Validation and Quality Assurance: Risk and Potential of Process Changes

Abstract

The development of biotechnical processes is a very complex operation. It involves the creation and verification of a strong expression system, selection and characterization of an appropriate host cell, optimization of a fermentation media, design of a fermentation process yielding high product titers, development of a tailor-made recovery process resulting in high yields and product quality, scale up of the biotechnical process to the commercial scale, formulation of the final product, validation of the entire process, analytical product characterization, and a comprehensive stability programme of the cell line and the final product.In many cases the time frame for such a development programme is determined by the competitive situation, therapeutic needs, patent life-span, and the return on investment. In addition, host vector systems, manufacturing technologies, and protein analytical methods improve rapidly and as a result regulatory standards become tighter.As a consequence of the rapid evolution in this field, a process can lose its economic value within five years after launch of the product and product quality might no longer correspond to the actual state of the art. Both facts can be the driving force for process changes in the vector system, the host cell, the cell culture media, fermentation technology, scale, purification process and the manufacturing site.In order to comply with the clinical results of the Process License Application (PLA) for the product, extensive development-chemistry is required to demonstrate product identity and efficacy after process changes.In cases where product quality is influenced by the manufacturing process, which is often the case for the production of complex glycoproteins, the question of the pharmacological significance of different glycoforms is raised. Process changes with this impact certainly require bioequivalence studies with the product derived from the modified process in comparison to the product derived from the previous process. If the results of such studies would show a significant difference between the products of both processes, phase III studies with an appropriate number of patients would have to be carried out.