CCRM Blog

When we think about cell and gene therapies (CGTs) what most often comes to mind is the early stage scientific innovation responsible for finding new ways to treat diseases. A lot of complex research and testing is performed to confirm Proof of Concept and that the therapy performs as desired. 

Cellular immunotherapies (e.g. CAR-T cells) are primarily used as an autologous therapy to treat cancer. As such, these therapies are currently generated in small batches for each patient. To generate enough modified cells for a single treatment, cells are expanded in volumes from 1-10 L. In the final step of downstream processing (DSP) for immunotherapies, cells cultured in large volumes must be concentrated and reformulated into smaller volumes (e.g. 20-100 mL) suitable for delivery to patients.

In an introductory post on lentiviral vector (LVV) manufacturing for cell and gene therapies (CGTs) we touched upon the challenges with transfection-based protocols for producing LVVs at large scale. Here we will take a closer look at the use of stable producer cell lines as an alternative to transient transfection for the manufacture of LVVs.

In Part 1 of our series on lentiviral vector (LVV) manufacturing we covered scale-up of upstream processing steps. In this post we will look at the key steps in downstream processing (DSP). The industry “gold-standard” for recovery of purified and concentrated LVV is 10-20 percent. Improving on this low recovery is an opportunity to reduce the cost of manufacturing and get viral vectors into the hands of researchers who need them.

Compliance with quality control (QC) standards is a basic requirement for products manufactured under good manufacturing practices (GMP) conditions. In this post we will explore the main compendial QC tests that ensure cell and gene therapies are safe for use in patients, and important considerations for integrating QC testing into the manufacturing process.

Lentiviral vectors (LVV) are a key component in the production of cell and gene therapies. They are most often used to deliver genetic material that will modify cells and confer therapeutic properties. Today, even with the proliferation of cell and gene therapies in development, LVV is still produced using legacy methods employed in basic research. Overcoming technical challenges in the scale-up of LVV production is a major focus for the industry. Scalable LVV production platforms are critical for manufacturing affordable cell and gene therapies and making them more widely available. For an overview of LVV manufacturing and process optimization considerations see our previous post.

In a previous post we introduced chimeric antigen receptor T-cell (CAR-T) therapy - a new form of cancer therapy based on genetically reprogramming the body’s immune system that has been described as a “breakthrough” and “revolutionary” by the medical and scientific communities.

Understanding the cell and gene therapy (CGT) development process from start to finish often comes down to learning the language. For individuals more familiar with the early R&D steps in this process, terms like IQ, OQ and PQ – associated with later manufacturing steps – may be completely new. To get us started: IQ stands for installation qualification; OQ is operational qualification; and, PQ is performance qualification. Simply put, these are three steps in a validation process that ensures the equipment used in manufacturing works the way it’s supposed to. 

Simply put, a bioreactor is a stand-alone cell culture vessel enabled with sensors. Bioreactors differ fundamentally from traditional R&D cell culture in their ability to monitor and control key parameters such as temperature, pH, and dissolved oxygen (DO). Continuous, in situ monitoring of these parameters allow for a deep understanding of the growth environment of a given cell population -- creating avenues for process improvement. Paired controls enable dynamic, real-time responses as cells grow and the culture changes over time. With these capabilities, bioreactors can overcome limitations of traditional cell culture enabling the use of cell culture for commercial or clinical purposes.

Making the Decision to Engage a Contract Development and Manufacturing Organization (CDMO)