Why raw material qualification matters

The complexity of manufacturing cell and gene therapies presents unique challenges that extend far beyond traditional pharmaceutical production. Among the most critical yet often underappreciated aspects of this manufacturing process is the qualification of raw materials.

Understanding what raw materials are and why their qualification matters is essential for any organization developing cell and gene therapies.

What are raw materials?

Raw materials are materials used during the manufacture of the active substance (the cell or gene therapy) that are not intended to form part of the final active substance or final product. They are process inputs that come into contact with cells, tissues or vectors during manufacturing, but are removed or consumed during the production process.

This definition is applied fairly consistently across regulatory frameworks, however in the United States, the term “ancillary materials” is more commonly used and is essentially synonymous with “raw materials” – much like the variation between the terms “Advanced Therapy Medicinal Products” and “cell and gene therapies”.

European regulatory framework:

The European Pharmacopoeia Chapter 5.2.12 specifically addresses “Raw materials of biological origin for the production of cell-based and gene therapy medicinal products” and defines raw materials as process inputs that are not intended to be part of the final product.

US regulatory framework:

The United States Pharmacopeia Chapter <1043> defines ancillary materials as materials that come in contact with cells, tissues, or cellular/tissue-based products during manufacturing but are not intended to remain in the final therapeutic product.

The spectrum of raw materials used in cell and gene therapy manufacturing is diverse and includes:
• Cell culture media and supplements
• Growth factors and cytokines
• Enzymes and dissociation agents
• Serum and serum replacements
• Cryopreservatives and stabilizers
• Viral vectors and plasmids

What is raw material qualification?

Raw material qualification is the systematic process of establishing the safety, quality and suitability of materials used in the manufacturing of cell and gene therapy products. This process involves comprehensive evaluation, testing and documentation to ensure that raw materials meet the necessary standards for their intended use in therapeutic manufacturing.

The qualification process is not a one-time event but rather an ongoing program that encompasses initial assessment, routine monitoring, and continuous evaluation throughout the product lifecycle.

Why is raw material qualification important?

Patient safety

Raw materials directly impact the safety of the final therapeutic product. Contaminated or variable raw materials can introduce microbial contamination, such as bacteria, fungi, mycoplasma, as well as viral contamination, endotoxins, adventitious agents and unwanted biological activity.

Given that cell and gene therapies are often administered to severely ill patients with compromised immune systems, the margin for error is exceptionally small. Any contamination or quality issue in raw materials can have devastating consequences for patient safety.

Quality and consistency

Raw material variability is a major challenge in cell and gene therapy manufacturing. Cells are inherently variable biological systems, and inconsistent raw materials can lead to:
• Batch-to-batch variability in the final product
• Unpredictable cell growth and differentiation
• Inconsistent potency and efficacy
• Difficulty in achieving reproducible manufacturing processes

Proper qualification ensures that raw materials meet defined specifications and perform consistently across multiple lots. This consistency is essential for demonstrating comparability between clinical and commercial manufacturing, a key regulatory requirement for product approval.

Regulatory compliance

Regulatory authorities including the FDA, EMA, and others have established clear expectations for raw material management, reflecting the critical role these materials play in therapeutic safety and efficacy:

United States Pharmacopeia Chapter <1043> provides a risk-based framework for classifying raw materials into four tiers based on associated risks, with corresponding qualification requirements for each tier.

European Pharmacopoeia Chapter 5.2.12 addresses raw materials for the production of cell-based and gene therapy medicinal products, providing specific guidance for raw materials of biological origin.

ISO 20399 provides international standards for biotechnology and cell therapy manufacturing.

Failure to adequately qualify raw materials can result in significant regulatory consequences that extend far beyond simple documentation deficiencies. Moreover, addressing raw material qualification deficiencies after they are identified by regulators is significantly more resource-intensive than implementing robust programs from the outset. Companies may need to conduct extensive bridging studies, revalidate manufacturing processes, or even repeat clinical trials with properly qualified materials, efforts that can cost millions of dollars and delay commercialization by years.

Supply chain continuity

Beyond the immediate quality considerations, raw material qualification includes comprehensive vendor qualification programs that assess multiple critical factors essential for long-term therapeutic manufacturing success. These programs evaluate a vendor’s manufacturing capacity and scalability to ensure they can support the transition from clinical to commercial production as demand increases. Additionally, they examine business continuity plans to guarantee uninterrupted supply, establish clear change notification procedures to maintain transparency, and verify the long-term availability of materials to support products throughout their entire lifecycle. This aspect of qualification is particularly critical because many cell and gene therapy products initially use research-grade materials that may not be available at commercial scale or may not meet the quality standards required for therapeutic manufacturing. Early qualification helps identify and mitigate supply chain risks before they impact clinical or commercial programs, allowing time to identify alternative suppliers or work with vendors to develop GMP-grade versions of critical materials.

Cost and time efficiency

While raw material qualification requires upfront investment, it prevents costly issues that can significantly derail development and commercialization efforts. Without proper qualification, organizations risk manufacturing failures stemming from poor-quality materials, which can cascade into clinical trial delays that set back entire programs. These quality issues may also lead to product recalls that damage both finances and reputation, as well as regulatory rejections that require extensive remediation efforts. Perhaps most costly is the need to reformulate or revalidate processes with alternative materials, which can set programs back months or even years. Organizations that invest in comprehensive qualification programs early in development consistently demonstrate more predictable timelines, fewer manufacturing deviations, and smoother regulatory pathways. This proactive approach not only reduces risk but also accelerates time to market.

As the cell and gene therapy field continues to advance, bringing hope to patients with previously untreatable conditions, the importance of raw material qualification will only grow.

This content is part of the RegMedNet Spotlight on raw materials and supply chain. Click here to view the full feature and discover expert insights on this topic >>>