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Cell and Gene Therapy Manufacturing and Commercialization

  

Cell and gene therapy manufacturing and commercialization are advancing rapidly due to the potential to improve how we treat various diseases and the outcomes of those treatments. While cell therapy involves transplanting cells into a patient to replace or repair damaged tissue, gene therapy involves inserting, deleting or modifying genes in a patient's cells to treat or prevent disease.

Both therapies can be tremendously beneficial for treating previously untreatable diseases, such as certain types of cancer, genetic disorders and autoimmune diseases.

Although early research in cell and gene therapy dates back to the 1970s, it wasn't until the 1990s that the first cell therapy products were approved for use in humans. The field has progressed rapidly since then, with numerous clinical trials underway and several products approved by regulatory agencies worldwide.

However, the manufacturing and commercialization of cell and gene therapies present significant challenges. Among them are the need for specialized manufacturing facilities, the complexity of the manufacturing process and the high cost of production.

This article will cover the challenges facing cell and gene therapy manufacturing and commercialization. It will explore opportunities in the field and look at the current state of research and development, as well as the regulatory landscape for these therapies and the ethical and societal implications of their uses.

Cell and gene therapy market

Cell and gene therapy are growing fields that use genetic material, cells and tissue to treat diseases. The size of the cell and gene therapy markets has grown thanks to rapid advancements in genetic engineering, biotechnology and regenerative medicine.

The global cell and gene therapy market stood at $17.4 billion USD in 2022, with a projected compound annual growth rate (CAGR) of 23.7% from 2023 to 2031. The market is expected to reach $113.64 billion USD by 2031 due to increasing demand for personalized medicine and rising cases of chronic diseases such as cancer, cardiovascular diseases, and rare genetic disorders.

The cell therapy segment currently dominates the cell and gene therapy market and has a large share of total revenue. That’s because cell therapies have existed longer and are more established than gene therapies. However, the gene therapy segment is expected to grow at a higher CAGR over the forecast period, driven by increasing investments in research and development and a growing number of clinical trials.

North America holds the largest market share due to its well-developed healthcare infrastructure, high awareness about CGT and supportive regulatory environment. But the Asia-Pacific region is expected to grow at the highest CAGR largely due to the increasing adoption of CGT in emerging economies such as China and India.

Cell therapy manufacturing process

Cell therapy uses cells, typically stem cells, to replace or repair damaged or diseased tissue because they can differentiate into various cell types. In other words, they can regenerate damaged tissue in conditions such as Parkinson’s disease, heart disease, and diabetes.

Another type of cell therapy is gene-modified cell therapy in which immune cells (T-cells or NK cells) are genetically modified to target cancer cells overexpressing certain cancer markers. To discuss the manufacturing process, the focus will be on gene-modified cell therapy and will use a typical autologous Chimeric Antigen Receptor T-cell (CAR-T) product as an example to illustrate the workflow:

Sourcing and Isolation of Cells

The cells used for this therapy are sourced from peripheral blood, usually in the form of an apheresis collection. Target cells are isolated or enriched using density gradient centrifugation, red clood cells (RBC) lysis or magnetic separation techniques. The isolated cells are commonly referred to as the starting materials, and the actual manufacturing process for different CAR-T products can vary depending on the desired cell composition (CD3 or CD4/CD8%).

Activation and Genetic Modification

After the desired starting materials are isolated or enriched, the T-cells are stimulated and activated through the CD3/CD28 pathway. Common practices during the procedure include introducing CD3 and CD28 tetramers or magnetic beads conjugated with CD3/CD28. When the T-cells are activated, their volumetric size increases and they are ready for the next step of genetic modification

This genetic modification involves introducing the CAR construct into the activated T-cells. The CAR construct usually consists of CD3 transmembrane domain, an intracellular costimulatory domain and an extracellular binding single-chain variable fragment (ScVf).

Expansion and Culture

After the cells have been genetically modified, they are expanded and cultured in a bioreactor to increase their numbers. That is done by providing the cells with the necessary nutrients, growth factors and environmental conditions to promote their growth and multiplication.

