Perspectives on quality, compliance, and innovation to accelerate CGT manufacturing

From your experience across clinical and commercial settings, how has the role of the qualified person (QP) evolved in CGT manufacturing, particularly in balancing speed and compliance?

HN: The role of the QP has become increasingly critical in CGT as the field has advanced significantly over the past decade. This evolution has been driven by the unique scientific and logistical challenges of advanced therapies, heightening regulatory expectations, and the growing pressure to balance rapid market access with rigorous compliance.

ATMPs are subject to stringent and continuously evolving regulatory frameworks, such as the European Medicines Agency (EMA) ATMP guidelines and the US FDA regenerative medicine framework. Consequently, QPs must now navigate not only GMP specific to ATMPs, but also issues related to tissue and cell sourcing, gene editing, and viral vector safety. In practice, this means ensuring compliance with both pharmaceutical and biotechnology standards.

The increasing adoption of digital technologies, including electronic batch records, laboratory information management systems (LIMS), and blockchain for traceability, has added further complexity. QPs are responsible for ensuring that these systems are validated, secure, and auditable. Similarly, automation and closed-system robotics offer opportunities to reduce human error; however, they also require QPs to validate new technologies and confirm process robustness, which is particularly critical in CGT, where the process itself defines the product.

Given the rapid pace of innovation, QPs must remain continuously informed about new regulatory guidelines, emerging technologies, and evolving case studies to effectively safeguard both compliance and product quality.

Further to this, what are the biggest challenges QPs currently face when overseeing batch release and ATMP production, and how can this be addressed?

HN: QPs encounter several unique challenges when overseeing the batch release of ATMPs. One of the most critical issues is managing out-of-specification results when ensuring compliance with evolving GMP guidance. Unlike traditional medicines, ATMPs may, under certain circumstances, be released even if they do not fully meet specifications. This is only provided there is a document request from the treating physician and appropriate risk assessment, and mitigation measures are in place prior to final release to the patient.

Batch-to-donor variability presents additional complexity. Variability in donor-derived starting material can significantly influence the final product’s quality and characteristics. This requires product specifications that are both robust and adaptable. The validation of analytical methods for ATMPs is also particularly challenging due to the heterogeneity of starting materials, making it difficult to standardize QC procedures fully and consistently demonstrate method reliability across batches.

Another key challenge is that some ATMPs are released as fresh products, without cryopreservation. These therapies must be administered to patients shortly after production, which imposes strict stability and shelf-life limitations. In such cases, QC testing must be accelerated, and release decisions may need to be made before all final test results are available. This necessitates the use of conditional release strategies, typically based on a risk-based approach to balance the urgency of treatment with the assurance of product quality and patient safety.

In your work with early clinical phase and commercial products, what strategies have proven most effective for accelerating product release without compromising patient safety?

HN: For advanced therapy developers, engaging with a CDMO at the earliest stage is essential. This ensures that QC strategies, analytical methods, and regulatory expectations are aligned well before clinical scale-up. Early dialogue supports an established QC framework that is fully compliant with regulatory standards and reduces delays later in development.

Accelerating the release of ATMPs while safeguarding patient safety remains a critical challenge, but several strategies have proven effective. The adoption of digital tools, such as manufacturing execution systems (MES) and LIMS, enables real-time monitoring, ensures data integrity, and supports faster batch release decisions.

Another important area is the early development and validation of analytical methods, particularly potency assays. Establishing potency assays early in the process prevents bottlenecks during clinical and commercial phases. Increasingly, multiplex analytical methods are being implemented to shorten testing timelines and reduce sample volumes. For example, the Bio-Techne Ella platform offers a high-throughput alternative to traditional ELISA, while the Charles River Endosafe accelerates endotoxin testing. These innovations contribute significantly to reducing the overall timeframe required before drug product release, without compromising safety or quality.

Can you share how cross-function collaboration between manufacturing, QA, and regulatory teams supports rapid yet compliant product release?

HN: Cross-functional collaboration between manufacturing, QA, and regulatory teams is essential to achieving both speed and compliance in the release of ATMPs. Each function contributes distinct yet complementary expertise that, when integrated, accelerates release timelines without compromising quality or regulatory adherence.

For manufacturing teams, real-time communications with QA are critical to immediately address deviations and unexpected results. Close collaboration with regulatory teams ensures that process optimization or changes are implemented without compromising compliance.

For QA teams, early involvement in manufacturing planning helps align quality requirements and testing strategies from the outset. Rapid review of batch records and test data, combined with timely feedback to manufacturing, enables swift resolution of issues and deviations. In addition, QA works with regulatory colleagues to conduct risk assessments that prioritize critical attributes and mitigate potential compliance risks.

For regulatory teams, proactive engagement with both manufacturing and QA is key. This includes interpreting evolving regulatory expectations, guiding process design, and streamlining documentation to align manufacturing outputs with regulatory submission requirements. Regulatory teams also play a central role in establishing and supporting change control processes to ensure that any updates to the manufacturing or quality system remain compliant.

Collectively, this triad of collaboration fosters an integrated approach that enables timely product release while safeguarding patient safety and regulatory compliance.

What innovations or tools have you seen reduce turnaround times for ATMPs while also ensuring robust safety data?

HN: One of the most impactful innovations has been the implementation of MES solutions specifically designed to track and document the transformation of raw materials into finished drug products in real time. For ATMPs, MES platforms provide end-to-end visibility and traceability of manufacturing processes, which is essential for ensuring both quality and safety. Automated data capture of critical quality attributes and process parameters reduces manual error and accelerates quality assurance review for batch release. Furthermore, integration with enterprise resource planning and process control systems facilitates seamless information flow and supports compliance with regulatory requirements.

