Development By Design

Unlike typical pharmaceuticals, cell therapies rely heavily on the manufacturing process for product attributes. As more products move out of the clinic and toward commercialization, the manufacturers of cell therapies are realizing that commercialization is unlikely to be successful without an effective methodology for manufacturing development.

At PCT, we recognize that a successful commercial manufacturing vision includes the ability to provide consistently high product quality at a reasonable cost of goods that meets demand over the commercial life of a product. To help our clients realize this vision, PCT is proud to offer its innovative scientific and engineering expertise to plan and execute development by design (DbD) methodology.

PCT’s industry-leading DbD approach applies a series of principles to our clients’ cell therapy manufacturing processes to help guide strategy and provide structure and discipline to plan for and address commercialization risks before it is too late to efficiently address those issues. DbD addresses critical aspects of quality, cost of goods sold (COGS), scale, and sustainability.

Attributes and Their Challenges

Quality: Quality is certainly foundational as recognized by the US FDA’s quality by design (QbD) framework. For cell therapy — where there is heavy reliance on process to meet critical quality attributes of a final product — the manual, open, and human-dependent nature of many process steps presents substantial risk. Automation, integration, and closed-system design are key tactics to elevate robustness of a process.

COGS: The current high COGS of cell therapy products (often driven by labor and testing costs for patient-specific products and media for off-the-shelf products) typically demands a sizable commercial-value proposition. As processes mature, the focus on COGS for commercial viability becomes critical. DbD methodology allows for prospective approaches to addressing COGS appropriate for scale and stage of development.

Scale: Migrating from clinical-scale to commercial-scale manufacturing can present significant comparability risks. In particular, cell therapy products inherently possess high complexity with one or more mechanisms of action that are often incompletely understood. Manufacturers of cell therapies must further develop analytical tools and in vivo models to judge product comparability.

Sustainability: Finally, even if quality, COGS, and scale objectives have been met, there is the very real risk that manufacturing cannot be sustained over a full product life cycle. For example, a key risk is disruption in the relatively fragile and immature supply chain currently supporting cell therapy that could halt manufacturing for an extended period of time until changes are made and comparability demonstrated. To mitigate risks to sustainability, companies need to assess the full range of supply chain inputs to every unit operation (process and testing), including reagents, consumables, equipment, and human resources.

A key challenge in any development program is that — although quality realization must occur early in development and be well-established by phase 2 trials — realization of the other aspects listed above are not required until much closer to commercialization. This puts significant pressure on cell therapy developers to defer investment in COGS, scale, and sustainability until, in some sense, it’s too late. To put it differently, developers often defer investment until the comparability risks of making changes to address these concerns is substantial. In addition, any extreme change in process scale as a developer moves toward commercialization can quickly create new quality risks.

Engineering and Innovation Center Services

At PCT, assessment of DbD needs for each client will draw upon the technological capabilities of PCT’s Engineering and Innovation Center (EIC), a key foundational part of our manufacturing development division. Our EIC services are designed to help our clients think beyond current practices and to develop long-term solutions to the unique challenges faced by the manufacturers of cell therapy products. EIC solutions accelerate and prioritize the use of automation, integration, closed processing, and other strategies to address the important issues of scale-up, cost of goods, quality control, and robustness of manufacturing processes in anticipation of commercial success.

PCT stands at the ready to help our clients develop strategic plans for commercial manufacturing success of their cellular therapy products. A thorough review of clients’ process using PCT’s DbD approach will help our clients move beyond clinical trials and realize their own successful commercial manufacturing vision.

Brian Hampson is vice president, Engineering and Innovation at PCT; 1-201-677- CELL; [email protected]; www.pctcelltherapy.com.