How have lessons from the pandemic influenced the way companies use technology to perform quality-control procedures?

A New View on Quality Control?

Preclinical and clinical research is improving ADC development.

ADC Development Improves on Research

Strategizing drug development in the preclinical phase has merit.

Preclinical Strategies Benefit Biopharma Development

Perfusion cell culture gains advantage with PAT tools advancement.

Perfusion Cell Culture is Gaining Momentum

Coating is an alternative to silicone oil as a lubricant. URL for article 

Syringe Coating Technology

Redefining Contamination Control for CGTs

Novavax COVID-19 Vaccine Receives EUA in Indonesia

FDA Grants EUA for Pfizer-BioNTech COVID-19 Vaccine Use in Children

FDA approved Genentech’s rituximab (Rituxan) in combination with chemotherapy for pediatric patients (6 months of age and older to 18 years of age) with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature B-cell acute leukemia (B-AL), according to a Dec. 2, 2021, press release.

When given as an intravenous infusion given in combination with systemic Lymphome Malin B (LMB) chemotherapy, the recommended rituximab dose is 375 mg/m

. Six total infusions of rituximab are given.

A global multicenter, open-label, randomized trial was performed, assessing patients six months in age or older with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL. Event-free survival was the main efficacy outcome measure. This was defined as a progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second Cytarabine Aracytine, Ara-C, Veposide course. There were 20 deaths in the LMB chemotherapy arm compared to 8 deaths in the rituximab plus LMB chemotherapy arm at the time of the interim analysis.

Articles

Subtitle FDA approved rituximab in combination with chemotherapy for pediatric patients with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL.

Rituximab Plus Chemotherapy Approved by FDA for Select Pediatric Cancers

On Dec. 1, 2021, Roche announced the completion of its share purchase agreement to acquire 100% of the outstanding shares of TIB Molbiol Group in a company press release. The companies will focus on the rapid development of polymerase chain reaction (PCR) assays and diagnostic tests for emerging pathogens and potential health threats, such as infectious diseases. TIB Molbiol will operate as a subsidiary within the Diagnostics division.

For more than 20 years, the companies have collaborated to address biological threats, including:

“I am very pleased that together with TIB Molbiol, we can significantly improve access for patients to a broader spectrum of diagnostic tests—from high volume routine tests to the diagnosis of rare diseases. TIB Molbiol will continue to be an innovation engine and frontrunner in our common fight against infectious diseases, such as SARS-CoV-2,” said Thomas Schinecker, CEO, Roche Diagnostics, in a company press release. “TIB Molbiol has helped to shape the future of PCR infectious disease testing and will continue to drive cutting-edge research so we can bring better healthcare outcomes to patients faster.”

The companies will focus on the rapid development of polymerase chain reaction assays for emerging pathogens and potential health threats, including biological threats.

Roche Expands PCR-Test Portfolio with Completion of Purchase Agreement of TIB Molbiol

GlaxoSmithKline (GSK) and the University of Oxford announced a five-year collaboration to establish an institute to improve the success and speed of research and development of new medicines, which will be based at the University of Oxford, according to a Dec. 2, 2021, press release. The institute, the Oxford-GSK Institute of Molecular and Computational Medicine, will build on insights from human genetics and will use advanced technologies, such as functional genomics and machine learning.

To understand detailed patterns of disease that vary among individuals, the institute intends to evaluate and integrate new approaches in genetics, proteomics, and digital pathology. The initial research will be focused on neurological diseases, such as Alzheimer’s and Parkinson’s diseases.

In the past decade, there have been datasets of promising targets for medicine discovery. These datasets can be combined with functional genomics to provide a deep understanding of disease at a molecular level, according to the GSK press release. The institute will harness this understanding along with machine learning to learn new predictors of the disease and accelerate drug discovery.

“I am delighted to see that GSK and the University of Oxford are today taking further steps to deepen our understanding of some of the most complex diseases, such as Parkinson’s,” Prime Minister Boris Johnson said in the GSK press release. “Together they will harness the power of scientific collaboration to progress cutting-edge technologies and accelerate drug discovery—helping to cement the UK’s role as a life sciences superpower.”

This collaboration aims to better understand Alzheimer’s and Parkinson’s disease and increase drug discovery and development success rates.

GSK and the University of Oxford Join Forces to Research Treatment Potentials for Neurological Diseases

Moderna announced on Dec. 1, 2021, a revised supply agreement with the UK government for the company’s COVID-19 vaccine and possibly authorized booster vaccine candidates as well. Specifically, this supply agreement encompasses up to 60 million doses of Moderna’s COVID-19 vaccine.

In 2022, as many as 29 million doses are expected to be delivered, and up to 31 million doses are expected to be delivered in 2023. The UK government retains a right to increase or decrease its purchases in 2022 and 2023, under to the agreement, by up to 20% above or below the contracted volumes.

“We thank the UK government for their support in this supply agreement for our mRNA COVID-19 vaccine and booster candidates, if approved, in 2022 and 2023,” said Stéphane Bancel, CEO of Moderna, in a company press release. “This agreement reflects the efforts of the UK government to address the ongoing pandemic and builds on our existing collaboration to protect people in the UK.”

Moderna’s agreement with the UK government includes 29 million COVID-19 vaccine doses for delivery in 2022 and 31 million doses for delivery in 2023.

