Prior to the regulatory inspection, one of the first documents to be put under scrutiny is the validation document and the teams prepare by reviewing protocols, reports, qualification documents and summaries of validation. While this is necessary, it is not sufficient.
It is possible that despite having a complete collection of validation documents, the performance during the inspection may still be lower than expected if the documentation used is not current with the equipment, facility, process or any analytical system.
To be more precise, I would not consider a site ready for validation just based on the availability of required protocols and reports; I want the current validated condition to be confirmed.
This means reviewing what has changed since the time of validation, whether the changes were reviewed correctly, if the deviations were dealt with properly and whether the constant monitoring continues to confirm the conclusions achieved in the course of validation.
One simple question: is the VMP still valid for the plant?
Some plant additions, changes in equipment, processes changes, introduction of new products, modifications of utilities, electronic systems, changes in production organization can invalidate the old validation strategy.
VMP provides an overview of the validation program and its current state.
Specifically, the guidance of PIC/S includes recommendations on topics related to the VMP along with installation and operation qualification, non-sterile and cleaning validation, etc.
For this reason, a helpful readiness review should compare VMP with the actual facility instead of examining it independently.
A certain method may have been successfully validated years ago. However, since that time there could have been some changes including the installation of a new mixer, introduction of new software, replacement of a supplier of a key raw material, modification of a production parameter, or making changes in cleaning procedures.
What is important is not whether the initial validation was successful. Rather, the crucial question should be whether the latest changes influenced the validated status.
Going through the change controls concerning the validation documentation helps to find out certain loopholes that may otherwise go unnoticed.
For every major change it is necessary to look whether the organization checked:
The presented information then should be adequate regarding:
So, before the inspection, I would pay special attention to what happened after the process validation. In other words, if the process was said to be managed before, whether the site still manages it nowadays according to the recent data about production.
One of the common mistakes is identifying a validation deviation as formally closed but making only cursory determination regarding its value. For example, if the temperature was out of control during the qualification study, the report should not just say that said incident was of "minimal" value.
In order to be of relevance, there must be a written justification of finding that the event affected or did not affect the goals of the qualification or validation studies. During the inspection, it would be more troubling to have unsupported statements in the report compared to the original deviation.
In the case of equipment qualification process, the connection between URS → DQ (if applicable) → IQ → OQ → PQ → maintenance/calibration → changes → requalification should be assessed.
It should be noted that different qualification lifecycles apply to different systems and regulations. Utilities must be taken into account as well.
Take, for example, an elaborate qualification documentation system for a pharmaceutical water system. It should be understood, however, that an inspection may be concerned about the recent history of monitoring, sanitization, maintenance, sampling outcomes and any changes occurring after qualification processes.
Some products might have been previously chosen as worst case. In the meantime, the product line may have evolved. Before the inspection, verify if the information regarding the product wiped out earlier is still relevant today.
Pay attention to the following aspects:
A good site has to be able to describe not only how cleaning was validated but also explain – and reason – why the current validation is scientifically sound.
Aspects to consider include transfer of methods, modifications in procedures, instruments, reference materials, systems stability and recurring issues with analysis.
In case of any significant alteration to analytical procedures, the organization should describe the process of evaluation of the changes and whether additional verification was performed.
The same approach has to be applied to computerized laboratory systems. Changes to software used, interfaces, calculations, access and data flow have to be considered using appropriate validation methods.
Compare the current state of the facility and process with what has been stated during validation.
For example, a qualification report can show one equipment state while the current equipment has a modified part. Such modifications can be totally justified; however, the organization must be able to prove that they were sufficiently assessed.
"Can you show me when this process was put into practice for a validation?"
"What has changed since the original validation?"
"What was your method of evaluation concerning this change?"
"Do you have continued process verification records?"
"Why is this product chosen for cleaning validation worst case?"
"Can you show me the qualification status of this equipment?"
"What happened with the parameter that was not valid?"
"How did you determine whether the valid state is being kept or not?"
The most reliable answers are those supported by files and not just a word of mouth.
In the EU, the provisions of EudraLex Volume 4, Annex 15 cover qualification and validation in detail and are referred to by the European Commission as the guidance annex on qualification and validation.
ICH Q9(R1) covers quality risk management with respect to validation decisions, including risk-based assessments of changes and follow-up reviews.
