Category: Gene Therapy

Gene therapies offer an unprecedented ability to treat — and even cure — genetic diseases, and their potential spanning diverse therapeutic areas, including oncology, cardiology, and infectious diseases, continues to expand. While innovations in the development and manufacturing of viral vectors for gene therapies proceed at a rapid pace, the industry remains immature, with considerable work needed to standardize production platforms, improve yields, and reduce costs to advance the sector to a place analogous to more mature modalities, like monoclonal antibodies. Success in producing viral vectors with the appropriate yields, purity, efficacy, and quality requires a development and manufacturing partner with deep process and product understanding, the ability to develop built-for-purpose production and purification platforms, and the expertise to navigate supply chain and regulatory hurdles.

Driven to Cure Patients

Formed to develop gene therapies for as many patients as possible with a wide variety of rare diseases that often otherwise have no hope for treatment, Andelyn Biosciences has worked with numerous adeno-associated virus (AAV) serotypes and genes of interest and learned to overcome many hurdles to production, testing, formulation, and regulatory approval. The scientific team at Andelyn has observed how the size of an insert, the specific promoter used, or the addition of introns to key areas of plasmids can influence the production capacity, purity, and other critical quality attributes (CQAs) of AAV vectors. 

This extensive and broad experience has placed Andelyn in a position to formulate responses to these many different challenges. We are able to select the appropriate components of our production, purification, and testing platform, choosing the right approach to manufacture each vector that also takes into consideration the required dosage, expected target, and required timeline. With our extensive process and product understanding, we apply the principles of quality by design (QbD) to ensure the highest possible yields, purity, efficacy, and quality for each product.

Andelyn’s deep knowledge in viral vector development and manufacturing is also being leveraged for the design of new development and manufacturing sites. We continue to further build capabilities to even better respond to known and as yet unidentified hurdles. 

Inherent Flexibility in a Tried-and-True Platform

Andelyn began platform development with an eye toward managing the complexity of possible programs, including considering multiple serotypes and multiple transgenes. Our team determined that we had to build a platform that was flexible from all perspectives, including both adherent and suspension processes. Using these platforms, Andelyn has produced clinical-grade material and supported approximately 70 investigational new drug (IND) applications. In essence, we have applied an established platform that was designed to adapt to each unique project while leveraging the learnings obtained during previous projects. We even used our extensive knowledge in adherent cell culture to develop our suspension cell culture platform, which is performed in single-use (SU) bioreactors. 

Key to our success is our experienced team, which we bring in very early at the proof-of-concept stage to discuss all aspects of a project with the client. By collecting all relevant information from clients at the beginning of a project, we can perform a yield assessment, typically using a full design-of-experiment (DoE) approach, to evaluate how best to match the unique characteristics of each program with our platforms. 

Importantly, Andelyn Biosciences was formed from a unique perspective focused on the science and patients and drawing on our roots in Nationwide Children’s Hospital. With this internal experience in clinical research from multiple points of view, we have a wealth of insights that allow us to address the manufacturing, quality, and other aspects of viral vector development and commercialization. That foundation in science and our extensive experience in viral vector projects — including supporting a wide range of AAV serotypes — enables us to anticipate potential issues and consider the deepest details when working with our clients.

Understanding Serotype Behaviors

Adherent cell culture approaches continue to dominate upstream processes for cell and gene therapies, especially during early development, but there has been increased innovation and application of suspension-based platforms. Suspension-based processes offer a range of appealing benefits, including easier scale-up, reduced costs owing to the utilization of less consumables, simplified supply chain compliance, and reduced contamination risks. 

The adherent approach is labor-intensive, and scale-up does not reduce the labor required, but adherent AAV production remains a strong option for several primary reasons. First, many indications, such as those with low required dosages (eye, scalp, mouth) or low disease prevalence, simply do not require enormous yields. For these products, sufficient amounts of vector can be quickly and efficiently produced in Corning^® HYPERStack^® vessels. Through our collaboration with BIA Separations, we have developed a process that affords a much cleaner harvested feed stream from our HYPERStack^® platform than is obtainable using other production routes. Second, for certain membrane-associated serotypes, the adherent route is optimal for avoiding additional process-related impurities.

Additionally, adherent cell culture presents a simpler solution for lentiviral (LV) vector production. With LV vectors, time and temperature are critical production factors. HYPERStack^® vessels afford high yields in concentrated volumes, and cooling of the harvest can occur quickly or can be bypassed altogether, allowing immediate purification.

In the absence of a definitive advantage of one of the manufacturing systems over the other, it is especially critical for gene therapy developers to partner with service providers that have extensive experience in commercial viral vector manufacturing. Without the benefit of the experience that comes from executing multiple programs spanning different serotypes, developers may gravitate toward one production platform without even realizing that, for their specific serotype, another platform might be more suitable. 

Supporting Regulatory Advances

As a pioneer in viral vector production and the first to manufacture for clinical use, we have a wealth of unique practical experience, which we leverage not only to continuously improve our platforms and processes but to provide feedback to the U.S. Food and Drug Administration (FDA).

Andelyn Biosciences has been working with the FDA to set expected purity levels for AAV products and has been developing methods for achieving them. We have consistently been able to deliver very high yields. The real challenge at this point is the quality of the raw materials and the purification. The question we have been aiming to answer since we started communicating about this issue with the FDA 15 years ago is what amount of DNA impurities are acceptable in the raw materials and final product.

At this point, we have determined the required purity levels for our raw materials, as well as the critical process parameters to monitor and the critical quality attributes to meet for our products.

Developing a Customized Single-Use Purification Solution 

One interesting problem that has resulted from working to minimize DNA impurities while maximizing yields is the issue of using SU tubing sets during purification. Optimally, SU items should be used for both plasmid and virus manufacture to remove concerns about DNA cross-contamination. The presence of even minute levels of DNA from other products can impact safety and quality. With SU tubing, however, there is a greater potential for product loss due to retention of product solution in the tubing. 

In addition, certain downstream processing steps required to achieve the necessary purity levels for viral vectors have not yet been supported by SU technologies. For example, iodixanol ultracentrifugation is commonly used to achieve the removal of partial and empty capsids to the extent required for gene therapies. This process is very complex, however, and chromatography is preferable. Achieving the same impurity profile when moving from the technique-heavy iodixanol ultracentrifugation to chromatography has been a monumental challenge, including the need to demonstrate the fundamental equivalence of the methods. 

