Drug development is inherently costly and time-intensive, with potential attrition a persistent burden on companies’ finances (1). As companies gain a deeper understanding of cell and molecular biology and seek to develop more complex therapeutics for patient populations, they will also need to be more innovative to ensure commercially-viable success is achieved (2).

An area that has witnessed significant breakthroughs over recent years has been that of cell and gene therapies. The market for these emerging therapies is projected to grow at a compound annual rate of 22.41% between 2022 and 2030 (3), driven by an expanding pipeline and increasing regulatory approvals.

Despite the successes that have already been achieved with emerging therapy development and manufacturing, companies are still facing numerous challenges. Aspects such as demand for accelerated development timelines, advancing technologies, and the growing issue surrounding sustainability are monopolizing the priorities of bio/pharma companies. However, through new opportunities, like allogeneic cell therapy, it is hoped that greater benefits to patients, particularly those in undertreated populations, will be achieved (4).

Continued investment in cell and gene therapies

Major players in the cell therapy and manufacturing industry are seeing a lot of changes that are heavily impacting the standard processes. The field continues to evolve, and it has been exciting to be a part of the new innovations in the industry, according to Daniel Palmacci, president of Cell & Gene at Lonza.

“While there has been a biotech funding slowdown, there remains a healthy pipeline for emerging therapies with nearly 3000 cell and gene products [currently] in development. Commercialization is high on the agenda as more products enter the market,” says Palmacci. “Cell and gene therapies are no longer on the fringe—they are now being used to treat several cancers and rare diseases.”

Steven J. Lynn, MS, executive principal consultant, pharma and biologics at Regulatory Compliance Associates, expands on this and how there is still continued investment in the research and development area to further discover the next breakthrough treatment. “We’ve seen multiple clients either just starting out and needing some upfront advice to the late Phase II company looking to get ready for commercialization,” Lynn says.

Tom Fletcher, scientific director at FUJIFILM Irvine Scientific, notes some examples of finding more cost effective, consistent ways to develop therapies, such as converting from adherent cell lines to suspension cell lines, or even finding new ways to use facilities to support automation and retain shipping flexibility.

In terms of regulatory and strategy expectations, certain companies are focusing on providing more information on cell and gene development and manufacturing. According to Shankar Iyer, alliance management lead at Pfizer CentreOne, companies feel it is important to reconsider when supply decisions must be made in this industry.

“It used to be that much of the supply of gene therapy products for late-stage clinical and commercial launches was decided at the early stage of clinical development. However, with advancements in biology, engineering, and data sciences, biotechs can establish or negotiate supply requirements in a more agile manner closer to the delivery of gene therapies to clinical subjects and patients,” says Iyer.

Addressing new short- and long-term challenges

Along with all the excitement that comes with innovations are the hurdles that developers and regulators are persistently working through. Topics such as cost reduction, manufacturing quality and efficiency, and increases in access are continuing to impact cell therapies in the short-term, according to Aaron Dulgar-Tulloch, PhD, technology leader for Genomic Medicine at Cytiva.

As for the long-term, however, Dulgar-Tulloch feels that there may be a completely shifted focus. “Long-term, I believe the most pressing challenge facing the cell therapy industry is demonstrating that it can move beyond blood-based cancers and into broader clinical utility in a way that will add differentiated value to the patients, relative to the continuing advancements that are expected from viral vector and nucleic-acid based gene therapies,” he says.

In addition to these points, Palmacci highlights how commercialization is the key challenge when looking from a developer standpoint. “Building specialist skills and regulatory know-how, investing in high-quality raw materials, establishing the right quality systems and analytical processes, and finding a partner with proven GMP [good manufacturing practice] commercialization experience are all critical,” he says. “The ‘capacity crunch’ continues to draw headlines, but building capacity alone is not enough to serve this growing market.”

Even with these challenges on the radar, Lynn notes that things are bound to continue changing, as regulators are still learning right along the side of the rest of the industry. However, staying up-to-date on the rapidly changing regulatory guidance across the globe is an ongoing challenge that he feels is never going to go away.

The benefits of utilizing allogeneic cell therapies

For years, almost all of the most recent cell therapies have used autologous therapies, which are when a patient’s own cells are used to make a therapy that is personalized for the patient. These therapies have been mostly positive for the long-term responses and can avoid issues that can stem from the immune response in patients.

A lot of recent developments in this area are focused on making more patient-centric therapies, with an overall outcome to better understand the patient for the most maximized therapeutic outcome. Some pharmaceutical companies have even developed the idea of involving patients in product design from an early stage, exploring their needs, and using their input into target product profiles (2).

Allogeneic cell therapies have been on the rise and look promising, which is where the cells of other healthy donors are used to make a more therapeutic option for multiple individuals at a time. Lynn highlights that some of the benefits of using allogeneic therapies is how they contain cells that are readily available from young and healthy donors who are screened, because they are not coming from a patient who is already sick.

Usually, allogeneic therapies are grouped together as one, but according to Dan Strange, PhD, CTO at Cellular Origins, there are very notable segmentations. “For example, donor-derived allogeneic therapies are manufactured with processes that still look fairly similar to the manufacturing processes for autologous process (albeit using donor derived material), and with slightly larger batch sizes,” he explains. “This approach eliminates a lot of the logistical complexity of the autologous approach, but there are still fundamental limits on how many doses you can make from a single donor—perhaps one batch makes one hundred doses. On the other hand, iPSC-derived allogeneic therapies offer a potentially unlimited supply of cells, but are less well characterized.”

According to Palmacci, these therapies are considered “off the shelf” models and have a lot of potential for patients. “As they use healthy donor stem cells as starting material, the viability of the cells in the end-product is improved,” he notes. “By enabling the development of many treatments from a single donor, a greater patient population can be treated—improving access and reducing costs.”

Although autologous models have been the “safer” option for years for their positive results, Dulgar-Tulloch shares that they can be very complicated to keep up with in comparison to allogeneic models.

“Autologous therapies can avoid many of the challenges around donor compatibility and immune rejection because they are created for a specific patient. Because you are developing and treating patients at an individual level, they are also often faster to develop and require less complex clinical trials,” he says. “However, this personalized therapy approach is also very difficult to scale from a commercial perspective. It brings increased complexity in manufacturing due to differences in the starting material, higher costs because you can’t benefit from economic scaling, and logistical challenges in increasing patient access.”

As for the future of allogeneic therapies, Lynn is hopeful to see many new approvals for these types of products that just a few years ago would have only been developed for a single patient via an autologous donation. One of the promises of allogeneic therapies is the ability to reach a wider patient population. “Cell and gene therapies can and have helped many patients eradicate their disease,” he says. “If approved allogeneics can hit the market and serve a much bigger patient population, it could be a game changer for many public health issues.”

Allogeneic therapies can also expand the access of breakthrough therapies on a worldwide scale by making them more affordable and easier to deliver off-the-shelf, according to Dulgar-Tulloch.