60 Million Doses of the COVID-19 Vaccine is Added to Moderna’s Supply Agreement with the UK

 Washington Editor, jillwechsler7@gmail.com.

The challenges in developing gene and cellular therapies have made headlines over the past year, as biotech companies have launched a wave of development programs despite ongoing concerns about treatment safety and efficacy plus unknown long-term effects. High price tags on these breakthrough treatments, moreover, threaten to block patient access to potentially life-saving cures and treatments. FDA scientists and reviewers are working to advance the field, with new guidances and advice for manufacturers on appropriate testing of treatments to minimize risks to patients and fill gaps in data.

New gene therapies for debilitating rare conditions stand to advance from an 

FDA collaboration with the National Institutes of Health (NIH) and a cadre of pharma companies, small biotechs, and patient groups

, formally announced Oct. 27, 2021. The Bespoke Gene Therapy Consortium (BGTC) will be managed by NIH’s Accelerating Medicines Partnership program and the Foundation for the NIH and will provide public and private resources to support the development of gene therapies to treat rare diseases.

To start, the BGTC plans to initiate preclinical and clinical trials for four to six monogenetic rare diseases that currently lack any treatment. Such advances will facilitate a better understanding of the biology and production of adeno-associated virus (AAV) vectors utilized to deliver gene therapies to individual patients. The consortium will provide $76 million over five years from NIH and private partners to fund a range of research, such as establishing standardized analytical test methods to improve AAV production and use and to advance toxicology testing for preclinical development. The term “bespoke” reflects the need for efficient methods for developing highly individualized therapies to fit the genetic specifics of one or two patients.

The BGTC initiative has been under development for several months, as seen in remarks at the September 2021 PDA/FDA conference by Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), on how the program could standardize methods for developing and manufacturing bespoke therapeutics. Marks outlined efforts to leverage methods and data from one application to another to reduce prohibitive R&D costs that threaten product development and patient access. In advancing the development of gene therapies for very rare disorders, he noted the importance of collecting baseline natural history data on target diseases and of public-private partnerships to enable streamlined production through a “cookbook” for developing bespoke therapeutics.

This public-private collaboration is particularly timely in the wake of recent patient deaths and safety issues linked to experimental gene therapies involving AAV delivery. 

FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee met in early September

 to discuss these concerns, noting the limitations of preclinical animal models in predicting potential risks from viral vectors. Panel members cited the need for clearer standards related to gene therapy development, for more comprehensive patient screening, and for longer assessment of patients following treatment to better track side effects that may emerge later.

Even though the experts stopped short of recommending specifics curbs on developing these advanced treatments, 

FDA suspended further testing of an experimental gene therapy for hemophilia from BioMarin Pharmaceutical due to early safety issues

Pfizer halted studies on two experimental gene therapies

 following reports of adverse events in early studies.

Meanwhile, CBER seeks to expand the resources and expertise for its Office of Tissues & Advanced Therapies (OTAT) to better oversee and provide advice on developing genetic and other advanced products. Despite a slowdown in biopharmaceutical research due to the pandemic, CBER officials continue to see a strong flow of applications to test experimental cell and gene therapies, many requesting meetings with OTAT staff to discuss research plans. OTAT director Wilson Bryan noted the importance of transparency on safety issues related to gene therapy in a Nov. 12, 2021, presentation at a meeting sponsored by Prevision Policy. One critical issue to explore is whether the effectiveness of gene therapy treatment wears off over time, warranting re-administration. To address these unknown and continuing safety concerns, Bryan emphasized the importance of long-term follow-up of all gene therapy patients—maybe following gene therapy patients “forever,” he commented.

High price tags threaten to block patient access to potentially life-saving cures and treatments.

FDA Grapples with the Promise and Perils of Gene Therapy

On Nov. 30, 2021, Atara Biotherapeutics announced that the European Medicines Agency (EMA) has fully validated the company’s marketing authorization application (MAA) for tab-cel (tabelecleucel), an investigational off-the-shelf allogeneic T-cell immunotherapy being developed to treat Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD). EMA is expected to announce a decision on approval for the MAA in the second half of 2022 based on an evaluation by the Committee for Medicinal Products for Human Use (CHMP).

The MAA is seeking approval for treatment of patients with EBV+ PTLD who have received at least one prior therapy following solid organ transplant (SOT) or hematopoietic cell transplant (HCT).

Tab-cel is Atara’s lead candidate for EBV-positive cancers, including EBV+ PTLD. It is currently being investigated in adults and children in an ongoing Phase III trial. The MAA includes positive data from the study, which demonstrates a 50% objective response rate (ORR), as measured by an independent oncologic response adjudication (IORA) assessment. The study has thus far demonstrated an ORR of 50% in PTLD following SOT and an ORR of 50% in PTLD following HCT, with a best overall response of complete response or partial response.

Atara will present its findings from the Phase III study and additional tab-cel data in eight abstracts at the 63rd American Society of Hematology Annual Meeting being held on December 11–14, 2021 in Atlanta, GA.

Tab-cel was granted breakthrough therapy designation for EBV+ PTLD following allogeneic HCT by FDA and priority medicines designation by the EMA for the same indication. Tab-cel has orphan drug designation in both the United States and European Union (EU).