For 15 years, the scale of most available chromatography equipment has not been appropriate for AAV purification, which requires a gradient approach to separate full capsids from empty and partially full capsids and partially assembled capsids. Since, for a systemically delivered AAV therapy, the total volume of 25 adult doses of an AAV product once purified may only measure 200 mL, the ability to achieve a highly pure and highly concentrated product with the SU systems on the market has been limited.

Therefore, approximately six years ago, Andelyn began collaborating with Verdot IPS to customize its VERDOT Ips² FlexiPro benchtop chromatography system. The new FlexiPro solution has four different tubing systems customized specifically for the purification of gene therapy products, ranging in flow rates from 10 mL/min up to 10 L/min. In addition, monitoring of UV, conductivity, pH, and other parameters is possible while maintaining the SU capability. Andelyn now has three of these customized FlexiPro systems on site that can be used for purification at multiple scales. It should also be noted that the system is currently being optimized to achieve all-column purification at a large scale.

At Andelyn, we employ a QbD approach, completing upfront development work to ensure the development of high-yielding processes. This additional work on the front end directly impacts the design of the manufacturing process and, in particular, downstream purification, saving a considerable amount of time and effort during scale-up and commercialization.

Improving Overall Yields

The question of yields is intuitive; the lower the yield of viral vector per cell, the higher the level of contaminating proteins, DNA, and other materials. A low-yielding process, even if it produces sufficient vector for a client, is not necessarily worth completing, because downstream purification results in too much product loss and the isolation of low-quality vector that will not meet release criteria. The harvest of a low-yielding product results in high rates of loss owing to non-specific binding and the selection of only highly pure chromatography fractions.

It is thus essential to push the envelope on yield for every product. At Andelyn, we employ a QbD approach, completing upfront development work to ensure the development of high-yielding processes. This additional work on the front end directly impacts the design of the manufacturing process and, in particular, downstream purification, saving a considerable amount of time and effort during scale-up and commercialization.

That upfront development includes evaluating all aspects of the process — from the original plasmids to all parameters — to ensure that we can develop an optimal solution. Plasmids have a tremendous impact on the performance of vector production processes. Replication of intact virus is a concern with all viruses but is generally minimized with AAV. With generation 1 plasmids, however, it is possible to get spurious packaging of Rep and Cap genes, which can result in the formation of replication-competent AAV (rcAAV). Generation 2 and 3 plasmids have been engineered to reduce rcAAV, which can have a significant impact on purification and the overall success of the project.

Andelyn can also help with vector plasmid design to ensure higher expression levels, because we have worked with such a diversity of vectors and can apply that knowledge to each new project. For instance, we can help control ITR (inverted terminal repeats) deletions, which can change the yield profile of a vector in very significant ways.

Managing Supply Chain Vulnerabilities

In addition to the challenges posed by the COVID-19 pandemic, maturation of the gene therapy field has created supply chain issues. In some cases, advanced, higher-performance reagent-grade materials have been developed that present considerable advantages but are offered by younger companies that are not able to offer large-scale quantities of GMP-grade materials. As a result, while it is possible to develop efficient processes with these new materials, they cannot always be easily scaled for commercial production.

For our critical raw materials, we continue to evaluate new options from new suppliers and leverage new strategic partnerships to find the best solutions for managing current supply chain issues. Multiple, redundant sourcing is necessary to confirm that, if both our primary and first backup supplier for a given medium or consumable become unavailable, we will have another alternative that will allow our clients’ programs to move forward.

Remaining Regulatory Hurdles

Dialogue with the FDA continues regarding aspects of viral vector manufacturing that remain unaddressed. Two further key issues that continue to be discussed include identifying sub-visible particles in release assays and reducing contaminating capsid proteins during the production process. 

Sub-visible particles in viral vector manufacturing are frequently aggregates of the vector product or of unassembled capsids. Unlike with protein-based biologic drugs, these impurities are not necessarily undesirable or detrimental to final gene therapy products. More information is needed to make such a determination. With respect to capsid protein impurities, the typical purification scheme for AAV vectors results in the presence of large amounts of these contaminants in the product. More discussion around this area is also needed. Andelyn is adding additional analytical capabilities so that we can understand what effects scale, capsid serotype, concentration, and formulation have on the AAV product.

There is also a need for additional harmonization and standardization going forward. Working with different requirements from product to product is not sustainable. Andelyn is very much active in that conversation and as a leader in the field is positioned to play an important role in helping to establish consistent standards.

Achieving that harmony in the short term will be difficult, because many players in the field are still working on platform development to achieve the scales that are needed to meet some of the evolving indication demands. Baculovirus, suspension HEK293, and adherent HEK293 platforms have different impurity profiles with respect to host-cell proteins (HCPs) and various other process- and product-related impurities.

Therefore, some base-level decisions will need to be made as an industry regarding what is and is not acceptable. The FDA is making progress in this regard, but these standards have not yet been well defined. Many questions remain. For instance, what should the base guidance be for HCPs? If a specific purity level is set, what would that purity mean? What can the contaminants be? How many and which ones must be defined? 

In addition, is the full-versus-empty capsid ratio important? In certain indications, absolutely, but perhaps not for others. In an intrathecal route, an eye indication, or certain other indications that require a high viral vector concentration, empty capsid impurities would reduce the concentration of the product. At the same time, there are other aspects that would make this issue less significant in those same indications. It’s a balancing act.

Indeed, concentration and formulation are further complex issues with gene therapies, both from an impurity perspective and with respect to stability. Unlike recombinant proteins and mAbs, viral vectors are biological organisms — not necessarily alive, but “live” viruses that have specific requirements. Formulation is very important in the drive to achieve higher titers, an omnipresent concern for developers. For instance, stability is different at different buffer ionic strengths, and higher vector concentrations typically result in higher concentrations of other viral proteins, such as HCPs and other contaminants. 

These uncertainties make it difficult to develop platform processes; the QbD approach is only optimal when based on sufficient basic guidance. On the other hand, it is difficult to set a base guidance without being able to refer to platform processes and the products they generate.

Facilitating Growth of the Gene Therapy Industry

The gene therapy field is moving beyond rare and terminal diseases to diseases that affect much larger patient populations. The goal is to be able to treat something like male pattern baldness, which affects a larger percentage of the adult male population. The industry will have truly arrived when gene therapies for quality-of-life indications are available at a large scale. 

That time has yet to come. From a big-picture perspective, the key issue is cost, which of course relates to the current manufacturing limitations. There are also concerns about increased use of SU technologies and the environmental impact that they will have if gene therapies move to very large-scale production. In addition, leveraging only SU systems is also one of the largest drivers of cost, outside of the unavoidable costs associated with drug development in general.

