Introduction: Miguel Forte
The mission of ISCT is to foster the development of innovative cell and gene therapies for the benefit of patients worldwide with unmet medical needs. The ISCT has the vision to achieve this goal through the joint and collaborative efforts of the membership involved in cell and gene therapy product development aiming at delivering thought leadership for the sector.
The ISCT Commercialization Committee (CC) is the forum of stakeholders to enable that collaboration in particular between the academic and the industrial sectors. To achieve that thought leadership and networking in the field, the CC has developed the Signature Series of focused meeting sessions where the leaders in the field discuss recent and future developments in cell and gene therapy.
The second ISCT Commercialization Committee Signature Series was held this past January at the Phacilitate meeting. After a successful inaugural event in 2016 at the ISCT North American Regional Meeting, focused on a broad overview of challenges and roadblocks to commercialization, this event turned it’s focus towards product characterization and comparability, essential topics to adequately harness and control any product development, but of particular complexity in the context of live replicating cell products.
Adequate and timely consideration and planning on these topics will be critical success factors for any organization involved in supporting or developing new products. The content of the information shared in this session and, above all, the level of engaged discussion throughout the event attest to the degree of expertise and passion of all those involved.
We hope that this document not only translates that passion and focus but represents a valuable tool for all those that are involved in this field and aim, like us, to bring new solutions to serious patient needs.
As a benefit of ISCT Industry Membership, all Patron and Partner members are entitled and welcomed to participate in this yearly event. Be sure to join us in Miami, next January. There, we will be addressing the expanding topic of launch and market access of cell and gene therapy products from a multiple stakeholder perspective, including physicians, payers and patients.
Citation: Cell Gene Therapy Insights 2018; 437-456.
The Road Forward For Uniquely Personal and Readily Identifiable Cellular Therapies
The cell therapy industry has seen huge gains in recent years with no end in site. Bruce Levine, Barbara and Edward Netter Professor in Cancer Gene Therapy at the University of Pennsylvania gave an overview of some of the industry’s most compelling research and highlighted potential improvements to increase success and access of cell therapies.
ALL patient Emily and CLL patient Bill were treated with CAR-T therapy 5.5 and 7 years ago, respectively, and are still cancer free. Levine showed data illustrating the long-term function of the transplanted T-cells. After only one administration, 3.5 years later, functional CTL019 T-cells are still present in the patients. Newer data shows that even after 7.5 years, CAR-T cells are still detected in the first two CLL patients. These patients and data exhibit the power and potential of CAR-T therapy.
One issue faced by cell therapy companies is variability of patients and incoming material. There is not yet enough data to apply AI technology to help in devising process conditions for greater consistency. Currently, even with conditional manufacturing, product function is inconsistent, even though product phenotype may be uniform. Levine uses an example of an exceptional responder who failed to respond until 51 days after transfusion, whereas most patients responded after only a few weeks. After a molecular analysis, it was found that the clinical response of this patient was due to a single clone, probably a single cell. It was the right cell to help this patient, but how is the “right” cell characterized so it can be selected up front? In addition, there is presently no correlation between number of cells infused and clinical response. There is still much room for improvement for consistency of CAR-T therapies.
A question plaguing the industry is why CAR-T therapy is so expensive? Levine shows that in a comparison between chemotherapy and CAR-T therapy, CAR-T therapy has a plethora of benefits. On average, patient treatment with chemotherapy takes 12 years, while CAR-T therapy only 3 months. Additional benefits of CAR-T therapy are ⅓ the amount of hospitalizations, a ⅙ the amount of doctors appointments, ½ the amount of surgeries, 1/7 the amount of bone marrow aspirations, 1/13 the number of spinal taps and ten times less pills taken compared to chemotherapy. The benefits of CAR-T therapy are clear. An analysis of the financial impact of pediatric patients with ALL showed that after five years, costs added up to over a million dollars. Taking into consideration the huge expense of alternative therapies to CAR-T and personal patient and family impact, the cost of CAR-T seems justified.
Demonstrating manufacturing comparability is also a challenge faced by the cellular therapy industry with processes that are constantly changing and improving. FDA guidance is available for comparability testing, which is helpful, especially in the tech transfer process. There are also considerations when deciding whether to centralize or distribute manufacturing, such as analytics, quality assurance, shipping of cells, and cost of location. All of these conditions factor into the availability and cost of therapies, which impact access for patients.
Finally, Levine brought up challenges and opportunities in cell therapy manufacturing, saying,
“what are our challenges and opportunities? Increasing consistency, managing challenging cases, manufacturing process development, implementing automation for media, vector manufacturing, developing rapid release testing, and securing the supply chain for our products, most of which have hundreds of complex components. We must have validated alternatives. We’re a mature field now and we have to think about the supply chain and transport logistics.”