In October 2021, Atara entered into an exclusive commercialization agreement with Pierre Fabre for tab-cel in Europe, Middle East, Africa and other select emerging markets for EBV-positive cancers. Under the agreement, Atara is responsible for the Phase III study currently underway in PTLD and is responsible for submitting the EU MAA. The company also remains responsible for a Phase II multi-cohort study, in which tab-cel is being evaluated in six additional patient populations. The goal of the Phase II study is label expansion in other EBV-driven cancers. Pierre Fabre will lead all commercialization and distribution activities in the territories, as well as medical and regulatory activities after the anticipated MAA approval in Europe.

“EBV+ PTLD is a rare and aggressive cancer where the patients we seek to treat only have weeks to a few months survival after treatment failure, with no approved options,” said Jakob Dupont, executive vice-president and global head of Research and Development at Atara, in a company press release. “Tab-cel is the first-ever off-the-shelf allogeneic T-cell therapy to be reviewed by a regulatory agency and is a watershed moment for the field and for patients with significant unmet need. We look forward to working with the EMA as the agency evaluates the transformative potential of tab-cel.”

EMA has fully validated the marketing authorization application for Atara Biotherapeutics’ off-the-shelf allogeneic T-cell therapy, tab-cel (tabelecleucel), with an approval decision expected in 2022.

Atara Biotherapeutics' MAA for Allogeneic T-cell Immunotherapy Gets EMA Validation

On Nov. 30, 2021, Chinook Therapeutics, a biopharmaceutical company specializing in precision medicines for kidney diseases, announced the formation of a joint venture with an investor syndicate led by Frazier Healthcare Partners and Pivotal bioVenture Partners China. The joint venture, SanReno Therapeutics, will develop, manufacture, and commercialize kidney disease therapies in the People’s Republic of China, Hong Kong, Macau, Taiwan, and Singapore (collectively called the “Territory”).

Under the agreement, Chinook has granted SanReno exclusive rights to develop and commercialize the therapeutic candidates atrasentan and BION-1301 in the Territory in exchange for 50% ownership of SanReno. The investor syndicate, which also includes Versant Ventures and Samsara BioCapital, both existing Chinook investors, has invested $40 million for the remaining 50% ownership of SanReno.

In addition to its equity stake, Chinook is entitled to receive progress-dependent milestone payments and royalties with respect to atrasentan and BION-1301. SanReno will be responsible for all development, manufacturing, and commercialization costs for the two therapeutic candidates in the Territory, while Chinook will supply clinical trial material and technical support until manufacturing technology transfer has been completed. Chinook and the investor syndicate also have an option to participate in future investment rounds for SanReno.

Furthermore, Chinook and SanReno have reciprocal rights of first negotiation in their respective territories for certain future kidney disease products developed or in-licensed by either company. Chinook retains full rights to atrasentan and BION-1301 outside of the Territory.

“Formation of this joint venture allows Chinook to expand our global reach and establish a strong presence in China by partnering with investors who are experienced in company formation, drug development, and commercialization in the region,” said Eric Dobmeier, president and CEO of Chinook Therapeutics, in a company press release. “Chronic kidney disease is a major public health concern in China, affecting over ten percent of the population, including several million patients with IgAN [immunoglobulin A nephropathy]. Working with SanReno will expand Chinook’s access to Chinese patient populations, key opinion leader networks, and on-the-ground operational support to accelerate enrollment and regulatory approval of our programs globally.”

“Frazier is excited to partner with Pivotal and Chinook to bring potentially best-in-class drugs to the Chinese market for patients suffering from serious kidney diseases. The high prevalence of IgAN and limited treatment options in China have driven significant market potential for SanReno,” said Patrick Heron, managing partner of Frazier Healthcare Partners, in the press release. “With Frazier’s background in company creation and Pivotal’s extensive expertise building joint ventures in China, we believe SanReno will have exceptional operational support and be well-positioned to address the large unmet medical need.”

Chinook Therapeutics has formed a 50/50 joint venture with investors to develop kidney disease therapies in China.

Chinook Therapeutics and Investors Form Joint Venture for Kidney Disease Therapies

Sartorius announced on Nov. 26, 2021 that it plans to invest a total of €100 million (US$113 million) between 2021 and 2025 to expand and upgrade its Aubagne, Cergy, and Lourdes facilities in France. The expansions will include:

of cleanroom space on top of the existing 5000 m

The deployment of new R&D laboratories covering close to 2000 m

 to strengthen the company’s innovation capacity

An upgrade in the company’s logistics platforms and buildup of over 10,000 m

 of warehouse facilities and storage depots

The digitalization and automation of equipment to increase capacity and competitive advantage

The investment will enable Sartorius to further boost performance, increase its innovation, and meet growing market demand. Under its growth strategy, Sartorius will create up to 400 new permanent employment positions at the four French sites between 2021 and 2025. The company is seeking new talent in operations, such as production managers, machine operators, continuous improvement managers; product development staff, including engineers, data analysts; and marketing personnel. Sartorius will also support its teams by facilitating the acquisition of new, cutting-edge skills, particularly in automation and digitalization of equipment used in workflows.

“We see our biopharmaceutical customers entering a new phase characterized by a high pace of innovation, substantial investments in their operations, and increasing demands on us as their suppliers. We are supporting their efforts, significantly adding capacity and increasing the speed of delivery,” said Luc Burgard, managing director of Sartorius Stedim FMT and head of operations of the Bioprocess Solutions Division at Sartorius, in a company press release. “The investments in our French facilities will strengthen our industrial capabilities in this country and secure the long-term future of our operations here.”