Once again, flexibility in manufacturing is absolutely critical. Andelyn remains focused on building flexible platform solutions that can serve the entire gamut of potential projects, from gene therapies that treat a dozen patients per year to those that will, in the future, help thousands to millions of people annually to improve their lives. 

Originally published on PharmasAlmanac.com on March 12, 2022.

Pharma’s Almanac’s Scientific Editor in Chief David Alvaro spoke with WuXi Advanced Therapies (ATU) CEO David Y. H. Chang about the state of the cell and gene therapy market today, the various challenges faced by innovators and their outsourcing partners, WuXi ATU’s recent acquisition of OXGENE, and some predictions of further developments for these new modalities and WuXi ATU over the next decade.

Q: How would you characterize the current landscape of the cell and gene therapy market overall, particularly in light of the high number of approvals expected in the next few years and beyond?

Well, 2020 was a very difficult year for the cell and gene therapy industry. Many companies saw their commercial license applications delayed, and some of those that received late complete responses were denied. Of course, this type of activity represents the typical growing pains experienced by any new therapeutic modality heading toward the finish line. The last big hurdle is achieving alignment with the regulators to ensure that only safe and efficacious products reach the market and patients.

As we gain a better understanding of the science involved in cell and gene therapy development — and thus better control over both manufacturing processes and products via advanced characterization — the types of challenges faced in 2020 will be greatly reduced, and approval rates will increase, possibly even in an exponential manner.

Cell and gene therapies are new modalities that likely will not be considered mature for at least another five years. Over the next decade, we can expect the industry to grow at 15–20% annually. Much of that growth will be driven by startup companies translating promising research into clinical applications and one by one reaching the commercialization stage. Ultimately, as a result, approvals will also increase exponentially.  

Q: How prepared do you think the industry is right now to meet that coming demand in terms of capacity, infrastructure, logistics, and other such factors?

There are definitely gaps in capacity and capabilities, given the exploding growth of startup companies and the increasing number of developers that are reaching the point of commercialization. Efforts to catch up and build capacity and capabilities to the necessary levels, which have already been going on during the past few years, will continue for the near future.

What is required is a concerted effort from both innovator companies and their service providers — contract testing, development, and manufacturing organizations (CTDMOs) in particular — to collaborate to address these deficiencies collectively.

Q: What are some of the primary pragmatic and logistical challenges facing the field going forward?

Right now, optimizing manufacturing of viral vectors for use in gene and gene-modified cell therapies presents one of the biggest issues. There is still significant need to boost production efficiencies and to improve yields in order to achieve truly cost-effective supply of viral vectors in the quantities needed to enable commercialization of the large number of therapeutic candidates in the pipeline.

For cell therapies, particularly autologous treatments, such as chimeric antigen receptor (CAR) T cell therapies, the primary manufacturing challenge relates to the scaling of processes. Because these are highly personalized, even patient-specific therapies, one batch often treats one patient. Scaling is currently achieved by scaling out rather than scaling up, and this requires assurance that no cross-contamination or crossover occurs between batches within the same manufacturing suites. It is also essential to ensure that the chain of identity is maintained throughout the entire manufacturing and transportation processes.

The logistics for both cell and gene therapies are complex. These products require cryopreservation and must be maintained at temperatures as low as –80 °C during storage and shipment. Some shipments have very short turnaround times as well — particularly autologous CAR-T cell therapies, which must be transported from the manufacturing facility to the patient within 48 hours in cold and non-cryopreserved state. The cold chain and rapid delivery requirements combine to create truly unprecedented logistics challenges.

At WuXi ATU, we believe that “every drug can be made and every disease can be treated” by building an open-access platform with the most comprehensive capability and technology in the global healthcare industry.

Q: What do you view as the key gaps and challenges that currently exist for testing and analytics in this space, and what solutions are possible?

For cell and gene therapies, there are three main types of testing that must be conducted to enable products to move into the clinic and onto commercialization: raw material release, in-process control and final product release, and biosafety testing. All three types of testing are complicated and currently require advanced cell-based testing methods, which typically require long turnaround times. For instance, it can take up to 60 days when testing lentiviral vectors, to receive the results needed to confirm that no replication-competent lentivirus (LV) is present.

As a result, one of the main challenges facing the industry with respect to testing is streamlining testing methods and processes. Those shortened turnaround times, however, must be achieved while still ensuring sufficient sensitivity, precision, and reproducibility.

There are two approaches to realize this goal: implementing automation and converting cell- and cultivation-based assays to rapid alternatives, such as quantitative polymerase chain reaction (qPCR)-based methods. Automation is important to reduce error, time, and labor costs, particularly around  sample preparation and manipulation. Many non-cell-based assays can be completed in hours to a few days, which will have a tremendous impact. Adoption of qPCR, digital droplet PCR (ddPCR), and similar methods is taking place rather slowly, but there have been some promising precedents.

With some effort, the combined use of automation and more rapid testing methods will enable the industry to overcome the very, very challenging testing requirements for cell and gene therapies. 

Q: To what extent is the industry facing a shortage of talent with the needed expertise to support all of the challenges posed by these new and evolving modalities?

I have been in the industry for more than 30 years and never seen such a “war” for talent as exists today within the cell and gene therapy field. This situation has arisen partly as a result of the exploding growth of the industry and partly due to the complicated competency training required to bring new employees on board.

Companies exploring cell and gene therapies must not only hire the right people, but train, develop, and engage employees so they can begin to contribute as quickly as possible but also maintain a commitment to stay with the company that hired them. Different firms are taking different approaches.

At WuXi ATU, we attract talent by not only offering competitive employment packages but also enacting intense engagement efforts that include career development opportunities and cross-functional training programs. This is helping us to build a winning, employee-centric culture. In addition, we have developed a unique onboarding training program that allows us to reduce the time required for new employees to gain proficiency in expected tasks, including special programs for training manufacturing technicians in a holistic manner and analytic technicians in advanced methods, such as flow cytometry.

Q: Do you think that the industry will soon converge on one or a small number of technology platforms, or will each program remain unique and custom over the near term?

This really depends on which processes you are considering. For more established viral vectors, such as adeno-associated virus (AAV) and LV, that have been used for years, the industry is more or less converging on a common platform that resembles the approach used for traditional biologic manufacturing. Similarly, for more established cell therapy modalities, most notably CAR-T cell therapies, the industry is mostly converging on one or two types of platforms in wide use.

