We generally don’t like to discuss cleaning failures because it suggests something is wrong. However, cleaning failures may occur and we need to be able to address them appropriately. So, this Cleaning Memo will focus on how to appropriately address those failures. The emphasis will be on failures that might occur during execution of initial validation protocols, during cleaning for routine manufacture, and for any “revalidation” protocols. Note that “failures” during the design/development phase are problematic, but they are addressed simply by recleaning (and re-evaluating) the equipment before any reuse (that reuse may be for subsequent development studies or for commercial manufacture of a previously validated product). Any failure might be one of two types. One is a process failure, such as equipment failure or lack of cleaning process parameter control. A second might be data errors, such as unacceptable analytical results for residues.
The general approach for dealing with failures should be use of the company’s “Corrective and Preventive Actions” (CAPA) program, which is typically covered by a Deviation Management policy or procedure. I have covered CAPA for cleaning validation in more detail in the July and August 2023 Cleaning Memos. However, I will discuss the general CAPA tasks briefly here. First is a matter of definitions for the three CAPA tasks. Below is what I use, which is consistent with ISO 9000 usage, although some companies might use variations, such as not clearly distinguishing between “correction” and “corrective actions”. The critical difference for cleaning validation is that correction is what is done to the equipment so it can be safely used for subsequent use, and corrective action is what is done to the cleaning process to make sure the root cause problem does not re-occur (although there may be situation where equipment changes are both a correction and a corrective action). .
For cleaning validation, a “Correction” to do something to the equipment so it can be safely used again. For example, if the failure was due to unacceptable residues, then the equipment should be cleaned as appropriate and tested again to determine that the equipment can be safely used for subsequent manufacture. A “Corrective Action” is to take steps to help make sure that the failure mode identified as the root cause in the investigation does not happen again in the future. For example, if it was determined in an investigation that a failure was caused by lack of control of a cleaning process parameter (such as temperature), then steps should be taken to do something to make sure temperature is adequately controlled within the specified range. A “Preventive Action” is to take steps to implement other improvements (other than the Corrective Action) identified in the investigation. For example, it might be as simple as extended the rinsing time, even though the rinse time itself was not identified as the root cause. For example, in the investigation it was found that while the residue levels for the detergent were within the acceptance limits; however, those residue levels were significantly higher than levels for previous studies found during development studies. To ensure that rinsing is adequate and robust, the rinse time of CIP process may be extended by five (5) minutes. As part of any follow-up to a change as a corrective action or a preventive action, there may be increased routine monitoring to demonstrate the effectiveness of the implemented change.
As suggested in the definitions above, before the CAPA elements are addressed, a thorough (and timely) investigation should occur to identify the root cause(s). This may include techniques such as a Fishbone (aka Ishikawa) diagram, Pareto Charts, and Fault Tree Analysis (FTA). Each company may have preferred approaches to root cause identification based on training and experience of the investigators. The key is to identify possible root causes and then confirm them as the root cause by data/document evaluation and/or by additional studies. What follow is a discussion of issues that might arise in each of the three CAPA steps.
For “Corrections”, one key is when the failure was identified. If it were identified during or after execution of the cleaning process, then the correction may be as simple as recleaning and retesting the equipment (using the same residue analysis techniques). It should be noted that before correction is made to the equipment, it is important to allow those investigators looking for the root cause of the failure to evaluate the equipment before recleaning is done. Not recleaning may allow additional visual observation and/or resampling. However, resampling alone is not generally for the purpose of invalidating a failing result unless following your OOS (Out of Specification) procedure the residue amount is identified as an invalid result. If no lab (or sampling) error is identified, the only purpose of resampling in an investigation is to determine the extent of the failure. Determining the extent of the failure may help in identifying the root cause, particularly if the cleaning process is a manual one. Once recleaning is done, the equipment should be released by standard QA procedures.
On the other hand if the failure is only identified after another product has been manufactured in the equipment, then part of the correction should be the disposition of that next product. That is, is that next product released or is it destroyed? This may include additional QC of that next manufactured product to confirm all release specifications are met as well as a more careful evaluation of the impurity profile, including any unusual chromatogram peaks that may be due to the previously cleaned product. It is also prudent to have QA reaffirm that the equipment can be safely released after use of the validated cleaning process for that next product.
Potential causes of failures to be considered in the investigation include the following:
Investigations should address the cleaning log, monitoring data, sampling records, analytical records, training records, personnel interviews, and observation of the cleaned equipment (the latter can only be done if recleaning has not already been performed).
There are also differences in terms of when the failure occurs, such as during the initial validation protocols, or during routine monitoring, or during a later revalidation protocol. If failure occurs in an initial protocol execution, the validity of the conclusion of the protocol execution must be determined. If the investigation show it to be a “true” failure (indicating the process was ineffective in meeting the acceptance criteria), then it back to design/development phase. However, this may be as simple as implementing any corrective actions and preventive actions before performing a new protocol under the changed conditions. In extreme cases it may involve significant design/development studies. If the failure investigation clearly shows the protocol run was an invalid run (such as being caused by an interruption of electrical service), then steps should be taken to prevent such electrical failure in the future; then that protocol run should be considered invalid and should not affect the requirement for three consecutive protocol runs (that is, if the “not valid” protocol run was the third run, it is not necessary that three additional runs be performed to meet the “consecutive” requirement). However, if the investigation does call into question the adequacy or sufficiency of the cleaning process, then it is generally necessary to start over and perform three consecutive runs.
If a failure occurs during routine monitoring, the focus is somewhat different. Certainly, a one-off excursion is not desirable, but also not unexpected. That is all the more reason to design a reasonable amount of robustness into the cleaning process. If the concern is just a routine monitoring parameter of the cleaning process (for example, temperature), then the extent of the excursion should be considered, especially in light of any design/development studies done to challenge temperature variations. Minor excursions may only require an investigation of the temperature controls (including calibration) with careful attention to unexpectedly high aberrations. Care should then be paid to any further monitoring results. Repeated monitoring failures for a specified parameter, even if only minor, should require corrective action to deal with that parameter.
The situation is more complicated if failure occurs in a revalidation protocol (such as one that might be required on a yearly basis). The same investigation and CAPA steps should be considered as was suggested for failure in the initial validation protocol. The more critical issue to address in this situation is to consider whether that failure only occurred in the revalidation protocol, or whether it implicates previous routine cleaning for that given product for batches after the last successful validation protocol. Carefully examining any routine monitoring documentation may be helpful in that investigation, buy it may also require examining retains of relevant batches as to impurity profiles, especially any peaks that may be due to residues of the prior active. Assuming that the revalidation protocol was performed on the “most difficult to clean” drug product, this investigation should be initially focused on drug products batches made immediately after any earlier batches of the drug product in the validation protocol.
This Cleaning Memo is designed to raise awareness of the need to be timely and thorough in dealing with possible cleaning process failures, whether in an initial validation protocol, during routine manufacture, or in a revalidation protocol.
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