Quality and Regulatory Challenges Surrounding New Cell and Gene Therapy Products

After decades of mixed success, including both significant advances and critical setbacks, cell and gene therapy stands at an inflection point. The sector has been buoyed by early successes that are driving more development and significant investment in the field, making it one of the most heavily funded sectors and the subject of over 1,000 current clinical trials. While some elements of the process chain, including viral vectors and adeno-associated viruses (AAVs) have been well studied and are approaching manufacturing and regulatory standardization, the field continues to rapidly evolve and generate new quality and regulatory challenges. It is critical that all stakeholders, including innovator companies, contract development and manufacturing organizations (CDMOs), and regulatory agencies, converge to establish frameworks and best practices as early as possible to assure the ultimate commercial success of these innovative and life-changing therapies.

Pharma’s Almanac Editor in Chief David Alvaro, Ph.D. recently spoke with Jennifer Cheung, Vice President of Quality Assurance and Regulatory Affairs at WuXi Advanced Therapies to explore the evolving quality and regulatory challenges facing cell and gene therapy developers and the progress the industry is making toward enduring, widely applicable solutions.

Q: To date, which aspects of cell and gene therapy manufacturing have become relatively standardized and which still pose considerable challenges from the quality and regulatory perspectives?

A: Although the cell and gene therapy industry has experienced a significant growth in the past years, several gene and CAR-T cell therapies have been approved in the United States and the European Union, the fact remains that it is still a very young industry.  Current market challenges include limited availability of some key raw materials, high cost for development, and the lack of well-established, fit-for-purpose manufacturing platforms.  As sponsors have rushed some of these early products to market, we have seen acceptance of non-optimal, less efficient processes, as well as the need for many post-approval commitments.  Repeatability, reproducibility, scalability, and comparability have all become very real challenges from quality and regulatory perspectives.  We have seen some level of standardization of plasmids, AAVs, lentiviral vectors, and RNA/DNA therapeutics manufacturing, as well as the cell expansion process.  The term platform technology is often used to describe a widely used and accepted process, especially those applied to enable IND filing. 

Q: What are the main sources of quality issues, and what solutions have been developed?

Cell and gene therapy manufacturers face a few unique quality challenges: starting from manufacturing, these include the availability and variability of raw materials, constantly evolving technology, scaling out versus scaling up a manufacturing process while ensuring process consistency and product quality, and the reliance on extensive manual manipulations in a cleanroom environment.  For patient and donor materials, challenges include maintaining the chain of identity and determining the donor screening requirements, potential contaminated incoming materials, and impact to the sterility and safety of product, process, facility, and personnel.  For testing and release, the short shelf-lives and limited quantity of materials allow no room for error, and patient administration and dosing decisions based on interim test results add considerable stress to quality systems. 

The industry is still working through solutions to overcome this range of challenges. To date, some potential solutions have been developed, including the use of platform process and analytical testing panel to standardize starting materials and release criteria, maximize the knowledge gained in terms of optimizing the technology, and drive consistency in manufacturing process, while leveraging our collective experience to minimize novel, unforeseeable issues that may continue to arise.  This is not to say that there is likely to ever be a single approach to this range of modalities and applications; there will always be differences from one patient and one process to another, but platform approaches to process and testing have the potential to minimize uncertainties and enable data-driven decision-making for quality events.

Q: What are the unique considerations for allogeneic vs. autologous cell therapies?

Allogeneic cell therapy is more aligned with the traditional model of biotech product manufacturing.  Once a preferred process is locked down, the process itself can be validated and repeated.  To increase production capacity means scaling up, and, over time, the process can be optimized to reach the desired process capability, which allows for significant reduction and optimization of product costs.  Autologous cell therapy, on the other hand, is truly individualized medicine.  For autologous therapies, capacity is gained from scaling out the process.  Economies of scale result from the ability to minimize differences between product units and to reduce the validation requirements. Locating manufacturing close to the clinical site would reduce the needle-to-needle time and thus ensure that the products can arrive at the clinical site in a timely fashion.  There will always be some variations in the process that cannot be fully controlled, such as the quality of starting material (e.g., patient tumor cells) and how well they will respond to the platform process. Minor adjustments may need to be made for every patient and every batch.  Because of this unique challenge, it is even more important to understand the design of the platform process.  Knowing how much variation the process can tolerate would determine to what extent an autologous therapy would need to be treated as a new product.

