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38 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m been a topic of vigorous debate between compendial author- ities, regulators, and the innovator and generic bio/pharma- ceutical industries for the past several years. Today, there is no single position among all pharmacopoeias and reg- ulators as to the need for product-specific monographs for complex biologics. The European Medicines Agency (EMA) and Official Medicines Control Laboratories (OMCL) have indicated their support for product-specific monographs, noting the benefit of having a single standard to help sur- veillance testing rather than having to use a specific man- ufacturer's methodology. As a result, the EDQM published the first of these product-specific monographs for etanercept and inf liximab concentrated solution in the Ph. Eur. using a f lexible monograph approach (9). FDA has not expressed similar support for USP monographs for complex biologics (24). In fact, opposition to these monographs is so strong that legislation was introduced to the US Congress stating that biological products would no longer have to comply with USP standards, including monographs (25). This stark difference in health authority views is a reminder of the important intersection of pharmacopoeias and regulatory agencies and why companies must monitor these situations to remain compliant and to inf luence both parties through appropriate advocacy. Among national pharmacopoeias, industry association surveillance has revealed that the Chinese Pharmacopoeia Commission (CPC) and National Institute for Food and Drug Controls (NIFDC) intend to establish reference stan- dards and monographs for seven monoclonal antibodies drug substances and products (26). These new monographs will likely be included in the 12th edition of the Chinese Pharmacopoeia (ChP), scheduled for publication in 2025. The ChP currently contains one monograph for a monoclo- nal antibody, nimotuzumab injection, a single-sourced or- phan product. The proposed addition of these seven multi- sourced products is an ambitious goal for the CPC. It will be important for companies who manufacture these products to participate in the ChP monograph elaboration process in partnership with CPC and NIFDC. It is not known how the CPC will address the complexity that comes with the analysis of these products from multiple manufacturers, as the "one-size-fits-all" approach will not work and could potentially block manufacturers from the market. Today it is unknown whether other national pharmacopoeias will publish monographs for complex biologic drug products. The pharmacopoeias are exploring other approaches for complex biotherapeutics. USP has announced a wide range of approaches that would be applicable to complex biolog- ics, including performance-based standards, product class standards, and general chapters (27). They are actively re- questing stakeholders to participate on project teams being established to develop these standards. The BP Commission is also exploring alternative approaches for complex bio- logics, notwithstanding their legal obligation to include Ph. Eur. monographs for complex biotherapeutic products in the BP. Recently, the BP Commission completed a consultation and announced a plan to develop performance-based stan- dards and product-class-based standards that would provide a foundation for manufacturers to follow, while retaining f lexibility for developing a complex biologic (28). Clinically relevant specifications. Health authorities are mov- ing toward requiring manufacturers to set clinically relevant specifications (CRS) for the registration of a new drug prod- uct. The specifications account for clinical impact of vari- ations in the critical quality attributes (CQAs) and process parameters. This ensures a consistent safety and efficacy profile of commercial product relative to product used in clinical trials. This contrasts with the approach previously used, which incorporates both safety and process capa- bility to establish specifications for a drug product. Both approaches are dependent on the manufacturing process and relevant data generated during product development. Because each company will have its own unique formulation, manufacturing, and product development process, it is not clear how this will impact the establishment of pharmaco- poeia monographs. The complexity of developing a single quality standard for drug substances and drug products that will be applicable to all manufacturers with approved CRS in their registrations will certainly be a challenge and require changes in how monographs are established. Impact of risk-management approaches Analytical quality by design. Analytical quality by design (AQbD) provides the ability to change method parameters within the method's design space, referred to as the method operable de- sign region (MODR) (29). The intent of AQbD is to develop a robust analytical method that is applicable throughout the lifecycle of the product to provide appropriate regulatory flex- ibility in the analytical method. The analytical target profile (ATP) defines the parameters that must be met to ensure a ro- bust analytical method. The ATP is designed to capture the quality attributes of a reportable value of a method through determining the level of acceptable variability of the method. A suitably designed and applied ATP can be a measure of assur- ance that an analytical method is fit for purpose throughout its lifecycle, from development through validation and into a commercial setting. The use of AQbD will widen the approved operating range of an analytical method without compromis- ing the integrity of the data it provides. Design of experiments (DoE) is a part of AQbD, representing the interaction among the input variables that ultimately affect the method response and results. The results from DoE define when results are acceptable and provide the acceptable ranges in which the method can be reliably run without the need for revalidation. Pharmacopoeia Compliance Series The pharmacopoeias are exploring other approaches for complex biotherapeutics.