INTAS PHARMACEUTICALS LIMITED, PHARMEZ

Department Quality Control ANNEXURE-II

SE/PQC1/F/OOS/
Title OOS Investigation Report OOS No.
2023/0139
Date of OOS
Product Name Carboplatin USP 03/07/23
Observed
Specification No. CRPL325-04 MOA No. CRPL325/M-10
WS Batch No. PS CARB 231 Page Nos. 1 of 5

 Objective: This annexure is prepared to impart details of laboratory investigation findings in context of
observed OOS result in assay test.

 Background of OOS:
 On dated 03/07/23, analysis of assay test of raw material Carboplatin USP WS No. –PS CARB 231 was
started by Mr. Ashok Anuragi on HPLC ID PC225 with sample set name as “PC225CABR020723A”.
 During data reporting, analyst Mr. Shiva Vagh observed that assay result found out of specification.
Hence, initiated the OOS investigation. Sample of OOS batches were prepared by analyst Mr. Ashok
Anuragi.
 Outcome of Hypothesis Study :
 As per recommendation, analyst Mr. Ashok Anuragi was performed the recommended hypothesis study
with sequence name as “PC225CARB040723A”.
 Analyst prepared the new standard preparation in duplicate and taken the necessary precaution and
following outcome derived.

Table No. 01 Outcome of Hypothesis Study

Study
Hypothesis Plan Purpose of Hypothesis
No.
Reinject the same solution from same Assay result found higher side to initial analysis,
1
vial. hence instrument related error ruled out.
Reinject the same solution from Assay result found higher side to initial analysis,
2
different vial. hence vial filling related error ruled out.
Re-inject the prepare of new standard Assay result found well within limit when assay
3
solution. calculated with new standard preparation.
Re-inject the prepare of new sample To check the sample preparation error for data
4
solution. information purpose.
INTAS PHARMACEUTICALS LIMITED, PHARMEZ
Department Quality Control ANNEXURE-II
SE/PQC1/F/OOS/
Title OOS Investigation Report OOS No.
2023/0139
Date of OOS
Product Name Carboplatin USP 03/07/23
Observed
Specification No. CRPL325-04 MOA No. CRPL325/M-10
WS Batch No. PS CARB 231 Page Nos. 2 of 5

Table No .02 Hypothesis Analysis Results

% Result
Study Standard Initial Analysis Hypothesis Analysis
Study Plan
No. Details Re-filling
Set –I Set –II Same vial from stock
vial

Reinjected sample Old standard 97.55% 101.44% Set-I 99.72 Set-I 80.11
solution from Set-II 112.34 Set-II 77.94
1
same vial.
PS CARB 231 New standard Set-I 98.4 Set-I 79.05
Set-II 110.85 Set-II 76.9
New sample Old standard 100.2
2 prepared New standard
PS CARB 231 98.85
Reinjected sample Set –I 112.44 Set –I 146.1
solution from Old standard
Set-II 112.25 Set-II 143.35
different vial.
3
PS CARB 221 Set-I 110.95 Set-I 144.16
Existing Working New standard 112.28% 112.51% Set-II 110.76 Set-II 141.45
standard
New sample Old standard 100.5
4 prepared
PS CARB 221 New standard 99.18
Inference:
 Assay result found for Batch no. PS CARB 221 is similar to initial analysis when calculated with old
standard preparation & new standard preparations, hence instrument and vial filling related error ruled
out.
 Assay result found lower side in WS Batch no. PS CARB 231 from re-filling standard & sample
solution due to degradation of sample solution in laboratory condition and over validity period.
 Assay result of re-injected sample solution in PS CARB 231from same vial set-I is similar with initial
result & refilling from stock vial result is similar & lower side, calculated with old standard & new
standard due to degradation of sample solution in laboratory condition and over validity period.
 Assay result found higher side in WS Batch no. PS CARB 221 from re-filling standard & sample
solution due to sample solution store in laboratory condition and over validity period.
 Assay result of both working standard PS CARB 231 & PS CARB 221 found well within specification
limit when calculated for new sample preparation with new standard preparations & old standard
preparation, hence standard area response found satisfactory and sample result preparation related error
INTAS PHARMACEUTICALS LIMITED, PHARMEZ
Department Quality Control ANNEXURE-II
SE/PQC1/F/OOS/
Title OOS Investigation Report OOS No.
2023/0139
Date of OOS
Product Name Carboplatin USP 03/07/23
Observed
Specification No. CRPL325-04 MOA No. CRPL325/M-10
WS Batch No. PS CARB 231 Page Nos. 3 of 5

