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www.biopharminternational.com March 2020 BioPharm International eBook 33 Regulatory Sourcebook Pharmacopoeia Compliance Series testing by second or third parties, additional assurance of identity may be needed. The additional test may include an IR identifica- tion or confirmation of the coun- terion in a drug substance that is a salt. The appropriate option in this situation is likely to "add" the new test to the quality stan- dard, increasing the workload in the laboratory. Again, no update to product registrations is neces- sary because the current testing still ensures compliance with what is approved; there is now addi- tional testing beyond the registra- tion 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 justifi- cation to document that the mate- rial "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 regula- tors 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 chal- lenging example of this is a chro- matographic 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 spec- ify a single method for assay and impurities in all monographs cov- ering the drug substance and the entire product line. At the time of monograph elaboration, this pref- erence makes sense to standardize the test method in the public stan- dard across the product portfolio. Considering the earlier stages in the product lifecycle, however, this approach is typically not reflected in a company's approved registra- tions, because the development of the drug substance, followed by the initial formulation of the drug product, and the subsequent intro- duction of other strengths and dos- age forms occur over several years. Some monographs may introduce a procedure that is significantly different than what is included in the approved registration. I n t h is case, t he compa ny 's compliance choices are either to "replace" the test method c ur- rently approved in the registration with the monograph method or to "keep" the approved method i n s t e a d o f t h e m o n o g r a p h method. Either of these choices requires a laboratory demonstra- tion of equivalency between the currently approved method and the new monograph method to ensu re compl ia nce w it h bot h. This equivalency data can be used to just if y t he compa ny 's dec i- sion, either upon submitting an update to the product registration or upon inspection of the manufac- turing and testing facilities by reg- ulators. 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 min- imize 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, run- ning both test procedures to ensure compliance with the registration and monograph. Alternatively, data showing the methods do not give equivalent results may be provided to the pharmacopoeia with a request to revise the procedure accordingly. Compared to the somewhat lim- ited impact to the testing 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 regulatory agen- cies requires updates to the prod- uct registrations to justify the switch from the currently approved method to the monograph method. This can have a significant impact on the resources in the company's regula- tory/chemistry, manufacturing, and controls (CMC) functions. For one large, multi-national company that was involved in the prospective harmonization pilot project, the decision to replace the approved method with the mono- graph method required the sub- mission of registration updates and variations in more than 150 coun- tries (6). Indeed, the company made the decision to adopt the harmo- nized monograph in its entirety— the tests, methods, and acceptance criteria—replacing the detailed information previously included in the registrations. Not only was this time-consuming 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 reg- istration update, the review process in many other countries had not yet been completed.