Building Frameworks To Support Complex Therapy Manufacturing

A conversation with Vadim Klyushnichenko, Calibr-Skaggs Institute for Innovative Medicines

Making a complex therapy — one with a short shelf life and inherent stability weaknesses — becomes orders of magnitude more complicated when a drug sponsor relies on a network of contract manufacturers for production.

Coordinating between them takes thoughtful stewardship. The Calibr-Skaggs Institute for Innovative Medicines is working on such a product, its CLBR001+SWI019, a CD-19 targeting cell therapy built on its switchable CAR-T (sCAR-T) cell platform.

To make the medicine, Calibr relied on five separate CDMOs in far-flung parts of the globe.

Calibr’s vice president of pharmaceutical development and quality, Vadim Klyushnichenko, Ph.D., broke it down for us.

• CAR-T cells were made in California.
• Plasmids and lentiviral vector were made at two CDMOs in Pennsylvania.
• Drug substance was manufactured in Germany.
• Formulation and filling happened at two separate CDMOs in Massachusetts.

Calibr relies on yet another vendor to manage the logistical complexity of delivering starting materials before production and drug product after it — both steps that are highly sensitive to temperature.

Klyushnichenko agreed to answer some questions to help us understand what it takes to keep a half-dozen companies moving in the same direction. His answers have been edited for clarity and brevity. Here’s what he told us.

Let's set the stage. What is unique about Calibr’s cell therapy platform?

Calibr has been actively advancing its cell therapy programs, particularly through collaborations with industry partners like AbbVie.

Our sCAR-T cell technology introduces a novel approach to CAR-T therapy, enhancing its control and precision in targeting cancer cells, versatility, and safety. This platform utilizes an antibody-based "switch" to regulate CAR-T cell activation, aiming to improve safety and efficacy, especially in solid tumors where traditional CAR-T therapies have shown limited success. Traditional CAR-T therapies involve engineering a patient's T cells to target specific cancer antigens, but they can lead to severe side effects like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) due to uncontrolled T cell activation.

In February 2024, Calibr expanded our partnership with AbbVie to further explore the sCAR-T platform for solid tumors and autoimmune diseases.

Calibr's first-in-human Phase 1 of CLBR001 + SWI019 has yielded promising preliminary results for patients with B-cell malignancies. Among the initial nine evaluable patients, the therapy achieved an overall response rate (ORR) of 78%, with 67% attaining complete responses.

These early results suggest that Calibr's switchable CAR-T platform could offer a versatile and safer approach to cell therapy, with potential applications extending beyond hematologic cancers to solid tumors.

What does the cell therapy outsourcing picture look like at Calibr-Skaggs?

Calibr has built a robust network of contract research, development, manufacturing, and supply chain organizations tailored to support the sCAR-T project. We reached out to multiple contract organizations in each category and evaluated them in terms of the technical capabilities, quality, proposed timeline, facility availability, project price, communication, and prior history of collaborations. Building this network required significant effort, but that allowed us to define the list of primary and backup contract organizations for each part of the project. Some functions were consolidated for the next generation of sCAR-T products and clinical supply programs, simplifying overall project execution. Now I can say that we have a strong and reliable framework for the development, manufacturing, and supply chain management of cellular products.

What is unique about Calibr-Skaggs’ CDMO selection matrix used for cell therapy that makes it effective? Tell us more about your selection criteria and process itself. 

Calibr employs a comprehensive and meticulous approach to selecting contract development and manufacturing organizations (CDMOs) for its cell therapy programs. This strategy ensures that chosen CDMOs align with Calibr-Skaggs' technical requirements, quality standards, and project timelines.

Technical capabilities

For example, for technical expertise and capabilities we pay extra attention to the process development and manufacturing proficiency. Calibr-Skaggs evaluates CDMOs based on their experience with specific cell therapy processes, including viral vector production and cell culture techniques. This assessment ensures the CDMO can meet the project's technical demands.

We prioritize CDMOs capable of developing and qualifying analytical methods essential for in-process control, product characterization, stability, and release testing. This capability is crucial for compliance with regulatory standards.