Palmacci seconds being hopeful for the future for the ultimate benefit of the patients, with an end goal for cell therapies to become so mainstream that they will continue to transform lives. “Greater standardization would help to manage the risk of bringing new therapies to market. Increased automation and digitalization would reduce reliance on manual lab-based manufacturing, and a widespread move from 2D to 3D manufacturing would boost efficiency,” he explains. “There also remains an important role for CDMOs [contract development manufacturing organizations] to help biotechs meet fluctuating demand.”

Industry players and allogeneic therapies

Some CDMOs look at autologous or allogeneic therapies as major opportunities for their business process. Lynn expands on how the use of allogeneic cells to make therapies does have multiple benefits to the manufacturer and ultimately the patient. “In theory, because allogeneics can aid in getting more cells to produce products for the various therapies, it could be a benefit to CDMOs and CROs because they would be able to produce more product, which leads to less line downtime and more return on the investment,” he says.

As for Dulgar-Tulloch, this topic is more complex due to the benefits of both kinds of therapies.

“If you consider CDMOs and CROs, whose business model is built around service revenue for generating therapeutic doses, both autologous and allogeneic cell therapies are attractive opportunities,” Dulgar-Tulloch highlights. “Autologous might even edge out allogeneic therapy as an opportunity given the sheer scale of manufacturing required to meet the potential patient need. If you look instead at pharmaceutical companies, allogeneic cell therapies are the clear winner from a business opportunity thanks to the increased scalability and decreased costs and logistics.”

Even with the rapid growth of allogeneic cell therapies, Palmacci predicts that autologous cell therapy options will still be here to stay. “Allogeneic cell therapies are easily scalable and do not require multiple manufacturing sites or a decentralized model—one site can serve patients globally,” he shares. “But whether allogeneic or autologous, any therapy that can significantly improve patient outcomes with high efficacy and safety standards is well positioned to generate interest and backing. Both allogeneic and autologous therapies have a role to play within patient treatment, and we do not expect allogeneic therapies to fully replace autologous ones any time soon.”

With the emergence of cell and gene therapy advancements comes other categories of therapeutic options for patients. For example, Palmacci mentions that the rollout of the messenger RNA COVID-19 vaccine has been a testament to the potential of emerging therapies and the speed at which they can transform the outcomes when there is a collective to support their development.

Other categories include antibody-drug conjugates (ADCs), cancer vaccines, adoptive cellular therapies, and tumor-infiltrating lymphocytes therapy, according to Lynn, which are more targeted cancer therapies that focus on killing cancer cells. For Fletcher, his first thought in this space is the continued use of exosomes, which are extracellular vesicles that make a powerful vehicle for drug delivery and can be a great tool for addressing different diseases. “Recently, we have learned more about how they operate naturally, which can help us utilize them more effectively,” he adds.

Larger patient populations and more polygenic diseases have continued to offer advantages of scale to move therapies out of the lab, and more technology has been trending to leverage multiple or combination platforms, according to Iyer.

“For example, gene editing with hematopoietic stem cells, viral vector and ADCs as a CAR-T [chimeric antigen receptor T-cell] therapy, and viral and non-viral vector technologies for gene therapy,” he says. “Therapies are starting to move beyond blood-borne cancers and towards treating patients with solid tumors to treat a larger range of cancers.”

Strange hopes that both through a combination of manufacturing improvements and therapeutic developments, the industry can bring the cost of cell therapies down to a point where they can be delivered to patients affected by some of the most widespread and devastating diseases of our time.

Oncology continues to see exciting breakthroughs on the horizon. Dulgar-Tulloch emphasizes these new advancements and what to look forward to in the near future. “In cancer, we continue to see advances in immunotherapies and bispecific antibodies, often in combination with other therapies, with several approvals pending,” he states. “[The year] 2023 is also poised to see two potential blockbuster drugs approved for Alzheimer’s Disease and a vaccine against RSV. With such promise on the horizon, it continues to be an exciting time to work in biotechnology.”

Agrawal, G.; Keane H.; Prabhakaran, M.; Steinmann, M. The Pursuit of Excellence in New-Drug Development. McKinsey & Company, Nov. 1, 

. https://www.mckinsey.com/industries/life-sciences/our-insights/the-pursuit-of-excellence-in-new-drug-development

McKinsey & Company. How AI Can Accelerate R&D for Cell and Gene Therapies. Article, Nov. 16, 

. https://www.mckinsey.com/industries/life-sciences/our-insights/how-ai-can-accelerate-r-and-d-for-cell-and-gene-therapies

Precedence Research. Cell and Gene Therapy Market (by Therapy Type: Cell Therapy and Gene Therapy; by Indication: Cardiovascular Disease, Cancer, Genetic Disorders, Infectious Diseases, Neurological Disorders; by Delivery Method: In-Vivo and Ex-Vivo; by End-Users: Hospitals, Cancer Care Centers, Wound Care Centers, Others)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 

Fontanillo, M.; Paulick, K.; Poda, P.; Silberzahn, T. Out of the Shadows: A Brighter Future for Pharma Technical Development. McKinsey & Company, Sept. 16, 

. https://www.mckinsey.com/industries/life-sciences/our-insights/out-of-the-shadows-a-brighter-future-for-pharma-technical-development.

Jill Murphy is an Editor for BioPharm International.

BioPharm International
Volume 36, No.5
May 2023
Pages 10-13, 20

When referring to this article, please cite it as Murphy, J. Expanding the Emerging Therapeutic Horizon. BioPharm International 36 (5) 2023.

Articles

Cover Story

New therapeutic opportunities are offering significant promise for the bio/pharma industry and patients.

Expanding the Emerging Therapeutic Horizon

Since the first FDA approval in 2017, chimeric antigen receptor T-cell (CAR-T) therapy has garnered excitement as a potentially curative option for hard-to-treat blood cancers (1). In this therapy, T cells are genetically engineered to recognize specific tumor-surface antigens. When the engineered T cells encounter the target antigen, they proliferate and coordinate an immune response to destroy the cells expressing that antigen. There are six approved CAR-T therapies in the United States that target blood cancers. These “autologous” treatments are manufactured from T cells obtained from the patient and are genetically engineered to express a CAR that recognizes an antigen specific to the patient’s blood cancer.

When CAR-T therapy works well, it puts patients with malignant, lethal blood cancers into long-term remission. However, approved CAR-T therapies remain ineffective for many patients, and no CAR-T therapies have been successfully developed for solid tumors (2). The high cost, clinical complexity, and dangerous side effects of existing CAR-T therapies have further limited the application of an otherwise exciting and novel treatment.

Significant obstacles remain before CAR-T therapies can be adopted to treat solid tumors. Persistent efforts to expand CAR-T therapies to solid tumors are focused on identifying solid tumor-specific antigens for CAR T to target, enabling the therapy to penetrate solid tumors and ensuring that the therapy persists and functions in the immunosuppressive microenvironment of the solid tumor.

