Why Pharmacopoeia Compliance Is Necessary

Home , British Pharmacopoeia, Pharmacopoeia

Pharmacopoeia Compliance Series Why Pharmacopoeia Compliance Is Necessary

J. Mark Wiggins and Joseph A. Albanese

ompliance 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 Cfundamental 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 MJH Life Stock.adobe.com - iQoncept Sciencesexcipients used in these products. Across the entire industry and within any given company, it is crucial that there In this series of articles, the authors provide an understanding is awareness and understanding of this need for pharma- about the need for pharmacopoeia compliance and practical guidance to assist thoseNot who perform for this work.public copoeia distribution compliance—from the CEOs of multi-national The following articles can be found within this ebook innovator and generic-drug companies to the leadership and online at www.PharmTech.com/compendia: at small start-ups and contract manufacturers, to manag- • Why Pharmacopoeia Compliance Is Necessary ers in their respective functional areas, to the analytical • Why Pharmacopoeia Compliance Is Difficult bench chemists and microbiologists testing active ingre- • A Brief History of Pharmacopoeias: A Global Perspective dients and excipients for use in drug products—so that • Global Pharmacopoeia Standards: global patients have uninterrupted access to the critical Why Harmonization is Needed medicines that extend and improve their lives. • Harmonization Efforts by Pharmacopoeias There is often insufficient understanding, however, by and Regulatory Agencies Upcoming articles in this series will include the following: stakeholders at all levels of the need to comply with re- • Revision Process for Global/National Pharmacopoeias quirements in the pharmacopoeias. This situation can lead • Surveillance Process for Industry: Monitoring to a lack of appropriate attention and resources allocated Pharmacopoeia Revisions to ensure compliance. The compliance risk can result in • Monograph Development: Why and When to Participate observations in FDA 483s, which may be summarized as • Monograph Development: follows: the company must comply with applicable com- How to Participate; How to Harmonize pendial standards in the United States Pharmacopeia–Na- • A Practical Approach to Pharmacopoeia Compliance tional Formulary (USP–NF). A more nuanced observation • A Case Study in Pharmacopoeia Compliance: is that the company must comply with “current” compen- Excipients and Raw Materials • Pharmacopoeia Compliance: dial requirements, which introduces the need to monitor Putting it All Together; What is on the Horizon 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 J. Mark Wiggins is owner and compendial in Europe, Canada, Australia, Japan, China, and in laws consultant with Global Pharmacopoeia Solutions and regulations around the world. LLC. Joseph A. Albanese is the director of Analytical The situation is made even more complex because Strategy and Compliance at Janssen Research and Development, LLC. a company must comply with the compendial requirements that are applicable in a particular country, and also