The same cannot be said for newer cell therapies, such as those based on stem cells and induced pluripotent stem cells (iPSCs). These therapies are still at the earliest stages, and translation from research into clinical development has just begun. As a result, significant customization and individual manufacturing solutions are needed at this point. Once several of these candidates have progressed through the development cycle and been fortunate to receive approval and undergo commercialization, we can expect platform technologies to be established for them as well.

Q: Any conversation about cell and gene therapy today has to touch upon cost concerns. Where do you see the potential for innovations or other changes that can help make these therapies more affordable?

The current high cost is unquestionably limiting accessibility to these lifesaving or life-changing treatments for patients. Innovators — and the industry as a whole — must work on reducing costs. There are several places to look for these needed changes.

First, as mentioned, it is absolutely necessary to increase the yield and efficiency of production processes for cell and gene therapies. Raw material and labor costs both need to be reduced. These issues can likely be addressed on an industry-wide basis.

In addition, developers of cell and gene therapies need to focus on drug products that allow treatment with a lower dose and that have improved safety profiles, such as no undesired adverse events, so that patients do not require extensive monitoring and management during treatment. 

Q: What can you tell me about the different priorities right now for innovator companies and CDMOs? To what extent are they aligned, and what else can be done to bring them more into harmony?

We classify innovators into two groups: early-stage companies with new product ideas and mature companies that are close to (or have just realized) commercialization. Each has its own priorities.

Early-stage companies are focused on advancing their products into the clinic as quickly as possible. These companies can benefit from a partnership with a service provider, such as WuXi ATU, WuXi AppTec’s cell and gene therapy Contract Testing, Development, and Manufacturing Organization (CTDMO) business unit.

WuXi ATU strives to provide a turnkey solution that supports rapid development of innovative gene and cell therapies from the earliest stages into the clinic with a full range of process and formulation development, analytical testing, and clinical trial material production services.

For companies close to or at the commercialization stage, a CTDMO like WuXi ATU provides agile, flexible capacity and capabilities to help meet evolving demands as companies move from the clinic to the market.

One key to successful development in the cell and gene therapy space for both innovators and CTDMOs like WuXi ATU is for both to share the risk associated with the development of these new, somewhat volatile modalities. There is room for greater alignment and agreement in this area.

Q: WuXi ATU’s recently acquired OXGENE. What was it about their technology or manufacturing systems that attracted WuXi ATU’s attention?

OXYGENE’s state-of-the-art, industry-leading plasmid technology for viral vector manufacturing piqued our interest, and talks began approximately one year ago. Initially, we were interested in in-licensing the plasmid technology in order to be able to manufacture and supply these products to the industry, as well as to use them internally.

During those discussions, we discovered that OXGENE has an ongoing, intense, and advanced effort to develop a next-generation production system for AAV and LV vectors in addition to its industrially leading plasmids. That type of technology was one key element that had been absent in WuXi ATU’s service offering. Concurrently, OXGENE realized that WuXi ATU has the mature GMP development, manufacturing, and testing capabilities needed to take their technologies to the next level.

This mutual recognition of our complementary capabilities quickly resulted in the dialogue advancing from an in-licensing deal to an M&A discussion. After constructive and pleasant negotiations, we reach the conclusion to acquire OXGENE and make it a WuXi ATU company on March 2, 2021. 

Q: How important was it to the company’s overall strategy to acquire a European facility? What new opportunities does that potentially open up?

OXGENE is a spinoff company from Oxford University, one of the most reputed universities engaged in gene therapy and viral vector development. Having a physical location near the university allows us to attract local talent and thus enrich our talent pool, which will definitely give us an edge in that war on talent we discussed. A presence in the EU also allows us to establish local cell therapy manufacturing capability for the European market. Local production is absolutely essential for autologous cell therapies given the short turnaround times for these products. 

We have developed WuXi ATU as a fully integrated CTDMO with capabilities in testing, development, and manufacturing, which allows us to provide a true turnkey solution.

Q: How do you see the OXGENE brand fitting in with, and integrating with, the rest of WuXi ATU?

With its advanced technologies in genetic modification and development of plasmids, viral vectors, and cell lines, OXGENE helps WuXi ATU to further establish itself as a turnkey solution for cell and gene therapy developers — from discovery to clinical and commercial production.

We will be fully integrating OXGENE’s manufacturing technology platform into the global WuXi ATU business. Its discovery and research technology platform will remain in OXGENE’s UK facility and continue to serve its existing clients, as well as support both existing and new global WuXi ATU clients. 

Q: As the cell and gene therapy space becomes more crowded, what do you see as the ultimate differentiators for WuXi ATU?

At WuXi ATU, we believe that “every drug can be made and every disease can be treated” by building an open-access platform with the most comprehensive capability and technology in the global healthcare industry. We have developed WuXi ATU as a fully integrated CTDMO with capabilities in testing, development, and manufacturing, which allows us to provide a true turnkey solution.

With information on a client’s gene of interest, we can provide GMP product for clinical and commercial phases. And now, following the acquisition of OXYGENE, we have even greater capabilities with respect to the development and optimization of plasmid DNA, viral vectors, viruses, and cell lines, and importantly the ability to leverage next-generation viral vector production using helper-free, plasmid-free systems, which we believe will revolutionize industrial viral vector–based gene therapy services.

Q: Where do you see WuXi Advanced Therapies positioned a decade from now?

A decade from now, WuXi ATU will be widely recognized as a leading turnkey solution provider in the cell and gene therapy space with the ability to provide end-to-end support for clients. Early-stage companies will look to partner with us for assistance with building their gene delivery vehicles and cell therapy products, developing efficient and cost-effective manufacturing processes and producing their products for clinical and commercial use, including all of the necessary analytical testing throughout the life cycle.  More mature companies will leverage our commercial-ready capability and capacity to help them cross the finish line and get these life-changing products to patients.  

WuXi ATU will also be seen as a technology leader as we continue to develop more robust and efficient manufacturing and analytical methods and even next-generation solutions that address the key challenges facing cell and gene therapy developers today.

Originally published on PharmasAlmanac.com on May 27, 2021.