Because the immune system uses antigens to identify targets, antigens are a key factor in the development of CAR-T cell therapies. To minimize off-target effects, an appropriate antigen target for a CAR-T therapy must be present on cancer cells but not significantly on healthy cells. If a patient receives CAR-T therapy that targets an antigen present on both tumor cells and healthy tissue, the subsequent immune response may attack normal cells and has the potential to generate difficult-to-manage serious side effects.

All FDA-approved CAR-T therapies target either CD19 or B-cell maturation antigen, which are antigens associated with cell development that are highly expressed on blood cancer cells but are only limitedly expressed on healthy cells. While CAR-T therapy for blood cancers has a few clear antigen targets, identifying antigen targets for solid tumors has proved much more complicated.

Solid tumors have a wider array of potential targets than blood cancers, and the antigens expressed on solid tumors are often also found at low levels on normal cells. The overlap in antigen expression between tumor cells and healthy tissue has led to severe toxicity in early solid-tumor CAR-T therapy clinical trials, despite promising results in earlier animal models. Along with the judicious selection of antigen targets, an important parameter for the clinical success of CAR-T therapy will be the development of animal models that better represent the human immune system and the differential expression of the target antigen.

The challenge of selecting a target antigen is compounded by the heterogeneity of antigen expression in solid tumors. This heterogeneity is likely one important reason for the diminished initial and durable CAR T response (3). Heterogeneous expression means that some tumor cells may express an antigen more strongly than others, and some may not express that antigen at all. A CAR-T therapy targeting a cancer-specific antigen that was heterogeneously expressed would miss tumor cells not expressing that antigen and would be less effective on cells weakly expressing that target.

One proposed approach to circumvent the lack of cancer-specific, consistently expressed antigens on solid tumors is engineering CAR T that can identify multiple targets. This could be achieved by genetically engineering multiple CARs into the same T cell or engineering a receptor that would recognize more than one target antigen. However, multi-target CAR Ts can carry an elevated risk of severe side effects from off-target effects (4).

Individual antigens for targeting solid tumors are also under investigation. Cancers sometimes express embryonic genes, such as CLDN6, which are silenced after birth (5). CLDN6, which enables cancers to metastasize, is present in most testicular cancers, as well as in some ovarian, non-small cell lung, gastric, breast, and endometrial cancers. Still, targeting CLDN6 carries some danger of off-target effects, as the protein is expressed at low levels in the pancreas and liver, and a protein with a similar structure, CLDN9, is expressed throughout the body.

A 2022 Phase I/IIa trial of CLDN6-directed CAR-T therapy, called BNT211-01, displayed one of the first examples of CAR T efficacy in solid tumors (6). Initial trial results reported tumor shrinkage in 33% of 21 patients with seven different tumor types, including one testicular cancer patient who went into complete remission. Two additional solid-tumor targets have also shown preliminary promise in clinical trials: a study treating glioblastoma with interleukin 13 receptor subunit alpha 2 (IL13Ra2)-directed CAR-T cells and CAR-T cells targeting prostate stem cell antigen for prostate cancer (7,8).

To attack solid tumors, CAR-T cells must first migrate from blood vessels to the tumor tissue. Then, they must be able to infiltrate and proliferate in the tumor microenvironment. This cell movement is challenging for a number of reasons. For instance, physical barriers, including the extracellular matrix and the vasculature surrounding a solid tumor, make it difficult for CAR-T therapies to penetrate the tumor. Once CAR-T cells penetrate the tumor, the therapy must overcome an immunosuppressive tumor microenvironment that impairs its function and efficacy.

Many strategies for migrating to and functioning within the solid tumor microenvironment are in development, and many more have been proposed. Several of these strategies aim to augment CAR-T function by arming CAR-T cells with additional molecules or combining them with an additional therapy.

For example, boosting expression of some cytokines could make it easier for CAR-T cells to infiltrate solid tumors (9). Cytokines—small proteins secreted by certain immune cells—can enhance tumor-destroying activities of other immune cells, including T cells. “Armored” CAR-T cells, engineered with specific cytokine receptors or engineered to express stimulatory cytokines, have the potential to improve CAR-T therapy’s efficacy (10).

Other proposed strategies for enhancing CAR-T function include engineering CAR-T cells to be insensitive to immunosuppressive conditions and combining CAR-T therapy with immune checkpoint inhibitors (2). However, many of these approaches raise the risk of cytokine release syndrome, a toxic and potentially lethal side effect of CAR-T therapy resulting from excessive inflammatory cytokines in the circulatory system.

One combination therapy approach that has already demonstrated promise in early clinical trials is a messenger RNA (mRNA) vaccine that enhances the proliferation of CAR-T cells. The mRNA vaccine leads to target antigen expression on T-cell-activating immune cells (i.e., antigen-presenting cells). The resulting cell proliferation helps the therapy persist in the immunosuppressive solid-tumor environment and allows the therapy to be administered at lower initial doses. The clinical trial investigating CLDN6-directed CAR-T therapy, mentioned previously, used this strategy in a subset of patients (6). In the preliminary study, 43% of patients treated with a combination mRNA vaccine and CAR-T therapy experienced tumor shrinkage. Still, the efficacy and safety of this method need to be tested and validated in additional trials—approximately 40% of patients treated in the CLDN6 study developed manageable cytokine release syndrome.

Many of the challenges facing CAR-T therapy for solid tumors remain unresolved. However, if history is a guide, these obstacles are not insurmountable. Blood cancers are often selected for development of novel therapies because tumor cells circulating in the blood are easier to access than tumor cells in tissue, and treatments are easier to deliver. Treatment options, such as chemotherapy and stem-cell transplant, were first developed for blood-based cancers and then were modified to treat solid tumors. A number of recent advancements—including the identification of solid-tumor-specific antigens, the development of armored CAR-T cells, and mRNA combination therapies—are bringing this targeted immunotherapy for solid tumors closer to reality.

1. Mullard, A. FDA approves first CAR T therapy. 

 (10), 669–669. DOI:10.1038/nrd.2017.196
2. Marofi, F.; Achmad, H.; Bokov, D.; et al. Hurdles to Breakthrough in CAR T Cell Therapy of Solid Tumors. 

 (1),140. DOI:10.1186/s13287-022-02819-x
3. Chen, N.; Li, X.; Chintala, N. K.; Tano, Z. E.; Adusumilli, P. S. Driving CARs on the Uneven Road of Antigen Heterogeneity in Solid Tumors. 

, 103–110. DOI:10.1016/j.coi.2018.03.002
4. Kailayangiri, S.; Altvater, B.; Wiebel, M.; Jamitzky, S.; Rossig, C. Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers. 

 (5), 1075. DOI:10.3390/cancers12051075
5. Du, H.; Yang, X.; Fan, J.; Du, X. Claudin 6: Therapeutic Prospects for Tumours, and Mechanisms of Expression and Regulation. 