Is there a scenario in our commercial reality where patients’ material could be collected earlier, to get starting material that’s better quality? Can we make the assumption that you’d have a better product if collected earlier?
|Bruce Levine: Logistically, we absolutely can collect earlier, but who is going to pay for it? It’s possible to do this under the auspices of a clinical trial, but who is going to pay for storage? I have had patients or families of patients saying that they want their cells collected and saved just in case they ever get cancer, similar to the cord blood bank model. I think we may see that in the future, based on what we’ve seen from the “stem cell clinics”. Someone will start a “bank your T-cells company” and promise something that they won’t be able to deliver on. It then becomes an ethical question. Overall though, yes, if we collected earlier, it would be easier to manufacture and we’d have better quality cells, but how do we get there?
|Mark Lowdell: I think the problem there is defining what is better quality. I started many years ago looking at mathematically modelling the immune system. What we concluded, is that the immune system is chaotic, purely mathematically it follows all the rules of chaos theory. It is completely unpredictable by its nature. That’s the story we need to pursue with regulators and the field. Wherever you start is where you start, and whatever you get is what you get. You can’t pick patterns. If anything, patterns show up when the therapy is put into the patient.
Product Characterization and CQA
|Ohad Karnieli & David Di Giusto
founder of Consulting on
Advanced Biologicals Ltd
Head of Analytical Development at Cell and Gene Therapy Catapult
Department Head of the
Department of Cellular Therapy at Oslo University Hospital OUS, RAD
ANALYTICS FOR PRODUCT CHARACTERIZATION REGULATORY ASPECT
The regulatory submissions of cell and gene therapies cover an array of metrology techniques applied to process control. Christopher Bravery, founder of Consulting on Advanced Biologicals Ltd. discussed common pitfalls in process control parameters related to metronomy using examples from real-life ATMP submissions and ultimately focused on the possible deficiencies of potency assays.
When testing process control parameters, together with the metrology, companies must justify that the assay used is appropriate for measuring that particular attribute, that the attribute’s measurement is critical to quality, and clinical qualification of the attribute. Common areas of process control criticized by the EMA are in-process testing and release testing. Bravery breaks down release testing and explains frequent issues such as “weak specification”, which means your release tests are not sufficiently broad, and the potency method, commonly criticized for the appropriateness of the assay. Potency measurements are a frequent issue because the measured potency does not correlate with the clinical outcome. Instead, as a minimum, the potency method should be able to detect sub-potent products.
Bravery highlighted EMA comments from several ATMP submissions, which showed trends regarding potency testing deficiencies:
•The testing for Oronera was considered too limited and the correlation between potency, biological function and clinical efficacy was not established.
•For the prostate cancer drug Provenge, CD4 is used as a surrogate marker for potency, but it’s unclear whether the acceptance criteria set by the market authorisation holder are relevant and able to detect sub-potent batches.
•For Hilograph C, the potency assay is not sufficiently correlated to biologic activity.
•Additional clarifications with respect of acceptance limit and suitability of potent tests to eliminate sub-potent batches is needed for Heparis.
A considerable problem with potency assays are that they quantitate an analyte, but that measurement may not sufficiently relate to the mechanism of action. Therefore, are they truly testing potency? Bravery said no. For a true potency test, results should be within a range, as opposed to a threshold. The threshold may distinguish between potent and sub-potent, but not correlate with clinical outcome. It may, however, be unrealistic to expect the quantification of true potency.
At approval, a combination of process capabilities are considered in potency specifications, including batch data, analytical capability, and clinical outcome. Analytical capability is often overlooked and describes the capability of the assay in terms of precision and repeatability. If a relationship between potency and clinical outcome can not be established, sub-potent product needs to be identifiable, at least.
When developing a process for the manufacturing of cell or gene therapies, a well thought out analytical strategy is critical. Analytics are used to get better process knowledge, understand the sources of variability to better manage it, and drive down the cost of goods for manufacturing. Damian Marshall, head of analytical development at Cell and Gene Therapy Catapult discussed the practicality of process analytical technologies (PAT) and how it can be applied to cell and gene therapies. Below are the major themes and points discussed in Marshall’s talk.
PAT is a framework for adding analytics into a manufacturing process and making measurements during product manufacturing, with the end goal of establishing a manufacturing process that ensures a quality product to pass release testing. The aims of PAT are to identify and manage sources of variability, reduce costs by optimising the use of raw materials, and minimising product cycle times. Since PAT is being adopted more frequently in the biologics manufacturing field, there are many technologies being developed to support the implementation. Unfortunately, many of these new technologies are not designed to measure cell quality or fit with current cell therapy manufacturing methods.
