Insight

Quality Control Strategy for Cell Therapy Products

As a category of “living medicines”, cell therapy products exhibit markedly higher complexity and variability compared with conventional pharmaceuticals. A risk-based quality control approach shall be implemented to define the Quality Target Product Profile (QTPP) and potential Critical Quality Attributes (CQAs). Corresponding holistic quality control strategies shall be established covering four dimensions: Critical Process Parameter (CPP) control, Critical Material Attribute (CMA) control, in-process control, and testing control.

Part 1 Overview of Cell and Gene Therapy Products

1.1 Definition of Cell Therapy Products

Cell therapy products represent a novel category of biopharmaceuticals. They are manufactured by ex vivo manipulation of living cells (including isolation, culture, expansion, genetic modification, etc.), followed by administration into patients for the treatment, diagnosis or prevention of diseases, essentially defined as “living medicines”.

The Center for Drug Inspection of the National Medical Products Administration (CFDI) clarifies in the Guidelines for the Production Quality Management of Cell Therapy Products[1] that cell therapy products refer to human autologous or allogeneic cells subjected to ex vivo manipulation (including but not limited to isolation, culture, expansion, genetic modification, etc.), which are infused or implanted into patients for therapeutic purposes.

The U.S. Food and Drug Administration (FDA) classifies such products as Cell and Gene Therapy Products, highlighting potential gene transfer, recombination or regulation involved therein. The European Medicines Agency (EMA) categorizes them as Advanced Therapy Medicinal Products (ATMPs), explicitly encompassing gene therapy products, somatic cell therapy products and tissue-engineered products.

1.2 Classification of Cell Therapy Products

Cell therapy products fall into two major categories: unmodified native cell products and genetically engineered cell products.

1.2.1 Unmodified Cell Therapy Products

This category mainly consists of stem cell products and immune cell products, detailed as follows:

Stem cell products: Mesenchymal stem cells exert immunomodulatory and tissue repair effects, applicable to the treatment of osteoarthritis, graft-versus-host disease (GVHD), etc. Hematopoietic stem cells are used for hematological disease treatment and immune reconstitution, such as hematopoietic stem cell transplantation for leukemia. Pluripotent stem cell-derived products cover retinal cells, cardiomyocytes and other cell types differentiated from induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs).

Immune cell products: Tumor-infiltrating lymphocytes (TILs) isolated from tumor tissues, expanded ex vivo and reinfused into patients.

1.2.2 Genetically Modified Cell Therapy Products

This subcategory includes the following types:

Chimeric Antigen Receptor T (CAR-T) cells: Multiple approved products have been launched globally, marking landmark achievements in cell therapy. T cells are genetically engineered to express tumor-targeting chimeric antigen receptors for oncology treatment.

T Cell Receptor T (TCR-T) cells: Genetically modified T cells capable of recognizing intracellular tumor antigens.

Genetically modified hematopoietic stem cells: Normal functional genes are transduced into patients’ autologous hematopoietic stem cells (HSCs) to treat monogenic disorders such as thalassemia and severe combined immunodeficiency (SCID).

Other genetically modified cells: Gene-edited and differentiated cells derived from iPSCs, among others.

1.3 Unique Quality Management Challenges of Cell Therapy Products

Regardless of definition and classification, cell therapy products exhibit substantially higher variability and complexity compared with conventional pharmaceuticals. Regulatory frameworks for ATMPs issued by European and American authorities classify these as complex medicinal products, whose risks vary by product type, starting material characteristics and process complexity. Diverse biological raw materials and intricate manufacturing workflows (e.g., cell culture, functional modulation of cells) introduce variable risks of different magnitudes.

Taking CAR-T cell products as an example, their active pharmaceutical ingredient is living cells, i.e., “living medicines”. Terminal sterilization, sterile filtration, microbial removal or inactivation cannot be implemented, leading to elevated risks of contamination and cross-contamination. Key unique challenges are summarized below:

1.Diverse sources of starting donor materials, including autologous and allogeneic origins;

2.Complex workflows for cell collection (e.g., leukapheresis, TIL isolation from tumor tissue) and manufacturing (cell sorting and purification, antigen priming, ex vivo activation, genetic modification/editing);

3.Multi-step production processes including cell purification, transduction and washing, with distinct cellular compositions and characteristics across unit operations, rather than simple expansion of a single cell bank;

4.Concurrent multi-batch manufacturing, carrying high risks of mix-ups with severe clinical consequences; production delays or failures may deprive subjects of scheduled therapeutic administration;

5.Highly personalized autologous products manufactured in small batches tailored to individual patients. Sufficient bulk samples for testing and retention are unavailable, imposing stringent timelines for sampling and testing;

6.High temperature sensitivity of cellular samples with limited ambient storage stability, requiring rigorous control over sampling operations, post-sample processing and preservation.

