Avoiding Costly And Time-Consuming Mistakes In Gene Therapy Process Development

The application for approval of Zolgensma, a gene therapy for spinal muscular atrophy (SMA) was granted Fast Track Breakthrough Therapy, Priority Review and Orphan Drug designations by the US FDA. Affecting about 1 in every 11,000 births, SMA is a genetic neuromuscular disease and the leading genetic cause of death in infants and toddlers. Many gene therapies are in development for similar diseases – those which strike early in life, significantly impact the quality and length of life and affect small patient populations. These factors combine to create a sense of urgency for both developers of these therapies and patients who anxiously monitor news from clinical trials and eagerly await access once approval is granted.

Our collective responsibility as participants in the gene therapy industry is to discover, develop and bring these innovative therapeutics to patients in need with a similar sense of urgency, effectively balanced, of course, with quality and safety. Success in the evolving and highly competitive gene therapy space, however, requires navigating many uncertainties related to process development and manufacturing of adeno-associated virus (AAV) and lentivirus vectors, especially when development and manufacturing teams are operating with compressed timelines.

While our confidence and familiarity in working with gene therapies continues to grow, the field is still its infancy. Consider monoclonal antibodies — the first was approved in 1986 — and now the industry has more than thirty years of experience with this modality, including robust, templated approaches for manufacturing. While we can apply some best practices and basic principles from our experience with monoclonal antibodies, unique challenges exist with gene therapies, one of which is the intense pressure for rapid development. Many gene therapies receive breakthrough designation from regulatory authorities This designation necessarily accelerates timelines; it is estimated that non-breakthrough therapy products are approved within 7.4 years from submission of the IND compared to 5.2 years for breakthrough therapy products.

A number of strategies can be leveraged to help facilitate and improve process development so that product yield, quality and patient safety are successfully balanced and progress against critical milestones is maintained at an accelerated pace.

Trust Your Quality System

A fundamental challenge when developing and manufacturing gene therapies is that we are still learning about the biology and the mechanisms of action. As more gene therapies are progressing through clinical trials and being commercialized, our understanding is certainly growing, but there is always more to learn. While regulatory guidance is being drafted, companies must determine their own approach and trust their quality systems and the specifications set for clinical trials in the face of uncertainty.

An example of how our understanding continues to evolve centers on empty capsids and their presence during viral vector manufacturing and what role, if any, do they serve. While a gene therapy process should ideally manufacture complete viruses (capsids containing genetic material) empty capsids, which lack the vector genome and therefore are unable to provide a therapeutic benefit, are also generated. Some data show that empty capsids can actually enhance gene transfer by mitigating the problem of preexisting humoral immunity to AAV. A different perspective is that the empty capsids are an impurity. A conclusive answer to the question of whether empty capsids are beneficial, or an impurity remains to be determined. Differing viewpoints can lead to uncertainty as to what the product is — only full capsids or a mix of full, empty or perhaps even semi-packaged DNA; in this case a robust quality system and clear specifications for the product are essential. While no guidance exists on this topic, internal quality and analytics can be relied upon while newer assays are being developed.

Quality systems are also essential as the qualification of raw materials can be more challenging than those used in mAb processes. For example, the plasmids used in upstream processes use an E. coli-based method and should be subjected to heightened scrutiny.

Take Time for Process Development

For gene therapies, time to the clinic is essential. Patients have unmet needs and companies must compete for small numbers of patients to power their clinical trials. And while speed is a critical success factor, so too is quality, which can never be compromised. Late stage process validation, understanding critical quality attributes and the control strategy are all extremely important.

With intense time pressure to deliver new gene therapies, the desire to rush through process development has the potential to become the new norm. Moving too rapidly through process development can lead to compromises on product yield as engineering runs may not be completed at manufacturing scale or processes aren’t fully optimized before moving into manufacturing. When new insights into the process are revealed at scale-up, it can mean a return to the lab, delaying timelines.

In the face of compressed timelines, it might be attractive to apply the upstream conditions used for program “A” to program “B” – leveraging what had already worked and extrapolating data to accelerate material to the downstream team. The same approach may be used in downstream – leveraging the same approach from project to project and then tackling any issues as they arise. Without the proper time and resources, however, it can certainly be challenging to optimize conditions. Ultimately, the long-term goal is to establish a platform approach for gene therapy development in which the gene of interest is changed but everything else remains the same. Until that day comes, we have to exercise caution and give process development the time needed to optimize conditions, enabling a proper balance of high yield and product quality.

Manufacturing as the Customer of PD 

It is easy to view the patient as the external customer of manufacturing. Along the same lines, it is beneficial for the manufacturing team to be viewed as the internal customer of process development, whether they are an external CMO or in-house team, as this can help ensure a seamless handoff and minimize delays. It is also the responsibility of the process development team to keep their manufacturing counterparts informed in terms of what to expect regarding technology transfer by engaging with them proactively, early and often. An example of this would be when the process development team makes significant changes or explores new technologies to improve workflows. Timely and transparent communication with the manufacturing team informing them of possible changes which impact their activities; this provides manufacturing with the time needed to purchase and stock materials, avoiding any delays in vendor and raw materials qualification.

Creating Synergy Across Departments

In addition to maintaining proactive and regular communication with manufacturing, it is also important for the process development team to maintain close ties with assay development and formulation teams. While these groups operate with their own timelines, critical junctures where the different groups must come together should be identified to ensure close alignment on mission critical activities. For example, process development must dedicate resources to provide the analytical team with material in a timely manner so that robust analytics and orthogonal assays can be implemented for key drug substance attributes such as potency, infectivity, empty/full ratio, host cell protein, DNA and residuals. Escalation strategies should also be defined and agreed upon by these departments. If timelines are tight or at risk of being missed, it is important to proactively raise the issue, alerting key stakeholders and positioning teams to more effectively resolve the issue.


While patients anxiously wait for new therapeutic options, gene therapy companies diligently advance their clinical candidates through development and manufacturing. All stakeholders understand that time is of the essence as well as the importance of ensuring quality and safety. The strategies described in this article can help better align internal teams and streamline workflows so that time-consuming and costly mistakes can be avoided in process development, laying the foundation for high quality, safe medications to reach the market in a timely manner.

  1. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease
  2. http://www.smafoundation.org/about-sma/
  3. https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/3/analysis-breakthrough-therapies-cut-development-timeline-by-two-years
  4. Hoffman BE., and Herzog RW. Covert warfare against the immune system: decoy capsids, stealth genomes, and suppressors. Mol Ther. 2013;21:1648–1650.

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Nice Insight, established in 2010, is the research division of That’s Nice, A Science Agency, providing data and analysis from proprietary annual surveys, custom primary qualitative and quantitative research as well as extensive secondary research. Current annual surveys include The Nice Insight Contract Development & Manufacturing (CDMO/CMO), Survey The Nice Insight Contract Research - Preclinical and Clinical (CRO) Survey, The Nice Insight Pharmaceutical Equipment Survey, and The Nice Insight Pharmaceutical Excipients Survey.