Sartorius is investing €100 million (US$113 million) between 2021 and 2025 to expand capacities for production, innovation, and storage at its French facilities in Aubagne, Cergy, and Lourdes.

Sartorius to Invest in Growing Operations in France

Sartorius is investing approximately €270 million (US$305 million) through the end of 2024 to expand its activities in South Korea, the company announced on Nov. 25, 2021. Using the investment funds, the company plans to launch cell culture media production in Songdo, Incheon, South Korea’s biopharma hub, in addition to assembling sterile systems for efficient and flexible biopharmaceutical manufacturing, among other operations.

Construction of new facilities at the 25,000-m2 (270,000-ft2) site will include an application center with laboratories as well as several buildings for manufacturing and logistics. Construction is slated to begin in the coming year with production operations scheduled to start by the end of 2024. The expansion will create approximately 750 new jobs. Sartorius’ existing activities for service as well as for marketing and sales will be relocated to the new site.

“The development of the biopharmaceutical industry in Asia and, in particular, South Korea, has entered a new phase characterized by a high innovation and investment pace on the part of our customers. With our significant investments in Songdo, we will be increasing capacities, moving production operations closer to our customers in the region and substantially accelerating our delivery speed,” said Joachim Kreuzburg, executive board chairman and CEO, Sartorius, in a company press release.

Sartorius will invest approximately €270 million (US$305 million) to expand its biopharmaceutical manufacturing activities in South Korea’s biopharm hub.

Sartorius Launches Expansion in South Korea with Mullti-Million Dollar Investment

Raymond P. Goodrich, PhD, is the founder of PhotonPharma, executive director of the infectious disease research center at Colorado State University, and professor for the department of microbiology, immunology, and pathology at Colorado State University.

Amanda Guth, DVM, PhD, is the chief scientific officer for PhotonPharma.

Jon Weston is the president and CEO of PhotonPharma.

Terry Opgenorth, PhD, is the executive in residence life sciences for CSU Ventures.

Gary Gordon, MD, PhD, is the president of Global Coalition for Adaptive Research.

Traditional approaches to treating patients with cancer are based primarily on maximizing the destruction of tumor cells while minimizing the damage to healthy cells. The ability of chemical agents, radiation, and surgical procedures to destroy or remove tumor cells while preserving the functionality of healthy tissue is the basis of every form of cancer therapy. The result of this quest has yielded therapeutic formulations targeting unique metabolic, genomic, and phenotypic characteristics of cancer cells for the treatment of patients with cancer.

Advances in our understanding of immunology and the body’s ability to defend itself against aberrant cells and tissue have afforded new tools in our search for better treatments and cures. Most of these approaches rely on the body’s inherent ability to distinguish between cancerous cells and healthy tissue and to respond through both the production of antibodies (humoral immunity) and the generation of cell-based immune responses. New formulations of autologous therapies for cancer are produced by culturing and expanding specific immune cell populations, specifically T cells (T lymphocyte), 

 and training them for seek-and-destroy missions when re-infused. These therapies have produced life-saving outcomes in patients, such as those suffering from B-cell lymphomas. Nonetheless, these methods have limitations such as non-specific targeting (e.g., destroying all B cells and not just the cancerous ones), cost of production, and complexities related to 

The complexity of steps involved in the production of targeted T cells require 

 expansion and manipulation of the immune cells, which in turn requires costly reagents to produce enough cells for administration. These manufacturing steps drive up cost, introduce logistical issues, and reduce the ability to treat the diverse nature of most tumors. For autologous therapies for cancer, new therapeutic formulations not only use the patient’s own immune cells but also their own tumor cells to generate therapeutic preparations for treating their specific cancer. This approach may address many of the current limitations of cell-based immunotherapy.

Patient-specific immune therapy limitations

The development of methods to manipulate immune cells from a patient 

 has greatly increased the utility and benefit of cellular therapy and autologous, patient-specific immune therapies. The most recent example of Chimeric Antigen Receptor (CAR) T-cell therapy targeting B-cell lymphoma is perhaps the most specific illustration of how personalized cell therapy approaches can be effectively implemented with great benefit to patients (1). By developing methods to target CD19 antigen, 

, T cells are generated with the ability to seek and destroy all cells expressing CD19 antigen. Both tumor cells and healthy B cells with this antigen are eliminated. The resulting reset of the immune system through triggering mechanisms that silence these altered T-cell clones can lead to the cure of the lymphoma that the patient has on board.

Unfortunately, a reset such as this is not possible with other cell types. While it is feasible for an individual to survive for a period without B cells, it is not possible for them to survive if all lung, colon, liver, and/or other solid organ tissue were similarly targeted for elimination. The limitation of T-cell therapies of this type are thus dependent on identifying antigens that are specific to the tumor (neoantigens) but not present on the healthy cells. The presence of such specific antigens allows the immune system to distinguish between healthy and cancerous and thus eliminate the tumor more specifically. Unfortunately, targeting against a specific neoantigen may prove insufficient since tumors may contain a plethora of these tumor-specific antigens, which are not expressed across every cell in an individual’s tumor. This issue can lead to the escape of some tumor cells, resulting in tumor regrowth if the targeting is too specific. In recent years, multiple new cell therapies have entered clinical trials and are reporting improved efficacy over the standard of care (2). These therapies are using genomic analysis and artificial intelligence to identify or predict neoantigens on individual patient tumors. Researchers then construct peptide vaccines or potentiate harvested patient immune cells to the neoantigens for reinfusion.

