Khanh Ngo Courtney, Ph.D. - Sr. Director of Biologics at Avomeen
Taking a new biologic therapeutic from a research bench to the market is a cumbersome process. Like small molecule drugs, biologics must be approved by the U.S. Food and Drug Administration (FDA); but, because they are composed of naturally-occurring components instead of chemically synthesized molecules, and tend to have extremely niche indications, their development process follows a distinct regulatory path.
Following preclinical research, companies must file sequential applications to first test their biologic in humans and subsequently produce it for distribution on the market. These are the Investigational New Drug Application (IND) and the Biologic License Application (BLA).Each of these applications has a chemistry, manufacturing, and controls (CMC) section. This section features an extensive series of reports, tests, and audits that ensure that the biomanufacturer has a rigorous plan in place to manufacture a high-quality drug product that will be consistently safe and efficacious. Submitting a rigorous CMC packet is essential to gaining regulatory approval. However, developers of biologics must walk a fine line and develop satisfactory CMC strategies while working against the clock to bring much-needed treatments to market as fast as possible, while still ensuring a high-quality product.
FDA Oversight of a CMC Strategy
Many biologics are designed to meet a high unmet medical need (i.e., they treat serious, rare conditions or will become personalized medicine). Biologics with these indications are often developed faster than blockbuster drugs because, after IND approval, they can receive Fast Track designation to accelerate the next stages of development. This designation renders later processes, such as BLA submission eligible for the Rolling Review program and potentially for Priority Review and Accelerated Approval. Rather than submitting one complete application, these programs enable a company to submit sections of a BLA when they’re ready and receive a faster evaluation from the FDA. Furthermore, the Fast Track designation entitles these companies to increased communication with the FDA.
It is vital that biomanufacturers are fully transparent with the FDA while making full use of this instructive communication channel. For example, if the FDA asks questions or makes requests, it may shed light on the agency’s expectations for the biologic or the future of the industry. Biomanufacturers can use their government access to ensure that all CMC data necessary for regulatory approval are being collected, and plan out clinical trial designs. Overall, companies that actively seek out information reduce the risk of being asked to fulfill last-minute requests or impossible expectations.
Although the Fast Track designation expedites the biologic development process, it also challenges biomanufacturers to assemble a CMC strategy for their BLA on a tighter timeline. To accelerate the process while meeting all FDA expectations, companies should start by considering CMC strategies as early as the target discovery and preclinical formulation stage, continually evaluating them through clinical studies. They should also consider more than one strategy simultaneously to increase the chance of developing a strategy that is optimally suited for the task.
Key Components of a CMC Strategy
The CMC segment of a BLA contains many sections that outline the biomanufacturer’s overall process, including information on the product development of the biologic, quality, compliance, and supply chain and manufacturing. These are assembled through numerous CMC processes, several of which are discussed below.
Formulation is an important CMC process that must contend with the fact that biologics are less stable than small molecule drugs. Shortened development timeline or not, companies must select a global target product profile, which formulation scientists then use to develop a safe, efficacious, and stable product. Formulation also consists of analytical characterization of the biological molecule, where biomanufacturers develop assays to test specific physical and quality attributes of their biologics. These tests characterize the biologic structure such as protein sequence, peptide map, protein folding, charge heterogeneity, and post translational modifications, while in vitro efficacy assays explore the mechanism of action.
Critical to all testing efforts is the development, characterization, and management of a two-tier system for reference materials: a primary and a working reference material. Biomanufacturers must ensure that the reference materials are well-characterized and representative of the drug substance or drug product.
Stability testing and forced degradation studies are conducted to understand how the quality of biologic products varies over time and under extreme stressed conditions. This includes measuring changes induced by environmental conditions like humidity, and temperature. Forced degradation studies are designed to put biologics under extreme conditions such as high heat, light exposure, agitation, and hydrolysis via acid and base to observe the impact on product quality attributes. Together, this battery of tests allows the biomanufacturer to carefully assess biologic’s stability and set the product’s shelf life.
Extractables and leachables (E&L) testing is used to identify and quantify any impurities that may have seeped into the biologic product from the manufacturing equipment, storage systems, or packaging. Extractables is a broad term meaning any chemicals that enter a drug following extreme chemical treatment, while leachables represent a group of extractables that incorporate into the drug following normal production, packaging, and storage.
To establish consistency and a set of specifications of the product, companies must develop, optimize, and validate analytical methods for batch release testing. These tests evaluate every batch of a biologic product to ensure consistent quality from batch to batch, and that the manufacturing process is robust and reliable. A biomanufacturer’s fully validated tests are subsequently used for manufacturing practice (GMP) batch release testing – a step that is essential prior to the sale, supply, and export of all biologics. GMP batch release testing determines if batches of the finished biologic product, and the compounds used to make it, match registered specifications. It also determines whether a compound’s attributes fall within the range established during safety and efficacy studies.
Compliance with current GMP (cGMP) regulations also requires biomanufacturers to undertake manufacturing and cleaning validation. They must provide evidence of a robust manufacturing process, also known as ‘process performance validation’, and demonstrate that the cleaning procedure for the manufacturing equipment is sufficient to prevent the introduction of impurities or cross contamination. Biomanufacturers select cleaning thresholds based on data inputs, including dose sizes, equipment surface areas, and safety factors. All elements of manufacturing and cleaning validation must be finalized before a product can be released to the market.
