A process and analytical development pathway to help bring gene and cell therapy breakthroughs to light

An evolving therapeutic space

The GCT space has rapidly evolved in the past 30 years, with technological advancements and a growing understanding of molecular biology and genetics allowing developers to realize the potential of these revolutionary medicines. As a result, there are now over 2,000 GCTs in the development pipeline, targeting indications ranging from cancer to metabolic disorders and neurological diseases [1].

In 2022, the global gene therapy market was estimated to be worth $7.3 billion, reflecting the rapidly growing potential of GCTs. The sector is predicted to grow at a compound annual growth rate of 18.6% to reach a value of $17.2 billion by 2027 [2].

Innovative medicines bring new requirements

Despite exciting progress, advancements within the GCT space have led to unique needs arising throughout development and manufacturing, including:

• Filling knowledge gaps
  The GCT space is still relatively new; as a result, relevant scientific literature and information are limited. However, access to experts with first-hand experience in GCT development and manufacturing can provide an understanding beyond available scientific literature.
• Navigating the complex regulatory landscape
  The rapid evolution of GCTs placed pressure on regulatory agencies to adapt quickly and provide guidance on best practices. To meet these changing requirements and successfully deliver GCTs to patients, developers and manufacturers must demonstrate flexibility and agility to adapt processes and capabilities as necessary.
• Meeting growing capacity demand
  With GCT demand intensifying over the last 10 years, finding solutions to scaling issues in development and manufacturing while minimizing production costs (and consequently the price of treatments) has been a key focus point for GCT producers.

The need for robust process and analytical development approaches

GCT producers have a duty to overcome the difficulties of working in a new and rapidly evolving therapeutic area and deliver safe and effective medicines at pace to patients. Many of these patients have limited therapeutic options and could rapidly succumb to their genetic disease without treatment, which further emphasizes the need for accelerated timelines.

Achieving speed relies on the adoption of development approaches optimized to produce high-quality therapies in a scalable, robust manner, which keeps in mind the unique needs of GCTs. Pressure to provide a robust development approach comes from the need to:

• Demonstrate regulatory compliance
  Regulatory agencies, including the FDA and EMA, mandate that developers and manufacturers identify and define their product’s critical quality attributes (CQAs). Developers and manufacturers must understand how their selected processes and parameters impact defined CQAs to safeguard the quality and safety of the GCT through suitable analytic tests.
• Accelerate therapies
  A holistic approach to both process and analytical development is needed to determine how each process could impact other elements in production. This allows for risks to be identified and minimized, enabling the acceleration of timelines to market so that therapies reach patients faster.
• Reduce production and therapy costs
  To prove cost-effective, single-dose GCTs must be priced according to the extensive handling, operative and control efforts needed in production. Processing techniques must be optimized to reduce these manufacturing costs and consequently lower GCT prices, helping to broaden patient access.

There are many approaches to development that can be adopted with the aim of meeting the needs outlined above. These include a “just get it done” approach, where companies will develop as many products as possible, regardless of the fact they do not have a standardized approach, which often leads to high attrition. The quality-by-design approach, on the other hand, closely follows the International Council for Harmonisation (ICH) guidelines and requires an all-encompassing knowledge that is not always available.

Ideally, a risk-based approach that focuses on the factors required to promote quality, safety and efficacy will be adopted. This approach encourages the use of artificial intelligence-enabled and predictive modeling, allowing for risks to be anticipated as the project progresses and enabling development acceleration.

Tactics for success in process and analytical development

Implementing the right development and analytical strategies from the onset of the project is critical to eventual scaling, as changing processes at later stages can be increasingly difficult and could impact timelines.

Successful approaches toward process and analytical development rely on an appreciation of the many factors that will come into play throughout the project. The factors that should be carefully considered include:

1) Understanding analytical development requirements

Process development and analytical development often happen in parallel. This can lead to bottlenecks, as the development and optimization of production processes depend on having the necessary analytical methods, techniques and technologies for assessment, and analytical tests can only be designed and performed on existing processes. Preventing possible delays relies on the development of suitable testing to ensure CQAs and process parameters are being met.

With suitable analytical methods in place, analytical testing can also help to accelerate the timeline to market by proactively predicting process development risk at later stages. By conducting potency assays as early as possible, for example, any issues surrounding the ability of the GCT to elicit the intended response at a certain dose can be identified, allowing processes to be adapted to ensure potency CQAs are achieved.

2) Expertise to overcome complex novel therapeutic needs

Throughout both process and analytical development, GCT producers will be faced with a number of unique requirements that differ from those of traditional biologics. The novel needs of GCTs are particularly evident in the availability of suitable equipment and technologies.

In downstream process development, issues stem from the majority of commercially available equipment being designed to purify traditional therapies, such as monoclonal antibodies. As a result, these technologies are not always suitable for GCT applications.

Similarly, even though the analytical technologies used in GCT assessment might not be new, the way they are applied typically is. Technologies used in viral vector assessment diverge from the well-established analytical process for traditional biologics. These include analytical ultracentrifugation for quantifying capsid content and qPCR or ddPCR for assessing viral genome titer.

3) Optimizing for quality and speed

To ensure the therapies produced are of the highest quality and safe for patients, GCT developers must have a set of quality standards that sit across the company and are harmonized across regulatory agencies worldwide. These standards should incorporate appropriate controls and risk assessments throughout GCT production.

Quality standards must be considered from the onset of the project to avoid issues that could arise at later stages that could delay critical therapies reaching patients. Once these standards are in place, GCT developers and manufacturers can then consider the tactics to accelerate timelines, such as the use of closed-process, single-use technologies.

Partnering with Pfizer CentreOne

Pfizer CentreOne’s team of 70+ experienced GCT Pfizer scientists working across approximately 300,000 sq ft of world-class manufacturing space in Sandford, USA, offers end-to-end capability for both drug substance and drug product.

Employing cutting-edge technology, Pfizer CentreOne can meet your needs for yield and productivity throughout process development. Our extensive network of analytical and quality control engineers means that we can help our customers overcome bottlenecks and troubleshoot to resolve issues quickly.

This is what makes Pfizer CentreOne your altogether different kind of CDMO.

Interested in learning more about how Pfizer CentreOne’s approach to GCT process and analytical development could advance your therapy?

Download our “Gene and cell therapy analytical and development methods: A path to success” white paper.

References

1. Gene, Cell, and RNA Therapy Landscape. Q1 2023 Quarterly Data Report. American Society of Gene and Cell Therapy.
2. https://www.globenewswire.com/news-release/2022/08/02/2490145/0/en/The-global-gene-therapy-market-is-valued-at-an-estimated-USD-7-3-billion-in-2022-and-is-projected-to-reach-USD-17-2-billion-by-2027-at-a-CAGR-of-18-6.html