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www.biopharminternational.com March 2020 BioPharm International eBook 31 nificant enough to make compli- ance with the new requirements difficult. This is indicated by the small red and blue arrows in Figure 2, which are pointing in a slightly different direction than the aqua registration arrow. Among the dif- ferences were significant changes to the chromatographic procedure used for assay and impurities, as well as tightening of impurity con- trols, changing a previously spec- ified impurity to an unspecified impurity with a new limit of 0.10%, because there was no practical way to identify that impurity peak in the chromatogram. The impact of these changes goes well beyond the US and Europe, because regu- lators in many countries around the world look at the USP and Ph. Eur. monographs as quality stan- dards that must be met for med- ic ines in t hese cou nt r ies. T he monograph situation in the figure becomes more complicated as other pharmacopoeias, such as those in Japan (Japanese Pharmacopoeia [JP]) and China (Chinese Pharmacopoeia [ChP]), subsequently develop their ow n requirements, which may differ from the USP and Ph. Eur. monograph, if not harmonized. Ultimately, there may be as many as 40 different pharmacopoeias that contain monographs applicable to the drug substance or product (10). The overall picture for pharmaco- poeias is represented by the large purple arrow, which is not fully aligned with the large aqua arrow for product registrations. At the point when the phar- macopoeia monograph has been p ubl i she d a s of f ic i a l, c omp a - nies must comply with the new requirements contained therein, in addition to comply ing w ith their approved registrations. The question is how a company can resolve d i f ferences a nd ensu re alignment with both the mono- graph requirements and the reg- istrations. The answer is that this is done t hrough mod if icat ions to testing procedures and limits in the qualit y standard and/or updates to the product registra- tions. It must be recognized that implementing these changes can have significant impact on avail- able resources, either performing additional testing or submitting updates to 150 or more registra- tions around the world. It is incorrect for a company to assume they do not need to comply with the monograph just because they have a separate regulatory approval (4). Regulatory agencies around the world expect compli- ance with the requirements in the phar macopoeia, including new monographs, that are applicable in their country. This is well under- stood, for example, in Europe and in Japan where it is known that compliance with the new mono- graph is required. It is not as well understood, but equally true (3), t hat F DA requ i res compl ia nce with the USP monograph as man- dated in the Federal Food, Drug, and Cosmetic Act. The challenge becomes how to resolve differences between the monograph and prod- uct registrations. ADDRESSING DIFFERENCES IN LIMITS In some cases, the monograph may include differences in acceptance criteria for certain tests when com- pared to the approved registration. The practical basis for these dif- ferences was discussed above. The monograph limits may be either tighter or wider, and the available options to ensure compliance are either to adopt or not to adopt the different limits in the monograph. However, the choice is not quite as flexible as suggested by this state- ment. Recalling that a company must comply with the approved registration and the monograph, if the monograph limit is tighter than that listed in the registration, then the tighter limit must be applied going forward to ensure compliance with the monograph. It is possible that a company may have difficulty meeting the tighter limit, which may necessitate communication with the pharmacopoeia regarding possible revision to the monograph, or discussion with the regulatory agencies about possible approaches to ensure the product will continue to be available for patients. If the monograph limit is wider (e.g., the assay limit has been wid- ened to reflect analytical variabil- ity), then a company can choose to apply the wider limit, but this requires updates to registrations with regulatory approval needed in 150 or more countries to allow the use of the wider criteria, even though this is listed in the phar- macopoeia. Different limits will be required in different countries if some of the regulators do not approve the registration updates. Alternatively, the company may choose not to apply the wider lim- its, which may seem somewhat counterintuitive. Maintaining the tighter limits as approved in the registration, however, rather than Regulatory Sourcebook Pharmacopoeia Compliance Series It is incorrect for a company to assume they do not need to comply with the monograph just because they have a separate regulatory approval.