The Value Triangle: Risk Management for RMATs

As intense competition to be the first to bring advanced, personalized therapies to market collides with an incomplete understanding of the radically different processes that will be necessary to commercialize these next-generation products, it is critical to evolve more robust models of knowledge management and risk assessment.

Process Understanding Is Critical

Regenerative medicine advanced therapies (RMATs) require greater early-stage process characterization, understanding and control. Regulatory agencies urge manufacturers to demonstrate process understanding, design quality into the process and establish a robust control strategy. Knowledge and life cycle management are essential to commercialization of these complex medicines, because initial product and process design choices must be scaled and transferred without impacting the commercial decisions and reimbursement strategies driving the clinical trial designs and data generation to support the intended patient population’s needs.

Robust PPK Accelerates Speed to Market and Minimizes Costs

The evaluation of personalized medicines involves smaller clinical trials and single-use batch sizes produced via a distributed manufacturing paradigm (“vein-to-vein”), introducing additional supply chain challenges that can impact consistency in product supply and administration. Whenever change is introduced, the supply of clinical material needed for a trial may be put at risk. There is no opportunity to build the large data sets required for classical QbD approaches. Instead, quality must be built through product process knowledge.

(PPK) management, combined with iterative process risk assessment and an evolutionary control strategy. Successfully bringing medicines from R&D to full-scale operations requires the development of robust PPK as early as possible and the maturation of a robust control strategy. 

The Maturity Concept

The value triangle — R&D/clinical stage, manufacturing technology and commercial operations — with PPK at its core, can help companies bridge the product development phase II/III divide and minimize exposure to additional bridging studies. Applying robust PPK early on provides a common basis for mitigating both planned and unplanned changes impacting the key commercial, R&D/clinical, and manufacturing drivers and acceptance criteria.

This approach involves applying a design space maturity model. A preliminary process risk assessment is conducted early and revised as the process matures. Beyond manufacturing, this assessment includes the indicated market and preliminary reimbursable strategy, which drive clinical trial design, and a plan for clinical material supply and management of the manufacturing process, which is often distributed for regenerative medicines and involves non-traditional personnel.

The risk assessment includes plans for various market demand scenarios and relies on access to robust PPK and a comprehensive PPK management system to facilitate rationalization of process changes.

Preliminary risk assessments that mature along the way can become instrumental in reducing unintended change, mitigating the need for bridging studies and accelerating time to market.

Addressing Translational Gaps (TGs)

There are two major translation gaps (TGs) when commercializing regenerative medicines. For technical feasibility (TG1), the value triangle and PPK provide a framework for helping companies establish controls and monitor activities to predict the likelihood of product failure, which is greatest in phase I/II. For organizational barriers (TG2), they provide a road map for advancing the maturity of the risk assessment and control strategy. They support decisions around process scaling, facilities and equipment design and the people and processes that will be needed to achieve full-scale manufacturing without introducing changes requiring bridging studies.

Making the Right Manufacturing Decision

There are two crucial manufacturing decisions: whether to scale out or scale up and whether to manufacture in-house or outsource. PPK and patient population needs are ultimately the drivers for designing a fit-for-purpose manufacturing and logistics strategy.

Allogeneic or personalized medicines require scaling out to achieve greater volumes. Autologous therapies are based on a limited election of starting cells and use more traditional culture methods. They may be scaled up or out depending on the cells used (adherent/nonadherent) or desired batch size using a ballroom-style modular approach in closed systems or production in larger bioreactors. 

By investing in a robust PPK management strategy and risk-assessment model, it is possible to develop a full-scale operations model that helps companies select the best route to achieving their goals and supporting their target therapy, PPK platform and commercial drivers.

Engaging a reliable manufacturing partner experienced in establishing successful process control strategies and quality systems can help companies respond effectively to change and lay the foundation for commercial success.