Unlike single-pass or dead-end filtration, cross-flow methodology continuously sweeps the membrane surface by circulating the feedstream across it. This minimizes blinding the membrane and promotes consistent, long-term productivity. It also allows units to be cleaned, stored, and re-used as needed. While the feedstream is pumped through the cassette or cartridge, the retentate (materials excluded by the membrane pores) continues through the circulation loop, whereas the permeate, including the solvent and solutes, is transported through the membrane.

Chromatography media are also widely used for manufacturing viruses. These unit operations need to be robust, produce high yields, achieve high purity and withstand cleaning-in-place with low ligand leakage from the media. A particular challenge for chromatography is productivity, because viruses, viral vectors, and plasmids are considerably larger than traditional biopharmaceuticals and cannot therefore easily enter the pores of microporous media, which is a prerequisite for achieving high capacities for the target of interest. Alternative strategies must be applied to achieve larger surfaces, for example, by reducing the bead size of chromatography media.

Adsorptive technologies, such as, affinity chromatography, can be used to purify adeno-associated viruses for clinical trials, thereby replacing low-yield and poorly scalable density gradient centrifugation.¹⁹ The same principle can be applied to isolate and concentrate influenza virus. Anion exchange chromatography can be used to polish viruses such as influenza or adenovirus because the charges of these targets and those of contaminants differ, depending on the pH and conductivity during binding and elution. Group separation on agarose-based gels is also a commonly-used technology to separate viruses from host cell protein and small DNA molecules based on the different sizes of target and contaminant. The target virus will elute in the void volume, but the contaminants will be delayed when applying isocratic elution conditions.²⁰

In the current biopharmaceutical market, companies must move quickly from discovery to patent, and then on to trials and efficient production to maintain or increase competitiveness and maximize revenue during the patent life of a drug.²¹

The cost of delay in R&D can be more than one hundred thousand dollars per hour.²² Time-to-market and flexibility are thus key issues that the biomanufacturing industry needs to address to improve its cost-effectiveness. One strategy that offers a good compromise in this respect is the use of disposable hardware and flexible facility designs.²³ Tanks can be replaced with bags and piping with tubing; disposable pump heads; and detection cells can be used, and both cleaning and certain validation efforts can be simpler to operate in the pilot facility compared to full-scale manufacture.

Installation lead times can be minimized and hardware can be moved based on day-to-day needs. Disposable solutions not only offer indirect cost benefits to flexibility and validation, but also a direct running cost advantage. The latter, however, is strictly dependent on scale; at the 500-L cell culture scale, for example, cost advantage has been calculated to be in the range of 8–14%.²⁴

According to the 3rd Annual Report and Survey of Biopharmaceutical Manufacturing, Capacity and Production,²³ the most often cited advantages associated with use of disposable components include reduced risk of cross-contamination (57%), elimination of cleaning requirements (55%), minimization of cost of down-time for cleaning, sterilization, and corresponding validation procedures (44%), and the labor and running costs associated with these operations. Reductions in operating cost are related mainly to smaller installations for process quality water systems and to the complete elimination of the handling and discarding of hazardous chemicals. Equipment maintenance is also minimized.

If we consider the preparation required for a pandemic influenza outbreak, disposable solutions would drive the speed of response and manufacturing economics, i.e., quick change of target molecule, flexible batch volumes, and the relocation of manufacturing facilities. These benefits would facilitate the mandatory quick response needed in countries not producing a seasonal influenza vaccine.

Secure Supply Ensures Deployment of Capacity

One aspect to consider outside the technology itself is that of the supply chain. Secure manufacturing processes are dependent on technology providers having quality systems and contingency plans in place. Some producers may need to evaluate options for alternative supplies should their primary supplier be unable to deliver under exceptional or unforeseen circumstances (such as during a pandemic or an accident). Qualified suppliers with a broad range of products and services can usually help minimize dependency on alternatives.