In the rapidly evolving landscape of the cell and gene therapy sector, drug developers are faced with two primary challenges: financial constraints and regulatory uncertainties. Emerging biopharma firms face mounting fundraising pressure due to microeconomic market dynamics. Simultaneously, regulatory guidance remains uncertain. Contract development and manufacturing organizations (CDMOs) like Viralgen Vector Core are vital to ensuring industry sustainability and quality standards. Despite financial and regulatory challenges, the scientific foundation of cell and gene therapy is robust. AAV vector–based platforms have gained FDA approval, promising precise therapy delivery and cost-efficiency. Through its innovative manufacturing platform and continuous improvement, Viralgen seeks to improve yield, quality, and ultimately the cost profile to expand accessibility. The Pro10^TM platform’s scalability and additional support services contribute to the cell and gene therapy sector’s growth. Collaborations and advancements in AAV manufacturing hold promise in addressing remaining questions in regulation, trial design, and reimbursement. Viralgen’s commitment to innovation and expansion underscores the pivotal role it is prepared to play in the future of gene therapies.

The Financial and Scientific Divide in the Cell and Gene Therapy Sector

The cell and gene therapy sector (in the second half of 2023) is characterized by two main challenges: Financing and regulatory uncertainty. The currently prevailing dynamics in capital markets are difficult and primarily driven by microeconomics, which has placed significant pressure on small biopharma companies with respect to fundraising. Such small and emerging biotechs must overcome numerous hurdles to gain access to the funds they need to conduct development programs and to successfully advance products to market.

At the same time, sponsors continue to face regulatory uncertainty and a lack of comprehensive guidance. Contract development and manufacturing organizations (CDMOs) — such as Viralgen Vector Core — have manufacturing platforms capable of supporting multiple programs from multiple clients and are playing a key role in establishing the level of quality needed for the long-term viability of the sector. Additionally, leading viral vector CDMOs are establishing realizable quality targets, as well as longer-term goals which the industry must eventually achieve.

On the other hand, the fundamental scientific foundation of cell and gene therapy is well established and on track to becoming truly exceptional and transformative. The value of adeno-associated viral (AAV) vector–based platforms has been demonstrated. In the last few months, the U.S. FDA approved two AAV-based gene therapy drugs: Roctavian, a gene therapy for the treatment of adults with severe hemophilia A; and Elevidys, for the treatment of ambulatory pediatric patients with Duchenne muscular dystrophy (DMD). Within the current development pipeline, there are several AAV-based candidates in clinical trials that are showing tremendous potential. Moreover, there is growing interest in accessing particular serotypes to enable more precise targeted delivery, which will include both leveraging the native diversity of AAV serotypes and creating novel serotypes by engineering new capsid proteins. CDMOs must be positioned to accommodate these new technologies, not only for manufacturing purposes but also with regard to capacity, as more precise therapies allow dosing adjustments, which can ultimately lead to better cost profiles.

Taking a Big Bite Out of Process Costs

The current high cost to patients of cell and gene therapies is a real and growing concern, presenting challenges not only in terms of reimbursement but also in terms of general accessibility, with prices restricting many of the already underserved patients that these therapies are designed to help from accessing treatment. A key focus at Viralgen is advancing our manufacturing process to improve the process economics with increased yields and improved costs. Our next-generation process, which leverages perfusion bioprocessing, is reducing the current costs of AAV production for later-stage customers and bringing commercial viability closer. In the future, stable cell lines will enable significant further cost optimization.

In fact, there are numerous parallels that can be drawn between the progress being made in cell and gene therapy manufacturing and the evolution that recently occurred in monoclonal antibody production to develop the cost-effective solutions available on the market today. Ultimately, increasing demands for scale and volumes will drive processes and the experience and expertise that developers and manufacturers acquire on the way must feed back into further innovation and optimization. Healthy competition is spurring development and accelerating the adoption of innovative technologies, while the comprehensive understanding that regulatory authorities need to set standards that are achievable and realistic — but also sufficiently flexible to meet specific needs for different indications — will come through collaborations with sponsors.

Partnerships between manufacturers and suppliers of equipment and raw material are also essential to continued progress by reducing the cost of cell and gene therapies. Such partnerships relate to everything from security of supply, effective integration of manufacturing equipment, and enabling efficient extraction and analysis of production data to access to novel, alternative technologies, such as enzymatic DNA (an emerging alternative to traditional plasmid DNA (pDNA)). For instance, Viralgen benefits from being in the Asklepios BioPharmaceutical, Inc. (AskBio) family along with TAAV Biomanufacturing Solutions, SLU (TAAV), which supplies neDNA to us in 12 weeks or less, compared with the four-to-six-month timeframe that is typical for pDNA supply.

Addressing a Key Market Need

Viralgen Vector Core, a wholly owned and independently operated subsidiary of AskBio, was originally founded in 2017 in the Basque Country region of Spain by AskBio and the venture capital fund Columbus Venture Partners to help address manufacturing capacity shortages in the viral vector space using AskBio’s manufacturing platform based on its proprietary Pro10^TM cell line.

Although Viralgen was initially created to be a producer of clinical trial materials (the first GMP batch was manufactured in 2018), a commercial production site was quickly added. Today, Viralgen serves over 60 clients, helping to resolve an important bottleneck in the cell and gene therapy manufacturing space and enabling sponsors to advance their AAV-based development programs.

Today, Viralgen remains focused on AAV production and clinical manufacturing, but with the addition of the commercial plant, we have become a fully integrated CDMO. We continue to build our capabilities to ensure that we can offer complete life cycle management of products, development services, and other ancillary support to customers as the sector matures and the needs of developers broaden. The intent is to focus on areas where clients typically struggle, such as overcoming plasmid access issues by providing synthetic DNA and bringing that next level of innovation into our platform manufacturing process. Ultimately, the vision is to contribute not only to the gene therapy field but to the full breadth of the advanced therapy medicinal products (ATMP) space.

Another fundamental aspect of Viralgen’s core vision and values is to partner with and assist foundations focused on the patient communities that these advanced therapies seek to help. Corporate social responsibility (CSR) is taken seriously by the company, as evidenced by the large number of collaborations and sponsorships Viralgen has established with foundations in the rare disease space to support compassionate use cases. Additionally, Viralgen has committed a percentage of manufacturing capacity to Columbus Children’s Foundation and Fundación Columbus, which devote themselves to the development of cures for ultra-rare disorders — with Viralgen performing all manufacturing management tasks.

Viralgen’s commitment to CSR is one of four pillars that make the company stand out, along with the manufacturing platform that truly accelerates time to market, our expertise in AAV supports our extensive development service offering, and our large, diverse, highly skilled group in San Sebastian, Spain, with tremendous intellectual power fueling continuous innovation.

