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Complex hurdles complicate the development of emerging therapies.
While traditional biologics continue to see strong market demand, the need for emerging therapies, such as regenerative medicines, has also given rise to a burgeoning pipeline. The biopharmaceutical industry has seen significant levels of investment going into clinical-stage projects for cell therapies, gene therapies, and other regenerative medicines over the past year (1) as efforts increase to tackle the development and manufacturing hurdles for these therapies.
Read the related sidebar article, "Emerging Plant-based Platform for Biomanufacturing," in the May 1, 2022 issue of BioPharm International.
Cell and gene therapies encompass a wide range of highly complex, manual and customized manufacturing processes, says Fatma Senkesen, executive director of Marketing and Commercial Development for the Cell & Gene Division of Lonza. From a manufacturing standpoint, the biopharma industry commonly groups cell therapies into two categories—allogeneic and autologous—because the manufacturing process and challenges are so different between manufacturing a batch from one donor for multiple patients in allogeneic cell therapy versus manufacturing one batch per patient in autologous cell therapy. Meanwhile, for gene therapies, the industry also splits the manufacturing processes into two main arms: ex-vivo gene therapies, which today are mostly autologous, and in-vivo gene therapies, which are mostly viral vector gene therapies, Senkesen notes.
Cell and gene therapy products are typically presented as highly product-specific dosage form, and this brings complexity to the drug product manufacturing process, says Susanne Jörg, chief customer delivery officer, ten23 health, a Switzerland-based contract development and manufacturing organization (CDMO) for sterile products. The complexity in the manufacturing process of the viral vector drug products can be attributed to the availability and variability of raw materials as well as incompatibility with typical aseptic manufacturing unit operations, such as sterile filtration and filling/dosing by pumps, which often require extensive manual manipulations in a cleanroom environment. Prior knowledge related to drug product formulation, suitable primary packaging materials, and related aseptic manufacturing processes is still limited compared to traditional monoclonal antibody (mAb) products.
There are two main challenges that create bottlenecking points within cell therapy manufacturing, says Ger Brophy, executive vice-president, Biopharma Production, Avantor. The first is the scalability of cell culture processes to produce cell therapies, such as chimeric antigen receptor (CAR) T-cells or genetically modified stem cells. According to Brophy, different cell types require different conditions for sustainable cell population expansion, thus, a large amount of manufacturing effort needs to be spent in process development and optimization before the volume requirements for clinical production can be achieved. The second is the availability of closed manufacturing systems vital to reducing contamination risks to cell therapies and maintaining safety. Recently, closed, automated manufacturing systems have become available to produce small volume autologous or personalized cell therapies, Brophy notes; however, these systems are unsuitable for large volumes of allogeneic cell therapies. One solution to this is to use more single-use fluid handling technologies in cell therapy production.
Viral vector production for cell engineering is also known to be a primary area where bottlenecks occur in cell therapy manufacturing, says Seokjin Chang, director of Market Intelligence at Samsung Biologics. Viral vector manufacturing using adherent culture methods often have low productivity considering the time and effort expended during the process; consequently, supply may not be able to meet the high viral vector demand coming from biotech companies, Chang states.
The manufacturing process itself, specifically for autologous cell therapies, is also time-consuming, requiring the extraction of cells from the patient, transportation to the facility, culturing of the engineered cells, and finally transporting these cells back to the patient. To solve this problem and reduce the bottleneck associated with transport, many biotech companies are working to commercialize “off-the-shelf” allogeneic cell therapy products, Chang notes.
Andres Castillo, market entry strategy manager CCT, Sartorius, confirms that a few key barriers in cell therapy manufacturing include laborious manual processes, variability within the process, complexity, and scalability. He explains that current workflows are highly manual, which increases the likelihood of operator error and contamination as compared to closed automated systems. Highly manual processes also create dose-to-dose variability, another problem in the manufacturing process. “This makes it difficult to identify process improvements that can drive down costs and reduce time to market,” Castillo says.
“Differences from donor to donor within the process also create variability in the overall manufacturing process and production timelines. To overcome this variability, robust characterization of both the cell and the process is necessary to streamline production. This requires investment in precise bioanalytical instruments and data management tools to glean insights to establish process knowledge,” Castillo adds.
As cell therapies hit commercialization, the biggest bottleneck appears to be scale-out of manufacturing, says Brian Newsom, senior director of Business Development, Cell Therapy, at KBI Biopharma. Bottlenecking at the point of scale out can be attributed to the labor-intensive process of one-at-a-time manufacturing combined with the limited pool of talent and limited ability to scale facilities cost-effectively, Newsom observes.