Formulation and Packaging

After cells have been cultured and expanded, they are formulated and packaged into the final product. CAR-T products are typically formulated in cryopreservation media and frozen below -80°Cbefore administration. This is because many quality control tests must be performed before drug release. Patients must undergo a pre-conditioning regimen before the CAR-T infusion. CAR-T products are typically filled in cryopreservation bags with an average of about 50 mL.

Quality Control

Before releasing the final product for clinical use, it must undergo a rigorous quality control process to ensure its safety, purity and potency. This step requires testing the product for various parameters such as identity, purity, potency and sterility.

Distribution and Administration

Finally, the product can be distributed to the clinics or hospitals where it is administered to patients. The administration process varies depending on the type of therapy and the disease being treated but may involve intravenous infusion.

Gene therapy manufacturing process

Several gene therapies exist, including viral vector, non-viral gene editing and gene silencing. The viral vector approach uses an engineered viral capsid — usually lentiviral, adeno and adeno-associated viral vector — to deliver the gene of interest to target cells. Here is the workflow for the viral vector approach with a typical adeno-associated viral vector (AAV):

Viral Vector Expression System

There are two common approaches for vector expression systems. The first approach uses HEK293 cells placed in adhere or suspension cultures. This approach provides more flexibility in producing different viral vector constructs. Depending on the desired vector construct, different plasmid DNA can be simply transfected to HEK293 cells.

The other approach is to prepare a producer cell line, commonly seen in Sf9 insect cells infected with a baculovirus. As a result, the cells can become stable producers of the desired viral vector construct.

Cell Growth

To produce HEK293 and Sf9 cells for biotechnology applications, cells are typically grown in a fixed bed or a stirred tank bioreactor. After the desired cell density is achieved, an additional step is required for HEK293 cells. That step involves the introduction of a designed plasmid DNA and PEI ratio to the cell culture through a process known as DNA transfection. In contrast, Sf9 cells are already stable producer cell lines and do not require plasmid DNA transfection.

During the cell expansion phase, viral vectors are expressed by the cells in both cases.

Harvest of Viral Vector

After the cells grow to the desired total quantity, cells are lysed to release the viral vector contained in the cytoplasm. It’s important to note that AAV is required for the cell lysis step, but lentiviral vector (LV) does not.

After the release of the viral vector, specialized DNAse (commonly endonuclease) is introduced to degrade the residual plasmid DNA and the HEK293 host DNA. This step is required for AAV and LV, as it helps the downstream filtration and purification process.

Filtration and purification

The next step in the manufacturing process is depth filtration, in which cell debris is removed through filters. Subsequently, the filtrate or pass-through is concentrated, and the buffer is exchanged in a tangential flow filtration (TFF) system. After TFF, the viral vector mixture goes through a chromatography system for a two-step purification process. First, affinity chromatography resin would bind to all viral capsids carrying a purification tag. Then, ion exchange chromatography would separate the capsids with genetic payload from the empty capsids. This ensures the viral vector product has a high full/empty ratio, a main quality indicator.

Sterile Filtration and Finish & Fill

After the chromatography system, the in-process product typically undergoes ultrafiltration or diafiltration to remove the non-specific binding protein impurities. Finally, before the final fill, the in-process product will pass through a sterile filter into the final fill vials or bags.

Manufacturing challenges for cell and gene therapies

Cell and gene therapies (CGTs) are promising therapies that can potentially treat various diseases, including genetic disorders, cancer and autoimmune diseases. However, manufacturing CGTs presents several significant challenges discussed in detail below.

Cell Sourcing

Cell sourcing is one of the biggest challenges in manufacturing cell therapies. The quality, purity and consistency of cells used for therapy can significantly impact the efficacy and safety of the final product. In addition, the variability in cell sources can complicate manufacturing processes, resulting in inconsistent outcomes. Allogeneic technologies aim to address this challenge with induced pluripotential stem cells (iPSC) or donor-induced allogeneic materials. However, allogeneic technology also has its challenges, such as reprogramming of iPSC at scale and its controlled differentiation.

