Validating Candel's BLA-Ready Analytics Profile

A conversation with Seshu Tyagarajan of Candel Therapeutics and Life Science Connect's Jon O'Connell

In Part 1 of this interview, Candel leadership discussed their CDMO partnership strategy, tech transfer experience, and supply chain readiness ahead of a planned 2026 BLA submission.

The company's lead candidate, aglatimagene besadenovec (CAN-2409), treats localized intermediate- to high-risk prostate cancer with an engineered adenovirus/prodrug combination. In this second part, they answered my questions on the analytical and validation work underpinning that filing, including in-house assay development, potency testing, cell line integrity, and the path to process validation.

Candel’s been open about its desire to keep analytics in-house in the name of flexibility. How does that make you more nimble?

Seshu Tyagarajan: Having in-house analytical capabilities lends itself to a lot of advantages of speed, control, expedited testing, and not having to wait in the queue of contract testing labs either for release testing, stability testing, or while conducting investigations. However, bringing assays in-house means more responsibility and we must ensure that we execute efficiently. This capability does make us nimble and well prepared to quickly accommodate shifting priorities. Currently, the compendial assays are with the CROs. The assays that we have to specifically develop for our platform are what we brought in-house. We may also use a CRO for some of the other product-specific assays.

This arrangement provides meaningful operational control. Because the workforce is Candel’s own, testing can be prioritized, expedited, or scaled as needed without competing with other clients for queue access. Critically, when deviations occur, the analytical and quality control (QC) teams can rapidly work together to resolve investigations directly, rather than navigating a CRO’s internal policies and procedures, which can add significant time to any inquiry. Having encountered that dynamic firsthand in prior roles, the decision to build in-house QC capability was deliberate, much needed, and something the program and the company will benefit from.

Having some of the critical assays in-house not only allows for rapid, responsive testing, it also enables direct control over any expediting that may be needed. The QC laboratory is now a significant build-out, but one that is already demonstrating value. Given our tight BLA timelines, having the flexibility and agility will be absolutely essential and critical to deliver on time.

Are you using a matrix-based assay for potency? With increased FDA focus on potency, describe how you're confirming viral entry and valacyclovir conversion.

Seshu Tyagarajan: Potency is always a matrix-based approach, where one needs to look at the strength, titer, functionality, and the mechanism of action of the product.

Specifically, our main functional assay, a cytotoxicity-based relative potency assay, directly mimics the mechanism of action of aglatimagene in patients. It measures the ability of aglatimagene to kill tumor cells in the presence and absence of the prodrug, thereby directly confirming both viral entry and valacyclovir conversion within a single assay. This is relatively rare in cell and gene therapy, where mechanism of action is often too complex to model faithfully in vitro. The correlation between in vitro assay results and clinical activity has been strong, providing confidence that the potency readout is a reliable indicator of product performance in patients.

Potency has been a major focus for the FDA for the past decade and a half, and cell and gene therapy programs are under particular scrutiny to demonstrate the right kind of potency and orthogonal assays. The full potency matrix for aglatimagene spans strength, functional titer, gene expression, and mechanism of action, all implemented and qualified for this program.

How are you managing phenotypic drift in your producer cell lines so infectivity matches Phase 3 material in every batch?

Seshu Tyagarajan: Preventing phenotypic drift begins at the cell bank level. Working cell banks (WCBs) are derived directly from the master cell bank (MCB), ensuring continuity of cell lineage throughout the life cycle of production. The cell banks are characterized as per ICH guidelines to confirm that the characteristics inherent to the MCB are maintained in the WCB. MCB, WCBs, and viral banks undergo comprehensive release testing to ensure that the banks are safe and genetically stable. Additionally, both cell banks and viral banks are placed on formal stability plans to ensure they can support commercial production while maintaining consistent aglatimagene quality over time. Finally, end of production testing is conducted on WCBs to ensure that cells in passage can support the production of aglatimagene consistent with the release characteristics.

These steps are taken to ensure that the most critical starting materials, which are the working cell banks and working viral banks, can support aglatimagene production. However, at the commercial level we have a significant responsibility to show that the material produced by the commercial process is comparable to material used in the Phase 3 trial. We test this using a comprehensive analytical comparability protocol that comprises analytical panels that include release testing and extended characterization testing. We have full alignment with the FDA on how to conduct the analytical comparability for our product.