ICH's quality guidelines also include Q8 on Pharmaceutical Development, Q9 on Quality Risk Management, Q10 on Pharmaceutical Quality System, Q12 on Lifecycle Management and other relevant quality guidance.
The process of readiness for validation prior to a regulatory audit is more than just gathering up documents. Rather, it is a question of whether the company can substantiate the fact that its operations are validated, justified on a scientific basis, qualified and under control.
The most effective way to prepare is to link the previous efforts on validation work to all the things that have taken place since then – changes, deviations, CAPA, monitoring, re-qualification, process performance and actual practice.
If asked why the process can be considered validated today, the answer should not be based on the report signed some time ago. The facility should be able to demonstrate by means of current evidence that the validated status of the process is maintained.
It is possible that despite having a complete collection of validation documents, the performance during the inspection may still be lower than expected if the documentation used is not current with the equipment, facility, process or any analytical system.
This means reviewing what has changed since the time of validation, whether the changes were reviewed correctly, if the deviations were dealt with properly and whether the constant monitoring continues to confirm the conclusions achieved in the course of validation.
Start With the Validation Master Plan
To begin the review of individual assessments, I will check the Validation Master Plan (VMP) of the site or its equivalent validation planning paper.One simple question: is the VMP still valid for the plant?
Some plant additions, changes in equipment, processes changes, introduction of new products, modifications of utilities, electronic systems, changes in production organization can invalidate the old validation strategy.
VMP provides an overview of the validation program and its current state.
Specifically, the guidance of PIC/S includes recommendations on topics related to the VMP along with installation and operation qualification, non-sterile and cleaning validation, etc.
For this reason, a helpful readiness review should compare VMP with the actual facility instead of examining it independently.
Review What Changed After Validation
This is a crucial element that I always look into prior to inspections.A certain method may have been successfully validated years ago. However, since that time there could have been some changes including the installation of a new mixer, introduction of new software, replacement of a supplier of a key raw material, modification of a production parameter, or making changes in cleaning procedures.
What is important is not whether the initial validation was successful. Rather, the crucial question should be whether the latest changes influenced the validated status.
Going through the change controls concerning the validation documentation helps to find out certain loopholes that may otherwise go unnoticed.
For every major change it is necessary to look whether the organization checked:
- Effect of the existing validation
- Need for additional qualification
- Necessity of revalidation
- Impact on regulatory submission
- Need for updating risk assessment
- Revising procedures
- Training needs
- Verification after implementation
Process Validation Should Tell a Consistent Story
Process validation is a field where inspectors often skip forward from one document to the next quite speedily. It is likely that validation protocols tell about important process conditions and acceptance criteria and subsequent reports show that the studies have been held as planned.The presented information then should be adequate regarding:
- Batch manufacturing records
- Process parameters
- Intermediate checks
- Continuous process control data
- Deviations
- Change control
- Product quality review
- Annual or periodic product observation
So, before the inspection, I would pay special attention to what happened after the process validation. In other words, if the process was said to be managed before, whether the site still manages it nowadays according to the recent data about production.
Check the Validation Deviations
A validation report that shows some deviations may not necessarily indicate an issue. Rather, it is important to investigate the manner in which the deviations were treated. In my assessment, I would determine whether the deviation had been recorded when it had occurred, assessed scientifically and evaluated for its possible implications on the outcome of the validation study.One of the common mistakes is identifying a validation deviation as formally closed but making only cursory determination regarding its value. For example, if the temperature was out of control during the qualification study, the report should not just say that said incident was of "minimal" value.
In order to be of relevance, there must be a written justification of finding that the event affected or did not affect the goals of the qualification or validation studies. During the inspection, it would be more troubling to have unsupported statements in the report compared to the original deviation.
Qualification of Equipment and Utilities
Readiness for validation involves considering not only process validation. Inspections would require an assessment of the continued qualification of any critical equipment and utilities.In the case of equipment qualification process, the connection between URS → DQ (if applicable) → IQ → OQ → PQ → maintenance/calibration → changes → requalification should be assessed.
It should be noted that different qualification lifecycles apply to different systems and regulations. Utilities must be taken into account as well.
Take, for example, an elaborate qualification documentation system for a pharmaceutical water system. It should be understood, however, that an inspection may be concerned about the recent history of monitoring, sanitization, maintenance, sampling outcomes and any changes occurring after qualification processes.
