A validation strategy refers to the methodology employed in the pharmaceutical industry to validate that their equipment, processes, utilities and cleaning methods are appropriate for certain purposes and under control during their entire life span. It answers such questions as what will be validated and why, what evidence is required, what guidelines and principles will be followed, etc.
Implementing an effective strategy is not merely compiling a list of actions as outlined in a validation master plan (VMP). It is connecting the entire knowledge in respect to the product and process, together with the concepts known in Quality Risk Management, qualification evaluations and validation tests.
Risk assessment determines the places where the evidence is the most crucial and the amount of qualification and validation work needed. For instance, if a product-contact mixer is changed, it could influence cleaning processes, mixing efficiency and consistency. Whereas changing a non-product-contact printer is not likely to influence validation.
The assessment must include the level of risk for patients, characteristics of the product, complexity of the process and what previous experience one has, equipment design, etc. The principles of ICH Q9(R1) provide the tools for implementing quality risk management throughout the entire pharmaceutical product life cycle.
A VMP may cover different areas of a facility including:
Common error consists in maintaining the VMP that only contains a list of equipment and procedures without taking into account the actual state of the facility. Retired equipment should be excluded, new systems included, overdue activities completed, changes made. The VMP should be treated as a properly controlled management document rather than as an inspection file.
Stage 1: Process Design: The process knowledge from the development and the scale-up processes are used to describe the commercial processes intended.
Stage 2: Process Qualification: The plant, equipment, utilities and manufacturing processes are analyzed to prove the process can deliver consistent commercial production.
Stage 3: Continued Process Verification: Regular production data is gathered for analysis in order to ensure that the process is under control.
Other validation processes must take into consideration other types of validations. Cleaning validation must consider scientifically supported acceptable limits of residue left over, the sample locations, the recovery issues and the methods of analysis. In the case of computerized system validation, the key points must include its intended use, functionality, level of risk and others. Utility qualification must rely on the type of evidence suitable for the utility’s application.
Some of the common terms like prospective and concurrent validation will also be found in various applicable guidelines and documents.
The preconditions may include available manuals of conduct, responsive devices, honorable instruments, proper operators, methods of analysis and available plans or drawings.
Sampling should represent the risks and variations being investigated. In particular, the sampling of process qualification should present various steps of the production cycle as well as necessary working circumstances. Cleaning validation should encompass the locations that are difficult to clean as well as the right way of sampling.
The rules of approval should have a scientific explanation concerning the need to carry out certain levels of approval. If the research fails to pass the approval, it needs to be investigated and analyzed for the consequences.
The assessment needs to answer if the change has an influence on validated assumptions, product quality, process capability and if additional qualification/validation is required. The necessary work may vary from providing documented justification without any testing to conducting focused studies or more extensive re-validation.
Deviations that occurred during the qualification/validation should also be assessed. One cannot say that the deviation that influenced the crucial parameter could be ignored just because the final result of the product complies with specification. One needs to investigate the referred data, possible influence on product quality and reliable reproducibility as well as whether the protocol is still adequate for reaching its tasks.
The ICH Q9(R1) states that risk-based approach should be utilized as soon as new data appears.
Depending on the task, relevant information can be represented by batch trends, deviations, out of specification/out of trend results, complaints, calibration failures, maintenance records, cleaning records, environment monitoring results, audit trails and effectiveness of corrective and preventive actions.
Review of the process from time to time will allow gathering enough evidence to see whether the assumptions of the validation are still valid. Re-qualification or re-validation needs to be done based on the requirements, past practices and risk assessment, but not on the assumption of conducting the same experiments in fixed time intervals.
For quality assurance professionals, the main question is whether there is enough proof that the current state of validation is still active. The inspector might ask how the company is aware of the fact that certain process has been kept under control for many years after the beginning of its qualification.
Finally, the quality of the strategy can be evaluated based on how good decisions it will produce. If the company is able to explain each action taken, meaning the reasoning behind it and proving it with enough evidence, the validation process will be a key component of the quality system instead of just a set of completed reports.
Build the Strategy Around Product and Process Risk
In creating a strategy, it is important to understand the product, production method and failure processes. In so doing, the validation team will establish critical quality characteristics, critical production parameters, attributes of the materials, equipment functionality and system control that may affect product quality.Risk assessment determines the places where the evidence is the most crucial and the amount of qualification and validation work needed. For instance, if a product-contact mixer is changed, it could influence cleaning processes, mixing efficiency and consistency. Whereas changing a non-product-contact printer is not likely to influence validation.
The assessment must include the level of risk for patients, characteristics of the product, complexity of the process and what previous experience one has, equipment design, etc. The principles of ICH Q9(R1) provide the tools for implementing quality risk management throughout the entire pharmaceutical product life cycle.