 (3), 677. DOI:10.3892/mmr.2021.12316
6. Mackensen, A. BNT211-01: A Phase I Trial to Evaluate Safety and Efficacy of CLDN6 CAR T Cells and CLDN6-Encoding mRNA Vaccine-Mediated In-Vivo Expansion in Patients with CLDN6-Positive Advanced Solid Tumours. Presentation at the 2022 ESMO Congress, Paris, France, Sept. 9–13, 2022.
7. Society for Neuro-Oncology, Session 3: Immunotherapy: Hype and Hope. Presentation at the First Annual Conference on CNS Clinical Trials, 

, Oct. 1–2, 2021.
8. Mustang Bio, Mustang Bio Announces Initial Phase 1 Data on MB-105 for Patients with PSCA-positive Castration Resistant Prostate Cancer. Press Release, Oct. 26, 2020.
9. Mollica Poeta, V.; Massara, M.; Capucetti, A.; Bonecchi, R. Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy. 

. DOI: 10.3389/fimmu.2019.00379
10. Hawkins, E. R.; D’Souza, R. R.; Klampatsa, A. Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy. 

Brian Huber is vice-president of Therapeutic Areas, Drug Development, and Consulting, and Tamie Joeckel is global business lead of the Cell and Gene Therapy Group; both at ICON.


Volume 36, No.5
May 2023
Pages 22–23,27

When referring to this article, please cite it as Huber, B.; Joeckel, T. Challenges of Expanding CAR-T Cell Therapy into Solid Tumors. 

Development

The development of CAR-T therapies for solid tumor cancers presents a myriad of challenges.

Challenges of Expanding CAR-T Cell Therapy into Solid Tumors

As it has gained increased prominence in the public sphere, sustainability has emerged as a predominant focus among manufacturing organizations. While total waste estimates are difficult to determine for various reasons, many individual companies have taken the initiative to publicize data concerning sustainability efforts.

For instance, Roche published a data set demonstrating that, from 2007 to 2022, general waste decreased by approximately 4000 metric tons, while chemical waste decreased by 23,000 metric tons; this represents total reductions of approximately 23% and 62%, respectively (1). Other companies have done the same, even when the data are not pretty. AbbVie, for instance, revealed in a five-year report that it produced more hazardous waste in its most recent year (18,200 metric tons) than at any other point in that five-year timeframe (2). Independent of what conclusions can be drawn from waste data, publishing the data represents a commitment to transparency and future sustainability efforts.

Notably, while this is of particular importance to many in the general public, it is weighted just as much, if not so, by pharma partners. 

Pierre Luzeau, CEO of Seqens, a pharmaceutical synthesis and specialty ingredients company, noted that customers were specifically looking for partners who could help them reach sustainability goals (3). Furthermore, he predicted that sustainability was rapidly becoming an exclusionary factor for companies who couldn’t keep up.

“We are convinced that the selection of suppliers will be based on the best supplier from that standpoint,” said Luzeau in the interview. “If you are not capable of proposing the best solution as far as [corporate social responsibility] is concerned, you will disappear in the ten years’ timeframe—this is for sure.”

It is in this vein that single-use technologies (SUTs) must be examined in terms of their current and future waste potential relative to comparable solutions, as it may speak volumes toward their future efficacy.

The benefits of SUT are well understood. According to Helene Pora, vice-president of Technical Communication & Regulatory Strategy at Pall, single-use systems offer a “level of flexibility, scalability, and cleanliness that is near impossible to achieve with glass and stainless-steel counterparts.” Per Pora, SUTs allow lines to be repurposed more easily, eliminate the need for cleaning and cleaning validation, save both time and money, and make the manufacturing process safer for operators (4).

The question, however, isn’t necessarily of the benefit of using SUT, rather, the question is of benefit relative to cost and how that cost benefit stacks against other cost-benefit calculations. One such calculation involves environmental impact vs. stainless-steel (or, for certain operations, glass) transport. Unfortunately for those who prefer simple answers, in terms of waste, there’s no clear better option.

SUTs are composed of plastics that need to be disposed of after use, generating plastic waste. To the untrained eye, this might lead one to believe that SUTs are going to inherently be more wasteful than stainless-steel containers. However, while stainless-steel fixtures are designed to remain in place indefinitely, in between batches they need to be cleaned using water, which generates significant water waste. In the aforementioned AbbVie report, for instance, 4.1 million cubic tons of water was consumed; the AbbVie report defined this as water that is used excluding non-contact cooling water that is drawn from and returned to the same source with equal quality.

Consequently, the amount of waste generated is dependent on the type of manufacturing that is being done at the facility. For extremely large volume-batches, this can make stainless-steel a stronger option; while one 2014 study found that single-use produced less waste in batches as large as 2000 liters (5), stainless steel experts have stated that once a manufacturer is producing more than 10 kgs per drug batch (or 3000 kgs per year) stainless steel leads to less overall waste (6).

As a result, depending on the type of operation, either stainless steel or single use could theoretically be the “more” wasteful option. For outsourcing organizations who need flexibility to produce various, small-batch operations, the requisite cleaning on stainless-steel facilities would create a larger energy burden than the disposable plastics. Conversely, if a company is producing medications on a large-scale, such as an insulin, stainless steel is the more energy-efficient option.

While SUT may be more energy efficient than stainless steel in many use cases, it is worth acknowledging that this perspective views energy expenditures agnostically. However, while the pharmaceutical industry burns plastics in a strictly controlled environment, many other industries have less rigorous processes, which has pushed plastic waste to the forefront of the public and government’s agenda.

For instance, a recent report from the United Nations Environment Programme found that there is 11 million metric tons of plastic waste entering the ocean annually, and that this number is expected to triple over the next twenty years (7). Because of known carcinogens in plastics and the downstream impact that these chemicals can have to both sea life and humans, this has placed a bullseye on plastic waste specifically; for example, in 2022 both Canada (8) and India (9) passed bans on most forms of single-use plastics.

For now, it appears that pharma has been spared the brunt of this plastics crusade, in large part because of its significant merits, but as pressure mounts to reduce plastic waste, increased scrutiny will be placed on all use cases regardless of merit. In particular, as scientists continue to study the impact of plastics in human cells (10), extractables and leachables (E&L) testing will likely endure further scrutiny in both manufacturing and packaging processes. In a scenario where all plastics are on trial, perhaps following high-profile incidents where plastic contaminants are conclusively linked to an E&L testing failure, regulatory guidelines could further tighten on E&L to assure consumers that these processes are not introducing additional carcinogens to consumers. Down the line, this could present significant challenges for manufacturers who use SUTs and do not have a robust E&L process.

In this view, perhaps the ultimate fate of SUT is tied to that of scientifically sound E&L testing. This may not necessarily mean more tests, although that is a potential avenue of change. As knowledge of the materials used and the process which cause chemical species to migrate increases, artificial intelligence that models chemical interactions may be used in lieu of traditional testing methods (11). This could present a viable alternative that allows the use of SUT to continue in its current fashion.