proved for observed out of specification result, hence no impact associated with quality of respective
OOS batches.
 Assay result of analyst –I found well within specification limit.
 Further, evaluated the area obtained in standard preparation during initial and hypothesis analysis for
verification of response factor and following detail found.
Table No.03 Standard Area Evaluation
Preparation Injection Standard Response Factor
Standard Area
Detail No. Weight (Mean Area / Weight )
1 2486.4160
2 2490.6201
Initial standard 3 2493.6026
preparation 4 2497.9883 10.140
(Set-I) 5 2499.1537 100.34%
6 2495.4199
Mean 2493.9168
Initial standard
1 2485.2579 10.139
preparation(Set-II)
Preparation Injection Standard Response Factor
Standard Area
Detail No. Weight (Mean Area / Weight )
New standard 1 2480.5902
preparation in 2 2473.1072
10.021
Hypothesis 3 2486.3559
101.36%
(Set-I) Mean 2480.0178
New standard
1 2446.6364 10.021
preparation (Set-II)
 Upon the above evaluation, response factor found inline in initial standard preparations (Set-I and Set-
II) as compare to new standard preparations,
 Based on above standard area evaluation, it is concluded that response factor found similar in OOS
analysis sequence as compare to initial sequences, which were analyzed on same instrument. It also
found satisfactory.
 Based on initial higher side result in respective existing WS probability of sample preparation error.
 Based on hypothesis plan and outcome result re-inject the same vial sample solution result found similar
with initial result and same sample solution from stock refilling vial result found higher side due to store
in laboratory condition and validity period is over side. New standard and sample preparation result
INTAS PHARMACEUTICALS LIMITED, PHARMEZ
Department Quality Control ANNEXURE-II
SE/PQC1/F/OOS/
Title OOS Investigation Report OOS No.
2023/0139
Date of OOS
Product Name Carboplatin USP 03/07/23
Observed
Specification No. CRPL325-04 MOA No. CRPL325/M-10
WS Batch No. PS CARB 231 Page Nos. 4 of 5

found satisfactory &\well with in specification limit. Initial result out of limit due to probability of
sample preparation error.
 As per discussed with analyst, discrepancy identified during analyst interview, sample prepared before
one hours & as per MoA sample preparation in dimethyl sulfoxide (use freshly opened GC-HS grade)
& inject immediately after preparation. Analyst prepared the sample, dissolve and dilute to volume with
diluent; mix well and further discussed with analyst for sample preparation and as per analyst sonicate
the sample for dissolve.
 As per valuation of initial investigation and hypothesis study data , sample result is higher side due to
probability of sample solution error during sample prepartion.

 Conclusion:
 Based on outcome of laboratory investigation it was concluded that result of concern unknown impurity
(RRT 1.36) observed out of specification due to sonicate the sample solution so degradation of sample
solution.
 To identify the mode of degradation in concern analysis, further hypothesis for degradation by sonicate
study shall be performed.

 Recommendation:
o Following study by sample solution sonicate shall be performed.

Table No: 02 Extended Hypothesis Plan

Study No. Hypothesis Plan Purpose of Hypothesis

To Check the material Quality
1 New Sample preparation as per MOA
and Sample preparation error.
To impact of impurity increased
2 New Sample preparation as per MOA.
and degradation.
New Sample preparation as per MOA and solution To impact of impurity increased
3
sonicate at Room Temperature for 5 & 10 min. and degradation.

 Injection Order:
 Follow the below injection order for, extended hypothesis study.

Table No: 03 Injection Order

Type of Injection No of Injections
INTAS PHARMACEUTICALS LIMITED, PHARMEZ
Department Quality Control ANNEXURE-II
SE/PQC1/F/OOS/
Title OOS Investigation Report OOS No.
2023/0139
Date of OOS
Product Name Carboplatin USP 03/07/23
Observed
Specification No. CRPL325-04 MOA No. CRPL325/M-10
WS Batch No. PS CARB 231 Page Nos. 5 of 5

Diluent 01
System Suitability Solution 01
Standard Preparation Solution 03
Freshly Sample preparation as per MOA 01
New Sample preparation as per MOA and solution sonicate for 5 min. at room
01
temperature.
Sample preparation as per MOA and solution sonicate for 10 min at room
01
Temperature.

Source of sample: Original sample.

Prepared By (QC) Checked By (QC) Approved by (QA)

Name

Sign/Date