In January 2020, the Food and Drug Administration (FDA) issued a guidance entitled Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). It focuses on safety, identity, strength, purity, and quality (SISPQ); critical quality attributes (CQAs); and the application of risk management processes to cell/gene therapy products developed in recent years. The guidance, which updates the previously released recommendations on CMC information for Human Somatic Cell Therapy from 2008, covers the following Common Technical Document (CTD) modules:
• Module 1 – Administrative Information
• Module 2 – Summary of Quality Information
• Module 3 – Manufacturing Process and Control Information
Cell and gene therapy (CGT), a.k.a. advanced therapy medicinal products or ATMPs, has gained significant momentum in recent years. The FDA has already approved over twenty CGTs, and many more are currently undergoing the approval process.
As with all product development processes, risk management is an important part of that process. This article covers risk and knowledge management considerations applied to the CGT environment.
Adopting a Risk-Based Approach
A risk-based approach should be leveraged for every aspect of a product throughout its lifecycle. Both development and manufacturing should be carried out under a mature pharmaceutical quality system to guarantee adequate, consistent product quality.
In determining the appropriate measures to address the identified risks, priority should be given to patient safety and product quality; the greater the risk to the patient, the greater the process understanding that should be generated, which, in turn, should promote the development of a higher-quality product.
A best practice is to leverage a quality by design (QbD) strategy, in which a significant amount of data is collected to support risk-based decisions. Principles of ICH Q9 should be followed to define the risk-based approach, ensuring that the level of effort and documentation is commensurate with the level of risk.
The QbD approach should be strongly considered by developers of these types of products, as it is a promising methodology to mitigate the significant risk posed by complex manufacturing processes.
Development of a well-controlled manufacturing process should begin with a set of predefined quality characteristics that are linked to the safety and efficacy of the product and define what the process intends to generate.
Typically, these attributes are summarized in the product’s quality target product profile (QTPP), a living document that emerges in early development phases. Developers use the QTTP to generate a list of product CQAs. A CQA is defined in IHC guideline Q8 (R2) as a “physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” Examples of quality attributes for CGT products include purity, potency, identity, and sterility — and in the case of engineered tissues, examples include structural or mechanical properties. To determine the criticality of these quality attributes, developers should subject each one to a risk assessment and to correlative preclinical or clinical studies to assess its impact on product safety and efficacy.
The Impact of CMAs and CPPs on CQAs
The attributes of raw materials and manufacturing process parameters that may vary and, consequently, impact CQAs are critical material attributes (CMAs) and critical process parameters (CPPs), respectively. Important attributes with variability that might impact product quality, CMAs, and CPPs should be measured and controlled to ensure that the process generates a product of the desired quality. The degree to which each identified CMA and CPP impacts CQAs is often evaluated initially in a risk-based analysis and subsequently by Design of Experiments (DOE) studies. The DOE studies screen for potential variability and assess the impact of CMAs and CPPs on the quality of process intermediates (e.g., cells, scaffolds, vectors) or the final product.
Measurements that quantitate the impact of variability on CQAs can be developed using methods like those described to develop potency assays. These methods include the collection of large amounts of characterization data from discovery-based multiple-omics platforms.
From the process characterization studies, which should include the causality studies to correlate inputs and outputs, it is possible to start defining specific failure modes for the high-risk areas identified. For this case, there is a broad scope of topics to cover, ranging from starting and raw materials, suppliers, process design, and overall operation. The evaluation should include, as appropriate, donor assessment, cell and/or tissue source materials, and specific manufacturing processes, such as cell expansion and viral reduction steps, which can affect viral spread.
This evaluation will allow for the establishment of robust control strategies, covering everything from materials management and application to process controls and analytical strategy. The control strategies should always be tested thoroughly and revised throughout the lifecycle, starting in the clinical studies phase and extending until the continuous verification stage.
It is vital that risk assessments are clearly documented and that the conclusions are well supported by technical and scientific data. For example, risk assessments may need to include a review of existing cleanroom processes and microbiological controls to prevent or minimize contamination.
Manufacturers should also consider revisiting their risk assessments as they gain more knowledge about their CGT products and manufacturing processes.
Recommendations
The development of cell and gene therapies calls for a standard application of risk management principles in line with the current guidelines for product development. They provide a strong reference that can be followed to support all the decisions made with a solid science-based rationale.
ValGenesis expertise in pharmaceutical risk management consistently shows us that a robust risk and knowledge management culture is key to successful product development. We recommend having a platform where all the information is centralized, shared, and used as a foundation for new developments. If you’d like further information, contact us at [email protected].