June 15, 2018 (Vol. 38, No. 12)

Disruptive innovation is the practice of reshaping a market or activity using novel processes and technologies. The idea has been around since the mid-90s, but it only started having a significant impact in the past decade, with companies like Airbnb and Uber being some of the best-known exponents.

Unlike the hotel and transport industries, the biopharmaceutical sector has been less receptive to disruptive innovation. Partly, this is because making a medicine in a cell is more complex than booking a room or hailing a taxi. However, it also reflects the industry’s unwillingness to disrupt processes which, while inefficient, are effective and approved.

But disruptive innovation does not necessarily need to involve disruption per se. Instead, the willingness to employ novel technologies on which the concept is based can be used to change how a sector addresses problems.

Downstream processing operations, specifically the bottlenecks they create in the biomanufacturing process, are one area where disruptive innovation is starting to be applied.

Downstream processing operations represent one area where disruptive innovation is starting to be actively applied. [borzywoj / Getty Images]

Sticking Point

Downstream bottlenecks are a sticking point for the biopharmaceutical industry. The basic problem is that advances in upstream operations—capacity for higher density cell cultures and larger titers—have not been matched downstream.

“While upstream process development has steadily increased biologic productivity with higher protein titers and cell densities, downstream process development improvements haven’t been able to keep pace with UPSD’s improvements, creating bottlenecks for manufacturers,” says Richard Ding, Ph.D., principal scientist, Downstream Development at Patheon.

This mismatch is compounded because, in contrast with upstream operations, downstream processing has multiple aims, according to Abraham Lenhoff, Ph.D., Department of Chemical and Biomolecular Engineering, University of Delaware.

“The downstream process is intended to recover a pure product by removing a wide range of impurities, most notably host cell proteins (HCPs), DNA, product variants such as charge variants, and other product-related species such as aggregates.

“Any downstream process in biopharmaceutical manufacturing will include multiple steps, most of which are considered orthogonal so as to work in concert to produce a product of adequate purity,” notes Dr. Lenhoff.

Removing Host Cell Proteins

The ultimate aim of downstream processing operations is to separate the desired protein or monoclonal antibody (mAb) from cellular components, HCPs or other impurities present in the process stream. Removing unwanted proteins is one of the most challenging and time-consuming parts of the process. It is also one of the most important from a product quality perspective, says Dr. Lenhoff.

“Problems have, for example, been reported due to the persistence of proteases that degrade the product, lipases that may degrade formulation components such as polysorbates, and other individual host cell proteins that may be immunogenic,” he adds.

Some HCP can be removed using chromatographic techniques, others are harder to eliminate. Being able to identify the latter type using assays is important for the development of effective removal strategies.

“For host cell proteins, an ELISA usually interrogates a significant number of individual HCPs and provides an overall measure; the total HCP content is typically less than 10 ppm in the final drug product.

“Once such impurities are identified it is usually possible to adjust or adapt the existing downstream process to improve clearance; an example is improved wash steps during protein A chromatography,” Dr. Lenhoff explains.

Protein assays are effective. However, they are time-consuming. This has increased interest in alternatives including proteomic techniques based on the mass spectrometry.

“In view of the prevalence of CHO as a host cell line, most of these studies have centered on CHO HCPs, but they can be performed similarly for any cell line for which genomic and or protein sequence data are available” according to Dr. Lenhoff.

Flocculation

Flocculation can also be used to remove unwanted proteins. The technique involves prompting them to come out of solution using a clarifying agent.

A key benefit is that it allows downstream technologies to function more effectively, points out Dr. Ding. “Higher cell densities mean more cell debris, DNA, and host cell proteins that can foul clarification depth filters. Flocculation and precipitation technologies can reduce filter load and improve filter performance.”

To address this, Dr. Ding’s approach is to “use flocculation prior to Protein A loading to remove impurities and then develop a two-column process for mAb or Fc-fusion protein purification.”

An approach called “right-sizing” is often used to eliminate downstream bottlenecks, according to James Stout, Ph.D., director of process science biologics at BioVectra.

“There are different technologies today that take advantage of right-sizing the process, so one can match the upstream productivity with the downstream productivity,” he says. In doing this, a productivity throughput rate can be achieved for a particular process train.

But while balancing capacity works to an extent, there are limitations. For example, it is difficult to increase downstream capacity for an established process if subsequent upstream process improvements yield higher titers.

“You are in a fixed plant and cannot increase the size of columns, filters, or hold tanks. So, increasing the titer in the same bioreactor dramatically affects the ability of the downstream process to be able to respond to the amount of protein to be processed,” explains Dr. Stout.

“You can stagger harvests for a run rate and process more per annum but with fixed columns, hardware, and tankage, there is only so much productivity you can gain before the downstream is outpaced by the large upstream bioreactors.”

A better, and potentially disruptive, approach is to combine capacity balancing with flexible process facility designs and disposable manufacturing technologies.

“The flexible facility approach, new technology downstream process options, and the ability to utilize run rate and or duplicate the manufacturing facility alleviate the bottleneck in the process,” Dr. Stout continues. “The best approach is to correctly pair the upstream process with the right-sized downstream process. This can be achieved using disposable technology approaches.”

Product Capture Technologies

Capture purification using Protein A is another bottleneck that is being addressed with disruptive technologies.

“Protein A is a great workhorse and does an amazing job at capture purification. However, it is expensive and to improve flow through the column, the ProA resin is underutilized and oversized,” explains Dr. Stout.

“It cannot be cycled quickly and therefore a large column is needed for large batches. To make it cost effective, many cycles need to be run across the resin to amortize the cost of the resin over many batches of protein.”

A number of non-resin Protein A alternatives with higher capacity are being developed, according to Dr. Stout, who explains that there are follow-on benefits.

“The ProA membranes can perform chromatography at membrane flow rates and cycle quickly. Therefore, the size of the column can be downsized and right-sized to the needs of the batch.”

Yuyi Shen, Ph.D., principal scientist at Spanish drug manufacturer Grifols, also backs the use of more modern membrane-based capture purification technologies, particularly when it comes to eliminating bottlenecks.

“The higher titers and high cell densities used upstream are driving the needs for greater downstream process efficiency and capacity. For example, mAb titers have increased two- to three-fold in the past several years,” Dr. Shen says.

Membrane chromatography has emerged as a potential alternative to resin-based capture technologies and it continues to gain ground because it is more efficient and there are cost advantages, notes Dr. Shen. The method reduces downstream processing costs up to five-fold compared with resin-based technologies, he says.

“For typical bioprocessing, the major driver for innovative technology will be processed efficiency, higher quality, and low cost. Any disruptive technologies that can make a significant change to those factors are most desired.”

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