Cell Expansion

For FDA-approved autologous CAR-T products, cell expansion remains a time-consuming process. The duration of the expansion process, usually taking several days, results in extended needle-to-needle time for patients. Additionally, researchers speculate that the extended expansion process may contribute to T-cell exhaustion, which is seen as a disadvantage for the long-term effectiveness of CAR-T treatments. Manufacturers are investigating methods to reduce the duration of the cell expansion process to address this issue.

Vector Production

Vectors, such as viral vectors, are commonly used to deliver gene therapies into cells. However, vector production is a complex and expensive process. Below are two examples to highlight the challenges. First, selecting an appropriate expression system, such as HEK293 or Sf9, is a complex decision that requires weighing flexibility and efficiency. While HEK293 offers versatility for expressing various vector constructs, this system involves costs such as DNA plasmids and transfection reagents.

In contrast, Sf9 can stably produce vector constructs without requiring DNA transfection, but it necessitates greater investment in creating the cell line. Furthermore, optimizing the production yield for viral vectors entails various process optimizations. Numerous steps, such as cell lysis and chromatography purification, followed by sterile filtration before the final fill, can result in a loss of up to 20% to 30%.

Process Automation and Process Scale up/out

Many cell and gene therapies are personalized and tailored to an individual patient. In many situations, scale-up is not applicable and can only be scaled out. Many manufacturing processes for autologous CAR-T require scale-out, which requires more space, skilled operators and manufacturing controls. Because many novel cell and gene therapies are under development, companies are exploring innovative processes, leading to many small variations in different CGT processes. This can be a challenge for process automation because automation generally scales better with standard processes.

Quality Control and Testing

Quality control and testing for cell and gene therapies are essential to ensure their safety and efficacy. The process includes rigorous testing of starting materials, intermediates and final products to ensure they meet predetermined specifications. However, developing accurate and reliable assays that detect impurities, contaminants and deviations from specifications can be tedious and challenging, particularly for complex therapies.

Regulatory Compliance

Regulatory compliance for cell and gene therapies can be complex and still nascent due to different requirements and guidelines from various regulatory bodies worldwide. Compliance with these regulations is important to ensure patient safety and facilitate market approval. However, navigating these regulatory requirements can be challenging and may require significant resources and expertise.

Commercialization challenges for cell and gene therapies

Despite the effectiveness of cell and gene therapies, commercialization poses several challenges. Here are some of the commercialization challenges:

High Cost of Development

Developing cell and gene therapies is a complex and time-consuming process dedicated to research and development. These therapies are manufactured with specialized equipment and facilities, further adding to the cost. That’s why cell and gene therapies are often expensive, limiting their availability to patients who cannot afford them.

Regulatory Challenges

Cell and gene therapies are regulated by different agencies worldwide, and the regulatory frameworks for these therapies are still evolving. That variability can create uncertainty for manufacturers and delay the approval process, increasing the development cost.

There are many regulatory challenges that can affect cell and gene therapy. One of the main regulatory challenges for cell and gene therapies is the lack of a clear understanding of manufacturing processes and quality control standards. Cell and gene therapies involve living cells or genetic material that require a dedicated manufacturing process, which can be difficult to standardize for commercial production.

A second challenge is the complexity of the clinical trial design and endpoints for cell and gene therapies that are needed to adequately evaluate their safety and efficacy, also increasing the approval process's time and cost.

Manufacturing Challenges

Manufacturing cell and gene therapies also has unique challenges due to complexity of the process and strict regulatory requirements.

One of the major challenges in the manufacturing process is ensuring the quality and consistency of the starting materials, including the source of the cells used for therapy. The isolation and characterization of these cells can be a complex and time-consuming process that requires specialized expertise and equipment.

Another challenge is maintaining the viability and functionality of the cells throughout the manufacturing process. That can require culturing and expanding the cell's controlled environment, which could lead to contamination from microorganisms or other external factors.

Distribution and Reimbursement

Cell and gene therapies are complex treatments that require specialized storage and transportation conditions. Additionally, reimbursement for these therapies can be challenging, as many healthcare systems and insurance providers are not equipped to handle the high cost of these treatments. That can limit the availability and affordability of these therapies to many patients.

