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Economics of a Disposable Virus Filtration Process
Over the recent years a trend towards more frequent utilisation of disposable equipment in biopharmaceutical processing could be observed. The driving forces for this innovation are the desire to minimise changeover times, enhance flexibility, expand manufacturing capacity, reduce sterility assurance efforts and to limit costs. In this case study we focus on the process economics of one unit operation, the virus filtration step.

Rentschler Biotechnologie GmbH is a contract services company offering flexible, integrated services from one source. Its history in pharmaceutical manufacturing started already in 1927 and two decades later the development of veterinary vaccines led to a focus in biotechnology. A hallmark of this novel strategic direction was the market approval for a natural ▀-interferon (IFN) compound (Fiblaferon) that Rentschler obtained as first company in 1983. Six years later followed the recombinant IFN-? interferon and topical IFN-▀-gel.
In 1993, all biotech activities were consolidated into Rentschler Biotechnologie GmbH, a contract development and manufacturing organisation offering full services in development and production of biopharmaceuticals. Subsequent investments have led to a facility with bioreactor capacities up to 2,500 L and nine state-ofthe- art suites for GMP production as well as three GMP filling lines and more than 600 fully trained employees.
Those facilities have been successfully used to manufacture a multitude of recombinant proteins and antibody products for many clients. Soon it was recognised that significant benefits could be achieved by introducing single use systems for upstream and downstream processing. Therefore a concept study was initiated to evaluate the suitability of existing processes for conversion to a complete single use system. Based on a positive assessment, the company decided to proceed with implementing a single-use upstream and downstream process for generic antibody manufacture.
One critical unit operation is the membrane filtration for viral clearance, which constitutes an integral part of monoclonal antibody purification processes. Typically hollow-fiber membrane cartridges are used in single-pass, direct-filtration mode, which is sometimes called dead-end filtration. The state-of-the-art are surface-modified, hydrophilic membranes with high void volume and precise fine-pore structure, ensuring minimum fouling and high viral titer reduction.
For this process step, Pall Life Sciences developed a customised automated skid for viral filtration for us. It contained following features: robust operation with minimal risk of operator error, precise control over parameters such as pressure and flow rate, built-in integrity testing, and flexibility for different processes and filtration modules. All types of virus filters can be mounted and manifold and filter assembly is easy, fast, and robust using sterile connectors. With a Siemens S7 control system (Win CC visualisation), the system is applicable to depth filtration and 0.2-Ám filtration as well.

Materials and Methods
In a conventional setting the virus removal is achieved by filtration of the drug substance containing solution through a stainless steel virus filtration skid between steel tanks containing the starting material and another tank receiving the permeate. The whole setting can be replaced as described above by disposable material based on plastics, also including single use pump heads.
Our case study analyses a generic monoclonal antibody process with a titer of 2 g/L in a volume of 1000 L. We have used Planova 20N/2 x 4 m2 filters from Asahi Kasei Ltd in both settings. For cost calculation we assumed the processing of 15 batches per year with a yield of 70 per cent. The major difference between both skids is the elimination of CIP/SIP steps for the tanks and filtration units in the disposable system. All calculations were performed with the BioSolve software of BioPharm Services Ltd that provides detailed manufacturing cost calculations. As benchmark, data provided by Pall Life Sciences was used. The different cost categories contained materials, consumables, labour and general facility operation costs.

Results
The cost of goods analysis was predicted to be within 5-8 per cent precision of Pall's BioSolve model. The different results of overall cost per batch, per year and per kg of drug substance are displayed in figure 1.
A more detailed breakdown of annual cost of goods as shown in figure 2 demonstrates an 18 per cent reduction of cost for the disposable virus filtration. This is the consequence of 88 per cent savings in materials. For instance 98 per cent less water is required by the elimination of high water consuming CIP and SIP processes. This has a direct effect on labor costs that were 63 per cent lower. Further savings of 52 per cent on facility costs could be achieved by avoiding CIP and SIP procedures that eliminate the need of capital intense infrastructure such as the provision of steam. Instead of expensive steel tanks plastic bags were used. However it should not be neglected that the cost for consumables increases by 28 per cent, which also causes 85 per cent more plastic waste. A closer look at labour costs of the stainless steel process in figure 3 reveals that only one third of the cost is related to direct work hours that are needed to perform the filtration. The majority of time is spent on cleaning. The reuse has also a huge impact on cost in quality control and assurance that have to deal with cleaning validation. In contrast to that, 84 per cent of the working hours spent on the disposable process are direct hours and the remaining hourly cost is needed for buffer preparation. Indirect costs that are worth mentioning are on one hand the increased efforts in logistics regarding disposable filtration and on the other hand more work for instrumentation maintenance in case of the stainless steel setting.
Interestingly the cost benefits of disposable virus filtration are diminished when the number of annual batches increases. This is primarily caused by the amortisation of the stainless steel equipment that has to be bought only once. The largest effect can be seen when only small numbers of batches are filtered per year. Here the cost difference can reach more than 30 per cent. However in this analysis also the capacity utilisation has to be taken into account. Although beyond 30 batches per year the savings per batch are just 14 per cent, it might be the case that the disposable filtration has not yet reached its capacity limit because the changeover times are much shorter. This is of primary interest for contract manufacturers that experience a high number of different projects being handled in the same facility. Besides capacity improvements, single use equipment also minimises the efforts to avoid cross contaminations.
Conclusions
This case study demonstrates significant reductions in annual cost of goods when replacing a stainless steel based virus filtration skid with a fully disposable unit. The majority of savings are related to labor, materials and facility operating costs but are accompanied by increased plastic waste. A change towards disposable filtration has a direct impact on productivity. Now resources can have a higher turnover, they can be allocated more flexibly and the whole capacity can be utilised more effectively.