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40 BioPharm International eBook March 2020 www.biopharminternational.com • Creation of new or revised ICH g uidance doc uments (e.g., Q12 or Q14). • I mp le me nt at io n o f ne w technology, such as contin- uous manufacturing. • N e w d r ug pro duc t pl at- forms, such as oligonucle- otides or gene therapies. • D e ve lopme nt of ne w or r e v i s e d r e g u l a t i o n s b y he a lt h aut hor it ie s (e .g., microplastics use in medici- nal products) (18). I n t he c o m i n g y e a r s , it i s expected the following issues will result in new requirements in the pharmacopoeia or changes to the approaches currently established, to ensure that quality standards exist for the medicines being man- ufactured. The evolving standards will impact the bio/pharmaceuti- cal industry and companies need to monitor these "on the hori- zon items" to try to influence the direction or advocate for change, if needed, and to quickly adapt the established processes in their com- pany's compendial affairs program to ensure compliance w ith the updated requirements. NEW APPROACHES TO SPECIFICATIONS Flexible monographs T he use of a "one-size-f its-all" approach for methods has always been challenging for the pharma- copoeia authorities, especially as drug substances and drug prod- uct formulations increase in com- plexity. The pharmacopoeias have used different approaches to solve issues when they arise from this complexity. Even today, there are new approaches being considered, which require the attention of the industry to advocate during the elaboration process or to comment on new draft proposals. The United States Pharmacopeia (USP) provides for the use of flexible monographs (8,9,19). In this approach, more than one test is listed for the drug substance or drug product. Other global pharmacopoeias use differ- ent approaches to solve this issue, while national pharmacopoeias currently have no defined policy or procedure to address the challenge. It is anticipated that the national pharmacopoeias will change in the coming years to address the con- flicts caused by more complex drug substances and drug products. For example, a notice was published by t he Japanese Phar macopoeia ( JP) indicating that the proposed monograph for eribulin mesylate, which contains 19 chiral carbons, results in a complex situation for impurities and degradants (20). The proposal requires manufactur- ers to share their control strategy, based on which starting materi- als are used, with the JP Expert Committee to ensure equivalency to the proposed monograph. Because each manufacturer uses a unique process and formulation for its drug products, differences in dissolution are not uncommon. For small-molecule drug products, the flexible approach is used rou- tinely for the dissolution test, which is not only dependent upon the drug substance solubility in a chosen medium, but on the excipients used in the formulation and the manufac- turing process. Because each manu- facturer uses a unique process and formulation for its drug products, differences in dissolution are not uncommon. The US Pharmacopeial Convention (USP) has solved this by listing all different dissolution tests in a monograph. It is a reasonable solution that provides relief when compliance to an existing standard might not be achieved due to the differences in chemical and phys- ical properties of the drug product formulation. By contrast, surveys are being conducted by the British Pharmacopoeia (BP) Commission and the European Pharmacopoeia (Ph. Eur.) Commission to gather stake- holder input in determining whether the dissolution test in drug product monographs should include specific methodology and limits or simply have the test and acceptance criteria listed "as approved by the compe- tent authority" (21,22). The absence of a specific dissolution test in the monograph would require each new manufacturer to develop an appro- priate dissolution method and have it approved by the health author- ity as part of the product registra- tion. The dissolution requirement listed in the general monograph for dosage forms would still be met to provide the proper quality for the drug product without the pharmaco- poeia including specific details. The approach allows for the needed flex- ibility resulting from different drug product formulations from different manufacturers. Flexible monographs provide the ability for drug manufacturers to comply with their registration and the pharmacopoeia with the recog- nition that one approach may not be suitable for all manufacturers. As technology and therapeutic drug products become increasingly more complex, it is necessary for the phar- macopoeias to continue to change. T he d i rec tor of t he Eu ropea n Direc torate for the Qualit y of Regulatory Sourcebook Pharmacopoeia Compliance Series