Applying disposable technologies

Compounding. Compounding of a biopharmaceutical product can be as simple as combining the contents of a few bottles of thawed material or diluting a solution to a defined concentration. For small batches (i.e., volumes up to 20 L), standard bottles made of glass, polypropylene, or polyethylene, or flexible bags may be used. If a custom design is required, these containers can be developed in collaboration with suppliers. Agitation can be achieved easily with disposable magnetic followers, paddle stirrers, or recirculation of the solution.

Larger batches (i.e., volumes in excess of 20 L) also can be manufactured using disposable technologies. Plastic and glass bottles may be used, but the manual handling of such containers needs to be considered as the batch size increases. Tank liners and large flexible containers supported in a specifically designed trolley may be a more suitable choice for the larger batch. Agitation can be achieved by employing similar techniques as those used for the smaller batch sizes. Sophisticated, purpose-built, disposable mixing systems are commercially available for batches of volumes of 200 L and larger, including features such as jackets for temperature control.

Filling. Most filling systems do not use disposable technologies for the dosing of the solution into the vial. For example, many filling systems use displacement pumps that are made from stainless steel. These filling systems often can be modified to accommodate disposable systems such as peristaltic pumps. Advances in peristaltic technology have improved the performance of peristaltic pumps. The accuracy and precision of doses are ensured, as are reliable performance, easy and quick setup, fast line turnarounds (with pre-prepared, sterilized disposable tubing, complete with filling needles), and low manufacturing losses. Peristaltic pumps have other advantages compared with traditional displacement pumps such as suitability for shear-sensitive compounds (e.g., proteins) and viscous solutions.

The solution can be filled from a disposable filling bag such as a flexible bag. Flexible bags are available in a wide range of sizes, typically from 1 L to hundreds of liters, which can make scaling up a much simpler process. The flexible bags are sterile and ready to use, thereby reducing the setup time by removing the need for autoclaving vessels. Companies can collaborate with the manufacturers of the disposable bags to facilitate fewer and less complex aseptic connections. The disposable bags can be designed to be physically strong and to have low gas permeability by using several layers of different plastics. Compatibility with typical pharmaceutical ingredients is optimized by making the inner layer polyethylene, a plastic commonly used in many dosage forms. Manufacturers of disposable bags have conducted extensive testing on the plastic components used to demonstrate compatibility with biological systems and can demonstrate compliance with US Pharmacopeia Class VI requirements. For small batch sizes, flexible bags can be designed to hang toward the end of the batch, so the solution is filled and gravity-fed to the dosing pump, thus reducing manufacturing losses.

Process design

Disposable equipment used to manufacture clinical-trial materials has certain advantages:

• Removes the need to clean product-contact equipment
• Eliminates the need for cleaning-verification methods
• Almost totally eliminates the risk of cross-contamination
• Reduces line changeover times
• Reduces the number of aseptic connections
• Simplifies the aseptic line build
• Reduces manufacturing losses
• Improves sterility assurance
• Improves waste management.

Waste management

Although the advantages of disposable technologies may seem compelling, disposable technologies' disadvantages need to be considered. The increased use of disposable technologies results in an increase in the quantity of solid waste, which frequently requires incineration. Disposable technologies, however, also lead to a reduction in the quantities of water for injection (WFI) and chemicals to clean reusable equipment. For example, in a study on the use of disposable technology in a concept biomanufacturing system, the estimated saving in WFI usage was 80%. Substantial reductions in the use of cleaning chemicals also were reported (3). The study also estimated a 72% saving in electrical power when compared with a similar manufacturing facility (3). These benefits outweigh the costs associated with disposal and incineration. Moreover, reducing chemicals and power not only produces cost savings, but also reduces the environmental impact of the manufacturing process.