As scaling out issues get solved, however, another constriction point will be in the supply chain, for example, a lack of blood-derived products such as human serum albumin and other factors used in the manufacture of many commercial cell therapies and those in development. “Synthetic derivatives are often not comparable and, in cases where they are, can be more expensive and still have production limitations. Other supply chain issues, including vector availability, plastics (consumables) shortages, and shipping constraints for highly labile products, are all bottlenecks that are starting to impact the industry,” Newsom states.
Bottlenecks throughout gene therapy manufacturing are common throughout almost every stage—from plasmid DNA (pDNA) sourcing to inserting DNA into viral vectors and purifying empty capsids—says Chang. “Overwhelmingly, the challenge in overcoming these obstacles seen throughout production seems to be because processes are not yet well-established and there are currently few highly-trained personnel in this area to conduct them,” he explains.
From Brophy’s perspective, given the high expected growth rate of the gene therapy market, a major question is simply whether manufacturers and suppliers can keep up with demand. “This is most keenly felt by emerging companies who may lack the time and resources to build the expertise required for vital workflow stages, such as plasmid and viral vector production, and downstream purification,” he states, adding that working with manufacturers who have the knowledge and resources to expand production capacity and scale up processes offsets some of these concerns.
Another significant constraint within gene therapy manufacturing is the low yield of the process caused by low efficiency of transfection, production of empty capsids, separation of those empty capsids, and removal of impurities during downstream processing, Brophy explains. These inefficiencies result in a manufacturing process that has approximately 30% yield. Implementation of strategies to increase process efficiency and yield are key for gene therapy manufacturers. “This can include the choice of transfection reagents and processes, selection of appropriate cell lysis reagents to increase release of viral vectors, exploring reagents to reduce system viscosity to aid downstream processing, and the use of high-quality chromatography resins to purify viral vectors and remove impurities,” Brophy elaborates.
“In gene therapy, viral vectors have proven their amazing ability to act as gene delivery vehicles in the clinic. To unlock the true transformative potential of viral vector-based gene therapies, however, a set of technological challenges relating to manufacturing and quality control must be overcome,” says Laetitia Malphettes, head of Gene Therapy Chemistry, Manufacturing & Controls—Development Sciences, UCB Switzerland, a biopharmaceutical company focusing on neurology and immunology.
Because of the complexity of viral vectors, analytical understanding and characterization of what constitutes quality and consistency of a gene therapy viral vector product is still at an embryonic stage, Malphettes states. The overall process production yields of functional capsids containing the desired genetic payload is also a major obstacle. “As a consequence, process and/or manufacturing site changes (or ‘tech transfers’) and scale changes, although often needed, are very difficult to implement during the clinical development lifecycle; and even more difficult if these changes occur after pivotal study supply,” she adds.
Other factors that have limiting effects on cell and gene therapy development and production include analytics and the sourcing of raw materials. The timeline and volume requirements for traditional growth-based microbial testing is perhaps only partially addressed for both cell and gene therapy applications, observes Lindsay Fraser, head of Technical Services at Symbiosis, a Stirling, UK-based contract manufacturing organization. Molecular based technologies, such as polymerase chain reaction (PCR) and next-generation sequencing (NGS), as well as rapid growth-based detection systems, have had some traction from regulators to address this bottleneck related to analytics, Fraser says.
“However, the compendial growth methods for sterility and mycoplasma remain the first consideration and is, therefore, a bottleneck in the same way as for mAbs,” Fraser adds. Furthermore, components such as viral vectors and nucleic acids, as well as process intermediates, such as plasmids, tend not to have the same volume and stability considerations as for cell-based therapies. Fraser anticipates, however, that alternative rapid microbial testing methods will be more generally accepted in this market segment ahead of the classical biologics such as mAbs.
Many products in development still require bioassays, which can be time-consuming, laborious, and difficult to qualify, adds Newsom. “As these processes scale-out, these assays can be difficult to batch and scale, as can be the analytics for these assays,” he notes. In addition, advanced therapies generate reams of data, which are often produced via incompatible systems that can be difficult to matrix. Newsom explains that, as the industry grows, the amount of data assessed will require automated systems that can provide real-time analysis and objective results, and platform technologies will need to be adopted by the industry.
Meanwhile, the performance and quality of raw materials is crucial, thus, inconsistencies found in raw materials or any unforeseen changes can lead to unexpected effects on the manufacturing process and slow down development, points out Mark Kline, chief technology officer and co-founder of X-Therma Inc., a biotechnology company specializing in the preservation of regenerative medicines and organs. “When developing therapies using cells, whether they are from the patient or a donor, it is difficult to collect and culture enough cells at the right therapeutic potency while maintaining that therapeutic potency after banking,” he adds.
As previously mentioned, scaleability for both cell and gene therapies can be a major challenge.
