GEN BiotechnologyVol. 2, No. 3 On the MoneyFree AccessUncovering Manufacturing Challenges Behind Cell and Gene TherapyGeulah LivshitsGeulah Livshits*Address correspondence to: Geulah Livshits, Chardan, E-mail Address: glivshits@chardan.comSenior Research Analyst, Chardan.Search for more papers by this authorPublished Online:19 Jun 2023https://doi.org/10.1089/genbio.2023.29102.gliAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Programming human cells for therapeutic function using cell and gene therapy is a rapidly evolving field showing clinical promise to treat diseases such as cancer, Duchenne muscular dystrophy, sickle cell disease, and more. However, manufacturing these therapies requires robust, scalable, and financially viable approaches. In this interview with GEN Biotechnology Senior Editor, Fay Lin, Geulah Livshits tackles key manufacturing facets underlying successful cell and gene therapy production, including supply chain constraints, scalability, financial climate, product purity, and more.Geulah, what are some high level takeaways from your recent Genetic Medicines in Cell Therapy Manufacturing Summit?Livshits: Three to 5 years ago, I would say there was a lot of discussion about the challenges of having limited cell and gene therapy manufacturing capacity—in other words, there were long wait times for manufacturing slots and few options in terms of manufacturing partners. Today, in discussions with companies in the space, there is less of a capacity crunch, particularly in AAV manufacturing as CDMOs have built out capacity for the past few years.There is also less discussion around supply chain constraints compared with the past few years. Recently, there has been more discussion about the financial climate and making manufacturing decisions in the context of potential cash runway constraints faced by some companies.There are other recurring points at our events that focus on manufacturing technology practice. The importance of establishing a robust and scalable process early keeps coming up. Companies talk about ideally going into the clinic with a process that could be used in late-stage studies as well as the commercial scale. Also, establishing potency assays early. These issues mean different things and present unique challenges depending on the modality, whether that is AAV, autologous cell therapy, or other modalities.Another recurring theme is engaging with the U.S. Food and Drug Administration (FDA) and other regulators. We have heard from companies who say that their interactions with the FDA have been useful—they are knowledgeable about the technologies and are able to give more specific suggestions regarding what kind of assays might be needed to show potency or comparability for a particular product. And while, of course, there are guidance documents available, they do leave room for interpretation on a product-by-product basis. We spoke to both companies and key opinion leaders who discussed the benefits of engaging with regulators early and as much as possible to get specific feedback on how to implement in their manufacturing processes.How does the financial climate and increasing CDMO capacity affect companies and their decisions regarding manufacturing?In the current financial climate, companies are coming up against their cash runways. Some have a runway to fund operations with timelines to the end of 2024 or 2025, which may not get them through to late-stage clinical or commercial stages, or even key clinical proof of concept in some cases. Although there have been some exceptions, market conditions for the past year or so constrained companies' ability to raise large amounts of money to extend their cash runways, particularly affecting early-stage companies.Companies starting out now are more cautious about how they are investing their cash early in terms of building out internal manufacturing capabilities. They may choose to build out that capacity later, for example, after achieving clinical proof of concept, in a more data-gated manner. CDMO capacity has played into that as well. As mentioned, CDMO capacity has come online for the past few years, and as CDMOs have also gained experience on various manufacturing processes, there are also more focused CDMOs that aim to work with companies from the earliest stages.In terms of process development through clinical and potentially commercial manufacturing, it is not just capacity. Expertise has also increased. Companies have more optionality regarding how they invest their cash and when they make strategic decisions regarding manufacturing capability. With the current financial climate, we have seen many companies trimming their pipelines, which could affect demand for manufacturing capacity for the next few years as the number of programs may be smaller than what was projected a few years ago.With increased CDMO capacity, what are the remaining advantages of having internal manufacturing?It is certainly not an all-or-nothing decision. There are different modules that can be internal or partnered. Some companies choose to have process or assay development or analytics internally, and then have a partner make the product. An advantage of having internal manufacturing is that it can be faster to implement changes, which is feedback we have heard from a number of companies that have invested in internal manufacturing capabilities: if you do have to make changes and you have a manufacturing partner doing the production, there could be delays associated with needing to find a new manufacturing slot with a partner if you missed your window. Whereas internally, the companies we have spoken to emphasize crosstalk between process development and manufacturing groups such that process development can be implemented fairly quickly.For new programs, there is still quite a bit of know-how that is involved in terms of process development. Even though companies may have a platform—say an AAV or a lentiviral vector—in some cases just swapping the transgene might have implications for manufacturing, and some things might need to be tweaked. Having the capability to do that internally seems to make a difference there. Even if you have internal capabilities, you can still work with the CDMO at various stages—so either doing process development internally and then transferring to a trusted CDMO to make sure things go smoothly. There is also discussion about having additional flex capacity, particularly at the commercial stage. For example, once the process has been locked down, we can then transfer it to partners to meet additional demands, say in different geographies or to support manufacturing for larger indications—for example, systemic AAV dosing where you might need a high amount of vector production.What are the major challenges that companies are dealing with regarding AAV gene therapy manufacturing?There are a number of those! One topic that has been discussed for a while is purity, such as characterization of full-to-empty capsid ratios. There are many approaches to assess that, as well as issues regarding development of potency assays. These can have different issues in vivo versus in vitro. Some of the challenges could include the following: if there is a transgene that is not an enzyme, how do we evaluate the function?Optimization can be a challenge. The process is not fully plug-and-play yet. You can have an AAV capsid and work out a manufacturing and purification process for one transgene, but according to companies at our event, you may need to do further optimization if you want to swap out that transgene for something else. The more times