Speeding Up CMC, Safely
It is a massive undertaking to develop a CMC strategy that includes the components listed above, in an expedited setting. Therefore, companies will often pre-design CMC strategies for entire product pipelines or platform technologies. These templates map out robust manufacturing and supply chain plans and provide historical stability data about the platform technology – all of which can be applied to a group of drugs in development. Pre-designing CMC strategies helps companies increase their efficiency and shorten development timelines, which is immensely important when working under the Fast Track designation; however, there is no one-size-fits-all solution to CMC. Companies must still create strategies tailored to every drug product they develop. That being said, because the indications of biologics render them more molecularly diverse, developing CMC strategies for large molecules requires more tailoring than most.
While companies should utilize pre-designed strategies to accelerate the CMC process, they must also be thorough when tailoring these for a specific drug. A CMC strategy is represented in a compilation of a vast array of tests, optimization, and validation. If a company submits a BLA and any of the necessary components are found lacking, the FDA may be forced to halt production and commercialization or dole out fines.
Adjusting to Change
CMC strategies should be comprehensive and reliable. They’re meant to maintain consistency from drug development through market approval and beyond, however, the company must be adaptable and ready to pivot if necessary. This may happen due to external factors, such as when new clinical data or business information emerges, or factors internal to the development process, i.e., if the biologic’s process is poorly defined, its formulation needs improvement, or if the molecule or disease pathway involved is incompletely understood. While these issues are not uncommon for biologics being developed through Fast Track regulatory pathways, making changes to a CMC strategy creates the risk of introducing deviations that may impact product quality and FDA approval.
To minimize the chance that a biologic’s CMC strategies will need to change, biomanufacturers can only negate factors internal to the drug development process. This includes providing well-rationalized scientific justifications for every aspect of CMC. Additionally, companies should take proactive steps to identify potential issues quickly. These include:
- Characterizing the product and selecting its controls simultaneously
- Identifying the biologic’s most critical attributes and developing quick in vitro read-out methods to monitor quality
- Using established methods to monitor for process impurities during process development and improvement
- Carefully tracking all data to continuously monitor trends.
Strategies for Success
Fulfilling each step of a CMC program requires extensive technology and labor resources; at the same time, addressing potential pitfalls within a CMC strategy requires a great depth of experience. While large pharma companies may have the necessary resources and know how to undertake CMC independently, smaller biomanufacturers likely do not. Regardless, it is the smaller companies that are carrying out the lion’s share of early drug development today. These companies often benefit from partnering with contract drug and research organizations (CDMOs) that provide the necessary resources and depth of experience to support them throughout CMC, and the rest of the drug development process.
An experienced CDMO understands the numerous approaches to CMC that biomanufacturers can take and has seen how the FDA has responded to each. They use this experience to guide biomanufacturers through the application process. CDMOs offer consulting services to help biomanufacturers prepare an exemplary CMC strategy, and they provide a depth of scientific rationale for all elements of it. Furthermore, CDMOs can share regulatory, quality, and technical experience as a company prepares to submit its application to the FDA for review. Ultimately, a CDMO’s support helps biomanufacturers develop high-quality CMC strategies quickly, enabling them to meet all requirements set by the FDA within the bounds of their own needs and goals.
Wrapped into the company’s needs and goals are its finances. Without cost-control, developing a CMC strategy can come with an exorbitant price tag. To address this, a CDMO can operate on a budget and estimate the costs associated with each step and decision throughout a biologic’s development. By taking these steps, a small company’s new product may be brought to market without breaking the bank, allowing the company to pursue additional projects and diversify its efforts to improve chances of long-term success.
While partnering with a CDMO to develop a CMC strategy can be advantageous, several considerations should be made to ensure maximum benefit. Facilities are an immediate consideration. Any companies developing biologics for orphan drugs or personalized medicines should seek out a CDMO with small batch manufacturing and sterile fill capabilities; these are vital to optimizing the manufacturing process. Biomanufacturers should also select a CDMO whose capabilities reflect the FDA’s increasing expectation for more precise, informative data in regulatory applications. For example, when developers measure impurities for advanced therapeutics such as gene therapies, HPLC methods are being replaced with LC-MS methods, since higher sensitivity for the analyte is becoming a more standard expectation. Moreover, ELISA for residual host cell protein and qPCR techniques are being replaced by more exact methods, such as proteomics and droplet digital PCR (ddPCR), respectively.
Navigating changes in the FDA’s expectations regarding CMC for Fast Track biologics can be difficult because the expectations are not all published. Advanced therapeutics such as cell and gene therapies are still relatively new. Instead, preferred testing methods are becoming industry standards because scientists operating within the field recognize their enhanced ability to evaluate biologics for safety and efficacy. Simultaneously, the FDA is tracking trends in the development of different modalities and incorporating best practices into official expectations. A CDMO can guide biomanufacturers through this changing landscape by drawing on its industry experience to ensure that the CMC process is carried out with tests that will meet provisional and future industry standards. In doing so, the partnership between a biomanufacturer and CDMO not only maximizes one biologic’s chances of regulatory approval, but also helps to grow and shape the field for years to come.
About the Author:
Khanh Ngo Courtney currently leads the biological pharmaceutical division of Avomeen, a CDMO recently acquired by Element. Her experience extends from R&D to analytical method development, validation, implementation, method transfer, and optimization of test methods for the cGMP setting per USP and ICH guidelines. These skills provide her with the foundation for effective authorship of INDs, BLAs and MAAs for biological therapeutic molecules, as well as responses to requests and questions from the FDA, EMA, and PMDA. Khanh holds a PhD in Biochemistry from the University of Wisconsin-Madison.
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