MANUFACTURING
technical and regulatory landscape in gene and cell therapy is changing much faster compared to the well-established biologics space. That’s why a deeper discussion of CMOs’ expertise – with specific viral vectors and cell cultures – is required during due-diligence visits. Some CMOs that I visited were hesitant to qualify their analytical methods for the phase-1 manufacturing run. This was not acceptable to our organisation since the sponsor is ultimately responsible for the quality of the final product. Other CMOs increased the price of services due to the claimed high number of CAR-T projects. However, during the due-diligence visit, their multifunctional facility appeared to be utilised at 20% – 30%, with the last CAR-T project having been performed a year ago. This means the CMO was trying to cover their expenses by setting high prices for prospective clients. As a result, we placed the project with the CMO that provided the highest level of quality, technical expertise, and transparency.
Q. Several sponsors are considering whether to outsource drug-product manufacture to India and China. How much does location matter in CMO selection? Does the autologous nature of a cell/gene therapy change how much location matters? A. Living in a global environment, we outsource our projects to the CMOs located in the US, EU, India and China. Outsourcing manufacturing overseas has certain advantages, but I would recommend paying additional attention to the quality systems and technical expertise of personnel over there. Some companies may satisfy local regulatory requirements, but they are not always US Food and Drug Administration (FDA) compliant. In terms of communication, the time-zone difference, decision-making culture, and language barriers may bring certain limitations, which should be taken into consideration. Since the autologous nature of cell and gene therapy brings additional requirements, locating manufacturing and clinical sites within the same country is preferred. It provides a better compliance with the local regulatory environment; easier logistics for human tissues and samples between clinical sites, CMOs and testing labs; and the immediate communication to address any issues related to manufacturing, analysis, logistics and
documentation. Thus, while manufacturing cell and gene therapies overseas seems to be less expensive, regulatory and logistical elements may increase the final project cost.
Q. What should sponsor organisations know about analytical development when seeking out manufacturing partners? A. In terms of analytical development, I would recommend paying attention to the availability of analytical equipment and the qualifications of personnel. It is always good to ask the following questions: • How many HPLC units does the CMO have in analytical development and quality control labs and how many of them are qualified? This will indicate possible delays during the analytical qualification, product release and stability studies.
• Does the CMO use the SDS-PAGE or SDS-CE? This will determine whether you can use this analysis for the quantitative determination of impurities and aggregates in the product specification.
• How many bench-top scientists are in the analytical development and quality control laboratories, and what is their level of GMP training? This will determine whether they can support the increasing number of analytical services when the project is moving to the manufacturing stage.
• Can the quality control (QC) scientists define the major parts of the analytical validation? You will be surprised how few people in QC labs can explain specificity, linearity, range, accuracy, precision, LOD/ LOQ, ruggedness, and robustness, while validating analytical methods daily. Also, it is important to outline the details of the required analytical services because you may need different sets of methods to be used for the in-process analysis, release, critical reagents,
“Develop a project roadmap with several technical options, such as the type of expression, purification, or analytical outsourcing. This will add flexibility to the scope of work.”
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