ElevateBio

Powering the creation of cell & gene therapies at a speed the world deserves.

Manufacturing

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Lentivirus is a commonly used viral vector for delivering genes to cells, both directly in vivo and ex vivo, for engineering cells prior to infusion back into patients. Over the past twenty years, lentiviral vectors (LVVs) have been extensively optimized to improve their functional and safety features.

Building on these advances, ElevateBio has recently developed an LVV manufacturing platform, which we now offer to strategic partners through our BaseCamp facility. Compared with other available options, our platform is differentiated along two key dimensions.

The first dimension encompasses our platform’s technological capabilities and adaptability, which allows us to take solution-based approaches for producing LVV at volumes and purities that meet our partners’ needs at any stage of product development. The second encompasses holistic, end-to-end support for our LVV products, which is rooted in our team’s extensive collective experience from construct design to GMP manufacturing, and connected to ElevateBio’s other core technologies in the same facility.

Both dimensions enable our strategic partners to accelerate their development timelines, better manage costs, and, above all, transform their product development and potential for clinical success so that life-changing medicines reach the patients that need them. In addition, we have teams that offer core services to make viruses at the research level for partners, using a scaled-down platform, which provides consistency early in development and can also enable acceleration of timelines. Let’s look at these two dimensions of our LVV platform and the advantages they offer.

Going straight to suspension from the start

First and foremost, our platform produces LVV utilizing a suspension-based process, where cells are grown in 3D culture systems, instead of an adherent-based process, in which cells are grown in a 2D monolayer culture attached to a surface. Our exclusive reliance on suspension allows for process scale-up and more streamlined transitions between stages of development that an adherent process does not.

Because Phase 1 programs do not typically require large amounts of LVV, most CDMOs and academic centers that provide vectors for Phase 1 trials use an adherent process. Still, there are a number of drawbacks associated with adherent processes. One is that adherent cells typically require culture media supplementation with fetal bovine serum (FBS), which carries unnecessary safety risks and adds complexity to downstream operations. Another is that adherent processes using static vessels can only be scaled out (as opposed to scaled up) by increasing the number of vessels, which results in laborious and inconsistent manufacturing processes. Despite these drawbacks, adherent-based processes are technically simpler and require lower capital investment in laboratory equipment, and for these reasons, Phase 1 trials typically use an adherent process to produce LVV.

However, many products require suspension to produce vector quantities sufficient for later development stages, which creates potential stumbling blocks. When a company switches from an adherent to a suspension process midway through clinical development, it must demonstrate the adherent process used to generate the earlier IND-related product is comparable to the suspension process used to generate product for pivotal trials. Switching processes costs time and money; moreover, if comparability between the two processes cannot be demonstrated, the company may have to repeat the earlier clinical trials using the suspension-generated product, costing even more time and money.

Our vector team thoroughly understands the drawbacks of navigating this switch, particularly for accelerated clinical development pathways where CMC timelines are critical. This is why we were determined to build an LVV platform that utilized suspension across the board. We can produce LVV at whatever scale and purity is appropriate to the phase of development and the type of gene therapy for which the LVV is used (in vivo or ex vivo) to de-risk vector production for our partners and save them time and money later — if early-stage clinical trials prove successful. Additionally, we can offer research viruses at scales from one to 10 liters, using a representative scale-down model of the GMP process.

A second advantage is the capacity of our facility. Most companies have to reserve capacity with a supplier a year or more in advance, introducing long wait times that impede product development. With two GMP production suites for LVV now available, ElevateBio currently doesn’t have these bottlenecks. While that availability could change as our capacity fills, we plan to grow and add additional capacity according to the needs of our partners, so that they can accelerate their product development relative to competitors.

Our platform is also completely customizable to the partner’s needs. While our platform has established processes for LVV production, we are not restricted to using them. If a partner has already developed their own process or wishes to create a custom process for their specific needs, we can rapidly transfer their process or build on our platform to establish a process that meets our partner’s requirements due to our extensive in-house LVV process development expertise.

Our platform is geared towards anticipating and meeting the partner’s exact needs, wherever they may be in product development.

Unrivaled end-to-end support

Our LVV platform’s technological features are complemented by the holistic, end-to-end support our team provides for LVV-based products. We can help a partner develop a therapeutic product from idea and IND to regulatory submission and GMP manufacturing.

This seamless integration, which other providers cannot offer, is possible because our LVV platform and team don’t operate in isolation from the rest of the ElevateBio organization. Both are closely connected to ElevateBio’s other core technologies and expertise, such as assay development, cell therapy development, and vector engineering for LVV construct design.

