By Gregory MacMichael, Ph.D., president, CMC Bioservices LLC
To ensure efficient throughput from drug development to commercialization, drug pipeline companies must structure their processes to control cost and compress timelines without sacrificing quality and safety. In the biopharmaceutical industry, we call this platforming. Platforms can be as complex as the molecules they develop, and biologics developers should consider the costs and benefits before standardizing their procedures as a platform.
Let’s walk through four considerations for developing more efficient platforms.
The majority of companies producing biologics (i.e., therapeutic proteins, vaccines, or cell and gene therapies) typically will produce products that are within the same class of molecules or viral vectors. Whether a company is producing monoclonal antibodies, conjugated polysaccharides for vaccines, or plasmids or viral vectors for cell and gene therapies, significant reductions in timelines and operational expenses can be realized by leveraging platformed technologies. Additional benefits are increased throughput in development and manufacturing, reduced full-time equivalent requirements per program, and standardization of documentation for development history reports, technology transfer, and regulatory filings. Furthermore, platforming improves the level of training of manufacturing personnel, resulting in fewer deviations. The analytics package is simplified with respect to qualification and validation, streamlining the transfer to quality control.
Platforms Should Match Their Target Product Profile And Vice Versa
The first step in planning for a new candidate is to develop a detailed target product profile (TPP). This is essential to determine if a candidate lends itself to a company’s established platform. The TPP will consist of the critical quality attributes, target indications and potential market size, projected maximum dose, and current standard of care, giving a baseline for reimbursement. These data are used to determine the minimum specific productivity and maximum cost of goods (total cost of producing the biologic). This guides molecular biologists in targeting the specific productivity during clonal selection. With a well-developed TPP, the capacity required for producing both clinical and commercial material can be determined as well. Additionally, formulation technologists can be more proactive in determining whether the product can be formulated with the company’s standard formulation or if significant formulation development is required.
Harmonization of technologies from discovery through manufacturing is critical in establishing a company’s platform technology. To streamline technology transfers and manufacturing, discovery and development personnel need to understand manufacturing’s capabilities and capacity. Changes to the platformed process can have a significant impact on manufacturing with equipment, raw materials, and capacity management.
An obvious example is the harmonization of upstream equipment. By standardizing the vendor and reactor specifications, parameters such as pH, dissolved oxygen, and mixing dynamics can be defined and harmonized. Additionally, the control software, data monitoring, and historian capabilities can be easily standardized for ease of data trending and demonstration of comparability at scale. This approach can be equally applied to harvest and downstream processing.
Streamline Production With A Well-Characterized Cell Line
Using a parent cell line to produce therapeutic proteins or viral vectors is one of the most effective approaches to developing a standardized platform. There are numerous parent cell lines with a proven ability to produce therapeutic proteins, monoclonal antibodies, viral vectors, and vaccines. These include cell lines such as HEK293, CHO, and SP20 myeloma. By using a parent cell line, various aspects of development can be streamlined. The parent cell line can be tested according to the FDA’s Points to Consider, adding more certainty that the cell line is free of adventitious agents. Medium requirements, growth profiling, and even productivity can be streamlined for the production of a similar class of molecules. Furthermore, the use of the parent cell line assists in establishing critical quality attributes, such as post-translational modifications.
The net result is a reduction in the number of batches required to define the process and demonstrate it is in control and capable. A similar approach can be applied to the downstream processes. With respect to viral vector production, the processes can be optimized around one preferred cell line, typically a HEK293 derivative. The HEK293 cell line can be used for traditional transient transfection or for higher commercial requirements, the company can opt for either packaging or producer cell lines, which will reduce the cost and complexity of manufacturing.
One effective option to reduce the timelines by greater than three months is the use of the master cell bank (MCB) as opposed to a working cell bank (WCB) for producing the preclinical and Phase 1 and 2 material. A typical MCB is at least 300. This is more than sufficient for the life of the product. Ten to 20 vials of the MCB can be used to accelerate the engineering runs and the Phase 1 clinical trials. Using the MCB would be justified if there is a lower probability of success in the clinic or if there is urgency to be first-to-market. For Phase 3 and registration, you will need the two-tier MCB/WCB approach. As with any WCB, you will have to demonstrate the WCB’s growth profile and product are comparable to the MCB.
Standardize Everything, Even Formulation
Drug product development can also be standardized. Within a given class of biologics, the requirement for extensive formulation development can be curtailed through a platform approach. Solubility, aggregation, nonspecific absorption, and the lability of the molecules can have similar behavior in the drug product.
Understanding the molecular family, the design of experiments can be reduced. For preclinical and Phase 1, formulations can be as simple as phosphate-buffered saline with a low concentration of surfactant, e.g., polysorbate 20 or 80 (0.02% to 0.3%) at a neutral pH and physiological tonicity. Preliminary and short-term stability can be ascertained using a portion of the material produced for the preclinical studies, which can be derived from engineering runs.
Consider The Hidden Cost Of Introducing New Technology
Significant reductions in time and cost can be achieved through a standardized platform approach to development. Introducing new technology will have an impact on time and cost and will place assimilation of the new technology on the critical timeline.
Therefore, the benefits of introducing new technologies to an active program must be carefully considered with respect to cost and the impact on the schedule. And finally, the introduction of new technology should be a partnership between discovery, development, and manufacturing for effective integration.
About the Author:
Gregory MacMichael, Ph.D., is the president of CMC Bioservices LLC, a consultancy focused on the development and manufacturing of cell and gene therapies, biologics, and vaccines. MacMichael has held senior roles in development and manufacturing with notable companies including Novartis, Wyeth, Eli Lilly, Chiron, and Centocor, where he developed Centoxin, Remicade, Reopro, Xigris, Forteo, Prevanr13, FluMist, and Kymriah (CART19). Reach him by email at email@example.com or telephone at 201-452-8350.