Gene Therapies: From Research To Reality | Cell and Gene Therapy (CGT) Guidance | Corning

This article was originally published by Cell & Gene on September 27, 2022.

Cell and gene therapy (CGT) companies transitioning from pure R&D and early preclinical work into clinical-phase development face several critical challenges. Key among them is the decision whether to outsource GMP manufacturing or to invest time, capital, and personnel toward development of in-house manufacturing capabilities.

Outsourcing is more often the rule than the exception in the complex CGT space and requires an organization to identify and interview reputable CDMO service providers with proven, documented success in the product-related vector and/or cell-manufacturing arenas. Unfortunately, a significant and ongoing manufacturing capacity shortfall — exacerbated by the COVID-19 pandemic — continues to undermine outsourcing efforts. It is not uncommon to see lead times longer than one year to reserve GMP manufacturing slots.

Additionally, some CDMOs might have manufacturing scalability limitations, which may inhibit their suitability as a partner beyond early-phase studies. This dilemma has led to technology transfer challenges when transitioning from one manufacturer to another between Phase 1/2 studies and pivotal late-phase studies. Finally, CDMO accessibility may be limited as firms embrace a more partnership-driven operating model rather than a traditional transactional one. In some cases, the CDMO merges with, or is acquired by, a larger pharmaceutical firm. Other times, a larger pharmaceutical partner monopolizes the majority, or the entirety, of a CDMO’s manufacturing capacity.

While in-house manufacturing can obviate some of these concerns, the sponsor faces the monumental task of building, equipping, validating, staffing, and operating a facility. This process is costly and forces the sponsor to overcome common CDMO industry challenges, such as talent acquisition, supply chain disruptions, and keeping pace with a continuously changing regulatory landscape.

CGT Production Scale-Up Considerations

It is vital to recognize each CGT program as unique and to carefully consider the inherent product needs — not only in early discovery but, more optimistically, through clinical testing and commercialization. An organization with high expectations for its product candidates and platforms will find it prudent to develop a customized process development plan for each product. That plan should include scale-up, but balance it against competing interests, such as time to clinical trial, phase of development, amount of product required per dose, need for single or repeat dosing, and justification of urgency (i.e., unmet medical needs where no suitable alternative treatments are available).

From this perspective, some product candidates undergo substantive scale-up activities intended to increase yields, increase quality, and minimize development and manufacturing timelines while building consistency across the manufacturing platforms. A key goal of the process development plan is to reduce the amount of specialized cleanroom space and the large number of personnel needed to perform operations, without sacrificing output. Accordingly, optimization and scale should be holistic, since changing some aspects of upstream production — for example, adherent to suspension culture — dramatically impacts downstream processing, key product quality attributes (e.g., titer), and product residuals (e.g., cellular host cell proteins, cellular and plasmid DNA levels).

Adherent Culture, Suspension Culture, or Both?

Cell and gene therapies represent the most complex drugs ever created. Acknowledging this, we are unlikely to be able to fully characterize or homogenize these products in the manner achievable for small-molecule chemical drugs or peptides. The best we can do is harmonize and consistently replicate the manufacturing process itself. Therefore, ideally, every step in CGT manufacture should be carefully considered and optimized.

Adherent cell culture has numerous benefits, including substantially greater purity of the starting harvest material, which reduces the number of downstream steps required and helps minimize product degradation. This is especially true for secreted products, such as coagulation factors and lentiviral (LV) or retroviral (RV) vectors, where the adherent cells are naturally segregated from soluble proteins and vectors without the need for additional separation techniques — often at a cost of introducing cell contaminants into the harvest.

A significant amount of biopharmaceutical discovery and proof of concept (PoC) science occurs using adherent cell platforms. Continuing to utilize an adherent platform throughout development allows the manufacturer to use one certified master cell bank (MCB) throughout development. Still, many organizations opt to switch to a suspension cell culture as they scale up, believing it to be the superior — or only — choice for CGT clinical and commercial production.   

To some extent, this perception may stem from the industry’s early experience with recombinant cytokines, monoclonal antibodies (mAbs), and coagulation factors. For many first-generation recombinant protein products, upstream manufacturing was performed using adherent cells in roller bottles. Quickly, the scale-up cost and complexity of roller bottle facilities became apparent, and several companies began transitioning to single-cell suspension culture in stirred tank bioreactors.

The need to produce larger lots and decrease cost of goods while maintaining quality led to the creation of progressively larger bioreactors capable of producing several thousand liters of material. As product and product candidate pipelines grew exponentially, many CDMOs manufacturing such products also explored the upper limits of single-use disposable technology in this familiar setting.

However, additional downstream process complexity is inherent in suspension cell harvesting, which requires additional steps to separate suspended cells from soluble product. Further, per-cell productivity can be lower using suspension cells versus adherent cells. And, it often is a difficult and expensive decision when and how to transition product development into a suspension platform, knowing there are likely to be challenges relating to one or more aspects of product manufacturing processes, yields, and quality attributes.