Adapting biologic analytic technologies to fit into the cell therapy manufacturing process is a significant challenge. PAT sensors should measure something related to the critical quality attribute that directly impacts the release specification of the product. The challenge is to adapt PAT sensors made for biologic manufacture and establish that they measure something applicable to cell therapy. Marshall points to Raman Spectroscopy as a technique that may be suitable for measuring multiple analytes and cell growth dynamics simultaneously within a cell therapy manufacturing process.
Raman Spectroscopy uses a laser to detect molecular vibrations paired with chemometric modelling to identify and quantitate molecules over time, such as known metabolites glucose and lactate. This technology requires calibration against reference data sets, which can potentially cause issues when reference data is not within the testing range. However, without a reference, another approach can be used to correlate shifts in the Raman spectrum with a characteristic of interest, such as viable cell density. This can be particularly useful when identifying cell growth phases are a critical part of the manufacturing process.
Once sensors are carefully chosen and integrated into the process, to fully capitalize on the data, adaptive manufacturing can be applied. To enable adaptive manufacturing, real-time product monitoring needs to be integrated with an automated process control system. Manufacturing decisions can then be based on an unbiased multi-parametric data approach. However, a significant challenge to achieving this idealized system is handling the data, since the various sensors report data in different formats. Additionally, the volume of data is enormous and needs to be handled appropriately for maximal efficiently. Some points to consider when developing computer integrated manufacturing include rapid analysis and decision making, handling data from multiple sites, moving large datasets, processing multivariate data, and data mining.
Is Raman spectroscopy ready for use in a cell therapy manufacturing process for testing metabolites and viable cell density?
|Damian Marshall: One of the reasons we selected Raman spectroscopy is because of the current use by the biopharmaceutical industry. The equipment is now available to fit into manufacturing processes. Five years ago, these were lasers bolted onto an anti-vibration table running only in academic labs. Now, the technology is fully developed and you can pretty much plug it in and get your Raman data, develop models, and then run it for real-time analysis once you’ve shown that your model is robust enough. It will probably take a while to see it used more regularly in our field. We’ll need a significant body of measurements to show the value of this evidence. Another challenge is the price. A Raman system will cost about £180,000 to monitor 4 bioreactors. You have to weigh the cost of the equipment with the value of the information it outputs in real time.
PRODUCT CHARACTERIZATION FROM ACADEMIA TO INDUSTRIALIAZTION AND ACADEMIC MANUFACTURING EUROPEAN PERSPECTIVE
With eight production rooms, a qualified QC area and a strong clinical research unit, the GMP facility at the Department of Cellular Therapy at Oslo University Hospital, built in 2009, is considered one of the largest and most modern facilities in Europe for cell and gene therapy manufacturing. There are 37 people working at the facility broken into the clinical somatic cell therapy, clinical GMP therapy and immuno-monitoring/T-cell therapy divisions. Gunnar Kvalheim, Department Head of the Department of Cellular Therapy at Oslo University Hospital discussed experiences and challenges faced at the GMP facility.
When working with stem cells, manufacturing cell and gene therapies, and producing products for different countries across Europe, GMP facilities are required to be inspected and accredited by a slew of regulatory agencies. Oslo University Hospital’s GMP facility has had its fair share of inspections and paperwork leading to several accreditations from within Norway, the European Union, and Germany. The GMP documentation required for the German Medical Agency alone weighed over 22 Kgs. Kvalheim said that submitting correct and sufficient documentation to regulatory agencies is a consistent problem faced by GMP facilities.
Regulations shape strategies for manufacturing and clinical trials of cell and gene therapy products. One way is through the Hospital Exemption (HE) scheme (discussed further in Mark Lowdell’s talk), which is highly debated across Europe. Oslo University Hospital’s GMP facility is in contact with the Norwegian medicine agencies and currently using the HE scheme as a strategy for early phase testing of cell therapy products. There is still a lot of testing and documentation required to apply for the exemption (approximately 5 Kg’s worth, according to Kvalheim), but there is less than what is required by an IMPD.
An interesting technique that Kvalheim discussed for GMP production of CAR/TCR T-cell therapies and dendritic cell (DC) vaccines was the use of electroporation of mRNA for transient gene expression, in lieu of a viral vector gene delivery system. The facility found it very complicated to produce viral vectors in an academic setting, especially with the requirements set forth by the health authorities and innovation medicine agencies, and therefore decided to use mRNA electroporation. Gene expression using their mRNA platform results in transient expression for 5 to 6 days. From a regulatory perspective, this short lived expression is not regarded as a gene therapy in Europe and has an easier time passing through regulatory agencies. Kvalheim showed data that illustrated the effectiveness of using transient expression of CAR/CD19 in T-cells in a mouse xenograft model, however acknowledged that for hematopoietic disorders, where perpetual CAR expression is favorable, using a virus for gene delivery is the best route.
