Validation Maintenance

The validation process is not a single activity that ends with the validation report approval. The validation status should be maintained in a state of control, in order to prove the consistent effectiveness of the process during routine use. This is the main goal of the continued process verification (CPV) stage 3 of the FDA validation lifecycle approach and of the GMP ongoing process validation (OPV). FDA states that the intent of the third validation stage is “continual assurance that the process remains in a state of control (the validated state) during commercial manufacture” and Annex 15, of EU-GMP, states that “Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated”. The maintenance of the state of control results first in monitoring, with an appropriate frequency, of attributes and parameters defined by a risk based approach, and then in trending data by using the correct statistical tool. Several statistical tools can be used to analyze data. The use of statistical process control techniques, such as control charts and capability indices is highly recommended in order to measure and evaluate process stability and process capability. In this context, a CPV/OPV program it is of strategic importance and must be clearly defined in a plan. Key elements include the definition of the approach, the strategy and the sampling and testing methods are detailed within the CPV plan. The extent and frequency of ongoing/continued process validation should be reviewed periodically, since changes may occur during routine manufacturing.

Regulatory agencies expect manufacturers to implement the CPV plan as highlighted in FDA warning letters. But in addition to the regulatory expectations, the importance of the maintenance of the validated state enables the identification of problems and the possible need to implement measures to correct, anticipate and prevent negative events so that the process remains under a state of control. FDA highlights the importance of process monitoring expected from validation maintenance since it provides the tools for dealing with variation. Detecting, understanding and reducing variation is at the heart of the FDA Process Validation Guidance. Furthermore, through the application of several periodic processes involving re-qualification, periodic reviews, environmental monitoring, change management and preventive maintenance, the maintenance of the validated status involves active participation and collaboration from multiple roles in the company with the ultimate goal of quality improvement and process optimization.

• Statistical process control
• Process capability
• Re-qualification
• CPV plan
• Support for periodic qualification activities