For example, we can assess the impact of process parameters on downstream development by testing the LVV potency in target cells, such as T cells or hematopoietic stem cells (HSCs), and looking at whether a given parameter alters the final product quality and potency. We can also develop vector potency assays in the early stages of development to better understand the product and process and, ultimately, help accelerate product development timelines. These capabilities de-risk development by alerting us to PD changes that will adversely affect the product’s critical quality attributes (CQAs), so that we can avoid those changes later and by assuring the partner that our vector itself is fully compatible with their final product.

Our end-to-end support spares our partners from the “piecemeal” approach of switching vendors at each stage of development. We also save them from having to develop a process in-house for one stage, only to discover that process does not translate to the next stage of development.

ElevateBio knows that delivering end-to-end support means balancing the science and the business. From a scientific perspective, we know that investing time and money upfront – for example, in developing the scalable suspension process for LVV production – can save much more of both down the line. From a business perspective, we understand the need to keep development moving ahead: if timelines slip by even a quarter, market opportunities could be missed. By striking the right balance between the value of the science and the needs of the business, we set up each partner’s product for potential success in the clinic.

Elevating the endgame

All of the foregoing shows ElevateBio bears no resemblance to a traditional CDMO. Instead of working with a host of customers, we work with a selection of strategic partners for whom we can utilize our expertise to further their development and drive their value, just as if they were our own company. For them, it’s like joining a country club: our partners gain access to our expertise and facilities, and they get our full attention every step of the way. Our “white glove” approach translates into the value-adds of lower development risks, accelerated development timelines, and better product quality for our partners.

Most importantly, we have the experience to help partners get it “right the first time,” – which means understanding the endgame that is essential for success. Our whole organization is structured with this endgame in mind. Many ElevateBio team members have been working in the gene therapy space since its earliest days, and collectively we have expertise across the entire life cycle of product development.

Additionally, our core technologies for vectors, cell therapies, gene therapies, and gene editing are under one roof at ElevateBio, which houses facilities built to support R&D, PD, and GMP manufacturing. The combination of these elements within one organization is a tremendous asset for our strategic partners and us because they don’t have to outsource any part of their development process.

Ultimately, our unique combination of facilities and experience greatly benefits patients. We are rewarded by being part of today’s revolution in medicines that can give patients a cure and give families more time with their loved ones. The production of LVVs and the therapies that utilize them isn’t just our job; it’s our passion.

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The development of cell and gene therapies (CGTs) is highly complex and challenging. While incredible strides have been made in the field, this area of the biotech industry is still maturing, especially when it comes to manufacturing. Because we’re just starting to see the first wave of cell and gene therapies reach commercialization, managing the entire life cycle of CGT product development is still a very specialized skill.

Along with specific technical challenges of CGT process development and manufacturing, CGT life cycle management involves complex supply chains, traceability systems and analytics to guarantee safety and navigating the CGT regulatory environment. The cost of failure is also quite high in terms of additional expenditures, lost time, and patients’ lives that may hang in the balance.

All of these factors underscore the importance of correctly managing the life cycle of a CGT product the first time around, by knowing upfront what’s needed for regulatory approval and then developing the product to meet those needs from the start. But the challenges of “getting it right, right from the start” are more than just technological. Success depends on having both the right processes across the life cycle and the right people to develop and execute those processes. Having one but not the other is a recipe for failure.

Process in the CGT product life cycle

The life cycle of a CGT product starts with procurement of materials, including reagents and cells from donors or patients for autologous products, and extends through dose administration for clinical use. All along that complex supply chain, many different controls must be in place to define, characterize, test and validate the materials. A key element in the supply chain is traceability, which is the process of keeping cellular materials segregated, safe, and well identified from their sourcing through manufacturing and into the patient, and it requires very specific systems and analytics.

Traceability is especially critical for autologous cell therapies. When a patient’s blood sample comes to the manufacturing facility and the starting cells are isolated from that sample, it is necessary to ensure the right patient’s cells are modified in the right way – to generate the needed CGT – and then sent back and administered to that same patient. Lack of certainty anywhere along that chain of custody creates a major safety concern: administration of the CGT product to the wrong patient will induce an immune response (rejection) that could severely sicken the patient.

Securing the CGT chain of custody is highly important, but so are the analytics needed to identify and validate the cells along that chain. For example, in-house release testing methods for an autologous therapy must be able to correctly identify the original patient’s cells, even after they have been genetically modified. The chain of custody also includes logistical components, such as training hospital staff to receive and administer the cells.

All of these factors come into play when navigating the complex regulatory environment, which is the primary hurdle that CGT companies face, especially on the manufacturing side. A CGT company must be in constant communication with the U.S. Food and Drug Administration (FDA) to get the Agency’s input and feedback. When a company does submit an IND for an autologous CGT product, the FDA’s top questions are always, “What is your traceability matrix?” and “What is your control around the traceability for the product?”