Kvalheim also discussed the costs associated with GMP-production of CAR/TCR T-cell therapies and DC vaccines with their optimized platforms. For each step in the manufacturing process, such as leukapheresis, cell culture, electroporation and product release, there are many professionals working dozens of hours and an abundance of disposables that need to be purchased. Facility maintenance, quality management and facility staff costs also factor into the costs of manufacturing. Kvalheim estimates that in Oslo, for only one patient, GMP-production for DC vaccines cost $20–30,000 and CAR/TCR T-cell therapies cost $40,000. The costs for a trial add up quickly when production costs for each patient are so high, but who pays? Grants from the government or private philanthropy funds partially cover costs, but Kvalheim asked about what role industry has in sharing the cost. The question of cost is something that academia is currently facing.
Does the Department of Cellular Therapy at Oslo University Hospital prospectively develop therapeutic products for eventual commercialization?
|Gunnar Kvalheim: Academia does not have money to run large-scale T-cell therapies, such as CARs. We have the skill, but academia could not handle 100 patients. What we do now, is explore the potential therapies in the first patients and then must collaborate with industry. The limitation is the number of patients we can serve.
|Gerhard Bauer & David Smith
||David Di Giusto,
Executive Director of Stem
Cells and Cellular Therapeutics
Operations at Standford Uni-
versity School of Medicine
Professor of Internal Medicine
and Director of the UC Davis
Professor of Cell and Tissue
Therapeutics, and Director of
Cellular Therapies at the Royal
Free London NHS FT
Project Management and
Scientific Director of
Business Leader, Technology
Development & GTP Services
at Hitcahi Chemical Advanced
ACADEMIC PERSPECTIVE ON CELL AND GENE THERAPY DEVELOPMENT AND MANUFACTURING
Academic institutions are not only a source for basic research, but also for translational research and comprehensive clinical studies. David DiGiusto, Executive Director of Stem Cells and Cellular Therapeutics Operations at Standford University School of Medicine spoke about the benefits and challenges of developing cell and gene therapy products at Stanford.
Between 2013 and 2015, 140 assets were licensed to biopharma by 44 universities. 100 of them were staged as “research projects” or “pre-clinical”, while only 4 assets were licensed at the Phase I/II stages. This shows that pharma is looking to academia for potential products and carrying them through development, which is risky and costly. But for cell and gene therapy products, development is even more risky with a large upfront investment and expensive manufacturing and clinical trials. It requires a close partnership with academic subject matter experts and novel regulatory processes. Therefore, a new model of development is required to bring cell and gene therapeutics to patients. This model enables you to de-risk a potential asset within the academic setting and thus building value into the asset before you push it towards the clinic.
Although cell and gene therapies show great promise, there is limited clinical success to date, and translation of these therapies requires new riskier territories. The field needs novel technology developments and mechanisms for translation. Bridging the gap between basic research and clinical science is needed to define critical quality attributes and treatment paradigms. Working directly with investigators and regulatory experts provides product-specific expertise, required to shepherd assets through the translational value chain and regulatory process. With the significant amount of customization required for cell and gene therapy manufacturing, new capabilities are needed, especially when considering that, in many cases, there are sole-sourced providers for either equipment or reagents that put the products at great risk.
Stanford is trying to satisfy the needs of cell and gene therapy development with a new state-of-the-art GMP facility, highly funded cell and gene therapy program, and access to hospitals and patient populations for clinical trials. DiGiusto said that his goal is to develop a pipeline of products that becomes the future of the service line at Stanford hospitals. To do this, every potential product is assessed for scientific, technical, regulatory, clinical and financial parameters. Once it’s established that a project is ready for manufacturing, the process is carefully developed, which can take between six months and a couple of years, depending on the project. Once a product is manufactured, clinical assessment is supported, by assessing safety, feasibility, efficacy, dosing and more. The idea is to develop a product, not just perform an academic assessment in a clinical trial.
One challenge to product development in academia is getting the principle investigators (PIs) on board with the idea of process development. Some have said that they want to take their product straight into Phase I clinical trials and don’t understand the value of developing a reliable process upfront. Others want to choose services from of a menu. Instead, it’s important for PIs to understand that working with a manufacturing and development group is a strategic partnership with a common goal of bringing new therapies to patients.
