Pharmaceutical Technology - September 2019

Pharmaceutical Technology - Regulatory Sourcebook

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Page 28 of 54

Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 29 with their product registrations as approved in countries around the world. This is true whether the pharmaco- poeia references are specifically listed in the registration, or because the pharmacopoeias provide additional, well- recognized quality standards. The compliance challenge is increased by t he sheer number of pharmacopoeias that exist in important markets, often with conf licting 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 f lexibility in how a company ensures appropriate compliance to the multitude of compendial requirements. But in this f lexibility, 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 ar- ticles intend to give consistent language to, and aware- ness 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 compli- ance 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 pharma- copoeia authorities. Along with the understanding and assistance provided to those who perform this work, there is the goal of ensur- ing 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. The legal and regulatory basis for pharmacopoeia compliance Pharmacopoeias are often referenced in the laws and regu- lations of countries around the world to help ensure drug quality, safety, and efficacy. In the United States, the Fed- eral 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 ar- ticles recognized in the official USP–NF. FDA has respon- sibility 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 Phar- macopoeia (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 De- vices 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 coun- tries 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 re- sponsibility for publishing the associated pharmacopoeias. Companies must comply with compendial requirements and must also remain up to date with changes made to the requirements. In an article published in 2004 on the bio/pharmaceuti- cal industry's pharmacopoeial surveillance process (2), the need to remain compliant with "current" compendial re- quirements was emphasized to ensure updated standards are incorporated into a company's testing procedures. If there is no process for sur veillance, 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 specifi- cations … failed to implement changes to testing meth- odology 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 ap- plicable pharmacopoeia requirements, even as the require- ments change over time. Similar regulatory expectations to comply w it h current pharmacopoeia requirements can be found in Europe, Japan, and other countries, be- cause 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 gen- eral monographs among the deficiencies observed (3). The

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