Identification of the Critical Steps for Drug Product Process
Introduction
This guidance provides recommendations for selecting critical process parameters (CPP) and critical process steps (CPS) based on the understanding of a drug product process.
This guidance describes guidelines for determining the steps of a drug product process that are critical. Steps or unit operations that are designated as critical must be included within the scope of validation.
Recommendations and Discussion
A “step” in the context of this guidance, may be a single manufacturing instruction or a series of instructions that constitute a unit operation. Typical unit operations in the manufacturing of tablets (a common solid dosage form) include, but are not limited to: weighing, sieving, mixing, granulating, drying, milling, tabletting, coating and printing.
The Master Batch Record is central to the process validation effort. It is important to review each step of the batch record with the appropriate technical or development staffs to evaluate all steps for their impact on product quality.
Steps, or unit operations, that include one or more critical process parameters shall be deemed critical steps and require validation. A step potentially identified as critical may become a non-critical step because the parameter(s) is well-controlled and the parameter’s normal operating range (NOR) is well within the Proven Acceptable Range (PAR).
Note: Key Process Parameters sometime used in Right First Time include CPPs but may also include non-quality related inputs, excipients, raw materials, safety, environmental, etc. Key Quality Attributes include Critical Quality Attributes and other important non-registered attributes of interest (e.g. customer requirements).
It may be a quality requirement that all critical steps of a drug product process be validated. The guidance requires the critical steps to be identified in the validation protocol. The protocol should also include or refer to documentation that identifies and justifies selection of critical parameters for the process. These steps require evaluation by means of qualifying the limits of the proven acceptable range of critical process parameters and, typically, more intensive sampling and testing in the validation.
The designation of one or more steps of the manufacturing process as ‘noncritical’ or ‘critical’ does not indicate that the remaining steps are non important or vice versa. In practice, the activity conducted at a ‘non-critical’ step may not carry through to subsequent steps. For example, early blending steps may be ‘noncritical’ if followed by additional blending steps. Designation is product and process dependent.
Non-critical steps still may contain process parameters that are desirable to be maintained to ensure consistent production of the final product. These non-critical steps and parameters do not require limit testing or extensive sampling, but they must still be controlled and documented. During validation report preparation, all steps of the executed batch record must be reviewed to verify they were accurately completed.