Putting aside the nuances of that consideration, the pharma industry must understand the tacit connotations the public places on plastics. Sustainability must not be viewed solely as an “energy in, energy out” practice, as many discussions of SUT tend to frame the dialogue, because it has inextricable ties to pollution and human health. An important context must be considered: for as long as plastics are at the forefront of environmental discussions, scrutiny surrounding SUTs will follow suit.

1. Mikulic, M. Pharmaceutical Industry: Waste Generated by Roche 2007-2022. 

. abbvie.com (accessed April 10th, 2023).

3. Playter, G. Setting Sustainability Goals with Pierre Luzeau. 

4. Playter, G. Weighing the Benefits of Single-Use Consumables. PharmTech.com, Oct. 4, 2022.

5. Flanagan, W.; Brown, A.; Pietrzykowski, M. et al. An Environmental Lifecycle Assessment of Single-Use and Conventional Process Technology: Comprehensive Environmental Impacts. 

6. Haigney, S. The Case for Stainless Steel. 

7. UN Environmental Programme. From Pollution to Solution. Oct. 21, 2021.

8. Newburger, E Canada is Banning Single-Use Plastics, Including Grocery Bags and Straws. 

9. ET Online. Single-Use Plastic Banned in India from Today. Here Are Some Eco-Friendly Alternatives. economictimes.indiatimes.com, July 1, 2022.

10. ACS. Methods for Microplastics, Nanoplastics and Plastic Monomer Detection and Reporting in Human Tissues. Press Release, Aug. 17, 2020.

11. Morley, N. The Future of E&L— A world without extractable studies? 

When referring to this article, please cite it as Playter, G. Contextualizing Single-Use Waste. 

Upstream Processing

It is crucial to examine the context in which single-use waste is viewed.

Contextualizing Single-Use Waste

Adherent cell culture is widely used, at least at small scale, for production of many next-generation therapeutics, including viral vectors for gene and gene-modified cell therapies and non-genetically modified cell therapies. With rapidly increasing demand for these advanced medicines, there is a need to overcome challenges with scale-out and scale-up of adherent manufacturing processes, including the cell harvesting step—whether the cells are discarded or collected as product.

Many different adherent approaches and product types

Adherent cell culture for the production of biopharmaceutical products can be implemented in a number of ways for many different types of biologics, according to Ian Goodwin, director of program design in FUJIFILM Diosynth Biotechnologies’ Program Design & Global Analytical Strategy group. Monoclonal antibodies (mAbs), recombinant proteins, and most viral vectors are grown in suspension and generally do not require the cells to be collected. For products secreted into the media, the supernatant is collected and the cells are discarded. If the product is not secreted or is both internalized and secreted, the cells must first be lysed to release the product, and then the lysate is collected. In both cases, the collected bioprocess fluid undergoes filtration, often depth filtration followed by sterile filtration.

Adherent cells, as the name implies, require a substrate or scaffold to which they can attach. At small scale, flatware systems provide the relevant surfaces. At larger scale, fixed-bed bioreactors provide the support. Microcarriers, or beads composed of various synthetic materials, can be used as surfaces for the cells to bind to if suspension-like conditions are preferred.

Regardless of the method used to support adherent cells and the scale of the process, the cells must be detached from their support(s). Common principles apply to all cell detachment operations for the different applications, according to Clément Dumont, product manager at Univercells Technologies. “Whether the cells are used to produce biologics or directly used as the final product, the detachment process will involve exposing cells to enzymatic and potentially mechanical actions. Specificities in the process will arise depending on different considerations, mainly the type of cells, their intended use, and the scale at which the operation is performed,” he explains.

For example, human embryonic kidney 293 (HEK293) cell cultures in T-Flasks for small R&D experiments can typically be detached by following a simple sequence of actions: remove media, add a detachment enzyme and incubate, then collect the cells, Dumont says. Typical enzymes include trypsin or Accutase (Invitrogen). Cell collection is often assisted by manual shaking of the flask (mechanical action) during the passage steps.

For most large-scale, multi-layer flask-based processes, enzymatic harvesting is typically employed. This method is also used to remove adherent cells from microcarriers and fixed-bed bioreactors, as the physical method is not suitable, notes Lee Seung-sun, lead scientist for the manufacturing, science, and technology upstream processing team at Samsung Biologics. “Particular care must be taken when harvesting the cells intended for use as cell therapies to avoid damaging the cell membrane and extracellular matrix, even when using enzymatic processes, as certain enzymes can degrade these important cellular features,” he adds.

When scaling up, however, the same actions as those used at the R&D scale must be reproduced, but for a much higher surface area. That can add complexity, according to Dumont. “Detaching cells from a 40-layer cell factory (CF40), for example, may require dedicated equipment for fluid and vessel handling or to apply mechanical action. These special requirements can become impractical when large numbers of vessels are involved,” he contends.

Microcarriers present a different scenario. “Cells and microcarriers may be chemically treated and, if the microcarriers are insoluble, the mixture passed through a mesh to separate cells. If the microcarriers can be dissolved with pectinase, treatment with this enzyme frees the cells for further processing,” observes Michael Baker, senior director of viral gene therapy process development for FUJIFILM Diosynth Biotechnologies.

There are cases where cell therapies are grown in adherent-like conditions but with somewhat loose attachment of the cells, eliminating the need for the use of dissociation reagents, according to Goodwin. He also stresses that critical process parameters and the design space for cell harvesting may change as projects move from pre-clinical through commercial stages or scales; even so, Goodwin recommends avoiding any changes to the harvest methodology whenever feasible.

Cell types that require adherent culture are subjected to scale-up and harvest challenges that do not impact suspension culture. Given that the maximum scale at which adherent cell culture can be performed in flatware is finite, scale-out rather than scale-up is required to produce larger product quantities, particularly for expressed products. “Scaled-out processes are more labor-intensive and require more space, time, and people, potentially placing product quality at risk,” comments Baker.

The fact that cell-culture processes run in flatware cannot be automated and involve large numbers of manual operations also means that manufacturers need experienced and well-adept cell scientists who can help reduce the potential for errors during the implementation of sophisticated harvesting processes, according to Seung-sun.

“Currently, efficient culture vessels are not available for production and harvesting of adherent cell cultures. While multi-layer flasks could be used, they present some limitations, such as minimal surface area for cell proliferation. Due to the lack of efficient culture vessels, harvesting such cells still requires help from CO2 incubators and manual operations,” Seung-sun adds.

It is worth noting, Seung-sun continues, that most cell therapy products (i.e., chimeric antigen receptor T cells, mesenchymal stem cells) manufactured today are autologous, patient-specific therapies that can be manufactured at small scale. In addition, Baker notes that many treatments produced using adherent cell culture target ultra-rare indications where commercial-scale manufacture does not require significant scale up, and therefore, 2D reactors can be a viable way of producing the drug substances.

