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Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 37 • Creation of new or revised ICH guidance documents (e.g., Q12 or Q14). • Implementation of new technology, such as continu- ous manufacturing. • New drug product platforms, such as oligonucleotides or gene therapies. • Development of new or revised regulations by health authorities (e.g., microplastics use in medicinal prod- ucts) (18). In the coming years, it is expected the following issues will result in new requirements in the pharmacopoeia or changes to the approaches currently established, to ensure that qual- ity standards exist for the medicines being manufactured. The evolving standards will impact the bio/pharmaceuti- cal industry and companies need to monitor these "on the horizon items" to try to inf luence the direction or advocate for change, if needed, and to quickly adapt the established processes in their company's compendial affairs program to ensure compliance with the updated requirements. New approaches to specifications Flexible monographs. The use of a "one-size-fits-all" approach for methods has always been challenging for the pharma- copoeia authorities, especially as drug substances and drug product formulations increase in complexity. The pharma- copoeias 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 Phar- macopeia (USP) provides for the use of f lexible monographs (8,9,19). In this approach, more than one test is listed for the drug substance or drug product. Other global pharma- copoeias use different 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 conf licts caused by more complex drug substances and drug products. For example, a notice was published by the Japanese Pharmacopoeia (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 man- ufacturers to share their control strategy, based on which starting materials are used, with the JP Expert Committee to ensure equivalency to the proposed monograph. For small-molecule drug products, the f lexible approach is used routinely 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 manufacturing process. Because each manufacturer uses a unique process and formulation for its drug products, dif- ferences in dissolution are not uncommon. The US Phar- macopeial 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 physical properties of the drug product for- mulation. By contrast, surveys are being conducted by the British Pharmacopoeia (BP) Commission and the European Pharmacopoeia (Ph. Eur.) Commission to gather stakeholder 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 competent 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 authority as part of the product registration. The dissolu- tion requirement listed in the general monograph for dosage forms would still be met to provide the proper quality for the drug product without the pharmacopoeia including spe- cific details. The approach allows for the needed f lexibility resulting from different drug product formulations from different manufacturers. Flexible monographs provide the ability for drug man- ufacturers to comply with their registration and the phar- macopoeia with the recognition that one approach may not be suitable for all manufacturers. As technology and therapeutic drug products become increasingly more com- plex, it is necessary for the pharmacopoeias to continue to change. The director of the European Directorate for the Quality of Medicines and HealthCare (EDQM) provided important perspective on the impact of innovation, stat- ing, "By listening attentively to the needs of both regulators and industry and rapidly incorporating new technological advances, pharmacopoeias can ensure that their content remains relevant and state-of-the-art and that their quality standards and methods are not only able to ensure the safety and efficacy of medicines but ref lect advances in technology and science. This proactive course is matched by an ability to react swiftly to emerging challenges and with a large de- gree of f lexibility (through alternative methods)" (23). Complex biotherapeutics: Monographs and general chapters. Monograph development for complex biotherapeutics has Flexible monographs provide the ability for drug manufacturers to comply with their registration and the pharmacopoeia with the recognition that one approach may not be suitable for all manufacturers.