Increasing Patient Safety by Closing the Sterile Production Gap-Part 1. Introduction.

Terminal sterilization is considered the preferred means for the production of sterile drug products because it affords enhanced safety for the patient as the formulation is filled into its final container, sealed, and sterilized. Despite the obvious patient benefits, the use of terminal sterilization is artificially constrained by unreasonable expectations for the minimum time-temperature process to be used. The core misunderstanding with terminal sterilization is a fixation that destruction of a high population of a resistant biological indicator is required. The origin of this misconception is unclear, but it has resulted in sterilization conditions that are extremely harsh (15 min at 121 °C, of F > 8 min), which limit the use of terminal sterilization to extremely heat-stable formulations. These articles outline the artificial nature of the process constraints and describe a scientifically sound means to expand the use of terminal sterilization by identifying the correct process goal-destruction of the bioburden present in the container prior to sterilization. Recognition that the true intention is bioburden destruction in routine products allows for the use of reduced conditions (lower temperatures, shorter process dwell, or both) without added patient risk. By focusing attention on the correct process target, lower time-temperature conditions can be used to expand the use of terminal sterilization to products unable to withstand the harsh conditions that have been mistakenly applied. The first article provides the background and describes the benefits to patient, producer, and regulator. The second article includes validation and operational advice that can be used in the implementation. Terminal sterilization is considered the preferred means for the production of sterile drug products because it affords enhanced safety for the patient as the formulation is filled into its final container, sealed, and sterilized. Despite the obvious patient benefits, the use of terminal sterilization is artificially constrained by unreasonable expectations for the minimum time-temperature process to be used. These articles outline the artificial nature of the process constraints and describe a scientifically sound means to expand the use of terminal sterilization by identifying the correct process goal-destruction of the bioburden present in the container prior to sterilization. By focusing attention on the correct process target, lower time-temperature conditions can be used to expand the use of terminal sterilization to products unable to withstand the harsh conditions that have been mistakenly applied. The first article provides the background, and describes the benefits to patient, producer, and regulator. The second article includes validation and operational advice that can be used in the implementation.