Viralgen Vector Core’s Pro10^TM Platform

The Pro10^TM platform, licensed from AskBio, is based on a serum-free HEK293 cell line designed to support triple transfection for production of all regular and novel AAV serotypes. Most genes of interest (GOIs) are well supported by the technology. As a result, only a relatively quick evaluation of a new client’s GOI and AAV serotype is needed before performing a feasibility run, after which point manufacturing can be initiated. To date, the Pro10^TM platform has been used for the production of more than 14 different AAV serotypes, of which nearly one-fifth are novel (engineered or chimeric).

The platform process is scalable and can accommodate AAV gene therapies for rare disease indications with smaller volume needs, as well as products targeting more prevalent conditions that require large volumes of viral vectors. Specifically, Viralgen has demonstrated consistent scalability from 50 L to 2000 L. Importantly, the cost-of-goods as the process scales are highly predictable.

The ability to produce high-quality AAV vectors at the 2,000L scale will become increasingly important as gene therapy candidates in preclinical and clinical development stages — many of which treat more prevalent indications and involve larger doses for more patients — progress to late-stage clinical trials and marketing authorization. The volume demand for these products will be much higher than has been seen for the AAV-based gene therapies targeting rare diseases. Viralgen is preparing itself to meet that large demand, which we expect to see in 2025 and beyond

Many Important Ancillary Services

In addition to accelerated manufacturing of AAV vectors of all serotypes, Viralgen provides additional support to customers electing to use mammalian cell culture. We believe strongly in the advantages offered by mammalian cell culture, particularly for downstream processing and in clinical research. As a result, one of our main areas of expertise is in mammalian cell line selection.

Viralgen aids AAV clients of all serotypes by providing extensive data as part of our platform manufacturing process. Our systems are digitally integrated, and all data points are collected in compliance with GMP requirements. In addition to using those data to continuously improve the platform, we can combine it with our experience in AAV production across many different GOIs and serotypes to provide invaluable insights to clients regarding not only process performance but construct design, GOI packaging, and more. Those insights will only improve over time as more data are generated. Ultimately, we hope to accumulate sufficient data to leverage artificial intelligence and machine learning tools for predictive applications.

Clients also benefit from the regulatory experience Viralgen has amassed through the enabling of more than 26 investigational new drug (IND) filings, half of which have resulted in active clinical trials, with some already in or nearing pivotal or late-stage trials. We have thus proven capability in this area, which again is particularly beneficial for smaller sponsors that are new to drug development.

A Note about Using Synthetic DNA

At Viralgen Vector Core, we have shown that synthetic DNA can be effectively used as an alternative to pDNA produced via fermentation for the manufacture of various AAV serotypes. The key benefit of using synthetic DNA for AAV vector production is simplification and shortening of the supply chain. Owing to the nature of its manufacturing process, synthetic DNA can be obtained in weeks rather than months, significantly faster than the typical expectation for pDNA, which is produced via fermentation.

A secondary benefit is the ability to reduce the quantity of DNA required for transient transfection to generate AAV vectors. This advantage derives from the nature of the synthetic DNA, which contains only the necessary genetic material needed for the transfection process. Plasmids on the other hand, contain extensive non-relevant microbial genetic sequences. As a consequence, more pDNA is needed for a given process than synthetic DNA. A related advantage of synthetic DNA is that its use avoids potential sources of additional microbiocontaminants, so synthetic DNA can potentially result in simpler downstream processing and superior product quality profiles.

Access to DNA starting material will become an even more critical issue as the many AAV pipeline programs at the preclinical and early clinical stages progress to later clinical stages and commercialization. Some of these programs involve more prevalent diseases (such as DMD) and will require larger doses for more patients, magnifying the raw material demand further. Synthetic DNA will be a key part of the solution.

Customer-Agnostic

The integrated offering from Viralgen makes us an attractive partner for all types and sizes of sponsors who are developing AAV-based gene therapies. Virtual and near-virtual companies, with just one program and little experience and resources, are suited to reap the greatest benefits from our platform process and supplementary development services. At the same time, large biopharma companies with strong development teams and counterparts for our experts at Viralgen can seamlessly transfer established technological processes to us to enable larger-scale production.

One common theme among all Viralgen’s customers is a focus on innovation — they all have a high level of expertise in AAV vectors and/or certain diseases. Many rely on Viralgen, with its end-to-end services, to act as their external chemistry, manufacturing, and control (CMC) arm, supporting early development through CMC package creation and IND and Clinical Trial Application (CTA)/ Investigational Medicinal Product Dossier (IMPD) filing.

In addition, larger and more established companies working to consolidate AAV programs acquired from smaller players who previously partnered with Viralgen often elect to maintain those relationships. As a result, Viralgen’s customer profile is gradually shifting to a balanced mix of small and large clients. With the new commercial facility, the company has the capacity and capability to support all these programs and help the advance to commercialization.

Some Big Questions Still Need to be Answered

There remain important questions that need to be answered. Regulatory uncertainty must be resolved, which will require further collaboration among the diverse stakeholders in the cell and gene therapy ecosystem, including biopharma and biotech companies, CDMOs, and regulators. More centralization and clarity are needed on what is required for AAV-based therapies, which can only be realized by sharing knowledge.

Furthermore, questions remain unanswered regarding the best designs for clinical trials investigating AAV-based therapies, particularly those conducted in rare and ultra-rare diseases. Many positive steps forward have been taken regarding novel trial designs and the use of different endpoints and indicators of performance, but there is still much opportunity for improvement.

De-risking programs remains an urgent area of focus for sponsors. Increasingly, de-risking is being achieved through partnership with CDMOs with experience working on a broad array of AAV manufacturing projects covering diverse GOIs and serotypes. However, this approach relies on the formation of true, two-way partnerships founded upon strong collaborations. Such collaborations will also accelerate advances in the gene therapy field more quickly than would be possible if each drug developer directed funds to building their own capacity, which reduces their ability to progress candidates through later development stages to commercialization.

Sponsors also face questions around reimbursement and how to commercialize products that do receive marketing approval. Notably, the answers can vary significantly across geographies. Viralgen anticipates ongoing debate and innovation around reimbursement systems. Circling back, the cost picture relates directly to this issue, and the development of cost-effective production platforms have the potential to impact this debate.

Small Changes Could Have a Big Impact

Even small advances/changes that can be made to existing AAV manufacturing processes could have enormous impacts on productivity, efficiency, and ultimately, process economics. Establishing stable cell lines is one potentially transformative change. While the underlying technical challenges are not trivial, they nonetheless represent a solvable problem that will eventually have a significant impact.

