A Quality by Design Approach to Overcoming the Bottlenecks in Gene Therapy Manufacturing

Introduction

Gene therapy holds extraordinary promise, but its path from lab to clinic is often slowed by manufacturing challenges. In this case study, TKD Solutions, a science-driven consulting firm for advanced therapies, applied a Quality by Design (QbD) framework to significantly improve the process for a viral vector-based gene therapy. The result? A tenfold increase in GMP yield and a robust process ready for clinical supply.

“The QbD method identified the root cause of failed batches, and a robust process was implemented for clinical supply”

The Market Is Ready.
But Is Manufacturing?

The gene therapy market is surging following its first FDA approval in 2017^[1]. Approved indications for gene therapies include cancer, spinal muscular atrophy, hemophilia, and sickle cell disease^[1]. The possible therapeutic targets of gene therapies continue to grow with 17 companies sponsoring gene therapy clinical trials—three of which are in Phase III^[1]. 

For most of these gene therapies, transgene delivery by viral vectors such as AAV or LVV are preferred. However, the technical complexities of these viral vectors lead to many challenges in their manufacturing scale-up. Notably, challenges are prevalent in the multi-plasmid design of gene therapy vectors.

Viral vectors require multiple DNA plasmids to deliver a gene therapy. To ensure safety and proper function, the necessary genetic material is divided into separate plasmids, including a vector plasmid, packaging plasmids, and envelope plasmid.

These plasmids contain specific sequences and modifications to ensure efficient viral vector production while preventing the generation of replication-competent virus. Following genetic assembly, the yield is further diminished by the purification process, which must eliminate process and product contaminants from the final product to maximize safety. The numerous components of the gene therapy manufacturing process make the process challenging to manufacture and scale, which can result in failed batches and low yield.

QbD to the Rescue

A QbD approach can be used to overcome the bottlenecks in gene therapy manufacturing. QbD employs a comprehensive program assessment to de-risk gene therapy manufacturing early in the process, enabling development and scale-up. QbD involves creating a quality target product profile (QTPP) to identify CQAs. Using the defined parameters, a control strategy is implemented to define the vector specifications. Taken together, QbD enables a systematic approach to using product and process data analysis and DoE to de-risk even the most complex gene therapy manufacturing processes.

TKD Solutions has extensive expertise in QbD for cell and gene therapies. Using our systematic approach to batch record and raw data analysis, TKD Solutions was able to increase the yield of gene therapy product for our client by ten-fold. By identifying the root cause of failed batches, TKD Solutions was able to save our client an estimated $900 million in production costs over the expected lifecycle of the product. 

Manufacturing a single dose of gene therapy can cost between $1 million and $2 million

Efficient and optimized manufacturing processes are imperative for complex, costly products such as gene therapies. The high cost of manufacturing cell and gene therapies continues to limit patient access to these therapies. The Institute for Clinical and Economic Review (ICER) reported the manufacturing costs of a single dose of gene therapy to be between $1 million and $2 million^[2]. Despite the incredible cost to manufacture, cell and gene therapies are in high demand for the therapeutic potential they possess. Gene therapies have provided patients with lifesaving and life-altering opportunities for oncological and immunological indications. Thus, mitigating costs where possible with QbD-optimized manufacturing process must be a priority for all cell and gene therapy manufacturers. Reducing manufacturing costs of gene therapies via QbD process improvements like those implemented by TKD Solutions ensures programs move forward towards commercialization.

Read the full white paper to learn more about our QbD approach to gene therapy manufacturing.

Resources:

^[1] Vigene Biosciences. “Growing pains for gene therapy manufacturing.” Nature News, Nature Publishing Group, www.nature.com/artickles/D42473-018-000160

^[2] Vigene Biosciences. “Three is the magic number in gene therapy production.” Nature News, Nature Publishing Group, https://www.nature.com/articles/d42473-018- 00017-z