THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 12

The goal of process validation is to demonstrate that a manufacturing process, when operated within established limits, produces a product that routinely and reliably meets its required quality standards. The principles of process validation were initially laid down in an FDA guidance document in 1987, which defined process validation as “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.” The requirements for process validation have since been adopted worldwide with similar definitions appearing in guidance documents and the GMP regulations promulgated by European regulatory agencies, ICH, and WHO.

In 2004, FDA published its GMP Initiative which focused on a risk-based approach to pharmaceutical product development. This risk-based approach was reinforced in 2005 with the approval of ICH Q9, formalizing the requirements of quality risk management for the pharmaceutical industry worldwide. A quality risk management program, shown schematically in Figure 12.1, encompasses risk assessment, risk control, and risk review, with risk assessment being the most critical aspect for process validation. Risk assessment should be based on sound science, process characterization information, and data collected from scaled-down experiments during process development to evaluate the source and quality of all materials used in a manufacturing process and each unit operation in the manufacturing process to determine the impact of each material or procedure on the overall quality, efficacy, and safety of the final product.

Figure 12.1.  Overview of Quality Risk Management

…With the introduction of QbD and quality risk management, process validation is evolving from the traditional concept of a manufacturing process being fixed following process validation to a “life-cycle” approach to process validation that should enable more continuous improvement of manufacturing processes. In this new approach, manufacturing processes are continually reviewed during routine manufacture to ensure that adverse trends are identified and corrected before the product fails to meet its final specifications. The life-cycle approach to process validation was defined in a draft guidance issued by FDA in November, 2008. This guidance specifies that traditional process validation, typically relying on three consecutive successful conformance runs should be replaced by a deliberate design process, commercial process qualification and ongoing review of processes with increased use of continuous process monitoring…

…As with other products, the critical quality attributes of a monoclonal antibody product will be those physical, chemical, biological, or microbiological properties and characteristics that must be controlled within an appropriate range to ensure the desired product quality. For monoclonal antibody products, the CQAs would be those parameters that affect product purity, potency, or stability, particularly post-translational modifications such as glycosylation and heterogeneity resulting from the presence of various glycoforms. Product-related impurity levels (e.g., aggregated or clipped forms) and other process-related impurities may affect product safety or efficacy and may also be included in the CQAs for a monoclonal antibody product. The CQAs of a monoclonal antibody product will always include product potency and immunogenicity. A key element of QbD and the new process validation standards is that these CQAs can be linked to certain critical process parameters in the manufacturing process. These critical operational parameters can be identified during the earlier stages of process design by an initial risk analysis but additional CPPs may be identified at any time during the product lifecycle as a result of continuous process monitoring. Besides its impact on the CQAs, the ability to control a process parameter within its intended range is a significant factor in defining its criticality, especially in the manufacture of monoclonal antibody products…

…An example of the validation of the critical process parameters for a cell culture process for a monoclonal antibody product has been reported by Moran, et al. In this study, the structure and functional activity of a monoclonal antibody produced at the outer limits of numerical ranges of fed-batch culture control parameters such as pH and temperature were examined using a half-factorial experimental design incorporating half of the thirty two possible combinations of five selected control parameters at high and low levels. Analytical characterization of the monoclonal antibody produced in each of the experimental conditions and statistical analysis of the data collected demonstrated that the purified product was identical throughout the set of experimental conditions and also to the reference standard for the product. Glycosylation analysis confirmed that the distribution of glycoforms of the antibody was not affected by the varying process control conditions of the fed-batch cultures when varied over the appropriate ranges…

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