Continued use of adherent culture throughout development provides sponsors the ability to maintain upstream process fidelity through later phases of product development (i.e., no need to perform bridging studies to establish equivalency between materials produced in the earlier studies, using adherent cells, and those produced later using suspension). While up-scaled adherent bioreactor systems either did not exist or existed in a form that was not sufficiently beneficial (e.g., microcarriers) in the past, introduction of systems such as the Corning® Ascent® Fixed Bed Bioreactor System have changed this paradigm. The Ascent FBR system preserves the performance of adherent cells and is scalable on par with common stirred tank bioreactors in a single-use format. 

Ultimately, every cell and gene therapy is a unique entity ill-suited to “plug-and-play” application of any manufacturing platform. Careful consideration must be made regarding the time available for process change development, anticipated challenges, and quantities of material expected to be required through clinical development and commercialization.

In some cases, a transition to suspension technologies may fit within these constraints or may even be required to meet product demands. However, many product development programs may be better served by applying new adherent platforms, preserving time and money that would otherwise be wasted in the attempt to transition to suspension cultures. Regardless, continued innovation can be expected to positively impact both platforms moving forward.

Case Example: Expression Therapeutics

Expression Therapeutics is an early clinical-stage biotech company with two in-house cell and gene therapy candidates in the clinic, and one out-licensed AAV candidate at a similar stage. Expression currently manufactures both in-house candidates in its 43,000-ft2 GMP manufacturing facility in West Chester, Ohio, which came online in August 2021.

Expression has a strong oncology discovery program that relies on LV vector production and genetically engineered cell product manufacturing. The combination of multiple clinical development programs with the potential for commercialization, along with a rapidly advancing preclinical pipeline, led Expression to focus on achieving a balance of product quality and quantity with high expectation of success. This mindset led Expression to the adherent platform — the gold standard for the organization’s GMP manufacturing team — to Corning Life Sciences, and to the Ascent FBR technology.

Expression’s original LV vector manufacturing platform utilized 30 Corning® CellSTACK® 10-layer Culture Chambers per 60L lot of GMP LV produced. This scale required a team of approximately 8 full-time employees (FTEs) and one large, dedicated cleanroom. The Ascent platform’s scale-up provides for seamless development of Expression’s adherent cell-based LV manufacture process. The Ascent PD system recapitulates LV production that previously required 2 to 8 CellSTACK 10-layer chambers, while the forthcoming Ascent Pilot systems can produce LV at existing to quadruple current scale. The Ascent Production system will produce GMP LV lots at more than 50 times the company’s previous GMP Phase 1/2 clinical capacity, per run, with manufacture occurring in existing (i.e., same-sized) cleanrooms and requiring fewer (2 to 4) FTEs.         

Like all CDMOs or companies with in-house manufacturing, Expression’s clinical manufacturing often uses multiple technologies or products from its partners. From Corning Life Sciences, Expression utilized many different types of cultureware including various bottles, conical tubes, T-flasks, Corning CellSTACK and HYPERStack® vessels, single-use disposables, custom-made fluid transfer sets, and a variety of buffers and media.

Expression currently has and expects to maintain excess cell and gene therapy manufacturing capacity. The company is working with multiple clients to manufacture their preclinical and Phase 1/2 clinical product candidates. As a CDMO, Expression follows the same process development meticulousness and manufacturing philosophy as it does within its own pipeline candidates: delivering high-quality material in the most efficient manner possible is preferred to testing and optimizing speculative approaches.

Find a Proven Partner You Can Trust

Due to the inherent complexity of cell and gene therapy products and manufacturing processes, it is crucial for sponsors to conduct due diligence before committing to a partner, be it a therapeutics company, a CDMO, or a supplier. For example, supplier selection has evolved from simply qualifying a few vendors to serve as primary or backup suppliers to more of a strategic partnership model between two equally committed teams and entities.

Obviously, shared corporate culture, vision, and mission are important parameters for evaluating partners. Robust and scalable platform technology approaches that provide seamless transition from scaled-down bench research to pilot GMP applications, through to large-scale commercial manufacture, are advantageous. The ability of the technology to interface with the eQMS, EBR, and ERP systems is desirable. And both partners need to have the depth, resources, and a record of success to attract each other and support relationship longevity.

Modern vendors should demonstrate a value-add focus that encourages joint development of opportunities to improve products and services where each organization can leverage the other’s expertise and resources. Relevant to Expression, Corning’s commitment to providing customers with tailored solutions for its unique products has facilitated resource allocation, leveraged expertise, and fostered timely problem resolution.

The collaboration with Corning has been very effective for Expression as they built their GMP manufacturing facility from scratch and, within a few months of opening, began GMP production. Frequent engagement between the Expression and Corning technical teams during critical steps of the site development process helped Expression keep projects on track and on schedule.

As a result, Expression has been empowered to hit key product development milestones faster and to satisfy eager investors. Likewise, entities partnering with Expression’s CDMO operation benefit from the same supplier relationships, which can grow collectively, yet maintain transferability when appropriate. Close collaboration of this nature can only help the development of novel solutions that will continue to drive the cell and gene therapy market.