A Holistic and Integrated CMC Development Approach: Committing to Quality, Reliability, and Speed

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Jerry Yang, senior vice president and general manager, HJB International

Yang introduced his company, HJB, as an integrated contract and development manufacturing organization (CDMO) with business centers in Boston, San Francisco, and Shanghai. The manufacturing site in Hangzhou City is about an hour-long drive from Shanghai City. The company’s mission is to maintain a global quality business standard, developing innovative technology to balance low costs with high quality, and to serve as a flexible, efficient, and reliable partner. Integrated platforms facilitate rapid development and efficient manufacturing.

Yang outlined three key components: candidate selection and assessment, for which antibodies and proteins are designed to be potent, stable, and manufacturable; process development, integrating processes and platforms upstream and downstream (along with analytical platforms) to allow for rapid development of a robust, high-yield process; and a modular biologics facility design that is flexible and expandable.

He presented a holistic summary of key milestones from investigational new drug (IND) to biologics license application (BLA) submission, emphasizing the need to develop the commercial process before the start of phase 3 so as not to delay first-in-human (FiH) clinical trials. His company’s approach is to perform development steps in parallel to enable IND development from sequence to filing in 15 months. An example from a parallel process during clone screening is to use the bulk pool to generate material for process, formulation, and analytical development. By the time a stable clone is chosen for master cell banking, a process and formulation can be locked in, and toxicology studies can begin. After a drug product undergoes stability testing, good manufacturing practice (GMP) drug substance manufacturing can begin.

Yang noted that some companies get to IND filing in 12 months from initial sequencing by using bulk-pool material for process development, formulation development, and method development as well.

He showed examples of a clone’s influence on the drug-quality profile by pointing to five common, critical quality attributes. Then he illustrated the effect of upstream cell culture media on a product profile. He outlined common attributes monitored closely for host-cell proteins at different steps (during capture, polish, and final drug-substance manufacturing) and summarized approaches to analytical method development. Analytical platform methods are suitable for most antibodies, but a few assays often will need some redevelopment and optimization. Because potency assays are based on mode of action, they usually need individual development.

Yang described two approaches to formulation development. In the first approach, companies perform a preformulation study to determine the choice of pH, buffer, excipient, and surfactant, then screen the top formulation for those attributes. The second approach involves combining those components and some other conditions into a large design of experiments (DoE), after which a formulation is finalized.

He outlined characteristics of buffer systems and examples of stable storage conditions. With a holistic approach, a company assesses developability first and then undertakes cell-line, upstream and downstream, analytical, and formulation development as a whole to evaluate the molecule and its process. Such an approach should enhance synergy between in-house and outsourced activities. Parallel activities must be managed closely, and high quality standards are needed to ensure compliance with regulatory requirements. Yang noted that HJB follows US and European guidelines, China’s GMPs, and ICH guidelines; and the company has seven quality management systems of its own. The company’s offerings are supported by a fully validated computer system for quality management, four levels of documentation, quality control capabilities, and sample/data tracking through laboratory information management system (LIMS) software. Intellectual property protection is provided by encryption systems and required passwords. Delta V automatic control systems track data and ensure data integrity. He concluded by describing a new drug-product manufacturing facility, on schedule to open in the first half of 2021.

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