PROCESS VALIDATION

Validation:

Validation is the action of proving or declaring something (Procedure, process & equipment etc) that actually capable to deliver expected results and is officially valid.

Process Validation:

Process validation is the action of proving or declaring that the established process is capable to deliver expected results and is officially valid.

Objective of process Validation

To generate a documented evidence, from the evaluation of data from process design stage through commercial production, that provides a high degree of assurance that a specific process will consistently results in a product that meets predetermined specification and quality characteristics.

Process validation should not be viewed as a one-off event. Process validation incorporates a life cycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.

The objective of process validation consists of following major steps. 

• The process design is evaluated to show that it is reproducible,
• The commercial manufacturing process is defined and controlled,
• Ongoing assurance is gained to show that the process remains in a state of control.

Types of Process Validation:

Process validation mainly divided in to following four types.

a) Prospective Validation (Premarket Validation)
b) Concurrent Validation
c) Retrospective Validation
d) Re-validation

A) Prospective Validation (Premarket Validation) 

This approach to validation is normally undertaken during development stage by means of a risk analysis of the process, generally whenever the process for a new formula (or within a new facility) must be validated before routine pharmaceutical production commences. 

In fact, validation of a process by this approach often leads to transfer of the manufacturing process from the development function to production.

Prospective validation should be completed before commercial distribution.

B) Concurrent Validation: 

Concurrent validation is carried out during normal production. 

This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process.

The first three production-scale batches must be monitored as comprehensively as possible. The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.

This validation generally used for batches produced infrequently and/or batches are produced by a validated process that has been modified.

Prior to the completion of concurrent validation, batches can be released.

C) Retrospective Validation: (Regulatory not considering this as on date) 

Retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process.

Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. 

Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule.

Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.

D) Re-Validation: 

Re-validation means repeating the original validation effort or any part of it, and includes investigative review of existing performance data.

Re validation is needed 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.

Possible reasons for re-validation:
a) Periodic re-validation
b) Re-validation after change in the starting material
c) Re-validation after change in the packing material
d) Re-validation after change in the process
e) Re-validation after change in the equipment or measuring instrument
f) Re-validation after change in the production area or supporting system.
g) Re-validation after significant change in the batch size

Traditional Approach of Process Validation:

Traditionally process validation was focused on testing, instrument qualification, and process robustness and repeatability.

Traditional approach includes following four elements

Design Qualification (DQ)

Installation Qualification (IQ)

Operational Qualification (OQ)

Process Validation (PV)

In this approach the manufacturer performs a minimum of 3 commercial batches for validation and if successful, the validation effort is considered complete, and manufacturer could then routinely use the process to produce the product, without further process validation and there was no requirement to perform any further ongoing life cycle validation efforts.

Modern Approach of Process Validation (Life Cycle Approach):

Against to traditional approach, the current enhanced process validation approach consists three phase continuous process with ongoing effort for the entire life cycle of the product called as life cycle approach.

Phase I. Process design

Phase II. Qualification and process verification

Phase IIA. Qualification

Phase IIB. Continuous process performance verification

Phase III. Continued process verification

Phase I. Process design:

The goal of this stage is to design a process suitable for routine commercial manufacturing process that can consistently deliver a product that meets its quality attributes. 

Process design should normally cover design of experiments, product & process development, and the manufacture of products for use in clinical trials, pilot-scale batches and technology transfer. 

Process design should cover aspects for the selection of materials, expected production variation, selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in-process controls, tests, inspection and its suitability for the control strategy. 

Product & Process development: 

The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. 

It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. 

At the completion of this stage technology transfer package containing information sufficient to plan and manufacture scale up & exhibit batches shall be made available. 

A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel, and formally accepted by manufacturing, engineering and quality personnel, should be prepared. 

Such a document may include information, desired clinical performance, bills of materials, approved suppliers, finished product specifications and test methods, in-process testing specifications, equipment recommendations, master batch production records, master batch packaging records, stability reports, critical quality attributes, critical process parameters, batch comparisons, data on formulation batches, stability batches, clinical/ bio batches and scale-up batches. These documents should be readily available to the manufacturing site. 

Scale up activities: 

The aim of scale up activities is to assess the impact of scaling up of manufacturing process on the performance of manufacturing process and product quality. 

At the completion of this stage, control strategy of for manufacturing process for validation batches should be made available. 

A scale up report, formally reviewed and approved by research and development personnel, manufacturing and quality personnel, should be prepared. 

Such a document may include information related to Product, Manufacturing process, process evaluation and recommended control strategy with conclusion as a minimum criteria. 

— As part of the process validation life cycle some process validation studies may be conducted on pilot-scale batches (corresponding to at least 10% or 100 000 units, whichever is the greater) of the production scale. Where the batch size is smaller and/or where the process is tailored to the geometry and capacity of specific equipment, it may be necessary to provide production-scale validation data.

— The number of batches included in the process design stage of validation should be appropriate and sufficient to include (but not be limited to) the expected variations in starting materials, and confirm the suitability of the equipment and manufacturing technology

— Manufacturers should define the stage at which the product is considered to be validated and the basis on which that decision was made. It should include a justification for the number of batches used based on the complexity and expected variability of the process.

Phase II. Qualification and process verification:

This phase consist of following sub-phases.

Phase IIa: Qualification of personnel, premises, utilities, and equipment’s where commercial scale batches will be manufactured.

Phase IIb: Continuous process performance verification.

Phase IIa: 

Personnel Premises, utilities, support systems and equipment should be appropriately qualified before process performance verification (as part of validation) is started. 

In a traditional approach, stages of qualification may include design, installation, operational and performance qualification. 

