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28 BioPharm International eBook March 2020 www.biopharminternational.com 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. At the other end of the range of choices is proactive participation early enough that the company is the only one involved in the initial elaboration of the mono- graph, ref lecting their position as the only company with regu- latory approval at that time. One of the benefits of this approach is the possibility of developing a monograph that is harmonized across multiple pharmacopoeias. Even when a company chooses to participate, there will likely be differences between the resulting monograph and the approved reg- istrations. These differences may be understood in the transition from a "private" standard applica- ble to that company alone, to the "public" standard contained in the monograph. Knowing why the dif- ferences emerge, however, does not make it any easier to address them and ensure ongoing compliance. WHY DIFFERENCES EMERGE In the example provided here, the impact of the publication of a new monograph in the pharmacopoeia is explored, based on the expe- rience of one of the authors (6). Although the perspective is that of an innovator company, the infor- mation helps explain the compli- ance challenges experienced by all companies across the broader b i o/ p h a r m a c e u t i c a l i n d u s t r y. The impact of a new monograph depends, to some degree, on the answer to the following question: which came first—the pharmaco- poeia monograph or the regula- tory approval? For an innovator compa ny, t he approva l comes f irst, t y pica lly by ma ny yea rs, and the resulting impact of the monograph is due to differences b e t we e n t he newly p ubl i she d monograph and registrations that have b een approved for ma ny years. It is important to note that the differences are in the specifi- cations—the tests, methods, and acceptance criteria—for the drug substance and product that are t he subjec t of t he monog raph. T he dr ug substance or product do not typically change after the monograph is published, rather the quality filter, or lens, through which the material is evaluated has been changed. If differences in the monograph are significant enough, the challenge of comply- ing with the requirements pub- lished in the pharmacopoeia may become so difficult that the com- pany may be forced to take the product off the market. This is clearly not in the best interest of patients who may rely on the medicine. If the monograph in the phar- macopoeia is supposed to reflect the requirements in the approved registration, why should there be any differences? The answer lies in the practical basis of converting the approved registration, which is used by a single company, to the public standard in the monograph that will be used by all companies who manufacture and market that drug substance and product. In the authors' experience, 80% or more of the compliance challenges are related to differences in the control of impurities. According to the International Council for Harmonization (ICH) Q3A (7) and Q3B (8) guidance documents, an organic impurity in a drug sub- stance or product is either spec- ified, meaning it is individually listed and limited with a specific acceptance criterion, or unspeci- fied, meaning it is limited instead by a general acceptance criterion. For the innovator company who developed and validated the ana- lytical procedure used to control impurities in a drug substance, a specified impurity may be iden- tified by a relative retention time (RRT) in the chromatogram, based on sta nda rd i zat ion of t he col- umn and equipment used across the company. The use of RRT to identif y the specified impurit y becomes problematic when the method is incorporated into the monograph, since equipment and column standardization are no longer g uaranteed. Any analyst who has run a chromatographic procedure recognizes the differ- ences that may be observed, for example, when using different C-18 columns, as allowed in mono- graph methods. To add ress t his cha llenge in identifying a specified impurity, the pharmacopoeias often require that a reference standard be avail- able t hat enables u nequ ivoca l conf ir mation that an obser ved peak cor responds to the speci- fied impurity. In many instances, the company that developed the chromatographic procedure does not have a sample of the specified impurity to provide to the pharma- Regulatory Sourcebook Pharmacopoeia Compliance Series