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20 BioPharm International eBook October 2021 www.biopharminternational.com For instance, many biologics gain a fast track designation from FDA. This designation, created to expedite the review process, is reserved for drugs and biologics that treat serious conditions and fulfill an unmet need. Receiving this designation often entitles a company to accelerated approval and priority review. It also enables a rolling review, where a company can submit sections of its BLA as they are completed, and FDA will begin reviewing the application imme- diately. This pathway vastly accelerates drug and biologic development, but it puts biomanufacturers under greater time pressure to build out a comprehen- sive CMC strategy. Biomanufacturers, therefore, must consider their CMC strategies as early as possible. CMC PROCESSES TO ADDRESS The CMC portion of a BLA includes a complex array of information, includ- ing materials on drug product develop- ment, clinical trials, supply chain and manufacturing, and quality and com- pliance. There is also a list of CMC processes that a biomanufacturer must address in the CMC portion of their BLA application to ensure their biolog- ics reach the clinic, a few of which are summarized below. First, there is formulation. Because biological molecules are less stable than small molecules and due to shortened development timelines, formulation development is often challenging. A biomanufacturer must develop a global target product prof ile early on, from which a formulation can be developed that is safe and effective, and ensures stability of the product. Second is ana ly tica l cha racter- ization of the biological molecule. Biomanufacturers must develop meth- ods to test def ined characteristics of their biologics, and identify the criti- cal quality attributes of the biological molecule. This testing often involves identifying, separating, and quantifying characteristics of the molecule, such as its mechanism of action by in-vitro effi- cacy assays, protein sequence and pep- tide map, charge heterogeneity, protein folding, post-translational modif ica- tions, etc. Biomanufacturers need to perform these tests to characterize and control the quality of the physical char- acteristics, purity, and potency of the biological molecule. Third is extractables and leachables (E & L) st ud ies. Biomanu fact u rers must perform E&L studies to iden- tify and quantify harmful impurities from container-closure systems, pro- cessing equipment, and packaging that can leach into the drug formulation. Extractables include all the possible chemical species that incorporate into a drug compound following the harshest chemical treatment, while leachables are a subset of extractables that enter the formulation through their normal manufacturing, packaging, and storage. Fourth is elemental and process impurities analyses. Throughout the drug development process, from initial design to large-scale manufacturing, contaminants, impurities, and residuals can make their way into biologic formu- lations. These impurities can impact the safety and efficacy of a product and delay its commercialization. Biomanufacturers must develop methods to reduce the risk of contamination and to test for impuri- ties in their products. Fifth is stability testing and forced deg rad at ion st ud ie s. T he qua l it y of a biologic can var y over time in response to environmental factors such as humidity, temperature, and light exposure. Biomanufacturers must ana- lyze all aspects of product stability, including the identity of degradants. Forced degradation studies put the drug substance under extreme con- ditions such as acid, base hydrolysis, extreme heat, and agitation, to more quick ly identif y degradation path- ways of the product. These data will help the company determine expira- tion dates, develop recommendations on storage conditions, and determine testing intervals for the product. Sixth is finished product batch release testing. Prior to batch release testing, however, analytical methods must be developed, optimized, and validated to ensure that the methods are acceptable for testing the quality of drug substance or drug product. The process of analyti- cal method development and validation can take a long time, so this activity is usually started when the product is still in Phase I or II clinical trial. A fully val- idated method must be available prior to BLA filing. Once validated, biomanu- facturers would then perform good man- ufacturing practice (GMP) batch release testing (i.e., lot release testing). This test- ing addresses whether a batch of drug substance or finished product matches its registered specifications. GMP lot testing, specifically, uses fully validated methods to test whether the compound's attributes fall within the range estab- lished during safety and efficacy studies. Seventh is raw material release test- ing. A biomanufacturer must test a raw material's identity, purity, and quality before it can be used in the manufacture of biopharmaceutical products. Different formulations may involve the use of doz- ens of raw materials, and some manufac- turers may choose to completely analyze each lot of raw materials they receive. Eighth is compendial testing of raw materials and product. This testing is required for manufacturing release and distribution of biopharmaceutical ingredients around the world. To deter m i ne sta nd a rd iz ed met hods and specif ications for testing raw materials and f inished products, a biomanufacturer can use pharmacopeial monographs such as the United States Pharmacopeia–National Formular y, Eu ropean Phar macopoeia, Japanese Pharmacopoeia, or British Pharmacopoeia. Ninth is reference standard char- acterization and management. It is critical that biomanufacturers develop, characterize, and manage reference standa rds per the t wo-tier system (i.e., Primary Reference Material and Working Reference Material system). Regulatory Sourcebook CMC Strategies