There is also tremendous excitement about combination treatments in which AAV-based therapies are administered in conjunction with more traditional medicines. As more AAV-based therapies receive marketing authorizations, and the volume of safety and efficacy data for these products expands, the benefits may become clearer, while risks may decrease. It may therefore become an established component of a larger range of delivery vehicles for use, depending on the indication. The biggest advances are likely to result from further innovations in capsid engineering and may be realized in the form of lower doses and increased tissue specificity.

While Viralgen is involved in all aspects of AAV development and innovation, the company’s focus is supporting companies in their transition from clinical to commercial manufacturing. That includes understanding their CMC strategy as early as possible to enable seamless scaleup from 2L development runs to 2000L commercial processes. Viralgen provides this support in part by being proactive and transparent regarding how customer products will evolve as they advance from one process scale to the next. We also offer capabilities such as manufacturing, science, and technology (MSAT) and development services, as well as an understanding of packaging biology and how each product will fit onto the Pro10 ^TM platform — everything needed to ensure successful commercialization of client AAV-based gene therapy products.

Expecting Significant Additional Growth

Viralgen Vector Core was launched in 2017 with a staff of just 10 people. The company now has over 400 employees. The combination of our highly skilled and talented team and our capacity position the company well to meet the growing clinical and commercial demand for AAV vectors anticipated over the near term.

With that, future expansions are expected. From 2026 to 2028, Viralgen will likely construct additional manufacturing modules beyond the three modules currently in the works. The first, with three suites and production scales up to 2000L, is fully commissioned. Construction of one of the two remaining modules could be accomplished in a matter of 15–18 months and would be accompanied by the addition of 100–200 personnel. The last module could potentially be used for GMP development services or production of an as-yet-unidentified modality.

Benefits of the Basque Country

The Basque Country of Spain is an interesting and beautiful area that is attractive to international talent. It is also very close to many different universities and institutions in both Spain and France that contain research groups focused on gene therapies, providing easy access to local talent. This combination leads to a very stable workforce for Viralgen. Our turnover is less than 3% (compared with 10–20% at CDMOs in the United States). As a result, the same experts support customers throughout the entirety of their development projects, which can last anywhere from three to eight years, and enables smoother transitions and often time and cost savings for our clients.

Originally published on PharmasAlmanac.com on November 28, 2023.

In the evolving cell and gene therapy sector, regulatory frameworks strive to keep pace with rapid advancements in development and manufacturing technologies and treatment approaches. The current guidelines, especially for viral vector production, remain a patchwork of broader biopharmaceutical regulations, necessitating a nuanced interpretation by manufacturers, who must adapt their quality systems to ensure safety and efficacy. Regulatory maturity in this sector mirrors the lengthy journey of monoclonal antibodies, which required decades of collaborative efforts between industry stakeholders and regulators to establish. The FDA has been proactive in issuing high-level guidance that balances the need for direction and manufacturing flexibility, while harmonization efforts continue internationally. As the industry progresses, it is crucial that emerging regulations foster innovation without sacrificing patient safety and that they are clear and adaptable enough to meet the diverse needs of therapies in development. For cell and gene therapy developers aiming to advance their novel therapies while navigating this regulatory complexity, a manufacturing partner who is well versed in the existing regulations — and has a strong understanding of the sensibility of regulators to anticipate expectations where details have not yet been defined — can be critical to success.

Navigating the Frontier of Biomedical Innovation: The Cell and Gene Therapy Explosion

The cell and gene therapy sector represents the forefront of biomedical innovation –– a burgeoning field that promises to revolutionize the way we treat disease. Over the past five years, the landscape has undergone clear shifts as regulatory bodies adapt to the rapid pace of scientific advancement. Despite these strides, the field remains in its formative stages, marked by a pressing need to fully understand the in vivo activity of these novel therapies and their therapeutic consequences.

With each therapeutic candidate progressing through pivotal first-in-human trials and onward toward Biologics License Application (BLA) filings, the intricacies of regulation grow more pronounced. This expansion is reflected in the guidelines that the U.S. Food and Drug Administration (FDA) has issued, driven by the growing numbers of cell and gene therapies seeking approval and the industry’s need to prepare for regulatory scrutiny. The trend suggests a future rich with regulatory refinement as the discipline flourishes.

The FDA has predominantly concentrated on the clinical trial spectrum in their guidance, with the manufacture of viral vectors receiving less direct attention. This lack of targeted guidance is felt acutely as the diversity of vectors, especially those subjected to complex engineering, expand in advanced therapeutic trials. Leveraging existing frameworks for finished products provides some direction, but the absence of explicit standards means that safety assurance falls heavily on manufacturers. This is a complex endeavor for contract development and manufacturing organizations (CDMOs), who must navigate a mosaic of client expectations and a variety of interpretations of the insufficiently detailed existing regulations.

While the roadmap for adeno-associated viral (AAV) vector production has been relatively well established, a unified guidance detailing explicit requirements for all types of vectors — including retroviral (RV) and lentiviral (LV) vectors — is essential. Standardizing expectations would not only clarify the regulatory pathway but could also expedite the journey of these cutting-edge therapies from conception to clinical reality.

Challenges with Evolving Tech

The continual introduction of improved technologies for the manufacture and analysis of cell and gene therapies is a double-edged sword that further complicates regulatory compliance. While new technologies promise enhanced efficacy and precision, they also introduce a complex layer to regulatory adherence. CDMOs like Genezen typically seek newer technologies and to be at the forefront of technology innovation. However, that commitment presents unique challenges, particularly when transitioning programs that were initiated using older technologies and methodologies. When these programs are transferred in, the ensuing data differences must be addressed by conducting bridging studies to clearly demonstrate the comparability of the product produced using both the old and newer technologies. Such diligence is crucial in demonstrating to regulatory agencies that, despite the evolution of technology, the core therapeutic value remains consistent and reliable.

Regulatory Differences for Raw Material and Drug Substance Vectors

Whether a viral vector is used for in vivo gene therapies or to modify cells ex vivo has thus far been the fundamental determinant of the level of regulation guidance that has been issued. AAV vectors are largely used for in vivo therapies and thus are considered drug substances formulated into drug products. RV and LV vectors, meanwhile, have largely been used for ex vivo cell modification, and as such are considered critical starting materials / drug substances.

It is natural that products being administered directly to patients require more regulatory scrutiny. The same is true in conventional biologic and small molecule manufacturing. Critical raw materials must meet minimum requirements, drug substances receive additional scrutiny, and drug products are the most heavily regulated, as they are directly administered to patients. Cells modified ex vivo with LV or RV vectors in the manufacturing plant undergo various clarification and purification processes, at the end of which most concerns associated with the vectors have been resolved.