Transform the Strategy into a Validation Master Plan
A Validation Master Plan (VMP) gives the overall context of qualification and validation within a facility. It should explain the site's plan regarding responsibilities, priorities and the current status of validation.A VMP may cover different areas of a facility including:
- Facilities and utilities including HVAC, pharmaceutical water
- Manufacturing and packing equipment
- Process validation and continued processing verification
- Cleaning validation
- Validation and verification of analytical methods
- Sterilization and aseptic processing validation, where relevant
- Computerized systems and automation
- Transport and time studies
Common error consists in maintaining the VMP that only contains a list of equipment and procedures without taking into account the actual state of the facility. Retired equipment should be excluded, new systems included, overdue activities completed, changes made. The VMP should be treated as a properly controlled management document rather than as an inspection file.
Selecting the Right Validation Approach
The method that is selected must keep in mind the validity of the subject matter and the method being employed to prove it. The FDA’s lifecycle model has three stages for process validation:Stage 1: Process Design: The process knowledge from the development and the scale-up processes are used to describe the commercial processes intended.
Stage 2: Process Qualification: The plant, equipment, utilities and manufacturing processes are analyzed to prove the process can deliver consistent commercial production.
Stage 3: Continued Process Verification: Regular production data is gathered for analysis in order to ensure that the process is under control.
Other validation processes must take into consideration other types of validations. Cleaning validation must consider scientifically supported acceptable limits of residue left over, the sample locations, the recovery issues and the methods of analysis. In the case of computerized system validation, the key points must include its intended use, functionality, level of risk and others. Utility qualification must rely on the type of evidence suitable for the utility’s application.
Some of the common terms like prospective and concurrent validation will also be found in various applicable guidelines and documents.
Establish the Evidence Before Execution
A proper validity strategy determines what proof will be collected prior to starting to work. Accepted procedures should point out the extent of the assessment, obligations, preconditions, instruments of testing, schemes of sampling and the rules of approval as well as reporting.The preconditions may include available manuals of conduct, responsive devices, honorable instruments, proper operators, methods of analysis and available plans or drawings.
Sampling should represent the risks and variations being investigated. In particular, the sampling of process qualification should present various steps of the production cycle as well as necessary working circumstances. Cleaning validation should encompass the locations that are difficult to clean as well as the right way of sampling.
The rules of approval should have a scientific explanation concerning the need to carry out certain levels of approval. If the research fails to pass the approval, it needs to be investigated and analyzed for the consequences.
Keep Changes and Deviations Connected to Validation
The validation status may be questioned due to events that have happened after the initial study. Thus, changes to the formula, raw materials, equipment, software, manufacturing parameters, premises and cleaning procedures should undergo change control assessment.The assessment needs to answer if the change has an influence on validated assumptions, product quality, process capability and if additional qualification/validation is required. The necessary work may vary from providing documented justification without any testing to conducting focused studies or more extensive re-validation.
Deviations that occurred during the qualification/validation should also be assessed. One cannot say that the deviation that influenced the crucial parameter could be ignored just because the final result of the product complies with specification. One needs to investigate the referred data, possible influence on product quality and reliable reproducibility as well as whether the protocol is still adequate for reaching its tasks.
The ICH Q9(R1) states that risk-based approach should be utilized as soon as new data appears.
Maintain the Validated State After Approval
The validation report signifies the start of new strategy. Continuous monitoring should be performed to ensure meaningful change in process efficiency and stability of the system.Depending on the task, relevant information can be represented by batch trends, deviations, out of specification/out of trend results, complaints, calibration failures, maintenance records, cleaning records, environment monitoring results, audit trails and effectiveness of corrective and preventive actions.
Review of the process from time to time will allow gathering enough evidence to see whether the assumptions of the validation are still valid. Re-qualification or re-validation needs to be done based on the requirements, past practices and risk assessment, but not on the assumption of conducting the same experiments in fixed time intervals.
For quality assurance professionals, the main question is whether there is enough proof that the current state of validation is still active. The inspector might ask how the company is aware of the fact that certain process has been kept under control for many years after the beginning of its qualification.
What Elements are Required for a Good Strategy?
A solid strategy connects together the VMP, risk assessments, qualifications documents, validation SOPs, reports, change controls and monitoring. It means that all of these documents must tell the same story as far as the risk identification, control demonstration and the process of control maintaining.Finally, the quality of the strategy can be evaluated based on how good decisions it will produce. If the company is able to explain each action taken, meaning the reasoning behind it and proving it with enough evidence, the validation process will be a key component of the quality system instead of just a set of completed reports.
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