The validation process does not guarantee the continued qualification of pharmaceutical equipment, systems, cleaning methods, or processes. Change in conditions of manufacture, modifications of equipment, occurrences of deviations, emergence of analytical trends and newly acquired process information may all affect the qualification status.
Validation Periodic Review is a proper method of analyzing whether the original validation status is valid based on science and good manufacturing practices.
A review is not meant to confirm that the validation report is available or the predetermined date for the review has come. It should look at all documentation and determine if the validated status is still valid.
Do the gathered data indicate that the validated process or system meets the original specifications in current operating conditions?
Regular reviews mean considering more than previously-established validation protocol. In manufacturing processes, data about operations, non-conformities, Out-of-Specification or Out-of-Trend results, complaints, change control, equipment history, maintenance, calibration, cleaning results and any other information related to the quality of the process should be taken into consideration.
According to FDA guidance, the third stage of validation process is called "Continued Process Verification" and implies ongoing providing of evidence that the process is still under control during its commercial use. It is also stressed that process and product data have to be collected and analyzed in order to identify any undesired variability.
This means that routine validation reviews should take place as a part of the overall life-cycle approach, instead of being conducted as an isolated annual procedure.
The reviewer is supposed to find out what exactly was validated originally and then compare it with the current process in operation.
This includes the following:
For example, granulation may have been validated under certain equipment design, apparatus and conditions. If some modifications to the equipment, software and formulations occurred, the periodic review has to verify whether any of those changes have been passed through validation impact assessment process.
At minimum, the review must take into account the following:
According to ICH Q9(R1), quality risk management is a process of life cycle, which comprises risk review and use of new information and experience. Specifically, it identifies product reviews, inspections, audits, change controls and failures investigations among the events that are the source of information that may need to reconsider previously made risk-related decisions.
The conclusion must be based on the data and risks of the respective system/process. The possible outcomes based on what was discovered may include:
As an example, if a validated HVAC system has remained within the defined range of functioning conditions and calibration/maintenance is updated and environmental monitoring data remains within required limits/standards and situation did not change significantly, it is valid to state that the system can maintain validated status. In contrast, numerous deviations, major modifications of devices or significant changes to the organization of the space may justify additional qualification or validation procedures.
EU GMP annex 15 defines both qualification and validation as processes during the production cycle. The European Commission lists Annex 15 as the appropriate EU GMP regulation guiding qualification and validation procedures.
The report must describe the system or process which is reviewed, the date of review, the original validation or qualification reference, the changes and important quality events that happened during the period, trends that were observed, risk assessments that were done and reasoning behind the conclusion of the report.
It is very important to pay attention to the places that do not have an explanation. For instance, the statement "no important changes took place" should be proven by actual evidence of review carried out by the relevant department.
Also, the statement "no deviations affected validation" must contain references to all deviations and impact assessments done.
Based on the conclusion it should be possible to answer whether the validated status has been demonstrated by objective evidence and if not, it should be stated which actions must be taken.
"How do you check whether the above process continues to be validated?"
One should not only rely on the original validation report for the answer.
It must be demonstrated by the organization how evidence has been gathered from the original validation through to production, including: changes, deviations, process monitoring, maintenance and calibration, investigations, CAPA and audits.
The lifecycle approach used by the FDA also stresses the importance of continual monitoring of the process performance and product quality after the validation is completed.
It is here that weak periodic review systems become apparent. Despite the company having collected years of quality data, how it was used compared to the valid state will be hard to defend.
The best reviews are the ones that point out possible new risks before they evolve into validation problems.
When I analyze such an exercise, I focus on three key questions:
1. What has changed since validation?
2. How do we know the process/system keeps performing well?
3. How do we know that the initial assumptions have been in place?
The answers to these questions backed by traceable data make periodic reviews much more than simply ‘updating a document’.
A review is not meant to confirm that the validation report is available or the predetermined date for the review has come. It should look at all documentation and determine if the validated status is still valid.
What Should be Included in a Regular Validation Review?
A routine validation review should provide a constant and simple answer to the following question:Do the gathered data indicate that the validated process or system meets the original specifications in current operating conditions?
Regular reviews mean considering more than previously-established validation protocol. In manufacturing processes, data about operations, non-conformities, Out-of-Specification or Out-of-Trend results, complaints, change control, equipment history, maintenance, calibration, cleaning results and any other information related to the quality of the process should be taken into consideration.
According to FDA guidance, the third stage of validation process is called "Continued Process Verification" and implies ongoing providing of evidence that the process is still under control during its commercial use. It is also stressed that process and product data have to be collected and analyzed in order to identify any undesired variability.
This means that routine validation reviews should take place as a part of the overall life-cycle approach, instead of being conducted as an isolated annual procedure.