Kline explains that constriction in the manufacturing workflow presents significant logistical barriers to scaling up for many regenerative medicine companies. For instance, in the case of autologous cell therapies, which require scale out rather than scale up, the manufacturing process from the point of collection of the individual’s own cells or tissues can take an average of three weeks before the therapy can be given to the patient. “This is often the case with CAR-T cells, for example. Once created, patient cell performance in the manufacturing process can also vary, leading to batch failures and other complications,” he states.
Furthermore, autologous therapies represent hard-to-reach revenue scales, making their manufacture difficult, especially to streamline the manufacturing process for efficiency while remaining profitable when each dose is custom-made, Kline adds.
On the allogeneic cell therapy side, these therapies are poised to face difficulties in the manufacturing process seeing as how they are produced in large batches, very often from unrelated donor tissues, says Kline. Among the difficulties encountered is the development of cells that do not activate the immune system and cells that get neutralized before they can be effective, he notes.
Senkesen points to the labor-intensive nature of traditional manufacturing processes used in allogeneic cell therapy manufacturing, emphasizing how these processes often rely heavily on manual operations, which require long processing hours that burden a highly trained and qualified workforce. Furthermore, many of these processes are open and, hence, at risk from contamination issues, even with stringent aseptic training and qualification.
“As we scale up, reproducibility could be affected by the long process duration and a large number of personnel required to complete all activities. One of the main challenges we need to address, from a manufacturing perspective for allogeneic cell therapy, is the scaling of the process. Some rare diseases need high cell dosage, while larger indications reach more patients and require a large batch size to be able to supply the market in a cost-effective way,” Senkesen explains.
“For allogeneic CAR-T cells, in particular, we need to work in parallel on overcoming upstream scale-up challenges by defining optimal solutions to generate the volume of cells needed for multiple doses (at the desired quality), as well as on the downstream technologies, to be able to select and purify the target cells at the given scale. These tools do not exist today. Significant development will be needed in sync with the fast-evolving pace of the manufacturing needs,” Senkesen states.
The scale of manufacturing for allogeneic immunotherapies is a significant challenge, says Newsom. He notes that, while the industry can manufacture a few to a few tens of doses from a single donor, it is not yet able to reach the scale of 100s or 1000s of doses from a single donor. “This creates a limitation in the availability of therapeutic doses and the cost of the therapies as well. While creating 10 doses from a single donor lowers the drug’s price, it does not lower it 10-fold, and the therapy will still have a price tag that is a considerable stretch for healthcare economics if implemented at a large scale. This may be an inherent biological issue we can only get around with the use of iPSCs [induced pluripotent stem cells] or other such sources of starting material,” Newsom cautions.
Operational logistics are another challenge in the industry when it comes to scaling up manufacturing processes for cell therapies, Newsom points out. Producing large quantities of small batches creates a tremendous amount of quality control testing, puts an enormous burden on quality assurance operations, and is a challenge for timely shipping (of inbound material, drug product, and many labile raw materials), he explains. “Creating and maintaining operational excellence in these areas is difficult and costly and requires its own network of specialists,” says Newsom.
In comparison, Senkesen says that autologous cell and gene therapies are ahead of other cell and gene therapies in the race to commercialization because most of the approved cell and gene therapies that have seen in recent years are autologous. These therapies come with some of the most complex roadblocks that have ever been seen in drug manufacturing, Senkesen emphasizes. “Obviously, scalability and commercial viability are incredibly difficult for autologous cell and gene therapies by nature because one GMP [good manufacturing practice] batch equals one patient. So the cost of producing the treatment for a single patient is exponentially higher than it is for traditional biologics,” she states.
“Automation through closed, GMP-in-a-box systems to manufacture single-patient batches bear the promise to address some of those scalability issues, but are not yet adopted at larger scales,” Senkesen adds.
Viral vector manufacturing processes are also labor-intensive and require highly trained staff, notes Senkesen. These processes can be scaled with suspension-based platforms, but 3D platform processes are far from a one-size-fits-all solution, she says.
“These processes often struggle to meet requirements, particularly for AAV [adeno-associated virus] therapies production and function, usually because the components used in these platforms are highly variable: the host cell line, capsids, or the transgene contained in the AAV can greatly impact productivity (overall titer), packaging efficiency (overall % of AAV containing the transgene of interest), overall yield, and overall function of the product. As a result, a single platform process will usually require some degree of optimization and extensive experience to obtain final overall commercial viability of the platform,” Senkesen states.
Thus, to ensure continuity from pre-clinical to clinical development and regulatory approvability, process performance, the scale-up or scale-out strategy and consistent quality must be addressed from the very beginning, says Malphettes. “This is achieved thanks to an integrated end-to-end chemistry manufacturing and controls strategy from research to patients,” she adds.
