Top Industrialization Challenges of Gene Therapy Manufacturing (Part 2)

July 15, 2019

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(Part 2 of 2) 


Welcome back the Top Industrialization Challenges of Gene Therapy Manufacturing (Part 2). In this blog, we will continue to explore some of the most significant manufacturing challenges in more detail. Missed part 1? View here


Adverse Events Post-Treatment


The challenges of gene therapy commercialization are not just limited to product development and manufacturing. Adverse events that may occur in patients post-treatment must also be considered and prevented. Although several gene therapies have been approved and adopted, patient death associated with these revolutionary inventions have occurred. Cytokine release syndrome,  neurological toxicity and anaphylaxis are adverse events that have been associated with gene-modified cell therapies. The critical stakeholders driving these novel treatments, including the drug company’s researchers, engineers and product development scientists, doctors, and patients must be mindful of potential pitfalls and they continue to implement strategies to mitigate the risks associated with these treatments.



Analytical Methods Used in Vector Manufacturing


Many of the well-characterized assays used to assess quality and safety of traditional biologic medicine products are not well-suited for use with gene therapies. Some of the early stage academic research-based assays do not appear to provide rigorous assessment of the new products because they are lengthy, cumbersome, expensive and non-cGMP compliant.


One of the most critical raw materials in the gene therapy supply chain is the vector used to introduce the therapeutic gene of interest into the patient. The complex nature of viral vectors poses a large challenge for the characterization and quality control testing methods. Many new methods need to be developed and refined in the coming years. The key in developing large scale viral vector is having accurate and reproducible analytical tools to monitor critical quality attributes (CQAs) of consistent efficacious product. 





Globalization of gene therapy and widespread distribution of treatments will provide another challenge for industrialization. Most approved commercial gene therapy products are currently only available in a small number of countries and regions, with very few adopted globally. No multi- agency regulatory clearances have yet been negotiated to allow for initiation of pivotal clinical trials on a global scale. The lack of cohesiveness surrounding many critical activities, including logistics of administration of drugs to patients, import/export regulations across borders, reimbursement policies of each nation, regulatory approvals, market variability and differences in clinical adoption has prevented global gene therapy products.





In general, the typical drug life cycle begins in research laboratories of academic institutions and small and large drug development companies. Scientists, doctors and engineers seek to identify the underlying cause of a disease state and subsequently search for potential treatments that correct the disorder. Once a potential therapy is identified, the drug candidate is transitioned into clinical trials. Currently, for a variety of reasons, many gene and cell therapies move into phase I clinical trials without significant optimization of production methods. Therefore, processes used to produce product for these early phase trials are rarely robust enough to generate quantities of the drug product to treat entire patient populations in a cost-effective manner. When promising results are obtained in early phase clinical trials, the sponsors of the trial typically begin to perform process optimization and begin to increase utilization of quality systems that comply with regulatory requirements. The vision is to generate a cost-effective, industrialized, manufacturing process that will generate safe products at yields which are adequate to not only treat entire patient populations but also to do so in a manner that allows for recoupment of developmental costs and leads to profit that can be used for future drug development.


Every stage of the product life cycle requires significant investment from various sources and the financial commitment is substantial. The cost-drug development for standard biologics has been well documented. The estimated to cost to bring newly-approved compounds to market is $1395 million dollars (2013 dollars)2. This burden of drug development is taken on by governments, private investors, entrepreneurs, private foundations, small biotech companies and large pharmaceutical companies. The funding entity involved is loosely related to the developmental stages where governments of developed countries and private foundations invest heavily in basic research and early clinical trials. These stages are also highly funded by biotech and large pharmaceutical companies2. Risk is inherent throughout the entire process because only approximately 14% of the drugs which enter clinical trials become approved and commercially available for treatment of patients4. If new revolutionary treatments are to continue to move us into the next generation of medicine, commitment to fund the overall process from all parties is required.  


In summary, the challenges associated with gene therapy manufacturing and the journey to industrialization are significant. But perhaps the greatest challenge is understanding how to overcome these difficulties. Manufacturers must find a way to successfully produce, supply, and scale-up therapies for gene therapy commercialization. 


The future of gene therapy is exciting. It’s evolving. It’s here to stay.





Learn more in the co-published ebook Key Considerations in Gene Therapy Manufacturing for Commercialization  from the Cell Culture Dish, featuring articles by Dr Clive Glover  and other industry specialists. 





  1. Business Insider. 
  2. JosephA.DiMasia, HenryG.Grabowskib,RonaldW.Hansen Innovation in the pharmaceutical industry: New estimates of R&D costs: Journal of Health Economics 47(2016) pp 20–33
  3. Matthew Herper, The Cost Of Developing Drugs Is Insane. That Paper That Says Otherwise Is Insanely Bad; Forbes Commentary Oct 16, 2017
  4. Chi Heem Wong, Kien Wei Siah, Andrew W. Lo Estimation of clinical trial success rates and related parameters Biostatistics 20 (2019), pp 273-286


♦Kymriah is a trademark of Novartis AG., Luxturna is a trademark of Spark Therapeutics, Inc., Yescarta is a trademark of Kite Pharma, Inc., Zolgensma is a trademark of AveXis Inc.




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