Creating A Roadmap For The Development And Manufacture Of Gene Therapies

In the 1800s, as railways began to revolutionize transit and industry in the United States, a key design flaw came to light: different railways used different gauges, and those gauges were often incompatible with one another. This meant cargo had to be unloaded from one set of rail cars and re-loaded onto another when transitioning from one railway to the next, a time-consuming and expensive process. The adoption of a "standard gauge" solved this problem, allowing for interconnectivity and interoperability between railway systems and resulting in considerable time- and cost-savings for the industry.

The cell and gene therapy sector is in need of a similar revolution, but instead of a “standard gauge,” there is a need for clear, evidence-based industry standards and best practices for manufacturing these innovative technologies.

The Goal of A-Gene

To date, no one has compiled a well-defined set of best practices for developing and manufacturing an in vivo gene therapy. For this reason, the Alliance for Regenerative Medicine (ARM) has brought together more than 50 experts from some of the preeminent gene therapy developers and manufacturers worldwide to create “A-Gene,” a reference guide for gene therapy development scheduled for release this summer. Drawing on the experience of contributors from across the development timeline, A-Gene will be a consensus-based guide for companies in the sector.

A-Gene is not the first time the biomedical industry has collaborated to create such a reference guide to facilitate future innovation. In 2008, as developers looked to monoclonal antibodies to treat a growing array of diseases and disorders, industry leaders found that the heterogeneity in methods drove up costs and inhibited workforce development. Representatives from across the industry assembled a CMC Biotech Working Group to develop a case study that would apply “Quality by Design” (QbD) principles to this new technology, enabling companies to establish a shared systematic approach to product development that emphasized data-based decision making and quality risk management.

The resulting document, called A-MAb, helped to harmonize developers’ experience with producing monoclonal antibodies and played a significant role in the decreasing the cost of developing these therapies. This helped to lower the barriers to entry for new developers and contributed to a new wave of therapeutic candidates using this technology.

A-Gene has the potential to provide a similar service to the rapidly expanding in-vivo gene therapy sector. As it stands, many existing gene therapy companies originally spun out of smaller academic research labs and utilize manufacturing processes that are neither scalable nor financially viable in larger commercial settings. In addition, proven strategies for scaling other biologics, like vaccines and antibodies, are not directly translatable to the production of a gene therapy viral vector. First-generation gene therapy developers have each had to cultivate their own strategies for manufacturing in order to meet timelines and deliver therapies for clinical evaluation; however, this has resulted in overtaxed small-scale systems lacking a clear roadmap or toolset for commercial scale production.

In the current gene therapy sector, when a company transitions from one manufacturing facility to another, or an employee transitions from one company to another, differences in technology, manufacturing, and analytical methods can create burdensome and costly delays. This becomes less sustainable as the gene therapy sector continues to mature, and may become a significant limiting factor in the number of patients that can be treated with gene therapies in the long term.

The goal of A-Gene is to provide a central source of knowledge regarding design, development, and scalable manufacture strategies for gene therapy. The document uses an AAV gene therapy case study to illustrate how these strategies can be implemented in a real-world setting. As CMC issues can pose a significant regulatory challenge – in many cases, the primary regulatory challenge – for companies, A-Gene could help mitigate time-consuming regulatory delays. In addition to creating consensus among industry experts on best practices, A-Gene will also represent a valuable tool for the next generation of gene therapy developers, allowing them to more effectively plan for manufacturing at scale earlier in the development timeline.

Areas of Focus

ARM’s A-Gene team has identified nine key areas for the development of best practices and standards, including:

• Quality Target Product Profiles: Quality by Design principles require that a Target Product Profile (TPP) and Quality Target Product Profile (QTPP) are developed at the outset of the development process. Potential critical quality attributes (CQAs) are identified from the QTPP. As defined in ICH Q8(R2), a CQA is a “physical, chemical, biological, or microbiological property or characteristic that should lie within an appropriate limit, range, or distribution to ensure the desired product quality”. CQAs are refined over time as a full understanding of the process develops. The goal is to clearly and distinctly define what the viral vector should do and how it will produce that effect, resulting in a more systematic and evidence-based approach to product development.
   
• Comparability and Lifecycle Management: As developers move throughout the timeline, they must continue to make their manufacturing processes more efficient. This is particularly true for developers who have utilized accelerated approval schemes such as PRIME or RMAT designation, who may receive approval before they’ve developed a scalable manufacturing process. However, developers also need to show that any improvements to manufacturing efficiency don’t affect the efficacy and safety of the final therapeutic product. By describing best practices for comparability, A-Gene will enable developers to improve upon manufacturing processes without creating burdensome delays or duplicative expenses.
   
