Case Study: Applicable Controls & their Classification, Together with Examples of Qualification or Validation Requirements
| Controls that Could be in Place to Mitigate the Risks Presented by this Failure Mode* | Classification of the Control—S, P or D?† |
|---|---|
| 1. Second Operator Check—while the pH reading is made and recorded by one operator, it is checked for accuracy by a second operator. | D & S Control: This second check is an example of both a detection and a severity-related control. It not only detects the error before the extraction occurs, it also can help eliminate the negative consequences of the failure mode, thus reducing the severity of the effects of the failure mode. As a result of this check, the wrong pH reading gets corrected immediately and the extraction is not carried out at the incorrect pH. It is like the failure mode never occurred. This is an example of a control that affects both the detectability and severity of the failure mode. It does not however prevent the failure mode from occurring. Note: While there will be no validation work associated with this control, the control will still have requirements associated with it—such as the need to document the control in the Master Batch Production Record and the need to train and qualify process operators for carrying it out. |
| 2. Carry out rework operations on the batch to increase the yield and to remove the high levels of impurity A. (See Note 1 below.) | S Control: This control serves to reduce the effects of the failure mode, as it will help ensure that the high level of impurity A is reduced and the yield is increased. This control does not detect the failure mode, nor does it prevent it from occurring. Note: There will be process validation requirements associated with this control, and these should be based on the critical process parameters (CPP) that are identified for the rework process. For example, if the reworked batch is to be purified using a centrifugation and washing process following recrystalisation, CPPs may relate to the centrifugation conditions to be used and the volume of solvent used to wash the cake. |
| 3. In-process testing of the methanol solution for assay. | D Control: This is a detection control. It detects the results of the error. This is not what we want to rely on, however, because by the time this control is applied, the erroneous extraction has already occurred. This control does not prevent the failure mode from occurring, but it can reduce the severity of its effects, as it will ensure that steps are taken to address the problem before the batch is released. Note: There will be qualification and validation requirements associated with this control. The laboratory instrument used when running the test will have to be qualified and the assay test method will have to be validated. If this control is not yet in place, staff will then have to be trained on 1) taking the in-process sample and 2) running the test. In addition, the Master Batch Production Record will need to be updated to include the sampling for the in-process test etc. |
| 4. In-process testing of the waste solution following the original extraction for the level of active substance still left in it. | D Control: This is a detection control. It detects the results of the error. Again, this is not what we want to rely on, because by the time this control is applied, the extraction has already taken place and a reprocessing step of the waste solution would be required (if it is still available). This control does not prevent the failure mode from occurring, but it can reduce the severity of its effects, as it will ensure that steps are taken to address the problem before the batch is released. Note: Again, there will be qualification and validation requirements associated with this control. The laboratory instrument used when running the test will have to be qualified and the assay test method will have to be validated. If this control is not yet in place, staff will have to be trained on 1) taking the in-process sample and 2) running the test. In addition, the Master Batch Production Record will need to be updated to include the sampling for the in-process test, etc. |
| 5. Training—the trained operator should never record the wrong pH! | P Control: This is a probability-related control, as the site training programme should reduce the likelihood of this failure mode occurring. This type of control will not detect the failure mode, nor will it reduce the severity of its effects, should it occur. Note: While there will be no validation work associated with this control, the control will still have “qualification” requirements associated with it—the operator will have to be qualified to execute this step in the batch record. This is achieved not only via the training event but also via a demonstration that the training was effective, so that the failure mode should not occur. There should be some assessment performed of the effectiveness of the training. |
| 6. Yield calculation of the API batch after drying. | D Control: This is a detection control. It detects the results of the error. This is not what we want to rely on, because the batch is now processed and the yield is OOS. A reprocessing step of the waste solution would be required (if it is still available) to recover the remaining active. This control does not prevent the failure mode from occurring, but it can reduce the severity of its effects, as it will ensure that steps are taken to address the problem before the batch is released. Note: If the yield calculation is to be performed manually, there will be no validation or qualification work associated with it. If, however, the calculation is to be performed using an automated system, there will likely be some level of software validation associated with it. |
| 7. Redesign the PLC operator/equipment interface so that the pH and Temperature readings are no longer next to each other and are more clearly labeled/displayed. | P Control: This is a control that will serve to prevent this failure mode from recurring. This is likely to be the most effective preventative control that may be implemented for this failure mode. Note: There will be validation work associated with this control. This will involve validation of the software changes that are made to the PLC operator/equipment interface. |
↵* These controls might already be in place or they might be new controls that could be put in place.
↵† S—the control can influence the severity of the effects of the failure mode; P—the control can influence the prob. of occurrence of the cause of the failure mode; D—the control can influence the detectability of the failure mode.
Note 1: The rework process could involve reworking the batch to reverse the extraction step and then repeating the extraction step at the correct pH—such a rework process will need to be developed, validated, and registered. Alternatively, the following two step approach could be taken. 1) Don't attempt to reverse the original extraction but rework the extracted batch in some other way to remove the high levels of Impurity A from it. 2) Perform a further extraction on the waste solution following the original extraction and ensure this it is performed at the correct pH.