Introduction: Process Issues in Cell, Gene, and Tissue Therapies

Accelerating cell growth has become a primary issue, as shown in the cover by Particle Works, which develops alginate and agarose hydrogel beads for three-dimensional cell culture growth. (WWW.PARTICLE-WORKS.COM)

It’s hard to believe that just six years ago, BioProcess International published its first cell therapy supplement, which included just one article on “cell therapy bioprocessing” (1). At the time, most such processing was conducted in special clinical laboratories and academic institutions. As BPI continued to cover this relatively new segment of the biopharmaceutical industry, we heard more about “the product is the process” and “scale out instead of scaling up.”

After many trials, errors, and milestones, regenerative medicine has become a mainstream part of the biologics industry, supported by at least 670 companies and clinics of all sizes and 20 products approved by the US Food and Drug Administration so far (2). As the following article from Swapna Supekar shows, markets for all segments of regenerative medicine are growing quickly and projected to extend well into the next decade.

Increased industrialized processing launches new process choices and potential difficulties. Such issues used to be topics of yearly conference tracks and keynote addresses. But now they are enough to make up entirely separate meetings. The Biotech Week Boston (BWB) conference (held 4–7 October 2016) featured presentations devoted to innovations, tools, and commercialization issues of cell and gene therapies, a few of which are presented herein. Although this report is not comprehensive, each article represents one or more major issues cell, tissue, or gene therapies. Specifically, the authors address the industry’s need for fast scale-up for cell production, efficient purification of viral vectors for gene therapy, and further development in biofabrication (bioprinting). For the past six years, BPI has covered similar topics, so we encourage you to check our archives.

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Current Cell Processing Demands
Presenters at the BWB meeting characterized a successful cell therapy platform as one that not only produces a therapeutically active product, but does so safely, robustly, and scalably. The next generation of platforms for manufacturing chimeric antigen receptor T (CAR-T) cells, for example, will be those that incorporate automation (typically around phase 2 or earlier) and in-process monitoring and control to lower variability and increase success rates to generate a robust pipeline. Such a system also must enable electronic data capture, analysis, and sharing with sufficient understanding of critical process parameters and their relationship to products’ critical quality attributes (3).

Although more targeted than traditional blockbuster biologics, allogeneic cell therapies are still produced for large populations such that scale-up can become problematic. Major associated process concerns include cost, timelines, and capacity. And for both immune cell therapies and stem cell therapies, many of the main process issues so far involve simply getting cells to grow and scale-up without compromising their quality and viability. Cell therapy manufacturers have a choice between traditional two-dimensional (2D) systems such as stacked trays (typically for immune cell therapies such as CART cells) and flasks and three-dimensional (3D) suspension bioreactors of various designs (e.g., for allogeneic therapies such as human mesenchymal stem cells, hMSCs) that typically require the use of 2D surfaces for adherent (anchorage-dependent) cells. As Erika McAfee and Chris Mach point out in the following article and sidebar, one platform does not fit all, and cell therapy manufacturers must take several factors into their decision, while considering how that choice will affect the efficiency of recovery and harvest.

Process Issues for Gene Therapies
Gene and gene-modified cell therapies currently do not take up much of the regenerative medicine markets, but they are definitely a promising segment. Since the 1990s, few such products have been approved — and some have been discontinued (e.g., early viral-vector products). For example, one the most-referenced milestone products is the Provenge (sipuleucel-T) immunotherapy, FDA approved in 2010. The process involves removing patient blood cells, modifying them to contain CD54+ T cells, and returning them to the patient. As Peter Olagunjur of Blubird Bio commented, it is a US success story. “When it first launched in the United States, it had a cost of goods (CoGs) >100%. For the first 18 months, it generated US$275 million in revenue. the product now has a CoG <40% (4).” In January, Valeant Pharmaceuticals sold Provenge-maker Dendreon to Sanpower (China) for $820 million.

Delivering therapeutic DNA into a patient’s cells to replace or correct a faulty gene or to encode a therapeutic protein is typically achieved by viral transduction of target cells with a therapeutic transgene (5, 6). Several types of viruses can be used as vectors, and such vehicles have propelled clinical advances in several disease areas such as HIV, hepatitis infections, age-related macular degeneration, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, arthritis, epilepsy, and chronic pain (7).

Currently, process concerns with using viral vectors for gene delivery are focused on effective purification, as pointed out in the Brindley et al. article here and past studies (5–8). For research into cell-delivered gene therapy platforms to continue toward development, process characterization and development work are still in need of refinement.

Opportunities in Tissue Therapy
Tissue therapies such as allografts and xenografts for burn and wound healing have seen steady success in regenerative medicine. The implementation of stem cells and cultured epithelial cells presents exciting opportunities in improving both patient comfort and therapeutic delivery (9). As described in the final article herein, novel application systems have been developed.

One of the most exciting research areas has been in the advancement of three-dimensional bioprinting (or biofabrication) of living tissues. Like all new fields, it brings about its unique processing issues and challenges. Specifically, it will require not only the seamless collaboration of raw-material cells, digital technology, hardware engineering, and biomechanics, but also an advanced understanding of complicated networks of human anatomy.

References
1 Brandenberger R, et al. Cell Therapy Bioprocessing. BioProcess Int. 9(3) 2011: S30–S37.

2 Orchard-Webb D. Progress Toward Commercial Scale and Efficiency in Cell Therapy Bioprocessing. BioProcess Int. 14(9) 2016: S8–S11.

3 Reitze RL. Biotech Week Boston, Cell and Gene Therapy Bioprocessing and Commercialization: Boston, MA, 6 October 2016.

4 Olagunju P. Biotech Week Boston: Boston, MA, 6 October 2016.

5 Pettitt D, et al. Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies. BioProcess Int. 14(4) 2016: S8–S17.

6 Symonds G. Cell-Delivered Gene Therapy: This Viral Vector Manufacturing Method Could Widen Its Applicability. BioProcess Int. 14(10) 2016: 18–21.

7 Terova O, et al. Innovative Downstream Purification Solutions for Viral Vectors: Enabling Platform Approaches to Advance Gene Therapies. BioProcess Int. 14(9) 2016: S20– S23.

8 Ausubel LJ, et al. Production of CGMP-Grade Lentiviral Vectors. BioProcess Int. 10(2) 2012: 32–43.

9 Ghieh F, et al. The Use of Stem Cells in Burn Wound Healing: A Review. BioMed Research Int. Article ID 684084, (2015), http://dx.doi.org/10.1155/2015/684084.

Maribel Rios is managing editor of BioProcess International; [email protected].