Continuous Processes: Disposables Integrate Upstream and Downstream Processing – Featured Report

15-5-FR-Coverby Cheryl Scott, Senior Technical Editor, BioProcess International

Continuous processing is pretty much a “given” in many industries — even the larger pharmaceutical industry that makes synthetic small-molecule drugs. But the concept has only just begun to make inroads with biomanufacturers, who have until recently worked mainly in batch or fed-batch mode. Single-use technologies largely have enabled them to consider the possibility of process intensification and going continuous. In support of this month’s featured report, I asked contributor Margit Holzer, PhD (scientific director at Ulysse Consult S.a.r.L in Luxembourg) a few general questions on the topic.

One question often asked of perfusion and other continuous culture approaches is “How do you define a batch?” Some experts say it isn’t even necessary to do so. Others say you can describe batches in terms of time. What do you think?

HOLZER: It is important to recall that traceability of the whole batch history of a drug substance or product is absolutely necessary for CGMP production. So there is no choice. A batch also needs to be defined for continuous upstream operations. This becomes especially crucial during investigations or product recalls. In the case of continuous production, a batch may correspond to a defined fraction of production.

The batch size of a continuous upstream process can be defined, for example, by a fixed quantity (e.g., volume, mass, or activity units of product) of harvested product; the amount produced within a fixed time interval (e.g., hours of production, residence time) between harvests; or the number of cell generations or doubling times to be produced, collected, and further treated in downstream processing as one batch. In addition, a minimum titer and/or viability and/or other quality requirements can be specified as acceptance criteria for pooling with the harvested product to assure batch homogeneity. For all those cases, downstream processing capacity must be in line with the harvested quantity of material.

What’s the most challenging part(s) of downstream processing to do continuously? Continue reading “Continuous Processes: Disposables Integrate Upstream and Downstream Processing – Featured Report”

Affordable Biologic Downstream Purification with Single-Use Protein A Membrane

This article was originally published on by Brandy Sargent, Editor in Chief

At this year’s Biotech Week Boston there were many exciting talks on downstream purification and associated new technologies. In particular, there were several talks about optimizing the downstream purification process. One very interesting talk, given by Renaud Jacquemart, PhD Principal Scientist, Director Vaccines Process Sciences, was titled “Enabling Manufacturing Of Affordable Biologics Through The Use Of A Protein A Membrane
 In A Single-Use Purification Strategy ” and focused on the application of a fully single-use chromatography purification process in place of resins. This strategy envisions the use of a unique Protein A membrane for which Natrix recently signed collaboration agreements with Merck & Co. and Sanofi.

Creating a more affordable purification strategy

In his talk, Dr. Jacquemart begins by talking about the goal of creating a more affordable purification strategy and how the Natrix approach incorporates a holistic vision of the entire manufacturing process. To meaningfully decrease total cost and create the most efficient process, companies must significantly reduce the physical scale of manufacturing facilities and enable greater flexibility. This permits faster turnaround and accommodates a wider range of scales and products for any given time period. Achieving these goals requires a large increase in productivity and much-simplified single-use architecture for purification.

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Downstream Processing Single-Use Technology

As single-use technologies have grown in importance and acceptance, offering more solutions every year, their biggest challenges have come in downstream separation, purification, and processing that follows product expression in cell culture. Many technologies in downstream processing present technical and economic problems. BioProcess International magazine has produced a featured report that delves into many of these issues and innovations. They discuss automation, depth filtration, continuous processing, alternatives to resin chromatography, and fill and finish technology.

In the drive for reduced costs and more economical manufacturing of biopharmaceuticals, alternatives to resin chromatography are being examined. One article in the featured report focuses on the use of membrane adsorbers. Here, we provide an excerpt of Membrane Adsorbers, Columns: Single-Use Alternatives to Resin Chromatography:

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Accelerating and Streamlining Downstream Process Development

An exclusive whitepaper

This report will discuss how to speed up the development and streamline up and downstream processing. You will see those opportunities at close reach to further increase speed to the clinic and accelerate biologicals purification processes. Besides, you will find answers to the following questions:  Are scaled-up, and budget operations with the predominant downstream processing (DSP) operations fit for a challenging market? Does DSP with state-of-the-art purification methods warrant biotherapeutics regulatory clearance? Does shifting processes from batch to continuous manufacturing pose unnecessary financial risks? Production processes for biopharmaceuticals using protein A chromatography still suffer from platform limitations. How can we overcome those setbacks and the high operation expenses associated?

