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Process monitoring ensures that the process performs within the defined acceptable variability that served as the basis for the filed design space.
The concept of "design space" requires that a biotech product is designed so that it will meet its desired clinical performance, and the process is designed to consistently deliver a product that meets the quality attributes necessary for this clinical performance. 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. To achieve the required level of process knowledge, however, process characterization studies will need to be extensive and encompass a wide range of process parameters.
Anurag S. Rathore
The concept of design space has been receiving a lot of attention lately in the biotech community. One of the foundational documents for this concept is the ICH Q8 guideline, which was finalized in November 2005 and went into effect in May 2006. This document provides guidance for the Pharmaceutical Development report (Section 3.2.P.2) contained in Module III of the Common Technical Document (CTD). ICH Q8 encourages manufacturers of pharmaceutical products to include a comprehensive understanding of a drug product and its manufacturing process based on "scientific approaches and quality risk management." It recommends including additional information in order to demonstrate a high degree of understanding of the manufacturing process, which can lead to more flexible regulatory overview. Most notably, this deeper understanding of process control allows for the development of an expanded design space, which is defined as:
"...the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval."1
This article is the eighth in the "Elements of Biopharmaceutical Production" series2and shows how three of the major biotech companies are approaching the application of the design space concept with respect to various aspects of development and manufacture of biotech products, such as process characterization, process validation, process monitoring, commercial manufacturing, and regulatory filings.
A well-designed process is expected to be robust, and to enable predictable productivity and product of consistent quality. The primary source of variability in complex processes, especially biological systems such as cell-culture-based production, is the interaction of two or more variables. The terms space and multidimensional combination in the above-mentioned definition imply the need for extensive use of design of experiments (DoE) to map primary effects and interactions between variables during process characterization (robustness) studies. As seen in Figure 1, first the acceptable variability in product quality and process performance attributes is established based on clinical exposure of the product, knowledge from other similar products, and general scientific understanding about the molecule. Next, process characterization studies are performed to explore the characterization ranges and establish acceptable ranges for key and critical operational parameters. Operating within these acceptable ranges, the combination of which will ultimately define the design space, provides the "assurance of quality." It is desirable to have the operating space nested comfortably within the design space, as illustrated in Figure 1. The characterization studies should cover wide ranges for product quality and process performance attributes, extending beyond what is typically tested based on manufacturing logistics and practicality alone.
Figure 1. Illustration of the creation of design space from process characterization studies and the relationship between design space and the characterized and operating spaces.
The impact of design space on process validation is an active topic of discussion among manufacturers of biological products. At a minimum, an enhanced understanding of the manufacturing process and an expanded design space should provide more manufacturing flexibility during process validation. Since the design space "assures quality" of the drug product, these limits also should provide the basis of the validation acceptance criteria. This can be observed in Figure 2, where the limits that establish the acceptable variability in product quality and process performance attributes would also serve as the process validation acceptance criteria. Once the design space has been created, process validation becomes an exercise to demonstrate (1) that the process will deliver a product of acceptable quality if operated within the design space and (2) that the small- and pilot-scale systems used to establish the design space accurately model the performance of the manufacturing scale process. Thus, unanticipated manufacturing excursions that remain within the design space should not jeopardize the success of the validation exercise.
Once the design space has been established and validated, the regulatory filing would include the acceptable ranges for all key and critical operating parameters (i.e., design space) in addition to a more restricted operating space typically described for biotech products.
Once a product has been approved, process monitoring would involve monitoring product quality and process performance attributes to ensure that the process is performing within the defined acceptable variability that served as the basis for the filed design space.
Figure 2. Application of the design space concept on process characterization, validation, monitoring, and regulatory filing.
The primary benefit of an expanded design space would be a more flexible approach by regulatory agencies. Process changes within the design space will not require review or approval. Therefore, process improvements during the product lifecycle with regard to process consistency and throughput could take place with reduced post-approval submissions. The burden, however, lies with the applicant to provide sufficient rationale for this, as stated in ICH Q8: "The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided." In addition to regulatory flexibility, the enhanced understanding of the manufacturing process would allow a more informed risk assessment, as per ICH Q9, of the effects of process changes and manufacturing deviations (excursions) on product quality.3
Design space and regulatory flexibility should not be confused with relaxed process control or increased process variability. Regardless of how wide the design space is, process consistency is still the goal and it is expected that the manufacturing process will be performed in a reasonably narrow operating space. Excursions outside the operating space would indicate unexpected process drift, and would initiate both an investigation into the cause of the deviation and a subsequent corrective action. As long as operating parameters remain within the design space, however, product release would not be in jeopardy. As manufacturing experience grows and opportunities for process improvement are identified, the operating space could be revised within the design space without the need for postapproval submission.
ICH Q8 points out that design space can also be derived from manufacturing experience. Although first produced for the original marketing application, process knowledge and design space can be updated as understanding is gained over the lifecycle of a product. For example and as illustrated in Figure 2, process understanding gained from process monitoring can be used in future changes to the design space. Such changes should be evaluated against the need for further characterization or revalidation.
Process Analytical Technology (PAT) has been defined as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality." As such, the goal of PAT is to "enhance understanding and control of the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design."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, firstname.lastname@example.orgRon 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.