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38 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 P h a r mTe c h . c o m industry associations that engage in constructive dialog with the pharmacopoeias. One recent advocacy development that has generated much interest is the elaboration of new compen- dial monographs and chapters that are prospectively harmo- nized from the beginning; an initiative that has been enabled by bilateral and multilateral agreements between pharmaco- poeias, and supported by monographs that are contributed by bio/pharmaceutical companies. The work of prospective harmonization—which is mutually beneficial to the industry, pharmacopoeias, regulators, and ultimately to global patients— has resulted in the successful development of many new com- pendial standards that are globally acceptable and applicable and serves as a model for proactive partnership between the industry and pharmacopoeias. There is another opportunity even further upstream to fa- cilitate compliance, which could be considered the beginning of compendial activities within a company. This opportunity may be described as compendial line-of-sight (C-LOS), which is aimed at developing analytical methods and specifications for drug products and their ingredients that are right-first-time (RFT). At a practical level, this means giving visibility to groups involved in product and method development regarding the expectations and norms of pharmacopoeias, so this understand- ing can be incorporated at the appropriate stage in the product lifecycle and reflected in the global drug product registrations. For all the potential benefit and simplification that could be achieved through C-LOS, it must also be acknowledged that it has rarely been incorporated in the processes for drug develop- ment in bio/pharmaceutical companies, due to limited resources and competing priorities. The goal of C-LOS, however, provides a potentially useful approach to compendial compliance, so consideration of how to move in this direction should still be pursued. Fundamentally, early conversation and collaboration across a variety of functional areas is necessary, with appropri- ate processes and tools developed to make C-LOS possible and sustainable. The overall compendial activities have long been carried out by multinational companies for changes published by the global pharmacopoeias, which may be defined as those that are accept- able to regulatory agencies well beyond the geographical bound- aries covered by the pharmacopoeia. For example, regulators in many countries around the world accept compliance with the compendial standards published in the European Pharmaco- poeia (Ph. Eur.), British Pharmacopoeia (BP), and United States Pharmacopeia–National Formulary (USP–NF). But the end-to- end description of compendial affairs activities is not complete without recognizing the need to also address compendial stan- dards listed in national pharmacopoeias, which form the legal requirements in these individual countries and are important for ensuring access to medicines for patients in these markets. Among the 40 pharmacopoeias published around the world that must be considered in order to ensure compliance are those in Japan, China, India, Brazil, Russia, and Korea. Given this end-to-end perspective, a company must ensure sufficient resources are available and organized within an ap- propriate functional area to enable and facilitate the specific work that must be performed by the individuals assigned to carry out these tasks. Cross-functional and cross-divisional processes, partnerships, tools, and training are needed to en- able effective execution of the activities that ensure ongoing compendial compliance. Challenges to pharmacopoeia compliance The challenges that make pharmacopoeia compliance dif- ficult (Table I) can best be examined through the end-to-end framework detailed previously to help address the impact of Table I. Challenges to pharmacopoeia compliance. Overall • Need to comply throughout entire product lifecycle. • Need to comply with both product registration and pharmacopoeia requirements on release and stability. • Complex compendial revisions and short time available to implement changes. External • Multiple regulatory expectations and processes around the world. • Multiple pharmacopoeia requirements published around the world. • Lack of broad regulatory and pharmacopoeia harmonization. • Significant number of compendial revisions published by pharmacopoeias. • Appropriate use of compendial reference standards; qualification of in-house standards. Internal • Lack of broad understanding of the need for, the complexity of, and the challenges to compliance. • Need to establish and maintain partnerships with internal stakeholders, with clearly defined roles and responsibilities. • Lack of compendial line-of-sight (C-LOS) in product and analytical development. • Need for effective compendial processes, with tracking and communication tools. • Complex change control processes that make on-time implementation difficult. Pharmacopoeia Compliance Series