Sourcing raw materials for cell therapy manufacture – Dieter Hauwaerts, Celyad

‘Start working on raw materials early on’ – for Dieter Hauwaerts, Vice President of Operations at Celyad, the way to combat one of the biggest challenges in cell therapy manufacture is clear.

Limited availability of raw materials is a major issue for large scale manufacture of new therapies, but planning well in advance can help mitigate it: ‘In process development, take into account the quantity and quality of raw materials you will need in a clinical stage or commercial manufacturing process and build good relationships with suppliers.’

However, even with the necessary raw materials, Hauwaerts still sees issues with ‘the way we can manufacture products in a reliable and consistent way’, though he hopes that in 2017 automation will begin to negate this.

Watch the full exclusive interview with Hauwaerts – filmed at Cell Therapy Manufacturing & Gene Therapy Congress 2016 – above or here.

[Whitepaper] Regulatory Perspectives and Considerations for Cell & Gene Therapies

An Exclusive Whitepaper

Whitepaper Overview:

Recent clinical trials in the field of cell and gene therapy demonstrate remarkable therapeutic benefits with excellent safety. Despite demonstrated therapeutic effects, the commercialization of cell and gene therapies and their patient outreach remain scarce. Much of the research and development on cell and gene therapies is performed either on an academic level or by small and medium enterprises, largely excluding large pharmaceutical companies. Regulatory approval for cell and gene therapeutic products is performed on an individual product basis and is classified based on the degree of manipulation and intended end use. The primary deterrents to the lackluster commercialization of cell and gene therapies include the inherent complexities of the cells, issues with scalability for manufacturing and logistics and the complex regulatory requirements and time-consuming clinical trials. Cell and gene therapy products also have to navigate through the disparities in the regulatory requirements across regions. Furthermore, the complexity of product classification, extra requirements for combination of cell and gene therapies with a medical device, extensive paperwork surrounding the often ambiguous certification procedures and most importantly, the lack of harmonization of regulations across regions deter new investments and innovation in the field.

Limited understanding of the complex interactions of cell and gene therapeutics, absence of established standards and relatively scarce research data on the mechanism of action of these therapeutics make it difficult for stakeholders to navigate the complex and stringent regulatory requirements.

We elaborate the fundamental regulatory concerns associated with the development of cell and gene therapy products, and the need for international harmonization of regulatory requirement for approval of cell and gene therapies. The paper also addresses specific regulatory aspects in the EU and Japan as well as the roll-out of fast track mechanisms for market authorization in the EU and Japan. Finally, the paper addresses the urgent unmet need to provide regulatory certainty in the field of cell and gene therapeutics in the fast evolving global regulatory landscape.


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Hacking The Cell

Computational systems as diverse as vending machines, computers, and cells have something in common: They are all finite-state machines. That is, they may have an initial state, accept inputs, pass to different states according to the inputs received, and even enter states that lead to specific outputs. This kind of activity has been exploited in cells, but not with the degree of control we take for granted with the humble vending machine, which can dispense the right snacks depending on whether we press, say, B4 or C2. The vending machine can even refuse to dispense anything until a certain threshold has been surpassed (the right combination of coins).

In hopes of installing this kind of control into cells, MIT scientists have developed a way to program cells to respond to up to three different inputs. Crucially, the programming is capable of recognizing the order of inputs and responding accordingly. Although three inputs permit just 16 states, the MIT researchers point out that their method is scalable. It could accommodate additional inputs and thereby enable many additional states, enough to permit complex processes such as disease progression and cell differentiation to be tracked. The new synthetic biology approach could even make it possible to intervene in these processes, leading to cancer therapies or guiding the outcome of stem cell development.

Continue reading “Hacking The Cell”

Progress Toward Commercial Scale and Efficiency in Cell Therapy Bioprocessing [Whitepaper]

Whitepaper Summary:

Currently there are 672 cell and gene therapy companies worldwide and 20 products approved by the food and drug administration (FDA). Dendreon’s Provenge autologous cell therapy although approved by the FDA ultimately failed commercially due to a manufacturing and distribution model that was not efficient. Cost of Goods (CoGs), manufacturing process and logistics are critical to the success of cell therapy commercialisation and these need to be considered from the inception of a cell therapy company in addition to the clinical science. Three key enablers for success are manufacturing automation/ single use technologies, a diverse pipeline in modularised facilities, and sophisticated data acquisition/ logistics.

Quality by Design (QbD) is a scientific, risk-assessment framework for process design based on relating product and process attributes to product quality. A risk assessment is conducted to prioritize the study of the most influential critical process parameters and material attributes. In addition to reducing risk QbD also increases efficiency as critical experiments are front loaded (Figure 1). This is particularly important in identifying required changes to the manufacturing protocol early reducing comparability risks.

Continue reading “Progress Toward Commercial Scale and Efficiency in Cell Therapy Bioprocessing [Whitepaper]”

eBook: A Look at Cancer Immunotherapies


Emerging cell- and protein-based cancer immunotherapies are a game-changer for treating cancers. Currently, medical science is on the cusp of delivering on the promise of making cancer a manageable disease. But the impediments to commercializing cancer immunotherapies are substantial.