download whitepaper

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Infrastructure for Cell Culture Process Acceleration

How to streamline development and production of cell culture acceleration and optimization

A surfacing trend in the industry is the interest in continuous bioprocessing. The continuous system makes an attractive option to increase the throughput of the plant allowing manufacture of large amounts of product in a facility with a flexible platform of smaller scale bioreactors. The challenges of the biotech industry offer opportunities to spur innovations in process development. Many biologics manufacturers successfully transition from batch processing to continuous processing to maximize flexibility and minimize the cost of goods (COGs), benefiting from standardization, simplified scale-up, and more consistent product quality. An integrated continuous biomanufacturing (ICB) platform has an advantage over conventional approaches, because of its reduced volumes and footprint, and no scale-up is required between development and manufacturing. Both mAb and non-mAb manufacturing-process architectures could converge in the future and be consolidated within the same facility, offering even greater flexibility and savings. At the same time, these platforms usually deploy a combination of single-use bioreactors that are assembled in a modular fashion and can feed simultaneously and timely into the same train. In fact, platform continuity, clarification built-in operational design, 10-15 fold higher cell densities, and easy logistics due to integration add up for an overall bioprocessing intensification. These kinds of setting converge with emerging tools to deliver a streamlined, high throughput, highly automated, pipeline that is easy to operate.

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Solve Production Challenges of Difficult to Express Proteins with Scalable, Continuous Manufacturing

By Brandy Sargent, Editor, Cell Culture Dish

xcellerator-full-height-logoAt this year’s Boston Biotech Week there were many interesting talks on continuous biomanufacturing and associated new technologies. In particular, there was a great deal of discussion around how to handle difficult to produce proteins. These manufacturing challenges included proteins that were difficult to express and/or were unstable. One very interesting talk, given by Scott Waniger, Vice President, Bioservices Division, Cell Culture Company, was titled “Solving Production Challenges of Difficult-to-Express Proteins with a Scalable, Continuous Manufacturing Bioreactor: A Case Study” and focused on the use of perfusion bioreactors (hollow fiber) to create both continuous upstream production and address the issue of cost effective manufacturing of difficult to express proteins.

Mr. Waniger began the talk by describing several of the protein production challenges in the market.

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eBook: Cost Effective Capture Using Agarose-Based Protein A Resins

It is well recognized that the cost of Protein A resins is substantial, especially if the cost of Protein A can’t be amortized over a large number of purification cycles. When monoclonal antibodies in development don’t pass the clinical trial stage, the money and resin are spent, raising the overall cost of bringing a successful therapeutic to market. So what can be done?

One solution is to use a less expensive Protein A resin designed specifically for early phase clinical trials, then switch to a resin designed for manufacturing.

This ebook, published in the November issue of BioProcess International,14-10-sprpt details a comparability study conducted in high-throughput format to support the strategy of switching resin between phase 2 and 3. The three resins evaluated are based on the same base matrix and immobilization chemistry and differ only in the type and amount of immobilized Protein A.

The study consisted of 20 purification cycles under identical conditions for each of the three resins studied. Comparability data for yield, product purity, host cell proteins, DNA, and leaked Protein A were assayed. The feedstock was a clarified CHO cell culture supernatant containing an IgG of subclass 1. All the resins passed the 20 cycles without changes in product or contaminant profiles. No significant difference was observed in performance or product quality among the three resins under the conditions used. Thus, from a scientific point of view, the three resins could be exchanged for each other without negative impact on the quality of the purified product.

The following three agarose-based resins were packed in 600-μL RoboColumn® units (Atoll, Germany) and used for the cycling study:

Praesto AC resin: recombinant Protein A, 35–50 g/L (native sequence, good binding to antibody fragments (Fabs) belonging to the VH3 family)
Praesto AP resin: alkaline stabilized Protein A, high capacity, 50–65 g/L
Praesto APc resin: alkaline stabilized Protein A, 35–55 g/L.

The feed stock (clarified CHO cell culture supernatant) was provided by Alvotech.

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