As a gene therapy scientist, you face an abundance of challenges when working to build an effective AAV therapeutic. Many steps of the development workflow have yet to be standardized and the regulatory parameters you’re required to meet are a moving target.
One workflow consideration that is often overlooked is formulation.
Regulatory bodies require characterization of the components in the final product formulation that is administered to patients. But formulation work goes beyond the contents of that vial that is administered to patients.
Formulation encompasses every solution, buffer, and eluant used in the many steps of AAV vector development – including the vector capsid proteins and genome.
And this is important because all formulation components influence the capsid.
In particular, the buffer environment either supports vector integrity and stability, or it stresses the capsids and causes problems for you and your development, manufacturing, or clinical teams.
Unstable capsids risk dissociating and leaking their contents. Leaky capsids are more prone to aggregation. Capsid aggregation causes more capsids to leak.
To avoid this domino effect, learn about the benefits of optimizing your AAV buffer formulation throughout development.
Limit AAV capsid leaking
From the moment capsids are collected from the bioreactor, your prep will contain some empty vectors. Empty vectors lack the genetic material that makes an AAV therapeutic effective. And they negatively impact potency and safety. Chromatography separates out these empty vectors for removal.
But it is also possible for purified capsids to lose their vector genome as they move through the rest of your development pipeline. By creating a stabilizing buffer environment throughout the entire workflow, more capsids remain intact. And this is reflected by a higher full/empty vector ratio.
Minimize batch-to-batch variability
A lot goes into vector development, including vector characterization, developability assessment, scale-up, production, and final fill and finish. And all of these processes require multiple batches of your vector. Each batch needs to be evaluated for yield and critical quality attributes (CQAs). With such large-scale production and a multiple-step workflow, there is always some variation between batches. But too much variability and uncertainty is costly.
By optimizing your buffer environment, your capsids remain stable, and stability leads to reproducible outcomes.
Batches with high yield and high quality enable you to plan, build, and scale an efficient workflow.
Extend the shelf-life of your AAV
Final formulation and fill/finish mark the end of your workflow. But an AAV therapeutic is still weeks or months away from being administered to a patient. And its journey is fraught with stressors and logistical challenges. While freezing an AAV therapeutic slows degradation, freeze/thaw stress decreases its efficacy. Storage, and shipping and handling a therapeutic that must remain frozen is a challenge. It is expensive and requires freezers at the treatment site, which can hinder patient access.
An optimized final vector formulation minimizes the negative impact of stressful storage conditions on vector stability, which means a more potent and safe product is delivered to patients.
Improve your SISPQ score
AAV therapeutics need to meet the standards set by regulatory bodies. These address quality attributes surrounding Strength (or potency), Identity, Safety, Purity, and Quality — the SISPQs.
A vector prep that is stable and in a supportive buffer environment has uniform, intact capsids. It is devoid of contaminants and disassembled capsids which, if present, are safety concerns for the patient, as they increase the risk of toxicity or eliciting an immune response. A pure and stable prep retains its potency.
Save time and money in AAV development and production
By investing time to optimize buffer formulations throughout your workflow, each batch consistently produces a higher yield of intact vectors, and is of higher quality. Higher yield means fewer batches. Fewer batches means your team gets their work done faster.
When you plan and scale an efficient and productive AAV development pipeline, you save your company time and money, and this helps get your AAV therapeutic approved.
To optimize AAV formulation in therapeutic development, take note of which buffer components at each stage have a negative or positive impact on the yield, aggregation, and stability of your AAV vector prep. That information allows you to improve the buffers used at each stage of the workflow — and even further guide your team through optimization of other production steps.
While it’ll take time to do the optimization work at the outset, your workflow and product will be better, and you will get your AAV to the clinic and regulatory approval faster.