T-cell culturing and dendritic cell manipulation 

 also require a complex logistical framework for manufacture. First, immune cells must be harvested from the patient in sufficient quantities to allow subsequent culturing and expansion. These processes often take weeks of 

 manipulation in cell bioreactors using reagents and culture conditions that promote cell expansion of specific cell types to the exclusion of others. An insufficient yield of cells at the end of culture could mean that the patient is unable to subsequently receive an effective therapeutic dose of the altered cells. The 

 manipulation of the product required also introduces challenges in maintaining sterility and covering high costs associated with the reagents and procedures needed to drive cell differentiation in culture along the desired pathways. The average cost of CAR-T therapy exceeded $400,000 per treatment in the initial introduction, and reimbursement today remains at $240,000 in most settings (3). This limits the number of patients for whom such treatment is accessible.

An alternative approach: CAR-T therapy in reverse

 manipulation of the immune cells is to modulate immune responses 

 by presenting the tumor antigens to the immune cells in an environment separate from the tumor microenvironment where immune suppressors may be expressed by the tumor cells, thus reducing immune response at the local site of the tumor. Such an approach would allow the type of cell modification that CAR-T therapy achieves 

 through the presentation of tumor antigen to the immune system that the patient has on board.

Several methods using specific tumor antigens or whole tumor cells, which have been inactivated before administration, have been utilized previously with moderate success (4). 

Single antigen approaches, however, face the same challenges that CAR-T cell therapy faces. Elimination of specific clones of a tumor may not lead to complete clearance of all tumor cells in a patient. The use of whole, inactivated cells requires that the cells be rendered incapable of replication post-infusion to prevent the regrowth of tumors in the patient. To assure complete inactivation, common methods employ chemical agents such as formalin, ultraviolet (UV) light, or gamma irradiation of sufficient energy and dose to destroy cell replication processes. The harsh and non-specific nature of the chemistry that these methods invoke results in cells that are not only inactivated but also rendered altered from the native antigen state that these tumor cells express. As a result, these methods often require large amounts of tumor material to induce a strong immune response, effectively increasing the dose to levels at which sufficient amounts of the native tumor antigen are still capable of generating immune reaction to those antigens.

Currently, we are exploring the ability of a method initially developed to treat blood products for the prevention of transfusion-transmitted infections to create inactivated tumor cells that can subsequently be used, in combination with Th1-promoting adjuvants, to stimulate an immune response 

 in preclinical models (5). This photochemical approach uses Riboflavin (vitamin B2) and UV light of specific wavelengths to generate specific modifications to tumor cell DNA that prevent replication of these cells (6). The specific nature of the chemistry for nucleic acid modification without alteration of proteins and antigens in the tumor cells yields cells that lack the ability to replicate but maintain their native antigen profile. In addition, these treated cells maintain cell metabolism and protein expression following treatment like blood cells treated similarly without the ability to replicate (7).

Tumor cells treated by this process were evaluated in immune-competent mouse models and shown to slow tumor growth, reduce metastatic disease, and stimulate immune cell responses to tumor tissue (8). In canine studies, preparations of tumor cells at doses as low as 1E+06 tumor cells per dose stimulate immune cytokine production and reduce tumor cell immunosuppressive cytokine expression. Doses of product sufficient to treat autochthonous tumors in dogs without inducing adverse acute reactions were reported previously (9).

The production of these materials does not require 

 expansion of the cells, thus reducing turnaround time and complexity of providing the therapy to patients. In a canine cancer trial conducted at the Flint Animal Cancer Center at Colorado State University, we tested the logistical practicality of using a biopsy or excised tumor tissue obtained at the Cancer Center, processing it at the PhotonPharma labs at the Research Innovation Center on campus, and returning the products to the canine subjects within one to seven days of their initial clinic visit. Production of the inactivated cells requires less than two hours using equipment and disposables that already received a Conformitè Europëenne Mark and are available in routine clinical use in blood centers globally (10).

Injection of the inactivated cells in an autologous fashion allows for the generation of immune response targeted to the patient’s specific tumor type and all tumor antigens that may be present in that patient’s tumor. The extensive experience of using treated blood products, which include nucleated leukocytes and lymphocytes from allogeneic donors, demonstrates the safety of the infusion of nucleated cells treated by this process. Riboflavin is a substance that has an extensive toxicology profile showing its safety after exposure to UV light in the process that is utilized here for creating inactivated tumor cells (11).

The low-cost profile of the equipment and disposables required for producing the inactivated cells via this method also has distinct advantages that may increase the accessibility of this therapy in patients with solid-organ tumors. As extensive 

 manipulation of the product is not required, production costs for such a therapy can also be limited and made more accessible for patients, healthcare providers, and national health services. Such an approach could make cellular therapy methods available to populations in many regions of the world today for which these procedures are currently inaccessible due to cost and complexity of implementation.

