Process Validation : An Overview

• "Validation is a systematic approach to gathering and analyzing sufficient data which will give reasonable assurance (documented evidence), based upon scientific judgment, that a process, when operating within specified parameters, will consistently produce results within predetermined specifications."

• “Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.”

• “Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.”

• “Validation is the act of demonstrating and documenting that a procedure operates effectively. Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality.”

Importance of Validation

• Increased throughput
• Reduction in rejections and reworking
• Reduction in utility costs
• Avoidance of capital expenditures
• Fewer complaints about process-related failures
• Reduced testing in-process and in finished goods
• More rapid and reliable start-up of new equipment
• Easier scale-up from development work
• Easier maintenance of equipment
• Improved employee awareness of processes
• More rapid automation

Stages/Phases of Validation

Stage 1: Process Design (Pre-Validation Phase)

This is the step where building and capturing of the process knowledge and understanding took place. Early design of processes and experiments should be performed during this stage. It covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, equipment qualification, installation qualification, master production documents, operational qualification, process capability. Also this is the stage in which the establishment of a strategy for process control is taking place using accumulation knowledge and understanding of the process.

Stage 2: Process Qualification (Process Validation Phase)

This stage is confirmation that the process design is capable of reproducing the manufacturing process. It confirms that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under “worst case” conditions. GMP compliant procedures must be followed in this stage and successful completion of this stage is necessary before commercial distribution of a product.

Stage 3: Continued Process Verification (Validation Maintenance Phase)

The Validation Maintenance Stage requires frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including change control procedures. Before any batch is distributed for marketing, the manufacturer must have full assurance of its performance. A successful validation program depends on the knowledge and understanding and the approach to control manufacturing processes. These include the source of variation, the limitation of the detection of the variation, and the attributes susceptible of the variation. It is the responsibility of the manufacturer to judge and provide evidence of a high degree of assurance in its manufacturing processes. They are also responsible for maintaining the degree of assurance accomplished, even if some minor changes occurred due to personnel, material and process changes.

Type of Validation

• Prospective Validation 

is process of gathering of data and documentary evidence about a product and its process before it is sent to market or for distribution, a new product validation or a validation after making a change in the master formula, to determine if the product meet its predetermined standards. The process starts with designing of batch record , raw material specification and in process specifications and limits ,establishing sampling plan, and equipment lists and required environment controls.

• Concurrent Validation 

Is a validation process where in current production batches are used to confirm the compliance of processing parameters and standards. Concurrent validation is the set of validation procedures following prospective validation. Concurrent validation is carried out for ensuring the product batches produced in prospective validation meet the required standards and quality so that those can be distributed in market. 
Concurrent validation is of great use when the test employed is not destructive and can determine the product meet predetermined standards and quality. Concurrent validation is also carried out on product or process which is previously validated process to ascertain that the product or the process meets required standards and is validated.

• Retrospective Validation 

 is a type of validation where in the product is already and established process such batches of products which are being sent to market are studied to gather documentary evidence about the efficacy of the process or any in process tests and the product it self, such type of validation can be adapted to validate product and the process even if the product and process is not validated earlier. It also makes use of data from old batches to establish the efficacy and compliance of product or process standards. 

•  Re validation

To ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.

Re-validation may be divided into two broad categories:

• Re-validation after any change having a bearing on product quality.
• Periodic re-validation carried out at scheduled intervals.

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.