OOS Investigation Case Study-8 (Organic Impurity)

In Pharmaceutical Industry, 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 to convince the regulatory auditors.

Here I am sharing another case study to understand it in a better way-

OOS observed in Organic Impurity test.
Description of Event:
OOS result is reported in Organic Impurity.
Result: 0.95%  (Known Impurity: Named X)
-Limit is NMT 0.70%.

Preliminary investigation:
Checked pressure graph,System suitability parameters, Calculation etc. and No laboratory error is identified from preliminary investigation.
Re-measurement  (Hypothesis testing):
Hypothesis testing is performed to rule out instrument error and vial filling error,  etc.
But no any error is identified and all above possibilities are ruled out.

Reviewed the trend of previous 10 released batches and stability trend data of Validation batches and no any failure observed for X impurity, even in ACC (40/75) condition the maximum impurity % is 0.3% and during batch release it never be more than 0.1%

Now what is the next step. . .Based on trend data it  looks like that, this is not a true failure.
But we can not perform the Re-analysis by saying that this is an erratic result.
Then what is our next step as an investigator.
Step- 1
Inject same subject sample on PDA detector along with impurity X preparation and record the spectra and peak purity of the subject impurity (it helps to rule out whether it is impurity X or some other extraneous peak eluted on same RT.

If you have facility of Mass Spectrometer (LC-MS) , develop a MS compatible method and inject the solution on LC-MS to know the Mass and can conclude whether it is Impurity X  or Y (extraneous)              or X+ Y . If it is Y or X+Y then by knowing mass of Y you can suspect the contaminated product.

If it is extraneous peak then we have to rue out whether it come from manufacturing or Laboratory.

First we have to rule out product contamination by injecting all steps previous product (Mfg) on LC-MS.

 Inject all product standard  which are used in manufacturing before this product (cover all equipment) in same chromatographic condition on LC-MS (If LCMS is not available then you can do activity  on PDA detector).

Inference: If root cause is identified from above exercise, then perform the reanalysis and release the batch, if not then.....
Step-2
Review the force degradation study to check in which condition Impurity X is increased and find the possibility for same during analysis in laboratory and rule out same by negative experiment (If required).

Then it's confirmed that this failure is not a product failure, further we have to rule out that this peak is come due to any product contamination during manufacturing to support this statement further follow step-3.
Step-3
Again re-look in laboratory investigation and rule out all probabilities i. e. filter interference (if sample required high pressure during filtration). Rule out all possible reasons through "SYSTEMATIC ROOT CAUSE ANALYSIS TOOLS like 6M, 5Why/2H, Brainstorming, Fault Tree Analysis, Graphical Analysis (Histogram, Pareto, Run chart). etc.
If required keep sample for stability study with reduce testing (3, 12 and 24 months) , which data help you to convince auditor that initial failure was not  product quality issue.

By all these efforts, if we still not have exact root cause, but we find some most probable cause in laboratory then we can do the Re-analysis and if Re-analysis is complying to the specification and with in trend to other previous batches then It will give confidence to auditor that there is no any issue with the product quality (Batch release/reject decision is conscious call of Quality Head).