At CELLforCURE by Seqens, we have chosen to implement Körber PAS-X MES 3.3 as a cornerstone of our digitalization strategy for manufacturing traceability and documentation. PAS-X MES is being deployed as a standard, out-of-the-box SaaS solution. Modern cloud-based MES platforms offer scalability, flexibility, and improved access to data across multiple sites, which is an especially valuable feature for ATMPs, given their complex, patient-specific workflows.

Another important innovation at CELLforCURE has been the establishment of internal QC laboratories. By internalizing >90% of QC activities, we can maximize responsiveness, ensure robust tracability of results, and strengthen the verification of safety, identity, and potency. This organizational model supports both rapid turnaround times and the generation of reliable safety data, which are critical requirements for ATMPs.

As manufacturing scales up, how can environmental monitoring systems be optimized to ensure ongoing compliance without becoming a bottleneck?

HN: At CELLforCURE, we have implemented the Growth Direct^® System from Rapid Micro Biosystems to manage environmental monitoring (EM) samples from our GMP facility, including in-process monitoring. This system, based on non-destructive microbial detection technology, enables fully automated incubation, detection, and enumeration of samples, significantly streamlining EM workflows.

The Growth Direct System detects the cellular autofluorescence of growing microcolonies. When illuminated with blue light, cells fluoresce in the yellow-green range, with oxidized flavin acting as a key fluorophore. This system distinguishes microbial colonies from non-biological fluorescent particles by superimposing multiple sequential images and subtracting static fluorescence signals that do not increase in size. Because the blue-light illumination is non-destructive, colonies can subsequently be identified using standard microbiological techniques.

Internal validation studies at CELLforCURE demonstrated that a final readout can be obtained after 56 hours of incubation, compared with a minimum of 120 hours using conventional incubation methods. This reduction in time has drastically accelerated EM sample management, preventing monitoring from becoming a bottleneck while ensuring compliance and maintaining high microbiological quality standards.

Looking ahead, what do you think will be the most critical changes or innovations needed in CGT manufacturing to ensure faster, safer, and more scalable delivery of advanced therapies to patients?

HN: CGT manufacturing is at a pivotal stage, with the potential to transform medicine, but still facing major challenges in scalability, cost, and speed. Several critical innovations will be necessary to accelerate delivery while maintaining safety and quality.

First, automation and closed systems will be fundamental. Fully automated, closed platforms for cell culture, gene editing, and cryopreservation can reduce contamination risk, improve reproducibility, and accelerate production timelines. Advances in QC technologies, particularly miniaturized and rapid-testing platforms, are also becoming increasingly important. Tools such as Ella, BioFire Mycoplasma, and Endosafe illustrate how innovative technologies can shorten release timelines while reducing manual steps, reagent consumption, and associated costs.

Second, the standardization of protocols will be crucial. Standardized methods for different cell therapy types, such as CAR-T therapies using lentiviral vectors, would facilitate faster deployment and simplify technology transfer between facilities. Initiatives such as T2EVOLVE, part of the European Union Innovative Medicine Initiative (IMI), are already advancing the standardization and acceleration of development, manufacturing, and QC for CAR-T cell therapies.

Third, regulatory evolution will play a defining role. In May 2025, the EMA released a concept paper proposing revisions to Part IV of the EudraLex Volume 4 guidelines on GMP for ATMPs. The aim is to align ATMP-specific GMP with the updated Annex I and to integrate recent advances in manufacturing technologies and quality management systems. Such regulatory updates are essential for Europe to remain competitive in the global ATMP landscape.

Finally, scale-up and product comparability remain central challenges. As ATMP manufacturing expands, ensuring product comparability after process changes is particularly complex. Regulatory authorities in the US (FDA), Europe (EMA), and Japan (MHLW) have each issued guidance addressing this issue. Sponsors are strongly advised to engage proactively with regulators, especially when introducing high-risk process changes, to avoid clinical holds or delays in approval due to failed comparability assessments.

Overall, the integration of automation, standardized protocols, evolving regulatory frameworks, and robust scale-up strategies will be critical to ensuring that advanced therapies are delivered to patients more rapidly, safely, and at greater scale.

Biography

Hélène Negre has developed her expertise in cell and gene therapy bioproduction with over 20 years of experience in ATMPs. Initially, she worked at Pitié-Salpêtrière Hospital in the Biotherapy department. In 2014, she joined Dana Farber Cancer Institute, Boston, and worked 5 years as Technical Director of the Novel Cell Therapy team in the Cell Manipulation Core Facility with Professor Ritz. From 2019 to 2023, she worked at Servier as Scientific Director—Biotechnology and Bioproduction and EFPIA project leader for the IMI program T2Evolve on engineered T cells. In 2024, she joined CELLforCURE by Seqens as Pharmaceutical Affairs Director.

Affiliation

Hélène Negre PharmD PhD, Pharmaceutical Affairs Director, CELLforCURE by Seqens, Les Ulis, France

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: The author is an employee of CELLforCURE by Seqens and was an industrial project leader for T2Evolve IMI consortium from 2020 to 2023.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & Copyright Information

Copyright: Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2025 CELLforCURE by Seqens. Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Interview conducted: Aug 29, 2025.

Revised manuscript received: Sep 11, 2025.

Publication date: Sep 19, 2025.