What is Pharmaceutical Validation?

What is Validation?

Validation is the procedure that authorizes documentary evidence that prove, the following process/ method or activity will consistently produce the product which leads to the expected result (predetermined requirements).

There are really 3 main parts in this definition of validation.

Validation is…

creating an evidence trail…

to show that an action, process, or system…

leads to a consistent and reproducible result.

Importance of Validation

1. Assurance of quality
2. Time bound
3. Process optimization
4. Reduction of quality cost.
5. Nominal mix-ups, and bottle necks
6. Minimal batch failures, improved efficiently and productivity.
7. Reduction in rejections.
8. Increased output.
9. Avoidance of capital expenditures
10. Fewer complaints about process related failures.
11. Reduced testing in process and in finished goods.
12. More rapid and reliable start-up of new equipment
13. Easier scale-up from development work.
14. Easier maintenance of equipment.
15. Improved employee awareness of processes.
16. More rapid automation.
17. Government regulation (Compliance with validation requirements is necessary for obtaining approval to manufacture and to introduce new products).

Planning for Validation

• All validation activities should be planned. The key elements of a validation program should be clearly defined and documented in a validation master plan (VMP) or equivalent documents.
• The VMP should be a summary document, which is brief, concise and clear. The VMP should contain data on at least the following:

1. Validation policy.
2. The organizational structure of validation activities.
3. Summary of facilities, systems, equipment and processes to be validated.
4. Documentation format: The format to be used for protocols and reports.
5. Planning and scheduling.
6. Change control.
7. Reference to an existing document.
8. In the case of large projects, it may be necessary to create separate validation master plans.

Documentation

• A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria. 
• A report that cross-references the qualification and/or validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification.
• After completion of a satisfactory qualification, a format release for the next step in qualification and validation should be made as written authorization.

Validation Setup 

• To establish the desired attributes. These attributes include physical as well as chemical characteristics. In the case of parenterals, these desirable attributes should include stability, absence of pyrogens, and freedom from visible particles.
• Acceptance specifications for the product should be established in order to attain uniformity and consistently the desired product attributes and the specifications should be derived from testing and challenge of the system on a sound statistical basis during the initial development and production phases and continuing through subsequent routine production.
• The process and equipment should be selected to achieve the product specification. For example; design engineers; production and quality assurance people may all be involved.
• The process should be defined with a great deal of specificity and each step of the process should be challenged to determine its adequacy. These aspects are important in order to assure products of uniform quality, purity, and performance.

Types/Methods of Validation

1. Prospective Validation

• It is defined as the established documented evidence that a system does what it purports to do based on a pre-planned protocol. This validation is usually carried out prior to the distribution either of a new product or a product made under a revised manufacturing process. Performed on at least three successive production-size (Consecutive batches).
• In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase, the production process should be categorized into individual steps.

• Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol.
• All equipment, production environment and the analytical testing methods to be used should have been fully validated. Masterbatch documents 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 a series of batches 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 to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving a product of the desired quality would constitute a proper validation of the process.

ALSO READ: Concept of Cleaning Validation in Pharmaceuticals

• In practice, it may take some considerable time to accumulate this data. Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated to commercial production, the operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation.
• During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages and should be documented comprehensively. Detailed testing should also be done on the final product in its package. 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 and packaging record or into appropriate standard operating procedures. Limits, frequencies, and actions to be taken in the event of the limits being exceeded should be specified.

• Prospective validation should include, but not be limited to the following:

1. Short description of the process.
2. Summary of the critical processing steps to be investigated.
3. List of the equipment/facilities to be used (including measuring, monitoring/recording equipment) together with its calibration status.
4. Finished product specifications for release.
5. List of analytical methods, as appropriate.
6. Proposed in-process controls with acceptance criteria.
7. Additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate.
8. Sampling plan.
9. Methods for recording and evaluating results.
10. Functions and responsibilities.
11. Proposed timetable.

• Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. 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 would constitute a validation of the process.
• Batches made for process validation should be the same size as the intended Industrial scale batches. 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, including the satisfactory outcome of the validation exercise and the marketing authorization.
  