Q: What are some of the unique challenges or bottlenecks relevant to raw materials and the supply chain for cell and gene therapies, and what will be required to overcome them?

There certainly were challenges in the supply chain overall and the availability of raw materials in the last year, but nothing truly unique to cell and gene therapies. During the COVID-19 pandemic, the availability and movement of materials became more limited and restricted, which impacted the timelines of new and existing projects. Additionally, the cost of some specialized materials and their short shelf-lives make it impractical, if not impossible, to maintain excessive inventories while waiting for projects to start. For the cell and gene therapy industry to advance, we all need to think in a more integrated and collaborative manner. One idea would be to push the Material Requirements Planning (MRP) of specialized raw materials upstream to the suppliers and give them the flexibility to help allocate and reallocate materials based on the changing demands of individual customers. The advantage of establishing MRP at the source is that it would help avoid stockpiling and wastage at the individual customer level owing to project timeline shifts and material expiration. Individual projects may come and go, but, if we can plan and strategically reconfigure the supply chain at the macro level, we can all contribute to advances for the entire industry while avoiding costly write-off and stock-out situations.    

Q: To what extent do comprehensive, risk-based CMC strategies and other regulatory guidelines exist across these modalities? How responsive have regulatory agencies been to the industry’s needs?

Both the U.S. FDA and the European Medicines Agency have an extensive list of guidances/guidelines on their websites that are relevant to cellular and gene therapies. The one that is routinely referred to, especially for IND submission, is the CMC Information for Human Gene Therapy Investigational New Drug Applications (INDs) issued by the Center for Biologics Evaluation and Research (CBER) in January 2020.  This guidance provides a very comprehensive list of information that the U.S. FDA expects to see in the CMC section of an IND, with a lot of emphasis on vector production, raw material control, cell line provenance, and analytical testing, especially those related to safety, like replication-competent virus. It seems, if anything, that the agency is choosing to err on the side of caution when it comes to the IND application for these new modalities, as there are still a lot to learn. On the GMP side, in 2017, the European Commission published the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products. Additionally, PIC/S recently released their own guidance, Annex 2A Manufacture of Advanced Therapy Medicinal Products for Human Use. These are very practical documents for manufacturers to assess and implement risk-based product and process control strategies for advanced therapies production.  In my experience thus far, agencies are very responsive in addressing industry needs in this space, from scientific advisory meeting and pre-IND meetings to emergency meetings to discuss risk/benefit considerations for patient administration decisions. 

Q: To what extent is there harmony among the various regulatory agencies in this space?

From what I have observed, one thing consistently practiced by all regulatory agencies is their willingness to work with the sponsors and support their needs, especially given that we are all learning in this new area. Sponsors are definitely encouraged to meet with their respective agency for pre-IND briefing and discuss program design from a high-level, from CMC to nonclinical and clinical issues. It is a good idea to establish alignment upfront and stay up to date with the current thinking of the agency, because the field is constantly evolving, and standards are being set and reset constantly. Among the areas of divergence are the details needed for starting materials, process description, and phase-appropriate GMP interpretation, especially for early-phase product development. In addition, the use of Drug Master Files for CDMOs to support client submission while maintaining the confidentiality of the proprietary information is generally well accepted and welcome in the United States, but it remains unclear in other regions.

Q: Where are there still gaps in regulatory oversight that require clearer guidance?

