specification setting, global drug product registrations, and inspection of facilities. Additional benefits come from the simplification of the supply chain and quality assurance processes for global medicines.
Another practical benefit is the improved utilization of resources by global stakeholders (i.e., industry, pharmacopeias, and regulators) who are directly impacted by compendial standards. This benefit is achieved by eliminating redundancies in industry, pharmacopeial, and regulatory processes. For the pharmaceutical industry, there is direct benefit in harmonized quality requirements which eliminate redundant testing that provides no additional benefit to the patient. Both the industry and pharmacopeias also benefit from simplification of processes for developing compendial standards (see Figures 2 and 3).
Figure 2: Current state of monograph development.
The current process for developing a new monograph for a single drug substance or product (see Figure 2) requires parallel and redundant work activities. A company may develop and submit multiple proposals to several different pharmacopeias. Each pharmacopeia then follows the steps of its own process for monograph elaboration, typically resulting in different outcomes that are published for review and comment in pharmacopeial forums. The company must monitor each of the respective forums, and respond to the different drafts. Once the pharmacopeias take account of the comments from all impacted stakeholders, including those from other companies and regulatory agencies, the different monographs are published as official. All impacted companies must then complete appropriate change control to their testing standards, as needed, to ensure compliance with the disharmonized monograph requirements.
Figure 3: Proposed state of monograph development.
The work for all stakeholders is simplified by compendial globalization (see Figure 3), where a harmonized monograph results from a single submission by the company. Using the standardized practices and collaboration, one pharmacopeia is able to develop the harmonized monograph and other pharmacopeias are able to adopt this standard, based on collaboration between the pharmacopeias and with the submitter of the monograph. This frees up resources for the other pharmacopeias, enabling them to develop other standards, rather than duplicating the effort for the first monograph. The resulting harmonized compendial standards reduce the complexity of regulatory review of registrations and inspection of facilities. One globally applicable quality standard would exist, regardless of which pharmacopeia might be referenced in a registration or used for release testing. These outcomes provide global patient benefit and make the pursuit of compendial globalization a worthwhile effort.
The goal of achieving globally harmonized compendial standards has been approached in several ways with limited success. The new approach for compendial globalization described here is intended to increase the pace of harmonization, and help promote global public health. The three principles of standardized pharmacopeial practices, pharmacopeial collaboration, and regulatory acceptance are relatively simple, but require new ways of thinking and working. With commitment by impacted stakeholders, the benefits of compendial globalization should extend to the pharmacopeias, regulators, industry, and ultimately, patients worldwide.
The authors are grateful to Janeen Skutnik-Wilkinson, Pfizer, Quality & Regulatory Policy, for helpful discussions during the initial development of this article.
J. Mark Wiggins* and Howard D. Schneider, Jr., are in Global CMC Regulatory Affairs, Quality Standards–Compendial Affairs, at Merck, WP82-10, 770 Sumneytown Pike, P.O. Box 4, West Point, PA, 19486-0004, tel. 215.652.3964, fax 215.652.0834, email@example.com.
To whom all correspondence should be addressed.
1. J.M. Wiggins, J.A.Skutnik, J.L. Shimek-Cox, and N.A. Schwarzwalder, Pharm. Technol. 32 (11) 122–125 (2008).
2. ICH, Q4B Guideline and Annexes: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions.
3. J.M. Wiggins, P.M. Travis, A. Park, and R.A. Fitzgerald, "Ph. Eur/USP Prospective Harmonization—API Pilot Project: Industry Perspective," Pharmeuropa, 22 (4) 415–418 (October 2010); Pharmacopeial Forum 36 (6) 1792–1796 (November–December 2010); Japanese Pharmacopoeial Forum 20 (1) 49–53 (March 2011).