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www.biopharminternational.com October 2021 eBook BioPharm International 21 These standards are well characterized and are batch(es) that best represent the drug substance. They are essen- tial for validating the qualitative and quantitative accuracy of testing meth- ods. The selection of the Reference Material requires planning ahead as it must be a large enough batch to be stored away to be run as a positive analytical control for future batches and as a comparator for the qualif i- cation of the next batch of designated Reference Material. F ina l ly, t here is ma nu fact u r ing and cleaning validation support. To comply with current GMP (CGMP) regulations, biomanufacturers must demonstrate a robust manufacturing process (also called a process valida- tion), and that the cleaning procedure of the equipment used during man- u fac t u r ing is adequate to prevent any cross-product contamination or impurities. This work must be done before the product could be released to t he ma rk et. Bioma nu fac t u rer s must establ ish c lea n ing l i m its in association with data inputs, such as equipment surface areas, batch and dose sizes, and safety factors. MAINTAINING A CONSISTENT CMC STRATEGY Because they do not have the same resou rces as la rge pha r maceut ica l companies, small biopharmaceutical companies, such as virtual companies, face a significant challenge in devel- oping a consistent CMC strategy that incorporates all the necessary testing and validation steps. CMC comes with many risks, and it takes experience and knowledge to understand them. While large phar- maceutical companies have the exper- tise and experience needed to perform CMC f unctions and de-r isk their BLA, smaller companies do not have the same resources. Because CMC involves a vast array of complex tests, optimization and validation steps, bio- manufacturers need to develop a strat- egy that enables them to collect the information they need and to reduce risk as much as possible. The expedited nature of the fast track pathway requires companies to ensure that their data are in line with FDA requirements early on during the drug development process. If the CMC process is ill-defined, the molecule or the etiology of the disease is not fully understood, or the formulation needs to be optimized, the CMC strategy might need to undergo signif icant revisions. For example, if a biomanu- facturer is not compliant with CMC regulatory requirements, it might have to withdraw the marketing application, suspend product production, and face f ines. Furthermore, major deviations from the strategy could impact product quality and the overall chance that the compound in question will reach the market. Therefore, it is critical that a biomanufacturer develop an FDA- compliant CMC strategy. Biomanufacturers should consider several CMC strategies throughout product development to ensure their strateg y is optimized to meet their needs and the safety and eff icacy of the drug, availability to patients, and to satisf y reg ulator y requirements. Companies shou ld consider CMC as early as target development and continue to hone in on the details of the CMC strateg y. By continuing to monitor and improve the CMC strategy throughout the lifecycle of the pro duc t , c omp a n ie s w i l l prote c t themselves from surprises late in the development process that can derail production and commercialization. ENHANCING CMC STRATEGY A biomanufacturer must do its due dil- igence in developing a CMC strategy that involves rigorous data collection to satisfy regulatory demands. It must provide scientif ic justif ication for all its decisions to remove risk from the workf low and to develop high-quality products. The company must closely monitor the development process to identify sources of risk and predict when and where challenges will arise. They should also ensure their testing meth- ods are robust, and strong quality assur- ance is the foundation of an effective CMC strategy. Companies should also pay attention to the advancement of new analytical technologies. For highly advance therapeutics, such as gene ther- apy, new technologies come on the mar- ket and can sometimes quickly become an industry standard for an analytical measurement. When this happens, the biomanufacturer will need to consider the possibility of incorporating the new technology into their panel of testing. Companies must respect the com- plexity of the process and craft their strategy delicately, since making com- promises can lead to wasted time and expenses down the road. To make sense of this process and build out an effective strategy, it might be helpful to partner with a contract development and manu- facturing organization (CDMO). Drug product submission applicants can benef it from the resources and experience made available by a CDMO partner. CDMOs have the technical, quality, and regulatory expertise, and the corresponding consulting services, to help prepare an effective CMC strat- egy. They can help enhance the quality and efficiency of a CMC strategy and help a company meet FDA expecta- tions. Finally, experienced CDMOs have seen the many different ways bio- manufacturers approach CMC and the variety of ways FDA responds, and they can use this experience to guide manu- facturers through the process of decid- ing the best approach for them. CDMOs can also help small compa- nies manage their costs. A CDMO can calculate how each CMC step and deci- sion will impact the budget throughout development. An effective budget man- agement strategy will make it easier for a small company to reach the market and initiate other projects to increase their chance at overall success. BP Regulatory Sourcebook CMC Strategies