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A symposium at the AAPS National Biotechnology Conference in Boston, June 19-22, 2006, addressed key concerns and new developments in manufacturing biologic products in a sterile environment.
A symposium at the AAPS National Biotechnology Conference in Boston, June 19–21, 2006, addressed key concerns and new developments in manufacturing biologic products in a sterile environment.
Several speakers reiterated a key point to remember: people working in manufacturing facilities are the single biggest source of contamination. Products and procedures are being developed to address this concern.
Several presenters said that restricted access barrier systems are an effective way to limit human contact with biological material. Otto-Ernst Schubert, PhD, of Hoffman-LaRoche, (Basel, Switzerland, www.roche.com), advocated aseptic processing using isolators, and provided details about how isolators can minimize human intervention. Isolators can be used to ensure product sterility or to protect operators by containing potent materials. Isolators are available in either closed (remains sealed through entire process), or open (continuous influx of materials through one or more openings) formats. Although isolators provide a more sterile working environment with a high sterility assurance, they are not without drawbacks, said Schubert. Examples include poor accessibility to the entire interior of the isolator for cleaning, and limited ability to transfer materials without risk of contamination. Additional concerns include a substantial increase in costs (30–70% over clean room use), and the necessity to adequately train personnel to use isolators for maximum effectiveness. In addition, the potential output of an isolator line is greatly reduced by the lengthy sterilization procedure, which usually is performed using vaporized hydrogen peroxide.
Joerg Zimmermann, of Vetter Pharma-Fertigung GmbH (Ravensburg, Germany, www.vetter-pharma.com), explained how RABS have been used in the aseptic filling of Vetter’s dual chamber syringes. Zimmermann observed that although RABS, when properly used, will result in a safe, aseptic process, he does not advocate RABS or isolators; instead, he advises using whatever system works best for each individual process and product.
Safe storage of formulated protein bulk was also discussed during the session. According to Satish K. Singh, of Pfizer Global Biologics (St. Louis, MO, www.pfizer.com), storage considerations for the bulk should be an integral part of the formulation development program for all biologics. Effective solutions for storing bulk volumes of biologic material can enable bulk production to be decoupled from drug product production, lengthen expiry periods, reduce contamination risk, and ultimately, prevent revenue loss, Singh said.
Storing bulk material in liquid form in bottles, bags, or stainless steel tanks is a viable short-term option. Biologicals are generally unstable in a liquid state, however, so liquid storage uses up valuable shelf life. Liquids, especially in large volumes, also are difficult to transport. Freezing offers drug makers a long-term option for stable storage, but processes and formulations must be developed with this option in mind. Lyophilization, said Singh, is an expensive alternative and not viable for large volumes.
Singh referenced the ICH Q5C guideline, issued by FDA in July 1996, Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products when discussing the selection of storage containers for stability testing of active pharmaceutical ingredients that would be representative of containers for commercial use. The guideline states, “The container/closure has the potential to affect the product adversely and should be carefully evaluated.” Factors to address include temperature, humidity, accelerated and stress conditions, exposure to light, container/closure product interaction, and temperature excursions. Disposable bioprocess bags and stainless steel tanks are currently the storage options that have proven to be most viable for large-volume, bulk biologic material, Singh said. He noted that appropriate studies have to be incorporated into the formulation development program to support their use, whether in the liquid state for short-term holding or in the frozen state for long-term storage.