ABSTRACT
Operating range validation is the component of process validation that entails identification of critical process variables and establishment of acceptable operating ranges for those variables. By the definition of the U.S. Food and Drug Administration, when a process is run within its validated state, it will "consistently produce a product meeting its pre-determined specifications and quality attributes" (1,2). The operating range of a process variable (e.g., flow rate over a chromatography column) is illustrated in Figure 1, based on the "pyramid" concept introduced by Chapman (3) involving a series of increasingly wider ranges about the setpoint. The setpoint, which may be a point value or a narrow range of values, is determined from process development studies that identify the optimal setting for the variable. The manufacturing records should instruct the operators to run the process or equipment at the specified setpoint. In practice, however, exact control of the variable at the setpoint is seldom achieved; rather, the variable is typically maintained within the range of values known as the "normal operating range" (NOR). The magnitude of the NOR can be established by trending process performance over the production of clinical trial or qualification lots of a product and assigning a multiple of the standard deviation to the NOR (usually two to three standard deviations).
