Developing Advanced-Therapy Products Through Global CDMOs

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Tremendous growth in the cell and gene therapy (CGT) industry is driving unprecedented demand for manufacturing services. To be sure, advanced-therapy developers increasingly are choosing to install in-house capabilities. Doing so can offer companies greater control of their processes, timelines, and budgets than they might have when outsourcing products (1). But industry experts agree that contract development and manufacturing organizations (CDMOs) will remain integral to CGT manufacturing and commercialization (1, 2), especially with veteran contract partners scrambling to acquire CGT capability and expertise.

As part of Cell and Gene Therapy Bioprocessing and Commercialization Virtual (19–22 October 2020), Vadim Klyushnichenko (vice president of pharmaceutical development at Calibr) will explore how CGT developers should select contract partners. Klyushnichenko oversees contract partner management, process development, good manufacturing practice (GMP) manufacturing, quality assurance, and supply-chain concerns for Calibr’s clinical product portfolio, which includes a novel “switchable” chimeric antigen receptor (CAR) T-cell platform. His presentation will describe lessons that he learned about working with CDMOs while developing that platform. I spoke with Klyshnichenko this past summer to learn more about Calibr’s projects and its experiences with contract manufacturers.

Innovating Translational Research
Your presentation will highlight an intriguing “bench-to-bedside” collaboration between Calibr and the Scripps Research Institute in La Jolla, CA. What makes that partnership so fruitful? Previously known as the California Institute for Biomedical Research, Calibr was founded as an independent nonprofit translational research institution by renowned biochemist Peter G. Schultz. Calibr’s mission was — and continues to be — to create new medicines and accelerate their development by pairing world-class biomedical research with state-of-the-art drug discovery and development capabilities. When Schultz became chief executive officer of the Scripps Research Institute in 2014, he merged the two organizations, incorporating and expanding the Calibr model within the novel scientific framework of Scripps Research. That enabled Calibr researchers to work directly with leading professors and principal investigators to speed up development of innovative drugs.

As Calibr integrated with Scripps Research, we developed a portfolio of advanced molecules that we advanced through investigational new drug (IND)–enabling studies and early clinical development. Our portfolio comprises innovative small molecules, conjugated peptides, engineered antibodies, and cell and gene therapy (CGT) products that treat cancer, degenerative diseases, and chronic conditions.

From a business standpoint, joining Scripps Research has enabled Calibr to form collaborations and strategic alliances with industry and nonprofit partners. Our approach is shaping a new paradigm for advancing nonprofit biomedical research to treat patients while reinvesting in further research.

Among Calibr’s most recent projects is a novel CAR T-cell therapy. What can you tell us about it? Led by Travis Young (vice president of biologics at Calibr), we have produced a CAR-T antibody that acts as a “switch,” activating an engineered cell and directing it to engage a cancer target. This first-in-class platform can confer the efficacy associated with engineered T-cell therapies but with greater safety and versatility through incorporation of that control switch. Currently, our technology is under evaluation for treatment of relapsed/refractory B-cell malignancies such as non-Hodgkins lymphoma and chronic lymphocytic leukemia.

Manufacturing a switchable CAR-T product can be challenging because its components are complex. Modification of autologous T cells requires a separate manufacturing campaign for each patient. Then, each campaign is supported by development of a complex analytical system for in-process control and product characterization, stability, and release testing. Besides that, apheresis material and modified cells require extended control and must be maintained under strict thermal conditions.

Because Calibr works on a wide range of projects, we usually outsource process development and manufacturing to CDMOs. Several contract development and manufacturing organizations (CDMOs) from the United States and Europe participated in the development and manufacturing of our switchable CAR-T product, and management of each CDMO required considerable expertise in technical details, quality concerns, and project management.

Basic Selection Criteria
Your presentation will emphasize that CDMO selection should begin with due diligence. What does that entail? Any interaction with CDMOs should include several basic documents to assure confidentiality, description of required services, assurance of product quality, and legal terms. The first step is execution of a nondisclosure agreement (NDA), which protects a sponsor’s intellectual property. Next, a sponsor submits a request for proposal (RfP) to a potential CDMO. That document is especially important because it describes the structure and details of a sponsor’s project. A CDMO will respond with a statement of work (SoW) that describes what services the company would perform.

