The cell and gene therapy (CGT) industry is booming, say Sergio Lainez Vicente (Senior Manager of Business Operations in the Cell & Gene Therapy / Large Molecule area) and Jaleel Shujath (Vice President of Marketing and Content), at Absorption Systems, a Pharmaron company.
Around 1200 potential cell and gene therapies are currently being investigated, with more than half in Phase II clinical trials1. Two gene therapies and five CAR T-cell therapies are currently approved by the US Food and Drug Administration (FDA),2 and it expects to approve between 10 and 20 CGTs a year by 20253.
A key driver for the rapid growth in this industry is that CGTs have the unique potential to provide safe and effective treatments and cures for many unaddressed and often rare diseases. This list includes the 5,000 – 8,000 monogenic diseases4 that together affect around 6% of people in their lifetime, as well as a host of multifactorial diseases, such as cancer and diabetes.
However, the process of bringing these therapies to market is complex. Technology is rapidly evolving, and regulatory requirements are constantly shifting to keep pace with advancements to ensure safety and efficacy. Additionally, translating a CGT from a biological concept to a scalable and manufacturable treatment is fraught with costs and complications that can threaten a treatment’s commercial viability. These issues arise because many CGT developers don’t have the in-house know-how to meet stringent Chemistry Manufacturing and Controls (CMC) requirements or the capacity to develop and manufacture CGTs at scale and in a cost-effective manner.
Such challenges are fueling the explosive growth of a new kind of CGT-oriented service provider – one that combines the capabilities of both a contract research organisation (CRO) and a contract manufacturing organisation (CMO) to deliver the entire spectrum of development services. Now, a CGT can be taken from early discovery to commercial-scale manufacturing by one full-service organisation.
This article explores how these ‘end-to-end’ contract development and manufacturing organisations (CDMOs) are uniquely placed to expedite CGT development and manufacturing while maintaining rigorous regulatory standards to create higher-quality therapies.
A sector full of promise – for patient and investor
We have made huge leaps in understanding human diseases in recent years, often down to the molecular level. This knowledge has fueled the advancement of CGTs, combined with the application of ever-more advanced technology and techniques that can turn promising therapies into marketable treatments. Recombinant viral vectors, particularly non-integrative adeno-associated virus (AAV) and lentiviral vectors, have been critical to the progression of CGTs through the development pipeline. When these vectors are combined with advanced cell-engineering capabilities, such as CRISPR-Cas9, their potential application is magnified. In addition, manufacturing processes have evolved with the growing adoption of automated and high-throughput technology, helping to reduce the costs and the time taken to produce treatments at scale while improving quality standards.
As more biological license applications (BLAs) and marketing authorisation applications (MAAs) are reviewed, regulatory bodies can better define the preclinical and clinical evidence needed for submission. This preliminary evidence then decreases the time necessary to take a CGT to market while increasing the chances of gaining regulatory approval.
Together, this combination of developments has made a viable and increasingly appealing CGT market. And the numbers speak for themselves: today, there are nearly 1,000 cell, gene, and tissue-based therapeutic developers worldwide, and in 2020, the industry raised $19.9 billion in investment5. We are already seeing encouraging results in the treatment of inherited monogenic diseases (including hemophilia, hereditary blindness, and many immune deficiency disorders) as well as complex diseases, such as cancers and Parkinson’s disease.
However, as more small biotechnology companies explore CGTs and their wide-ranging benefits, greater need is being generated for optimised development and scalable manufacturing capabilities.
The challenges of bringing a CGT to market
Bringing a CGT from the bench to the bedside is no mean feat. To compete in this space, developers must address the following four key challenges.
CGT developers are not alone in facing the challenges of this new, dynamic field; regulatory bodies are navigating it too. And, although authorities can now set more precise parameters for the clinical and preclinical work needed for approval, requirements are still frequently adjusted. In contrast to traditional drug review, much of the CGT review process is centered on product manufacturing and quality, around 80% according to the FDA6.