PRODUCT MANUFACTURING IN AN ACADEMIC ENVIRONMENT
Gerhard Bauer, Professor of Internal Medicine and Director of the UC Davis GMP Facility spoke about the great strives that UC Davis has taken in the past eight years since their 6,000 sq. ft. GMP facility was opened. It was constructed in a way to maintain a one way personnel product and waste flow, where each room can be individually pressurised to positive or negative pressure, keeping every room clean. There is room for two manufacturing scenarios, although two products cannot be manufactured simultaneously, as this could lead to cross-contamination.
The facility supports investigators from the entire University of California system, as well as biotech companies. Due to their expertise, companies and academics have partnered with the facility for products requiring CD34+ cell expansion, growth of stem and progenitor cells, CAR-T manufacturing, and creation of gene therapy vectors. Bauer explained that it’s important to develop closed systems when making gene therapy vectors because open systems are not easily adaptable to future larger scale manufacturing scenarios. Aerosolisable material transmission issues arise in an open system, frowned upon by regulatory agencies. In an open system, special rooms, personnel and working environments are needed. Therefore, a closed system is more practical. Viral gene therapy vectors are of particular interest because of the growing production of CAR-T cells. The UC Davis GMP facility has adapted their bioreactor for the manufacture of viral vectors in a closed system, and found the vectors to be comparable to what was made in the open system.
EUROPEAN PERSPECTIVE COMMENTARY
80% of new ATMP and cell therapy products are coming out of academic labs. Mark Lowdell, Profesor of Cell and Tissue Therapeutics, and Director of Cellular Therapies at the Royal Free London NHS FT discussed the capabilities of academic labs and highlighted challenges specific to European development of cell and gene therapy products.
At the CCGGT (Center for Cell, Gene, and Tissue Therapeutics), there are a slew of immunotherapy and regenerative medicine products currently in development or clinical trials. They are an example of a small facility that has achieved big things because of their access to a broad range of experts and equipment within the entirety of the institution. This is an academic advantage over any single company and has proven to push products forward.
Process development, the closing of processes and regulatory filings are all achieved in-house at the CCGGT. Their perspective is that process development should be done before the start of Phase I so that the product is immediately ready for commercialization if successful and avoids process backtracking which can cause major delays. If the product is successful through clinical trials, it can either continue in academia a bit further on, or immediately be handed off to industry for commercialization. This decision depends on the product and how well funded and business oriented the academic is.
The development of cell therapies in Europe has regional challenges pointed out by Lowdell. In terms of regulations across the EU, there is a lack of harmonisation. The interpretation of the legislation across the EU is not uniform. The Hospital Exemption (HE) scheme is an example of this. The HE scheme allows the use of ATMPs “prepared on a non routine basis and used within the same Member State in a hospital in accordance with a medical prescription for an individual patient,” originally authorized to give hospitals flexibility over regulatory requirements. However, some companies are using academia to apply the HE scheme for first-in-man trials because the commission ruled that first-in-man does not fall under the definition of “clinical trial”. Instead, a “clinical trial” only applies to trials for the aims of a marketing authorisation. Not all European countries agree on this ruling though. Each country, or Member State, decides how to interpret the HE scheme adding to the lack of harmonisation across the EU.
The EU is also adding new GMP guidelines relating to cell and gene therapies, which Lowdell said is the biggest challenge to the field to come in the near future. He also said that U.S. companies looking to manufacture in the UK should be aware that the facilities will not be implementing the new GMP guidelines, as the UK will be outside of the EU by the time the guidelines become legislation.
Another problem faced in Europe is the licensing of procurement. For example, procurement of a starting material for CAR-T can only be done in a facility that is licensed to procure, which then requires a contract. One can’t go to any hospital for procurement adding inconvenient red tape and convoluting the process of procurement. Reimbursement for cell and gene therapies is also setting itself up to be a huge problem in Europe. The novelty of these therapies requires new pathways to reimbursement, a challenge that companies are just starting to address.
Regarding the CAR-T clinical trials in China that Mark Lowdell mentioned in the summary discussion, how are they manufacturing the virus, are they able to support late stage clinical trials, and do they run into the same problems that other regions have?
Mark Lowdell: I don’t know how they are manufacturing their virus, but they plainly have a lot of it. From what I’ve seen in Changchun, the clinical trials unit is in a 6 story, 18,000 bed hospital. The GMP unit takes up 2 floors of the building and it seems that they have no limit to the resources they are willing to commit. I’ve been told that post-docs are sent to centres at places like the UK to learn the technology and come back to develop it in China. Due to the size of the domestic market, there is little motivation in going outside of China. It can be challenging and a missed opportunity that many of these studies are not published in peer reviewed journals outside of China. I think that in China they are manufacturing in huge facilities and making lots of vector, but until results are published globally according to international standards, it will be difficult to learn whether the same issues, notably regarding GMP, are being faced.