Quality and compliance

In terms of quality systems and regulatory compliance, the CDMO of choice should have robust quality management systems. Calibr-Skaggs conducts thorough due diligence to confirm that potential CDMOs have established quality systems adhering to GMP guidelines. We review the CDMO's history with regulatory inspections to ensure a strong compliance record, minimizing risks of future regulatory issues.

Project management and communication are also essential parts of the due diligence process. Calibr-Skaggs values CDMOs with effective project management practices that facilitate seamless coordination across production, supply chain, and quality control functions. We emphasize the importance of clear and timely communication to address challenges promptly and maintain alignment throughout the project life cycle.

Capacity

To address capacity and flexibility, Calibr-Skaggs assesses whether the CDMO has the necessary resources and capacity to meet current and future project demands, ensuring scalability and adaptability. We consider the CDMO's ability to adapt facilities to accommodate specific manufacturing needs, which is vital for the dynamic nature of cell therapy production.

Proximity

Geography and proximity to clinical sites are also important factors for autologous cell therapies. Calibr-Skaggs prefers CDMOs located near clinical sites to streamline logistics, reduce transportation risks, and ensure timely delivery of patient-specific products.

What is it about cell therapies that require heightened attention and stronger frameworks? Is it simply because they're more complex?

Cell therapies do indeed require heightened attention and stronger frameworks, but the need extends beyond their inherent complexity. Several interrelated factors contribute to the demand for rigorous frameworks in their development, manufacturing, and clinical application.

Product variability

For example, in terms of biological complexity and variability, cellular therapeutics are living products. They involve live cells as the therapeutic agent, which are inherently variable and sensitive to their environment. This makes them far more challenging to standardize compared to small molecule drugs or traditional biologics. Patient-specific variability in autologous cell therapies (using a patient's own cells) introduce additional complexity due to differences in patient biology, disease states, and sample quality.

Scalability

Rigorous manufacturing requirements for cell therapy products include scalability, stringent cleanliness standards, and customized manufacturing. Manufacturing cell therapies is challenging to scale while maintaining consistency and quality. Small deviations in cell culture conditions can lead to significant differences in the final product's efficacy and safety. The living nature of cells demands highly controlled environments to prevent contamination and ensure product viability.

Unlike traditional drugs, many cell therapies are produced on a per-patient basis, requiring adaptable manufacturing processes and logistics. With that, each patient has a set of unique disorders that brings higher variability in the results of clinical testing.

Quality

Quality control challenges for cell therapy products include complex and lot-specific bioanalytical testing. Cells must be evaluated for viability, potency, identity, and purity at every stage of manufacturing. This testing is more complex than for other therapies. Since each "batch" may represent a single patient’s treatment, testing requirements must be robust to ensure safety for that individual.

Safety

Safety in cell therapy products is very important. Cell therapies can provoke immune responses, even when derived from a patient’s own cells. Modifications to cells (e.g., genetic engineering) can increase the risk of unintended effects, such as uncontrolled cell growth or mutations. CAR-T therapies, for example, can trigger severe immune responses such as CRS, requiring protocols to monitor and manage these risks.  However, sCAR-T technology significantly reduces the risks of CRS, thus improving the safety of the patients.

Regulatory

Since cell therapy products are relatively new, regulatory scrutiny is an important factor in their development. The regulatory agencies are still developing frameworks to address the unique aspects of cell therapies. As first-in-class treatments, cell therapies undergo heightened regulatory oversight to ensure patient safety and establish standards for future therapies.

Logistics

Finally, logistics and supply chain complexity and time-sensitive handling require thorough development and risk mitigation assessment. Cells have a limited shelf life and require strict temperature control, making transportation and delivery highly time-sensitive. Autologous therapies demand a robust tracking system to ensure that a patient's cells are correctly matched to their therapy throughout manufacturing and delivery.

You may see that while complexity is a major factor, it is the interplay of biological variability, safety concerns, manufacturing challenges, and regulatory requirements that necessitate heightened attention and stronger frameworks for cell therapies. These frameworks are essential not only to ensure safety and efficacy but also to establish reproducibility, scalability, and accessibility for these advanced treatments.

Discuss the GMP/quality due diligence in CDMO selection for biologics and cell therapy. Are there any steps in which companies often trip up and miss big warning signs?

