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.
SUMMARY
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, arathore@amgen.com
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.
REFERENCES:
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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