CMC data is therefore vital, and developers need to demonstrate consistent and safe manufacturing through quality control and stability tests and evidence of reproducible scaling for therapy production. CMC evidence is needed from the outset and encompasses the design, qualification, operation, and maintenance of the manufacturing facility and its supporting functions. For smaller biotechnology and academic developers, this evidence can be difficult to generate in the early stages of development.
Since the production of gene therapies requires materials of biological origin, the final treatment will always contain trace levels of process-related impurities, such as DNA, non-infectious capsids, and endotoxins. These contaminants can trigger immunogenicity in patients, both through the production of antibodies and cell-mediated immunity. Immune responses can pose a significant safety risk and potentially reduce the gene therapy’s efficacy by eliminating transduced cells. Analytical characterisation of advanced therapy medicinal products (ATMPs) is complex but must be carried out to identify and minimise these impurities.
The presence of adventitious agents must be tracked starting at the earliest stages of development, meaning sponsors should use materials from animal or human sources that are fully traceable and certified. This traceability helps ensure smooth regulatory review and supports compliance with quality assurance as part of current good manufacturing practice (cGMP).
Every element of CGT manufacturing is complex and subject to inefficiencies. The entire manufacturing process must be optimised as much as possible, carefully evaluating each step to avoid pitfalls such as low full versus empty capsid ratios that can reduce product potency, batch-to-batch variability that may result in lost lots and re-runs, and unnecessary manual processes that can lead to human error.
Such issues can be magnified when a CGT is taken from research-scale to commercial-grade manufacturing, where inconsistencies become a more significant challenge. Production processes should be clearly defined and must be adhered to from the outset. Where possible, developers should avoid significant process changes during a product’s development cycle to protect program viability. Any needed process changes require a detailed understanding of how the therapy’s components may be impacted. Satisfactory comparability assessments are also critical – without them, material comparability concerns can arise, and Phase III trials are delayed as a result. In this sense, a suitable potency assay should be validated as soon as possible in development, as this is the best way to ensure material comparability in later stages.
In all circumstances, bespoke production processes are needed to deliver the highest product quality and safety standards. However, many developers don’t have the funds to invest in the technology required to scale manufacturing processes, or they lack an understanding of the manufacturing capacity considerations.
Gaps in know-how
Although some organisations outsource parts of the process where their experience, technology, or techniques are lacking, this doesn’t fix the whole problem. Detailed knowledge of the entire process is still needed, especially regarding safety, identity, strength, purity, and quality (SISPQ) standards, defining and meeting critical quality attributes (CQAs), and conducting robust risk assessments.
Without access to specific expertise, at the right time, developers can experience delays that lead to missed opportunities and escalating costs, particularly in later stages requiring manufacturing at scale. Despite this need, there is a critical shortage of experienced, qualified personnel in the CGT sector.
A new generation of CDMO is mobilising the CGT industry
A new breed of CDMO is stepping up to support CGT developers as they face the many challenges presented by this exciting yet demanding sector. Some leading CDMOs have evolved to deliver a truly end-to-end model of CGT development and manufacturing capabilities. This model covers the full spectrum of knowledge, technology, and techniques needed to successfully bring a novel CGT to market in an efficient, cost-effective way while maintaining the highest safety and efficacy standards (Figure 1).
Perhaps the most significant benefit of these specialised CDMOs is their many years of experience and deep know-how. Although the field is relatively new, these CDMOs typically have experience working on multiple CGT programs and have unique access to the limited talent pool that can understand and rapidly troubleshoot emerging issues. Often, teams will have open lines of communication with regulatory bodies that enable right-first-time submissions.
But submission is only part of the picture. CGT-specialised CDMOs have the tools and resources to conduct the robust analytical testing needed to maximise the safety and quality of therapy. This approach is supported by a deep understanding of the biological approaches, platform technology, possible biological contaminants, and the actions that can minimise them.
Since CMC data is so crucial to regulatory sign-off, it must be designed into the development program from the outset. By using highly automated, high-throughput technology and workflows, end-to-end CDMOs can remove the manual tasks that cause errors and delays, ensuring adherence to the highest manufacturing standards. Single-use bioreactors, proprietary vector platforms, and the latest gene-editing techniques are regular features of the manufacturing arm of these organisations.
