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This article provides the legal and regulatory basis for pharmacopoeia compliance and illustrates pharmacopoeia impact throughout the drug product lifecycle.
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 fundamental principle of pharmacopoeia compliance is an important consideration for the bio/pharmaceutical industry, including innovator, generic, virtual, and start-up companies who discover, develop, manufacture, and distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products. Across the entire industry and within any given company, it is crucial that there is awareness and understanding of this need for pharmacopoeia compliance-from the CEOs of multi-national innovator and generic-drug companies to the leadership at small start-ups and contract manufacturers, to managers in their respective functional areas, to the analytical bench chemists and microbiologists testing active ingredients and excipients for use in drug products-so that global patients have uninterrupted access to the critical medicines that extend and improve their lives.
There is often insufficient understanding, however, by stakeholders at all levels of the need to comply with requirements in the pharmacopoeias. This situation can lead to a lack of appropriate attention and resources allocated to ensure compliance. The compliance risk can result in observations in FDA 483s, which may be summarized as follows: the company must comply with applicable compendial standards in the United States Pharmacopeia–National Formulary (USP–NF). A more nuanced observation is that the company must comply with “current” compendial requirements, which introduces the need to monitor and implement updates published in USP–NF. The situation is not limited to the United States, as similar expectations to comply with the applicable pharmacopoeia exist in Europe, Canada, Australia, Japan, China, and in laws and regulations around the world.
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The situation is made even more complex because a company must comply with the compendial requirements that are applicable in a particular country, and also with their product registrations as approved in countries around the world. This is true whether the pharmacopoeia references are specifically listed in the registration, or because the pharmacopoeias provide additional, well-recognized quality standards. The compliance challenge is increased by the sheer number of pharmacopoeias that exist in important markets, often with conflicting requirements due to lack of harmonization among the pharmacopoeias. This lack of broad harmonization is the current reality, despite long-term commitment and effort by pharmacopoeias to narrow the divide between their published standards. Somewhat balancing this high-level view of the compliance challenge is the fact that there is some flexibility in how a company ensures appropriate compliance to the multitude of compendial requirements. But in this flexibility, there is also complexity, due to the number of approaches that may be taken to demonstrate compliance, with the potential for different situations to drive the approach in different directions.
It is against this challenging backdrop that the authors have undertaken the preparation of a series of articles to provide a common understanding of this far-reaching and complex situation and to detail practical ways that pharmacopoeia compliance may be addressed. The articles intend to give consistent language to, and awareness of, the tasks associated with the effort and to give specific guidance to those groups and individuals within a company who are charged with ensuring ongoing compliance with pharmacopoeia requirements. While focusing on the situation for innovator and generic companies, the information is also potentially helpful in bringing greater awareness and understanding to regulatory and pharmacopoeia authorities.
Along with the understanding and assistance provided to those who perform this work, there is the goal of ensuring continued availability of medicines with consistent quality, which comply with compendial and regulatory expectations. Achieving compliance for these medicines ensures meeting the needs of patients around the world, regardless of where the patients live, where the medicines are manufactured, or which pharmacopoeias may apply.
Pharmacopoeias are often referenced in the laws and regulations of countries around the world to help ensure drug quality, safety, and efficacy. In the United States, the Federal Food, Drug, and Cosmetic Act (FD&C Act) defines the term “official compendium” as the official USP–NF or any supplement to it and the term “drug” to include articles recognized in the official USP–NF. FDA has responsibility to enforce compliance with USP–NF requirements. In Europe, the European Union Directives on Medicines for Human and Veterinary Use (2001/82/EC and 2001/83/EC) maintain the mandatory character of European Pharmacopoeia (Ph. Eur.) monographs, which are applicable to all substances, preparations, and pharmaceutical forms appearing in it when requesting marketing authorization. In Japan, the Law on Securing Quality, Efficacy, and Safety of Products including Pharmaceuticals and Medical Devices indicates the need for compliance with the Japanese Pharmacopoeia (JP) in order to standardize and control the quality of drugs. The legal and regulatory framework for pharmacopoeia compliance in these and other countries can be found in a useful summary prepared by the World Health Organization (WHO) in conjunction with recent International Meetings of World Pharmacopoeias (IMWP) (1). This information, with appropriate updates by the authors, is provided for several countries/regions in Table I, along with a list of the authorities that have responsibility for publishing the associated pharmacopoeias.