However, there are also many opportunities for cell and gene therapy commercialization. These are described below.

Opportunities for cell and gene therapy commercialization

Despite the challenges, there are several opportunities for cell and gene therapy commercialization. Here are some key opportunities:

Precision medicine

Cell and gene therapies can be customized to target specific genetic mutations or disease pathways. This precision medicine approach can improve treatment outcomes and reduce side effects, making these therapies safer for patients and healthcare providers.

Orphan disease market

Many cell and gene therapies target rare diseases with limited treatment options. That can open the door for opportunities for manufacturers to target the orphan disease market, providing a pathway for regulatory approval and reimbursement.

Collaborations and partnerships

Collaborations and partnerships between manufacturers, academic institutions and government agencies can help accelerate the development and commercialization of cell and gene therapies. These partnerships can provide access to funding, expertise and infrastructure, reducing the cost and time required for the development.

Innovative payment models

Innovative payment models are being developed to address the high cost of cell and gene therapies, such as value-based pricing and installment payments. These models can help make these therapies more affordable and accessible to patients.

Navigating commercialization challenges

Cell and gene therapy development and commercialization involves a complex landscape requiring clinical trials, manufacturing processes and regulatory approvals. In addition, the expenses associated with research, development and manufacturing can further increase the challenges of commercializing these therapies. To deal with these challenges, here are some key steps to successfully navigate the commercialization process:

Developing a business plan

Developing a comprehensive business plan for navigating the commercialization process is fundamental to navigating the commercialization challenges. It requires identifying the target market, assessing the competition, and creating a product development, manufacturing and distribution strategy.

Securing funding

Securing funding is an important step in the commercialization process because it enables companies to invest in research and development, manufacturing, and marketing. Funding can come from various sources, including venture capital, grants or strategic partnerships.

According to PitchBook, venture capital remains the largest funding source for startups globally, with more than $300 billion invested in 2021.In the same year, angel investors invested over $24 billion in startups, and corporate venture capital firms invested over $100 billion.

Obtaining regulatory approval

Obtaining regulatory approval from agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) can be complex for many reasons, including safety, compliance, data requirements and legal or ethical factors. That’s why companies must demonstrate their products' safety, efficacy, and quality through preclinical and clinical trials and submit extensive documentation to regulatory agencies.

Manufacturing and distribution

Manufacturing and distributing cell and gene therapies is a highly specialized process that involves advanced facilities, equipment and expertise. Companies must develop a robust manufacturing process, establish quality control procedures\ and ensure the stability and integrity of their products during distribution.

Marketing and sales

Marketing and selling cell and gene therapies require a targeted approach that considers the preferences of healthcare providers, payers and patients. A comprehensive marketing strategy highlighting their products' benefits and value and navigating complex reimbursement and pricing issues can go a long way to ensure good marketing and sales.

Accelerating cell and gene therapy treatments

Accelerating the development and commercialization of cell and gene therapies is crucial for addressing the unmet medical needs of patients and improving health outcomes. Below are some key strategies for accelerating the development and commercialization of these treatments:

Investing in research and development

Investing in research and development is essential for advancing the science of cell and gene therapy manufacturing and developing new treatments for various diseases. Governments, academic institutions and private companies can support research and development efforts.

Streamlining regulatory pathways

Streamlining regulatory pathways can help accelerate the development and approval of cell and gene therapies. Regulators can work with industry stakeholders to establish clear and predictable product development and approval guidelines.

Scaling up manufacturing

Scaling up manufacturing is critical for making cell and gene therapies more accessible and affordable. Companies can invest in new manufacturing technologies, such as automation and continuous processing, to increase production capacity and reduce costs.

Building robust ecosystems

Building robust ecosystems that bring together industry, academia, healthcare providers and patients can help accelerate the development and commercialization of cell and gene therapies. These ecosystems can facilitate collaboration, knowledge sharing, innovation, and support patients and caregivers.

Learn more about cell and gene therapy manufacturing

To learn more about cell and gene therapy manufacturing, look at the following resources from Avantor Sciences: