Charles River Laboratories International, Inc. (CRL) Earnings Call Transcript & Summary

Hello, and a very warm welcome to the Cell and Gene Therapy Insights Webinar titled Expediting Development and Manufacturing of Advanced Therapies: Critical Starting Materials Case Study. I'm Lauren Coyle, an editor at BioInsights. And joining me today is Andrew Frazer, who will explore common manufacturing and quality standards for eXpDNA and how they align with regulatory guidance. After the presentation, we'll have a live Q&A session. [Operator Instructions]. I'd also like to draw your attention to the Resources tab on the right, where you can find more information on the topics covered today. Now I'd like to introduce our presenter. Dr. Andrew Frazer holds a commercial role as Associate Director of Scientific Solutions within the Charles River CDMO Services with a focus on the plasmid DNA manufacturing platform and service offering. Since graduating with a PhD in biochemistry from Queen's University Belfast, Andrew has attained over 10 years of experience in the design, implementation and tech transfer of processes for the manufacturing of biocatalysts, small molecule APIs and biologics. So without further ado, I'll hand over to Andrew to kick us off with the presentation.

Welcome, everyone and thank you for taking the time to join me for today's webinar where we will be looking at expediting the development and manufacture of advanced therapies. So I'll begin with a brief overview of Charles River and introduce our Cell and Gene Therapy CDMO network and how that's developed over the last few years. We'll then move on to plasmid DNA and how it's used within advanced therapies with a particular focus on its role as a critical starting material. I'll talk about how the regulatory guidance for plasmid starting materials is evolving and how this has helped to shape Charles River's service offerings to support advanced therapy applications with 2 case study examples and some key takeaways. So this slide provides a very high-level overview of Charles River. And you can see that the company also have an extensive history being founded in 1947. More recently and today, the Charles River does have a worldwide presence, over 110 facilities in more than 20 countries. And this has recently been extended through the acquisition of 6 cell and gene therapy companies since 2020 and it has helped to build [indiscernible] portfolio of services for drug development. And we are very proud to have been directly involved with the development of more than 86% of novel FDA-approved drugs in the last 5 years. This included over 900 studies on cell and gene therapy products, including 11 that have been approved by the FDA. Testing still remains at the core of Charles River's business and we have been able to leverage that extensive testing capability to support our global network of CDMO manufacturing sites, with 100% in-house testing for cell and gene therapy programs. Our gene therapy sites shown here in orange include viral vector development, the manufacturing at Rockville in the U.S. with dedicated plasmid DNA production, our Keele and Alderley Park sites in the U.K. Cell therapy manufacturing, showing in blue, is located in Memphis and Baltimore in the U.S. And together, these 5 sites cover all of the major CDMO platforms within advanced therapies. And when we combine them with our research, discovery and safety assessment divisions, they put Charles River in a very strong position for the delivery of advanced therapy products. Following that very brief intro to Charles River and our capabilities, kind of focusing on advanced therapies. I'll now introduce plasmid DNA and the key role that it plays. And we'll look in more details specifically at the role of plasmid DNA as a critical starting material. So to begin, we'll have a very quick look at what's plasmids are and what they do. So a relatively simple representation here but at high level, plasmids are small circular pieces of double-stranded DNA. They replicate independently from wholesale chromosomal DNA and they're naturally found in bacteria for the most part. But certainly within modern science, they're artificially produced and used to store and transfer genetic information. And they do this through the [indiscernible] biology which is shown here on the top right, where we have DNA that is transcribed to RNA and then translated into protein which in the case of advanced therapies has a therapeutic effect. When we look at this in a bit more detail, we can see how plasmids can be used on their own as a direct therapeutic drug products. But importantly and really the focus of our discussion today is that the plasmid also plays a key role as a critical starting material for onward processing for a range of different advanced therapy applications. And this ranges from gene therapies like adeno-associated virus, templates for linearization and messenger RNA production, transient protein expression and also for a wide range of cell therapy applications. And in the case of plasmids that are used for critical starting materials, it is important to recognize that the plasmids alone are not the drug product or the drug substance but they are incorporated structurally into the drug substance or directly determine quality attributes of the drug product. So it is important that we have very high levels of quality control in order to deliver safe and effective treatments to patients. But certainly, from a manufacturing and a quality perspective, it's important to differentiate between plasmid drug substance and plasmid critical starting materials. On this next slide, I will look at some of the key regulatory guidance for plasmid DNA that's used for advanced therapy applications. And we can see that historically, guidance has focused on plasmid DNA that's used as a drug substance, where some common benchmark specifications such as 80% supercoiled were established back in 2007. And these types of specifications have become industry standard for all types of plasmids that are produced within the industry. Then C plasmid is defined as a starting material with guidance for CMC INDs for gene therapy. However, up until relatively recently, it has been challenging to clearly define exact specifications and quality attributes for plasmids. And manufacturers and product developers have typically been taking different approaches and assigning a range specifications and quality standards, particularly when it comes to plasmids that are used as critical starting materials versus plasmid drug substance. That being said, the guidance has definitely improved. And recently, the -- or more recently, the 2021 EMA Q&A document on principles of GMP, definitely provide some clear regulatory guidance on the quality standards for plasmid DNA used for all the major advanced therapies. And we also -- it's not shown on this slide but we have the currently unpublished [ USP ] chapter dedicated to quality considerations of plasmid DNA as a starting material, it's expected very soon and will also help to further clarify and underline quality standards. And also with plasmids playing such a key role for too many different advanced therapy applications and being in high demand, manufacturers and also end users of plasmids really need to drill down into their quality requirements for their specific application, while also thinking about ever present pressures that everyone has on cost of goods, on speed to market, which is particularly prevalent for advanced therapy programs. So to address these challenges, Charles River launched our eXpDNA platform just over 12 months ago, with a focus on delivering both an industry-leading time lines but also with a very strong focus on process and product quality attributes. The eXpDNA platform is based around 3 core