In an article published in 2004 on the bio/pharmaceutical industry’s pharmacopoeial surveillance process (2), the need to remain compliant with “current” compendial requirements was emphasized to ensure updated standards are incorporated into a company’s testing procedures. If there is no process for surveillance, or if the process is ineffective in identifying and addressing compendial changes, the resulting lack of compliance may be listed in regulatory observations. Specific examples from FDA 483s are included in the article, with observations such as: “… the firm did not follow the current USP specifications … failed to implement changes to testing methodology as required by USP … and did not address raw material monograph updates.” Examples of more recent compendial compliance observations from FDA 483s are summarized in Table II.
The common theme in all these observations is the need to maintain alignment with applicable pharmacopoeia requirements, even as the requirements change over time. Similar regulatory expectations to comply with current pharmacopoeia requirements can be found in Europe, Japan, and other countries, because the regulatory and compendial landscape is truly global. A review of data from inspections conducted by the European Directorate for the Quality of Medicines and HealthCare (EDQM) between 2006 and 2018 includes compliance issues with Ph. Eur. general methods and general monographs among the deficiencies observed (3). The takeaway message is clear; companies must comply with compendial requirements and must also remain up to date with changes made to the requirements. This ongoing revision to the pharmacopoeias around the world poses one of the main challenges for companies and will be further addressed in later articles in this series.
Having highlighted the need to comply with compendial requirements, with examples of observations resulting from non-compliance, it is helpful to have an overall understanding of the role pharmacopoeias play to support the availability of medicines. This understanding may be found in the history, purpose, and content of pharmacopoeias. Many of the pharmacopoeias from around the world have met during the past several years, under the guidance of WHO, to discuss collaboration and harmonization in today’s globalized compendial, regulatory, and supply situation for drugs. The main suggestion to come out of these meetings was the development of Good Pharmacopoeial Practices (GPhP) recently published by WHO (4).
WHO’s GPhP states, “The primary objective of the GPhP guidance is to define approaches and policies in establishing pharmacopoeial standards with the ultimate goal of harmonization” (4). This focus on compendial harmonization is reflected in the origins of several of the pharmacopoeias (to be detailed in another article in this series) and is critical to the ongoing goal of providing medicines with consistent quality to patients around the world. The WHO document goes on to list the purpose and role of the pharmacopoeias: “A pharmacopoeia’s core mission is to protect public health by creating and making available public standards to help ensure the quality of medicines. Pharmacopoeia standards support regulatory authorities in controlling the quality of pharmaceutical substances, their finished pharmaceutical products (FPPs), and related materials and will provide a tool with which the user or procurer can make an independent judgment regarding quality, thus safeguarding the health of the public.”
A search through the pharmacopoeias reveals that they contain general notices, general chapters, general monographs, specific monographs for drug products, drug substances and excipients, and additional information related to packaging, labeling, storage, etc. All this information must be taken together to determine the specific quality requirements for bio/pharmaceutical products.
Within each pharmacopoeia, there is a section referred to as general notices, which is critical to the full understanding of the scope and technical approaches in that pharmacopoeia. As stated in the USP–NF, the general notices section presents the basic assumptions, definitions, and default conditions for the interpretation and application of the USP–NF, and the requirements apply to all articles recognized in the compendia and to all general chapters, unless specifically stated otherwise. Similarly, the general notices in Ph. Eur. and other pharmacopoeias apply to all monographs and other texts in the pharmacopoeia. The general notices provide a wide range of important information, from a statement of what conformance to compendial standards means, to a description of specific monograph components, considerations for the use of alternative methods, rules for rounding, and a definition of “about”. They have been described anecdotally as the most important pages of the pharmacopoeia that most users have never read. Thus, reading and understanding the general notices is critical to ongoing pharmacopoeia compliance.
There are more than 350 general chapters in USP–NF, and more than 370 general texts in Ph. Eur., including general monographs and chapters. Many of the general chapters in the pharmacopoeias are mandatory and enforceable by regulatory authorities, containing information on specific chemical, biological, and microbiological test methods and assays, as well as specific requirements for particulate contamination and packaging components, for example. Other general chapters may instead be informational and not necessarily enforceable, intended to provide background knowledge and practical considerations that are useful to bio/pharmaceutical manufacturers’ understanding of the production, testing, and overall quality of their products. In the USP–NF, these informational chapters are numbered above <1000> and include <1079> “Good Storage and Distribution Practices for Drug Products,” <1121> “Nomenclature” and <1226> “Verification of Compendial Procedures.” The Ph. Eur., JP, and other pharmacopoeias similarly contain general chapters that are mandatory and enforceable, as well as chapters that are stated as being for information and non-mandatory. It is worth noting that Ph. Eur. Chapter 5.4 “Residual Solvents” represents the information contained separately in the International Council for Harmonization (ICH) Q3C guideline, a reminder of the important connection that may exist between regulatory guidance and pharmacopoeia requirements. This is also true for Ph. Eur. Chapter 5.20 “Elemental Impurities,” USP <232> “Elemental Impurities–Limits,” and the ICH Q3D Guideline on Elemental Impurities, along with the associated removal of the compendial test for heavy metals from the pharmacopoeias, which further serves as an example of the significant challenges for the bio/pharmaceutical industry to ensure compliance with updated regulatory and compendial requirements.
