Disposables Solve Tomorrow's Manufacturing Problems

Disposable technology has been used effectively as a process solution for over 25 years and new uses and applications are constantly being developed. The key to all applications is the ability to pre-sterilize components and systems with gamma radiation and package them against contamination.

Disposable (or single-use) processing provides a number of benefits, such as elimination or reduction of cleaning and cleaning validation; reduction of cross-contamination risk; less operator error; and minimization of capital expenditures and space requirements. Each of these advantages benefit drug companies differently. For example, biotech start-ups are seeking to avoid capital costs associated with hard-piped systems, while the use of disposables helps contract manufacturers eliminate cross-contamination.

Disposable technologies also deliver unique benefits to specific drug manufacturing processes. The expected surge in FDA-approved large-molecule drugs, like gene therapies and cancer vaccines, looms ominously over predictions for a manufacturing capacity crunch beginning around 2008. This article addresses some of the latest developments in disposables technology.

Ian Sellick

HIGH-CAPACITY CHROMATOGRAPHY

Traditional chromatography technologies used to capture and polish macromolecules are inefficient. A new ion-exchange chromatography membrane-capsule has been developed which is more convenient, more reliable, and quicker to use compared with chromatography resins because it is provided in a unit that does not require any packing of media. Ion-exchange chromatography membranes are known for their ability to polish (remove) large molecules at high dynamic flowrates, but they have not been available in the high-capacity range needed to perform large-scale capture (bind and elute) steps.

The new 5-L membrane capsule (Mustang XT5000) removes contaminants such as DNA, viruses, endotoxins, and host cell proteins from product feeds (Figure 1). It enables good resolution with high yields and minimal elution volumes for capture of large biomolecules due to characteristics of the membrane, a uniform flow path, and the low ratio of total volume to membrane volume. The capsule is ideal for new drugs and therapies that utilize recombinant proteins, plasmids, and other viral vectors as well as blood plasma fractions.

Figure 1. Mustang XT5000 chromatography capsules are modular and easily plug together for high capacity systems or multi-step processes.

Ion-exchange membrane chromatography allows biomolecules to access all binding sites by direct fluid convection. Because the binding is not diffusion limited, high dynamic binding and sharp breakthrough curves are achieved over a wide range of flowrates and molecular sizes. By contrast, resin chromatography is limited due to the speed with which large molecules diffuse through the pore structure of the media. Capital investments in hard-piped columns, coupled with the recurring expense of resins, column packing, cleaning, and cleaning validation make this chromatography method very costly when compared to membrane capsules.

MULTI-COMPONENT ASSEMBLIES

Disposable technologies are available for virtually every aspect of biopharmaceutical manufacturing and can be bundled into pre-assembled, pre-sterilized systems. The benefits of disposable processing multiply as single-use technologies expand from stand-alone devices to multi-component assemblies.

Multi-component disposable systems are used for filtration, clarification, purification, and separation applications for numerous vaccines, monoclonal antibodies, and other therapies. Disposable components used in these systems include wide-ranging configurations of direct flow filtration (DFF) filters, tangential flow filtration (TFF) cassettes, chromatography membrane capsules, depth filters, aseptic connection devices, tubing, adaptors, clamps, and bags. These systems can be supplied pre-sterilized (by gamma irradiation) and pre-assembled to eliminate the need for sterilization and sterilization validation procedures. This reduces maintenance costs of sterilization equipment as well as time and labor associated with validation documentation. These bundled solutions can literally be taken out of the box and placed onto the manufacturing floor, reducing the potential for cross-contamination and operator exposure to hazardous biological materials.

Equipment suppliers are making it even easier to incorporate more complicated single-use systems by integrating them with critical unit operations. Modular TFF skids assembled with disposable filters, bags, tubing assembly and aseptic connection devices provide the latest example of these customizable solutions (Figure 2).

Figure 2. All fluid contact parts of the Centrasette production-scale tangential-flow filtration system consist of pre-assembled, single-use plastic.

ASEPTIC CONNECTORS

Smaller components such as aseptic connection devices reduce the steps required to make connections between sterile equipment and disposable systems. These connections will impact the speed and safety of the whole process as the number and complexity of disposable systems increase.

Traditional methods include quick connectors and tubing welders that mandate the use of a welding device. Despite the name "quick connector," it can take over 20 minutes to make a connection. The operations must be performed under a laminar flow hood, which generally requires 15 to 20 minutes to set up, or in a laminar flow environment, which may or may not be readily accessible, depending upon the layout of the facility. Laminar flow hoods are also costly, require maintenance, and take up precious space.

Figure 3. The new Kleenpak HT connector withstands elevated sterilization temperatures.

The Kleenpak HT is an aseptic assembly that allows connections to be made anywhere in the facility in seconds, because it does not require the use of a laminar flow environment, or any other capital equipment (Figure 3). These connectors can be supplied pre-sterilized by gamma irradiation or they can be autoclaved up to 130°C. We ran some timing estimates for connection methods. The results are in Table 1.

Table 1. Comparison of Time Taken to Make a Connection with Kleenpak Connector, a Tubing Welder, and a Quick Connector.

DISPOSABLE PROCESSING ADVANTAGES

Eliminating cleaning and cleaning validation is the most widely recognized benefit of disposable processing. Additionally, disposable technologies offer benefits that help drug companies streamline operations and shorten processing times. While there is a baseline of benefits that all disposable technologies offer, carefully consider equipment selections based on scalability, throughput and product performance, sterilization options, and availability of customized solutions and services. However, the degree to which drug companies benefit from this processing paradigm will depend on the number and sophistication of the disposable systems they implement.

Ian Sellick is director of marketing , Pall Life Sciences, Pall Corporation, 2200 Northern Boulevard, East Hills, NY 11548, 516.484.5400, fax 516.801.9548. ian_sellick@pall.com

Holly Haughney, Ph.D., is vice president of BioPharmaceuticals marketing with Pall Corporation 516.484.5400, fax 516.801.9548, holly_haughney@pall.com