PSC Handbook – Applications for Cell Therapy

While it may seem that the promise of stem cells in cell replacement therapies has long been on the horizon, the first hESCs were only isolated in 1998 [1], and the first human iPSC was generated in 2007 [2]. In less than two decades, researchers have:

• Identified and streamlined conditions for maintenance and expansion of human PSCs
• Discovered an approach for generating PSCs from human somatic cells
• Optimized protocols for differentiation to clinically relevant cell types
• Developed tools for characterization of those cells
• Introduced human mesenchymal stem cell and hematopoietic stem cell therapies into clinical trials for different disease indications—both allogeneic and autologous
• Introduced and commercialized T cells as a new paradigm to treat cancer via CAR T cell therapy

The next step in moving cell therapies from the bench to the bedside is to translate this process to a clinically compatible system. This means that ancillary materials for clinical applications will need to be generated under GMP so that quality control measures are in place to ensure patient safety.

cGMP refers to a quality assurance system that is defined by both the European Medicines Agency and the US Food and Drug Administration as a means of ensuring that clinical-grade cells and products meet preset standards for quality and safety in cell transplantation. These standards encompass both the manufacturing and testing of the final product. Key requirements include the traceability of raw materials and the adherence to validated standard operating procedures.

The use of animal origin–free components (e.g., media, substrates, and reagents used in the expansion, passaging, and cryopreservation of cells) significantly reduces the risk of inducing immune reactions against animal proteins.

The most desirable materials are those that already have regulatory approvals. However, these are not always available and/or suitable. In those cases, additional testing may be needed to ensure the safety and quality of reagents.

Qualifying and validating reagents for use in cell therapy manufacturing can be a complicated and time-consuming process, requiring multiple levels of testing and documentation to support appropriate risk assessment of incoming materials. Qualifying reagents and raw materials begins with the following:

• Obtaining documentation to demonstrate traceability of components and potential contact with animal-sourced materials
• Incorporating procedures for inactivation or removal of infectious agents or toxic impurities when necessary
• Developing quality control and quality assurance systems to appropriately assess the risk of using incoming raw materials in the clinical manufacturing process

As the field matures, an increasing number of off-the-shelf prequalified reagents are becoming available that will make the task of qualifying materials easier for the teams responsible for ensuring quality and safety of cellular therapies. In fact, the field may soon develop a complete clinical-grade set of solutions that encompasses the full workflow from iPSC generation to final cell product.

To find solutions and support for your pluripotent stem cell therapy needs, go to thermofisher.com/ctsstemcells

There has been immensely exciting potential demonstrated in the cell therapy field in a number of disease states, most notably the recent clinical successes in oncology and gene-modified CAR T therapy commercialization. The promise of cell therapy is bright, and developing technologies for raw materials, isolation, expansion, differentiation, cryopreservation, serum-free media, and large-scale manufacturing protocols will be the drivers to bring this promise to reality. The following sections are intended to provide a broad overview of several considerations needed to translate a basic research program forward to clinical evaluation. Consulting with an expert in regulatory affairs, preferably with experience in cell therapy, is highly advisable as research is prepared for the clinic.

Materials, manufacturing, and process considerations

The first thing needed is to ensure current methods of isolating and expanding cells of interest are consistent and can support reproducible results in preclinical models. The selection of the model and protocol are critical because the data generated at this phase will support the investigational new drug (IND) application. Therefore, the raw materials used to isolate, expand, reprogram, engineer, or differentiate cells of interest are also critical because they will form the basis of the protocols that will get translated into cGMP processes.

Changing critical components, including cytokines, small molecules, serum, media, and culture systems that may affect the biology and phenotypes of therapeutic cells, is considered high-risk after the completion of preclinical evaluations. Discovering that a common material used on the bench presents a risk profile would require finding an alternative while filing your IND. This discovery could significantly delay clinical programs and could even change the profile of the therapeutic cells and the clinical application. For these reasons, understanding the sourcing, quality, and risk profiles, and having as much information as possible about the components being used, are of paramount importance to generating preclinical data sets.

Once raw materials, which have been obtained with proper regulatory documentation, consistently generate cells that are characterized to match a profile correlated to a clinical benefit, you can begin to think about the manufacturing process and whether it has the potential to scale. Scale will be critical for realizing the number of cells needed to treat a patient population. Selecting and developing a scalable manufacturing process is also critical for raw material selection, since cell phenotypes can also be affected by the culture systems used to generate them. For example, changing from planar culture to suspension culture can significantly impact cells. Finally, having characterization tools with the necessary sensitivity and resolution to detect process or raw material changes is a critical adjunct to the raw materials and culture system selection.