General monographs typically provide overall quality requirements that are applicable to a specific dosage form or route of administration for drug products. In the Ph. Eur., there are general dosage form monographs for capsules, tablets, eye preparations, nasal preparations, parenteral preparations and many others. In USP–NF, the general chapters numbered <1> through <5> serve the same function as the Ph. Eur. general monographs, and include quality requirements for injections, oral drug products, topical and transdermal products, mucosal products, and inhalation products.
Specific monographs provide the minimum quality requirements that must be met for drug products and ingredients, and apply to all manufacturers of these materials, both innovator and generic-drug companies. A monograph includes the name of the ingredient or preparation; the definition, packaging, storage, and labeling requirements; and the specification, consisting of a series of tests, procedures and acceptance criteria. In the USP–NF, there are currently more than 4900 specific monographs, and in Ph. Eur., there are more than 2400 monographs. These specific monographs cover the entire range of bio/pharmaceutical products, including excipients, small-molecule drug substances, biological products, and vaccines. A few examples are the monographs for the excipient hypromellose, the drug substances acetaminophen (as it is named in the USP) or paracetamol (as it is named in Ph. Eur.), and sitagliptin phosphate, and a variety of drug products, including sitagliptin tablets, infliximab concentrated solution, and human papillomavirus vaccine. Monographs often require official reference standards, which are physical materials that may be purchased from the pharmacopoeia to be used in conjunction with the test methods in the monograph to assess specific quality attributes of the drug product or ingredient, including assay and impurities.
Information contained in the pharmacopoeia is inter-related, and the requirements from one section must be utilized in conjunction with other sections. A specific monograph may include a reference to a general dosage form monograph, along with references to applicable general chapters, with the basic underpinnings contained in the general notices. Bio/pharmaceutical companies must understand and apply these pharmacopoeial requirements within this context. A guide, titled “How to Use the BP,” was posted on the British Pharmacopoeia website (5) that provides an overview and illustration of the inter-relation of pharmacopoeia content. This guide forms a framework for navigating compendial requirements in the BP, and should be helpful, especially for those who may be less familiar with the structure and use of pharmacopoeias.
Pharmacopoeias impact drugs and their ingredients throughout the entire product lifecycle (Figure 1). Beginning with the development of a new drug substance or API, many of the pharmacopoeia general chapters should be considered for potential quality and functionality testing. For example, the compendial tests listed in general chapters for water content or loss on drying, residual solvents, elemental impurities, and microbiological evaluation will likely be used for quality release of the material later in the lifecycle. Similarly, information listed in the chromatography chapter should be considered during analytical method development, because many of the compendial requirements can be incorporated into the test procedures, such as method repeatability and resolution for system suitability. Consideration should also be given at the appropriate stage of product development to compendial requirements for method validation, such as USP <1225> “Validation of Compendial Procedures,” because this information will ultimately be used to support the product registration.
Once dosage form development is initiated, additional compendial content becomes important. General chapters and general product monographs provide requirements for a given dosage form that must be considered before a product is registered or licensed. Drug product quality and functional characteristics should be evaluated according to these compendial requirements, because this is the regulatory expectation. Depending on the dosage form being developed, applicable chapters include uniformity of dosage units (content uniformity or mass variation), dissolution, particulate contamination, microbiological tests, sterility, and chromatography for assay and impurities. Pharmacopoeias also contain general chapters and general dosage form monographs that provide core requirements for drug products, including USP <1> “Injections,” Ph. Eur. monograph  on Parenteral preparations and Ph. Eur. monograph  on Tablets.
During formulation development, consideration must also be given to compendial monographs for excipients. As stated in the pharmacopoeias, and perhaps more importantly, as expected by health authorities around the world, excipients used in drug products must comply with the applicable monograph requirements published in the pharmacopoeias. Lack of awareness or attention to this point jeopardizes drug product approval and ultimate compliance. The existence of so many pharmacopoeias around the world with excipient monographs that do not broadly align is a significant complicating factor for compendial compliance and global product registrations.