GMP/quality due diligence in CDMO selection for biologics and cell therapies is crucial because these therapies are sensitive, complex, and require stringent regulatory compliance, as we already discussed.

Below are the key steps in GMP/quality due diligence practice developed at Calibr-Skaggs:

• Perform an assessment of quality management systems (QMS) that aligns with GMP requirements for biologics and cell therapies; review quality policies, standard operating procedures (SOPs), and training programs; and analyze the history of deviations and corrective and preventive actions (CAPAs).
• Examine regulatory compliance history, including the inspection history with regulatory bodies like the FDA, EMA, or local agencies and requesting recent audit reports and responses to inspection findings.
• Perform a facility and equipment assessment to ensure their suitability for biologics or cell therapy manufacturing, including cleanroom classifications, contamination control measures, and equipment qualifications (IQ/OQ/PQ). It is important to assess whether the infrastructure supports the unique requirements of cell therapies, such as cryopreservation and patient-specific batch handling.
• Determine whether manufacturing and process capabilities can meet the technical specifications of the biologics or cell therapy product. Make sure that the CDMO has recent experience with similar products and processes.
• Evaluate supply chain management in terms of the robustness of their supply chain, especially for raw materials, reagents, and critical components specific to cell therapy, such as growth media or viral vectors. Check for risk mitigation strategies for supply chain disruptions.
• Assess analytical testing and quality control, including validated methods for all necessary quality control testing, such as potency assays, sterility testing, and identity verification. Evaluate their internal ability to handle product-specific testing complexities, such as flow cytometry or genomic analysis for cell therapies.
• Documentation and traceability compliance require verifying that the CDMO has systems for batch record documentation, chain of custody, and chain of identity (critical for autologous cell therapies). Review their documentation practices for GMP compliance and traceability.
• Ensure the facility has the scalability and capacity to scale production as needed without compromising quality. Assess their contingency plans for handling surges in production demand or facility downtime.
• Review personnel expertise and stability, particularly in biologics or cell therapy processes. Investigate staff turnover rates, as high turnover can signal potential problems with consistency and expertise.

With that, I would recommend paying attention to common pitfalls and missed warning signs, such as:

• overlooking historical regulatory issues,
• underestimating the importance of facility-specific audits,
• failure to assess analytical capabilities,
• inadequate review of quality metrics,
• ignoring scalability risks,
• lack of contingency planning, and
• insufficient focus on chain of custody/identity.

Companies that fail to conduct thorough on-site audits, assess historical trends, or evaluate scalability risk undermining their product's success.

How can sponsors protect themselves against overpromising CDMOs who can't deliver?

Implement a robust due diligence process. Sponsors can establish clear contractual agreements and continuously monitor performance.

Besides the rigorous GMP/quality due diligence process discussed above, sponsors should put in place detailed contractual documentation that includes signing of confidentiality agreements (CDA), sending the detailed request for proposal (RFP), receiving the scope of work (SoW) with the proposed budget and timeline, and reviewing the quality assurance agreement (QAA) and master service agreement (MSA).

I would say that one of the most important documents in this list is the detailed RFP that should be sent to several CDMOs. Sponsors should design and outline every part of the project and list all required analytical methods, processes, deliverables and required documentation, timelines and budget, including labor, raw materials, consumables and components, and outsourced activities, including handling and overhead fees for each category of services.

This way, the sponsor can compare the multiple SoWs using the established metrics and clearly see the overvalued and undervalued. Frequently, the services are undervalued when CDMOs are overoptimistic, eager to get a contract no matter what, and not experienced in particular areas of bioprocessing.

Overpriced proposals are more common for large CDMOs that need to cover the cost of their extensive infrastructure. If budget is limited and risk seems to be tolerable, I would recommend splitting a contract into two or three separate parts (process biochemistry in small scale, process development, and GMP manufacturing) to better evaluate the CDMOs’ performance and communication instead of committing to a large program from the beginning. Also, I recommend establishing the following project parts:

• ongoing project management oversight and communication plan,
• escalation plan,
• risk assessment and mitigation plan, and
• periodic and post-performance reviews.

You talk about "constant control" regarding managing multiple CMO contracts. What does it take to do that? Robust systems? A big team of relationship managers? Tough lawyers?