Materials used for CGT manufacture are defined, tested and regulated very differently than materials for other drug products. Regulations for each CGT material differ among regulatory agencies around the world.

Therefore, knowing the domestic and global regulatory environment, especially from a CMC perspective, is critical to success. If the CGT team hasn’t lived this life cycle approach to CGTs and their regulation, it has to start from scratch; and without someone who has that hands-on experience, the learning curve is very steep.

The importance of getting it right the first time

In addition to managing the life cycle components described above, it’s also necessary to understand how each of those components ties into manufacturing, and how to make critical development decisions around them, early on the development of a product. Whether the issue is raw materials, developing a process or gaining regulatory approval, waiting to think about these things until the product is approaching the clinic – or even after it has completed clinical testing – makes it harder to introduce the necessary changes later.

The main regulatory hurdle for CGTs is not getting FDA to accept an IND; the agency does accept INDs based on how products have been characterized for Phase 1 testing. The real hurdle comes later, when a company has to conduct process performance qualification (PPQ), which is the characterization and validation required to produce commercial batches of CGT product.

If the PPQ hasn’t been worked out before submitting the IND and entering the clinic, then later clinical development and commercialization will be an uphill battle. The company will have to demonstrate comparability between the previous (IND-related) and newer (approval-related) processes; otherwise it will not be able to use the data generated throughout clinical development to seek regulatory approval. If comparability cannot be shown, the company may have to repeat clinical trials using the new PPQs.

In fact, one of the main reasons the FDA puts products on clinical hold relates to CMC activities or deficiencies, such as lack of comparability. Therefore, a CGT company must anticipate where its product will need to be at the commercial end of the life cycle and develop the product with those needs in mind from the outset. Doing this may involve more work on the front end of the cycle, but it ultimately results in lower costs and development burdens downstream – both of which accelerate the commercialization of the CGT product.

Building the right team

People are just as critical to successful CGT product development as the processes. If a CGT company has one but not the other, the potential for failure is high, because developing and implementing processes correctly requires a team with experience and know-how across the entire life cycle. Putting together the right team comes down to recruiting, hiring and, above all, retaining the right people.

Given that the CGT sector is still in the early stage of growth, the talent pool is quite limited, and it’s practically impossible to staff an entire company only with people who have CGT expertise. But finding the right people is achievable by viewing people’s backgrounds and experiences through the appropriate lenses rather than strictly seeking CGT experience.

To be sure, at any CGT company there are some roles where it is essential to have people with prior CGT experience in order to accelerate development. These include such roles as managing technical operations across the entire life cycle and developing the specialized electronic systems for traceability. However, there are other roles that can be filled by people who don’t have any CGT experience but do have transferable skills. The key is educating and training those people to redeploy their extensive expertise for CGT applications.

This redeployment approach can work well for many, but not all, potential CGT employees. For example, it’s hard to teach someone who has “lived” small molecules throughout their entire career how to reapply that knowledge to CGTs; whereas for people who have worked with proteins, enzymes, and antibodies, the transition to CGT comes more naturally.

In the end, the real challenge in assembling the right CGT team isn’t hiring people; it’s retaining them, because the still-limited pool of CGT is highly sought-after and competitive as the field continues to grow. Therefore, the key to keeping an experienced team on board is offering them a variety of products, projects, roles and opportunities, so that they remain happy, excited and fulfilled.

How the ElevateBio model gets it right

At ElevateBio, we have everything it takes to get CGT development and manufacturing right the first time: an infrastructure for the entire product life cycle; a world-class team of drug developers and operators who can get the job done successfully; and a diverse and growing portfolio of innovative CGT products. Having all three – infrastructure, people and product diversity – in one place benefits us in several ways.

First, because we don’t have to line up CDMOs, we can control our own timelines which saves us time and money.

Second, we have a great deal of talent under one roof; this promotes rapid knowledge transfer among team members and gives us the flexibility to assign our people to multiple products, platforms and technical areas.

Third, we anticipate our employee retention will be higher than conventional CGT companies precisely because we can offer people a wide variety of opportunities within one organization, and we believe this variety will continue to draw additional talent to us.

Together, these benefits translate into an ability to accelerate the development of affordable CGTs and deliver them to as many patients as possible.

The CGT sector continues to grow at a rapid pace. There are now many sophisticated CGT companies and a host of exciting new technologies, from electronic traceability systems to robotics, that are advancing how CGT products are developed and manufactured. However, all of the technology and automation in the world will not guarantee success without having the right processes and the right people in place across the whole life cycle of a CGT product.

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