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J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions LLC.
Janeen A. Skutnik is director of Quality & Regulatory Policy–Global Regulatory CMC at Pfizer.
Neil A. Schwarzwalder is a global compendial consultant for the Global Quality Laboratories at Eli Lilly and Company
This position paper describes a model for the future that would provide appropriate standardization, facilitate drug registration and support regulatory agencies.
There are currently more than 30 pharmacopeias operating in the world, according to the World Health Organization (WHO) (1). Some of these organizations have been in existence for quite a long time—in some cases more than 100 years—while others were recently created. Pharmacopeias, in general, are national, meaning that they provide standards for a particular country (e.g., United States Pharmacopeia [USP], Japanese Pharmacopoeia [JP]) and others serve as regional bodies (e.g., European Pharmacopoeia [Ph. Eur.]) or even global bodies (e.g., the WHO's International Pharmacopoeia [Ph. Int.]). Their standards are published in a wide variety of languages to meet the needs of those using them. In terms of updates, several pharmacopeias have active processes for revision, with new editions and supplements published on a regular basis, but not all pharmacopeias have the resources to publish revisions as frequently.
Clearly there are differences between pharmacopeias, but there are also important similarities such as their purpose and content of their publications. Given today's global pharmaceutical environment, it is instructive to consider the current pharmacopeial situation with a goal of defining the "ideal" state. This concept was jointly discussed in May 2006 between industry representatives from the Pharmaceutical Research and Manufacturers of America (PhRMA) and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This article presents the conclusions from that discussion, with further development by PhRMA's Compendial Liaison Team.It is hoped that the industry vision provided herein will stimulate further discussion to ensure a continued beneficial role for pharmacopeias in our global healthcare system.
A pharmacopeia's purpose
A pharmacopeia includes published, public quality standards for pharmaceutical ingredients and dosage forms. A standard may include acceptance criteria as well as test methods for determining the conformance of an ingredient or dosage form to the standard. The existence of a pharmacopeia is often a legal mandate, referenced in national law and enforced by governmental bodies. The fundamental purpose of the pharmacopeia is to promote public health, as stated in the mission and preface to USP 31, the preface to JP 15, and in the following text from the introduction of Ph. Eur. 6.0 (2–4):
"The purpose of the European Pharmacopoeia is to promote public health by the provision of recognized common standards for use by healthcare professionals and others concerned with the quality of medicines. Such standards are to be appropriate as a basis for the safe use of medicines by patients and consumers."
The Ph. Eur. introduction continues by noting that Ph. Eur. is widely used internationally, and that its standards are developed by working with all users of the pharmacopeia to satisfy their needs and facilitate cooperation.
Pharmacopeias, along with regulatory agencies and pharmaceutical manufacturers, play a role in supporting the availability of safe, effective, and quality medicines worldwide. The ultimate beneficiaries of pharmacopeial standards are healthcare professionals and patients. However, it should be recognized that physicians, pharmacists, and patients do not directly use the pharmacopeias. With the exception of a few general chapters aimed specifically at pharmacists (e.g., USP General Chapters <795> and <797>, which address pharmaceutical compounding), the benefit to these parties is indirect through the published pharmacopeial standards that are implemented by the pharmaceutical industry and enforced by regulatory authorities. The direct impact of the large majority of pharmacopeial standards is on industry and regulators; this direct impact is key to the discussion of an ideal pharmacopeia.
To establish characteristics associated with the ideal pharmacopeia, it is helpful to have some historical perspective of the initial creation and purpose of the pharmacopeias. The early history of USP serves as an illustrative example. In 1820, a small group of physicians met in the US Capitol building to "create a compendium of the best therapeutic products, give them useful names, and provide recipes for their preparation" (2). The resulting Pharmacopeia of the United States was intended to meet a critical need that existed at that time, when there was little consistency in the ingredients, preparation, and quality for drugs that were typically compounded by physicians and apothecaries. The early pharmacopeia provided standards to ensure uniformity for medicines to benefit patients and practitioners, whether they lived in New York, Boston, or any other city in the nation.
