The periodic review is an essential part of a suitable Pharmaceutical Quality System. It allows examining the ongoing processes and understanding if a process, equipment, system, document or validated system still performs according to the requirements.
In pharmaceutical production, problems arise not as a result of one major malfunction but are developed over time through continuous failures, maintenance issues, calibration problems, OOS results, process trends or repeated corrective actions. The periodic review combines numerous pieces of information into evidence suitable for evaluation of the systems or processes and their performance.
Well-organized periodic review is not just a formality but rather a management technique that allows evaluating quality deterioration, assessing control and taking required measures to strengthen control.
Depending on the subject of the review, the assessment could include:
Regular reviews can identify:
For important pieces of equipment, the focus of the review can be on:
1. Testing outcome: To check if the equipment has always complied with the requirements of testing.
2. Maintenance record: To analyze the instances of breakdowns, corrective maintenance, repairs and malfunctions of equipment.
3. Deviations: To find out if it is possible to record deviations related to equipment operation.
4. Changes: To trace all modifications of the equipment or its software, operating conditions or procedures operated with these pieces of equipment.
5. Qualification status: To check whether qualification is still valid and if all the necessary corrections are made in this field.
6. Performance indicators: To look for signs of deterioration of equipment performance.
In the case of a review for processes, it is more likely for the process to emphasize performance of a batch, process capability, deviations, OOS results, yield trends, complaints and the data on continuous process verification.
In particular, the evaluator must seek answers to the following questions:
The review includes:
For example, if the same component has experienced three minor failures, it can indicate the problem with the system as a whole.
A review may record:
However, there is a major issue in that merely confirming that records were reviewed does not mean they were actually analyzed. Stronger reviews describe what information indicates.
For example,
“During the review period, calibration was done four times. All the instruments were in compliance with the acceptance criteria with no observed trend. There was no effect on the quality of the product.”
This conclusion is much better than just saying that “calibration was reviewed.”
Factors affecting frequency includes:
- Importance
- Requirements
- Past performance
- Number of changes
- Effect of product
- Complexity of systems
- History of failures
The review of important computer systems should be different from that of systems with low risks. The organization should determine the frequency using written procedures.
Various helpful techniques include:
However, how the information is interpreted determines its usefulness. Collecting documents and filing them does not give the same level of assurance as an evaluation of the trends, risk assessment and verification that any previous problems have been sufficiently addressed.
The key periodic review should provide answers to three questions:
Well-organized periodic review is not just a formality but rather a management technique that allows evaluating quality deterioration, assessing control and taking required measures to strengthen control.
What is a periodic review?
A periodic review is a documented assessment done at predetermined intervals to establish whether a system, process, equipment, documentation or another GMP element is still fit for its intended use.Depending on the subject of the review, the assessment could include:
- Deviations
- CAPA
- Change control
- Out of Specification (OOS) and Out of Trend (OOT) results
- Complaints
- Calibration history
- Preventive maintenance
- Environmental monitoring
- Validation state
- Audit findings
- Regulatory changes
- Previous review outcomes
- Performance trends
Why Regular Reviews are Necessary
The main aim is to identify decline or potential risk. An apparatus is capable to keep functioning effectively but at the same time is starting the process of losing the original control system.Regular reviews can identify:
- High number of equipment malfunctions
- Continuing deviations
- Grown maintenance need
- Process fluctuation
- Obsolete procedures
- Poor control
- Gaps in validation
- Frequent laboratory failures
- Ongoing CAPA effectiveness problem
What Should be Included in the Review?
The review shall be based on the established procedure or review plan.For important pieces of equipment, the focus of the review can be on:
1. Testing outcome: To check if the equipment has always complied with the requirements of testing.
2. Maintenance record: To analyze the instances of breakdowns, corrective maintenance, repairs and malfunctions of equipment.
3. Deviations: To find out if it is possible to record deviations related to equipment operation.
4. Changes: To trace all modifications of the equipment or its software, operating conditions or procedures operated with these pieces of equipment.