To ensure cell therapy products meet predefined therapeutic quality requirements, a risk-based approach aligned with quality risk management principles shall be adopted. Starting from raw materials, comprehensive risk assessments shall be performed across the entire manufacturing workflow, batch scales and inherent product variability. A holistic quality control system shall be established to guarantee product quality, safety, efficacy and traceability.

Quality risk management tools shall be deployed to conduct thorough quality research and accumulate multi-batch datasets. Lifecycle-wide hazards shall be periodically identified, followed by formal quality risk assessment, formulation of risk mitigation strategies and implementation of corresponding quality control measures. Continuous updates and optimizations shall be performed to maintain quality risks under control and ensure products meet intended clinical use specifications.

Part 2 Establishment of QTPP, CQA, CPP and CMA

Manufacturing processes shall be built upon sufficient research and process comprehension. During product development, continuous process understanding, potential risk identification and practical experience accumulation enable the formulation of customized quality control strategies, stabilizing manufacturing processes and guaranteeing consistent product therapeutic quality.

ICH Q8 defines the Quality Target Product Profile (QTPP) as “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product”. Centered on product safety, identity, quantity, purity and other core dimensions, QTPP defines mandatory product attributes to deliver reproducible therapeutic effects as labeled. QTPP shall be defined in early-stage development and updated iteratively as scientific knowledge advances. Post-approval, QTPP serves as the foundation for continuous quality improvement throughout the product lifecycle, bearing critical significance. Typical QTPP elements include:

1.Drug product design: Broadly referring to descriptions of physical product attributes;

2.Drug product quality attributes: Product characteristics correlated with pharmaceutical quality, covering safety, identity, assay, purity, potency and other quality-related features.

Critical Quality Attribute (CQA) identification constitutes a multidisciplinary activity integrating scientific literature, preclinical and clinical data, coupled with formal risk assessment. CQAs are defined as “physical, chemical, biological or microbiological properties or characteristics that must be within an appropriate limit, range, or distribution to ensure the desired product quality”. Consistent with principles outlined in ICH Q9, risk analysis methodologies (e.g., Failure Mode and Effects Analysis, FMEA) linking probability of occurrence and severity of harm shall be utilized to identify and periodically review CQAs, with dynamic adjustments based on updated knowledge of target indications and clinical settings.

Process parameters exerting direct impacts on CQAs are defined as Critical Process Parameters (CPPs). Manufacturing workflows shall be characterized by process inputs (starting materials, raw materials, controllable parameters, equipment and associated operations) and process outputs (process performance and product quality attributes). Statistical analysis of process development datasets shall be conducted to characterize variable sources affecting product quality. Comprehensive process mapping shall be performed to evaluate variable impacts and parameter interactions, facilitating CPP identification. Following full characterization of correlations between process parameters and quality attributes, a preliminary CPP inventory shall be established for manufacturing.

Raw materials used in production represent another major risk factor affecting product CQAs. Development of material control strategies commences with classification of raw materials and clarification of their functions across unit operations. Following inventory compilation, materials shall be assessed to identify critical materials correlated with product CQAs. Each critical material shall undergo comprehensive evaluation to define its Critical Material Attributes (CMAs), with corresponding controls implemented to guarantee compliance with target product quality specifications.

After mapping correlations between CQAs, CPPs and CMAs and finalizing respective inventories via risk evaluation, the overarching holistic control strategy can be structured and implemented.

Part 3 Formulation of Quality Control Strategies

A control strategy represents an integrated quality management framework encompassing four core dimensions: process parameter control, raw material attribute control, in-process control and testing control. This section uses CAR-T cell therapy products as a case study validated via CQA, CPP and CMA risk assessment.

3.1 Process Parameter Control

Governance of critical process parameters covers the following key domains:

Cell collection parameter control at clinical sites: Standardized cell collection protocols shall be formulated aligned with product development workflows to ensure collected cellular materials meet downstream manufacturing requirements.

Manufacturing process control at production facilities: Magnetic bead dosage ratios during cell sorting; multiplicity of infection (MOI) or equivalent metrics for viral transduction; incubation temperature and CO₂ concentration for cell expansion culture; washing program parameters designed for process impurity clearance.

Logistics and transportation control: Donor starting materials shall be transported under temperature specifications defined by manufacturing protocols (e.g., leukapheresis products maintained under 2°C–8°C cold chain transport). Final formulated drug products shall be shipped under product-specific temperature regimens (e.g., deep cryopreservation via dry ice or liquid nitrogen)[4].

3.2 Raw Material Attribute Control

Raw material attribute control covers three primary categories:

Control of starting donor materials: Cell therapy manufacturing workflows generally lack dedicated viral clearance steps; pathogenic infectious agents originating from donor materials cannot be eliminated via standard cell production processes. Therefore, a pathogen screening framework shall be implemented for all cell donors[2,5]. Clinics shall employ authorized diagnostic kits for infectious pathogen testing, with screening results complying with raw material acceptance criteria defined by manufacturing processes.