Oncology remains a prominent field toward which emerging therapies are targeted, but work is also being done to apply these therapies, particularly allogeneic cell therapy and ex-vivo gene therapy, in other disease areas. For instance, one area of development that appears to have high near-term potential is allogeneic natural killer (NK) cell therapy, according to Newsom. Genetic engineering and gene editing are not required with NK cell therapy, which simplifies the workflow, and NK cells have been shown to have a profound clinical impact, he notes. The dominant applications are in oncology, but NK cells also have applications in infectious diseases. Long term, however, the clear winner on potential is iPSCs, Newsom says.
“The ability to bank a cell type with seemingly unlimited proliferative potential and totipotency is a compelling proposition as long as this potential can be harnessed and directed appropriately. As far as where iPSCs can have an impact, it appears the sky is the limit, in the long run. Near term, the emphasis seems to be on retinal diseases, neural diseases, and tissue engineering; developing iPSCs into immune cells for the treatment of cancer, infectious disease, and autoimmunity is on the forefront of research, but it is a bit early for application,” Newsom states.
Senkesen says that, due to their cost structure, allogeneic cell therapies are intended to be significantly more economical and hence likely to raise strong interest from all parties. Today, allogeneic therapies are popular with cell restorative therapies, for example, diabetes, Parkinson’s disease, or stroke—where the cell is secreting trophic factors into the body and target sites that are immune-privileged, such as the eyes. Furthermore, Senkesen adds, a panoply of allogeneic cell therapy sub-segments, such as allogeneic CAR-T and NK cell products, are coming into the limelight because they have the potential to address some of the bottlenecks of autologous cell therapies, including cost-of-goods, scaling-up and the flexibility to ramp up or down based on demand. These come with their own challenges, however, such as gene editing methods to limit the rejection of the donor cells by the patient’s immune system, says Senkesen.
Shanya Jiang, market entry strategy manager CCT, Sartorius, says that relapsed blood cancers (e.g., B-cell leukemia and lymphoma) are currently the major indications targeted by CAR-T cell therapy, but the next-generation CAR-T cell therapy candidates are also targeting solid tumors. There is additionally an ongoing study where researchers are using CAR-T cells to fight human immunodeficiency virus infection, she adds.
Meanwhile, with stem cell-derived cell therapies, neurodegenerative diseases (e.g., Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury), Type I diabetes, heart failure, and end-stage liver disease requiring liver transplantation are the diseases currently being tested for in-the-clinic applications; thus stem cell-derived cell therapies have the potential to reach larger patient populations, Jiang states.
On the gene therapy front, rAAV has come to the forefront in recent years for treating rare diseases, and there is a strong showing of these candidates in the clinical pipeline, Lara Nascimento, market entry strategy manager CCT, Sartorius,emphasizes. Two such gene therapies are approved by FDA: Luxturna (voretigene neparvovec-rzyl) for treating Leber’s congenital amaurosis and Zolgensma (onasemnogene abeparvovec-xioi) for treating spinal muscular atrophy. “The success of rAAV for use in rare disease gene therapies has sparked pre-clinical and clinical studies in its wider use, notably to treat a range of cancers which is boosting the need for rAAV manufacturing globally,” Nascimento points out.
“For gene therapies, the most immediate impact is likely to be felt in rare, monogenic disorders. These disorders are often pediatric conditions with high clinical impact and a lack of disease-modifying or curative therapies,” says Brophy. One disorder where patients could benefit from gene therapies soon is Duchenne muscular dystrophy, an incurable muscle degeneration disorder that primarily affects young boys. Pivotal clinical trial data from several gene therapy pipelines are expected by the end of 2022, according to Brophy.
Brophy further states that gene therapies may also have clinical impact in more common blood disorders, such as hemophilia A and B, beta thalassemia, and sickle cell anemia, with one such company expected to seek approval for their hemophilia B gene therapy in 2022.
Beyond all these challenges discussed, the fact that cell and gene therapies are highly complex, emerging fields dictates a requirement for experienced talent that is currently scarce and highly coveted because the field is still so young, concludes Senkesen. Significant competition exists not only among CDMOs but also among drug developers striving to attract professionals with the skillset and experience needed to develop and manufacture these highly complex therapies. Underlying much of the effort that industry is putting into developing these emerging therapies is the imperative that companies must not only hire and train specialized talent, but also keep talented personnel engaged by exposing them to a variety of projects and modalities.
1. ARM, “Cell & Gene State of the Industry Briefing,” alliancerm.org, Jan. 10, 2022.
Feliza Mirasol is the science editor for BioPharm International.
Vol. 35, No. 5
Pages: 10–16, 48
When referring to this article, please cite it as F. Mirasol, “Emerging Therapies Face Development Hurdles,” BioPharm International 35 (5) 10–16, 48 (2022).