28 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 PharmTech.com with their product registrations as approved in countries macopoeia (Ph. Eur.) monographs, which are applicable to around the world. This is true whether the pharmaco- all substances, preparations, and pharmaceutical forms poeia references are specifically listed in the registration, appearing in it when requesting marketing authorization. or because the pharmacopoeias provide additional, well- In Japan, the Law on Securing Quality, Efficacy, and Safety recognized quality standards. The compliance challenge of Products including Pharmaceuticals and Medical De- is increased by the sheer number of pharmacopoeias vices indicates the need for compliance with the Japanese that exist in important markets, often with conflicting Pharmacopoeia (JP) in order to standardize and control requirements due to lack of harmonization among the the quality of drugs. The legal and regulatory framework pharmacopoeias. This lack of broad harmonization is the for pharmacopoeia compliance in these and other coun- current reality, despite long-term commitment and effort tries can be found in a useful summary prepared by the by pharmacopoeias to narrow the divide between their World Health Organization (WHO) in conjunction with published standards. Somewhat balancing this high-level recent International Meetings of World Pharmacopoeias view of the compliance challenge is the fact that there is (IMWP) (1). This information, with appropriate updates some flexibility in how a company ensures appropriate by the authors, is provided for several countries/regions compliance to the multitude of compendial requirements. in Table I, along with a list of the authorities that have re- But in this flexibility, there is also complexity, due to the sponsibility for publishing the associated pharmacopoeias. number of approaches that may be taken to demonstrate compliance, with the potential for different situations to drive the approach in different directions. Companies must comply with It is against this challenging backdrop that the authors have undertaken the preparation of a series of articles compendial requirements to provide a common understanding of this far-reaching and must also remain up to and complex situation and to detail practical ways that pharmacopoeia compliance may be addressed. The ar- date with changes made to ticles intend to give consistent language to, and awareness of, the tasks associatedMJH with the Lifeeffort and toSciences give the requirements. specific guidance to those groups and individuals within a company who are charged with ensuring ongoing compliance with pharmacopoeiaNot requirements. for While public focusing Indistribution an article published in 2004 on the bio/pharmaceuti- on the situation for innovator and generic companies, the cal industry’s pharmacopoeial surveillance process (2), the information is also potentially helpful in bringing greater need to remain compliant with “current” compendial re- awareness and understanding to regulatory and pharma- quirements was emphasized to ensure updated standards copoeia authorities. are incorporated into a company’s testing procedures. Along with the understanding and assistance provided If there is no process for surveillance, or if the process to those who perform this work, there is the goal of ensur- is ineffective in identifying and addressing compendial ing continued availability of medicines with consistent changes, the resulting lack of compliance may be listed quality, which comply with compendial and regulatory in regulatory observations. Specific examples from FDA expectations. Achieving compliance for these medicines 483s are included in the article, with observations such ensures meeting the needs of patients around the world, as: “… the firm did not follow the current USP specifi- regardless of where the patients live, where the medicines cations … failed to implement changes to testing meth- are manufactured, or which pharmacopoeias may apply. odology as required by USP … and did not address raw material monograph updates.” Examples of more recent The legal and regulatory basis compendial compliance observations from FDA 483s are for pharmacopoeia compliance summarized in Table II. The common theme in all these Pharmacopoeias are often referenced in the laws and regu- observations is the need to maintain alignment with ap- lations of countries around the world to help ensure drug plicable pharmacopoeia requirements, even as the require- quality, safety, and efficacy. In the United States, the Fed- ments change over time. Similar regulatory expectations eral Food, Drug, and Cosmetic Act (FD&C Act) defines to comply with current pharmacopoeia requirements the term “official compendium” as the official USP–NF or can be found in Europe, Japan, and other countries, be- any supplement to it and the term “drug” to include ar- cause the regulatory and compendial landscape is truly ticles recognized in the official USP–NF. FDA has respon- global. A review of data from inspections conducted by sibility to enforce compliance with USP–NF requirements. the European Directorate for the Quality of Medicines In Europe, the European Union Directives on Medicines and HealthCare (EDQM) between 2006 and 2018 includes for Human and Veterinary Use (2001/82/EC and 2001/83/ compliance issues with Ph. Eur. general methods and gen- EC) maintain the mandatory character of European Phar- eral monographs among the deficiencies observed (3). The

Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 29 Pharmacopoeia Compliance Series

Table I. Legal/regulatory basis for pharmacopoeia compliance (1). Source: World Health Organization.

