In Pharmaceutical Industries, OOS investigation and root cause identification is very important topic. If you are not able to identify the exact root cause, then your effort should be looked in your investigation.
Here I am sharing case study to understand it in a better way-
Description of Event:
An OOS result was observed during a dissolution test for a pharmaceutical product.
One unit showed an aberrant result of 800%, while the other 5 units were well within the limit of NLT (Not Less Than) 75% Q, at approximately 98%.
Hypothesis testing is performed to rule out instrument error, vial filling error, dilution error.
But no any error is identified and all above possibilities are ruled out.
A good investigator would take the following steps to make the investigation more robust and adequate
Step 1: Chromatographic Analysis
To determine if the aberrant result is due to contamination, the subject vial sample and a reference vial sample should be run on a PDA (Photodiode Array) detector. The peak purity and spectrum of both samples should be checked.
Step 2: Evaluating Peak Purity
If the subject vial’s peak purity fails while the reference vial’s passes, it suggests potential contamination with foreign materials that produce a response at the same retention time.
Step 3: Identifying Contamination Source
The next step is to identify the source of the contamination. One possibility is that a previous sample trace remained in the dissolution bowl due to improper cleaning. To rule this out, a solution of a previous product (e.g., at 10 ppm or less) should be injected into the same chromatographic system.
- If a peak is observed at the same retention time, it strengthens the hypothesis that the contamination originated from the dissolution bowl.
- If no peak is observed, further investigation is necessary, potentially by injecting solutions of other products that were previously handled in the same area
- To identify the interference initial solution should be injected on LCMS with suitable chromatography.
- After identification of molecule, manufacturing investigation to be carried out for previous product at all stage i.e. mixing, granulation, compression, coating etc. to rule out any possibility of product contamination.
Conclusion:
By taking these steps, a thorough investigation is conducted to identify the root cause of the aberrant result. If the investigation provides a strong justification, a re-analysis can be performed, and the batch can be released. This detailed and systematic approach demonstrates to auditors that there is no underlying issue with the product quality and that the initial OOS result was an isolated, non-representative event.
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