Today's situation is quite different. In our modern, global healthcare environment, medicines are typically manufactured by pharmaceutical companies in highly controlled facilities operating under current good manufacturing practices (CGMPs). New drug applications are reviewed by regulatory agencies throughout the world to ensure the products are safe, effective, and of appropriate quality. Regulators inspect manufacturing facilities to ensure compliance with agreed-upon quality standards. While uniformity for medicines remains an important goal, the scope has changed dramatically. It is now essential to have safe, effective, and high-quality medicines available for patients and practitioners in New York, Paris, Tokyo, or any other city in the world.
The ideal pharmacopeia
Today, drug products are subject to significant control by manufacturers and regulators worldwide to ensure safety, efficacy, and quality. But even taking into consideration the quality control achieved through modern manufacturing capabilities, and the expertise and diligence of regulatory agencies, there is still an important role for pharmacopeias in today's marketplace. The concept of an ideal pharmacopeia, therefore, must address the content, purpose, role, and applicability of pharmacopeial standards in the current environment. The ideal pharmacopeia sets a benchmark and establishes the direction and effort necessary to achieve its goals.
The following fundamental principles are proposed:
The ideal pharmacopeia would provide appropriate standardization to facilitate drug registration and support regulatory agencies through a single, global compendial standard.
The various components of this statement are described below.
Provide appropriate standardization. A discussion of "appropriate standardization" necessarily focuses on the specific content of the ideal pharmacopeia. Many aspects of quality standards for pharmaceutical ingredients and dosage forms should be applied to all manufacturers, and other aspects may be unique to a particular manufacturer, location, or process. Pharmacopeial requirements should not be based on a particular manufacturer's process capability but should instead reflect science and risk-based, technical standards for ensuring that the needs of the patient are met in terms of the identity, strength, quality, and purity of drugs.
An ideal pharmacopeia would provide appropriate standardization through specific monographs for pharmaceutical ingredients, general monographs for dosage forms, and appropriate General Chapters and test methods. Specific monographs for excipients and drug substances provide benefit through a consistent quality standard that is applicable to the same ingredient from various manufacturers. Pharmacopeial monographs include a list of tests, references to analytical procedures, and appropriate acceptance criteria as minimum requirements to ensure the pharmaceutical ingredients are acceptable for their intended use. General monographs on dosage forms (as provided in Ph. Eur.) and general rules for preparations (as published in JP) also provide benefit through appropriate, but not necessarily comprehensive, quality standards that are applicable to all drug products of the type defined (e.g., tablets, capsules, or parenteral preparations). Similarly, General Chapters provide value through standardized test methods and procedures that may be applied to a large number of pharmaceutical ingredients and dosage forms.
Properties and quality attributes of pharmaceutical ingredients and drug products that are unique to a particular manufacturer or dosage form such as those that may arise from different synthetic or manufacturing processes or particular excipients used are more appropriately provided to regulatory agencies through product registrations, rather than through public standards in the pharmacopeia. Specific tests, methods, and acceptance criteria for these unique characteristics of ingredients and products are appropriately evaluated by regulatory agencies to ensure quality, safety, and efficacy. In particular, the value of including monographs for specific drug products in the pharmacopeia is not apparent due to the unique aspects of the finished dosage form from various manufacturers. The ideal pharmacopeia should focus on general monographs for dosage forms, rather than on specific monographs for each particular drug product.
In addition, general chapters that are only applicable to a limited number of ingredients or drug products, or which represent technology that is not mature or generally used throughout the industry provide limited usefulness as pharmacopeial standards. Finally, GMPs are addressed by regulatory authorities who can ensure compliance through inspections and enforcement. It is not helpful, and in fact can be counterproductive, for the pharmacopeia to publish independent GMP requirements.
Facilitate drug registration. The ideal pharmacopeia can simplify and facilitate the preparation and assessment of regulatory applications by providing common standards for generally accepted quality parameters for pharmaceuticals. By defining test methodology and acceptance criteria, the pharmacopeias ensure that standardized approaches may be used by all regulatory authorities and by industry. This permits regulators and manufacturers to focus on the evaluation of unique attributes of the drug substance or dosage form. The evaluation of many of these unique attributes can also be based upon the standardized test methods and criteria established in the pharmacopeia.
