Annexure – I

OOS investigation

Product Name : Pseudoephedrine HCl

Batch Number : 503117

OOS Number : OOS/017/17

Test Parameter : Related substance by HPLC(BP)

Description of the OOS:

 During the analysis of Pseudoephedrine HCl related substance by HPLC method

TMD/QC/FP/003/K , Unknown impurity found Not detected and 0.46% test T1 and T2
respectively (RRT 0.42) against the limit of NMT 0.10% for the batch number 503117.

1. Phase-I Investigation:

 The analysis was performed in LC-007, Verified its calibration status found satisfactory.

 The initial investigation performed as per the laboratory investigation check list and verified
the possibility of any laboratory error like method, sample preparation, instrument error and
working standard etc., and no obvious error noticed.

 Interacted with the analyst , training on the analysis technique and test method and found
satisfactory.

 Reviewed the raw data (Preparation of sample standard) and system suitability chromatogram
there is no discrepancy observed.

 In the same sequence B.No: 502917 and 503017 has been analyzed and obtained result meeting
the acceptance limit. The results were tabulated below.

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 Initial analysis result

Batch no Unknown impurity

Area % of impurity Spec limit
RT RRT
T1 T2 T1 T2

502917 ND ND ND ND NA NA

503017 ND ND ND ND NA NA NMT
0.10%
503117 ND 148512 ND 0.46% 6.48 0.42

 As part of Phase-1 investigation, the original solution was retested and the impurity results are
not found the initial analysis. The results are tabulated below.
Retesting of original solution

Batch no Unknown impurity (RRT 0.42)

Area % of impurity Spec limit
RT RRT
T1 T2 T1 T2

NMT
503117 ND ND ND ND NA NA
0.10%

 Retesting of original solution initial same T2 vial was retested and the impurity results are not
found the initial analysis. The results are tabulated below.

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 Batch no Unknown impurity (RRT 0.42) Spec limit

Area Area % RT RRT

503117 ND ND NA NA NMT 0.10%

 Hence suggested to go with hypothetical study for identify the impurity which shows in the
sample.

 Hypothetical study was carried out and outcome of the result tabulated as below,

S.NO Product Name Retention time

1 Phenylephrine Hydrochloride 4.96
2 Bosentan monohydrate 4.52
3 DOTA 2.94

 Based on the above analytical data the unknown retention time observed at Pseudoephedrine
hydrochloride is not matches with above samples. Hence product contamination is not occurred
during the analysis of Pseudoephedrine hydrochloride.

2. Full scale investigation:

 Based on the full scale investigation, Retest-1 initiated for B.No 503117 the results are
tabulated below.
Retest-1

Batch no Unknown impurity (RRT 0.42)

Area % of impurity Spec limit
RT RRT
T1 T2 T1 T2

NMT
503117 ND ND ND ND NA NA
0.10%

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 Retest-1 results comply with specification. Hence, Retest-2 with another chemist was
performed along with passed batch and the results are tabulated below.
Retest-2

Batch no Unknown impurity (RRT 0.42)

Area % of impurity Spec limit
RT RRT
T1 T2 T1 T2

NMT
503117 ND ND ND ND NA NA
0.10%

 The Retest-2 results meeting the acceptance limit and no peak detected at RRT of 0.42. The
obtained results are comparable with Retest-1 and original sample analysis.

 Same sequence batch 502917, 503016 and Passed batch 502617 was tested along with OOS
batch Retest-2 analysis. The obtained test results comparable with initial analysis.

Same sequence batch and Passed batch analytical results

Batch no Results
Any other Sum of impurities
impurity other than impurity Status
Impurity A
A

Initial BDL BDL BDL

502917
Retest BDL BDL BDL

Initial BDL BDL BDL

503017 Complies
Retest BDL BDL BDL
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Initial BDL BDL BDL
502617
Retest BDL BDL BDL
  The batch analysed in same sequence and passed batch results concludes, no analytical issues
in Retest-1 and Retest-2
 Hence, the impurity found at 0.42 RRT of unknown might have been the contaminant
unknown peak.

 Detailed investigation as below,

- There may be column problem, because if column not properly washing it may be
possibility of elute the impurity. If we consider chance of carry over after few runs and it
will be eluting the impurity after four or five injections but respective sequence there is no
abnormal/ extra peak found so it was ruled out.

- Analyst having good exposure this particular analysis, so it will be eliminated

- HPLC vials which used for analysis is new ie use and through which concludes that there is
no possibility of vial contamination

- Glassware's are dedicated and it was cleaned and ensured before usage by respective
analyst and moreover glassware's are again rinsed with mobile phase by respective end
users which indicates eliminates the glassware's contamination

 After completion of Retest 2 it is not able to identify the proper route cause of the investigation, it
may be concluded that due to unknown laboratory error.

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3. Root cause of the OOS and conclusion:

 Based on the above detailed investigation the root cause of the OOS it may be concluded that
contaminant peak due to unknown laboratory error.

 Based on the retesting of the sample the initial analysis OOS result is invalidated and the material
is conformed as passing.

 The material can be released with the retest-2 result as per the OOS procedure.

4. Corrective and preventive action:

 Training will be given to the chemist to prevent the occurrence of the problem in future.

Prepared by Reviewed by

Date : Date :

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