Move Your Gene Therapy from Strategy to Reality

Introduction
Gene therapies are delivering on the promise to transform modern medicine. With continued growth in the number of clinical trials and regulatory approvals, the global gene therapy market is estimated to grow from USD 3.8 billion in 2019 to USD 13.0 billion by 2024, at a compound annual growth rate (CAGR) of 27.8%¹. Currently, there are over 2,300 cell and gene therapy medicine trials underway worldwide². While most current trials are still in Phase I or Phase II, there are more than 200 trials in Phase III². “2022 is likely to be a record year for the approval of new gene therapies to treat rare diseases, with five such therapies up for approval in the US and Europe,” according to Alliance for Regenerative Medicine².
Due to the therapeutic successes and regulatory approvals, gene therapy investment has also increased significantly, with gene therapy raising USD 10.2 billion and cell based immuno-oncology with USD 10.1 billion². This represented a year over year increase of 12% for gene therapy and 26% for cell based immuno-oncology.

Manufacturing for Commercialization
With continued clinical success and increased investment, many gene therapy companies are looking toward manufacturing and commercialization of their lead therapies. The majority of gene therapies in clinical trials (92%) utilize viral vectors to carry the therapeutic gene into the target cells². The most common method of making virus involves transfecting mammalian cells with one or more plasmid DNA to generate the viral vector. Once produced and harvested, the vector is then clarified, concentrated, purified, sterile filtered, quality-tested, and stored for use either ex vivo or in vivo depending on the therapy and the virus type being used. There is no “one size fits all” approach for these complex gene therapy products and as such, they can be manufactured using a variety of processes, viral vectors, and cell lines. Among current clinical trials, adeno-associated viruses (AAVs) are used most often, in at least 66% of all gene therapy trials with a known viral vector, followed by lentiviruses (LVs) at 11%, and adenoviruses (AV) at 10%².
While gene therapy manufacturing and commercialization strategies have improved significantly over the last five years, there are still several challenges to overcome when looking at how these products can be manufactured consistently, at appropriate scale, and in a cost-effective way. Similar to other biotherapeutics, gene therapy commercialization focuses on managing and balancing risk during decision-making. There are many choices to be made in the clinical, financial, and manufacturing domains and getting all of these to work together cohesively can be a significant challenge.
To complicate matters, the industry is experiencing a manufacturing capacity shortage. While there have been several strides made toward increasing capacity, the continual rise in therapies entering the clinic likely mean that this shortage will remain for the near future. Capacity shortage is not the only challenge—gene therapies require specialized equipment and bioprocessing knowledge to manufacture. This need for specialized skills has resulted in an increase in demand for personnel trained in cell and gene therapy manufacturing. As a result, in person courses and e-learning are on the rise at training centers such as BioCentriq™ and Biofactory Competence Center along with digital training tools hosted by suppliers such as Pall Corporation®.

Integrated Solutions
Being first to market is essential for most gene therapies to maximize the chances of commercial success.
Thus, manufacturing processes must be designed early on the path to commercialization. Identifying fit-for-purpose technologies with the right implementation strategies from the outset are essential if the vision of the full-scale process is to be realized swiftly and without excessive risk.
An integrated solution means that all the unit operations are harmonized together in the project quoting and execution phases, and that the consumables are appropriately specified and qualified for their intended function for the entire process. This allows for a reproducible process, and as long as the incoming raw materials are well controlled, there is a high level of assurance that the process will run at optimal productivity routinely.
Bottom line: good integration can be the key to getting your process and systems to work to set performance criteria every time.
In a rapidly expanding industry, it’s important that access to operator training for a new process is easily available. Digital tools including e-learning and virtual reality can help to reduce the amount of training time required in a cleanroom and are always available to support the workforce.
Setting up projects for success means delivering a manufacturing process on time and on budget that achieves and maintains quality standards. An experienced and knowledgeable integrated solutions partner can provide the necessary expertise to support these goals and, in turn, shorten time to market.

