ABSTRACT
INTRODUCTION In September 2004, the Food and Drug Administration (FDA) Guidance for Industry PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance was issued to encourage pharmaceutical manufacturers to develop and implement effective and efficient innovative approaches in providing quality pharmaceuticals to the public (1). The linkage of rapid microbiological methods (RMMs) to Process Analytical Technology (PAT) is largely based on real-time release, which is the ability to evaluate and ensure the acceptable quality of in-process and/or final product on the basis of the collection and analysis of in-process data. As stated in the FDA guide, the PAT component of real-time release typically includes a valid combination of assessed material attributes and process controls. Material attributes such as bioburden, endotoxin content, and sterility could be assessed using direct and/or indirect process analytical methods. The combined process measurements and other test data gathered during the manufacturing process could serve as the basis for real-time release of the final product and would demonstrate that each batch conforms to established regulatory quality attributes. The FDA considers real-time release to be comparable with alternative analytical procedures to the compendial microbiological tests for final product release. It is notable that the guidance document stated that real-time release as defined in this guidance builds on parametric release of terminally heat sterilized drug products, a practice in the U.S. large-volume parenteral industry since 1985. In real-time release, material attributes such as formulation, bioburden, container size, and load pattern, as well as process parameters such as sterilization parameters, are measured and controlled.