Similarly, the numbers of cells required for typical cell therapy applications are lower than those required to produce biologics. For these products, the challenge then becomes, according to Goodwin, the need to produce them in closed, single-use systems to minimize the sterile boundary of the manufacturing process and reduce the risk of contamination.

While autologous cell therapies dominate the market today, many candidates in the pipeline are allogeneic, or donor-derived. As such, Seung-sun believes that the ability to effectively scale up adherent cell-culture processes will be crucial for the commercialization of future cell therapies.

For processes that do require scaling, Baker points out that fixed-bed bioreactors attempt to overcome issues of scaling out by concentrating surface area into a single unit using intricate fiber matrices or scaffolds that are conducive to cell growth. Microcarriers, meanwhile, enable the use of stirred-tank reactors and suspension-like conditions. “These attributes make 3D reactors and microcarriers good options for products made in adherent cells lines intended to treat larger patient populations and/or that require larger volumes,” he concludes.

Scaling up is not problem-free, however. Products that are retained intracellularly in adherent cells require cell collection. In very small-scale settings such as well plates and dishes, the cells can be mechanically manipulated (scraping) and collected at a very high efficiency, according to Baker.

Larger fixed-bed bioreactors must also be seeded with cells. In the context of seed train operations, Dumont emphasizes that the increasing number of flatware units required to generate sufficient cell quantities pose operational constraints. “Large equipment and associated labor are needed to manipulate the large number of units, leading to large CAPEX [capital expenditures] and OPEX [operating expenses], while also requiring more manual (not automated) manipulations that increase the risk of contamination and low reproducibility,” he says. Large harvesting volumes can also be a challenge. “Further processing and concentration of the cells might be required before the next steps, which is especially problematic for seed-train operations as multiple passages are required during the whole process,” Dumont remarks.

Processes using microcarriers, meanwhile, can be difficult to transfer and tend to require more optimization to reach a suitable process at scale, according to Dumont. “Shear stress and bead aggregation are common drawbacks that need to be addressed. Those bioreactors have a large volume leading to large footprint[s] as well,” he says.

In addition, chemical releasing agents must then be removed from the final product matrix as they are considered process-related impurities, Baker observes. He also notes that when microcarriers are used to grow adherent cells in suspension, extractable and leachable concerns for either dissolving the microcarrier or extracting the microcarriers should also be considered.

Finally, Seung-sun notes that it is not possible with current fixed-bed bioreactors to sample cells and obtain direct analytical data on the cell condition, metabolic changes, or the number of viable cells. “At best, it is possible to estimate the number of viable cells based on the glucose concentration in the media,” he explains.

Nearly all aspects of the adherent cell-culture process can be optimized in one way or another. First, the detachment process can be optimized to account for different types of cells with different attributes and behavior profiles with respect to fragility/resistance to degradation, aggregation, etc., according to Dumont. Such optimization will result in different choices of enzymes, incubation times, and levels of mechanical action. “The choice of technology for industrializing this process is crucial. A good balance between rapid and simple operation on one side and flexibly accommodating various process types on the other needs to be found,” he states.

Optimization of conditions during enzyme treatment for cell detachment can also be an important strategy, Seung-sun observes. “Investigation of concentration, time, and temperature, along with maximization of the contact area of the culture vessel with the enzyme can help minimize cell damage and improve harvest yield,” he says. Goodwin adds that a design-of-experiment approach can be beneficial for optimizing cell lysis and removal of the lysis reagent (through various purification steps).

For cells grown as therapeutic products, beyond the use of a closed environment to ensure sterility and reducing the risk of contamination, Goodwin observes that any process for disruption of cell attachment must be optimized for release of the cells while minimizing degradation of the structural integrity of the cells, which can potentially impact efficacy, potency, and/or safety of the cell-therapy product.

The biopharmaceutical industry, while conservative, has its foundations in innovation. Cell harvesting operations have benefited from the ongoing drive to improve performance and reduce the cost of biologic drug manufacturing. Novel chemical dissociation reagents and physical disruption methods continue to be developed and published to help investigators improve cell collection procedures, according to Baker. He adds that automated procedures for flatware have also been recently introduced that can reduce labor-intensive procedures by 30–50% for cell culture and cell collection steps.

Seung-sun highlights new culture devices such as Wilson Wolf’s G-Rex, Terumo’s Quantum, Lonza’s Cocoon, and Miltenyi Biotech’s CliniMACS systems, but does note that most of these “cell-therapy-production-in-a-box” solutions are designed to support suspension-based cell culture. Univercells Technologies, meanwhile, focuses on improving viral vector manufacturing with technologies that enable process intensification and chaining.

Recent efforts at the company, Dumont notes, led to the development of an efficient solution for harvesting cells from its scale-X fixed-bed bioreactors at the bench scale to support optimized seed trains. “The bench-top scale-X cell collect module allows for intensified cell growth in a fixed-bed bioreactor, significantly increasing the process intensification, reducing footprint, and operation required,” he says.The module retrieves cells through a combination of enzymatic and mechanical action, providing high cell harvest yields (up to 2.1x109 cells/m²) with excellent viability (>90%), according to Dumont. “The automated control system supports configurable harvest protocols and the pre-sterilized closed system reduces the reproducibility and aseptic risk issues associated with flatware while also reducing material and labor costs,” he adds.

Hope is for closed, automated processing in the future

In the end, Dumont emphasizes that successful cell harvesting depends on the specific process and the technologies selected for industrializing that process. “The production platform needs to support rapid and simple operations while offering the flexibility to accommodate various process types,” he states.

Continued advances in technology are expected. Goodwin points to improved solutions for cell collection that will enable maximization of cell recovery, particularly in closed systems. “Either cell collection procedures will continue to evolve to support large-scale processes, or culture vessels will be engineered specifically for the purpose of cell collection,” he comments.

The move to closed systems will continue and adoption of automated controls will also increase—both to reduce risk of operator error and contamination and minimize operational differences between production batches, according to Goodwin. These advances will also help drive down manufacturing costs, he says.

Separately, Seung-sun expects the cell therapy market to gradually shift toward suspension-based cell culture. “Adherent cell culture is much more inefficient compared to suspension culture. The progress seen in industrial biologics manufacturing provides incentive to achieving similar improvements for next-generation therapeutic production,” he observes. One technology that may facilitate this shift is single-use 3D vertical wheel bioreactors, which Goodwin notes have been shown to be successfully used to convert adherent cells to a suspension growth model with and without microcarriers.

Dumont agrees that moving away from scale-out manual cell culture and harvest will fundamentally change the paradigm of this type of operation. “Choosing a closed, automated solution for cell culture and harvest can de-risk the operations and reduce costs significantly. Ultimately, this will lead to increased quality and cost-efficiency for the industry,” he concludes.

