From the elimination of cleaning and cleaning validation to a reduction in capital costs, labor, and space requirements, the
myriad benefits of using disposable systems are well-established. However, presterilization is one area that deserves more
attention. Presterilization goes to the heart of the disposables concept, which is to minimize opportunities for contamination,
whether through operator error, the process, or the product.
As the size and complexity of disposable systems continue to increase, presterilization will become increasingly advantageous
and, in some cases, necessary. For example, conventional sterilization techniques such as autoclaving do not always fit a
manufacturer's timeline, especially in the case of campaign-based vaccine production. Steam used during autoclaving is also
known to damage paper, some plastics, and other heat-labile products and does not always ensure complete sterilization.
In addition to providing validation strategies for presterilization using gamma irradiation, this article addresses the overall
benefits of disposables and explains how to minimize revalidation during scale-up.
Validation: An Important Early Process Consideration
Regulatory agencies around the world are focusing on validation, and it is becoming an increasingly important topic to consider
early in the drug development process. For example, Annex 13 in Eudralex, the European Union's source for governing medical
products, affirms that for investigational medicinal products, the manufacturing process should be validated in its entirety;
it also focuses on critical steps, such as sterilization. Annex 13 further defines the process in the following manner:
Figure 1. A fully integrated, single-use filtration system
The different production operations shall be carried out in accordance with GMP; manufacturing facilities must be laid out
to allow effective cleaning and reduce cross-contamination risk; equipment used for manufacturing operation, which are critical
to the quality of the product, shall be subjected to appropriate qualification and validation.
In North America, FDA's January 2006 draft guidance INDs — Approaches to Complying with CGMP During Phase I — states that there are a number of technologies and resources available for use that can facilitate conformance with current
good manufacturing practices (cGMPs) and help streamline product development. More specifically, these include the use of
disposable equipment and process aids, prepackaged Water for Injection (WFI) and presterilized containers, and process equipment
that is not exposed to the environment during processing.
Example: Virus Particle Filtration
Presterilized Filtration Systems
Filtration systems exemplify disposable technologies that can be presterilized. Disposable filtration systems are offered
in a range of sizes, so that corresponding filters and bags are available for every stage of development, ensuring that the
most appropriate and economical disposable filter scheme is used. By using the same materials of construction, these systems
also generate reproducible results during scale up. Also, like presterilized filter cartridges, the entire single-use filtration
system can be gamma irradiated before delivery to the biopharmaceutical manufacturing site. These systems, which generally
comprise disposable bags, capsule filters, tubing, clamps, adaptors, and connection devices, also simplify many biopharmaceutical
processes, such as preuse filter integrity testing.
To make certain that the process is scaled up with minimal material revalidation, biotechnology and pharmaceutical companies
should use components that are made from the same materials from small scale-up to manufacturing scale.
A variety of capsule filter configurations are available to support processes as they are scaled up. Ideally, these differently-sized
capsules contain identical filter media and hardware materials. This helps ensure that scale-up and scale-down studies yield
relevant information and minimum requalification for various batch sizes.
The availability of a variety of capsules for small-scale operations is especially beneficial for new product development.
Since all new biopharmaceutical products may not become commercialized, capital investment can be a concern. Single-use capsules
and systems make it possible to produce new products during the early development stages without a large capital investment.
Together, these factors can streamline drug development to increase manufacturing capacity, while meeting validation requirements.