Provided that those services are sufficient, sponsor representatives can visit the manufacturer for due diligence on its quality systems and GMP compliance. Due diligence culminates in execution of a master services agreement (MSA), which defines each party’s legal responsibilities, and a quality agreement (QA), which define’s each party’s quality-related responsibilities. Then comes the work itself.

Although NDAs, MSAs, and QAs are important documents, they can be outsourced or reviewed by external consultants based on existing templates. An RfP should be kept in house, however. It is a core document, and it is critical that a sponsor describes its project’s structure and provides all details on existing data and required services, including optional ones, because an RfP will define the SoW structure, cost, and timeline. Missing or underarticulated sections often generate additional expenses, delays, and legal issues.

What parts of the screening process do drug sponsors tend to neglect or overemphasize? What criteria should they prioritize, and why? Frequently, project sponsors focus on project cost and timeline. However, a CMO’s technical capabilities and quality are much more important criteria. Most CMOs will offer whatever a client wants, and in some cases a manufacturer’s executives will agree to lower costs and shorter timelines because their technical teams do not understand the projects’ complexity.

That’s why visiting CMOs is important when evaluating their manufacturing facilities, available equipment, scope of current and past projects, team skill sets, and quality systems. Such evaluation is particularly important when you initiate contracts with relatively new CMOs because they often focus on their own growth instead of serving their clients. For all those reasons, due-diligence visits to your top prospective CMOs must be a priority before selecting a final candidate.

Many of the factors you identified for CDMO selection are important for all biologics: e.g., technical capability and expertise, quality, timeline, facility availability, cost, and communicative capability. How do selection criteria change for CGT production? Calibr generally uses the same selection criteria for CGT CMOs. However, the technical and regulatory landscapes in the CGT industry are changing much faster than those in the well-established biologics space. That’s why a deeper discussion on CMO expertise — specifically with viral vectors and cell culture — is required during due-diligence visits.

Some CMOs that I visited for our switchable CAR-T product were hesitant to qualify their analytical methods for a phase 1 manufacturing run. That was not acceptable to our organization. Other CMOs increased the price of their services due to allegedly high numbers of CAR-T projects. However, during our due-diligence visits, their multifunctional facilities appeared to be using 20–30% capacity, with the last CAR-T projects performed over a year ago. Those CMOs were trying to cover their expenses by setting high prices for prospective clients. As a result, we placed our project at the manufacturer that provided the highest level of quality, technical expertise, and transparency.

Several sponsors are considering whether to outsource drug-product manufacture to facilities in emerging bioregions. How much does location matter in CMO selection? And how would the autologous nature of a CGT change how much location matters? Calibr outsources projects to CMOs located in the United States, European Union, India, and China. Manufacturing overseas has certain advantages, but I recommend paying close attention to quality systems and technical expertise in developing bioregions. Some companies may satisfy local regulatory requirements but might not be US Food and Drug Administration (FDA) compliant. In terms of communication, time zone differences, decision-making culture, and language barriers may bring certain limitations, which also should be taken into consideration.

Because autologous CGTs have more requirements than allogeneic ones, keeping manufacturing and clinical activities within the same country is preferred. Doing that facilitates shipment of human tissues and samples across clinical sites, CMOs, and testing laboratories. Proximity also streamlines compliance with local regulatory authorities and enables immediate communication to address issues related to manufacturing, analysis, logistics, and documentation. Thus, even though manufacturing CGTs overseas seems to be less expensive than it does in the United States or the European Union, regulatory and logistics aspects can increase a project’s final cost.

Scrutinizing Special Services
What should sponsor organizations know about analytical development when seeking out manufacturing partners? I recommend paying attention to the availability of analytical equipment and a CMO’s personnel. To that end, it is helpful to ask the following questions.