Publication Published by Legal/regulatory basis

Published by the USP Convention The USP and NF are recognized as official compendia United States Pharmacopeia (a private, not-for-profit organization under the Federal Food, Drug and Cosmetic Act (FD&C and National Formulary that is independent of the US Act). See, for example, 501(b), 502(e)(3)(b) and others. See (USP–NF) government). also USP general notices section 2.30. European Union (EU) Directives 2001/82/EC and 2001/83/ Published by the European European Pharmacopoeia EC, as amended, on medicines for human and veterinary Directorate for the Quality of (Ph. Eur.) use maintain the mandatory character of European Medicines and HealthCare (EDQM). Pharmacopoeia monographs. Published by the British Pharmacopoeia Commission under The BP is authorized under terms of the Medicines Act British Pharmacopoeia (BP) the guidance of the Medicines and 1968 (Section 99), superseded by the Human Medicines Healthcare Products Regulatory Regulations, 2012 (Section 317(1)). Agency (MHRA). The JP is published in accordance with the Act of Published by the Japanese Securing Quality, Efficacy, and Safety of Products Japanese Pharmacopoeia government as a ministerial including Pharmaceuticals and Medical Devices, which is (JP) notification by the Ministry of Health, the most fundamental law for pharmaceutical regulation in Labour and Welfare (MHLW). Japan. The ChP is published under laws established in 1950 by the Ministry of Health. The Drug Administrative Law issued Published by the Chinese by the National People’s Congress, effective from 2001 Pharmacopoeia Commission of and updated in 2015, states that the Pharmacopoeia of the Chinese Pharmacopoeia the National Medical Products People’s Republic of China and the drug standards issued (ChP) Administration (NMPA), formerly the by the drug regulatory department under the State Council China Food and Drug Administration shall serve as the national drug standards. The Drug (CFDA). Registration regulation issued by CFDA in 2007 defines the MJH Life Sciencesrole of ChP in drug registration. Published by the Indian Pharmacopoeia Commission on Notbehalf offor the Ministry public of Health distribution The IP is authorized under the Indian Drugs and Cosmetics Indian Pharmacopoeia (IP) and Family Welfare of India, with Act (1940) and Rules (1945). oversight from the Central Drugs Standard Control Organization (CDSCO). The State Pharmacopoeia of the Rules of elaborating general monographs and Russian Federation (SP RF) is Russian Pharmacopoeia (SP monographs and including them in the State published by the Ministry of Health RF) Pharmacopoeia were enacted by Federal Law No. 61-FZ (MoH) as the authorized federal on Circulation of Medicines (2010). executive body. takeaway message is clear; companies must comply with the guidance of WHO, to discuss collaboration and har- compendial requirements and must also remain up to date monization in today’s globalized compendial, regulatory, with changes made to the requirements. This ongoing re- and supply situation for drugs. The main suggestion to vision to the pharmacopoeias around the world poses one come out of these meetings was the development of Good of the main challenges for companies and will be further Pharmacopoeial Practices (GPhP) recently published by addressed in later articles in this series. WHO (4). WHO’s GPhP states, “The primary objective of the Purpose and content GPhP guidance is to define approaches and policies in of pharmacopoeias establishing pharmacopoeial standards with the ultimate Having highlighted the need to comply with compendial goal of harmonization” (4). This focus on compendial har- requirements, with examples of observations resulting monization is reflected in the origins of several of the from non-compliance, it is helpful to have an overall un- pharmacopoeias (to be detailed in another article in this derstanding of the role pharmacopoeias play to support series) and is critical to the ongoing goal of providing the availability of medicines. This understanding may medicines with consistent quality to patients around the be found in the history, purpose, and content of phar- world. The WHO document goes on to list the purpose macopoeias. Many of the pharmacopoeias from around and role of the pharmacopoeias: “A pharmacopoeia’s core the world have met during the past several years, under mission is to protect public health by creating and making

30 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 PharmTech.com available public standards to help ensure the quality of cific monograph components, considerations for the use medicines. Pharmacopoeia standards support regulatory of alternative methods, rules for rounding, and a defini- authorities in controlling the quality of pharmaceutical tion of “about”. They have been described anecdotally as substances, their finished pharmaceutical products (FPPs), the most important pages of the pharmacopoeia that most and related materials and will provide a tool with which users have never read. Thus, reading and understanding the user or procurer can make an independent judgment the general notices is critical to ongoing pharmacopoeia regarding quality, thus safeguarding the health of the compliance. public.” A search through the pharmacopoeias reveals that they contain general notices, general chapters, general mono- During formulation graphs, specific monographs for drug products, drug substances and excipients, and additional information related development, consideration to packaging, labeling, storage, etc. All this information must be taken together to determine the specific quality must also be given to requirements for bio/pharmaceutical products. Within each pharmacopoeia, there is a section referred compendial monographs for to as general notices, which is critical to the full understanding of the scope and technical approaches in that excipients. pharmacopoeia. As stated in the USP–NF, the general notices section presents the basic assumptions, defini- There are more than 350 general chapters in USP–NF, tions, and default conditions for the interpretation and and more than 370 general texts in Ph. Eur., including application of the USP–NF, and the requirements apply to general monographs and chapters. Many of the general all articles recognized in the compendia and to all general chapters in the pharmacopoeias are mandatory and en- chapters, unless specifically stated otherwise. Similarly, forceable by regulatory authorities, containing informa- the general notices in Ph. Eur. and other pharmacopoeias tion on specific chemical, biological, and microbiological apply to all monographsMJH and other texts Life in the pharmaco Sciences- test methods and assays, as well as specific requirements poeia. The general notices provide a wide range of impor- for particulate contamination and packaging components, tant information, from a statement of what conformance for example. Other general chapters may instead be in- to compendial standardsNot means, tofor a description public of spe- formational distribution and not necessarily enforceable, intended to