It is beneficial to be able to reference a particular excipient monograph or General Chapter to indicate the tests and methods used, and the quality standards that apply. Specific pharmacopeial monographs can streamline communication between manufacturers and regulators by providing a common understanding of suitable quality attributes for the ingredients. For example, reference to "Hypromellose USP, Ph. Eur., and JP" as an excipient in a solid oral dosage form enables a manufacturer to indicate to regulators the quality attributes based on the monograph standard for this excipient without the need for additional details on the tests, methods, or acceptance criteria.
Similarly, dosage-form monographs and General Chapters provide a common language around analytical methods that may be applied to products or ingredients. For example, indicating that a drug product complies with the pharmacopeial requirements for "uniformity of dosage units" facilitates preparation and review of a product registration, while still providing clear understanding of the applicable quality attribute for the product. References to pharmacopeial standards in drug product registrations provide a common understanding through succinct language, with clear and precise meaning. This mutual understanding facilitates interaction between pharmaceutical manufacturers and regulatory agencies, thereby bringing clarity and efficiency to the processes for regulatory review of drug applications and inspection of facilities.
Additional benefit to industry and regulators resulting from pharmacopeial standards can be derived through the compendial revision process. As monographs and General Chapters are updated to reflect improvements in materials, methods, and technology, reference to appropriate pharmacopeial requirements enables drug product registrations to stay up-to-date with current standards of quality, thereby providing enhanced public health protection.
Support regulatory agencies. Alignment between the pharmacopeias and regulators is essential. In practical terms, the ideal pharmacopeia should include standards that are consistent with the needs and expectations of regulatory authorities. Drug product availability may be jeopardized and costs may be increased without benefit if industry is compelled to meet conflicting pharmacopeial and regulatory requirements. The need for alignment emphasizes the extremely important supporting role that pharmacopeias play in today's regulatory drug product review and approval process. Differing expectations and requirements for a particular method or process, as may be created by general chapters in the pharmacopeia that are in conflict with guidelines from regulatory agencies, provide little more than a roadblock to drug review and compliance. Pharmacopeial standards are only meaningful in the context of an effective regulatory framework. An ideal pharmacopeia, therefore, should align with and support the laws, regulations, and guidelines of the relevant regulatory authorities.
A single, global compendial standard. The ideal pharmacopeia should provide a single compendial standard that can be used worldwide. While the goal of a single global standard may seem the most difficult to achieve, it is also the most critical. Today's global healthcare system operates across country and regional boundaries. A patient in the US may have a prescription filled from a pharmacy in Canada for a drug product that was manufactured in Europe. A global pharmacopeial standard can help ensure that patients anywhere in the world receive consistent quality medicines no matter where the products are manufactured or sold.
Skeptics of a harmonized pharmacopeia need to realize that there is already an important example of the creation of a single, unified, international standard where many differing standards had previously existed. The model for a global standard can be found in the European Pharmacopoeia. When it was created in 1964, Ph. Eur. was intended to guarantee the quality of medicines throughout European countries, an objective not unlike that which led to the creation of USP in 1820. However, there were two important differences: First, by 1964, modern systems were in place for drug manufacturing by pharmaceutical companies with review and approval by regulatory agencies throughout the world. Second, there was a clearly defined legislative and regulatory goal to ensure consistent drug quality throughout Europe. Ph. Eur. represents a model of international cooperation to forge a single pharmacopeial standard in Europe where multiple standards existed before. The Ph. Eur. standard is now the legal pharmacopeial requirement in 36 European countries, along with the European Union (EU). In addition, there are more than 20 observer states, including WHO, the Russian Federation, China, Australia, Brazil, and Canada who follow the work of Ph. Eur. It is suggested that this model can be further extended to result in a global or unified pharmacopeia.
There are several practical approaches for moving toward a single global standard embodied in the ideal pharmacopeia. Currently, the Pharmacopeial Discussion Group (PDG), with representatives from USP, Ph. Eur., and JP, is actively engaged in pharmacopeial harmonization efforts. Continuation of this challenging but important work by PDG is strongly encouraged, along with regulatory review of the harmonized outcomes through the International Conference on Harmonization (ICH) Q4B: Evaluation and Recommendation of Pharmacopeial Texts for Use in the ICH Regions process. Consideration should also be given to novel approaches that might speed up PDG harmonization efforts, as well as provide new opportunities to move toward globally consistent pharmacopeial standards. Discussion is underway to develop a process for prospective harmonization through even greater collaboration among the pharmacopeias in partnership with industry to achieve consistency for new monographs and general chapters. Mutual acceptance by regulatory agencies of the standards in USP, Ph. Eur., and JP could also help to eliminate non-value-added duplicate testing that results from the lack of pharmacopeial harmonization.