  • How many high-performance liquid chromatography (HPLC) units does a CMO have in its analytical development and quality control (QC) laboratories, and how many of those units are qualified? Investigating such concerns can indicate possible delays during analytical qualification, product release, and stability studies.
  • Does your CMO use sodium dodecyl sulfate–polyacrylamide gel electrophoresis and/or capillary electrophoresis (SDS-PAGE and SDS-CE, respectively)? Answering that question can determine whether your CMO can provide quantitative determination of impurities and aggregates in your product specification.
  • How many benchtop scientists are in the analytical development and QC laboratories, and what is their level of GMP training? Such factors will help you determine whether those units can support an increasing number of analytical services when your project moves into manufacturing stages.
  • Can the QC scientists define the major parts of analytical validation? You might be surprised by how few people in QC laboratories can explain the requisite specificity, linearity, range, accuracy, precision, limit of detection and quantitation (LoD and LoQ), ruggedness, and robustness in spite of validating analytical methods daily.

It is also important to outline the details of required analytical services because sponsors might need different sets of methods to be used for in-process analysis, release, critical reagents, reference-material characterization, and stability studies. The term stability studies typically covers tests of drug substance and drug product as well as scale-up and GMP batches. But it also can include bulk drug substance (BDS) retests, analyses of different reference standards generated during process development and manufacturing, and compatibility and comparability studies. Sponsors need to define what studies to perform and the temperature ranges and timepoints for each of those studies. Including such details in your RfP and SoW can prevent pricey change orders at later manufacturing stages.

Does process development raise similar concerns? Process development preceding GMP manufacturing is less strict but still requires extended technical knowledge of the latest trends in upstream, downstream, and formulation development as well as in scale-up and technology transfer to GMP manufacturing. A process development team should be flexible enough to support multiple projects and different modalities, and it must communicate closely with analytical teams to resolve different types of challenges. When selecting a CDMO, it is important to ask its process development team open-ended questions to gauge their experience and approach in different situations. Also, some CMOs declare that they specialize in late-stage and commercial manufacturing. That often means that they do not have proper process development teams and expertise.

You mentioned that drug sponsors should be attentive to under- and overestimated budgets and timelines in RfPs and other early documents. What could those concerns indicate? A CMO might underestimate timelines and budgets if it wants to get your project. CMOs may exclude essential activities intentionally to reduce their proposed budgets. Later, when a project is under way, change orders may need to be added at a premium cost. Frequently, costs for the following items are missing from consideration: scale-up/down studies, demonstration or engineering runs, stability studies, production and characterization of reference material, viral clearance studies, endotoxin reduction studies, retests, outsourced development and testing, raw materials, consumables, and components.

On the other hand, CMOs might inflate timelines when they are understaffed, overbooked, or lacking in experience. Overestimated budgets suggest that a CMO needs to support large infrastructure, makes many mistakes and needs to cover its costs, or outsources a significant portion of activities, charging an extra 15–20% in service fees. Also, these days, the majority of CMOs use disposable systems to minimize their capital expenses. However, costs for consumables can be higher than those for provided services. That is why we at Calibr always send RfPs to several CMOs, asking them to indicate the ratio of in-house to outsourced services and to provide the fair cost of raw materials, components, and consumables, including service fees.

What advice do you have for developing risk-mitigation plans? Develop a detailed project roadmap with several technical options, such as the type of expression, purification, or analytical outsourcing. Doing so will add flexibility to your SoW.

Define a primary CMO but keep lines of communication open with your second-choice CMO or a contract research organization (CRO). You might run some portions of your project in parallel at two CMOs to leverage their expertise. That can ensure timely project completion.

Ask each CMO for a fixed project price, and let them know that change orders will not be placed in the future. That strategy can yield a realistic budget. However, I recommend keeping an extra 20–30% of budget contingency. That should cover additional expenses, which are likely to happen.

Split your project into several portions: e.g., process biochemistry, scale-up and non-GMP batches, and GMP manufacturing and stability studies. Source your project step by step, and do not sign a contract for an entire project up front. That should prevent penalties for project termination if you are not satisfied with outcomes along the way. However, I recommend balancing project components with available CMO capacity to prevent project delays.