Managing multiple CDMO contracts effectively under "constant control" requires a blend of robust systems, skilled personnel, and clear legal frameworks. The goal is to maintain high-quality deliverables, timely execution, and clear communication across all CDMOs without overburdening the sponsor organization. Here’s what it takes:

Robust systems and tools

• Establish a centralized contract management system that tracks contract terms, milestones, deadlines, and performance metrics for all CDMOs.
• Develop project management platforms to manage timelines, tasks, and dependencies across multiple CDMOs.
• Use data integration and analytics to collect and analyze real-time data from CDMOs, including batch performance, deviations, and regulatory compliance.
• Document control systems to maintain a secure, centralized repository for all GMP documentation, audit findings, and correspondence.

A skilled and balanced team

• Assign project managers who develop strong working relationships with CDMOs, acting as the primary point of contact to address issues proactively.
• Use technical experts or specialists in biologics or cell therapy manufacturing to evaluate technical details and assess risks.
• Appoint quality assurance (QA) professionals to oversee compliance with GMP standards and manage quality control across CDMOs.
• Identify regulatory affairs specialists to ensure all CDMO activities align with regulatory requirements and prepare for inspections or filings.
• Hire supply chain coordinators to manage logistics, raw material sourcing, and delivery schedules across multiple CDMOs.

The team size depends on the number of CDMOs and the complexity of the projects. A small, well-coordinated team supported by robust systems can often outperform a large but fragmented one.

Clear and comprehensive contracts

• Define roles and responsibilities to clearly delineate what each CDMO is responsible for, minimizing overlaps and confusion.
• Use performance metrics and milestones to establish measurable KPIs and tie payments or future engagements to performance.
• Establish conflict resolution mechanisms to include clear procedures for dispute resolution to avoid prolonged conflicts.
• IP and confidentiality protections will safeguard proprietary technologies and data shared across multiple CDMOs.
• Force majeure and contingency clauses can account for unexpected disruptions and outline mitigation strategies.
• The role of lawyers is critical for drafting and negotiating contracts that protect the sponsor's interests while ensuring flexibility for unexpected changes.

Effective communication frameworks

• Schedule regular update meetings with each CDMO to review progress, address bottlenecks, and ensure alignment.
• Host joint CDMO meetings when CDMOs need to collaborate, such as for integrated supply chains or shared resources.
• Implement systems to provide instant communication of critical updates, deviations, or regulatory changes.

Strong oversight and governance

• Establish a risk management framework to identify and assess risks across all CDMOs, implementing mitigation plans where necessary.
• Conduct regular on-site and remote audits and reviews to verify compliance with GMP and contract terms.
• Identify escalation paths and protocols for issues that require higher-level intervention.
• Establish governance structures, including a steering committee comprising senior leaders to provide oversight and resolve conflicts between CDMOs.

Contingency planning

Reliance on multiple CDMOs increases the risk of disruptions due to delays, quality issues, or regulatory actions. In order to mitigate the risks, the following strategies should be developed:

• dual sourcing to maintain backup CDMOs or in-house capabilities for critical steps,
• redundancy in supply chain to diversify suppliers for raw materials and logistics services, and
• scenario planning to develop contingency plans for worst-case scenarios, such as a CDMO’s inability to deliver.

Conclusion

The evolution of cell therapy has brought unprecedented opportunities and challenges to the biopharmaceutical landscape. As demonstrated by Calibr's sCAR-T platform, the ability to merge science with operational frameworks is critical to advancing these transformative therapies.

The promising results from the first sCAR-T clinical trials highlight the potential of switchable CAR-T technology to redefine the safety and efficacy of cell-based treatments. Beyond the science, the strategies discussed — from developing resilient supply chains to implementing robust management systems — underscore the importance of aligning technical, operational, and regulatory rigor in the development of cellular products.

About The Expert:

Vadim Klyushnichenko, Ph.D., is vice president of pharmaceutical development and quality at Calibr-Skaggs Institute for Innovative Medicines. He has more than two decades of experience developing pharmaceuticals and biologics. At Calibr, he is responsible for developing small molecules, biologics, and cell and gene therapies. He received his Ph.D. in chemistry from the Russian Academy of Sciences and completed postdoctoral research in Germany and Canada.