Implementing an Integrated Solution
Successful implementation of integrated solutions does require a great deal of experience and a deep understanding of manufacturing processes, equipment, automation, and engineering. An efficient way to access this type of experience and deep knowledge is to work with an end-to-end solution provider with skilled process experts and end-to-end project management. A provider with extensive viral vector manufacturing process knowledge paired with a broad equipment portfolio can simplify the complex gene therapy manufacturing process. Process experts will be able to design a process with the right equipment and consumables based on process needs. In most cases standard platform offerings can also be leveraged to drive down start-up risk. The provider will also consider facility layout to ensure the required equipment fits into the clean room designs and will recommend compatible automation concepts. This approach ensures the project is managed based on process needs rather than fitting the process to the selected equipment.
All in all, an integrated solution approach can provide better process economics, risk mitigation, and shorter timelines to maximize the chance for overall project success. The final fit-for-purpose manufacturing system should consist of scalable well-defined and performance-qualified unit operations that are harmonious and cGMP compliant. The right partner can manage the entire project from start to finish and allow the developer time to focus on other critical tasks.
Support from partners should not be limited to design and installation of equipment – other aspects such as process design, development, validation, and regulatory support for single-use technologies, are also important to ensure a smooth start to manufacturing. A knowledgeable partner can provide validation documentation for the single-use technologies adopted by the users, which meets industry guidelines and is easily accessible via a digital portal.

Leveraging Pall’s Accelerator^SM Integrated Solutions
Pall utilizes its Accelerator Integrated Solutions program (Figure 1) to help developers and contract development and manufacturing organizations (CDMOs) secure speed to market using robust manufacturing platforms as a starting point. The team at Pall, backed by extensive bioprocess expertise and a diverse equipment and consumables portfolio, can walk their partners through every step of the process. Pall provides a streamlined, integrated approach that includes engineering, process scale-up, and project management services³. By looking at the entire process from end-to-end, Pall starts with a clear understanding of the full process and project objectives to deliver a high-quality process on time and on budget that ultimately de-risks and reduces time to market.

A Robust Platform Tailored to Specific Process Requirements
Pall’s Accelerator Integrated Solutions begins with a robust and highly configurable platform process such as those for AAV, lentiviral, adenovirus or mRNA (Figure 2)³. The platform can be tailored to meet specific process requirements, thus ensuring that the equipment is perfectly matched to each unique manufacturing process to deliver a solution that is right for manufacturing as quickly as possible.

A Collaborative Partnership
Pall’s philosophy is to use a collaborative approach to create an appropriately considered and designed integrated solution, which meets customers’ needs, within the target timeline and budget. Furthermore, if companies need help to optimize and scale-up their processes, Pall’s Process Development Services are available to lend their expertise. Such services can bridge a small-scale process with the manufacturing scale integrated solution thereby reducing start-up time and risk.

Accelerator Vision Platform
The team at Pall will use tools such as a manufacturing mass balance to fully characterize all the inputs and outputs from each unit operation. This, combined with the known facility footprint, allows the team to develop specific solutions recommendations that include a full equipment list, recommended layout, and process flow diagrams to ensure optimal factory floor space utilization. The Accelerator Vision software allows an interactive and virtual reality view of the facility design. In Figure 3, you can see how the Accelerator Vision Platform has been used to layout an AAV adherent manufacturing process.

This permits full visualization of the process with the capability of optimizing workflow and maximizing operator efficiency. Figures 4 and 5 shows an AAV suspension manufacturing process.

Full Project Management
Drawing on an extensive product portfolio, and the added benefit of access to the full portfolio from other Danaher companies, Pall has all the necessary systems for manufacturing; from cell culture, media and buffer prep, all the way to bulk drug substance filling – and everything in between. Once the process design is established, it is expert project management that aligns the hardware, the single-use components, and the automation strategy to bring the project to reality.
Once the integrated solution is agreed upon and finalized, a delivery schedule is created, and from this point on during the execution phase there is constant communication with the client. Pre-agreed milestones are reviewed on an ongoing basis and activity scheduling is coordinated.

