Quality by Design Implementation for an Allogeneic Cell Therapy

The Situation: Driving Control and Consistency Across Commercial Cell Therapies

The client was advancing allogeneic cell therapy products through late phase clinical development to commercial launch. Quality by Design (QbD), Design of Experiments (DoE) and use of statistical tools had not been firmly embedded in the company from the outset of program development. A number of the release and in-process assays had high variability. This, combined with poorly understood proven acceptable ranges (PAR or design space) and normal operating ranges (NORs or control space) for the manufacturing process, led to unnecessary batch rejections. The client requested technical support for these specific challenges. However, the review highlighted a broader need for introducing a structured QbD approach across the product lifecycle, from cell banking & manufacturing, through to cryopreservation to reduce batch failure and provide narrower ranges for the product’s Critical Quality Attributes.

GRA Solution: QbD Deployment and Improved Assays

GreyRigge introduced a comprehensive QbD framework across the program, including definition of Target Product Profiles (TPPs), Quality Target Product Profiles (QTPP), Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs) together with supporting risk assessments.

Activities included:

• Parameter Attribute Matrices (PAMs) and process risk assessments

• Process limit evaluation and design space definition

• DoE-driven optimisation across formulation and cryopreservation

• Assay robustness studies using DoE, variance component analysis (VCA) to understand assay precision and design assay replication strategies

• Visual inspection assessment and error source reduction

• Statistical training and coaching to embed capability internally

This strengthened both manufacturing processes and analytical control strategies, aligning with regulatory guidance, specifically ICH Q11, ICH Q2(R2) and ICH Q14. Furthermore, the work enabled more appropriate specifications based on the data that justified the values selected across the products.

Value Added: Improved Control, Faster Path to Filing and Cost Efficiencies

By applying QbD approaches during mid- to late-stage product development, the client achieved:

• Significantly reduced assay variability and improved robustness
• Clear operating ranges and control strategies for the product
• Improved and efficient regulatory interactions and filing readiness
• Reduced development costs through focused experimentation
• Improved knowledge transfer across sites
• Organisational adoption of a sustained QbD mindset

The enhanced control strategy supported both product robustness and regulatory confidence as well as reducing batch rejections associated with both assay variability and a subjective visual inspection.

Consultants: CMC, Analytical Development & QC, MSAT, Statisticians.