In some cases process validation may be conducted concurrently with performance qualification. 

Phase IIb: 

After completion of qualification, commercial batches should be subjected to continuous process performance verification as part of process validation. It should confirm that scale up in batch size do not adversely affect the characteristics of a product. 

Demonstrates that a process that operates within the predefined specified parameters consistently produces a product which meets all its critical quality attributes (CQAs) and control strategy requirements 

The process should be verified on commercial-scale batches prior to marketing of the product. 

Extensive in-line or at-line controls should be used to monitor process performance and product quality in a timely manner. In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production. 

Manufacturers should describe the appropriateness and feasibility of the CPV strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed. 

It is expected that additional monitoring for the first commercial batches should be done where continuous process verification is implemented. 

Phase III. Continued process verification: 

Manufacturers should monitor product quality of commercial batches after completion of Phase I and Phase II of process validation. This will provide evidence that a state of control is maintained throughout the product life-cycle 

Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement. 

Process trends such as the quality of incoming materials or components, in-process and finished product results and non-conformances should be collected and assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy. 

The extent and frequency of ongoing process validation should be reviewed periodically and modified if appropriate throughout the product life-cycle. 

Traditionally process validation was focused on testing, instrument qualification, and process robustness and repeatability.
Traditional approach includes following four elements
Design Qualification (DQ)
Installation Qualification (IQ)
Operational Qualification (OQ)
Process Validation (PV)

In this approach the manufacturer performs a minimum of 3 commercial batches for validation and if successful, the validation effort is considered complete, and manufacturer could then routinely use the process to produce the product, without further process validation and there was no requirement to perform any further ongoing life cycle validation efforts.

Modern Approach of Process Validation (Life Cycle Approach):
Against to traditional approach, the current enhanced process validation approach consists three phase continuous process with ongoing effort for the entire life cycle of the product called as life cycle approach.

Phase I. Process design

Phase II. Qualification and process verification

Phase IIA. Qualification

Phase IIB. Continuous process performance verification

Phase III. Continued process verification


Phase I. Process design:

The goal of this stage is to design a process suitable for routine commercial manufacturing process that can consistently deliver a product that meets its quality attributes.
Process design should normally cover design of experiments, product & process development, and the manufacture of products for use in clinical trials, pilot-scale batches and technology transfer.
Process design should cover aspects for the selection of materials, expected production variation, selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in-process controls, tests, inspection and its suitability for the control strategy.


Product & Process development:
The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product.
It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design.
At the completion of this stage technology transfer package containing information sufficient to plan and manufacture scale up & exhibit batches shall be made available.
A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel, and formally accepted by manufacturing, engineering and quality personnel, should be prepared.
Such a document may include information, desired clinical performance, bills of materials, approved suppliers, finished product specifications and test methods, in-process testing specifications, equipment recommendations, master batch production records, master batch packaging records, stability reports, critical quality attributes, critical process parameters, batch comparisons, data on formulation batches, stability batches, clinical/ bio batches and scale-up batches. These documents should be readily available to the manufacturing site.


Scale up activities:
The aim of scale up activities is to assess the impact of scaling up of manufacturing process on the performance of manufacturing process and product quality.
At the completion of this stage, control strategy of for manufacturing process for validation batches should be made available.
A scale up report, formally reviewed and approved by research and development personnel, manufacturing and quality personnel, should be prepared.
Such a document may include information related to Product, Manufacturing process, process evaluation and recommended control strategy with conclusion as a minimum criteria.
— As part of the process validation life cycle some process validation studies may be conducted on pilot-scale batches (corresponding to at least 10% or 100 000 units, whichever is the greater) of the production scale. Where the batch size is smaller and/or where the process is tailored to the geometry and capacity of specific equipment, it may be necessary to provide production-scale validation data. — The number of batches included in the process design stage of validation should be appropriate and sufficient to include (but not be limited to) the expected variations in starting materials, and confirm the suitability of the equipment and manufacturing technology — Manufacturers should define the stage at which the product is considered to be validated and the basis on which that decision was made. It should include a justification for the number of batches used based on the complexity and expected variability of the process.

Phase II. Qualification and process verification:





This phase consist of following sub-phases.





Phase IIa: Qualification of personnel, premises, utilities, and equipment’s where commercial scale batches will be manufactured. Phase IIb: Continuous process performance verification.





Phase IIa:
Personnel Premises, utilities, support systems and equipment should be appropriately qualified before process performance verification (as part of validation) is started.
In a traditional approach, stages of qualification may include design, installation, operational and performance qualification.
In some cases process validation may be conducted concurrently with performance qualification.


Phase IIb:
After completion of qualification, commercial batches should be subjected to continuous process performance verification as part of process validation. It should confirm that scale up in batch size do not adversely affect the characteristics of a product.
Demonstrates that a process that operates within the predefined specified parameters consistently produces a product which meets all its critical quality attributes (CQAs) and control strategy requirements
The process should be verified on commercial-scale batches prior to marketing of the product.
Extensive in-line or at-line controls should be used to monitor process performance and product quality in a timely manner. In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production.
Manufacturers should describe the appropriateness and feasibility of the CPV strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed.
It is expected that additional monitoring for the first commercial batches should be done where continuous process verification is implemented.


Phase III. Continued process verification:
Manufacturers should monitor product quality of commercial batches after completion of Phase I and Phase II of process validation. This will provide evidence that a state of control is maintained throughout the product life-cycle
Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement.
Process trends such as the quality of incoming materials or components, in-process and finished product results and non-conformances should be collected and assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy.
The extent and frequency of ongoing process validation should be reviewed periodically and modified if appropriate throughout the product life-cycle.