How to Achieve Regulatory Approval for Viral Vectors

I am fortunate enough in my role to work with various customers across all stages of the development pipeline for pharmaceuticals, from small-scale research and development, right up to manufacturing campaigns for clinical material and beyond, to commercialization of products. Each step on the pathway to regulatory approval comes with its own considerations and criteria that must be satisfied before being able to progress to the next. Firstly, the product has to be shown to work, and must be able to be sufficiently scaled-up to produce an appropriate number of doses per batch. Secondly, the product must pass through several clinical trial stages in order to demonstrate it is safe and effective. That being said, there are still some key principles with regards to process development that must be adhered to in order to ensure that these products successfully progress through clinical trials into commercialization. Covid-19 has shown us that products can be developed, scaled-up, manufactured, and approved in very short time frames (under exceptional circumstances), but it cannot be expected to be the new normal for every new biologic developed. Underpinning all of this work is the documentation – key to any regulatory submission: Chemistry, Manufacturing, and Controls (CMC).

At any point in time during the process of developing and commercializing a new drug, failure or setbacks can cause significant delays at best, or cancellation of the project at worst. In 2020, no less than 14 gene therapy submissions or study requests have been delayed or openly rejected by regulators due to a lack of CMC documentation. Despite the advances in gene therapies over the last several years, and the increase in the number of products in development and clinical trials year-on-year, the field is very much still in its infancy compared to other biologics in the field, such as monoclonal antibodies and recombinant proteins. We can take learnings from these other therapies and apply it to the field of gene therapy, but as our understanding on how to best manufacture these products (and the technologies available) evolves, so will the regulatory guidance surrounding them. Regulatory expectations towards CMC for gene therapies is still not clear to the industry.

So how do we get a product, which has very little regulatory guidance for CMC documentation, to the market with as few setbacks as possible? At Pall, we have worked to provide an example roadmap to aid customers in developing their regulatory submissions. This uses Quality by Design (QbD) principles, where the rationale is to achieve product quality through process design and prior knowledge as opposed to just relying on final quality testing alone. In the area of gene therapy this can be quite difficult! Unlike other biologics, which often have a wealth of historical information, it is somewhat slim pickings for gene therapy. Given the (relatively) small number of patients who have currently been administered any type of gene therapy product, combined with a lack of freely available information with regards to how process and product related impurities may affect the end user, trying to define a strategy is difficult, to say the least.

In order to understand how changes within a manufacturing process changes the product, it is important to define the Quality Target Product Profile (QTPP). Essentially this is a summary of the quality characteristics of a drug product to ensure quality, safety, and efficacy, taking into account the various product and process related impurities that are generated. QbD bridges product and process knowledge to help define the relevant quality attributes and parameters in the process that impact product quality, and their operating ranges and control options. It must be noted that not every quality attribute identified for a product needs to be considered: Some may pose little risk to the end user whilst others may have a very low likelihood of residing within the product stream by the end of the process. Through a preliminary hazards analysis, the list of quality attributes can be whittled down into a core group of Critical Quality Attributes (CQAs) – properties of the product that should be within an appropriate limit to ensure product quality.

By controlling these CQAs, you are demonstrating that your end product does not significantly vary from batch to batch, ensuring patient safety. To do this, it is necessary to consider how best to control, maintain or eliminate these quality attributes across your process, from initial media filtration all the way down to final sterile filtration. This is where we begin to define what are known as Critical Process Parameters (CPPs) – parameters that can have an impact on a CQA if varied and must be monitored or controlled to ensure product safety. It must be noted that each CQA identified within a process must be addressed in some form by at least one CPP somewhere within the process.

Through a combination of industry data and expert opinion, we do have a somewhat solid idea of how to apply QbD to gene therapy processes. However, this has also highlighted that there are significant gaps in the data that can only be plugged by expert opinion. Within the Upstream Process (USP), the main sources of product-related impurities are heavily impacted by plasmid design, choice of transfection reagent and complexation conditions, the issue here being that we have relatively little knowledge on how changes in these factors can help to modulate impurities. Downstream processing suffers greatly due to the variance in design space from product-to-product as whilst there is a strong indication towards an optimal purification process, it is not as well accepted as being the “gold standard” compared to the well-established mAb processes. Such variance makes it difficult to identify at which step each CQA should be considered for any given gene therapy product, as this will change from process to process, based on the inclusion or exclusion of various technologies. Nevertheless, identification of a suite of suitable analytical techniques to aid the control strategy should help to mitigate variances in technologies between processes.

I am hopeful that as we begin to obtain a better understanding of gene therapy processes as a whole, and learn how to streamline their production through platform processes (A topic I touched on in an earlier blog post), that we will begin to see much more data in this area that can really help to define the regulatory roadmap for these products. Applying QbD early on in drug development is vital to support solid and successful CMC documentation.