Some of the more advanced end-to-end CDMOs have the flexibility to manage many projects in parallel, increasing the manufacturing capacity available to CGT developers. This capability will be critical in reducing the approximately 18-month average lag period currently facing CGT developers as they attempt to enter manufacturing stages7. A CDMO that can flexibly change with the needs of the CGT developer and its multi-product pipeline means a stable and lasting partnership can be formed, further fueling success for all stakeholders.
How are end-to-end CDMOs meeting CGT industry demand?
Currently, the industry has 5-10% of the manufacturing capacity needed for the CGTs now in development,7 but that is rapidly changing. CDMOs are expanding capabilities through acquisitions and mergers, incorporating development and manufacturing functionalities where gaps previously existed. Several significant investments have already taken place, including Thermo Fisher’s recent acquisition of viral vector manufacturing company Brammer Bio, and Pharmaron’s acquisition of US-based CRO Absorption Systems and a multi-purpose Liverpool-based biologics facility from AbbVie. Some CDMOs are building out their infrastructure through organic growth, although this is a slower approach.
Critical considerations for a successful end-to-end CDMO partnership
As the CGT sector advances and ever-more therapies seem destined to make it from the bench to the bedside, end-to-end CDMOs will be vital in helping developers compete. Innovation in this sector will continue at speed, and as it does, developers must collaborate with the right end-to-end CDMO partner. Here, several key considerations can maximise the chances of success.
It is essential to engage with CDMO partners in the earliest stages of preclinical development, keeping commercial manufacturing goals in mind. This proactive engagement ensures more efficient transitions between program phases and that preclinical stages are optimised for later-stage challenges, such as scale-up or scale-out activities. On top of this, developers should explore whether a partner can offer the following:
- True end-to-end capabilities, from preclinical stages all the way through to post-approval stages.
- A proven track record of developing highly complex CGTs and, ideally, extensive CMC experience paired with a portfolio of successful CMC submissions. This will ensure smoother regulatory review and increased chances of approval.
- Deep process customisation to fulfil quality and cost-effectiveness expectations. CDMOs must have access to the latest technology to do this. A suite of automated analytical capabilities for thorough CGT characterisation is also beneficial.
- Extensive capacity to cope with varied, multiple CGT developments, as well as the ability to meet rising demands. This is critical, particularly with the growing use of systemic indications for gene therapies, for which commercial vector genome estimates may be staggering.
- Highly optimised processes that can reduce the cost of goods sold through purification or efficient scale-up and scale-out.
The new generation of end-to-end CDMOs presents the logical partnership for CGT developers of all sizes as they fiercely compete to gain market share. They have the technology, know-how, and flexibility to streamline development, increase manufacturing efficiency, and reduce costs while ensuring the highest safety and quality standards.
Sergio Lainez Vicente, Ph.D., serves as Senior Manager of Business Operations in the Cell & Gene Therapy / Large Molecule area at Absorption Systems, a Pharmaron company. Dr Vicente received his Ph.D. in Biochemistry from the University of Valencia, Spain. He has over 12 years of experience within the regenerative medicine space. He has contributed to 17 peer-reviewed publications in prestigious journals, including Nature Genetics, Science Translational Medicine, and Stem Cells. His current role involves helping developers to design and complete pre-IND analytical, bioanalytical, and in vivo studies to support their ATMP development programs.
Jaleel Shujath is Vice President of Marketing and Content at Absorption Systems, a Pharmaron Company. Before joining Absorption Systems, Shujath defined and marketed technology solutions to the life sciences sector, including GE Healthcare, PBL Assay Science, ATCC, and OpenText. Jaleel is a Six Sigma Green Belt and a member of the Drug Information Association, Parenteral Drug Association, International Society of Pharmaceutical Engineers, and the Editorial Board of the American Pharmaceutical Review.
- In: Rodwell, C., Aymé, S. (eds.) (2014). 2014 Report on the State of the Art of Rare Disease Activities in Europe Part Ii: Key Developments in the Field of Rare Diseases in Europe in 2013. 1–90