5. Qualification status: To check whether qualification is still valid and if all the necessary corrections are made in this field.
6. Performance indicators: To look for signs of deterioration of equipment performance.
In the case of a review for processes, it is more likely for the process to emphasize performance of a batch, process capability, deviations, OOS results, yield trends, complaints and the data on continuous process verification.
Periodic Review of Documents
It is necessary to carry out periodical assessment of all GMP documents. However, the evaluation should not only check whether any given document has reached its review date but rather whether the content remains relevant.In particular, the evaluator must seek answers to the following questions:
- Did the process change?
- Did equipment change?
- Did the regulations change?
- Did the deviations indicate deficiencies?
- Did the audit confirm the deficiencies?
- Are the instructions still correct?
- Does the procedure comply with factual actions?
Periodic Review of Validated Systems
Validation-performed regular reviews are very significant for computer and critical GMP systems.The review includes:
- Modifications on the system
- Incidents
- Deviation
- Changes in access control
- Audit trail concerns
- Backup recovery and performance
- Events related to security
- Management of users
- System upgrades
- The state of being validated
How to Conduct an Effective Review
An effective review can be carried out in simply a few steps as follows:1. Determine the Time Frame of Review
It should be specified beforehand what period will be analyzed, e.g., past year.2. Gather Required Information
Collect all quality and operational data relevant to the process/system.3. Analyze Patterns
It is not sufficient to merely enumerate events. It is important to look for the patterns.For example, if the same component has experienced three minor failures, it can indicate the problem with the system as a whole.
4. Evaluate Risks
It should be decided whether observed trends may have impact on the quality of products, safety, data integrity, of regulatory compliance.5. Define Actions
In case any weaknesses have been uncovered proper actions should be identified, e.g. corrective and preventive actions, preventive maintenance, retraining, change control, requalification or document changes.6. Confirm the Review
The final assessment should be verified and approved by the authorized personnel.Periodic Review Should not Become a Checklist
The periodic review should not simply be perceived as a checklist task.A review may record:
- Deviations reviewed
- CAPA reviewed
- Changes reviewed
- Calibration reviewed
However, there is a major issue in that merely confirming that records were reviewed does not mean they were actually analyzed. Stronger reviews describe what information indicates.
For example,
“During the review period, calibration was done four times. All the instruments were in compliance with the acceptance criteria with no observed trend. There was no effect on the quality of the product.”
This conclusion is much better than just saying that “calibration was reviewed.”
Frequency of Periodic Review
This paragraph talks about how often periodic reviews should happen.Factors affecting frequency includes:
- Importance
- Requirements
- Past performance
- Number of changes
- Effect of product
- Complexity of systems
- History of failures
The review of important computer systems should be different from that of systems with low risks. The organization should determine the frequency using written procedures.
Common Periodic Review Deficiencies
Common weaknesses identified in audits include:- Reviews done late
- The criteria for reviews not stated clearly
- Definition of trends not conducted in sufficient depth
- Lack of supporting evidence for conclusions
- Issues that have been noted repeatedly with no small errors in the past
- No assessment of efficacy of corrective actions
- Allows to use regulatory changes not being assessed
- Using practices providing insufficient expertise in reviews
- The assessment not being confirmed by data
- Periodic review that is mere formality
Making Periodic Reviews More Valuable
Organizations can make their review systems better by linking the review system to the Pharmaceutical Quality System.Various helpful techniques include:
- Adopting risk-oriented review criteria.
- Analyzing and monitoring trends rather than just reporting specific events.
- Reviewing current performance in previous review periods.
- Recognizing common weaknesses.
- Linking key results to CAPA or to the change control system.
- Reviewing findings of past activities.
- Formulating unambiguous conclusions.
- Reporting significant information to the management.
However, how the information is interpreted determines its usefulness. Collecting documents and filing them does not give the same level of assurance as an evaluation of the trends, risk assessment and verification that any previous problems have been sufficiently addressed.
The key periodic review should provide answers to three questions:
- What happened during the review period?
- How do the trends look?
- Is there anything that needs to be done?
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