CSL

What do you envision as the potential impacts of recent advancements in CRO Management on overcoming the hurdles your business encounters in fulfilling its requirements?

Gene therapyhasrevolutionisedthe concept of medication by offering the exciting possibility of curing an underlying disease within a specific patient population. Becausegene therapy products often offer the only hope for a devastating illness, the FDA/EMA tends to grant the expedited regulatory review for such gene therapy products, which has shown an impressive outcome in clinical trials.As a result, Chemical Manufacturing Control (CMC) developmentand validation timeline for gene therapy products is typically compressed in order to support pivotal clinical studiesas well as aggressive regulatory timelines.

It is not uncommon for a gene therapy product developer to outsource manufacturing and/or analytical activities in order to speed up the CMC timelineas well as to establish additional manufacturing capacity by leveraging the commercial-ready GMP facility and Quality Management System (QMS) as well as the state-of-art analytical platforms offered by well-establishedContract Development and Manufacturing Organisation (CDMO) and/or Contract Research Organization (CRO) partners.

Historically, CDMO tends to focus on essential analytics to support rapid in-process testing, compendial methods, and routine product release testing (such as pH, Osmo, appearance, bioburden, endotoxin, process-related residuals, etc.), while subcontracts biosafety testing (such as adventitious virus testing, mycoplasma, sterility, etc.) and product-specific release testing (such as cell-based bioassays, product-specific residuals, etc.)to its CRO partner.

Due to the compressed CMC development/validation timeline prior to market authorisation, a gene therapy product developer would often require additional process characterisationstudies to increase manufacturing process robustness, need additional analytical support to demonstrate product comparability after tech transfer and process improvement, and implement the state-of-art analytical method(s) to fulfil regulatory commitments, even after such product is approved. Therefore, it would be highly desirable for CRO management to build a business relationship with CDMO and for CDMO management to expand its process and analytical development capability either in-house or through a business relationship with CRO.

It is important for Sponsor, CDMO, and CRO to continuouslyimprove collaboration models for increased efficiencies and controlled costsso that gene therapyindustry can maintain its momentumsto achievethe commercial success after product approval. Ultimately, more and more patients could truly benefit from gene therapy products.

"Gene therapy products are exciting new therapeutical modalities with a great potential to cure diseases."

Can you share your experiences from one of the projects that you were recently involved in?

I have shared the challenges facing to my tech transfer project in general to answer the other 4 questions. I hope that you are OK for me not to further elaborate on any specific point, due to confidentiality concern. Thank you for your understanding.

What are some of the challenges in your business that current services are unable to provide an optimal solution?

As mentioned earlier, due to the significantly compressed CMC development and validation timeline in order to accommodate expedited regulatory approval pathway for gene therapy products, sponsorsoften need the tailored process and analytical development capacity and capability at CDMO or simultaneously partnering with CDMO and CRO even after product commercial launch to meet various CMC requirementsduring product life cycle management. Sponsors also need to carefully balance between the benefit by process and/or analytics improvement and the complexity of additional regulatory submission and approvalby worldwide regulatory authorities, which, unfortunately, are not yet fully harmonisedfor gene therapy products. Therefore, it would be highly attractive if the CDMO partner could seamlessly incorporate continuous improvement activities into its standard service offering of cGMP manufacturing. It is well recognised that state-of-the-art technologies and platforms are constantly evolving not only to significantlyincrease process robustnessand drastically reducethe cost of goods (COGs) but also to accurately and precisely measure the critical quality attributes (CQAs) and dramatically increase the understanding of gene therapy product quality. As a result, it would be quite challenging for a typical CDMO to have everything (including technologies, knowledge, and experience) in-house.

A typical partnership between CDMO and CRO is to use CRO as subtractor testing for biosafety testing, such as sterility, adventitious virus agent (AVA), mycoplasma, etc, as well as for more specialised cell-based potency assay testing, in order to support product release. This type of partnership between CDMO and CROwill not be able to support much-needed CMC needs (such as process and analytical improvement, etc.)post-approval for product life cycle management. Even though CDMO has started to add in-house process development capacity and capabilities, specialised analytical support is often missing.

It would be interesting to see how CDMO and CRO could buildadditional alliances, whichnot only mutually benefit its business growth but also fill important service gaps for the gene therapy industry.

Are there any specific warnings or cautionary advice you would give to professionals working in the pharmaceutical industry across various companies?

Gene therapy products are exciting new therapeutical modalities with great potential to cure diseases. Nevertheless, both the process and analytics understanding of gene therapy products are still evolving.The industry as a whole is still learning what would be exact Critical Quality Attributes (CQAs)based on the Quality Target Product Profile (QTPP) of a gene therapy product and how Critical Process Parameters (CPP) precisely control such CQAs.Meanwhile, state-of-the-art analytical and technical platforms are being developed or adapted to evaluate multifaceted attributes (including delivery vehicle and carried payload at protein and nucleic acid level) of a gene therapy product. Once greater details of gene therapy products could be characterised, measured, and quantified, the requirementfor an overall control strategy, as well as the bar for regulatory approval, might be significantly increased. Learned from the trajectory of recombinant protein products, the gene therapy industry is still in its infancy, with uncertainty and challenges to be weathered ahead.

In the realm of biotechnology technology, which trend do you find most exciting, and what elements contribute to making it particularly compelling for you?

Once multi-attributes analytical method(s)together with additional biophysical/biochemical assays can be adapted to the cGMP environment and validated for the QC release method, I would like to imagine that gene therapy products can be directly and adequatelymeasured and evaluated at the protein level for payload delivery efficiency as well as at nucleic acid level for therapeutical protein expression in intended patients based on comprehensiveanalysis of DNA / protein sequencestogether with all modificationsin combination withaccurate quantification and sufficient characterisation of various components in a product (e.g. empty vs partial vs full particles).As a result, cell-based potency assay with greater inherent variability will not be a must-to-have testing on the product release panel and could just be reserved for product development and characterisation, in particular consideringgene therapy products are designed to provide a blueprint for patients to make functional proteins using their own cellular machinery.