The cleaning validation report must not stop at declaring equipment cleaned. It must also show a crystal clear, traceable and scientifically validated account of whether the validated cleaning process met its intended purpose.
Often, weaknesses in cleaning validation originate not from cleaning itself, but arise in the course of analysis of the final report. Missing raw data, ambiguous acceptance criteria and unexplained deviations as well as poorly justified sampling, insufficient recovery data, and conclusions that are lacking support make it difficult to defend an otherwise successful study.
Acknowledging these usual mistakes in cleaning validation reports is therefore essential for QA examination and readiness for inspection.
A report should state clearly what equipment or equipment train was evaluated, what cleaning process was validated, which residues were taken into account, and what predetermined acceptance criteria were determined.
A vague statement like "the cleaning procedure was found to be satisfactory" does not give enough context.
The USDA's cleaning validation inspection guidance stresses that the purpose of validation must be established and that scientific data have to show that the cleaning system is able to achieve the results expected from it.
The report should give the reviewer an idea of how the acceptance criteria were established and whether the analytical method in use is scientifically justifiable to determine residues at the established limit.
The report should make use of different types of residues if applicable (i.e. active pharmaceutical ingredients, cleaning agents, degradation products, other forms of contaminants).
FDA suggests that residue limits should be meaningful and scientifically supported, in addition to being achievable and verifiable from a practical point of view.
If the report indicates acceptance limits without making a proper connection to the underlying rationale, it creates a gap in information.
This is especially problematic in the case of hard-to-clean areas.
Ideally, the relevant texts should show the logical connections among equipment design, cleaning procedures, and sampling points.
This may include:
Thus, these reports must show that sampling has a scientific meaning rather than being just convenient.
The particular testing process must be performed using an adequate method that should be capable of detecting the compound.
In instances when recovery tests are performed, the full report has to describe the recovery method, type and amount of obtained samples, concentration levels, and obtained results.
It is of special importance when the analytical value is close to the borderline.
The FDA states that recovery tests should be conducted on relevant equipment and the extraction methods should be appropriate.
I always make sure whether the report considers "not detected" equal to "no compound."
Rinse solvent has to have the ability to collect the residues of interest and sampling method should provide sufficient coverage of the equipment being sampled.
cGMP equipment guidance provided by FDA states that use of rinse samples alone may not be sufficient where direct surface sampling is possible and enforces the idea of scientifically sound sampling and analytical techniques.
A report must state the connection between rinse sampling, equipment access, residue solubility, and validation goal.
That is not enough.
A report must indicate what happened, what validation activity was disrupted, what were the results of the investigation conducted, and whether the deviation influenced the meaning of the cleaning study.
For example, if an invalid cleaning hold duration, was applied during a validation run, the report should not state just the fact of deviation but should also explain the reasons for deviation occurrence, if the utilized parameter was a validated one or at least a worst-case condition, and whether further testing was meaningful from the scientific point of view.
So a deviation must be correlated with the final conclusion of validation.
The original pieces of evidence are necessary for validation.
The FDA's guideline for cleaning validation asserts a clear prohibition of repeating tests and checks until the agreed level of contamination is met. In particular, it points out that repeating tests may indicate that the cleaning process, in itself, is not validated.
Where additional tests have a scientific basis, the report should include sufficient information on the conduct of repeated tests and account for the ending of the tests carried out for the first time.
The quality assurance personnel should be able to reconcile the reported results back to the sample number, lab results, raw data, computation, location of sampling, and relevant acceptance criteria.
The report will not be complete if the summary table is not capable of being reconciled back to the original laboratory and validation records.
For electronically-based systems, data integrity must also take into account the relevant electronic records and audit-trail information where applicable.
In this way, the conclusion should reflect the results obtained from the validation study.
For instance, the correct conclusion can state that the cleaning process allows obtaining the amount of residues lower than the indicated acceptable threshold.
There should not be any excess of the conclusions in respect of what the study can actually confirm.
If CAPA is necessary, the report must indicate the link to the related quality system record.
Also, the cleaning validation program must match the actual equipment being used and the process conditions. According to the FDA’s Q7A guidance, cleaning validation must demonstrate the real patterns of equipment usage and impact such characteristics of the residue as its solubility, ease of cleaning, potency, toxicity, and stability.
The majority of errors encountered include the use of inappropriate acceptance criteria, weak justifications of the sampling of the study, lack of information regarding recoveries, changes that were not explained, deficiency of traceability of the data, or conclusions that go further than the collected facts.
Hence, the QA audit has to check the results of the research not only for their success but for scientific coherence of the cleaning validation.
Acknowledging these usual mistakes in cleaning validation reports is therefore essential for QA examination and readiness for inspection.
The Report does not Clearly Establish the Validation Objective
When reviewing a cleaning validation report, the first thing I check is whether the objective is stated in relation to the cleaning process being validated.A report should state clearly what equipment or equipment train was evaluated, what cleaning process was validated, which residues were taken into account, and what predetermined acceptance criteria were determined.
A vague statement like "the cleaning procedure was found to be satisfactory" does not give enough context.
The USDA's cleaning validation inspection guidance stresses that the purpose of validation must be established and that scientific data have to show that the cleaning system is able to achieve the results expected from it.
Acceptance Limits are Reported without Adequate Rationale
There is also the common problem of presenting acceptance limits simply as fixed values without proper scientific justification behind the given limit values.The report should give the reviewer an idea of how the acceptance criteria were established and whether the analytical method in use is scientifically justifiable to determine residues at the established limit.
