Driving innovation of industry tools
Analytical innovation is often overlooked in discussions of biotechnology product development and manufacturing processes. For example, in the DNA area, most “state of the art” analytical methods in use were developed in the 1980s, or even earlier. Industrywide, there is a need to continuously innovate in the analytical space due to the tremendous advances in enabling technologies.
There is a growing focus on analytical innovation, not only for the characterization of RNA, but also the characterization of DNA and proteins. This added focus on analytical innovation has helped drive the development and implementation of higher resolution and higher throughput analytical methodologies. At Aldevron, we target manufacturing process improvements and technical innovations intended to enable research programs as well as safe clinical trials. Building up our analytics capabilities offers several advantages, providing a path to overcome what we see as bottlenecks in the development process.
Buckets and bottlenecks
Analytics can be put in two buckets. The first comprises analytical innovation and method development. The other bucket comprises method validation, which has more quality oversight and serves manufacturing readiness.
The RNA development bottleneck arises from a lack of the appropriate tools to measure analytes of interest, or process and product related impurities in a high throughput operation. In some instances, techniques used are suitable but outdated, or techniques are suitable but time-consuming, with low throughput in a GMP environment.
These time-consuming tasks may add significant processing delays, with additional paperwork and related tasks that require a significant amount of time. Based on this gap, we must conceive and develop new methods with higher throughput technologies that can provide accurate, relevant, and timely measurements to enable data driven decision making.
One methodology requiring innovation is in characterizing the fidelity of the RNA itself. A sensitive, accurate method is needed to parse through the clutter to identify and describe how many, and which bases, are incorrect. While we are making great strides with Next Generation Sequencing (NGS) and similar techniques, we do not feel we yet have the sensitivity and specificity level of analytics suitable and are working to develop the next generation of analytical innovations.
Regarding purity, certain gel-based methods are so sensitive and technique-driven that they are typically not used as a release assay due to the potential for disparate results. For example, a silver stain gel may demonstrate a significant amount of false positive or spurious data, incorrectly showing that the product is carrying a significant load of impurities. We continue to make progress with capillary electrophoresis and UPLC based assays to provide sensitive, specific and quantitative results.
Another potential bottleneck is that while there are many analytical tools available, they may not be suitable for the intended application. What is needed are the right method development teams that can develop a suitable method for a molecule. New methods require you to convince regulatory agencies that these approaches provide superior performance before they can be accepted. Upon acceptance of the improved method and supporting multiple projects with that method, the goal shifts towards guiding the industry to implement the improved assay. Development and acceptance is not one or a few steps; it's multivariate.
Analytical Innovations Necessary for Progress
In the background of these concurrent processes, a primary driver is to get the new molecule into pre-clinical and clinical studies as soon as possible. As such, analytical innovations take a backseat to product development. The first few programs of a new modality may require a lower level of characterization and analysis, but it is safe to assume that there will be increased rigor from regulatory agencies.
USP issued draft guidance earlier this year on the proposed release assay panel for RNA. However, that is merely one step on this journey that has just begun; continuous improvement and innovation are required for this industry sector. It takes time and effort to implement the full new analytics processes, but we are confident we can reach that goal.
- Want to learn more? Contact Venkata Indurthi with your questions
- Watch Venkata Indurthi’s webinar, mRNA/saRNA Manufacturing - Considerations to Accelerate the Path to Clinic
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