Implementation of a manufacturing process that assures a predefined quality of product is a critical requirement for the licensing and marketing of every cell and gene therapy (CGT) product.
Generally, extensive development is needed to mature an early-stage process to commercial manufacturing because of the biological complexity of the products. However, inadequate process knowledge and understanding constricts implementation of process changes as the impacts on product safety and efficacy are unknown. This often leads to the adoption of processes that, although compliant with established regulations, are not optimal for assuring broad availability to patients who depend on those therapies.
To improve the manufacturing of CGTs, quality-by-design (QbD) principles, widely recognized as integration of scientific knowledge and risk assessment into process and build products, can be adopted. Given the complexity in manufacturing CGTs, incorporating QbD principles at an appropriate stage of development of the product can be significantly advantageous.
Risk Assessments and Design of Experiments
The manufacturing of a CGT product should start with defining a quality target product profile that includes all desired properties to ensure the quality, safety and efficacy of the final product. A risk assessment is conducted to determine critical quality attributes (CQAs), which are properties that are directly connected to product efficacy and safety. CQAs should be monitored, assayed or assessed during manufacturing to ensure that the product profile is met. Another risk assessment is performed to identify critical process parameters that affect CQAs.
The effects of such parameters are then quantified in a design space, typically by using design of experiments (DoE) studies and analytical assessments implementing systems modeling. The knowledge that is generated is used to develop a control strategy for maintaining process parameters within operating ranges to ensure consistent performance of a process with respect to established CQAs. Such a strategy, however, needs to be validated, continually monitored and improved as needed, especially as knowledge and understanding of CQAs increase over time.
Process Performance Qualification
Before commercial production can commence, process performance qualification (PPQ) runs are conducted at commercially relevant scales using qualified facilities, utilities, equipment and personnel to demonstrate consistency in manufacturing within predefined operating parameters.
Such runs are usually scrutinized more than manufacturing runs in terms of sampling, testing and monitoring. The results can be used to determine the sampling frequency of commercial batches. For processes in which inline or real-time measurements of parameters affect process changes, the focus is on qualifying the measurement systems and control loops for measured attributes. The overall goal of PPQ runs is to qualify designed manufacturing processes as capable of reproducible commercial manufacturing. For process validation, scientific evidence that a process can consistently produce a predefined quality of products is established by gathering and analyzing data from process design through commercial manufacturing.
Prioritization of speed to early clinical trials – where the focus is on maintaining a supply of clinical materials and aversion to the risk of early overcommitment for unproven products – can lead to limited opportunities for process development. With a QbD approach, manufacturing a CGT product starts with defining a target profile, which includes all desired properties in the final product, ensuring its quality, safety and efficacy.
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