The report should make use of different types of residues if applicable (i.e. active pharmaceutical ingredients, cleaning agents, degradation products, other forms of contaminants).
FDA suggests that residue limits should be meaningful and scientifically supported, in addition to being achievable and verifiable from a practical point of view.
If the report indicates acceptance limits without making a proper connection to the underlying rationale, it creates a gap in information.
Sampling Locations are not Properly Justified
Some cleaning validation reports include a lot of sampling results but don’t explain fully why some locations were selected.This is especially problematic in the case of hard-to-clean areas.
Ideally, the relevant texts should show the logical connections among equipment design, cleaning procedures, and sampling points.
This may include:
- Corners and joints of the equipment
- Gaskets and seals
- Spray ball shadow areas
- Valves
- Transfer pipes
- Discharge areas
- Product contact surfaces with limited access
Thus, these reports must show that sampling has a scientific meaning rather than being just convenient.
Swab Recovery Data is Missing or Poorly Explained
When swabs yield negative results, it does not necessarily mean that no compound remains.The particular testing process must be performed using an adequate method that should be capable of detecting the compound.
In instances when recovery tests are performed, the full report has to describe the recovery method, type and amount of obtained samples, concentration levels, and obtained results.
It is of special importance when the analytical value is close to the borderline.
The FDA states that recovery tests should be conducted on relevant equipment and the extraction methods should be appropriate.
I always make sure whether the report considers "not detected" equal to "no compound."
Rinse Sampling is Used Without Demonstrating its Suitability
Rinse sampling has its benefits, particularly with difficult to reach and large equipment; however, it has to be shown in the report why the rinsing method is appropriate.Rinse solvent has to have the ability to collect the residues of interest and sampling method should provide sufficient coverage of the equipment being sampled.
cGMP equipment guidance provided by FDA states that use of rinse samples alone may not be sufficient where direct surface sampling is possible and enforces the idea of scientifically sound sampling and analytical techniques.
A report must state the connection between rinse sampling, equipment access, residue solubility, and validation goal.
Deviations are Mentioned but Their Impact is not Assessed
In a validation report, one could find the wording: “one deviation occurred during the execution process,” but the consequences of this occurrence are not disclosed.That is not enough.
A report must indicate what happened, what validation activity was disrupted, what were the results of the investigation conducted, and whether the deviation influenced the meaning of the cleaning study.
For example, if an invalid cleaning hold duration, was applied during a validation run, the report should not state just the fact of deviation but should also explain the reasons for deviation occurrence, if the utilized parameter was a validated one or at least a worst-case condition, and whether further testing was meaningful from the scientific point of view.
So a deviation must be correlated with the final conclusion of validation.
"Test Until Clean" is Allowed to Influence the Conclusion
A grave mistake occurs when successive tests are run on a device until a satisfactory conclusion is reached and announcing the success, while at the same time the earlier bad tests are barely mentioned.The original pieces of evidence are necessary for validation.
The FDA's guideline for cleaning validation asserts a clear prohibition of repeating tests and checks until the agreed level of contamination is met. In particular, it points out that repeating tests may indicate that the cleaning process, in itself, is not validated.
Where additional tests have a scientific basis, the report should include sufficient information on the conduct of repeated tests and account for the ending of the tests carried out for the first time.
The Report does not Reconcile Raw Data with the Final Results
The final document must be based on the following protocols and supporting documents.The quality assurance personnel should be able to reconcile the reported results back to the sample number, lab results, raw data, computation, location of sampling, and relevant acceptance criteria.
The report will not be complete if the summary table is not capable of being reconciled back to the original laboratory and validation records.
For electronically-based systems, data integrity must also take into account the relevant electronic records and audit-trail information where applicable.
The Conclusion is Stronger Than the Evidence
An error in writing a report can be appearing absolute when it says, “the equipment is totally uncontaminated,” while the tests indicate that the amount of the residues is lower than the limit set beforehand.In this way, the conclusion should reflect the results obtained from the validation study.
For instance, the correct conclusion can state that the cleaning process allows obtaining the amount of residues lower than the indicated acceptable threshold.
There should not be any excess of the conclusions in respect of what the study can actually confirm.
CAPA and Follow-Up Actions are not Connected to the Findings
If the validation study has determined the problem in the form of a procedural gap, sampling issue, equipment problem, or operator mistake, the report must indicate clearly the way the problem has been solved.If CAPA is necessary, the report must indicate the link to the related quality system record.
Also, the cleaning validation program must match the actual equipment being used and the process conditions. According to the FDA’s Q7A guidance, cleaning validation must demonstrate the real patterns of equipment usage and impact such characteristics of the residue as its solubility, ease of cleaning, potency, toxicity, and stability.
A Practical QA Review Before Approval
Before approving the cleaning validation report, the QA representative must have knowledge of the following:- Was the protocol approved prior to actual execution?
- Were the deviations explained?
- Are the limits of acceptance scientifically proved?
- Are the sampling sites chosen correctly?
- Is there enough material for working on recovery?
- Are the analytical techniques sensitive enough?
- Are the results traceable back to the original data?
- Were the unexpected results dealt with in a transparent manner?
- Does the summary reflect the actual results?
- Are corrective actions mandatory?
The majority of errors encountered include the use of inappropriate acceptance criteria, weak justifications of the sampling of the study, lack of information regarding recoveries, changes that were not explained, deficiency of traceability of the data, or conclusions that go further than the collected facts.
Hence, the QA audit has to check the results of the research not only for their success but for scientific coherence of the cleaning validation.
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