Table II. Examples of compendial compliance observations from FDA 483s. USP is United States Pharmacopeia. Year Observation The firm has not established that your purified water system is adequately designed, controlled, maintained, and 2018 monitored to ensure it consistently produces water that meets Purified Water USP monograph specifications and appropriate microbial limits. The firm has not established or implemented all appropriate specifications for the active pharmaceutical ingredient 2017 in accordance with the accepted USP standards and consistent with the manufacturing process. Specifically, the firm has not included a control of all process impurities such as residual solvents. The firm does not always follow official USP monographs when testing drug products for release and distribution to 2017 the United States. 2016 Growth promotion test is not performed in accordance with standard pharmacopeia. The USP test method for Loss on Drying, which is used for the release of finished product to market has not been 2016 verified. The firm could not provide documentation to show that you did not use an expired batch of USP reference standard. 2016 The laboratory staff does not document and record the expiration dates for official USP standards. USP-grade active pharmaceutical ingredients are not always fully tested against USP monographs (e.g., 2013 Identification, Acidity, Alkalinity, Chloride, Sulfate, Residue on Ignition). Compendial methods for active pharmaceutical ingredients are not verified under actual conditions of use (e.g., 2012 Water Determination, Loss on Drying, Reside on Ignition). The firm does not perform current USP monograph testing (e.g., Assay, Identification, Distillation Range) on the final 2010 active pharmaceutical ingredients prior to distribution for use in human and veterinary drug products. USP active pharmaceutical ingredients have been released for distribution by the firm prior to testing and/or which 2009 did not meet USP specifications (e.g., Assay, Loss on Drying). The firm’s procedure for stability testing is insufficient. The firm does not test the stability samples of USP-grade 2009 material to ensure compliance with the USP method and limit for moisture content.

Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 31 Pharmacopoeia Compliance Series

Figure 1. Impact of pharmacopoeia throughout drug product lifecycle.

API Development Regulatory Submission/Approval

Dosage Form Development Marketing Exclusivity

Clinical Trials Patent Expiration Generic Entry

Early Development Commercialization Supply

Nomenclature API Monographs

Excipient Monographs Product Monographs

General Chapters (e.g.): Water/Loss on Drying, Elemental Impurities, Residual Solvents, Chromatography, Dissolution, Dose Uniformity, Microbial Limits, Sterility

provide background knowledge and practical consider- eral chapters numbered <1> through <5> serve the same ations that are useful toMJH bio/pharmaceutical Life manufac Sciences- function as the Ph. Eur. general monographs, and include turers’ understanding of the production, testing, and quality requirements for injections, oral drug products, overall quality of their products. In the USP–NF, these topical and transdermal products, mucosal products, and informational chapters Notare numbered for above public<1000> and inhalation distribution products. include <1079> “Good Storage and Distribution Practices for Drug Products,” <1121> “Nomenclature” and <1226> “Verification of Compendial Procedures.” The Ph. Eur., Specific monographs JP, and other pharmacopoeias similarly contain general chapters that are mandatory and enforceable, as well as provide the minimum quality chapters that are stated as being for information and non- requirements that must be mandatory. It is worth noting that Ph. Eur. Chapter 5.4 “Residual Solvents” represents the information contained met for drug products and separately in the International Council for Harmoniza- tion (ICH) Q3C guideline, a reminder of the important ingredients, and apply to connection that may exist between regulatory guidance and pharmacopoeia requirements. This is also true for all manufacturers of these Ph. Eur. Chapter 5.20 “Elemental Impurities,” USP <232> “Elemental Impurities–Limits,” and the ICH Q3D Guide- materials. line on Elemental Impurities, along with the associated removal of the compendial test for heavy metals from the Specific monographs provide the minimum quality re- pharmacopoeias, which further serves as an example of quirements that must be met for drug products and ingredi- the significant challenges for the bio/pharmaceutical in- ents, and apply to all manufacturers of these materials, both dustry to ensure compliance with updated regulatory and innovator and generic-drug companies. A monograph in- compendial requirements. cludes the name of the ingredient or preparation; the defini- General monographs typically provide overall quality tion, packaging, storage, and labeling requirements; and the requirements that are applicable to a specific dosage form specification, consisting of a series of tests, procedures and or route of administration for drug products. In the Ph. acceptance criteria. In the USP–NF, there are currently more Eur., there are general dosage form monographs for cap- than 4900 specific monographs, and in Ph. Eur., there are sules, tablets, eye preparations, nasal preparations, paren- more than 2400 monographs. These specific monographs

FIGURE COURTESY OF THE AUTHORS. THE OF COURTESY FIGURE teral preparations and many others. In USP–NF, the gen- cover the entire range of bio/pharmaceutical products, in-