Moving to regulatory submissions and product commercialization, it is important to understand the compendial requirements for packaging, storage, and distribution. Failure to take these general chapters into account as contained in the various pharmacopoeias may again have adverse impact on regulatory approval and long-term compliance. Consideration of these requirements may also be important when planning for and evaluating drug product stability. The use of compendial reference standards for pharmacopoeial testing, or alternatively, of qualifying in-house primary or secondary standards, must also be considered at an appropriate stage in product and analytical development to meet the expectations of regulatory agencies.
Nomenclature used in pharmacopoeias for excipients, drug substances, and drug products must also be considered during the product lifecycle. The link between a product’s generic name and the content of the active ingredient can be important in clinical trials to support dosing studies, in developing product strengths, and for filing and labeling purposes, especially in the United States. USP <1121> states that USP–NF titles for monograph articles are legally recognized under the FD&C Act as the designations for use in labeling the articles to which they apply and relate to the adulteration and misbranding provisions of the Act. USP <1121> also contains a section on the monograph naming policy for drug products containing salt drug substances. The USP Salt Policy stipulates that USP will use the name of the active moiety, which is the molecule or ion responsible for the physiological or pharmacological action of the drug substance, instead of the name of the salt, when creating drug product monograph titles for such a drug product. The policy also stipulates that USP will base the strength of the product on the active moiety. Companies need to be aware of the USP Salt Policy, which is enforced by FDA (6, 7), to avoid issues with the name and strength listed on drug product labeling and in registrations. The FDA guidance (6) states that a drug product with labeling that contains a name that is inconsistent with the applicable USP monograph title risks being misbranded. Another example of the impact of pharmacopoeia nomenclature is the transition from the excipient name hydroxypropyl methylcellulose to the shortened title hypromellose, which resulted in significant revisions to the ingredient listing on labels and in registrations.
Once a product is launched and reaches the end of exclusivity, compendial monographs for drug substances and drug products will be developed by the pharmacopoeia. This is generally accomplished with the support of companies who have received regulatory approval for these products, to provide a public quality standard in the pharmacopoeia that is applicable to the product or material from all approved sources. Considerations for monograph development, looking at the impact to both innovator and generic-drug companies, will be provided in a later article in this series.
In this article, the first in a series about compendial activities in the bio/pharmaceutical industry, the basis for pharmacopoeia compliance expectations was provided, along with consideration of how the pharmacopoeias impact drugs throughout their product lifecycle. The increasingly global environment for industry, regulators, and pharmacopoeias, where expectations and standards do not always agree, represents one of the significant challenges to ensuring consistent and sustained compendial compliance.
Subsequent articles in this series will cover a wide range of topics: providing information to help in the creation of an effective compendial review process; presenting a case study in compliance for excipients and raw materials; discussing considerations for monograph development; giving recommendations concerning global vs. national pharmacopoeias and the need for harmonization in order to establish consistent, global pharmacopoeia standards, which will help industry deliver medicines with consistent quality to extend and improve the lives of patients around the world while meeting health authority expectations. It is the authors’ goal for these articles to provide clear understanding about the need for pharmacopoeia compliance and practical guidance to assist those who perform this work to establish effective processes, partnerships and tools to maintain appropriate and timely compliance across the bio/pharmaceutical industry to the benefit of patients.
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.
1. WHO, “Review of World Pharmacopoeias,” World Health Organization, Working Document QAS/12.512/Rev.1 (March 2013).
2. N. A. Schwarzwalder and R. H. Bishara, American Pharmaceutical Review 7 (4), pp. 53-57 (July-August 2004).
3. EDQM, “EDQM Inspections and Trends of Deficiencies–Overview 2006 to 2018,” EDQM, Certification of Substances Department, Public Document PA/PH/CEP (18) 56 (April 2019).
4. WHO, Good Pharmacopoeial Practices, WHO Expert Committee on Specifications for Pharmaceutical Preparations Fiftieth Report, Technical Report Series No. 996, Annex 1, pp. 67-85 (2016).
5. BP, “How to Use the BP,” British Pharmacopoeia Website.
6. FDA, Naming of Drug Products Containing Salt Drug Substances, Guidance for Industry (CDER, June 2015).
7. FDA, Naming of Drug Products Containing Salt Drug Substances, Manual of Policies and Procedures (MAPP 5021.1 Rev.1) (CDER, Office of Pharmaceutical Quality, Effective December 7, 2017).