In general, Baker insists there should be a strong emphasis on forward-looking, scalable options. “For both biologics and cell therapy applications, adherent or adherent-like culture should use technologies that reduce the sterile boundary and incorporate up-to-date manufacturing contamination control strategies. Staying current on industry trends and technology will lead to more manufacturing batch success (less loss), more efficient operations through automation, and less safety concerns around product integrity,” he concludes.

Cynthia A. Challener, PhD, is a contributing editor to 

When referring to this article, please cite it as Challener, C. Overcoming Harvesting Challenges for Adherent Cell-Culture Processes. 

Downstream Processing

Optimization strategies that leverage advanced technologies are essential for maximizing yield and quality.

Overcoming Harvesting Challenges for Adherent Cell-Culture Processes

Given the rapid advances being made in technologies such as cell and gene therapies, personalized vaccines, and oral biologics, odds are high that there’s some hot ticket item demanding one’s attention at any given time. While it would be foolish to detract from the monumental discoveries being made in the biopharma field, new technologies should nevertheless be approached with some degree of caution. While innovation is crucial for the benefit of patients and industry alike, many start-ups, often brimming with ideas and ultimately unrealized potential, have been felled by trying to sprint before they even stand. Leadership cannot afford to split their attention if the nuts and bolts of an organization aren’t properly fitted.

Nowhere is this more evident than in data integrity, which measures data accuracy, completeness, and cohesiveness. It certainly doesn’t have that je ne sais quoi that entices ones like a monumental technological, but it is nonetheless foundational to the day-to-day operations and overall success of a company. Perhaps Big Pharma companies can afford the occasional $8.9 billion misstep (1); but whether your Amazon (2) or Santander (3), regulatory fines can easily balloon to a painful price point.

Particularly in an industry as heavily regulated as pharma, where data silos, compliance errors, or security breaches must be taken gravely serious because of their direct impact on patient outcomes, maintaining property data integrity is absolutely paramount to a company’s success. In this vein, this article explores the common pitfalls companies run into, the consequences thereof, and how one can structure their data integrity programs.

The crux of good data integrity are software and data management tools, as they are an immense boon when working with the voluminous amounts of data typical of the pharma industry. However, one must consider the types of data they are using before building out a data integrity process. Paige Kane, member of the Pharmaceutical Regulatory Science Team at TU Dublin, and Garry Wright, European laboratory compliance Specialist at Agilent Technologies, spoke at length on this topic in an episode of 

“We need to understand what our processes are, what data we are trying to capture, and make sure that we have the right tool for that application,” said Kane. “And when we do that, we need to take a risk-based approach and understand where the risks are, and where the operators are intersecting with that and where we can be error-proof. Leveraging automation is a great way to do that.”

Per Kane, companies that are looking to tighten up their operations should consider the purpose of the data they are collecting and why they need it. Superfluous data can result in greater system and operator burden, while missing requisite data fundamentally undermines the purpose of the system.

However, this doesn’t just apply to collection methods—it also impacts who can interface with the data, and in what ways. Wright noted that some of the most common pitfalls in data integrity concern have been plaguing the data integrity industry for as long as it has existed.

“We’ve been talking about data integrity for the last 10 years, but there’s still a lot of repeated data integrity violations out there,” said Wright. “Some of them are very basic, fundamental requirements of using software in order to protect data.”

Some of the most common problems Wright listed in the interview include:

 This obfuscates which users accessed a particular system, and if given out broadly can make it difficult to trace the origin of errors or cases of intentional falsification. To enable a broadly successful data integrity system, it’s crucial to have unique logins that operators can track.

Often, scientists and various technicians are given more access to systems than needed for their role. This can lead to a conflict of interest where a bad actor approves a failed batch, or where bad test data are altered or deleted to avoid investigations or re-tests.

 Many companies have received warning letters because they have chosen to not activate certain audit privileges—making it impossible to track changes and properly oversee a system. Similarly, even when they are activated, users who shouldn’t be able to access audit technology are often able to do so, allowing bad actors to compromise data integrity.

While implementing a wholesale data integrity program can seem daunting, Kane was quick to note that there are many guidance documents and resources available that can help companies get over initial hurdles. What is pivotal is that company leadership act in good faith and invest in the types of processes and technologies that keep pharmaceutical data honest and intact—in short, enact a full-scale data governance policy.

“It’s more than just the audit trails,” said Kane. “There needs to be a holistic view and approach as to how we’re going to manage our data so that we can put forth that holistic picture to our inspectors and customers.”

Inherent to the discussion of data integrity is the discussion of automation, and within that the de-emphasis of human intervention in various tasks throughout the pharma lifestyle. Human error is a major concern for pharma companies, as one mistake (or deliberate falsification) can have severe knock-on effects for the patients ultimately receiving the compromised medicines. Automated processes are a fantastic alternative, particularly for precise, time-intensive tasks that need to be repeated thousands of times a day—the ubiquity of automated
production lines is a prime example of this principle in action.

However, it is crucial that companies understand that “de-emphasis” does not mean “elimination.” It’s common corporate philosophy to have workers perform to the highest function available—a CEO isn’t typically charged with data entry, even if they’re perfectly capable of doing so, because there are higher-level functions that they are uniquely qualified for. While automated services are doing tasks that would otherwise be performed by humans, that does not mean these people are eliminated—it means that their role must shift.

Claudio Fayad, vice-president of Technology, Process Systems, and Solutions at Emerson, tackled this misperception in a video interview with 

“We’re not doing automation to eliminate humans—we’re eliminating human errors by upscaling them, by augmenting their capacity,” said Fayad. “As we can automate the more repetitive tasks, as we can give them a platform that is autonomous at the end but is giving them situational awareness all of the time, they are free now to look at the most important things and intervene when they need to intervene.”

Consequently, it is pivotal that humans maintain oversight over automated tasks. In terms of data integrity, automated digital tools are a fantastic tool for standardizing data collection and maintenance, but this is not a solution in of itself. There is consensus among experts that a proper data integrity process will conduct regular audits, consult with external regulatory experts, and implement crucial oversight systems operated by trained professionals; this, in turn, comes back to a proper data governance policy.

In practice, this could manifest itself as having an operator review random sections of internal log data generated by a regulatory program for inconsistencies. If there are mislabeled, incomplete, or missing logs, that operator can take the necessary actions to find out what caused it, determine what the potential impact may be, and work with colleagues to devise an appropriate solution as needed. In this sense, even though humans are not given edit access, minimizing the potential for human error, they provide oversight as a complementary force that is vital for proper software utilization. In other words, while software provides the means to data integrity, the humans interacting with it must engage in proper data governance to actualize its efforts.

“Every software platform can have different functionality and different controls, and different companies use different software in different ways,” said Wright. “Having that high-level governance strategy is your company’s commitment to how you’re going to control data within that individual software platform. It’s a starting point for the people who are going to configure and validate those systems, because they know what functionality they need to activate and what the best options are to control data.”