Some initial progress has been made in this respect through the European Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials, which states that reference to either Ph. Eur., USP, or JP is acceptable (5). Further progress can be found in the US Food and Drug Administration's Manual of Policies and Procedures on Acceptability of Standards from Alternative Compendia, which states that it is reasonable to accept an applicant's proposal to use a quality standard from Ph. Eur. or JP as part of the specifications for an excipient, drug substance, or drug product in the drug application, if the standard in Ph. Eur. or JP is equivalent to or better than the corresponding standard in USP (6). All these concepts—PDG/ICH harmonization, prospective harmonization, and mutual acceptance—form the basis for a unified pharmacopeia and were presented by industry to EU and US regulators at the Transatlantic Administrative Simplification (TAS) workshop on Medicines Regulation held in Brussels in November 2007 (7).
Pharmacopeial development and revision
The ideal pharmacopeia should be developed and revised through a transparent, consensus-based process that allows for public review and comment (e.g., Pharmeuropa, JP Forum, and USP Pharmacopeial Forum). It is counterproductive for the pharmacopeia to unilaterally develop standards. Using a consensus-based approach involving and preferably driven by primary stakeholders (regulatory agencies and industry), the pharmacopeias can continue to play an important role in healthcare through the development of monographs and applicable general test methodology for pharmaceutical ingredients and dosage forms.
Pharmacopeial public standards provide benefits to patients, practitioners, regulatory authorities, and industry. For patients and practitioners, pharmacopeias promote consistency in medicines by establishing quality standards applicable to all drug manufacturers. For regulatory agencies and industry, pharmacopeias provide a resource for methodology and guidance on non-GMP topics. Pharmacopeias can facilitate drug registration and support regulatory agencies through appropriate standardization. Globally aligned pharmacopeial standards can help ensure the quality and facilitate free movement of medicinal products worldwide.
Pharmacopeias clearly have a continuing role to play in assuring the availability of quality pharmaceuticals to meet the demands of today's global healthcare environment. Moving toward an ideal pharmacopeia would further enhance their role in supporting and promoting global public health through safe and effective medicines of appropriate quality for patients throughout the world.
J. Mark Wiggins* is a principal scientist in Regulatory and Analytical Sciences–Compendial Affairs at Merck & Co., WP82-10, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486-0004, tel. 215.652.3964, fax 215.652.0834, firstname.lastname@example.org. Janeen A. Skutnik is director of Quality & Regulatory Policy–Global Regulatory CMC at Pfizer. Judy L. Shimek-Cox is recently retired from her position as a principal regulatory scientist at Eli Lilly and Company, and Neil A. Schwarzwalder is a global compendial consultant for the Global Quality Laboratories at Eli Lilly and Company. All authors are current or former representatives on the Compendial Liaison Team at the Pharmaceutical Research and Manufacturers of America (PhRMA).
*To whom all correspondence should be addressed.
1. WHO, "Index of Pharmacopoeias" (2006), available at
, accessed Sept. 25, 2008.
2. USP, US Pharmacopeia 31–National Formulary 26, p. v (2008)
3. JP, Japanese Pharmacopoeia 15, p. i (2006).
4. Ph. Eur., European Pharmacopoeia 6.0, p. v (2008).
5. Committee for Medicinal Products for Human Use, "Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials," EMEA, London, Mar. 31, 2006, available at www.emea.europa.eu/pdfs/human/qwp/18540104en.pdf, accessed Sept. 25, 2008.
6. FDA Center for Drug Evaluation and Research, "Manual of Policies and Procedures: Acceptability of Standards from Alternative Compendia" (MAPP 5310.7), Nov. 3, 2007, available at. www.fda.gov/cder/mapp/5310.7R.pdf.
7. EMEA/FDA, "Transatlantic Cooperation in Pharmaceutical Regulation: Identifying Opportunities for Admnistration Simplification," Nov. 28, 2007, available at
, accessed Sept. 25, 2008.