Overcoming Quality Control Challenges in Viral Vector Development

Despite marketplace volatility, industry investment and regulatory buy-in have pushed gene therapies to the forefront of pharmaceutical innovation. Heightened interest in this category is reflected in the more than 450 clinical trials that are currently underway to investigate gene therapy products, according to the Alliance for Regenerative Medicine.¹ As the gene therapy sector becomes more competitive, drug developers face increasing pressure to expedite clinical development and get products to market as quickly as possible. Many of their efforts focus on accelerating the development of viral vectors, which serve as vehicles to deliver therapeutic genetic material into cells. Of these vectors, adeno-associated virus (AAV) vectors remain the most popular, while others such as lentivirus and oncolytic viruses are also gaining traction.²

Viral vector manufacturing can pose quality control challenges such as ensuring product purity and potency, mitigating contamination risks, and scaling up production. These issues can be daunting for small and emerging drug developers that lack the requisite in-house expertise and developmental capacity to manage them efficiently. The fallout from these challenges becomes more acute amid evolving regulatory requirements for robust quality management systems, trained personnel, suitable facilities, validated processes, and meticulous documentation.

The quality control-related challenges of viral vector process development and manufacturing make partnering with a contract development and manufacturing organization (CDMO) a prudent option for many drug developers. With their deep expertise in current Good Manufacturing Practices (cGMP), process development (PD), and manufacturing, science, and technology (MSAT), CDMOs can map out a viral vector’s development journey, accounting for each milestone with checkpoints to help ensure compliance with all required quality standards. In doing so, CDMOs can help their drug development partners overcome quality control issues and bring therapies to market efficiently.

Addressing purity and potency challenges

Achieving and verifying high purity and potency in viral vectors is a complex task, given the diversity and variability of vector types. Impurities (e.g., residual levels of proteins, nucleic acids, or other components present in purified AAV vectors that are not the desired product) or suboptimal potency can compromise therapeutic efficacy and jeopardize regulatory approval.³ Robust, comprehensive analytical assays are therefore essential to demonstrating vector compatibility and product stability. Examples include flow cytometry-based assays, which quantify transduction efficiency and transgene expression in target cells, and digital droplet PCR, which provides highly sensitive and accurate viral genome titers.⁴

However, the lack of standardized assays across the industry complicates product characterization and release. The solution lies in developing and validating comprehensive analytical methods that are tailored to the specific critical quality attributes—identity, potency, purity, safety, and stability—of each product.⁵ Such methods are often used in process characterization studies, process performance qualification (PPQ), and final product release testing to ensure that every batch meets stringent quality standards.

CDMOs help their partners build strong chemistry, manufacturing, and controls (CMC) systems that address purity and potency challenges by integrating analytical development with process optimization and conducting comparability studies to ensure product quality, safety, and efficacy following change(s) in the manufacturing process.⁶ Such integration can be facilitated by deploying dedicated analytical teams that work alongside process development and MSAT experts to create and optimize functional and potency assays, enabling identification of process inefficiencies and their solutions. Depending on the variability of the process, multiple PPQ runs are executed just prior to commercialization to demonstrate that the process is validated and robust. The PPQ runs typically culminate with the preparation of an extensive validation report that becomes a cornerstone of the drug developer’s biologic license application (BLA)—a key step toward product launch and commercialization.

Preventing contamination

Cross-product contamination is a critical concern in viral vector manufacturing, especially in facilities that handle multiple modalities. Contamination can result in costly batch failures and lengthy investigations, hampering speed-to-market. To mitigate the risks of contamination, manufacturing facilities and processes must be designed and operated according to strict aseptic and GMP guidelines. Such precautions include the use of closed processing systems, appropriate cross-contamination strategies in-place, comprehensive documentation, and rigorous traceability throughout the manufacturing lifecycle.

CDMOs are proficient in addressing these challenges through systematic solutions. Many operate purpose-built facilities for cell and gene therapy manufacturing, featuring modular cleanrooms, single-use systems, and closed processing environments. These facilities are supported by MSAT and operations teams that work to ensure all procedures are meticulously documented and recorded while complying with cGMP standards. Aseptic process simulations are regularly conducted to confirm the effectiveness of contamination controls, supporting both internal quality assurance and external regulatory inspections.

Enhancing scalability

Scaling up viral vector production from lab-scale to commercial quantities is a significant challenge, as it requires maintaining consistent quality and yields across all batches. When processes are not robustly developed, manufacturers may experience variable product quality and yields, as well as failed batches, which can lead to clinical and commercial delays.

To overcome these risks, it is essential to implement structured process development and scale-up strategies, including manufacturability assessments and identifying potential gaps at each stage. CDMOs address these challenges by having MSAT and process development teams collaborate with drug developers to design scalable, reproducible processes with flexible cGMP capacity. Such processes can be especially valuable in the early stages of drug development, when innovations such as high-yield adapted cell lines, standardized CMC methods, and quality assays can optimize downstream production and accelerate the overall development program.

Ensuring a sustainable future for viral vector manufacturing

As demand for gene therapies increases, the pharmaceutical industry must continue addressing quality control challenges associated with viral vector manufacturing. In particular, the need for comprehensive process standardization and robust potency assays is expected to remain a rate-limiting factor. To navigate these issues, CDMOs are already investing in manufacturing platforms and analytics-powered digital tools for process modeling and optimization. Integrating automated control systems into these platforms has been key to increasing process efficiency and lowering the cost of goods.

Through offerings such as ready-to-use proprietary cell lines and plasmids, pre-defined manufacturing unit operations, pre-qualified assays, and streamlined technology transfer documentation, CDMOs provide a global quality and regulatory infrastructure to de-risk gene therapy products’ path to commercialization. Collaborations between CDMOs and drug developers can also facilitate the development of future technologies and the improvement of current platforms. Drug developers that establish strategic partnerships with CDMOs will thus play a pivotal role in enabling the safe and efficient delivery of the next generation of gene therapies to patients in need.

References

1. Alliance for Regenerative Medicine. Clinical Trials. Available at: https://alliancerm.org/wp-content/uploads/2025/11/ARM-Data-Q3-2025.pdf. Accessed December 3, 2025.

2. Zhao Z, Anselmo AC, Mitragotri S. Viral vector-based gene therapies in the clinic. Bioeng Transl Med. 2021;7(1):e10258.

3. Wright JF. Product-related impurities in clinical-grade recombinant AAV vectors: characterization and risk assessment. Biomedicines. 2014;2:80-97.

4. Wang W, Zheng C, Ding N. Strategy and application of viral potency assays in cell and gene therapy. Methods Mol Virol. 2025;2940:215-240.

5. Mitchell DA. Analytical method development for GMP viral vector production: Establishing product appropriate critical quality attributes. Matica Biotechnology Inc., 2023.

6. European Medicines Agency. Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP) – Scientific guideline. 2019. Available at: https://www.ema.europa.eu/en/questions-and-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp-scientific-guideline. Accessed December 17, 2025.

Wenling Dong is Head of Upstream Process Development, Lonza Specialized Modalities