capabilities. The first is our recently expanded plug-and-play screening toolbox where we offer various levels of screening and quality control checks to mitigate some of the manufacturing risks that are associated with very complex or challenging plasmid types. The second is a standardized platform manufacturing process, which allows -- streamlines supply chain and documentation. And lastly, we have the ability, as mentioned previously, to implement 100% in-house analytics. And this is for both plasmid cell banking on final plasmid product release testing. So we're integrating all these capabilities we can deliver, our industry-leading time lines, while also maintaining a strong focus on end product quality. Very briefly, just to mention our Keele and Alderley Park sites, as you all know, well established as our plasmid centers of excellence. And the sites do bring over 20 years of CDMO experience with Keele holding an MHRA license for GMP manufacture and testing. And Alderley Park acting as a dedicated high-quality grade plasmid manufacturing site operating to principles GMP. And both sites now operate multiple independent production streams with fully single use processing line, full segregation of manufacture for multiple plasmid products, in parallel providing production scales from milligrams up to multi-gram production. The plasmids that are manufactured at CRL, as with many providers do provide options and quality grade based on a number of factors, so it can be clinical, phase, scale or volume requirements and also compliance with respect to onward applications. So we have research grade, which is merely used for in vitro or R&D or preclinical studies or high quality or HQ grade plasmid is our intermediate grade quality and that's typically adopted for toxicology studies or as a critical starting material for GMP vector production in Phase I or II clinic and also as a template for GMP messenger RNA production. And then finally, we have a long-standing GMP plasmid, which is our highest quality standard. And effectively, this can be used for all stages of clinical supply, commercial viral vector manufacturing or DNA vaccine drug substance. One of the more recent developments in our service offering and a complement to the eXpDNA platform is the introduction of off-the-shelf viral vector packaging plasmids. When we look 2 of the main viral vectors that are used within cell and gene therapy, we have adeno-associated virus or AAV and also lentivirus or lentiviral vectors or LVV. We can see that gene of interest plasmids are therapy specific. They require custom manufacture, however, the other plasmids that are used for different products offer an opportunity to standardize. So in the case of AAV helper plasmids, they're relatively universal. For lentiviral vectors, the VSV-G, Gag-Pol and Rev plasmids are commonly used with different genes of interest. So these 4 plasmid types formed our initial kind of off-the-shelf product portfolio that was launched last year. And I'm very pleased to say that following the success of these products, we then took the decision to expand this portfolio and launch 5 new off-the-shelf Rep/Cap plasmids last month. And these cover all the major serotypes that are currently used within AAV gene therapy. So moving on now from Charles River service offering. I think it was important just to describe where we are with cell and gene therapy at the moment. But what I'd like to do is look at a couple of case study examples to highlight manufacturing or supply scenarios that we commonly see for plasmid starting materials and strategies that we have implemented to support rapid delivery, while again, also maintaining our focus on -- and product quality. So our first case study is an experienced product developer who wanted to build out their product pipeline and progress manufacturing of multiple plasmid products while also performing development work in parallel at their own manufacturing site in order to fast track their route to clinic. So there was very much a priority focus on the quality of the products that we are producing and the consistency and they also wanted to establish continuity in their approach so that effectively they would have an established platform for rapid progression of future pipeline products. So when we look at how this project was addressed and the strategy dossier had some interesting considerations for phase-appropriate supply solutions and how they can be leveraged to build in quality but also accelerate time lines. When we initially think of phase-appropriate supply, we generally think about quality standards increasing as the product moves through its development and clinical stages and eventually on to market. And this is definitely the case. But additionally, the high-quality plasmid offered by CRL's platform is very, very closely matched to a GMP plasmid, particularly with regards to process unit operations, raw materials and testing. So in this case, it does provide a solid option for fast and cost-effective supply with an easy transition to GMP later on, particularly from a [ CMC projective ]. So looking at the project due to the plasmids that we were running being ITR containing AAV constructs and that are prone to instability, we performed screening evaluation as part of our platform and master cell bank pre-banking to ensure that we had selected intact plasmids from our initial transformation. Then in order to meet the necessary time lines and rapidly deliver multiple constructs without incurring very, very high costs associated with full GMP supply, we manufactured HQ-grade plasmid that was able to support the client's internal R&D requirements even through to toxicology studies with full confidence in the consistency of supply, so if a plasmid candidate was then selected for GMP manufacture. When the time came to progress a construct to clinical supply, the pre-MCB was progressed to a full GMP Master Cell Bank with full analytics and release testing and then that was used to supply the GMP-grade plasmid. So looking at some of the key outputs of this case study. First of all, the quality control was maintained and prioritized throughout this project, particularly around the cell bank and we were able to avoid issues that are commonly incurred with challenging around stable plasmids that could have resulted in significant setbacks, interestingly in this particular case because we were performing -- manufacturing multiple constructs represented by an estimated 75% reduction in overall project time lines versus sequential production for those multiple constructs and it did allow this developer to parallel track multiple product candidates while also sticking within their internal budget. Finally, it did also demonstrate proof of concept for future products with this type of approach. Key learning or takeaways are, firstly, the key one, again, is to maintain that focus on quality control at early stage, particularly for challenging plasmid types like ITR containing plasmids and they can be very difficult. So establishing a reliable cell bank is really critical. In this case, parallel tracking was very important to meet time lines. But in order to do that without incurring a huge financial challenge, phase appropriate quality grade supply with our high-quality platform was very, very important. And then finally, the last kind of takeaway message for this case study was that long-term progress should always be part of the decision-making. Certainly, the immediate cost and time benefits of phase appropriate supply solution like high quality or soon negated if there is a need to perform comparison studies at a later day when moving to GMP. So certainly for a developer who's considering their plasmid supply and maybe looking at intermediate-grade plasmid, is very, very important