that companies run through this process, the more they learn the rules, so to speak. At some point, it will become increasingly more plug-and-play, or at least the key levers that affect the different process elements will be worked out. But the field is not quite there yet.What are the challenges for cell therapy modalities?The challenges are different depending on whether you are talking about autologous, donor-derived, or pluripotent stem cell-derived therapies. For autologous, one of the common issues is variability in starting materials. Every patient's own material might be slightly different in terms of the number of cells, the quality of the material and getting it shipped to the manufacturing space. There are also issues with maintaining chain of identity and chain of custody to make sure that logistically you give the person's own cells back to them rather than giving someone else's cells, which could be dangerous. There is also scaling—you cannot scale up for autologous cell therapy manufacturing. You have to scale out to develop a product for each person.For donor-derived cell therapies, there is also a degree of starting material variability—you have to show that there is some kind of donor screening to make a reproducible product with every batch, such that product from one donor is consistent with product from another donor, batch to batch. For a pluripotent stem cell-derived therapy, the issues include genome integrity or making sure that there is no residual pluripotent stem cells in the product, which might be a safety concern. It is also important for showing that you produced a functional product. It is less about making an exact copy of a specific cell type, but making sure that you are making the same thing again and again, and that you do not accumulate mutations in genes, such as p53, which could cause cancer.For pluripotent stem cell expansion and differentiation, the processes are pretty complex and the space is still emerging. There are lots of variables that could affect the process. I think more generally, issues with the qualification of materials, making sure that the viral vector, or the other components that are used to make the cells, are appropriately qualified and are produced at a sufficient scale to meet needs.Potency assays are more established for CAR Ts. Companies know to look for a cytotoxic activity. Those are a bit more established as that space is mature, but it becomes more complicated if you have a therapeutic transgene that is not an enzyme that is designed to replace a mutated gene, such as in lentiviral gene therapies. If you have a more complex cell therapy product with the same multiple components in a circuit, you have to make sure that you have evidence of how those things work together. If you have a polyclonal product such as TILs, where the specific targets are not defined, you need additional potency assay development. That is where a discussion with the FDA could help.What are the downsides for a company changing a manufacturing process if they develop something better?In the genetic medicine space, we have seen a lot of programs come out from academic laboratories. Sometimes those programs start with a process that is not scaled for use in the commercial setting. Companies often need to scale up, for example, going from adhesion to suspension culture during a manufacturing process. Or if there is not a robust and reproducible process—for example, if there is a different person doing it—you get a different result if there is a lot of manual open handling steps or if there is not defined critical quality attributes or critical process parameters.So sometimes changes need to be made. The question is whether that change gets made before something goes into the clinic or after, and whether that change might impact a product's safety or activity profile. When you make a change, you can change a critical quality attribute, such as a full empty capsid ratio, for example, which could affect safety. This is something that came up in the recent [FDA Advisory Committee Meeting] briefing documents and the presentation on gene therapy for Duchenne muscular dystrophy that is being looked at right now.The commercial scale process had more empty capsid, which in theory could affect the safety profile because dosing is based on vector genomes, but if you are delivering more capsid material, that is essentially an impurity that comes with the vector that is being delivered. So regulators closely look at process changes to understand the potential implications, and can make a range of recommendations to demonstrate comparability. Depending on the situation and the process, companies can sometimes get away with just doing in vitro comfortability analysis, but they may need to do animal studies or could have to dose more patients in a bridge study to show comparability. That can translate to delays, which we have seen. And it can also obviously cost more as you have to spend more time and money running a trial.How do cell and gene therapy companies see manufacturing evolving in the future?This is another topic that has been in discussion for a while. Issues that come up include automation, implementation of a closed process, and in process analytics, eventually being able to monitor things such as metabolites, and automatically adjust culture conditions in real time, which could reduce variability and cost with fewer hands-on steps. New technologies under discussion are producer cell lines for AAV and enzymatically developed DNA constructs. Programs now in later stage clinical studies are based on manufacturing technologies and decisions from several years ago, but these are some of the technologies that could reduce variability and potentially costs as new programs are going through preclinical studies and approaching the clinic.Some other topics include the increasing use of next-gen sequencing (NGS) to characterize impurities. It is not necessarily something that would change release assays for individual products, but for example, during process development, we can use additional tools to understand what is being made. This is already being looked at, to some extent, with companies using NGS to look at AAV production to go beyond full empty capsid ratios. The AAV manufacturing process can lead to partial genomes being incorporated into capsids, they would not look like empty capsids, but they might not be functional. The focus on full versus partial genomes in AAV manufacturing is increasing. In the cell therapy space, companies are using single-cell analysis techniques to gain a deeper understanding of their product characteristics.And then there are also maturing CDMO capabilities: there are more CDMOs with expertise, some with more focus on specific technologies such as AAV, and more capability to help with the initial process development. The science continues to move as new technologies enter the clinic. Things such as base editing, prime editing, and various RNA medicines will have to figure out assays targeted to some of these emerging technologies as well, for example, techniques optimized to characterize unintended consequences of base editing or prime editing. The science here is emerging but advancing quickly.FiguresReferencesRelatedDetails Volume 2Issue 3Jun 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Geulah Livshits.Uncovering Manufacturing Challenges Behind Cell and Gene Therapy.GEN Biotechnology.Jun 2023.178-180.http://doi.org/10.1089/genbio.2023.29102.gliPublished in Volume: 2 Issue 3: June 19, 2023PDF download
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