The Replication Competence Issue

A crucial regulatory mandate for RV vectors used in cell and gene therapies is ensuring that they are devoid of their natural replication ability. Engineered vectors must be demonstrably replication-incompetent to preclude any risk of proliferation within the body. This stringent requirement has tempered the widespread adoption of RV vectors in gene-modified cell therapy production. Genezen has scientists with extensive experience developing and performing the required assays for detecting the presence of replication-competent viruses and is thus well positioned to guide clients through the complexities of employing RV vectors, ensuring regulatory compliance, and advancing therapeutic innovation.

Reaching Full Regulatory Maturity Will Take Time

Regulatory maturity is only reached once a deep understanding of both manufacturing processes and clinical behavior and performance is realized. For monoclonal antibodies (mAbs), it took the industry about three decades to reach that point. A similar timeline can be expected for cell and gene therapies and the associated regulatory landscape.

As the industry makes advances in product designs and manufacturing and formulation technologies, it takes time for regulators to learn how these changes will affect the behavior of the new therapies and to determine what regulations should be put in place. In addition, regulatory authorities remain very cautious because these treatments involve patient cells and genes, which is quite different from a small molecule drug that adjusts blood pressure. Fully understanding how these treatments affect different individuals is going to take longer than would be required for simpler therapies.

It is also worth noting that progress in the cell and gene therapy field from the perspectives of both product development and regulatory science was impacted by the COVID-19 pandemic. Access to needed materials was limited for developers, while regulators shifted much of their focus to evaluating novel vaccines and therapeutics against the SARS-CoV-2 virus. With the pandemic behind us, the shift toward cell and gene therapies that had begun before its emergence is picking up pace, and the focus of regulatory authorities is shifting as well.

The Imperative of Robust Quality Systems 

To assure the safety and quality of cell and gene therapy products, it is essential for any manufacturer, whether a biopharmaceutical company or CDMO, to implement robust quality systems. Ensuring the safety and efficacy of these therapies requires systems that can meet not only current regulatory and client needs but also anticipate future standards, and CDMOs do so with a view to supporting the full range of possible clients, from emerging pharma and biotech firms to large, international biopharmaceutical companies, for the manufacture of critical raw materials, drug substances, and drug products.

Genezen’s approach has been to ensure that our quality systems meet the expectations from clients and foresee as much as is possible the future expectations of regulatory authorities. As such, our quality system initially supported clinical manufacture of RV and LV vectors. It has successfully been extended to AAV vectors as well through the additional visual inspection and other final drug product–specific capabilities. As our clients progress towards market approval, our comprehensive and adaptable quality systems stand ready to support their commercial manufacturing ambitions. Moreover, for startups primarily versed in R&D, we offer invaluable guidance on Good Manufacturing Practice (cGMP) standards, fostering a culture of excellence and compliance.

Recent FDA Guidances

Even if a CDMO is focused on process development and manufacturing and does not support clinical trial design, implementation, or management, it is still important for regulatory experts to understand regulatory guidance regarding clinical studies. To act as true partners for their clients, particularly younger biopharma companies new to the regulatory approval process, CDMOs that provide preclinical and clinical manufacturing services must be knowledgeable about regulatory expectations for the materials used in those studies.

While the limited guidance covering the manufacture of viral vectors has been around for a while (Recommendations for Microbial Vectors used for Gene Therapy (September 2016); Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products (August 2015); Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products (March 2015); and Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013)), the FDA has been actively issuing new guidances pertaining to clinical trials.

These newer guidances include Human Gene Therapy for Rare Diseases (January 2020), Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations (September 2021), Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial (November 2022), Human Gene Therapy for Neurodegenerative Diseases (October 2022), and Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products (January 2024).

Some of these guidances, such as the one focused on neurodegenerative diseases, open pathways for cell and gene therapy developers and provide them confidence in their ability to prove clinical performance to regulators, which will likely trigger the development of more treatments for these types of diseases.

The guidance on CAR-T cell therapy is equally important. It is now finalized, removing many of the previous uncertainties faced by developers. It also includes some specific requirements for the viral vectors used to produce CAR-T cell therapies, which are beneficial for manufacturers as well. That a guidance for these therapies has been issued reflects the fact that these treatments are better established than most others in the wider cell and gene therapy field.

The most recent draft guidance on Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products, which was issued in July 2023, does impact viral vector manufacturers. Specifically, this document outlines the types of data needed to demonstrate comparability when making a process change. It is particularly important for CDMOs such as Genezen, where cutting-edge technology platforms often introduce enhancements beyond the original processes of our clients. Clarification of what data are needed to justify such manufacturing changes is therefore highly relevant.

Genezen prides itself on being thoroughly informed of the latest regulatory updates. Our commitment to regulatory compliance is more than procedural—it’s about partnership. We align closely with our clients’ ambitions to pioneer cell and gene therapies, dedicating ourselves to the collective goal of advancing treatments that hold the promise to transform patient care and outcomes.

More Regulatory Actions Anticipated

The key to successful pharmaceutical industry regulation is to provide appropriate guidance with appropriate regulatory requirements. It is difficult for manufacturers if sufficient guidance is lacking, as that often means deciphering which aspects of all other existing regulations may be potentially applicable — a massive undertaking. It is equally challenging if too much guidance and requirements must be followed, as that prevents flexibility and innovation, which are both essential to the effective performance of CDMO services. The middle ground is best.

In the case of viral vectors, there’s a pressing need for more precise guidelines that clarify which existing regulations apply and what the FDA and other regulatory authorities intend in the context of viral vector manufacturing, a task that is currently as challenging as it is critical, requiring seasoned expertise for accurate interpretation. While the EU has taken a stricter stance in its most recent Annex, efforts toward regulatory harmonization are ongoing, including a mutual recognition program that promises more alignment in the future. After all, the fundamental goal for all is to make sure patients are safe.

As the sector grows and cell and gene therapies advance through clinical trials, we expect more comprehensive guidance to emerge. There is also the possibility that the FDA, following the EU’s lead, may revise longstanding underlying regulations to better fit modern advancements. To navigate these changes, continuous dialogue and collaboration within the industry and with regulatory bodies are paramount. Together, we can forge a regulatory environment that safeguards patient health while fostering the development of transformative therapies.

Originally published on PharmasAlmanac.com on April 12, 2024