Overcoming 3 Key Plasmid Manufacturing Challenges

February 25, 2026 by Rubin Joshi

Advanced therapeutics are shifting the narrative on historically challenging diseases, offering new, innovative ways to treat patients and change lives. Plasmid DNA is a key driving force behind these new medicines, offering a customizable, easy-to-design and high stability option for therapeutic delivery. Yet for many programs, plasmid DNA can be a critical bottleneck. Supply delays, stability challenges and evolving regulatory requirements can slow promising therapies from reaching the clinic.

For discovery scientists and CMC leads, the challenge lies in balancing speed, quality, and compliance while advancing novel therapies through the pipeline. A phase-appropriate approach means ensuring data are reliable, risks are managed, and regulatory expectations are met without over-investing early.

Why plasmid DNA supply is a hidden bottleneck
Plasmids underpin many advanced therapeutics, from viral vectors to mRNA vaccines. Applying the right grade of plasmid DNA aligned with the stage of development, helps to address three critical challenges:

• Risk mitigation
• Cost optimization
• Timeline delays

By 2019, 14 advanced therapies had received marketing authorization, heralding critical new advancements in medicine. In 2024, this number grew to 32 new advanced therapies on the market. However, of those 32, approximately a quarter were withdrawn. Most withdrawals were due to challenges ranging from reimbursement issues to data-related incongruencies, international pricing challenges, and manufacturing and controls related issues.

This withdrawal rate showcases the dire impact of not thinking ahead. Without adequately considering risk, cost, and manufacturing reliability, the likelihood of a therapy succeeding in the market can be jeopardized.

While initial research may not require cGMP grade plasmid, working with partners that cannot scale to cGMP means that a technology transfer may be required, adding additional time and risk to development. When not considered from the start, the limited capacity of cGMP facilities can create a knock-on effect of additional costs and clinical trial material delays.

Overcoming plasmid challenges

• Forecast early: Engage with CDMO partners well before IND/CTA preparation
• Use phased strategies: Start with high-quality research plasmids for discovery, then plan for GMP-ready plasmids ahead of regulatory submission
• Explore synthetic alternatives: Enzymatic or cell-free systems may accelerate turnaround while meeting quality standards.

Incorporating a phase-appropriate approach for plasmids

• Early phase: Discovery, IND, and Phase 1-2
  To effectively demonstrate feasibility and safety, research grade or high-quality plasmids are sufficient. It is integral that plasmids at this stage are consistent enough to enable reliable safety and efficacy assessments, but full cGMP rigor is not yet required. The validation focus of this phase includes:
  • Accuracy and precision
  • Specificity to distinguish analytes from interferences
  • Linearity across the relevant concentration range
  • Robustness under varied conditions

• Mid-phase: Engineering and Optimization
  To build a bridge toward commercial readiness, and strengthen robustness as trials expand, GMP-like or pre-GMP plasmids are crucial. This phase helps to refine methods and ensure that processes can scale smoothly into pivotal trials. The validation focus of this phase includes:
  • Intermediate precision across days, analysts and instruments
  • Enhance robustness to accommodate a wider range of sample conditions

• Late-phase: Phase 3, BLA/MAA, and Commercial Production
  Achieving full regulatory requirements for product release, stability and long-term supply relies on using cGMP-certified plasmids manufactured under strict regulatory oversight. Here, plasmids serve as a critical quality foundation for commercial success and regulatory approval. The validation focus of this phase includes:
  • Comprehensive validation of all parameters: accuracy, precision, linearity, specificity, range, robustness, detection, and quantification limits.
  • Method transfer to confirm reproducibility across laboratories and sites.

Looking to the future
Innovations in assay validation and plasmid DNA production are reshaping the advanced therapeutics landscape. High-resolution mass spectrometry, next-generation sequencing, and advanced bioinformatics enhance the characterization of complex biologics. Meanwhile, automated and digitalized platforms reduce human error and streamline timelines.

Regulators are also adapting, providing more flexible pathways to approval while maintaining safety standards. These shifts are making phase-appropriate strategies even more critical – they ensure that new technologies integrate seamlessly into established development lifecycles.

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