PATH FORWARD

Ultimately, QbD adoption boils down to a company- and product-based decision about what has the perceived lower risk and cost profile: to understand the process before licensure and be able to leverage this knowledge to address variability, or to license a less understood process used to produce the initial batches for validation and then use investigations and corrective actions to improve it in a limited fashion over time within the bounds of the license (21). The calculation of ROI is highly sensitive to its assumptions and their projected accuracy. This dependence makes it exceedingly difficult to match QbD investment to its eventual benefits to assess ROI. Consequently, the pursuit of QbD during product and process development often has been rationalized based on qualitative improvements and the (often invaluable) benefits of systematic approaches, especially for delivable tracking, technical reviews, and communication. A key example is an organized, aligned, and justified approach to risk mitigation, pre-investment, and decision-making. A well-defined QbD strategy, and its implementation prior to incorporation into a submission, can be used to support and justify QbD costs during the early phases of product/process development.

Continued refinement of quantitative and qualitative ROI analysis is needed, especially based on actual case studies. Most urgently, several significant benefits remain to be quantified. Specifically, the evolution of QbD consensus among both industry and regulators is likely to highly influence ROI. Thus, outcomes from the FDA Office of Biotechnology Products pilot program, as well as industry case studies/mock submissions, are eagerly awaited.

1. Manage benefit expectations to justify resource allocations based on product and process risks and timing for pre-investments on the probability of technical and regulatory success (PTRS)

2. Match the expected QbD benefits to the company's vision of its future QbD state including its risk management strategy

3. Gain solid sponsorship from senior and middle management

4. Sustain enthusiasm through benefit examples for staff at all levels, especially at the bench.

Although a solid business case is important for sustaining strong management support, some argue that solid case study application examples may outweigh the business case in encouraging initial adoption at the bench level. This tilt in the balance might be because QbD heavily overlaps with traditional approaches to bioprocess development in some companies. Regardless, it remains necessary to continue to collect information to improve and refine business case estimation for sustained application.