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30 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m Pharmacopoeia Compliance Series Add. In elaborating the new monograph, the pharmaco- poeia may introduce an entirely new test and analytical pro- cedure to ensure appropriate quality for the material. The new method may also be added to ensure consistency with the testing typically requested in the pharmacopoeia technical guides for monograph content. A simple example of this is the addition of a new test in the monograph to ensure the identity of the drug substance. For the innovator company, identification for the material can often be assured through manufacturing process controls, so the approved registra- tion may include only the chromatographic retention time for the main peak to identify the drug substance. When the quality standard in the monograph is developed to apply to materials from other manufacturers, with possible testing by second or third parties, additional assurance of iden- tity may be needed. The additional test may include an IR identification or confirmation of the counterion in a drug substance that is a salt. The appropriate option in this situ- ation is likely to "add" the new test to the quality standard, increasing the workload in the laboratory. Again, no update to product registrations is necessary because the current testing still ensures compliance with what is approved; there is now additional testing beyond the registration and no compliance gap. An alternate decision in this scenario is for the company not to add the new monograph method, given the process controls for the material. There should be technical justification to document that the material "will pass if tested". In this risk-based approach, the company would not necessarily need to file this justification, but it should be available on inspection if regulators ask how the company ensures compliance with the additional test in the monograph. Replace. Some monographs may introduce a procedure that is significantly different than what is included in the approved registration. A challenging example of this is a chromatographic procedure for assay and impurities that is significantly different than what is registered. This situation may arise for several reasons, including the preference by the pharmacopoeias to specify a single method for assay and impurities in all monographs covering the drug substance and the entire product line. At the time of monograph elab- oration, this preference makes sense to standardize the test method in the public standard across the product portfolio. Considering the earlier stages in the product lifecycle, how- ever, this approach is typically not ref lected in a company's approved registrations, because the development of the drug substance, followed by the initial formulation of the drug product, and the subsequent introduction of other strengths and dosage forms occur over several years. In this case, the company's compliance choices are either to "replace" the test method currently approved in the reg- istration with the monograph method or to "keep" the ap- proved method instead of the monograph method. Either of these choices requires a laboratory demonstration of equiv- alency between the currently approved method and the new monograph method to ensure compliance with both. This equivalency data can be used to justify the company's deci- sion, either upon submitting an update to the product regis- tration or upon inspection of the manufacturing and testing facilities by regulators. The equivalency evaluation requires allocation of laboratory resources, creating challenges due to competing priorities. However, this one-time activity to document the equivalency outcome can help minimize the impact to the company for ongoing, routine testing. On the other hand, if the methods cannot be demonstrated to be equivalent, then a company might instead have to default to the "add" option, running both test procedures to ensure compliance with the registration and monograph. Alterna- tively, data showing the methods do not give equivalent re- sults may be provided to the pharmacopoeia with a request to revise the procedure accordingly. Compared to the somewhat limited impact to the test- ing laboratory, the choice to "replace" an approved method has the opposite impact on product registrations. Switching from a test method that has already been approved by regu- latory agencies requires updates to the product registrations to justify the switch from the currently approved method to the monograph method. This can have a significant im- pact on the resources in the company's regulatory/chemistry, manufacturing, and controls (CMC) functions. For one large, multi-national company that was involved in the prospective harmonization pilot project, the deci- sion to replace the approved method with the monograph method required the submission of registration updates and variations in more than 150 countries (6). Indeed, the company made the decision to adopt the harmonized mono- graph in its entirety—the tests, methods, and acceptance criteria—replacing the detailed information previously included in the registrations. Not only was this time-con- suming on the front end, the registration updates began a process that took several years to complete, with different timelines for review and approval in different countries. As the regulators in some countries began to approve the regis- tration update, the review process in many other countries had not yet been completed. This created a compliance issue in the interim, with the adoption of the monograph approved in some impacted countries, but not yet in others. How can a company comply with both the monograph and existing registrations during this transitional period? One option is to perform testing Some monographs may introduce a procedure that is significantly different than what is included in the approved registration.