Regarding the CAR-T clinical trials in China that Mark Lowdell mentioned in the summary discussion, how are they manufacturing the virus, are they able to support late stage clinical trials, and do they run into the same problems that other regions have?
|Mark Lowdell: I don’t know how they are manufacturing their virus, but they plainly have a lot of it. From what I’ve seen in Changchun, the clinical trials unit is in a 6 story, 18,000 bed hospital. The GMP unit takes up 2 floors of the building and it seems that they have no limit to the resources they are willing to commit. I’ve been told that post-docs are sent to centres at places like the UK to learn the technology and come back to develop it in China. Due to the size of the domestic market, there is little motivation in going outside of China. It can be challenging and a missed opportunity that many of these studies are not published in peer reviewed journals outside of China. I think that in China they are manufacturing in huge facilities and making lots of vector, but until results are published globally according to international standards, it will be difficult to learn whether the same issues, notably regarding GMP, are being faced.
Although some academic institutions have facilities for the scale-up and GMP manufacturing of cell and gene therapy products, most are confined to small-scale production and must transfer manufacturing to a contract development and manufacturing organization (CDMO). Gisèle Deblandre, Project Management and Scientific Director of Masthercell spoke about the best practices for successful tech transfer from academia to industry.
The goal of technology transfer activities is to transfer product and process knowledge between facilities and laboratories. For the transfer to be considered successful, the quality of the product needs to be equivalent in the originating lab and new manufacturing facility. Deblandre stressed the importance of having sufficient analytics to characterise the cell product before tech transfer begins to predefine success criteria with the originating lab. Reproducible quantitative assays are required to characterize the cell product and used throughout the transfer process to ensure that the product remains the same. If possible, it is also preferred to have reference samples from the originating lab for equivalence testing.
Tech transfer isn’t only the transfer of documentation or materials, but also first-hand knowledge and hands-on experience of the process from academic experts to the CDMO. Observation in the originating lab by the CDMO is critical, as is training in the new lab by expert references. Tech transfer needs to be an open, transparent, and trusting collaboration with clear roles and responsibilities. There is continuous interaction during the process to review data, troubleshoot and run back-crossed analyses. New equipment needs to be installed and qualified, and raw materials procured and tested against raw materials from the originating lab. Manufacturing training runs can then be performed, at first with reference operators, and eventually without any help from the lab.
Tech transfer from academia is just the start to a larger goal of medium- to large-scale clinical manufacturing. For scale-up, there is a significant amount of process development needed as well as GMP translation to satisfy regulations and qualify the process. Deblandre emphasized the use of a diagnostic to understand the gap between the current and final clinical processes to develop an implementation plan.
A main part of the diagnostic is a “gap analysis” with the first step as a thorough understanding of the current process from the originating lab. Second, the target, or optimal process, needs to be defined, which includes cell specifications, regulatory and clinical requirements, improvements in reproducibility and decrease in number of operations. Lastly, all of the process parameters are mapped out in table format to directly compare each step in the reference process versus the targeted clinical process. Priority numbers are assigned to each step in the process so that the items with highest priority can be included in the development plan, while lower priority items may be suggested in secondary phases of development. Once the gap is identified, a plan can be created and executed within an average of 12-18 months depending on the extent of optimization and duration of the process.
Incorporating changes into an established manufacturing process is inevitable in the field of cellular therapy where products are highly variable and manufacturing technology quickly changes. Risks, costs and impact to the product should be carefully assessed before implementing a change to avoid complications that could result in shortages or compliance obstacles. Thomas Heathman highlighted several important points to consider when the need for a process change arises. He also presented tried and true methods for mitigating risks and challenges associated with process development, summarized below.
Making a change to a manufacturing process is a monetary and time investment and should be aligned with the overall product strategy. It’s important to understand the goals of the proposed change and the payback period on your investment. Are you trying to achieve reduced product variation or costs, increased scalability, or a faster route to the clinic? Also, assessing how the change will impact risk, labor, materials and services is critical for developing an estimate on the costs and timeline for process change implementation. One must not forget to include the various stakeholders that may be affected by a process change. Clinical sites, for example, may be greatly impacted by a change in formulation or therapy administration. This information should form a strategic plan, taking all of these factors into account, which will minimize the inherent risks of making a process change.
