Biopharmaceutical companies need to make critical chemistry, manufacturing, and controls (CMC) decisions during clinical development of recombinant protein biologics and advanced therapies. In a 17 December 2019 “Ask the Expert” webinar, Nigel Shipston (director of program design at FUJIFILM Diosynth Biotechnologies, FDB) reviewed key aspects of selecting and working with a contract development and manufacturing organization (CDMO). He also highlighted important factors that should be considered during early stages of process development.

Shipston’s Presentation
The sheer magnitude of investment required to assemble a technically skilled workforce, procure increasingly sophisticated but expensive equipment, and maintain good manufacturing practice (GMP)-compliant facilities — together with large portfolios and increasing competition — is compelling even the largest biopharmaceutical companies to select suitable CDMO partners. With careful selection, a strong partnership can be sustained through an entire product lifecycle, from preclinical development, to investigational new drug (IND) and biologic license application (BLA) filings, and finally to commercial launch.

Technological capability and capacity rightly top the list of factors for sponsors to explore when selecting a CDMO. But sponsors should identify one that is not only focused on technical excellence, capacity, and delivery at the desired price point, but that also has a strong track record of investment and innovation. Statements of work, master services agreements, and quality agreements are essential elements of a contract, but those documents alone will not guarantee project success. Effective and long-term partnerships always are underpinned by a stable, motivated, and skilled workforce having excellent communication and people skills.

Ultimately, sponsors and CDMOs have different business objectives. To align their priorities, they must build trust, which requires each party to understand what its counterpart needs. It also is important for sponsors to be realistic in their planning processes. Completing even an early phase CMC program can take 12–18 months, not including upfront time for contract negotiations. Thus, all parties involved must be transparent with each other.

For gene therapies or recombinant proteins such as monoclonal antibodies (MAbs), cytokines, and replacement enzymes, selection of a suitable expression system is just one example of a critical decision that needs to be made during early CMC development. A poor expression system choice can have far-reaching consequences.

Another challenge is to develop a process that is capable of delivering sufficient quantities of product of a requisite quality. That exploration should support not only critical-path activities during early phase clinical development, but also provides a design space that facilitates late-phase development. In some cases, platform approaches can help expedite process development; in other cases, suitable platforms do not exist.

Questions and Answers
How would you approach expression-platform selection? It should begin with consideration of known critical quality attributes (CQAs) and prior art. For example, if a recombinant protein needs to be glycosylated, then a mammalian expression host such as Chinese hamster ovary (CHO) cells will be appropriate. If glycosylation is not required, then Escherichia coli could be a better choice because its overall development timeline and cost of goods are likely to be lower. If there is no obvious host, then expression feasibility studies might be appropriate. FDB frequently performs them, sequentially or in parallel, to compare product expression in CHO, E. coli, and Pichia pastoris, evaluating both product titer and quality.

What process-development concerns occur downstream? Product-related impurities, host-cell proteins (HCPs), and endotoxins must be removed to appropriate levels. A key challenge is always to balance purification with recovery.

What are the biggest challenges in cell and gene therapy process development? Scaling transient production poses inherent problems, and process complexity creates high costs. Scale-up and lack of suitable platforms are key challenges that will require process innovation and new paradigms. Also, a skills shortage makes it difficult for biomanufacturers to keep up with industry growth.

More Online
The full presentation of this webcast can be found on the BioProcess International website at the link below.

Watch the full webcast now.