Cleaning Validation: Identify the Current Worst Case
Cleaning validation is another area where historical records may not be an accurate reflection of what is happening today.Some products might have been previously chosen as worst case. In the meantime, the product line may have evolved. Before the inspection, verify if the information regarding the product wiped out earlier is still relevant today.
Pay attention to the following aspects:
- Potency
- Toxic profiles
- Solubility
- Cleanability
- Batch size
- Train of the equipment
- Composition of the product
- Processes used
A good site has to be able to describe not only how cleaning was validated but also explain – and reason – why the current validation is scientifically sound.
Analytical Method Validation and Laboratory Systems
Verification is a part of the QC laboratory efforts. Analytical procedure verification documents are to be reviewed and confirmed to reflect the versions being used.Aspects to consider include transfer of methods, modifications in procedures, instruments, reference materials, systems stability and recurring issues with analysis.
In case of any significant alteration to analytical procedures, the organization should describe the process of evaluation of the changes and whether additional verification was performed.
The same approach has to be applied to computerized laboratory systems. Changes to software used, interfaces, calculations, access and data flow have to be considered using appropriate validation methods.
The Most Important Review: Current State vs Validated State
Before a regulatory audit, I would conduct an easy but useful task:Compare the current state of the facility and process with what has been stated during validation.
- Visit the production area.
- Examine the actual facility.
- Verify the current standard operating procedure.
- Examine the existing batch record.
- Compare the current equipment configuration with the qualification report.
- Check the existing deviations and modifications.
- Analyze the existing monitoring and monitoring trends.
For example, a qualification report can show one equipment state while the current equipment has a modified part. Such modifications can be totally justified; however, the organization must be able to prove that they were sufficiently assessed.
Practical Validation Readiness Checklist
In order for an inspection to take place, the recognition of the validation team and the QA is needed to ensure that:- The verification management plan is up-to-date and conformable to the current operational status of the facility
- The actual validation status of essential systems has been properly recorded
- The validation actions currently open have been monitored and managed
- Changes have been reviewed for their validation implications
- The re-qualification prerequisites have been detected and fulfilled if applicable
- Process validation is supported by appropriate process monitoring
- Validation deviations are scientifically justified
- Cleaning validation provides for up-to-date production and equipment correlational matrixes
- Utility qualifications comply with the current monitoring information
- The equipment qualification is actual
- Analytical methods are sufficiently verified to serve their purpose
- CAPAs relating to validation are closed out and their efficiency checked out
- The validation documentation is easily found
What Would an Inspector Ask?
Validation readiness can be much easier to assess when the team rehearses for "real-life" questions from the inspector. Examples of some questions that an inspector might ask include:"Can you show me when this process was put into practice for a validation?"
"What has changed since the original validation?"
"What was your method of evaluation concerning this change?"
"Do you have continued process verification records?"
"Why is this product chosen for cleaning validation worst case?"
"Can you show me the qualification status of this equipment?"
"What happened with the parameter that was not valid?"
"How did you determine whether the valid state is being kept or not?"
The most reliable answers are those supported by files and not just a word of mouth.
Regulatory Perspective
According to the FDA's process validation guidance, validation involves a lifecycle approach and includes process design, process qualification and ongoing process verification.In the EU, the provisions of EudraLex Volume 4, Annex 15 cover qualification and validation in detail and are referred to by the European Commission as the guidance annex on qualification and validation.
ICH Q9(R1) covers quality risk management with respect to validation decisions, including risk-based assessments of changes and follow-up reviews.
ICH's quality guidelines also include Q8 on Pharmaceutical Development, Q9 on Quality Risk Management, Q10 on Pharmaceutical Quality System, Q12 on Lifecycle Management and other relevant quality guidance.
The process of readiness for validation prior to a regulatory audit is more than just gathering up documents. Rather, it is a question of whether the company can substantiate the fact that its operations are validated, justified on a scientific basis, qualified and under control.
The most effective way to prepare is to link the previous efforts on validation work to all the things that have taken place since then – changes, deviations, CAPA, monitoring, re-qualification, process performance and actual practice.
If asked why the process can be considered validated today, the answer should not be based on the report signed some time ago. The facility should be able to demonstrate by means of current evidence that the validated status of the process is maintained.
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