When developing an updated process for therapies that use patient specific manufacturing, patient material is not readily available for process experimentation and optimization. Instead, volunteer (or healthy) donor material is used, which is not representative of patient material and can lead to inconsistencies moving from development to manufacturing. In this case, an assessment of the differences between the quality profiles of patient versus volunteer donor material should be performed. It is possible to modify the volunteer donor material to more closely represent patient material. For example, if the only difference between your patient and volunteer material is numbers of particular types of cells, you can artificially deplete out different cell types to achieve a more representative starting material. There are also companies that will supply material from diseased patients, which could be more representative. Small volumes of material from previous patient studies to use for process development could also be obtained, although it’s important to have a small scale version of your process to use this small amount of patient material.
Another significant problem that can occur in process development is the use of reagents from a single source. Having only one supplier leaves you at the mercy of their price, quality, and quantity. All manufacturing of your product could be shut down instantly due to an issue with only one supplier. It is critical to have backup suppliers, especially when the number of patients is growing. Another mitigation to this problem is to partner with suppliers. In this case, the strategy is to create value for both companies, rather than viewing the relationship with your outsourced partners as purely transactional.
Finally, due to the lack of a globally harmonized regulatory system for managing post approval changes, revising a process that has already been accepted by various regional regulatory agencies can become extremely cumbersome. Cell therapy companies should have a system in place, such as a quality management system (QMS), that will update process changes among the regions simultaneously and avoid repetitive process updating.
Mark Lowdell, Profesor of Cell and Tissue Therapeutics, and Director of Cellular Therapies at the Royal Free London was the moderator for the 2018 ISCT Commercialization Signature Series meeting and gave some closing thoughts based on the talks given at the meeting, summarized below
|CHINA AS A DRIVING FORCE IN CAR-T THERAPY
Bruce Levine brought up that there are a shocking 285 trials that come up when ‘chimeric antigen receptor’ is searched for on clinicaltrials.gov., the majority of which are being conducted in China.
- Lowdell spoke about his time as a chair at an international meeting in China, 2 years ago, where Chinese researchers presented on trials with hundreds of patients.
- Their data will be instrumental to the industry, however, very little clinical trial data generated in China is shared:
►Government funding is tied directly to their results and those of their competitors
►Patients that enroll in clinical trials receive free healthcare
►If a competitor’s product is performing better during clinical trials, funding can be immediately cut from your company and patients’ healthcare coverage also cut
►Therefore, it is considered rude to ask for trial data
- The benefit gained in the industry by sharing is lost
- This phenomenon could end up leading to China as the main driving force in the CAR-T therapy market-place.
|SUPPLY CHAIN CHALLENGES
One of the main themes of the meeting was the challenges faced with the supply chain.
- Security of the supply of raw materials is critical in manufacturing.
- Lowdell discussed his previous experience with this issue where trials never finished because one supplier decided to no longer support one piece of equipment. The result was having to go back through process development, validation, and eventually running out of money.
|UNPREDICITIBILITY OF DONOR MATERIAL
Unpredictable donor material is another central issue to the manufacture of cell and gene therapies.
- The logistics of the donor pathway matter:
►Donor material received 20 minutes after apheresis from within the same hospital is not the same as donor material received 18 hours later and shipped from a different country.
- Significant problems arise when the variability of starting material isn’t considered when developing a process.
|THE VALUE OF ACADEMIC FACILITIES
Four talks featured academic manufacturing units from Europe and the US.
- These displayed the considerable value that academic facilities add to commercial and academic developers of cell and gene therapies.
- However, not all units are created equal (a concept that is also true for CMOs) – these four had very experienced leaders.
- Therefore, one must be careful when choosing a manufacturing collaborator, whether they be academic or a CMO.
- Furthermore, academic investigators need to be educated on what information is necessary to share with a manufacturing collaborator to develop a robust process.
|INTERNAL PRESSURES DRIVING MANUFACTURING
Manufacturing has many drivers, which change during a product and company’s evolution, as was discussed by Thomas Heathman.
- Pressures from within a company can change based on what the board, or shareholders want and conflict with what the developer thinks is best from a manufacturing perspective.
- Lowdell shared a quote he remembered from a few years ago, that “when your company IPOs, it becomes two companies; a company that does the job, and the company that manages the shareholders.”
- Accordingly, companies need two sets of experience within to be successful.
