Documenting what you are doing as part of change control for cleaning validation is critical to ensure compliance with USA 21 CFR Part 211 and EU Annex 15 as well as to help make sure that internal implementers of the change control properly follow through so that things are done correctly. This may apply to changes in a cleaning process, changes in the validation program, changes in how validation protocols are designed, and to changes in how regular monitoring/verification is performed. It applies to both planned changes and unplanned changes.
While the approach given in this Memo is one way to address change control, it is not the only way. Basically the approach discussed here includes these main elements.
A detailed description of what elements of the cleaning program are being changed.
A detailed description of what specific parameters) are being made to that element of the cleaning program.
A discussion of the reason(s) for the change.
A discussion of how those changes might affect the validation status of the cleaning process. Include any scientific principles or rationales as to why or why not any changes in outcomes might arise upon implementation of the change.
A discussion of what outcomes should be measured to help ensure maintenance of the validation status.
If laboratory studies or scale-up studies have been done, refer to those studies and their conclusions. Any change in analytical methods should be specified.
A table or listing of past actual results for those measured outcomes that were actually achieved with DetA before the proposed change.
A table or listing of the acceptance criteria for measured outcomes to be achieved once implementation of the change is made. The acceptance criteria might include absolute values, a certain percentage of a MACO calculated limit, and/or a target value around the past values measured before the change is made.
A discussion of how many batches and/or elapsed time those measured values under the change should be collected.
A discussion of what should be done for a “correction” of equipment in cases where clearly unacceptable measured values are obtained in evaluating the performance of the change.
A close-out report shall be prepared and approved as to the acceptability of implementation of the change. A requirement that routine verification/monitoring should be evaluated on a specified frequency to evaluate the need for change frequency or nature of that routine morning/verification on the changed process.
Note that the amount of documentation for each item above may vary depending on the complexity (or simplicity) of the change.
Below is an example of what might be covered using the above change in the cleaning process from the use of Detergent A (DetA) to Detergent B (DetB).
For this example, the change is only the detergent. All other elements of the cleaning SOP (like time, temperature, cleaning method, and dirty hold time) are unchanged (except as given in #2 below).
The change is from use of 2% DetA to use of 1% of DetB. That concentration difference reflects both the different ”solids” content as well as the different surfactant concentration in each detergent.
The reason for the change is that DetA is being discontinued by the detergent supplier. However, that supplier has set asides sufficient DetA to provide us with 12 months of use.
The major concern for possible effects are unacceptable residues of the cleaned active and unacceptable residue of the detergent itself following cleaning. Since both detergents have similar alkalinities, deleterious effects on equipment should not be an issue.
The measured outcomes to confirm acceptability of the change are residues of the cleaned active, residues of DetB and the visual cleanness of the equipment. Since this involves manual cleaning, input from any observed issues by cleaning operators should be evaluated.
Laboratory studies using manual cleaning with each detergent have been compared stressing the time of scrubbing. The cleaning results with the two detergents are not significantly different. The analytical method for DetB shall be validated.
Below is a summary of past swabbing API results in the validation protocol following cleaning of the “most-difficult-to-clean” drug product with DetA. It is not expected that the relative “difficulty-of-cleaning” of different drug products will be different with use of DetB.
Run No.
API result
DetA result
1
1.3
2.5
2
1.0
2.9
3
0.9
2.1
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Average Result
1.1
2.5
Calculated limit
7.3
10
Average % of Limit
15%
25%
The maximum acceptable measured value of the API after cleaning with DetB is 50% of the calculated limit, or 3.6. The calculated limit of DetB is 8 (not 10 as for DetA). Therefore the maximum acceptable measured value of DetB after cleaning is 50% of the calculated limit for DetB, or 4.0. While this may result in measured API values above those previously obtained, they still reflect a robust cleaning process. In addition, in each run the equipment shall be visually clean by inspection.
The target for number of runs for the “most-difficult-to-clean” drug product is three. Unless acceptable measured results are obtained before the processing of the next drug product, the equipment should be recleaned again with DetA (to avoid possible contamination concerns if unacceptable measured results were later to be obtained due to that run with DetB). In addition, if other drug products are processed between the three runs for this evaluation, the cleaning following those other products should continue with use of DetA. All three runs shall be completed within an elapsed total period of six months.
Should unacceptable measured results be obtained after cleaning with DetB, the company’s CAPA procedures shall be followed. Unless cleaning with DetA has already been done (see #9 immediately above), there should be an investigation which may include resampling to determine the extent of the aberrant result.
The results of the evaluation for the change to DetB shall be given in a report. Following acceptable results for the three runs, and approval for implementation of the change to DetB, routine monthly monitoring (for all drug products) and yearly verification run (for the “most-difficult-to-clean” drug product) shall continue as previously done for DetA.
The example given is just an example. Your actual specifics will vary depending on the nature of the change as well as your individual situation (including your risk tolerance).
