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Process validation is defined in International Conference for Harmonization's (ICH) Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients as, "The documented evidence that the process, operated within establish parameters, can perform effectively and reproducibly to produce an intermediate or API [active pharmaceutical ingredient] meeting its predetermined specifications and quality attributes."
The European Medicines Agency (EMA) has finalized guidance on process validation for a host of biological active ingredients, such as recombinant proteins and recombinant polypeptides, and may be applicable to other biological products such as vaccines or plasma-derived products. The guidance will come into effect on November 2016.
EMA breaks process validation up into two main components: process characterization and process verification. Process characterization is further divided into process development and process evaluation, and involves a sponsor defining its manufacturing process for an active ingredient and evaluating the process to ensure it is adequately designed. Process verification involves studies done at manufacturing scale to confirm the performance of the processes the manufacturer has specified.
According to the guidance, sponsors should conduct studies to inform the design of their manufacturing process. Then, based on those processes, sponsors should identify any key inputs and outputs that need to be evaluated and verified through additional studies.
This can either be done through a traditional approach, relying on studies of processes, through an "enhanced approach," whereby a sponsor use risk management principles and existing scientific knowledge to select and characterize its manufacturing process.
When evaluating a manufacturing process, EMA recommends that sponsors focus the "potential criticality" of the inputs and outputs identified during process development. According to EMA, sponsors should use small scale models to enable evaluation of input material and parameter variability to an extent that may not be feasible at manufacturing scale.Once a sponsor has developed and evaluated its manufacturing processes, EMA expects them to verify that their processes will perform as expected on a commercial scale by producing batches of an active substance.
According to EMA, the number of batches required to verify a sponsor's manufacturing process is based on four criteria:
1. "The complexity of the process being validated
2. The level of process variability
3. The amount of experimental data and/or process knowledge available on the process and
4. The frequency and cause(s) of deviations and batch failure.
According to the guidance, for continuous process verification, the sponsors should consider the following points
• Prior development and manufacturing knowledge from similar products and/or processes
• The extent of process understanding gained from development studies and commercial manufacturing experience
• The complexity of the product and/or manufacturing process
• The level of process automation and analytical technologies used
Under exceptional circumstances, such as urgent medical need, sponsors may rely on concurrent validation by demonstrating that the studies done under process evaluation are appropriate representations of the commercial process and the control strategy will properly verify that the process has performed as intended and that the active substance and intermediates comply with pre-defined acceptance criteria.