Quality by design (QbD) was a hot topic at IBC’s BioProcess International Conference and Exhibition, 20–24 September 2010 (Providence, RI). For her keynote address, Helen Winkle (director of the FDA’s Office of Pharmaceutical Science) discussed the agency’s continuing efforts to improve product quality regulation as well as opportunities and challenges of implementing QbD for biotechnology products (1). Since introducing its 21st Century Initiative in 2002, the FDA has made some headway toward enhancing product quality through QbD (2). The QbD pilot program originally designed for small-molecule drugs has been extended to biotechnology products. However, according to a recent McKinsey & Company study summarized by Ms. Winkle, there is significant confusion and disagreement within the agency over how QbD should be applied to biotechnology products and what type of data should be required to define a biotechnology design space.

The study reports that QbD implementaion is being hindered by a lack of tangible guidance for industry and a misalignment of the expectations of international regulatory authorities. Moreover, the McKinsey study found that collaboration and consensus between field inspectors and the FDA review and compliance sectors on how to handle QbD remains an unmet challenge. We wonder why such collaboration is viewed as something new when those groups supposedly collaborate in their normal course of operations. Is it really possible that the QbD initiative is forcing the agency to deal with this issue for the first time?

On the positive side, the study found that the biotechnology industry is “stepping up to the plate” in adopting QbD and that QbD is “evolving, gaining momentum, and passion throughout the industry.” Although Ms. Winkle didn’t indicate whether the FDA is satisfied with QbD’s implementation to date, she acknowledged that the agency should clarify its position through appropriate guidances and that incentives to industry for adopting QbD should be defined and codified.

QbD offers potential business benefits, and many companies have adopted its concepts as standard business practice (3). However, QbD implementation requires cooperation across multiple disciplines, including process development, manufacturing, and quality control. A biotechnology process design space requires careful process data analysis obtained during development and routine manufacturing supported by data from statistically designed experiments. For example, a factorial design of experiments (DoE) used to rough out an operational design space early in process development can apply QbD principles to upstream process development and accelerate development (4).

Based on recent publications and presentations, however, we believe that the amount of data currently being submitted in support of QbD may be more than is strictly necessary. Most efforts so far have focused on a retrospective design space definition of existing processes based on several years of process experience, multiple DoE studies, and detailed multivariate analyses (5,6,7). Although these efforts may be necessary to convince the FDA that existing processes are well controlled, this large volume of data may not be available when filing a biologics license application, nor should it necessarily be required.

As the FDA wrestles with its internal contradictory views, companies continue to struggle with QbD implementation. To facilitate broader acceptance and implementation, the agency must provide a clearer picture of which data and how much would constitute an acceptable QbD-based submission. Such guidance is definitely needed to help companies achieve the overall goal of “… reliably produc(ing) high-quality drug products without extensive regulatory oversight” (8). We hope the agency gets its house in order soon and provides industry with a unified clear path forward.

Author Details
Howard L. Levine, PhD, is president and principal consultant; corresponding author Susan Dana Jones, PhD, is vice-president and senior consultant; and Alex D. Kanarek, PhD, is senior consultant at BioProcess Technology Consultants, 12 Gill Street, Suite 5450, Woburn, MA 01801-1728; 781-281-2701, fax 781-281-2702.

REFERENCES

1.) Winkle, H. 2010.Regulatory Modernization: FDA’s Desired State for Product Quality IBC BioProcess International Conference and Exhibition.

2.) US Food and Drug Administration 2002. Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach.

3.) Rathore, AS and R 2009.Quality by Design for Biopharmaceuticals, John Wiley and Sons, Inc., New York:288.

4.) Snee, RD. 2010. Robust Experimental Strategies for Improving Upstream Productivity. BioPharm Int. 23:28-33.

5.) CMC Bio Working Group 2009. A-Mab: A Case Study in Bioprocess Development, version 2.1, California Separation Science Society.

6.) Cook, G, and M. Wellin. 2009.Industry Case Study 5: QbD Development of a Novel Therapeutic ProteinEMEA/Efpia QbD Application Workshop, London.

7.) Rathore, AS. 2009. Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes, Part 2: Understanding the Relationship Between the Process and CQAs. BioPharm Int. 22:18-22.

8.) Woodcock, J. 2005. Pharmaceutical Quality in the 21st Century Defining Quality of a Pharmaceutical Product.