Process
Validation in Pharma
The purpose of this SOP is to define the approach to be followed to establish documented evidence that a specific process will consistently produce a result meeting its predetermined specification and quality attributes.
Approaches to Process Validation: Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
There are three approaches to process validation.
Prospective Validation
Concurrent validation
Retrospective validation
Prospective Validation (PV): Prospective validation shall be performed on processes of API for new drug substance, new manufacturing process, new route of synthesis, change in manufacturing location, change of equipments (unlike equipments with respect to existing equipments), change in utilities, change in critical process parameters and change in final specification. Prospective validation should extend to those operations determined to be critical to the quality of the drug substance.
For prospective process validation, following criterion shall be considered:
Three consecutive successful production batches shall be considered.
Minimum three consecutive batches shall be kept for stability study at
- Long Term Stability (25°C ± 2°C / 60% ± 5% RH) and
- Accelerated condition (40°C ± 2°C / 75% ± 5% RH).
Batches can be released, after the completion of prospective validation with consecutive three batches and the satisfactory compliance of minimum three months Accelerated stability data.
Concurrent Validation (CV): Concurrent validation shall be performed on processes of API for:
When data from replicate production runs are unavailable because only limited number of API batches have been produced, API batches are produced infrequently, API batches are produced by a validated process that has been modified for following changes e.g.
Vendor change for key starting material, Process changes that shall have no impact on the API quality, Change in in-put qty. of intermediates or raw materials proportionally with respect to validated process of API, Solvent qty. to be increased or decreased for purification of API, Modification in existing equipments.
Minimum one batch among of the selected batches for concurrent validation, shall be kept for stability study at Long Term Stability (25°C ± 2°C / 60% ± 5% RH).
Prior to completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.
Retrospective Validation (RV): Retrospective validation can be conducted based on the historical data of batches, for well established processes that have been used without significant changes to API quality due to:
Equipment changes
Changes in raw materials,
Systems changes
Facilities changes
For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches should be taken if the number of process run are less than the ten and it should be justified and documented.
Selected batches 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 number to demonstrate process consistency.
Appropriate in-process acceptance criteria and controls have been established.
There have not been significant process / product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability.
Impurity profiles have been established for the existing API.
Retain samples can be tested to obtain data to retrospectively validate the process.
Validation report shall be generated based on the activities performed according to the protocol, Recorded observations
Summary ( summarising the stability samples details, validation activity etc., Justification / Recommendation (for any deviation and / or for process improvement), Conclusion (for comment on approval or rejection of the process validation)
Periodic Review of Validation Systems: Process and system shall be periodically evaluated to verify that they are still operating in a valid manner and where no significant changes have been made to the system or process. The quality shall be evaluated based on the PQR (Product Quality Review) for API. The quality review should confirm that the process or system is consistently producing material, meeting its specifications. The quality review can conclude and recommend the need for revalidation.
The purpose of this SOP is to define the approach to be followed to establish documented evidence that a specific process will consistently produce a result meeting its predetermined specification and quality attributes.
Approaches to Process Validation: Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
There are three approaches to process validation.
Prospective Validation
Concurrent validation
Retrospective validation
Prospective Validation (PV): Prospective validation shall be performed on processes of API for new drug substance, new manufacturing process, new route of synthesis, change in manufacturing location, change of equipments (unlike equipments with respect to existing equipments), change in utilities, change in critical process parameters and change in final specification. Prospective validation should extend to those operations determined to be critical to the quality of the drug substance.
For prospective process validation, following criterion shall be considered:
Three consecutive successful production batches shall be considered.
Minimum three consecutive batches shall be kept for stability study at
- Long Term Stability (25°C ± 2°C / 60% ± 5% RH) and
- Accelerated condition (40°C ± 2°C / 75% ± 5% RH).
Batches can be released, after the completion of prospective validation with consecutive three batches and the satisfactory compliance of minimum three months Accelerated stability data.
Concurrent Validation (CV): Concurrent validation shall be performed on processes of API for:
When data from replicate production runs are unavailable because only limited number of API batches have been produced, API batches are produced infrequently, API batches are produced by a validated process that has been modified for following changes e.g.
Vendor change for key starting material, Process changes that shall have no impact on the API quality, Change in in-put qty. of intermediates or raw materials proportionally with respect to validated process of API, Solvent qty. to be increased or decreased for purification of API, Modification in existing equipments.
For concurrent process validation,
following criterion shall be considered
Three consecutive
successful production batches shall be selected.Minimum one batch among of the selected batches for concurrent validation, shall be kept for stability study at Long Term Stability (25°C ± 2°C / 60% ± 5% RH).
Prior to completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.
Retrospective Validation (RV): Retrospective validation can be conducted based on the historical data of batches, for well established processes that have been used without significant changes to API quality due to:
Equipment changes
Changes in raw materials,
Systems changes
Facilities changes
For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches should be taken if the number of process run are less than the ten and it should be justified and documented.
Selected batches 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 number to demonstrate process consistency.
For retrospective process
validation, following criterion shall be considered for the existing process:
Critical quality attributes
and critical process parameters have been identified.Appropriate in-process acceptance criteria and controls have been established.
There have not been significant process / product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability.
Impurity profiles have been established for the existing API.
Retain samples can be tested to obtain data to retrospectively validate the process.
Validation Documentation: A written validation
protocol should be established that specifies how validation of a particular
process will be conducted. The protocol should be reviewed and approved by the
quality unit (s) and other designated units. The validation protocol should
specify critical process steps and acceptance criteria as well as the type of
validation to be conducted (e.g. prospective, retrospective, concurrent) and
the number of process runs. A validation report that cross-references the
validation protocol should be prepared, summarising the results obtained,
commenting on any deviations observed and appropriate conclusion. Any
variations from the validation protocol should be documented with appropriate
justification.
Process Validation
Protocol: Process Validation Protocol shall consist of the
following points:
- Protocol Approval
- Overview
1.
Objective
2.
Purpose and Scope
3.
Role and Responsibility
4.
Validation
Team
- Process details of API.
1.
Process flow diagram of API and Intermediates stages
2.
Batch
Production and Control Records (BPCR) of API and Intermediates.
3.
Sampling
Plan for process validation.
4.
Critical
in-process parameters and specification
of API and Intermediates.
5.
Critical
process parameters in-process of API and
Intermediates stages.
6.
Solvent
usage details in process of API and Intermediates stages.
7.
Water
quality used in process of API and Intermediates stages.
8.
Specification
of API and Intermediates.
9.
Packing and Storage details of API.
- Equipment Details.
- Validation Procedure
- Acceptance Criteria
- Stability plan for
selected validation batches
- Revalidation Criteria
- Documentation
1.
Compilation (Format designs for the In-process,
Intermediate and the API for
exhibit batches)
2.
Summary Report (Summarising validation data)
3.
Conclusion and Approval (for observations,
justification, action and approval / rejection of the
Validation.)
Validation report shall be generated based on the activities performed according to the protocol, Recorded observations
Summary ( summarising the stability samples details, validation activity etc., Justification / Recommendation (for any deviation and / or for process improvement), Conclusion (for comment on approval or rejection of the process validation)
Periodic Review of Validation Systems: Process and system shall be periodically evaluated to verify that they are still operating in a valid manner and where no significant changes have been made to the system or process. The quality shall be evaluated based on the PQR (Product Quality Review) for API. The quality review should confirm that the process or system is consistently producing material, meeting its specifications. The quality review can conclude and recommend the need for revalidation.
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