Start With the Current Validated State
My first point of concern is whether the assessment is performed based on the existing situation, or only the contents of the original validation report were copied.The reviewer is supposed to find out what exactly was validated originally and then compare it with the current process in operation.
This includes the following:
- Current production equipment and configuration
- Current operating conditions and ranges
- Current batch volumes and scales
- Current materials and their suppliers
- Current analytic methods
- Current cleaning methods
- Current utilities and facilities
- Current computerized systems
For example, granulation may have been validated under certain equipment design, apparatus and conditions. If some modifications to the equipment, software and formulations occurred, the periodic review has to verify whether any of those changes have been passed through validation impact assessment process.
Review the Events That Could Challenge Validation Status
One should be able to conduct smart periodic reviews relying on information and scientific evidences. The assessment will not be deemed over until the reviewer analyses the quality events which can threaten validated status.At minimum, the review must take into account the following:
1. Change Controls
The adjustments related to equipment, utilities, premises, process conditions, formulations, trash materials, analytical methods or cleaning procedures need to be assessed regarding their influence on validation.2. Deviations and Investigations
The repeated instances of nonconformances may show that the process is not producing the results that it was supposed to do. Even one incident of nonconformance may lead to assessment of validation, if it touches upon critical control or parameter.3. OOS, OOT and Process Trends
Achieving quality specifications does not mean that the process is successful now and in the future. In fact, trends in critical quality characteristics and process parameters may give the first signs of loss of quality.4. Maintenance and Calibration History
Frequent breakdowns, repeated corrective maintenance, or calibration failures may be a sign that the performance of the equipment requires more detailed analysis.5. Complaints and Product Quality Issues
It is important to analyze relevant complaints, rejects, recalls, as well as adverse trends in quality in order to find possible links with the validated process or system.6. Previous CAPA
It is the duty of the reviewer to check the effectiveness of validation-related CAPA as well as to verify if the problems recur because the first corrective action had not eliminated the base problem.According to ICH Q9(R1), quality risk management is a process of life cycle, which comprises risk review and use of new information and experience. Specifically, it identifies product reviews, inspections, audits, change controls and failures investigations among the events that are the source of information that may need to reconsider previously made risk-related decisions.
Do Not Treat Every Review as Automatic Revalidation
It is not uncommon to assume that every scheduled review would require the completion of a complete revalidation exercise.The conclusion must be based on the data and risks of the respective system/process. The possible outcomes based on what was discovered may include:
- Validation is still acceptable
- Further monitoring is required
- Further qualification/validation study is needed
- Requalification is required
- Partial revalidation is adequate
- Entire investigation or CAPA is required
As an example, if a validated HVAC system has remained within the defined range of functioning conditions and calibration/maintenance is updated and environmental monitoring data remains within required limits/standards and situation did not change significantly, it is valid to state that the system can maintain validated status. In contrast, numerous deviations, major modifications of devices or significant changes to the organization of the space may justify additional qualification or validation procedures.
EU GMP annex 15 defines both qualification and validation as processes during the production cycle. The European Commission lists Annex 15 as the appropriate EU GMP regulation guiding qualification and validation procedures.
What QA Should Look for in the Review Report
An effective quality assurance review report should include information that makes content easy to read and interpret.The report must describe the system or process which is reviewed, the date of review, the original validation or qualification reference, the changes and important quality events that happened during the period, trends that were observed, risk assessments that were done and reasoning behind the conclusion of the report.
It is very important to pay attention to the places that do not have an explanation. For instance, the statement "no important changes took place" should be proven by actual evidence of review carried out by the relevant department.
Also, the statement "no deviations affected validation" must contain references to all deviations and impact assessments done.
Based on the conclusion it should be possible to answer whether the validated status has been demonstrated by objective evidence and if not, it should be stated which actions must be taken.
A Question that Must Be Prepared For
At an inspection, an inspector might ask:"How do you check whether the above process continues to be validated?"
One should not only rely on the original validation report for the answer.
It must be demonstrated by the organization how evidence has been gathered from the original validation through to production, including: changes, deviations, process monitoring, maintenance and calibration, investigations, CAPA and audits.
The lifecycle approach used by the FDA also stresses the importance of continual monitoring of the process performance and product quality after the validation is completed.
It is here that weak periodic review systems become apparent. Despite the company having collected years of quality data, how it was used compared to the valid state will be hard to defend.
Make the Review a Decision-Making Tool
An effective Validation Periodic Review must engage more than just meeting compliance requirements. It must collect data that is usually scattered across an array of departments, from QA and QC to manufacturing, engineering and validation, maintenance and regulatory departments.The best reviews are the ones that point out possible new risks before they evolve into validation problems.
When I analyze such an exercise, I focus on three key questions:
1. What has changed since validation?
2. How do we know the process/system keeps performing well?
3. How do we know that the initial assumptions have been in place?
The answers to these questions backed by traceable data make periodic reviews much more than simply ‘updating a document’.
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