to look at the manufacturing quality, the quality systems around that supply and the quality attributes of the plasmid so that you can avoid that in the future. So next case study is quite a different situation. But again, focuses on plasmid DNA supply as a critical starting material for AAV gene therapy. In this case, we got a relatively new developer who is aiming to progress their AAV product to first in-human clinic and they require GMP-grade plasmid DNA. They had unfortunately experienced significant manufacturing issues with their previous supplier and had incurred a significant spend without any product issue for effectively. In this case they'd require GMP supply for all 3 AAV plasmids. So in addition to the gene of interest also a helper plasmid on a Rep/Cap plasmid and they were in a difficult position as they kind of wanted to recover their lost time lines but also minimize cost for this manufacture. So in this case, when we look at the solutions and how we approached it, there were certainly lots of different options that were discussed. However, the one that made the most sense was to look at off-the-shelf supply. So the first step, as was the case in the previous study was to focus on the gene of interest plasmid. And it was certainly on the critical class, certainly the most challenging to manufacture based on the previous issues that they'd had. So in this case, in addition to the clone screening and QC checks like NGS sequencing and whole cell line evaluation was performed. And this is something that's relatively new addition to CRL's platform but it's definitely one where we have observed significant benefits for challenging plasmid types. And particularly, this step only adds about 1 week to the manufacturing program and it's consistently delivered stable plasmids and significant uplifts in productivity during production. At the same time, research-grade, off-the-shelf helper and Rep/Cap plasmids were supplied to the customer to allow them to assess them within their AAV platform while we progressed manufacture the gene of interest MCB. For other support reduction in time lines, the MCB was progressed directly to manufacture with minimal testing prior to full release. And then, we were then able to offer expedited release of the gene of interest GMP plasmid, in line with the full release. And importantly, the last kind of piece of the puzzle was to coordinate delivery of the off-the-shelf GMP Rep/Cap on helper plasmids to support AAV manufacture and clinical supply. So in reflecting on this case study and I am kind of looking at the outputs, it's obviously apparent that there were time and cost savings, as you would expect, based on the simple manufacturing overview that I've added at the top of this slide. As we're effectively only progressing a single manufacture for the gene of interest plasmid versus 3 custom batches but importantly and what I'd like to get across today is that there were a number of additional advantages to the use of off-the-shelf products. So preproduction or prior to production, the use of the off-the-shelf plasmids made the slot allocation much less critical, which is certainly an advantage. The client also, they needed to focus on the supply of starting material and documentation review and approvals for a single plasmid versus 3, which is actually quite a significant reduction in workload for a small company if we're really trying to push time lines. If we then look ahead to immediate postproduction benefits, there is obviously a reduced risk of encountering things like deviations or either specification testing, which obviously, we all want to avoid but it's certainly is something that's inherent to GMP manufacturing. It's something that is critical within a comprehensive quality system to make sure the manufacturing is compliant and the product is of good quality. Additionally, because of the Rep/Cap and helper were manufactured in advanced, the gene of interest plasmid was the only item which is on the critical path for this campaign and delivery of all 3 plasmids could be planned very reliably and certainly well in advance of the AAV manufacturing slot. And importantly, the amounts of Rep/Cap and helper were tailored to the AAV production process requirements and this helped avoid wastage rather than relying on outputs from a custom batch manufacture. Looking further ahead, post-manufacture, off-the-shelf products also were able to offer full stability data for each of the plasmids that were sort of -- that were supplied and also regulatory support and also offer the option of immediate resupply should the program encounter an issue later, manufacturing or testing stage. So to summarize and again, provide some kind of key takeaways, off-the-shelf products definitely can provide immediate cost and time savings versus custom manufacturing but the secondary benefits are also extensive. And the overall -- I guess the overall manufacturing effort should be considered in addition to the live processing requirements that typically get all the focus. Immediate resupply offered by off-the-shelf plasmids is a great option to have at your disposal, certainly within what are typically complicated advanced therapies programs. Gene of interest plasmids obviously will always require custom manufacture. But again, it's much easier to remanufacture for a single plasmid rather than 3 or even better still a nice approach would be to establish a contingency stock for the gene of interest plasmid and then offer or order off-the-shelf helper and Rep/Cap and then as needs basis to help manage cost and also kind of fully mitigate risk of any supply issues. So to summarize on the discussion today, on plasmid critical starting materials. First of all, regulatory guidance is evolving and improving. And there's no dedicated guidance for how to manage plasmid critical starting materials versus plasmid drug substance. And I really feel that this will, in turn, support greater range of manufacturing options for developers, depending on particular applications and this can ultimately help with costs and time lines for advanced therapies. We covered some of the main existing guidance today but as I mentioned, please look out for the upcoming [ USP ] chapter on plasmid DNA starting materials, which will also help provide further support and alignment in this area. And we looked at some of the key learning examples within the case studies on the supply of plasmid critical starting materials. But one of the things that really stands out for me is that in order to get the most of what plasmid suppliers have to offer, it is important to understand the necessary quality attributes of the plasmids that you need and how they align with your specific application. Use of intermediate plasmid quality grades like HQ, may not suit every project but for many of those provide a viable option to support reduced costs and time line. And it does open up, as we saw in the case study possibilities, the parallel track development activities for larger programs. Lastly, we'd always advise to work very closely with your plasmid supplier. Plan ahead as far as you can and develop strategies, which deliver the best options for both immediate needs but also for the success of longer-term programs. Definitely, utilization of off-the-shelf products can be a real game changer in certain circumstances. And the utilization of platform screening and manufacturing with proven delivery can also help embed quality at a very early stage and avoid delays later on in the program. So with that, I'll finish. Thank you for taking the time to join the presentation. Certainly, if you're interested in any of the discussion topics I've covered or any of our wider service offerings at Charles River, please don't hesitate to reach out and get in touch. Thank you.