In this eBook, author Angelo DePalma dives into the economic and processing problems that the industry faces in developing these life-changing therapies. He examines protein immunotherapies and cell-based immunotherapies that have made it to the clinic, providing an overview of the current state of the industry in delivering these biotherapeutics. DePalma also gets into the manufacturing strategies involved and how companies are approaching product and process development.


Issues In Protein Immunotherapy
Immunotherapy Squared:
Bavituximab, a monoclonal antibody from Peregrine Pharmaceuticals (Tustin, CA), is a classic protein immunotherapy targeting phosphatidylserine (PS), a novel immune system checkpoint. PS exists on the inside membrane layer of every cell, but it externalizes when cells die. “In circulation, PS signals the immune system to engulf dying cells,” explains Steve King, Peregrine’s chief executive officer (CEO). PS also limits the immune response. As tumors proliferate, they often outgrow their blood supply so that many cells die, sending more PS into circulation. Tumors also release microparticles containing PS, ultimately suppressing immune response to the tumor by keeping the host’s immune system busy fighting particles and dead cells.

Peregrine’s collaboration with AstraZeneca for clinical development could be described as “immunotherapy squared.” Bavituximab’s presumed mode of action is to block immunosuppression while activating a tumor-killing T-cell immune response. AstraZeneca’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab, targets the programmed cell death ligand PD-L1, which helps tumors go undetected by the immune system. Both companies believe that combining the enhanced T-cell–mediated antitumor activity with a checkpoint inhibitor will extend the ability of tumor-specific T-cells to attack cancerous cells.

Like many small biopharmaceutical companies with a promising pipeline product, Peregrine chooses to emphasize clinical development over manufacturing or process development, confident that if bavituximab succeeds in the clinic, then CoG issues will resolve themselves. “Our process flexibility assures that we could duplicate the entire facility and all its infrastructure in an open warehouse space almost anywhere,” King affirms. “We built the current facility with the idea of supporting production lots early in commercialization. At that point you have substantial revenue, so all your manufacturing avenues open up. And the risk of sticking with the same systems, at the same scale, from a comparability standpoint is negligible.”

Downstream operations could very well become a bottleneck. Peregrine has learned through its contract manufacturing business, Avid Bioservices, that high yields — even from 1,000-L or 2,000-L bioreactors — impose operational and financial pressures on downstream processing and purification. Protein A affinity chromatography columns, for example, begin at about $1 million for resin alone and go up from there. “That’s a big investment for a small-to-midsized company,” King admits. Peregrine is handling such challenges through a hybrid approach of maintaining a revenue-generating manufacturing business that mitigates the cost of preparing for commercialization of its own products. “Not many companies have that flexibility.”

Read the Cancer Immunotherapies eBook from BioProcess International magazine.

The Future of Cell Therapy Manufacturing

By Brian Hampson, Vice President of Global Manufacturing Sciences and Technology, PCT

Patient-specific cell therapies (PSCTs—those in which cells extracted from the patient or a donor matched to the patient are processed and then returned as therapy to the patient) are still, in many ways, the new kid on the block in medicine; researchers, therapeutic developers, manufacturers, FDA, and payers are still exploring and developing an understanding of the powerful benefits and unique challenges of this growing industry. As we all become more familiar, an evolution will need to occur—as it had to for automobiles, computers, and every technological advance in human history—in order for these therapies to become widely adopted, cost-efficient, market-scalable, and sustainable over the long-term. We must seek to understand what is needed from a manufacturing perspective for us to achieve the future of patient-specific cell therapy. Continue reading “The Future of Cell Therapy Manufacturing”

Setting the Stage for NextGen MSCs

hiPSC-derived iMSCs as an advanced therapeutically active cell resource for regenerative medicine

Mesenchymal stem cells (MSCs) are being assessed for ameliorating the severity of graft-versus-host disease, autoimmune conditions, musculoskeletal injuries and cardiovascular diseases. While most of these clinical therapeutic applications require substantial cell quantities, the number of MSCs that can be obtained initially from a single donor remains limited. The utility of MSCs derived from human-induced pluripotent stem cells (hiPSCs) has been shown in recent pre-clinical studies. Since adult MSCs have limited capability regarding proliferation, the quantum of bioactive factor secretion and their immunomodulation ability may be constrained. The hiPSC-derived MSCs (iMSCs) are transpiring as an attractive source of MSCs because during the reprogramming process, cells undergo rejuvination, exhibiting better cellular vitality. The autologous iMSCs could be considered as an inexhaustible source of MSCs that could be used to meet the unmet clinical needs.

Human-induced PSC-derived MSCs are reported to be superior when compared to the adult MSCs regarding cell proliferation, immunomodulation, cytokines profiles, microenvironment modulating exosomes and bioactive paracrine factors secretion. Strategies, such as derivation and propagation of iMSCs in chemically defined culture conditions and use of footprint-free safer reprogramming strategies have contributed towards the development of clinically relevant cell types.

Continue reading “Setting the Stage for NextGen MSCs”