The Future of CGT Manufacturing
Industry insiders continue to decry shortages of CGT expertise. Does that complicate CMO selection (e.g., in terms of timelines and a sponsor’s ability to be “choosey” about its partners)? I would have agreed with that statement three to five years ago. At that time, just a handful of CDMOs worked on CGTs with a facility-availability lead time of 12–18 months. That suddenly increased demand for viral vectors led to ironic situations, with some CMOs being acquired at an incredibly high price and others selling manufacturing timeslots in their just-planned but still nonexistent commercial facilities two to three years ahead based on a client’s projections.

Fortunately, that situation is changing fast these days, particularly with viral-vector production. First, small-scale CMOs and GMP units increasingly are being placed directly in hospitals and universities. That enables services to be performed faster and more efficiently than in a conventional CGT manufacturing model.

Second, the vast majority of gene therapy studies are in early-stage clinical trials. At that stage, the structure of viral vectors still is being modified, the number of patients is relatively low, and patients frequently are limited to one dose. Unlike the kilogram-scale batch of drug substance and several thousand vials of drug product used in clinical manufacturing of monoclonal antibodies (MAbs), phase 1–2 gene therapy studies can be covered by 100–200 vials of drug product and another hundred vials used for release and stability studies.

Third, viral-vector manufacturing technology is evolving rapidly. Currently, it is balancing among planar systems used for adherent cells, bioreactors for cell suspensions, and hybrid systems. Within the next several years, the CGT industry will define which system is most efficient and then make that the standard manufacturing process. Then, we can expect to find higher production titers, reduced volumes and sizes of manufacturing suites, and faster delivery of final products. Single-use systems and highly efficient cell lines have replaced large-scale stainless-steel bioreactors used for recombinant proteins within the past 10–20 years; the same changes are occurring now with the manufacturing of viral vectors for gene therapy.

Meanwhile, autologous cell therapy products still require production of a separate batch for each patient, which drives prices up. Extra time is needed to establish new CMOs, optimize manufacturing and analytical techniques, and streamline supply-chain concerns to make such therapies affordable. The development of allogeneic cell-therapy products also should free up CDMO capacity.

What else would you recommend for partnering successfully with CMOs? A sponsor should consider a CMO as a flexible extension of its own company, one that offers great opportunities to address changes quickly. To that end, it is important to build and maintain a partnership with a CMO through clear communication of goals and expectations and with a willingness to understand a manufacturer’s limitations.

Visit your CMO frequently. Face-to-face communication is the most efficient way to resolve technical and business-related issues. Travel to a CMO costs less than a delayed or failed product.

Make sure that a CMO is working with required technology currently. A CMO’s past experience is irrelevant because of the high turnover of personnel.

Analyze the background of a CMO’s development team. Choose the “A team,” or be prepared to change team members to ensure project success.

Stay on top of your project, and update your CMO with relevant information and suggestions to resolve complicated issues.

At the end of the day, a sponsor owns its project, and a CMO is a tool in the sponsor’s hands. Choose the right tool to sculpt your drug-development project.

References
1 Stanton D, Hsu F, Rininger J. Will In-House Manufacturing Capabilities Give Cell and Gene Therapy Developers Competitive Advantages? BioProcess Int. 18(7–8) 2020: s40–42; https://bioprocessintl.com/bpi-theater/bpi-theater-bio-2020/will-in-house-manufacturing-capabilities-give-cell-and-gene-therapy-developers-competitive-advantages.

2 Miller D, et al. The Role of New Technologies in Enabling Cell and Gene Therapies. BioProcess Int. 18(7–8) 2020:  s43–45; https://bioprocessintl.com/bpi-theater/bpi-theater-bio-2020/vector-production-the-role-of-new-technologies-in-enabling-cell-and-gene-therapies.

Brian Gazaille is associate editor of BioProcess International (brian.gazaille@informa.com). Vadim Klyushnichenko is vice president of pharmaceutical development at Calibr, a division of the Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037; vklyushnichenko@scripps.edu.

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