Thank you, Andrew, for a great presentation. Now we're going to start Q&A. So I invite you to join me on the camera. So our first question from the audience, Andrew, is what has the biggest impact -- sorry, what was the biggest impact on time lines for plasmids?

Yes. So I think that there are a number of different reasons why people could experience delays with plasmids. There's definitely challenges across, certainly in the CDMO industry for plasmids supply that can impact timeline, so things like long waiting times for slots, material procurement, there are things like, coordinating with different suppliers. And it's one of the reasons why CRL has put quite a bit of effort into developing things like [Technical Difficulty]. Can you hear me now? Okay. So I'll just cover that question again then, yes? Yes. Okay. So yes, so regarding time lines and what was the biggest impact for plasmid. So I think definitely there's a number of challenges, certainly across different suppliers with things like long lead time, waiting for slots for material procurement and that's mainly related to the kind of worldwide demand for plasmids. And it is definitely one of the reasons why CRL has been focused on the entire platform and developing the ability to fully segregate our production lines, using single-use materials and holding on-site batch pack materials, so those are ready to go and it gives us a lot better flexibility on our scheduling and helps avoid kind of upfront delays on time lines. I think if we assume that slots are available and everything is ready to go and we look more at the process and release side of things and it's very clear that the testing side of things is quite often the biggest impact on time lines for plasmid supply. And again, it's an area that we've been able to see quite significant improvements by bringing all of our testing in-house within the CRL network. And we are definitely looking to take that further by bringing more of our what you would call historically longer lead tests like GMP sequencing and bringing those directly on to the manufacturing sites and that will definitely help us further reduce those time lines in the future.