32 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 PharmTech.com cluding excipients, small-molecule drug substances, biologi- ties, and microbiological evaluation will likely be used for cal products, and vaccines. A few examples are the mono- quality release of the material later in the lifecycle. Similarly, graphs for the excipient hypromellose, the drug substances information listed in the chromatography chapter should be acetaminophen (as it is named in the USP) or paracetamol considered during analytical method development, because (as it is named in Ph. Eur.), and sitagliptin phosphate, and a many of the compendial requirements can be incorporated variety of drug products, including sitagliptin tablets, inf- into the test procedures, such as method repeatability and liximab concentrated solution, and human papillomavirus resolution for system suitability. Consideration should also vaccine. Monographs often require official reference stan- be given at the appropriate stage of product development to dards, which are physical materials that may be purchased compendial requirements for method validation, such as USP from the pharmacopoeia to be used in conjunction with <1225> “Validation of Compendial Procedures,” because this the test methods in the monograph to assess specific qual- information will ultimately be used to support the product ity attributes of the drug product or ingredient, including registration. assay and impurities. 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 prod- Moving to regulatory uct is registered or licensed. Drug product quality and func- submissions and product tional characteristics should be evaluated according to these compendial requirements, because this is the regulatory ex- commercialization, it is pectation. Depending on the dosage form being developed, applicable chapters include uniformity of dosage units (con- important to understand the tent uniformity or mass variation), dissolution, particulate contamination, microbiological tests, sterility, and chroma- compendial requirements tography for assay and impurities. Pharmacopoeias also contain general chapters and general dosage form monographs for packaging,MJH storage, Life and Sciences that provide core requirements for drug products, including USP <1> “Injections,” Ph. Eur. monograph [520] on Parenteral distribution. preparations and Ph. Eur. monograph [478] on Tablets. Not for public Duringdistribution formulation development, consideration must also be given to compendial monographs for excipients. As Information contained in the pharmacopoeia is inter-re- stated in the pharmacopoeias, and perhaps more importantly, lated, and the requirements from one section must be utilized as expected by health authorities around the world, excipi- in conjunction with other sections. A specific monograph ents used in drug products must comply with the applicable may include a reference to a general dosage form monograph, monograph requirements published in the pharmacopoeias. along with references to applicable general chapters, with the Lack of awareness or attention to this point jeopardizes drug basic underpinnings contained in the general notices. Bio/ product approval and ultimate compliance. The existence of pharmaceutical companies must understand and apply these so many pharmacopoeias around the world with excipient pharmacopoeial requirements within this context. A guide, monographs that do not broadly align is a significant compli- titled “How to Use the BP,” was posted on the British Pharma- cating factor for compendial compliance and global product copoeia website (5) that provides an overview and illustration registrations. of the inter-relation of pharmacopoeia content. This guide Moving to regulatory submissions and product commer- forms a framework for navigating compendial requirements cialization, it is important to understand the compendial re- in the BP, and should be helpful, especially for those who may quirements for packaging, storage, and distribution. Failure be less familiar with the structure and use of pharmacopoeias. to take these general chapters into account as contained in the various pharmacopoeias may again have adverse impact Pharmacopoeia impact on regulatory approval and long-term compliance. Consid- throughout drug product lifecycle eration of these requirements may also be important when Pharmacopoeias impact drugs and their ingredients through- planning for and evaluating drug product stability. The use of out the entire product lifecycle (Figure 1). Beginning with the compendial reference standards for pharmacopoeial testing, development of a new drug substance or API, many of the or alternatively, of qualifying in-house primary or secondary pharmacopoeia general chapters should be considered for standards, must also be considered at an appropriate stage in potential quality and functionality testing. For example, the product and analytical development to meet the expecta- compendial tests listed in general chapters for water con- tions of regulatory agencies. tent or loss on drying, residual solvents, elemental impuri-

Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 33 Pharmacopoeia Compliance Series