Our initial focus of work is the development of this therapy for treating patients with breast cancer. These tumors are generally accessible via biopsy or surgical excision. Breast cancer patients also experience high levels of metastatic relapse potential due to the nature of these tumors and the fact that chemotherapy or radiation therapy may allow for the survival of small populations of resistant cells. An autologous therapy approach as outlined in this article has the potential to reduce the likelihood of disease relapse in this patient population. Such an approach could also add another dimension to treating other solid organ tumors. This could include follow-up in such patients in a way that boosts the efficacy of more conventional treatments. The specificity of the therapy to the patient’s own tumor makes a response in each patient more relevant to their specific tumor composition, providing a lower likelihood of immunological escape. In the end, tumor material that is otherwise discarded can be applied to defeat the disease that led to its existence to begin with.

F. Locke and J. Lin, “Are CAR T-Cell Therapies Worth the Costs?” 

R. Goodrich, et al., “The Antiviral and Antibacterial Properties of Riboflavin and Light: Applications to Blood Safety and Transfusion Medicine,” in 

, E. Silva and A. Edwards, Eds. pp. 83-113. (RSC Publishing, Cambridge, UK, 2006).

Raymond P. Goodrich, PhD, is the founder of PhotonPharma and executive director of infectious disease research center and professor, department of microbiology, immunology, and pathology, for Colorado State University. 

Amanda Guth, DVM, PhD, is the chief scientific officer of PhotonPharma. 

 is the president and CEO of PhotonPharma. Terry Opgenorth, PhD, is the executive in residence life sciences for CSU Ventures. 

MD, PhD, is the president of the Global Coalition for Adaptive Research.


Volume 34, Number 12
December 2021
Pages: 

When referring to this article, please cite it as R. 

Formulating Autologous Therapies for Cancer

Autologous tumor cells engineered for immune system stimulation can target unique metabolic, genomic, and phenotypic characteristics of cancer cells.

Jennifer Markarian is manufacturing editor of BioPharm International.

The use of isolators for aseptic manufacturing has increased, driven by the effectiveness of the equipment for product safety and by the increasing number of products that must be processed aseptically (1). Isolators operate as closed systems and can be designed with attached gloves for manual intervention or as “gloveless” for fully automated systems. The draft revision to the European Union’s Annex 1 good manufacturing practices (GMP) for manufacturing sterile medicinal products (2) provides direction for designing and cleaning isolators (1). Evaluating the design of the isolator system in relation to the contamination control strategy is crucial, explained Richard Denk, a senior consultant for Aseptic Processing and Containment at SKAN (1).

Automation inside isolators further reduces human intervention. Comecer, an ATS company, displayed a containment isolator integrated with the company’s new automated SuperTrak Pharma platform for asynchronous conveyance at INTERPHEX 2021. The automated system offers flexibility with individually controlled shuttles, which increases throughput while while using a less complex and smaller footprint than traditional automation systems.

Although isolators have been commonly used in larger-scale or automated aseptic fill/finish, the technology is pushing into smaller-volume areas. Robotic automation is beneficial for small batches because it allows flexibility and more rapid changeover (3). Syntegon introduced the modular, small-batch Versynta FFP [Flexible Filling Platform] in 2021. It uses a four-axis robot inside the isolator to handle containers for filling aseptic or highly potent liquid products and can fill up to 3600 containers per hour (4). The isolator’s air flow is optimized so first air is supplied to the containers without obstruction.

Syntegon’s Versynta microBatch is an automated production cell in a gloveless isolator for smaller batches in the range of 120–500 containers per hour. This system, which is being developed in partnership with Vetter, is planned to be launched in 2022 (3).

Innovative isolator equipment is being developed and used in cell and gene therapy (CGT) manufacturing, as more companies get involved in the emerging area of advanced therapy medicinal products (ATMPs). While these small-volume processes started out primarily as manual processes in biosafety cabinets, new equipment offers the option of closed and automated processing. Biosafety cabinets have lower initial capital costs, but they present higher risk of microbial or cross-contamination and must be used in a Grade B cleanroom. Isolators, however, are closed systems that reduce contamination risk. Another advantage of using an isolator are that they can be used in a Grade C or D cleanroom, which requires less capital expenditure and lower energy use. The lower cleanroom levels require less personal protective equipment (PPE), which is more comfortable for operators as well as saving in costs and environmental impact of PPE disposal, explains Matt Pridden, standard product development manager at Extract Technology. Inquiries into isolator technology for ATMPs have been increasing, says Pridden, primarily because of the higher level of safety and the need to meet the requirements of Annex 1. Use of a Grade A isolator is known by regulators and the industry as the lowest level of risk to sterility, he adds.

Cellectis, for example, is a gene-editing company that recently opened a facility where it is performing clinical-stage manufacturing of allogeneic, universal chimeric antigen receptor T-cell (UCART) immunotherapies. In each the facility’s two manufacturing suites, a custom designed, four-chamber isolator encloses all parts of the UCART manufacturing process. Glove ports allow operators to perform manual process steps in the isolator. A separate isolator is used in the filling suite for automated fill/finish of the vials. Steve Doares, Cellectis’ senior vice-president of US manufacturing and the site head of the new Raleigh, NC manufacturing site, explained that the isolators were chosen instead of biosafety cabinets to maximize product quality assurance and maintain aseptic conditions throughout (5).

SKAN’s new Cellana isolator is designed for GMP manufacturing of ATMPs. A modular design allows different components to be integrated as needed for the specific process, and it can be integrated with semi-automatic or automated filling systems. The Cellana isolator uses technology already established in SKAN’s other isolators, such as the SKANfog decontamination technology and a catalytic convertor that completely decomposes hydrogen peroxide before the air is exhausted. The isolator uses a Grade A unidirectional airflow with high efficiency particulate arrestance filtration in both the air supply and the air return ducts, which allows it to handle viral vector and potent compounds (6).