That's great. Thank you, Andrew. So the next question is, is it possible to provide small samples of off-the-shelf plasmids so they can be tested at customers' lab?

Yes, absolutely. Yes. So I think we kind of saw in the case study example. That's a really common thing that we do. We do have small volume research samples available. Those can go out for testing in your own labs or with your own production platforms. Definitely within our own handling and use of the plasmids, we find that they perform very favorably versus similar products. So there are a number of CDMOs that we offer off-the-shelf plasmids. And in order for our customers to get the most out of them, we can definitely provide technical support from our plasmid and vector SMEs just to help optimize that performance with those kind of off-site evaluations in our customers' labs.

And our next question is, do you have any advice on a risk-based approach for plasmid critical starting materials?

Yes. I mean it's definitely -- it's something that we do, routinely support for our customers. Yes, it's a very, very important step in kind of deciding which plasmid grade to use and how this will kind of develop through the life cycle of a product. And I see in the question, folks, we're definitely not going to get to cover all of them. We could talk about this for a very long time. But I can see some questions around comparability between different plasmid grades and how that's managed and all that type of thing. So I think from our point of view, we've tried to make our platform as standardized as possible. So not necessarily totally avoiding the requirement for any form of comparability assessment between quality grades but making that as easy as possible. So if you do have to transition between quality grades, it's a much easier task. I think generally, with regards to risk assessment and a risk-based approach on the use of plasmids as critical starting materials, the general rules are, the further the plasmid is from the patient the -- sorry, the closer the plasmid is to the patient and the higher the quality grade needs to be or the further to the clinic, the higher the quality grade must be. And this is something that's covered. There's some really good existing guidance with the EMA Q&A document to provide support for this kind of risk-based approach. And we also expect this to be covered in the upcoming [ USP ] chapter that I mentioned earlier on plasmid critical starting materials.

That's great. And we have time for one more question. So what manufacturing production scale do you have? And what is a typical batch size?

Sure. Yes. So Charles River, on our Keele site, so our GMP manufacturing site, typical manufacturing scale is 50 liters for GMP plasmids, yields range depending on plasmid type but we do have process solutions to deliver batch sizes, all the way from kind of milligrams through to multi-gram quantities. And then it's the same at Alderley Park. There's a range of different process options that we can implement depending on the plasmid amounts that are required but typically, we're running a 15-liter bioreactor size for high-quality plasmids at Alderley Park.

Amazing. Andrew, so thank you for answering those questions. And that is all we have time for today. So any questions we didn't get into, we will reply to by e-mail. The webinar will be available on demand tomorrow. So look out for an e-mail from us with the link. And all I have to say is to thank Andrew once more for a great presentation. Thank you. We hope you'll join us again soon.