To ensure proper functionality of the systems, factory acceptance tests (FATs) are conducted, and then upon delivery, site acceptance tests (SATs) are performed. Pall continues to work with clients after delivery to make sure that all operators are trained and fully familiarized with the equipment. A comprehensive scheduled maintenance, calibration and repair service is also available to minimize disruptions and keep production running smoothly.
As the production process matures, Pall can support the continued lifecycle of the product, for example to install process improvements or for capacity expansion. Figure 6 shows Pall’s end-to-end manufacturing solutions for largescale AAV adherent production.

REAL WORLD EXAMPLE
Integrated end-to-end gene therapy manufacturing solutions provide a fast track to the clinic that can give a company a strategic advantage over competitors. When supported by strong technical, analytical and bioprocess know-how, these solutions also minimize the potential risks and unanticipated surprises during development. Pall Corporation recently partnered with Exothera, a viral vector CDMO, to expand their manufacturing capabilities by adding a large-scale suspension-based AAV manufacturing platform, from upstream through downstream processing of viral vectors of up to 2000 L⁴ (Figure 7).

Modular Integrated Solution
Modular integrated solutions at the facility scale are also available through Cytiva with their KuBio offering. Adoption of such a strategy can provide an excellent solution for a company that has a greenfield or brownfield site as they can be rapidly deployed and provide an excellent off the shelf solution³.

Summary
Gene therapies have been called the future of medicine and stand to revolutionize the current healthcare paradigm because they offer a curative treatment in many instances, rather than just managing the symptoms of the disease. They also represent hope for patients since many gene therapies are aimed at addressing unmet medical needs where there is either no treatment available or where other treatments have failed.
However, it is important to remember that manufacturing and providing these therapies in a standardized and safe way can be a challenge. As such, it is important for companies to understand all manufacturing options available to them and to select one that best fits their product’s process, scale, and manufacturing timelines. Working with an integrated solutions provider can help companies achieve efficient manufacturing as quick as possible. Deploying standardized and platform technologies as a starting point enables speed to market and provides the manufacturing expertise to navigate manufacturing and commercialization. On-going provision of services for training, equipment maintenance, and validation support ensures that the process is optimized for the full life-cycle of the product.

References
1. Markets and Markets: Gene Therapy Market by Vectors [Non-viral (Oligonucleotides), Viral (Retroviral (Gammaretroviral, Lentiviral)), Adeno-associated], Indication (Cancer, Neurological Diseases), Delivery Method (In Vivo, Ex Vivo), Region – Global Forecast to 2024. Accessed June 1, 2022. https://www.marketsandmarkets.com/Market-Reports/gene-therapy-market-122857962.html?gclid=CjwKCAjw77WVBhBuEiwAJ-YoJPX48pysZjfmUnQsmBmIzBeBEc1kosu-Xvwlzo0wP_Fes1QevnvPs-BoCW0MQAvD_BwE
2. ARM 2021 Regenerative Medicine: Disrupting the Status Quo. Accessed June 1, 2022. https://alliancerm.org/sector-report/2021-annual-report
3. Pall Corporation. Pall’s Acceleratorsm Integrated Solutions: Supporting Exothera to meet the high demand for viral vector GMP manufacturing. Webinar accessed June 1, 2022. https://go.pall.com/exothera-webinar.html?utm_source=cell_culture_dish&utm_medium=website&utm_campaign=22-04-121-GTEND&utm_content=banner
4. Using End-to-End Integrated Solutions to meet the High Demand for Viral Vector GMP Manufacturing. Podcast Cell Culture Dish. Accessed June 14, 2022. https://cellculturedish.com/using-end-to-end-integrated-solutions-meet-high-demand-viral-vector-gmp-manufacturing

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