Getting more gene and cell therapy treatments to patients

Center for Breakthrough Medicines, Cell and Gene Therapy

Getting more gene and cell therapy treatments to patients

By Peri Morris and Emily Moran

Regulatory Momentum Drives Vector Demand

The year 2022 was an exceptional one with respect to approvals of gene and gene-modified cell therapies. For the first time, more than one gene therapy was approved in a single year.1 In July, the European Commission (EC) authorized PTC Therapeutics’ Upstaza, the first-ever gene therapy approved to treat the rare genetic nervous system disorder aromatic L-amino acid decarboxylase (AADC) deficiency. In August, the EC granted marketing authorization to BioMarin for Roctavian, the first-ever gene therapy to treat Hemophilia A.

Also in August, FDA approved bluebird bio’s betibeglogene autotemcel (beti-cel; Zynteglo) (previously approved in the EU in 2019) to treat beta thalassemia in adults and children. That was followed by FDA approval in September of bluebird bio’s elivaldogene autotemcel (eli-cel; Lenti-D)2 for the treatment of early, active cerebral adrenoleukodystrophy (CALD) in patients without an HLA-matched donor. This was capstoned by the November FDA approval for uniQure & CSL Behring’s Hemophilia B treatment.1

Two chimeric antigen receptor (CAR) T-cell therapies were also approved in 2022: Carvykti (ciltacabtagene autoleucel) from Legend Biotech and Janssen in the U.S. in February and Breyanzi (lisocabtagene maraleucel) from Juno Therapeutics, Inc., a Bristol-Myers Squibb Company, in the EU in April. There are now two CAR T therapies approved in the U.S. as earlier line treatments. Kymriah from Novartis and Breyanzi were also granted approvals for additional indications.

In 2023, a number of companies are expecting decisions, including Krystal Bio, bluebird bio, Pfizer, Orchard Therapeutics, PTC Therapeutics, CARsgen Therapeutics, BioMarin, CRISPR Therapeutics, Vertex Pharmaceuticals, and GenSight Biologics. The FDA expects the number of investigational new drug applications filed with the agency for cell and gene therapies per year to increase.3 One estimate suggests more than 50 gene and gene-modified cell therapies could be approved in the next few years.3

Meeting the demand: Manufacturing scalability is a must

Of the nearly 1100 gene and gene-modified cell therapy trials, 45% involve treatments produced using viral vectors, with lentivirus (LV) accounting for 48% of those (due to the higher percentage of CBIO candidates), followed by adeno-associated virus (AAV, 26%), retroviruses (14%) and other viral vectors (2%). The remaining 4% of therapies use nonviral vectors.1 Furthermore, while most of the approved gene therapies treat rare diseases, a growing percentage of gene and gene-modified cell therapy candidates (as many as 60%) target more prevalent diseases that require systemic administration of large doses5, and some are being developed as first-line treatments.5

The implication: demand for viral vectors will increase dramatically in the coming years, which will require significant scaling of production. Early gene and gene-modified cell therapies intended to treat small populations or areas of the body (e.g., the eye) that only require small doses have typically been manufactured in plasticware/flatware, even to meet clinical and commercial needs.6 Such processes often involve numerous manual operations, occupy larger facility footprints, and are not practical for large-scale manufacturing in compliance with Current Good Manufacturing Practices.

Disparate analytical & sourcing issues must be overcome

Most viral vectors, however, are currently produced via transient transfection, a complex process for which scaling presents challenges. Process development requirements differ from one vector type to the other (even among serotypes of the same vector type), which makes platformization difficult. Upstream, mixing, transfer, and volume issues exist due to the need to produce and transfer unstable and shear-sensitive plasmid DNA-transfection reagent complexes. The transfection of three or four plasmids also tends to be less efficient than protein expression and can decrease as scale increases. Downstream, chromatographic purification can be an issue for viral vectors for many different reasons, ranging from the large size of LV vectors to the need to separate empty from full AAV capsids.

Clearly, to meet the much greater expected demand for gene and gene-modified cell therapies, solutions that enable cost-effective production of large quantities of high-purity, high-quality viral vectors are needed. Simply adding additional capacity will not be sufficient. Increases in transfection efficiency combined with higher levels of transgene expression and improved post-translational packaging are needed.7

Even if these improvements are realized, viral-vector manufacturing will still face supply chain and in-process and release testing challenges if they work with outsourcing partners that do not have plasmid DNA production and comprehensive analytical capabilities in house.6 Wait times to secure capacity for tailored plasmid DNA supply, which is essential for achieving high transfection efficiency and productivity, can be 12 to 18 months or more. Contract development and manufacturing organizations (CDMOs) without established supply agreements with multiple suppliers of other key raw materials and single-use equipment components can suffer further delays. Lack of comprehensive analytical expertise specifically related to viral vectors and the need to send samples out to third parties for analysis can add significant time and cost to development programs as well.  