Once dosage form along with consideration of how the pharmacopoeias impact drugs throughout their product lifecycle. The development is initiated, increasingly global environment for industry, regulators, and pharmacopoeias, where expectations and standards additional compendial do not always agree, represents one of the significant challenges to ensuring consistent and sustained compendial content becomes important. compliance. Subsequent articles in this series will cover a wide range Nomenclature used in pharmacopoeias for excipients, of topics: providing information to help in the creation of an drug substances, and drug products must also be consid- effective compendial review process; presenting a case study ered during the product lifecycle. The link between a prod- in compliance for excipients and raw materials; discussing uct’s generic name and the content of the active ingredient considerations for monograph development; giving recom- can be important in clinical trials to support dosing studies, mendations concerning global vs. national pharmacopoeias in developing product strengths, and for filing and label- and the need for harmonization in order to establish con- ing purposes, especially in the United States. USP <1121> sistent, global pharmacopoeia standards, which will help states that USP–NF titles for monograph articles are legally industry deliver medicines with consistent quality to extend recognized under the FD&C Act as the designations for use and improve the lives of patients around the world while in labeling the articles to which they apply and relate to the meeting health authority expectations. It is the authors’ goal adulteration and misbranding provisions of the Act. USP for these articles to provide clear understanding about the <1121> also contains a section on the monograph naming need for pharmacopoeia compliance and practical guidance policy for drug products containing salt drug substances. to assist those who perform this work to establish effective The USP Salt Policy stipulates that USP will use the name of processes, partnerships and tools to maintain appropriate the active moiety, which is the molecule or ion responsible and timely compliance across the bio/pharmaceutical in- for the physiological or pharmacological action of the drug dustry to the benefit of patients. substance, instead of the name of the salt, when creating drug product monographMJH titles for such Life a drug product.Sciences Acknowledgment The policy also stipulates that USP will base the strength The authors gratefully acknowledge the contribution of of the product on the active moiety. Companies need to Susan J. Schniepp for her technical review and helpful sug- be aware of the USP SaltNot Policy, which for is enforced public by FDA gestions distribution during the preparation of this series of articles. (6, 7), to avoid issues with the name and strength listed on drug product labeling and in registrations. The FDA References guidance (6) states that a drug product with labeling that 1. WHO, “Review of World Pharmacopoeias,” World Health Or- contains a name that is inconsistent with the applicable USP ganization, Working Document QAS/12.512/Rev.1 (March 2013), www.who.int/medicines/areas/quality_safety/quality_ monograph title risks being misbranded. Another example assurance/resources/InternationalMeetingWorldPharmaco- of the impact of pharmacopoeia nomenclature is the tran- poeias_QAS13-512Rev1_25032013.pdf?ua=1 sition from the excipient name hydroxypropyl methylcel- 2. N. A. Schwarzwalder and R. H. Bishara, American Pharmaceu- lulose to the shortened title hypromellose, which resulted tical Review 7 (4), pp. 53-57 (July-August 2004). in significant revisions to the ingredient listing on labels 3. EDQM, “EDQM Inspections and Trends of Deficiencies–Over- view 2006 to 2018,” EDQM, Certification of Substances De- and in registrations. partment, Public Document PA/PH/CEP (18) 56 (April 2019), Once a product is launched and reaches the end of ex- www.edqm.eu/sites/default/files/cep_edqm_inspections_ clusivity, compendial monographs for drug substances and_trends_of_deficiencies_2006_2018_pa_ph_cep_18_56. and drug products will be developed by the pharmaco- pdf poeia. This is generally accomplished with the support 4. WHO, Good Pharmacopoeial Practices, WHO Expert Commit- tee on Specifications for Pharmaceutical Preparations Fifti- of companies who have received regulatory approval for eth Report, Technical Report Series No. 996, Annex 1, pp. these products, to provide a public quality standard in the 67-85 (2016), www.who.int/medicines/publications/pharm- pharmacopoeia that is applicable to the product or material prep/WHO_TRS_996_annex01.pdf?ua=1 from all approved sources. Considerations for monograph 5. BP, “How to Use the BP,” British Pharmacopoeia Website, www. development, looking at the impact to both innovator and pharmacopoeia.com/how-to-use-the-bp 6. FDA, Naming of Drug Products Containing Salt Drug Sub- generic-drug companies, will be provided in a later article stances, Guidance for Industry (CDER, June 2015), www.fda. in this series. gov/media/87247/download 7. FDA, Naming of Drug Products Containing Salt Drug Sub- Conclusion stances, Manual of Policies and Procedures (MAPP 5021.1 In this article, the first in a series about compendial ac- Rev.1) (CDER, Office of Pharmaceutical Quality, Effective December 7, 2017), www.fda.gov/media/85022/download PT tivities in the bio/pharmaceutical industry, the basis for pharmacopoeia compliance expectations was provided,

34 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 PharmTech.com