Preparing your regulatory submission

Once raw materials with acceptable risk profiles have been selected, a process providing line of sight to future scaleup is developed, and characterization methods that ensure production of intended cells is confirmed, it is appropriate to start pulling the components of an IND together. The chemistry, manufacturing, and controls (CMC) section of the IND will describe everything needed to manufacture cells, including: 

• The procedure used to obtain tissue or other cell sources and how it is transported to the lab/clinic
• The raw materials used during the process and how suitability is verified
• The plasticware and pipettes used
• Preparation of final cells for storage and delivery to the patient
• The sterility, mycoplasma, endotoxin, and final release testing used to characterize incoming materials and the final product

Other parts of the IND include the clinical protocol that will be followed to administer the cell therapy to the patient as well as the pharmacology and toxicology data developed to show cells are safe for administration.

Prior to gathering all of the information to prepare an IND, scheduling of at least one pre-IND meeting with the FDA is recommended, to advise them of clinical intent and to present current thoughts and intentions about moving forward. These pre-IND meetings are critical to prepare a program towards clinical evaluation.

Moving through the clinical phases

As preparation for clinical trials begins, quality control, quality assurance, regulatory affairs, process development, and manufacturing teams should be established to interact with the FDA or other regulatory agencies. These teams will oversee the implementation of quality systems, batch records, personnel training, change control systems, and all other aspects of cGMP needed to ensure that the final cell therapy products are safe and in compliance with regulations. Clinical trials progress from small patient number safety studies in phase 1, to slightly larger efficacy studies during phase 2, and on to pivotal phase 3 studies that will test the manufacturing systems intended to support commercial production and hopefully demonstrate clinical efficacy in large patient populations. During this progression, quality will be tightened and systems validated to demonstrate reproducible production at scale, and with an acceptable cost of goods, to provide for a reasonable profit margin and reimbursement profile to ensure commercial success.

The Gibco Cell Therapy Systems (CTS) brand offers a broad array of high-quality products designed for use in clinical research applications, including media, reagents, growth factors, enzymes, selection beads, and devices, which are manufactured in compliance with 21 CFR Part 820 Quality System Regulation and/or are certified to ISO 13485 and ISO 9001. Regardless of the type and source of cells, the CTS portfolio offers tools to help with every step of the cell therapy workflow and enables progress through each stage of clinical development and scale-up.

CTS products are designed to help you translate your cell therapy to clinical applications with extensive safety testing and traceability documentation required for regulatory review, so you can transition your cell therapy to the clinic with confidence. All CTS products are supplied with unified documentation, including:

• Access to authorization letters for the FDA Drug Master File
• Certificates of Analysis
• Certificates of Origin

For more information on cell therapy products, go to thermofisher.com/celltherapy

Transition your cell therapy to the clinic with confidence

We’re here to help meet your needs with high-quality products, services, and support that can scale with you from research to commercialization.

As process development defines manufacturing systems and operating parameters needed to produce a consistent product at a phase-appropriate scale, customized containers or media may allow for optimization. Filling media into bags with appropriate connectors that facilitate manufacturing and help close the system to potential contaminants can lead to more robust processes. In some instances, slight adjustments to media and feed systems can also help the process. Gibco media can be produced in formats that meet process and scale-up requirements through preparation and progress of clinical evaluations.

If interested in custom CTS services, please send an inquiry to custommedia@thermofisher.com

Large-scale cGMP custom media

For large-scale clinical or commercial biomanufacturing applications, rely on our validated cGMP custom services.

• Liquid in batches from 10 to 10,000 L
• Dry powder media (DPM) in batches from 1 to 8,000 kg
• Advanced Granulation Technology (AGT) media in batches from 50 to 6,000 kg

Custom packaging options

Receive your Gibco custom media in the packaging that best suits your needs. We have many different options for liquid and powder media in a variety of package sizes— available in both bottles and bags—to manage small-, intermediate-, and large-scale needs.

cGMP manufacturing sites

We maintain two primary Gibco cell culture manufacturing locations—in the US and Scotland—and three primary Gibco serum and/or protein product manufacturing locations—in the US, New Zealand, and Australia. For reliable global service and contingency planning, we welcome visits and audits of our cGMP facilities to help facilitate regulatory approvals of your products and services.

Process development custom services

Choose the Gibco Custom Services team to help reduce process development inefficiencies, and improve time and cost performance using our latest technologies.

MediaExpress and Rapid Research services

Gibco MediaExpress and Rapid Research services are specifically designed for small-scale, non-cGMP custom orders when speed matters most. We offer Gibco product quality in small batches for quick turnaround and smooth transitions to cGMP scale-up.

1. Thomson JA, Marshall VS (1998) Primate embryonic stem cells. Curr Top Dev Biol 38:133-165. 
2. Takahashi K, Tanabe K, Ohnuki M, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861-872.