In July 2021, powder-containment equipment specialist Dec Group acquired Extract Technology, which manufactures aseptic and containment work environments including CGT isolators (7). The company’s Modular Cell Therapy Isolator can be configured from chambers for transfer, centrifuge, and processing that form a Grade A environment, which is decontaminated using vapor-phase hydrogen peroxide. Patent-pending dockable incubators can be connected and disconnected as needed to allow multiple cell cultures to be processed. Another key aspect is the ability to integrate equipment specific to a client process, says Pridden. Extract Technology’s isolators have been used for several years to produce allogeneic stem cell transplant therapies. The systems can also be used for autologous cell therapies. The closed system allows open manipulation within a Grade A environment.

Comecer offers several isolators specifically designed for CGT. For example, a standalone isolator workstation is designed for applications that require cell manipulation and incubation under GMP conditions. The company makes a docking incubator system that can be connected to its CGT isolators using the Comecer Flexy interface. Modular components allow more flexibility to adapt and scale any manufacturing process. In June 2021, Comecer partnered with G-CON to provide its CGT closed aseptic systems (isolators and fillers) prequalified and installed inside G-CON’s prefabricated POD cleanrooms. (8).

ILC Dover extended its single-use, flexible containment isolator technology to aseptic isolators with the introduction of the soloPURE flexible aseptic isolator (9). The isolator’s closed, Grade-A aseptic environment can be used for aseptic processes and fill/finish tasks, including small-scale vial filling. The equipment has a small footprint, and the chamber has glove ports on both sides. The flexible chamber is gamma irradiated for use one time before disposal, or it can optionally be sterilized-in-place with vaporized hydrogen peroxide. The disposable chamber eliminates the need for cleaning and validation, which allows rapid changes from one product to another.

EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2020).

Syntegon, “Versynta FFP,” Press Release, March 10, 2021.

J. Markarian, “Cellectis Opens GMP Manufacturing Facility,” 

SKAN, “Cellana Cell & Gene Therapy Isolators: Interview with Our Cell & Gene Task Force (3),” 

Dec Group, “Dec Group Announces Acquisition of Extract Technology,” Press Release, July 1, 2021.

Comecer, “Comecer Partners with G-CON to Speed Up the Implementation of Your Cell and Gene Therapy CGMP Manufacturing Facility,” Press Release, June 3, 2021.

ILC Dover, “ILC Dover Defines the Future of Sterile Manufacturing with the soloPURE Flexible Aseptic Isolator,” Press Release, April 13, 2021.

Jennifer Markarian is the manufacturing editor for 


Vol. 34, No. 12 
December 2021 
Pages: 26–27

When referring to this article, please cite it as J. Markarian, “Trends in Isolator Equipment,” 

Isolators move into smaller-volume processes, including cell and gene therapy manufacturing.

Trends in Isolator Equipment

For biological molecules to be safe and possess both high quality and efficacy, raw material quality control strategies are of the utmost importance. According to an article published by the Parenteral Drug Association (PDA), to achieve safety, quality, and efficacy, the following must be considered (1):

Supplier qualification system to assess raw material: origin risk, supply risk, and quality risk

Raw material quality testing strategies, including if specific tests are needed for particular raw materials.

Assessing supply risk, specifically, can include evaluating raw material availability, secondary options for supply, audits, and contractual agreements, while gauging quality risk may include evaluating consistency between lots, according to the PDA article (1). Raw material quality control strategies are essential to help ensure product quality and mitigate adventitious agent contamination risk (1).

Udo Losehand, head of global technical developers, Roquette—a supplier of biopharmaceutical raw materials—as well as Nate Fillipan, senior specialist, quality assurance; Stephanie Walsh, director, supply chain; and Paul Schildgen, director, manufacturing process optimization, all of Catalent Biologics—a manufacturer of biopharmaceutical raw materials—share with 

 how to determine the quality of raw materials, regulatory requirements to be aware of, supply chain challenges, and what factors must be considered when sourcing raw materials.

Behind the scenes: supplying raw materials

 What is the general procedure for making raw materials?

: Roquette is vertically integrated, and, therefore, performs every step of the manufacturing process in-house. This starts with the selection of appropriate grains and the extraction of starch, through to the manufacture of a high-quality product via enzymatic processing, hydrogenation, purification, packaging, and release testing.

 When a client approaches you for raw materials, what is that process like? Do you provide a consult as to whether specific materials are suitable for the client’s intended purpose?

: Indeed, for every customer request we receive, we evaluate the purpose and intended use of the ingredient in detail. This enables us to identify a product from our portfolio that is fit for purpose.

 What testing strategies do you have in place to ensure the quality of raw materials?

: We produce our raw materials according to good manufacturing practice (GMP) guidelines using processes validated for the manufacture of 

-compliant products. A combination of testing specifications for every batch, as well as routinely monitoring key performance indicators, means we can ensure the highest quality ingredients possible.

 How can the quality of biopharmaceutical raw materials be determined, specifically if it isn’t suitable for an intended application?

