Issue link: https://www.e-digitaleditions.com/i/1224576
42 BioPharm International eBook March 2020 www.biopharminternational.com Regulatory Sourcebook Pharmacopoeia Compliance Series viously used, which incorporates both safety and process capabil- ity to establish specifications for a drug product. Both approaches are dependent on the manufacturing process and relevant data gener- ated during product development. Because each company will have its own unique formulation, man- ufacturing, and product develop- ment process, it is not clear how this will impact the establishment of pharmacopoeia monographs. The complexity of developing a single quality standard for drug substances and drug products that will be applicable to all manufac- turers 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 A n a l y t ic a l q u a l it y b y d e s i g n (AQbD) prov ides the abilit y to change method parameters within the method's design space, referred to as the method operable design region (MODR) (29). The intent of AQbD is to develop a robust ana- lytical method that is applicable throughout the lifecycle of the product to provide appropriate reg- ulatory flexibility in the analyti- cal method. The analytical target profile (ATP) defines the parame- ters that must be met to ensure a robust 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 assurance that an analy tical method is fit for purpose through- out its lifecycle, from development through validation and into a com- mercial setting. The use of AQbD will widen the approved operat- ing range of an analytical method without compromising the integ- rity of the data it provides. Design of experiments (DoE) is a part of AQbD, representing the interac- tion among the input variables that ultimately affect the method response and results. The results from DoE define when results are acceptable and provide the accept- able ranges in which the method can be reliably run without the need for revalidation. It remains to be seen how AQbD will be integrated into the pharmacopoeia. It remains to be seen how AQbD will be integrated into the pharma- copoeia. Certainly, general chapters will be adapted to provide guide- lines on how to properly imple- ment AQbD for a method. Relevant chapters have been updated in the USP and Ph. Eur., in which flex- ibility is allowed for an analytical method to be changed without the need for revalidation if an AQbD approach has been implemented. The BP Commission is exploring an approach to allow AQbD, following their evaluation of how this could be done for a small-molecule drug product (30). The flexibility provided by the AQbD approach can be used in drug substance and drug prod- uct monographs. A key question is whether monographs will continue to contain a single method with spe- cific operating parameters and sys- tem suitability requirements as they are today, or if they will evolve to present an ATP/MODR that can be applicable to a particular method for the material. This will certainly be an area for bio/pharmaceutical com- panies to follow and provide com- ments as needed. Continuous manufacturing Many small-molec ule bio/phar- maceutical companies are moving toward a continuous manufactur- ing (CM ) plat for m for produc- tion of drug substances and solid oral drug products. The CM plat- for m moves the industr y away from the traditional batch or lot manufacturing and takes advan- tage of the QbD pr inciples for manufacturing. The CM approach necessitates the use of constant monitoring of the materials as they move through the manufac- turing process. As a result, "typi- cal" release specifications are not applied in the same way as with batc h test i ng. T h is c ha nge i n manufacturing approach is gain- ing acceptance by global regula- tors for more products, and the i mpac t to t he pha r macop o e ia may still be a few years away. The pharmacopoeias will have to evolve to understand how mono- graphs will differentiate between release and shelf-life criteria in a quality standard that is applica- ble to all manufacturers using dif- ferent manufacturing approaches. Currently, monographs only list one set of acceptance criteria that apply to both release and shelf-life. Although it is possible to differen- tiate specifications in a regulatory filing, it will be a future challenge to the pharmacopoeias to accom- plish this task. Pharmacopoeias m a y p e r h a p s u s e t h e AQ b D approach with an ATP for a given method or some other approach. Certainly, this will be important for all companies interested in CM to follow as the situation unfolds. It is interesting to note that USP has developed a week-long inter- active training course for techni-