Non-Sterile Process Validation-Prospective Validation

During product development the production process should be broken down into individual steps.  Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical factors/parameters that may affect the quality of the finished product.  A series of experiments should be devised to determine the criticality of these factors. Representatives from Production, QC/QA, Engineering, and in some cases Research and Development will normally be involved in this process.These experiments may incorporate a challenge element to determine the robustness of the process. Such a challenge is generally referred to as a "worst case" exercise. The use of starting materials on the extremes of the specification may indicate the ability of the process to continue producing finished product to the required specification. 

Each experiment should be planned and documented fully in an authorized protocol.This document will have the following elements:

• A description of the process, 
• A description of the experiment, 
• Details of the equipment/facilities to be used (including measuring / recording equipment) together with its calibration status, 
• The variables to be monitored, 
• The samples to be taken - where, when, how and how many, 
• The product performance characteristics/attributes to be monitored, together with the test methods, 
• The acceptable limits, 
• Time schedules, 
• Personnel responsibilities, 
• Details of methods for recording and evaluating results, including statistical analysis.

All equipment, the production environment and analytical testing methods to be used should have been fully validated,  (Installation/ Operational Qualification). Staff taking part in the validation work should have been appropriately trained.  In practice, Operational Qualification may be carried out using batches of actual product. This work may also fulfil the requirements of Prospective Validation. This approach to validation should not be adopted as a standard practice however. 

Master Batch Documentation can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. Using this defined process (including specified components) a series of batches of the final product should be produced. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate this data.

It is preferred that the batches made should be the same size as the intended batch size for full scale production.This may not always be practical due to a shortage of available starting materials and in such cases the effect of the reduced batch size should be considered in the design of the protocol.  When full scale production starts, the validity of any assumptions made should be demonstrated. 

During the processing of the batch/run, extensive testing should be performed on the product at various stages. Detailed testing should also be done on the final product and its package. 

The batches/runs under validation should be documented comprehensively. 

The following items should be included in the validation report: 

• A description of the process - Batch/Packaging  Document, including details of critical steps, 
• A detailed summary of the results obtained from in-process and final testing, including data from failed tests.  When raw data are not included reference should be made to the sources used and where it can be found, 
• Any work done in addition to that specified in  the protocol or any deviations from the protocol should be formally noted along with an explanation, 
• A review and comparison of the results with those expected, 
• Formal acceptance/rejection of the work by the  team/persons designated as being responsible for the validation, after completion of any corrective action or repeated work. 

Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production.These should be incorporated into the  Batch Manufacturing or Packaging Record or into appropriate standard operating procedures (SOPs).Limits, frequencies and actions to be taken in the  event of the limits being exceeded should be specified. 

If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice and the Marketing authorization (if applicable).  The premises used should be named on a Manufacturing Authorization and this authorization should allow the manufacture/assembly of the particular type of product. Where appropriate, the batch must be formally certified by a Qualified Person before release.