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Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 29 new monograph is required. It is not as well understood, but equally true (3), that FDA requires compliance with the USP monograph as mandated in the Federal Food, Drug, and Cos- metic Act. The challenge becomes how to resolve differences between the monograph and product registrations. Addressing differences in limits In some cases, the monograph may include differences in acceptance criteria for certain tests when compared to the approved registration. The practical basis for these differ- ences 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 f lexible as suggested by this statement. 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 ap- plied going forward to ensure compliance with the mono- graph. It is possible that a company may have difficulty meeting the tighter limit, which may necessitate commu- nication with the pharmacopoeia regarding possible revi- sion 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 widened to ref lect analytical variability), then a com- pany 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 pharmacopoeia. Different limits will be required in different countries if some of the regulators do not approve the registration updates. Alterna- tively, the company may choose not to apply the wider limits, which may seem somewhat counterintuitive. Maintaining the tighter limits as approved in the registration, however, rather than switching to the wider monograph limits means no updates would be needed to the registrations. Meeting the filed limits, which are tighter, obviously ensures compli- ance 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 maintain- ing the tighter limits is a source of supply change, shifting from internal manufacture of the drug substance to an ex- ternal partner, or from one external partner to another. The company must now insist that the contract manufacturer meet the tighter limits 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 company 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 lexibility in how a com- pany chooses to comply with the monograph and regis- trations. However, in considering differences in analytical methods, the range of options is limited and includes the following: Merge, Add, Replace, or Keep. These choices can be denoted as the "MARK" principle (Table I), and the deci- sion of which to apply will depend on the specific situation and the level of risk a company is willing to take. The most appropriate option often becomes clear when considering how significant the analytical method differences are. This is detailed below, with an indication of the potential impact to the analytical procedures and to the product registrations. Merge. The "merge" approach to compliance involves in- corporating or merging any additional requirements from the monograph into the testing already performed by the com- pany per the approved registration. This approach is generally applicable to minor method differences, such as additional system suitability criteria listed in the monograph beyond what is currently done. The additional criteria for a chromato- graphic procedure may include peak symmetry, resolution, or tightening of the %RSD for multiple injections. It would be difficult to defend a decision not to include these addi- tional criteria since they are intended to demonstrate that the method is suitable to provide a valid result. If the laboratory can meet the additional system suitability criteria, they may be simply merged into the existing analytical procedure used for quality testing. If the criteria cannot be met, then discus- sion with the pharmacopoeia may be necessary for guidance on how to comply with the criteria, or to consider a change to the criteria in the monograph method to reflect the labora- tory's experience. No update to the procedure in the product registration is necessary with the "merge" option because the company is still complying with the requirements already ap- proved by the regulators, and doing even more by complying with the additional criteria in the monograph. 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).