Quality: Design Space for Biotech Products - - BioPharm International


Quality: Design Space for Biotech Products

BioPharm International
Volume 20, Issue 4

The concept of PAT is complementary to that of design space. The design space is defined by the key and critical operational parameters identified from process characterization studies and their acceptable ranges. These parameters are the primary focus of on-, in- or at-line PAT applications. In principle, "real time" PAT assessments could provide the basis for continuous feedback that results in improved process robustness. For example, process adjustments could be implemented to mitigate a reasonable amount of variability in raw materials (commodity and source) and other aspects of the manufacturing process. The collected data are also suitable for justifying process changes within the design space and, potentially, to support expansion of the design space.

The application of PAT should only be considered after it is determined that an innovative technology is appropriate for monitoring, analyzing, and controlling the process. FDA's expectation is that the processes selected for PAT be robust and contain algorithms that are self-adjustable to accept reasonable variability in raw materials (commodity and source) and inherent process variability. This is to be achieved through adequate control of process parameters within the design space to ensure protection of product quality.


The ICH Q8 guideline encourages the development of an expanded design space based on an enhanced understanding of the manufacturing process for a pharmaceutical product. The primary benefit of an approved design space is regulatory flexibility, most notably the potential to make process improvements within the design space without regulatory oversight. However, in order to achieve the required level of process knowledge, process characterization studies will need to be extensive and to encompass a wide range of process parameters. ICH Q8 suggests a more science-based rationale for drug substance specifications. Thus, factors such as a mechanistic understanding of the drug substance activity and clinical experience could help justify drug substance specifications that are wider than those derived entirely based on process capability.

Anurag S. Rathore is the director of process development at Amgen, Thousand Oaks, CA, 805.447.4491,
Ron Branning is vice president of quality operations at Genentech, San Francisco, CA. Doug Cecchini is a principal investigator in the department of bioprocess development at Biogen IDEC, Cambridge, MA.


1. US Food and Drug Administration. Guidance for industry: Q8 pharmaceutical development. Rockville, MD; May, 2006.

2. Past articles in the "Elements of Biopharmaceutical Production" series include:

2A. Rathore AS, Nofer JF, Arling ER, Sofer G, Watler P, O'Leary R. Process validation: How much and when. BioPharm. 2002 October; 15(10):18–28.

2B. Rathore AS, Levine H, Latham P, Curling J, Kaltenbrunner O. Costing issues in production of biopharmaceuticals. BioPharm Int. 2004 February; 17(2):46–55.

2C. Rathore AS, Wang A, Menon M, Riske F, Campbell J, Goodrich E, Martin J. Optimization, scale-up and validation Issues in filtration of biopharmaceuticals–Part I, BioPharm Int. 2004 August; 17(8):50–58. Part II, BioPharm Int. 2004 September; 17(9):42–50.

2D. Rathore AS, Krishnan R, Tozer S, Rausch S, Seely J. Optimization, guidelines and examples for scale-down of biopharmaceutical unit operations–Part I. BioPharm Int. 2005 March; 18(3):60–68. Part II. BioPharm Int. 2005 April; 18(4):58-64.

2E. Moscariello J, Lightfoot E, Rathore AS. Efficiency measurements for chromatography columns. BioPharm 2005 August; 19(8):58–64.

2F. Rathore AS, Sharma A, Chilin D. Applying process analytical technology to biotech unit operations. BioPharm Int. 2006 Aug. 19(8):48–57.

2G. Rathore AS, Karpen M. Economic analysis as a tool for process development: harvest of a high cell density fermentation. BioPharm Int. 2006 Nov. 19(8):56–63.

3. US Food and Drug Administration. Guidance for industry: Q9 quality risk management. Rockville, MD; June 2006.

4. US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Veterinary Medicine, Office of Regulatory Affairs. PAT guidance for industry-a framework for innovative pharmaceutical development, manufacturing and quality assurance. Rockville, MD; Sept. 2004.

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