: Risk assessment and collaboration with the project sponsor [Catalent’s clients] are necessary for all instances where materials may not be suitable for an intended purpose. Specific use-testing, process development activities, and material qualification can be employed to help justify the use and mitigate risk.

 What does GMP mean for your company and its products?

: Excipients play a critical role in the manufacture of medicines, helping to preserve the efficacy, safety, and stability of active pharmaceutical ingredients (APIs). That’s why GMP manufacturing is such a significant part of Roquette Pharma Solutions’ DNA, to ensure each and every one of our customers’ products deliver its promised benefits to patients. Roquette has over 50 years of experience in the manufacture of pharmaceutical raw materials, complying with the appropriate GMP, for instance with ICH Q7 [International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use] for the APIs produced by Roquette (2). Meanwhile, our entire portfolio of biopharma raw materials meets GMP requirements for the International Pharmaceutical Excipients Council Federation’s validation of excipients. Our manufacturing site for biopharma raw materials is registered by the French Health Authority and audited regularly by the various regulatory agencies (e.g., FDA) as well.

 GMP can mean different things to different suppliers. How can a company ensure a supplier’s GMP standard meets its bioprocessing needs?

 From a supply chain perspective, providing our suppliers with clear expectations and regular feedback with regard to the GMP standard is critical to assuring that these suppliers will operate in a manner—and supply products—that will meet our needs. We do this at the site level with our material on-boarding process (including impact assessment), material specification process, and supplier complaint process. At the corporate level, expectation-setting and feedback are facilitated through supplier-relationship management (SRM) programs and the global supplier quality management audit process.

 When deciding where to source raw materials and what suppliers to work with, what factors must be considered? What could constitute an automatic pass for select raw materials?

 Biopharmaceutical manufacturing now includes single-use consumables, which make up the majority of raw materials. Single-use consumables and equipment technologies are interdependent, and identifying a supplier means looking at the capability, reliability, and compliance of both the equipment and supporting consumables.

: Generally, for other materials, the highest grade with the most appropriate compendial label claims is often the most desirable. Materials that are sold as research-grade are often much harder to justify because they may not have appropriate controls to prevent ingress of adventitious agents, may lack transparency to the original manufacturer, or are unsupported by change management, which would complicate their use.

 Normally, we also prefer to purchase directly from the manufacturer of a raw material or consumable. If we end up having to source from a distributor, transparency, with regard to the actual manufacturer, is paramount, as is the ability of the distributor (and manufacturer) to deploy rigorous change controls on the products that they distribute (or manufacture). A major factor in our decision to appoint a new supplier is our routine material impact assessment.

Supplying raw materials from a regulatory perspective

 What regulatory requirements do you have to be mindful of when supplying raw materials?

: Alongside GMP manufacturing and compliance with the standard monographs from the 

, Roquette ensures that additional requirements, specific to the needs of the biopharmaceutical manufacturing process, are met. This includes low endotoxin levels as well as the absence of relevant organic impurities, controlled bioburden, and more.

 Describe the difference between raw materials standards in the United States vs. globally.

: Typically, regulations for different regions are set by individual medical agencies. For example, the European Medicines Agency in the European Union or FDA in the US. Differences amongst such regulations are largely historical and stem from different manufacturing or quality standards. In recent years, thanks to the ICH program, significant steps have been initiated to standardize monographs as well as analytical methods (3).

 What supply chain concerns are present for sourcing raw materials?

: Roquette reduces the potential risk of a fragmented supply chain via its vertical integration, through which we can control every step of the manufacturing process of our biopharma raw materials in-house. In addition, close collaboration with our customers and a global distribution network, with the potential for local stock-keeping, further reduces the risk of a supply chain disruption.

 Critical biopharmaceutical raw materials are often proprietary and single-sourced. An effective sales and operations planning process drives appropriate mitigations to any potential supply-chain risks. Managing a reliable supply chain during extreme market volatility is also a critical concern. Keys to success in these challenging times are regular communication to raise awareness, transparency (both internally and externally), adaptive replenishment models, and operational flexibility.

 Effective and adaptive SRM programs, which include executive-level participation from both the supplier and the customer, where materials are single-sourced are also a means of mitigating potential supply chain challenges. Regular reviews and, if necessary, rapid adjustment to replenishment models are further mitigating actions. With regard to the need for flexibility, I would say that includes actively deploying backup sources of supply or working with what materials are available, versus those in constrained supply. Good internal communications, to raise awareness of situations, can further reduce risks. These should span all functional areas, with customer-facing functions, and even with customers themselves.

Constant and effective communication is necessary for every step of the process for sourcing biopharmaceutical raw materials, along with being aware of GMP guidelines as well as other guidelines (e.g., ICH) and regulatory expectations for different regions. While single-sourced biopharmaceutical raw materials can present supply chain challenges, adaptive replenishment models, operational flexibility, and general flexibility can help to mitigate these risks. But before all of this, it’s important for manufacturers and suppliers to carefully assess the capability, reliability, and compliance of both the equipment and supporting single-use consumables. As in most things in life, communication and upfront research are key.

A. Möritz, “Strategies for Controlling Raw Materials in Biologics Manufacturing,” PDA, 


Volume 34, Number 12
December 2021
Pages: 21–23

When referring to this article, please cite it as M. Rivers, "Ensuring Quality When Sourcing Biopharmaceutical Raw Materials," 

Defining expectations, such as GMPs, is paramount for sourcing the right biopharmaceutical raw materials.