Process characterization is critical to any cell therapy program. Not only are validated processes required to consistently produce safe and effective therapeutics, but developers must also outline the details of their process characterization to regulators to bring their therapeutic to market.

In this blog post, we’ll explore why process characterization is important, especially for complex cell therapies, and the stages of process characterization that developers must complete throughout the life cycle of their therapy. We’ll also share insights and best practices for effective process characterization — and the steps developers can take today to lay the foundation for success. 

What is process characterization?

Process characterization focuses on consistent performance: Ensuring your process will reliably produce a safe and effective product that meets the desired quality attributes.

Process characterization is important for any therapeutic, but it’s especially crucial for cell therapies because the starting materials used to create these therapeutics tend to be highly variable and sensitive. Done well, characterization helps address this variability and establishes process controls that maintain consistent product quality.

It’s also essential for the viability of the program overall. Characterization is a critical step for regulatory approval, ensuring that manufacturing meets the necessary standards. In addition, validated processes are more likely to be robust and scalable enough to support successful commercialization. And, finally, characterization creates an opportunity for risk identification and management, which helps to prevent costly manufacturing failures and ensure a reliable supply of the therapy once it reaches the market.

Process characterization across the life cycle of a therapeutic

Process characterization is made up of three stages:

Stage 1: Process Design

This stage occurs during process development and is a blueprint for later stages of characterization.

In this stage, developers select the appropriate starting materials for their needs and begin developing processes optimized for these materials. They gather clinical manufacturing experience, helping to identify bottlenecks and sources of variability that may affect the consistency of the final product. And they identify and measure critical quality attributes (CQAs) — the metrics by which they measure consistency achieved through a suitable combination of control elements, including raw material specifications, procedural and process controls, in-process specifications, and a comprehensive testing strategy covering release, stability and characterization.

Process characterization in stage 1 focuses on developing a deep understanding of the variation in starting materials — particularly for autologous therapies, which differ significantly from patient to patient. Many developers may not fully appreciate the inherent variability in patient-derived starting materials. They may simply not have enough patient material to support process development and performance qualification. As a result, they may need to compare differences in product quality among starting materials derived from healthy donors and patients.

Stage 2: Process Qualification

Process qualification occurs in the late stages of process development, with the goal to demonstrate that the established process can consistently reproduce a commercial product.

At this stage, developers justify their chosen starting materials, as well as any other components (raw materials) in the process, demonstrating that the selected materials can yield a consistent final product. They also conduct a robust risk assessment for manufacturing and commercialization — including potential risk factors related to product knowledge, process understanding, control strategy and facility controls and capabilities. Each process qualification protocol must specify the acceptance criteria, encompassing all critical process parameters (CPPs) along with their proven acceptable ranges, all critical material attributes and their specification limits, all in-process controls (IPCs) with their characterization acceptance criteria or action limits, and all release specifications.

Finally, developers will craft a blueprint for ongoing quality control, including determining the appropriate number of qualification batches to demonstrate consistency.

Stage 3: Life Cycle Management

Process characterization isn’t simply a two-step process — it’s an ongoing one. Developers must continue monitoring and assessing processes to ensure they remain in a validated state. Developers should also consider adaptive process control —adjusting the process as needed, for example to adapt to unexpected changes in starting materials — which helps ensure they can continue to offer a safe and effective product.

Doing this well requires a multifaceted approach

Throughout each stage of process characterization, developers will need to:

Leverage robust analytical methods

To accurately characterize starting materials, in-process materials and final products. This includes methods to measure CQAs and other relevant attributes. In-process, release and compendial assays used for specification testing should be validated before use in characterization lots.

Implement risk assessment tools

To systematically identify and evaluate potential risks throughout manufacturing. This helps prioritize characterization and allocate resources effectively.

Develop process control strategies

To monitor and control process parameters (CPPs, IPCs, hold times, processing times, etc.) within acceptable ranges. This may involve statistical process control and other control methodologies.

Establish data management systems

To effectively collect, store and analyze data generated during process development and characterization. This supports process understanding and facilitates decision-making.

Deploy statistical analysis software

To analyze process data, identify trends and assess process capability. This is crucial for demonstrating process consistency and reproducibility.

Use adaptive process control technologies

To leverage technologies that enable real-time monitoring and adjustment of process parameters in response to variability (e.g., in starting materials) to improve process robustness and consistency.

Developers face a number of challenges during each stage of characterization

While process characterization is critical, it’s also difficult for many cell therapy developers to complete on their own.

That’s because successful process characterization requires access to specialized expertise — which can be difficult and time-consuming to source. Even with the right expertise, developers face an uphill battle. In the early stages of development, the team may have a limited understanding of the CQAs and their relationship to process parameters, which results in trial and error to create validated processes.

Raw materials, excipients and consumables also pose a challenge. Unlike traditional biologics, cell therapy products often use raw materials that can vary significantly from batch to batch. This variability can affect the consistency and quality of the final product, making it essential to have robust control strategies. In effect, this means developers must thoroughly test and validate raw materials to ensure they meet predefined specifications and do not adversely affect manufacturing. Raw materials can directly affect the CQAs of cell therapy products. For instance, the use of animal-derived materials to support cell growth can introduce variability and potential contaminants, which need to be carefully managed and validated.  

Finally, cell therapy manufacturers are in a race against time. Cell therapy product development programs often have significantly shorter timelines compared with traditional biologics. That means the team must assess the quality of the starting materials, adapt their processes accordingly and deploy flexible controls on a limited timeline.

Table 1: Common bottlenecks to cell therapy process characterization

Access to advanced tools and technologies

Process development and characterization rely heavily on access to the right technologies, and CDMOs offer access to these innovations without the significant up-front costs of securing them in-house. CDMOs have established facilities, equipment, capabilities, data management systems and risk assessment tools required to capture data throughout product development so developers can identify product characteristics and success criteria for downstream characterization.

Guidance for quality control and regulatory compliance

CDMOs provide extensive regulatory expertise, as well as the ability to execute robust quality control. Working with a CDMO helps ensure you understand — and meet — regulatory guidelines across multiple jurisdictions, helping to streamline time to market, as well as maintain comprehensive quality control to support conversations with regulators.

Strategic support from day 1

CDMOs bring specialized knowledge and extensive experience in cell therapy manufacturing. They have the technical expertise to optimize processes for efficiency and ensure they meet stringent regulatory standards. CDMOs will also have robust characterization strategies to help you qualify raw materials throughout clinical development.

What’s more, CDMOs can incorporate the monitoring and establishment of CPPs and how they influence CQAs from the outset, laying the foundation for consistency throughout development. And, finally, CDMOs can aid in risk mitigation throughout clinical development, reducing the risk of cost delays — and helping you deliver on your mission to bring novel, lifesaving cell therapies to patients in need.

Catalent offers holistic support for process characterization throughout clinical development. Learn how we can help you streamline time to market with consistent, validated processes.

Catalent, Inc. is a leading global contract development and manufacturing organization (CDMO) championing the missions that help people live better and healthier lives. Every product that Catalent helps develop, manufacture and launch reflects its commitment to improve health outcomes around the world through its Patient First approach. Catalent provides unparalleled service to pharma, biotech and consumer health customers, delivering on their missions to transform lives. Catalent tailors end-to-end solutions to meet customers’ needs in all phases of development and manufacturing. With thousands of scientists and technicians and the latest technology platforms at more than 40 global sites, Catalent supplies billions of doses of life-enhancing and life-saving treatments for patients annually. For more information, visit www.catalent.com.