Cell and gene therapy (CGT) drug sponsors make important program and business decisions every day in a rapidly evolving technical and regulatory landscape.

As our industry continues to innovate, the result is often CMC and regulatory uncertainty. In fact, the integration of innovations frequently demands further innovation! Oftentimes, a notable tension exists between innovating and adhering to regulatory requirements. In many cases, there may not even be a clear regulatory pathway for those innovations.

So staying abreast of both technical and regulatory thinking is essential if a drug sponsor wishes to take advantage of accelerated regulatory frameworks and avoid mistakes that can turn into costly delays in bringing lifesaving therapies to market.

For virtual biotechs, your business strategy may be to position your CGT program for a robust exit, via licensing or acquisition. To that end extending the financing runway by ensuring every dollar is spent wisely to create the highest-value program package for due diligence is essential. Success requires staying on top of the latest industry thinking and solutions to successfully bring a program through its development lifecycle. Additionally, development supply chains are now global, taping expertise and capabilities on a worldwide basis.

Does This Sound Familiar?

Imagine a scenario where a company successfully completes Phase I clinical studies in Asia. The next step is filing an Investigational New Drug (IND) application in the United States, with a goal of convincing the FDA to allow direct entry to Phase II.

But a detailed review of the clinical and safety reports and supporting data reveals critical gaps in reporting. If left unaddressed, these gaps would have prevented the program from moving forward. A clinical hold would lead to rewriting the submission package, regulatory resubmission, and reevaluation by the FDA costing the drug sponsor both time and money.

In the above scenario—an actual case handled by the Pharmatech Associates team—failure was avoided by identifying deficiencies and laying the scientific groundwork for acceptance and negotiating with the FDA to address known deficiencies as post-approval commitments. Working closely with the drug sponsor, Pharmatech was able to avoid the clinical hold and set their program on a trajectory for success.

Efficiency and Cell & Gene Therapy Research

Thomas A. Edison once said, “There’s a way to do it better— find it.”

In any emerging field, there are many opportunities to do things better and CGT is no exception. This post identifies some of the key efficiency challenges faced by today’s CGT researchers and suggests how to overcome them.

Reduce Turnaround Times

Lengthy manufacturing processes plague cell and gene therapy production, with typical timelines ranging from a couple of weeks to nearly a month. Shortening product production cycles can substantially lower costs and free up capacity. Strategies like semi-continuous processing designs, rapid-release testing methods, and minimizing cell expansion steps can help streamline manufacturing workflows.

Facility Design

The layout of your facility can have a profound impact on capacity, productivity, flexibility, contamination controls, and more. Traditional, dedicated cleanrooms limit throughput. Newer modular panel ballrooms that can be rearranged to accommodate multiple products using off-the-shelf systems can achieve shorter turnaround times and increased utilization efficiency. Fully automated technologies can also reduce errors while enabling parallel processes with minimal to no human intervention.

When designing facilities, companies must balance flexibility, containment, and turnaround times tailored to product needs while keeping regulatory requirements in mind. Regulators scrutinize the chain of identity controls in unconventional builds. Standardized testing and checks ensuring that the chain of identity is maintained within ballroom-type GMP areas builds necessary trust with regulators.

Implement Cutting-Edge Platforms

From single-use, recipe-driven bioreactors to closed transfer systems and inline analytics, advanced platforms introduce automation with real-time monitoring. Scaling out multiple small volume units aggregates capacity. Combined unit operations capabilities like cell sorting and incubation with newer platform off-the-shelf technologies can achieve consistent yields and quality with less handling risk and variability.

While these technologies are often used in clinical phases, their benefits warrant consideration for commercial manufacturing. The potential to reduce contamination and manual errors builds a strong case for addressing potential quality risks.

Reevaluate Downstream Steps

Continuous countercurrent and periodic countercurrent chromatography systems offer ways to develop semi-continuous downstream processes. By connecting columns in alternating wash/elute cycles, companies can improve resolution, increase efficiency, and eliminate holding times. Such innovations may better integrate polishing flows compared to traditional serialized batch chromatography and can easily integrate into manufacturing flows that use upstream semi-continuous, perfusion cell culture processes.

Rapid microbiological release testing methods significantly shorten post-manufacturing timelines allowing faster lot release times. BacT/ALERT and other platforms far outpace compendial incubation-based sterility assays. Reducing analytical release testing turnaround times accelerates overall speed from bench to bedside. CGT patients are typically very ill and time to administration is an essential consideration.

Navigate the Complex Regulatory Landscape

Bringing a cell or gene therapy from concept to clinic involves navigating an intricate regulatory landscape. Rapid innovation in characterization technologies means continuously evolving industry and regulatory expectations.

Integrate High-Efficiency Innovations

The quest for efficiency in CGT is bringing advances like high-yield viral vector production, and single-use automation to the forefront. Any tool for keeping costs and development times down while expanding capacity is bound to get industry traction.

Streamline Complex Manufacturing Workflows with Single-use Systems

Cell and gene therapy production requires bringing together sensitive, multifaceted processes. Their biological complexity is a good fit for single-use systems that use enclosed, functionally combined platforms. These turnkey technologies offer enhanced control and traceability for intricate production workflows like viral vector generation. They also enable the parallel unit operations central to efficient scaling.

By ensuring closed processing and enhancing control, the risks associated with scale-out are reduced. Combined functionality bioreactors with attached harvest lines followed by enclosed filtration or chromatography address upstream and downstream needs in one system.

Increase Yields with High Efficiency Viral Vector Production

Viral vectors are a central component of the overall C&GT mechanism of action. They are manufactured today using lengthy, manual bioreactor culturing. High-efficiency vector generation methods like suspension cell perfusion bioreactors or intensified processes using advanced analytics may significantly concentrate yields over comparable platforms. They present opportunities to investigate ways to scale productively.

Meet the Challenges Head On

The development roadmap for any emerging drug modality is often loaded with risk and uncertainty. Currently, there are 32 approved CGT products in the United States. Developing complex biologics for large-scale production comes with significant challenges. From high costs to long turnaround times and a rapidly evolving regulatory environment, companies must navigate myriad hurdles on the path to commercialization.

The principles identified here to drive efficiency represent an ever-changing landscape for drug sponsors and health authorities. Having access to experts who hold both the experience and insights to apply these strategies to your program is essential to realizing the benefits of each.

Specialized CGT therapies require distinct manufacturing capabilities, so we advise all our clients to choose their consultants and manufacturing partners carefully. Focus on teams that offer solutions specifically for CGT and offer a demonstrable track record of reducing turnaround time, meeting maturing standards and processes, and navigating regulatory pressure on the road to commercialization.

In what ways will increased efficiency boost your efforts to bring new assets to market?

Contact us to learn more about our capabilities and discover how we can help you with your next CGT project.

Pharmatech Associates is the consulting arm of US Pharmacopeia (USP), a globally recognized leader in establishing drug quality standards for more than 200 years. From product development to navigating the regulatory landscape, we specialize in enhancing efficiency and bringing your products to market.

Our team is equipped with unparalleled knowledge and experience and is ready to partner with clients of any size, from startups to multinationals in developing solutions across the pharmaceutical product and medical device life cycle.