• Regulatory Considerations: Because clinical gene therapy is a relatively new area of science, the regulatory landscape for gene therapies is very fluid. Many regulatory guidance documents that were not originally written for gene therapies are being applied to the sector, which can create confusion among developers. By creating a comprehensive list of guidance relevant to the development of clinical gene therapies, A-Gene will help to clarify regulatory expectations for developers and manufacturers.
   
• Development & Use of Standards: Reference and documentary standards are an essential component of modern biologics production, with organizations such as the Standards Coordinating Body working to assemble and define standards for cell and gene medicine. By collating knowledge from multiple standard development organizations and other stakeholders, A-Gene will provide information not only on existing reference standards, but on the development of internal reference standards.
   
• CQA & Risk Assessment: A core concept in a QbD approach is that defining your CQAs for a product sets the foundation for your CMC program. As such, risk assessment methods should be applied to define a true CQA and to align a development team on parameters which need to be most stringently adhered to and/or monitored. By highlighting the critical role of this exercise, and providing tools and recommendations on CQA definition and risk assessments, A-Gene provides a key educational resource.
   
• Upstream/Downstream Processing: In order to achieve cost effective production scale, developers must apply best practices in planning for their upstream process development, downstream process purification, and scalability of both. In addressing challenges in CMC scalability, A-Gene provides developers a single resource for prospective therapeutic developers.
   
• Process Control Strategy: Generation of a high quality, reproducible product requires implementation of a well thought out and clear Process Control Strategy to ensure quality is met across numerous site and runs. Building on risk assessment, Process Control Strategy is essential to long term success. A-Gene presents recommendations, examples, and tools to enable a developer to create a robust Process Control Strategy fit for their product and process.

The Increasing Need for Scalable Manufacturing Strategies

The regenerative medicine field is growing rapidly, and the time for developing standardized protocols to address challenges in gene therapy manufacturing is now. There will be a considerable increase in the number of patients who receive gene therapies over the next five to 10 years. Of the 352 ongoing gene therapy clinical trials worldwide, there are 32 in Phase 3. The FDA has said that by 2025, they expect to be approving 10-20 regenerative medicine products annually, and ARM projects that the number of approved gene therapies could more than double over the next 1-2 years.

But approved products are not the only drivers of demand for gene therapies. The clinical pipeline is increasing as well. The FDA soon expects to receive 200+ INDs each year for gene and cell therapy clinical trials. By 2030, the MIT NEWDIGS consortium predicts that 500,000 thousand people will have been treated with cell and gene therapies in the United States alone.

In addition to the increase in available products and clinical trials, gene therapy developers are also often required to meet shorter development timelines, driven by the availability of expedited approval pathways such as RMAT, Breakthrough, and Fast Track designations in the US; PRIME designation in the EU; and SAKIGAKE designation in Japan. These designations help to ensure that patients are able to access innovative therapeutics as efficiently as possible, but shorter timelines mean that developers must begin to plan their large-scale manufacturing strategy early on in the development process – often before they begin to dose patients. While this results in greater efficiency in the long term, this earlier timeframe for considering manufacturing represents a significant shift in the paradigm for biologics development.

The Future of Gene Therapy Manufacturing

Gene therapy manufacturing technology is advancing rapidly as experts develop new strategies to address scalability, immunogenicity, payload, viral vector production, and other key issues. With a new wave of next-generation gene therapies poised to receive approval in the near future, these advances will be vital to ensuring that there is a robust scientific and manufacturing infrastructure in place as these innovative therapies begin to reach the market.

A-Gene represents an important piece in this evolution of gene therapy manufacturing: an expansive undertaking by preeminent experts in the field to create a centralized, consensus-based book of knowledge on gene therapy manufacturing. The best practices put forward in this document will help to standardize key elements in manufacturing among existing gene therapy developers, as well as reduce barriers to entry for new gene therapy developers. A-Gene will also help to mitigate CMC-related regulatory delays, which are often the primary delay experienced by developers in the field. As a result, we expect to see a more competitive sector with a greater number of companies developing these therapies; greater manufacturing capabilities for gene therapies for a wide range of rare and more prevalent conditions; lower production costs; and – ultimately – improved opportunities for patient access.

As the science in this space continues to advance, we at ARM are excited to see how this sector will progress – and projects like A-Gene demonstrate how great that progression can be when we work together. It’s been a great privilege to work with our members on this project, and we’re excited to share the final document with the sector writ large later this year.

Janet Lambert, CEO, and Michael Lehmicke, Director, Science and Industry Affairs, represent the Alliance for Regenerative Medicine (ARM), an international multi-stakeholder advocacy organization that promotes legislative, regulatory, and reimbursement initiatives necessary to facilitate access to life-giving advances in regenerative medicine worldwide.

For more information on ARM’s manufacturing initiatives, including A-Cell, the sister project to A-Gene, expected to be released in Q4 2020, please visit: https://alliancerm.org/manufacturing/