Research and Development Quality

Jay Newman

Cell and Gene therapy (CGT) has seen a substantial market expansion in recent years. But, as an emerging treatment modality, large companies can be reticent to invest in commercial scale manufacturing capacity, and smaller start-ups and biotechs often lack funding for such an endeavor.  Furthermore, the existing experience and talent pool for these products is relatively shallow when compared to its older recombinant protein cousin.  Whether driven by  start-ups, with resource and capacity limitations or  establish pharmaceutical companies looking to supplement existing manufacturing or subject matter expertise, third party contract development and manufacturing organizations (CDMO) are playing a critical role in filling these gaps.

While CDMO manufacturing in all cases requires clear oversight, dedicated staff, and well-defined objectives, externalization of CGT product, specifically viral vector manufacturing, has challenges that traditional well-established large-molecule manufacturing do not. Key success criteria include having a rigorous selection process, understanding the skills available, and clearly defined governance.

Selecting the Right Partner

Rigorous assessment of third party capabilities against critical business needs should be data-driven.  There are several problem solving and decision-making tools that provide an appropriate rigor to CDMO selection. We use a modified Kepner Tregoe Analysis, wherein key CDMO partners are ranked against several criteria that focus, not only technical competency, capacity and timelines, but, as an extension to CSL, alignment with our corporate values.

An example of the scope of criteria evaluated for analytical capabilities might include questions focusing on historical execution, development, qualification/validation experience, equipment availability, and development methodologies, where each activity is assigned a specific weighting. For example, of the number of assays developed, the number successfully transitioned into cGMP production may have a higher priority than overall monthly sample throughput.

Of course, all responses should be verified, the staffing levels and staff experience at CDMO must support the claims; these are ascertained via another set of questions relating to appropriate staffing levels, not just in operations but also in support functions (such as quality control, validation, and engineering).  Too often, failing to confirm FTE availability can have a significant impact in achieving timelines.

Recognizing limitations

It is essential to understand and not overestimate experience within internal development teams or those at the contract manufacturing partner.  While having been in practice for more than two decades, CGT is still in its infancy and with only a handful of commercial approvals, broadly skilled individuals are hard to come by.  Many development houses attempt to marry CGT with traditional recombinant protein development methodology, only to find divergent paths and roadblocks due to material availability and limited data sets. Understanding what is and what is not transferable, remaining open to flexible approaches and recognizing the CDMO may have more relevant development experience within this modality.

Building Collaborations and Credibility

The externalization of cGMP production may include transferring knowledge to third party PD groups, who then transfer knowledge to cGMP MSAT/manufacturing teams, and supporting QC/QA functions. Understanding the roles and responsibility of each participant, their respective functional groups, specific points of contact, key deliverables, and sending/receiving handoff requirements become critical in preventing cGMP manufacturing delays.

Credibility must be established and not assumed.  As the CGT space is constantly changing with emerging technology, no one group has “all the answers,” but each group comes with their collective experience making externalization seem more of a “collaboration” in practice than a mere contract for hire experience.

As with all successful partnerships, appropriate engagement and relationship oversight is necessary. One way of supporting this is by creating a well-defined relationship management role. We at CSL R&D have established this senior level position to ensure clear accountability for the CDMO output.  This role allows the CDMO to have an advocate at the table during internal meetings and provides astounding boarding and direct point of escalation during issue resolution by actively engaging the CDMOs at the right frequency and management level. A tie into strategic understanding and decision making around long term product strategy is recommended for this role to align execution at CDMO against that strategy.