Investigations into Pharmaceutical Deviations – How One Deviation Triggered Five Others
This case study demonstrates how interdependent pharmaceutical manufacturing processes are and how a deviation in one area can go on to have unintended consequences in another area.
Here we share with you four deviations and an OOT that occurred in the same batch and discuss the root cause from each.
Background information: the product is formulated as 2 sub-lots, which are combined as a single batch for sterile filtration, aseptic filling, lyophilisation, inspection and then packaging.
From extended hold times and filter blockages to low assay results, prolonged lyophilisation, and critical visual defects, each deviation was traced back to the original delay. Through detailed root cause analysis and critical thinking, EPiC worked closely with the site personnel to review the investigations into these deviations and OOT and implement effective CAPAs. The case underscores the importance of thorough investigations and the value of asking “why” repeatedly to reveal systemic vulnerabilities.
Deviation #1 – Hold time exceeded between completion of sublot A and Prefiltration
During formulation of the product, the hold time between completing sublot A and the start of pre-filtration of the combined sublots was exceeded. This was as a result of a delay occurring during the dispensing of materials for sublot B. When the operator came to dispense the required quantity of Solvent for sublot B, there was an insufficient quantity in the bottle. An immediate action was taken to request more Solvent from the warehouse, but this resulted in the hold time being exceeded by 1 hour 49 minutes.
The root cause was attributed to the insufficient quantity of solvent received for dispensing. An opened bottle, which had been used on a previous batch, was initially issued to this batch, but due to evaporation, there was a shortage of 15ml from the expected quantity.
CAPA is to evaluate if the solvent is available in smaller containers and only issue unopened bottles to be dispensed.
Deviation #2 – Filter clogged during manifold filtration activity of the batch
After approximately 80% of the batch had been filtered through a manifold, the filter clogged and collection of filtrates completely stopped. The remaining quantity of unfiltered solution was discarded.
It was known that when the product is stored for extended periods at lower temperatures, loose aggregates can form, and in this case these caused the filter to block.
The root cause goes back to the delay during dispensing, due to insufficient quantity of Solvent, causing the batch to be held longer and allowing the aggregates to form.
OOT #1 – Low assay result during In Process testing of filtered solution
Before the product is filled, an in-process sample is collected for assay. The result for this batch was 93%. An adjustment was made for the filling volume so the final product result would meet finished product specification.
Deviation #3 – Lyophilisation cycle duration exceeded
The lyophilisation cycle exceeded its typical duration by 1 hour 06 minutes. When the executed recipe was compared to the approved recipe parameters, it was noted that the sublimation and the secondary drying times were extended. The lyophilisation cycle is fully automated and the lyophiliser will extend phases until the set values for shelf temperature and vacuum are achieved.
The cause of the longer cycle time is attributed to an increase in the fill volume, where there is a higher water content in the filled vials compared to routine batches. This resulted in the lyophiliser taking longer to reach the required shelf temperature and the equipment automatically extended the cycle until this was achieved.
The root cause goes back to the delay during dispensing, due to insufficient quantity of Solvent, causing the batch to be held longer and allowing the aggregates to form, causing blockage of the filter, causing low assay of the solution to be filled, which meant the fill volume was increased.
EPiC provided advice to review the range of fill volumes that had been validated and restrict the range of fill volumes that can be used, based on acceptable validation ranges.
Deviation #4 – Critical rejects found out of limit during visual inspection
After completion of 100% manual visual inspection of the batch, the number of critical defects detected exceeded the action limit. The highest number of critical rejections was due to shrinkage / melt back.
Good vials were reinspected twice more to ensure there were no other instances.
Due to the low assay value, the fill volume was increased which resulted in an increase in the time to reach the correct shelf temperature in the sublimation phase of the lyophilisation process. This is the critical phase of lyophilisation which led to the melt back of the lyophilised vials, that were identified during visual inspection.
Summary
- Why was there shrinkage / melt back in the vials – because the lyophilisation cycle was extended
- Why was the lyophilisation cycle extended – because the fill volume was increased
- Why was the fill volume increased – because the assay post filtration was low
- Why was the assay post filtration low – because API particles blocked the manifold filter
- Why did the manifold filter block – because of the extended solution hold time
- Why was the solution hold time extended – because there was a delay during dispensing
- Why was there a delay during dispensing – due to insufficient quantity of solvent received
So, the true root cause goes back to the delay caused by having insufficient solvent at dispensing.
When you keep asking why (note it is asked more than 5 times!) it becomes apparent how sensitive pharmaceutical manufacturing processes can be to changes, and a deviation in one part of the process can have a knock-on effect downstream.
EPiC worked closely with the site personnel to review the investigations into these deviations and OOT. We challenged assumptions and applied critical thinking to ensure the investigations had determined the true root cause, identified appropriate CAPA and were clearly documented.
If you or your team need support reviewing complex deviations and non conformities or would benefit from training on Critical Thinking and Performing Effective Investigations please get in touch.
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