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The historic pace of new therapy development has challenged biopharmaceutical manufacturers to find new ways to make processes more efficient and ensure safe treatments get to patients faster — and the stakes are high. To capitalise on the opportunities new therapies offer and advance them to market without delay, manufacturers must address numerous challenges, from pilot to production, starting with clinical trial materials manufacturing.
Because of their typically small sizes, Phase I and Phase II trials do not require large quantities of manufacturing materials or equipment capable of handling large volumes. While volumes may not be high, absolute rigour is required in early-stage phases to maintain quality within production and storage cycles. Every effort must be taken to ensure patient safety. In addition, early phase outcomes will determine whether development of the drug continues. Any quality issue early on can generate false results, misinforming development investment decisions and the potential of advancing life-changing medicines to market.
Scaling materials manufacturing is also a challenge. As trials move from clinical Phase I to Phase III to commercialisation of drug products, the volume and quality requirements increase. In certain cases, the in-house quality raw material may be acceptable in early clinical development. However, the same raw material quality may need to be controlled using cGMP manufactured raw materials.
Likewise, each time a trial changes equipment, material of construction or cGMP requirements during scale-up, the change may require additional testing, production process verification and documentation to validate sterility, consistency and performance. Any of these delays creates the potential for increasing costs and even compliance issues if the changes are made after product development.
The Value of Flexibility
Manufacturers who can incorporate flexible processes position themselves to advance production to avoid delays and move therapies to market faster. For example, patient participation levels may change during the trials as patient retention rates vary, impacting material volume needs. Likewise, sometimes a patient will drop out of a trial after receiving the Investigational Product. When a new patient joins, material resources will need to support the addition of a new patient starting the trial from the beginning.
Building flexibility into every aspect of the process, from manufacturing to kitting to storage, allows drug developers to not only adapt to changing conditions but scale up as needed through each phase and into commercial production. The ability to remain flexible also positions developers to scale up in unexpected situations, such as cases in which a first-in-class molecule receives conditional approval to treat broader or larger patient populations.
Adhering to cGMP Guidelines
Clinical trial material manufacturing presents different challenges than manufacturing for large-scale production. A Phase I clinical trial is the first time that the investigational product will be used in a human. That makes it critical to consider quality systems early, as well as the regulatory guidelines established to prevent cross-contamination and environmental contamination. Even more stringent guidelines must be followed for clinical trial materials used in monoclonal antibodies (mAbs), biologics and cell and gene therapy (C>) products.
Scaling up with Flexibility and Compliance
Early planning is the foundation for creating a scalable, compliant process.
Navigating raw material supply: Insufficient material planning can lead to inefficiencies, validation failures and market delays. The use of cGMP grade materials, like reagents, from the start of a clinical trial can ease the transition to later trial phases and larger-scale manufacturing. The material will maintain its quality and viability across the full workflow and eliminate material requalification due to unavailable grade or quantity after transfer.
In addition to creating a more seamless path to commercial production, the use of cGMP materials in early clinical Phase I can help minimise contamination risk, provide material traceability, ensure product consistency and regulatory compliance.
Use of cGMP materials is not always possible during development of advanced therapeutics, such as C> therapy. Labs sometimes use a unique material or ingredient that has been successfully used in the lab but has not been used in manufacturing processes. It is critical to conduct a risk assessment to establish a quality standard. It is also important in advanced therapeutics trials to have a plan to acquire cGMP-quality materials.
Likewise, investigators must consider the quantity of materials early in the process to avoid potential delays and bottlenecks. An early production run may only require a small amount of a specific material, so it’s common to assume that quantity will be easy to acquire. However, the supplier may have already allocated their current supplies to another customer. In addition, the value of considering larger amounts of raw material for production in later phases cannot be underestimated. Ordering supplies early —regardless of the quantity — helps minimise costly delays.
Another important materials consideration is planning for cGMP documentation. If a lab uses a material before acquiring documentation, a supplier may not be able to supply the documentation for a variety of reasons, such as the material is not assessed for a specific requirement. Risk assessment during the trial planning phase is an ideal opportunity to identify and prepare for these future needs and avoid delays.
Leveraging technology to scale production: Technology can be a key tool to help avoid setbacks as production scales. A platform approach that uses a fluid handling system can help de-risk and improve processes during the transition from development to final production volume.
For example, peristaltic pumps used in research and development require much lower flow rates. Smaller lab-scale units cannot support the transition from bench to full-scale production. To ensure a project can scale quickly, it’s faster and more efficient to use the same pump technology in the lab as when it is time to transition to equipment that can handle higher flow and volume.
Considering automation platforms during the clinical trial material manufacturing process can also ensure seamless scale-up. Peristaltic pumps with built-in automation capabilities ensure technicians can set and recall commonly used programs and continuity in controls.
Likewise, single-use technology can be key to processing clinical trial materials. Single-use offers customised, scalable technology with a wide range of component choices, from filters and connectors to tubing and bags. By engaging early on in single-use technology with smart industrial design, an open architecture approach with as many agnostic components as possible, manufacturers can ensure their processes have the agility and secure scalability to support later product volumes.
Collaborating with solutions partners: From selecting qualified products to storing materials in cGMP-compliant biorepositories, manufacturers must balance a myriad of considerations on the path to commercial production. Choosing solutions partners with pilot-to-production expertise, deep regulatory understanding and a comprehensive portfolio can be key for scale-up success and allow researchers to spend more time on science.
For example, experienced, cGMP-compliant kitting suppliers are well positioned to offer flexible services that scale as the trial progresses, no matter how simple or complex the kit or logistics required. By collaborating with a partner early in the process, drug developers can provide solutions that conform with all internal and external protocols as well as regulatory requirements.
Safe and secure storage of production materials and patient samples are also essential for supporting clinical trials and commercial manufacturing as they scale. cGMP-compliant biorepositories help ensure proper asset management across the full chain of custody. During the planning state, consider how much storage of bulk manufacturing material will be needed as the clinical trial progresses, as well as any specific storage requirements, such as temperature or humidity control.
Trial planning for therapeutics like C> creates unique challenges compared to more standard biopharmaceutical clinical trials. For example, since each specimen is used to create the therapy, it must be stored and returned under the most stringent safety and cryopreservation conditions and aligned with regulatory requirements. In addition to the extraordinary care a biorepository must provide, it must also support the stable, multiyear storage C> trials demand.
Preparing for Scalability Success
Careful planning during clinical trial materials manufacturing can ensure flexibility and compliance as processes scale. From high-quality raw materials to innovative equipment technology to long-term storage, drug developers can leverage these opportunities to advance production, focus more time on science and move treatments to market faster.
Nandu Deorkar, Ph.D., MBA, senior vice president, research & development, biopharma production; and George Marquez, vice president, operations, Avantor.