A successful comparability study will result in demonstrating that the commercial process and clinical process are comparable. This will be executed by a prospective analytical comparability protocol, followed by a comparability study and a report that analyzes the data against the protocol acceptance criteria. Additionally, we have to show that the commercial process is not only comparable to the clinical process, but the commercial process is validated. This is achieved by setting prospective validation criteria in a validation protocol. Testing is conducted post execution to determine if the batches met the validation criteria set forth in the protocol. Upon successful evaluation, the process is considered validated. Together with a successful comparability report and a successful validation report, we will be able to say that aglatimagene produced from the commercial process is comparable to the product from the clinical process and that the manufacturing process is validated to support commercial production.

A successful comparability study, combined with comprehensive testing on the cell banks and viral banks, ensures that the infectivity of the commercial process is similar to the clinical Phase 3 process. The most important thing we have to demonstrate is that the new product is as efficacious and as safe as the one that was used in Phase 3. That’s a primary goal that we have for the CMC program.

Do your RMAT and Fast Track designations open the door for concurrent validation? If so, how are you mitigating risk of a complete response letter (CRL) if a late-stage validation run indicates shortcomings?

Seshu Tyagarajan: With Regenerative Medicine Advanced Therapy (RMAT) and FDA Fast Track designations, Candel has enhanced access to FDA dialogue, and that benefit is being actively used throughout the CMC program. On the specific question of concurrent validation, we decided to follow a traditional validation strategy rather than concurrent validation, and that decision was deliberate. In fall 2025, Candel aligned with FDA on the traditional approach. Switching strategies at this stage would require FDA realignment, and with a December BLA filing planned, there is simply insufficient time to do that. Furthermore, beyond the U.S. filing, this program is also designed to meet global regulatory standards, where the traditional validation approach will be expected.

From a CMC perspective, we have de-risked the program to the best of our abilities. We have strategically aligned with the agency on all the major pillars and we are now looking to execute the validation studies. Based on the consistency of the data we’ve received so far, we have very high confidence that the validation is going to be successful. But after executing the validation studies, in case there are areas that need further discussion with FDA, we will do so in a staged manner. We will assess the data and evaluate the shortcomings, if any, present a scientific justification where possible to the agency, and seek alignment. For now, we are applying the traditional validation plan to the program. Our contract manufacturer plans to conduct process validation in Q2 2026 to potentially enable filing of a BLA in Q4 2026.

What have been the most difficult steps to qualify in your adenovirus manufacturing process? Do these steps hobble the prospect of a true plug-and-play platform?

Seshu Tyagarajan: To start, it’s a standard upstream cell culture process and a platform downstream purification process that yields a drug product in a simple formulation. Overall, it’s been a relatively straightforward process to scale up and manufacture.

Now, have there been steps that were challenging? Absolutely. There were a couple of bioreactor steps that needed slight modification to ensure cells were at the right stage for infection to maximize yield and reduce impurities. During the downstream development, I mentioned previously that we had one specific area, namely the first tangential flow filtration (TFF) step, that was a hurdle. However, I am happy to say they have all been addressed and the process is performing as expected.

The next step for this process post-launch will be to assess the next scale-up exercise. What do we need, and by when, to meet commercial demand, and is it scale out or scale up? Will there be additional hurdles as we scale up to the next level? Possibly, but we will cross that bridge when we get to it; as of now, the manufacturing process is running very well.

Regarding the plug-and-play question, I didn’t think about it until you asked, but the answer is definitely yes. What if the next gene comes along? Will I be able to apply the principles that I have today? Absolutely. We had the clinical process, we took that, we transferred it to Millipore Sigma, and it’s working very well.

Previously, this clinical process was run on another program to produce a different adenovirus product, and the cross-program learnings have been significant. We will need to tweak this process to suit the next gene of interest, but we can see a path forward on how to establish it. Once validation is complete and several commercial batches have been produced, adapting this platform to a next-generation gene insert is expected to be highly feasible. We will align with regulatory agencies on the work package needed to designate it as a genuine platform. The adenovirus manufacturing infrastructure Candel has built represents a genuine platform asset, not just a single-program capability.

About The Experts:

Seshu Tyagarajan, Ph.D., RAC, is chief technical and development officer at Candel Therapeutics. Previously, she was executive director and global head of late-stage CGT-CMC Strategy at Novartis. She has led successful BLA campaigns, including a key role in submitting the BLA for Kymriah. Previous roles include posts at Merck, Roche, Biogen, and ImClone, an Eli Lilly and Company subsidiary. She received her Ph.D. in chemical and biochemical engineering from Rutgers, an M.S. in bioengineering from Purdue University and an M.Sc. in biotechnology from University of Pune, India.