2. Concurrent Validation

• It is similar to prospective, except the operating firm will sell the product during the qualification runs, to the public at its market price, and also similar to retrospective validation.
• This validation involves in-process monitoring of critical processing steps and product testing. This helps to generate and document evidence to show that the production process is in a state of control.

1. In exceptional circumstances, it may be acceptable not to complete a validation program before routine production starts.
2. The decision to carry out concurrent validation must be justified, documented and approved by authorized personnel.
3. Documentation requirements for concurrent validation are the same as specified for prospective validation.

3. Retrospective Validation

• It is defined as the established documented evidence that a system does what it purports to do on the review and analysis of historical information. This is achieved by the review of the historical manufacturing testing data to prove that the process has always remained in control.  This type of validation of a process for a product already in distribution.
• Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.
• Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.
• The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance logbooks, records of personnel changes, process capability studies, and finished product data, including trend cards and storage stability results.
• Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet the specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process.
• For retrospective validation, generally data from ten to thirty consecutive batches should be examined to access process consistency, but fewer batches may be examined if justified.

ALSO READ: SOP for Concurrent Process Validation

Some of the essential elements for Retrospective Validation are:

• Batches manufactured for a defined period (minimum of 10 last consecutive batches).
• A number of lots released per year.

1. Batch size/strength/manufacturer/year/period.
2. Master manufacturing/packaging documents.
3. Current specifications for active materials/finished products.
4. List of process deviations, corrective actions and changes to manufacturing documents.
5. Data for stability testing for several batches.

Change Control

• Written procedures should be in place to describe the actions to be taken if the change is proposed to the starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. 
• Change control procedures should ensure that sufficient support data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications.
• All changes that may affect product quality or the reproducibility of the process should be formally requested, documented, and accepted. The likely impact of the change of facilities, systems, and equipment on the product should be evaluated, including risk analysis. 
• The need for, and the extent of, requalification and revalidation should be determined.

4. Revalidation

• Re-validation provides evidence that changes in a process and/or the process environment that are introduced do not adversely affect process characteristics and product quality. 
• Documentation requirements will be the same as for the initial validation of the process. Facilities, systems, equipment, and processes, including cleaning, should be periodically evaluated to confirm that they remain valid.
• Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.
• Revalidation becomes necessary in certain situations. Some of the changes that require validation are as follows:

1. Changes in raw materials (physical properties such as density, viscosity, particle size distribution and moisture, etc., that may affect the process or product).
2. Changes in the source of active raw material manufacturers.
3. Changes in packaging material (primary container/closure system)
4. Changes in the process (e.g., mixing time, drying temperatures, and batch size)
5. Changes in the equipment (e.g., the addition of an automatic detection system). Changes of equipment that involve the replacement of equipment on a “like for like” basis would not normally require re-validation except that this new equipment must be qualified.
6. Changes in the plant/facility.
7. A decision not to perform revalidation studies must be fully justified and documented.

CONCEPT OF PROCESS VALIDATION

1. Calibration, verification and maintenance of process equipment.
2. Prequalification or revalidation.
3. Establishing specifications and performance characteristics.
4. Selection of methods, process and equipment to ensure the product meets specifications.
5. Qualification or validation of process and equipment.
6. Testing the final product, using validated analytical methods, in order to meet specifications.
7. Challenging, auditing, monitoring or sampling the recognized critical key steps of the process.

Phases in Process Validation

The activities relating to validation studies may be classified into three phases:

Phase 1

• Pre-validation phase or the Qualification phase, which 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.

Phase 2

• Process validation phase (Process Qualification phase) is designed to verify that all established limits of the critical process parameters are valid and that satisfactory products can be produced even under the “worst case” conditions.

Phase 3

• The validation Maintenance phase requires a frequent review of all process-related documents, including validation audit reports to assure that there have been no changes, deviations, failures, or modifications to the production process and that all SOPs have been followed, including change control procedures.
• At this stage, the Validation Team also assures that there have been no changes/deviations that should have resulted in prequalification and revalidation.

ALSO READ: SOP for Continued Process Verification