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32 BioPharm International eBook March 2020 www.biopharminternational.com Regulatory Sourcebook Pharmacopoeia Compliance Series switching to the wider monograph limits means no updates would be needed to the registrations. Meeting the filed limits, which are tighter, obviously ensures compliance with the wider limits in the monograph. This approach requires no work by the company's regulatory group, but it could have major impact to other groups, including quality and supply. One situation showing the impact of maintaining the tighter limits is a source of supply change, shifting from internal manufacture of the drug substance to an exter- nal partner, or from one external partner to another. The company must now insist that the contract manufacturer meet the tighter lim- its in the registration, rather than the wider limits in the monograph (which would be suitable for all other customers). This results—at best—in higher cost paid by the company for the material or—at worst—the inability for the com- pany to obtain material meeting the tighter limits, with the obvious impact on supply of the medicine. ADDRESSING DIFFERENCES IN METHODS–"MARK" PRINCIPLE As noted previously, there is some f le x ibi l it y i n how a compa ny chooses to comply with the mono- graph and registrations. However, i n c on sid e r i n g d i f fe r e nc e s i n analytical methods, the range of options is limited and includes the following: Merge, Add, Replace, or Keep. T hese choices ca n be denoted as the "MAR K" princi- ple ( Table I), and the decision of which to apply w ill depend on the specific situation and the level of risk a company is willing to take. The most appropriate option often becomes clear when consid- ering how significant the analyti- cal method differences are. This is detailed below, with an indication of the potential impact to the ana- lytical procedures and to the prod- uct registrations. Merge The "merge" approach to com- pliance involves incorporating or merging any additional require- ments from the monograph into the testing already performed by the company per the approved reg- istration. This approach is gener- ally applicable to minor method differences, such as additional sys- tem suitability criteria listed in the monograph beyond what is cur- rently done. The additional criteria for a chromatographic procedure may include peak symmetry, reso- lution, or tightening of the %RSD for multiple injections. It would be difficult to defend a decision not to include these additional cri- teria since they are intended to demonstrate that the method is suitable to provide a valid result. If the laboratory can meet the addi- tional system suitability criteria, they may be simply merged into the existing analytical procedure used for quality testing. If the crite- ria cannot be met, then discussion with the pharmacopoeia may be necessary for guidance on how to comply with the criteria, or to con- sider a change to the criteria in the monograph method to reflect the laboratory's experience. No update to the procedure in the product registration is necessary with the "merge" option because the com- pany is still complying with the requirements already approved by the regulators, and doing even more by complying with the addi- tional criteria in the monograph. Add In elaborat ing t he new mono - graph, the pharmacopoeia may introduce an entirely new test and analy tical procedure to ensure appropriate quality for the mate- rial. The new method may also be added to ensure consistency with the testing t y pically requested in the pharmacopoeia technical guides for monograph content. A simple example of this is the addi- tion of a new test in the mono- graph to ensure the identit y of the drug substance. For the inno- vator company, identification for the material can often be assured through manufacturing process controls, so the approved registra- tion may include only the chro- matographic retention time for the main peak to identify the drug substance. When the quality stan- dard in the monograph is devel- oped to apply to materials from other manufacturers, with possible Merge • Incorporate additional requirements from the monograph into the method already used to comply with the registration (e.g., system suitability). Add • Include the monograph method in addition to the registered method (e.g., additional identification test). Replace • Switch from the registered method to the monograph method. Keep • Maintain the registered method instead of the monograph method. (NOTE: The "replace" or "keep" options require demonstration of method equivalency) Table I: Addressing differences in methods ("MARK" principle).