Clear guidance for plasmid manufacturing and GMP requirements based on application would be extremely helpful. Custom plasmids often are the longest lead-time items for many projects. As a contract testing, development, and manufacturing organization (CTDMO), we have constant discussions with our clients from the grade of plasmids based on application (direct, indirect in vivo, and indirect ex vivo) to the testing and release requirements. Expanding this to other animal-derived materials and the expectations for process-specific viral clearance validation in early-phase product development would help the suppliers to line up the required information to support customers’ IND submissions.  Finally, for aseptic processing validation, there is a unique challenge for current cell and gene manufacturing, owing to the manual process and people-dependent execution. Clear guidance on which parts of the process require aseptic processing validation and the possibility to leverage data based on similar unit operations would help to reduce the cost and time needed for early-phase product development. 

Q: Are there any other particularly cumbersome regulatory hurdles for these products or unique considerations for inspections?

We have heard about submission delays attributable to the potency method being insufficiently robust. The fact remains that developing an in vitro assay to evaluate the proposed biological activity is not easy, owing to the complex mechanisms of action of these products. In many cases, multiple assays may be required to characterize different aspects of potency. The time required to develop such complex methods and the practicality of implementing them in a commercial setting continue to create additional concerns for sponsors. The risk of overburdening the routine control system and having a product rejected for its inadequacy, which leads to approval delays, has become a ubiquitous struggle for every sponsor. 

What is unique to these products is the number of changes often needed from development to commercialization due to the evolving regulatory landscape. During an inspection, special attention should be given to traceability and verification of raw data to support different changes, as well as the justification for comparability. Scientific and technically justified comparability data should indicate that — regardless of manufacturing process — the identity, strength, quality, purity, or potency of drug product must be equivalent and able to be measured and compared meaningfully.

Q: What would you recommend as best practices for a robust regulatory strategy? How different is that across modalities?

The regulatory framework encompassing cell and gene therapies is still developing as manufacturers continue to make progress in the consistency of products and the understanding of the processes. Some best practices to consider are early engagement with regulators, innovative clinical trial design, acceptable post-marketing studies and flexible post-approval changes. As an industry, we need to advocate for regulatory convergence and harmonization. 

These practices are not much different from what is typical for the pharma and biotech industries, only with slightly different arrangements. For example, a comparative study of regulatory submissions between advanced therapeutic medicinal products (ATMPs) and biologics found that ATMP marketing authorization needs to comply better with post-approval commitment. Also, typical conventional clinical trial requirements are shifting for gene therapies. It is becoming common to consolidate the phase I, II, and III processes into phase I, phase II/III, and post-approval trials.

Q: Are we approaching a critical shortage of talent with the appropriate quality and regulatory expertise to support all these new products?

I believe we are absolutely at the precipice of a critical shortage of talent, not only to support these new products but to support the pharmaceutical/biotechnology industry as a whole.  Aside from continually pushing for CMC and GMP convergence to simplify the landscape of quality and regulatory requirements, a separation of centralized versus localized roles and finding new ways to flexibly leverage expertise regardless of geographic locations would be a way to overcome shortage of talent in a specific location and region.  Ideally, we can define what needs to be done at the manufacturing facility and source that talent locally, while setting up virtual teams with members who can be situated anywhere to handle everything else and supporting their collaboration and teamwork using robust systems and tools. After all, the pandemic has shown us that how close we are is not measured by physical distance and how productive we are is not determined by location or time zone. As the saying goes, “Where there is a will, there is a way,” and there is definitely a will across the industry and beyond to optimize these life-changing and lifesaving products and have a real impact on patients’ lives.

Jennifer Cheung

Jennifer brings nearly 27 years of quality, compliance, and regulatory experience in biotechnology and pharmaceutical manufacturing prior to joining WuXi Advanced Therapies, a contract testing, development, and manufacturing organization (CTDMO) in 2020. In her current role, she is supporting many cell and gene therapy clients by interpreting and applying the phase-appropriate GMP regulations and requirements to accelerate development and manufacturing timeline, focusing on client satisfaction and the right-first-time performance. She is passionate about promoting GMP convergence, inspection reliance, and data-driven, risk-based decision-making to maximize patients’ benefit.