Companies developing biopharmaceutical products range from large multinational pharmaceutical companies to small, virtual companies financed by venture capital. One common factor these companies share is the need to develop products as quickly and efficiently as possible without compromising quality.
The majority of biopharmaceutical products are parenteral products that require aseptic manufacturing as opposed to terminal sterilization because biopharmaceutical molecules generally are heat-labile. Aseptic manufacturing of parenteral products may at first appear to be a simple and straightforward process. One may ask, "What is difficult about filling an aqueous liquid into a vial?" Aseptic manufacturing, however, is probably one of the most complex processes in the pharmaceutical industry because of the large number of variables that can affect the sterility assurance of the product. These variables include process design, facility design, the sterilization of materials, equipment, components, and the competency and training of personnel. The whole process also needs to be validated to show that a sterile product will be produced reliably.
Process benefits from disposable technologies have been shown many times (1, 2). This article examines the use of disposable technologies in the fill–finish of clinical-trial supplies as a means of improving production economics and process efficiencies.Process design
Early-phase clinical trials are often small studies that require low volumes of material to support them. Even if the clinical trials are relatively large, the quantities of the biopharmaceutical active ingredient of a suitable quality are typically small. As a result, the batch size for the manufacture of the clinical-trial material typically is a few liters. Manufacturing losses (e.g., solution remaining in the bottom of vessels and in pipe work or filling lines at the end of the batch manufacture) need to be minimized so that yields of the often costly biopharmaceutical product are maximized. The manufacturing plant must be flexible enough to accommodate all these requirements.
If the plant is a multiproduct facility with components of fixed stainless-steel or other materials, methods for cleaning the equipment need to be developed. Analytical methods and associated sampling techniques for determining the residues of the active materials after cleaning also need to be developed and validated. These methods must be in place before any manufacture can take place, as without verified clean equipment, no other products can be made. This requirement can add as much as two months to the development program. The cost of developing and validating these methods can be in the thousands of dollars; therefore, it is advantageous to remove this requirement from the program.
Disposable technologies for manufacturing clinical-trial materials allow for flexibility in the manufacturing plant and low manufacturing losses. Because the product-contact parts are disposed of, there is no need for cleaning methods and the development and verification of analytical methods for these cleaning procedures. There are many different ways in which a parenteral biopharmaceutical product may be made. However, the process can be broken down into three distinct activities: compounding (i.e., the preparation of the solution to be filled); filtration (i.e., the method of sterilizing the solution); and filling (i.e., dosing the sterile, filtered solution into sterile vials and sealing them with sterile stoppers and collars). Disposable technologies can be used in each of these subprocesses as outlined below.