1. Playter, G. J&J Proposes $8.9 Billion Payment in Talc Powder Litigation.

2. BBC. Amazon Hit With $886m Fine for Alleged Data Law Breach. 

3. Shome, A. FCA Fines Santander UK £108 Million for Prolonged AML Breaches. 

4. Playter, G. Drug Digest: Unpacking the Science Behind Data Integrity.

5. Playter, G. Addressing Data Security with Claudio Fayad.

When referring to this article, please cite it as Playter, G. Data Integrity Pitfalls. 

Analytics

Avoiding missteps in data integrity is contingent on the development of a holistic data integrity approach.

Data Integrity Pitfalls

Novel and emerging biotherapeutics are commanding a larger portion of the development pipeline at an inflated rate. As drug companies focus greater efforts on these complex therapies, regulatory authorities have been working on various guidelines to ensure these drugs are manufactured to a high level of quality with minimum risks. Focusing on good manufacturing practices (GMPs) for emerging therapies across the United States and the European Union (EU) in particular, 

 spoke with Elena Meurer, principal consultant at Biopharma Excellence, to learn more about current regulatory expectations, the evolution of guidelines, and potential regional variances.

 Could you provide an overview of current GMP expectations for emerging therapies?

 Both FDA and the European Medicines Agency (EMA) have published regulatory guidelines related to the implementation of GMP across the different clinical phases (1,2). Many emerging therapies fall under the definition of advanced therapeutic medicinal products (ATMPs) in the EU or cell and gene therapies in the US. Only EMA has published specific GMP guidance that is applicable to the manufacture of ATMPs.

When assessing the required application of GMP in clinical phases, there are many similarities between the EU and US GMP requirements in that they both focus on the identification and assessment of the risks to the quality of an investigational phase medicinal product. The main difference between the EMA and FDA approaches is the recognition by EMA that ATMPs require explicit GMP guidelines that take the specifics of this product class into consideration, and places a heavy emphasis on a risk-based approach for the broad application of GMP across the product lifecycle (2). It is important to note that not all emerging therapies are classified as ATMPs. Nevertheless, as with ATMPs, such novel therapeutics may also require specific manufacturing solutions that should be addressed case by case in a risked-based manner.

The vast majority of emerging therapies are developed as sterile drugs and, due to the heat sensitivity of many of these therapies, final sterilization is not feasible. Therapeutics in this class are usually sterile filtered (unless they are cell-based therapies and this is not possible) and are manufactured through aseptic processing using modern barrier technology including single-use fluid pathways and isolators, for instance.

Early clinical research is likely to be more relevant for the discussion about emerging therapies. While quite a few cell and gene therapies have moved into later clinical phases and beyond, there are new examples of emerging therapeutics such as extracellular vesicles, peptide-based vaccines, complex molecules produced by chemical synthesis, or approaches using combinations of different technologies in the development/research phases.

For early clinical phases, patient safety is a primary focus. For many emerging therapies that are sterile, fully validated aseptic manufacturing processes are required to support clinical supply, even for Phase I. There is more flexibility in areas that do not have a direct impact on patient safety such as QC [quality control] method validation, where verification may be sufficient but, at the outset, a phase-appropriate GMP assessment is required—to determine the areas where full GMP is required to ensure patient safety, and balance these areas with others that may require less rigor for the clinical program. This approach is valid for both regulatory regions—EU and the US—but in practice expectations can differ depending on the inspector and their knowledge of the product. This can be one benefit of the expedited pathways available from FDA and EMA which include built-in scientific meetings for exchanges of information between inspectors and clinical researchers—long before an MA/IND [marketing authorization/investigational new drug application] is granted and an inspection is scheduled.

 How has the guidance for GMPs for emerging therapies evolved over recent years?

 Over recent years, the landscape for the regulation of GMP has changed in response to innovation and the broader range of therapy types being developed. Due to the huge variety of platforms and technologies, a ‘one size fits all’ approach is no longer practical nor feasible. With this change, the emphasis is being placed on the identification, assessment and control of risk. This has been a major focus in the revision of key guidance documents such as the 

 Volume 4 Annex 1 ‘Manufacture of Sterile Products’ and the recent revision of ICH [International Council for Harmonisation] Q9 on quality risk management (QRM) (3,4). Each revised guidance document includes a much more focused emphasis on managing the risk to product quality to safeguard patients.

The introduction of the European guidelines on GMP specific to ATMPs demonstrates a recognition of the difficulty in legislating for ATMPs, and of the important role QRM plays in the future regulation of all emerging therapies (2).

 Are any major changes to GMP guidance for emerging therapies expected in the near future?

 The GMP for ATMP guidance published for the EU was a good start, in recognizing that GMP manufacturing of innovative drugs requires more flexible guidance to account for all different modalities. However, not all emerging therapies are covered by the ATMP guideline. One good example is personalized cancer vaccines consisting of peptide-based neoepitopes. Such therapies do not fall under the ATMP definition, yet share many common features—such as manufacturing and testing challenges imposed by their small batch sizes. Most importantly, the composition of each batch of such a personalized therapeutic differs, which requires a special approach (e.g., to their validation and stability studies).

Another important development is the increased use of prediction programs using artificial intelligence in designing personalized therapeutics. These emerging applications should drive adaptations of existing GMP regulations to further develop approaches for algorithm validation in a GMP environment, for example.

There are also more subtle changes that are already occurring such as the widening of the scope of Annex 1 in terms of applicable territories and manufacturing platforms. This further highlights the acceptance, particularly between the US and EU, that a more common approach is needed for the regulation of GMP for all product types, not just emerging therapies.

It is also evident, based on the focus on QRM in the industry, that this will be the driver for future GMP regulation—rather than relying on unilateral instructions for an industry that is now highly diverse.

 Are there specific differences between the GMP guidance for emerging therapies in the US versus Europe and other parts of the world?

 There are no specific GMP regulations for emerging therapies in the US; this is a gap currently. The GMP applied to US emerging therapies is interpreted from existing regulations, and the US is now placing more focus on the application of QRM for emerging therapies that have unique or unusual characteristics that impact GMP. In the EU, there is an existing document (2), which although set apart from the existing GMP regulations contained in EU GMP Volume 4, is largely an amalgamation of existing documents, in addition to references relating to application of QRM where black and white guidance is impossible or unavailable.

Guidance for GMP manufacture of emerging therapies has evolved to accommodate innovation and the broader spectrum of products in development, but greater harmonization is still needed.

BioPharm International, May 2023

Expanding the Emerging Therapeutic Horizon

Challenges of Expanding CAR-T Cell Therapy into Solid Tumors

Contextualizing Single-Use Waste

Overcoming Harvesting Challenges for Adherent Cell-Culture Processes

Data Integrity Pitfalls

Optimizing the Manufacture of Emerging Therapies

FDA and Industry Prepare for End to COVID-19 Emergency

Measuring Quality in a Culture

The Smart Benefit of Digital Systems in Preclinical Studies

Springing Forward!

Young Pups and Leopards