Control of manufacturing raw materials: Genetic transduction and modification systems represent critical raw materials[6], whose process stability and quality controllability directly determine cell product safety and efficacy. Quality audits shall be conducted on Contract Development and Manufacturing Organizations (CDMOs) supplying such systems to verify full GMP compliance across their production lifecycles. Extraneous agent safety risks associated with all manufacturing raw materials shall be identified and assessed to eliminate TSE/BSE and adventitious agent contamination risks for biologically derived materials. For biologically sourced culture supplements such as fetal bovine serum, comprehensive adventitious agent safety evaluations shall be completed to safeguard final product safety.

Control of single-use sterile consumables: Driven by the fully sterile manufacturing requirements of cell therapy products, compatibility between consumable materials in direct contact with products, validation of consumable sterilization processes, and manufacturing environments for consumable production shall be verified to meet product specifications for sterility, endotoxin, visible particles and subvisible particulate matter.

3.3 In-Process Control

Multi-layered governance shall be implemented to ensure GMP compliance and process controllability:

Personnel management for manufacturing staff: Mandatory training and qualification assessments for all personnel with direct production exposure, including Aseptic Gowning Qualification (AGQ) and Aseptic Operation Qualification (AOQ).

Segregated production zones for infectious donor materials: Manufacturing operations involving donor materials positive for infectious pathogens shall be conducted within dedicated independent production suites equipped with isolated HVAC systems, maintaining negative pressure within zones with exposed cell products.

Cross-contamination prevention for autologous cell products: Autologous products are manufactured as single-patient single batches with concurrent multi-batch production scenarios. Facility design and production management shall incorporate risk-based cross-contamination and microbial contamination mitigation measures. For parallel identical production lines within a single manufacturing suite, environmental monitoring strategies shall be defined for background areas and individual lines based on formal risk assessment.

Facility layout and equipment configuration aligned with process workflows: Manufacturing batch scales vary drastically between autologous and allogeneic products (single-patient batches vs. multi-patient batches). Facility layouts and production equipment shall be configured according to process requirements (closed vs. open processing systems).

Cleanroom classification matching open/closed processing workflows: Manufacturing operations shall be executed within cleanrooms of appropriate classification corresponding to open or closed processing workflows, securing controlled production environments.

Environmental monitoring programs: Periodic cleanroom classification monitoring; surface microbial testing for all staff performing direct cell manipulation per batch; simultaneous viable and non-viable particle monitoring for Grade A open operations under Grade B background environments.

Aseptic process management: Regular Aseptic Process Simulation (APS) trials covering all full-length aseptic manufacturing workflows; sterility validation for media preparation processes used in production.

3.4 Testing Control

Sampling protocols shall be formulated in accordance with sampling objectives, regulatory requirements, product characteristics and manufacturing workflow architectures (continuous unitized processing), governing in-process sampling and quality monitoring.

1.Testing items and analytical methodologies shall comply with product quality specifications, ensuring representative samples are selected for corresponding test parameters. Sterility testing, bacterial endotoxin testing and other compendial assays shall preferably be performed on final formulated drug products post-compounding to meet regulatory mandates[7].

2.Sampling points shall be embedded within manufacturing workflows via risk assessment and quality research validation, confirming samples collected at defined unit operations adequately reflect final product characteristics to fulfill quality control objectives.

3.Sampling quantities shall be standardized based on analytical methodology requirements and product/process characteristics while adhering to regulatory thresholds. For scenarios with limited available sample volume, high-sensitivity low-volume analytical platforms such as quantitative real-time PCR (qPCR) may be developed where feasible.

4.Sampling operations shall be conducted within cleanrooms of specified classification to minimize contamination and cross-contamination risks.

5.All collected samples shall bear unambiguous traceable labeling to eliminate mix-up risks, including cross-sample confusion within a single batch and cross-batch sample misidentification.

6.Sampling utensils and sample containers shall be selected to match product and process properties. Sampling operations, post-sample handling, preservation and testing shall strictly adhere to defined storage conditions. Closed sampling systems are recommended, with validation confirming sample representativeness and accounting for dead volume interferences.

Part 4 Conclusion

Cell therapy products shall be manufactured via robust, risk-controlled processes. Comprehensive quality control strategies covering raw material governance, in-process manufacturing controls, cleanroom environmental management and sampling/testing oversight shall be formulated based on formal risk assessment, product workflows and quality attributes. Such systems ensure each drug product batch complies with predefined safety, identity, purity and potency specifications, ultimately safeguarding patient medication safety.

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Quality Control Strategy for Cell Therapy Products

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