Integrated End-to-end Solutions for Vector Manufacturing

One approach to meeting the growing demand for viral vectors used in gene and gene-modified cell therapies is to rely on a CDMO with extensive expertise in transient transfection process development and scale up that also offers integrated, end-to-end services through a single source.

The Genesis Vector Manufacturing Solution from Center for Breakthrough Medicines includes capabilities for parallel plasmid manufacturing, first-time right process development, high-throughput GMP vector manufacturing in adherent and suspension processes, integrated analytical and testing capabilities, and regulatory, supply chain, and R&D services, at a fully integrated campus. Comprehensive manufacturing including starting material (e.g., plasmids), drug substance, drug product, and custom sterile components and buffers significantly simplifies clients’ supply chains.

For viral vectors, CBM offers a purpose-built manufacturing facility focused on scalable production of viral vectors. Processes can be developed for adeno-associated virus (AAV), lentivirus, adenovirus, retrovirus, herpes simplex virus, baculovirus, and other novel vectors that consistently deliver high yields and higher throughput to achieve optimum batch success in terms of both quality and quantity. Client programs can be supported throughout the entire product lifecycle from development to commercialization in both adherent and suspension batches up to 2,000 L on high-performance fill lines to minimize drug product loss and maximize doses for patients.

In-process and release testing located across the hall from the manufacturing suites expedites GMP batch release to six weeks from the industry average of 22 weeks. Avoiding the need to outsource testing to multiple laboratories also reduces sample volume requirements by up to 50%. For AAV gene therapy developers, CBM recently began offering its cohesive set of 40+ GMP AAV platform assays and domain-specific modules with the Analytical Accelerator for AAV Testing.


  1. Alliance for Regenerative Medicine, “Regenerative Medicine: The Pipeline Momentum Builds,” H1 2022 Report, September 2022
  2. Joanne S. Eglovitch, “FDA explains plans to bolster cell and gene therapy approvals through wider messaging,” RAPS Regulatory News, May 19, 2022. 
  3. David H. Crean, “The Cell & Gene Therapy Market: Excitement Abounds,” Pharma Boardroom, December 16,.2021. 
  4. Alliance for Regenerative Medicine, “Cell and Gene Therapies Poised to Disrupt Health Care Status Quo with Wave of New Treatments” Press Release, March 31, 2022.
  5. Janet Lynch Lambert, “Regenerative medicine: new paradigms,” Cell & Gene Therapy Insights 2022; 8(1), 53–58, DOI: 10.18609/cgti.2022.018
  6. Sybil Danby, “Overcoming AAV Manufacturing Challenges,” Contract Pharma,. May 5, 2021.
  7. Mirus Bio, “Thinking Big: Optimizing Large-Scale Viral Vector Production,” White Paper, November 1, 2022. 
Peri Morris, CBM Peri Morris is the Director of Strategic Programs and Continuous Improvement for Viral Vector Manufacturing at Center for Breakthrough Medicines. She has over 10 years of clinical and biologics experience, including in AAV, Adeno, lentiviral, and BEVS manufacturing for numerous products to support IND submissions, BLA submissions, and PAI audits. On top of this, Peri has worked on over 20+ technology transfers in support of new product introductions. She has also produced and released over 120 viral vector batches of varying modalities, and over 30 cell therapy batches over her career. Previously, Peri was the Lead MFG SME for the pre-approval inspection (PAI) to support the commercialization of Breyanzi (CART cell therapy for B Cell Lymphoma). She is the primary manufacturing reviewer for BLA, MAA, and PMDA submissions at CBM. Peri holds a B.S. in Biology from South Carolina State University and a masters in Biotechnology from Texas A&M.
Emily Moran, CBM Emily Moran is Sr. Vice President of Vector Manufacturing at Center for Breakthrough Medicines. She is an experienced leader in cell and gene therapy and biologics manufacturing with a focus on commercial readiness, industrialization, and manufacturing stabilization. She most recently served as Head of Viral Vector Manufacturing at Lonza in Houston Texas. While at Lonza, she facilitated the scale out and scale up of multiple clinical and commercial gene therapy programs as well as the expansion of the viral vector facility. Prior to Lonza, Emily worked in multiple areas of operations at Sanofi Pasteur. She is experienced in gene therapy and large scale biologics manufacturing, aseptic processing and filling, supply chain and demand planning, and quality auditing, all with a focus on operational excellence. Emily enjoys leading and developing large, high-performing teams and building patient and asset centricity. She has a B.S. in Biology from Ursinus College and an MBA in Project Management from New York Institute of Technology.