If in 5-10 years, CAR-T is successful for more than just CD19 and cures cancer, where do you see it being manufactured? Will it go back to the hospitals?
|Mark Lowdell: I don’t see near patient manufacture of products. Hospitals wouldn’t want to manufacture because of the liability they’d be taking on. So, I think these are going to be manufactured by companies, either in a distributed or semi-distributed system. There may be elements of the process handed back to hospitals, but not the actual manufacturing. I don’t see them as a fit place for it.
|Audience Member: I feel the same way in the US. We have a handful of great GMP facilities in academia, but there are many that aren’t equipped and don’t have the personnel required for cell and gene therapy manufacturing. We need industry partners to collaborate with. The product needs to be professionally manufactured with with guidance of academics in the field. Not all products can be transported within a reasonable amount of time to where they need to be, and not all products can be cryopreserved, so fresh products are often being transported. We need to figure out where we’re going to place manufacturing centres strategically and how to supervise them with the appropriate personnel. We’ve found that experienced personnel is the problem, and not the technology. Where do we train them? We need to have a training program for this. I am currently teaching in a master’s degree program for GMP manufacturing. I’m one of the few doing this in the US.
|Miguel Forte: ISCT offers a cell therapy training course, which we now recognize has a much greater demand than we’re offering every 2 years. The next one is in Philadelphia and Bruce Levine is hosting, but we plan to expand that to a much greater offering.
Interested in Joining the ISCT Industry Community and participating in the Commercialization Committee and future Signature Series events? Contact Brian Poole (email@example.com)
The 2018 Commercialization Signature Series Attendees
Julie Allickson,Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, United States► Gerhard Bauer,UC Davis, Sacramento, CA, United States► Christopher Bravery,Consulting on Advanced Biologicals Ltd, London, United Kingdom► Gisèle Deblandre,Masthercell, Gosselies, Belgium► David DiGiusto,Stanford Health Care/Stanford School of Medicine, Stanford, CA, United States► Dawn Driscoll,Cell Therapies Pty Ltd, Melbourne, Australia► Matthew Durdy,Cell and Gene Therapy Catapult, London, United Kingdom► John Fink,Brooks Life Sciences, Chelmsford, MA, United States► Mark Flower,Hitachi Chemical Advanced Therapeutics Solutions (HCATS), Allendale, NJ, United States► Miguel Forte,Zelluna Immunotherapy, Oslo, Norway► Richard Harrison,Loughborough University, Nottingham, United Kingdom► Brian J Hawkins,BioLife Solutions, Bothell, WA, United States► Thomas Heathman,Hitachi Chemical Advanced Therapeutics Solutions (HCATS), Allendale, NJ, United States► Robert Jones,Fisher Bioservices, Bishops Stortford, United Kingdom► Ohad Karnieli,ATVIO Biotechnology, Tivon, Israel► Gunnar Kvalheim,Oslo University Hospital, Oslo, Norway► Bruce Levine,University of Pennsylvania, Philadelphia, PA, United States► Duncan Liew,Irvine Scientific, Irvine, CA, United States► Mark Lowdell,Royal Free Hospital & University College London, London, United Kindom► Stephen MacNamara,Athersys, Cleveland, OH, United States► Nuno Madeira do O,Cell and Gene Therapy Catapult, London, United Kingdom► Behzad Madhavi,Lonza, Walkersville, MD, United States► Elisa Manzotti,BioInsights Publishing, London, United Kingdom► Damian Marshall,Cell and Gene Therapy Catapult, London, United Kingdom► Aby J Mathew,BioLife Solutions, Bothell, WA, United States► Linda McAllister,BD Biosciences, San Diego, CA, United States► Ruth McDermott,Sartorius Stedim Biotech, Royston, United Kingdom► Michael Mendicino,Hybrid Concepts International, Grand Island, NY, United States► William Milligan,Steminent Biotherapeutics Inc. , Vancouver, BC, Canada► Julie Murrell,MilliporeSigma, Bedford, MA, United States► Katsuhiko Nakashima,Hitachi Chemical Advanced Therapeutics Solutions (HCATS), Tokyo, Japan► Mara Neal,Cook Regentec, Indianapolis, IN, United States► Ben Nelson,Fresenius Kabi USA, LLC, Lake Zurich, IL, United States ► Brian Poole, ISCT Head Office, Vancouver, BC, Canada ► Mitchel Sivilotti,CCRM, Toronto, ON, Canada► David Smith,Hitachi Chemical Advanced Therapeutics Solutions (HCATS), Allendale, NJ, United States► Nathan Smith,Cell Therapies Pty Ltd, Melbourne, Australia► Madeline St. Onge,ISCT Head Office, Vancouver, BC, Canada► Kunihiko Suzuki,FIRM/Medinet, Yokohama, Japan► Anthony Ting,Athersys, Inc, Cleveland, OH, United States► Erika Trauzzi,Sartorius Stedim Biotech, New York, NY, United States► Sowmya Viswanathan, OIRM – Ontario Institute of Regenerative Medicine, Toronto, ON, Canada► Xiaokui Zhang, Celularity, Inc., Warren, NJ, United States
The 2018 Commercialization Signature Series is supported by ISCT Industry Patron and Partner Members: