1.

PURPOSE:
1.1. To lay down a procedure for investigating and handling of Out of Trend (OOT) results during testing
of Active materials, In-process, Finished product and Stability samples

2. SCOPE:
2.1. This procedure is applicable to Critical chemical tests such as but not limited to Assay, Related
substances, Loss on drying, Water Quality, Dissolution and Content Uniformity / Uniformity of Dosage
units performed for all types of samples in Quality Control Department.
2.2. Investigations for “Out of Trend (OOT) “will be done in cases of:
2.2.1.Batch approval testing and testing of starting materials.
2.2.2.In-process control testing: if data is used for batch calculations/decisions and if in a dossier and on
certificates of analysis.
2.2.3.Stability studies on marketed batches of finished products and or active pharmaceutical
ingredients, on –going / follow up stability (no stress tests).
2.2.4.Previous approved batch used as reference sample in an OOT/OOS investigation showing OOT
or suspect results.
2.3.

3. RESPONSIBILITIES:
3.1. All QC personnel to comply with the SOP.
3.2. QC Analyst to initiate and report any OOT results.
3.3. QA Manager to ensure implementation and compliance with the SOP.
3.4. Responsible Pharmacist to ensure compliance with the SOP.
3.5. QC Manager to ensure implementation of the SOP

4. DEFINITIONS/ABBREVIATIONS:
4.1. Abbreviations
4.2. Definitions
4.2.1.OOT: An analytical result or sequence of results that are within specification limits, but are
unexpected and not in line with other results. This shall be identified during analysis by comparing
against trend and results obtained at the extreme of specification. In general, Out of Trend can be
described as a
4.2.2.Hypothesis/Investigative Testing: It is testing performed to help confirm or discount a possible
root cause from assumptions made i.e. what might have happened that can be tested. This may
include further testing regarding sample filtration, sonication/extraction; and potential equipment
failures etc. Multiple hypotheses can be explored.
4.2.3.Reinjection: Is defined as the re-chromatography of the original aliquot solutions as part of the
OOT procedure.
4.2.4.Retest: Performing the test over again using material from the original sample composite, if it has
not been compromised and / or is still available. If not, a new sample will be used after
authorization from QA.
 4.2.5.Resample: A new sample from the original container where possible, required in the event of
insufficient material remaining from the original sample composite or proven issue with original
sample integrity.
4.2.6.Obvious error: An evident/apparent/clear reason for obtaining an OOT results such as
Calculation error, Spillage of sample solution, incomplete transfer of sample, incorrect instrument
parameters and sample preparation etc.
4.2.7.Assignable cause: An identified reason for obtaining an OOT result.
4.2.8.No Assignable cause: No clear reason identified for obtaining an OOT result.
4.2.9.Atypical Result: Those that are unusual on the basis of experience, trending, or data review but
still are within specification.

5. REFERENCES:
5.1. WHO TRS 986 ANNEX 2

6. INTERNAL DOCUMENT REFERENCES:

6.1. SOP 1019 ANNUAL PRODUCT QUALITY REVIEW
7. PROCEDURE:
7.1. General OOT shall be classified into three categories as follows;
7.1.1.Analytical Alert: When a single result is OOT.
7.1.2.Process Control Alert: A succession of stability data points or successive batches showing OOT.
7.1.3.Compliance Alert: When a stability study or release results are OOS at the end of shelf life.
7.2. Identification of OOT
7.2.1.After obtaining critical tests results for stability batches the analyst shall determine whether the
obtained results are (OOT) out of trend based on the trending criteria outlined in Annexure 1.
7.2.2.In case of commercial batches OOT results are those that fall outside of the upper and lower
control limits as defined in the APQR for the previous year or any unexpected, atypical,
questionable, irregular, deviant or abnormal results i.e., significant change in result, which are
within the limit.
7.2.3.OOT investigation shall be initiated by QC, logged in the OOT Logbook as per Annexure 5 and
issued a unique identification number by QA using the format OOT/XXX/YY, Where,
OOT = Out of Trend
XXX = Three-digit sequential number starting from 001 each year.
YYYY = running year.
7.3. Preliminary Laboratory Investigation
7.3.1.Upon obtaining Out of Trend results, Analyst shall inform the QC Manager as soon as possible.
7.3.2.To the extent possible, the analyst shall retain aliquots of original solutions, and / or portions of
samples used for analysis under suitable storage conditions to facilitate investigation.
7.3.3.The analyst will request an OOT investigation form from QA and be issued with a unique number.
7.3.4.The summary of results shall be indicated in the space provided in the “Investigation report for Out
of Trend results’’ form.
 7.3.5.Investigation shall be carried out along with QC Manager and findings shall be recorded in the
Investigation report form for Out of Trend results as per Annexure 2.
7.3.6.The QC Manager shall use the checklist for laboratory OOT investigation as per Annexure 3 to
aid the investigation.
7.3.7.During the initial investigation, Hypothesis testing shall be done as follows (but not limited to):
7.3.7.1. Re-injection from same vial of standard and test solutions.
7.3.7.2. Re-filtration / re-centrifugation of the original test solution.
7.3.7.3. Re-dilution from original stock solution.
7.3.7.4. Additional sonication/shaking of the same solution.
7.3.7.5. Hypothesis testing results will not be used to replace the original suspected analytical
results. They will only be used to confirm or discount a probable cause.
7.3.8.If assignable cause is identified, then the analysis shall be repeated using original solutions /
sample portion by the 1st Analyst (If 1st Analyst is not available then analysis can be performed by
an equally competent Analyst by taking prior approval of QA Manager) taking care to omit all
errors identified during the investigation.
7.3.8.1. If original solutions / sample portions are found to be not suitable, then freshly prepared
solutions / fresh portion from the original sample shall be used.
7.3.8.2. If the repeat analysis results are not OOT, then the initial results shall be invalidated.
7.3.8.3. A review of the reasons for Analyst/ laboratory errors shall be assessed with respect to
Training needs, Procedural revisions, impact on other batch analyses done during the
same run, impact on previous analyses done by the Analyst shall be done.
7.3.8.4. Report the re-analysis results as final result and forward the investigation report to QA
Department for comment.
7.3.9.If no assignable cause is identified during preliminary investigation, then Production, or R&D will
be notified for further investigation.

7.4. Manufacturing Investigation

7.4.1.QA Head or designee and Production Pharmacist or designee shall investigate the manufacturing
and packing process to identify any possible error. Investigation can be extended to the other
departments, if necessary such as Engineering, and R&D.
7.4.2.The investigation shall include but not limited to review of Batch manufacturing record, to verify
any deviation/ incident from manufacturing procedure or equipment operation procedure or
environment monitoring parameter and yield at different stages.
7.4.3.In case of stability OOTs review, the following points shall be verified but not limited to,
7.4.3.1. Time delay in stability initiation from the day of manufacturing.
7.4.3.2. Review of initial analytical data.
7.4.3.3. Change in source of input materials if any.
 7.4.4.Trend of results of starting materials, stability data and impact of the trend on related quality
attribute etc. Trend data of past batches, equipment maintenance record, changes in
facility/equipment/process shall be reviewed.
7.4.5.Record the investigation along with OOT form.
7.4.6.If any assignable cause is identified from the manufacturing investigation, then complete
investigation report along with CAPA shall be forwarded to QA for review and comments.

7.5. Extended Laboratory Investigation

7.5.1.If no assignable cause identified from the manufacturing investigation, then a second QC Analyst
will retest in triplicate using original samples.
7.5.1.1. If the repeated results are not OOT then the first result in case of Related
substances / Impurities shall be reported as final result.
7.5.1.2. If the repeated results are not OOT then the mean of the triplicate results other than for
Related substances / Impurities shall be reported as final result.
7.5.1.3. If the repeat analysis results are OOT, then report the original result and confirm OOT.
7.5.2.All results obtained along with the conclusion of the investigation shall be forwarded to QA for
review and comments.
7.5.3.If original sample not sufficient to complete the investigation testing or sample is compromised or
sample integrity is suspected, re-sampling may be performed with proper justification and approval
by QA Department.
7.5.4.If the repeat analysis result is found to be ‘Out of Specification’, then the same shall be
investigated by following the SOP 4013 for handling of Out-of-Specification (OOS) test results.
7.5.5.When OOT is investigated and concluded as OOT and is not due to laboratory error, then QA shall
inform contract giver and R&D Department as applicable for further course of action.
7.5.6. If OOT is confirmed, previous approved batches data & stability data of the same product is
evaluated for impact on quality of product till expiry of the product.
7.5.7.Based on evaluation of stability data and trends of previous approved batches, carry out a risk
assessment on the impact on product quality, Generate the CAPA and the batch disposition shall
be determined by QA. If the batch is approved, then it will be put on stability monitoring.
7.5.8.If impact on product quality of the same batch is found high, the batch shall be disposed and
documented.

7.6. Closure of OOT

7.6.1.OOT investigations shall be closed within 30 working days from date of reporting including
manufacturing and further laboratory investigation.
7.6.2.If the OOT is not closed within 30 working days, then closure of OOT can be extended to 50
working days by QA with proper justification.
7.6.3.Justification for extension of OOT investigation shall be documented as per Annexure 4 and it
should be approved by head QC and head QA.
 7.6.4.All Investigations regarding Out of Trend results should be documented and preserved for one
year after batch expiry.
7.7. Trending of OOT
7.7.1.OOT results shall be trended quarterly for but not limited to
7.7.1.1. Repetitive OOT in a particular test for a product
7.7.1.2. Repetitive OOT by an analyst.
7.7.1.3. Repetitive OOT at a particular stage of processing.
7.7.1.4. Repetitive OOT on a particular instrument.
7.7.1.5. Repetitive Human errors.
7.7.2.QA shall issue CAPA fir repetitive OOTs and monitor effectiveness of the CAPA.

8. RECORDS:
8.1. N/A
9. ANNEXURES:
9.1. ANNEXURE 1 OOT CRITERIA FOR STABILITY DATA
9.2. ANNEXURE 2 OOT INVESTIGATION REPORT FORM
9.3. ANNEXURE 3 OOT INVESTIGATION LABORATORY CHECKLIST
9.4. ANNEXURE 4 OOT INVESTIGATION EXTENSTION REQUEST FORM
9.5. ANNEXURE 5 OOT LOGBOOK

10. DISTRIBUTED TO
10.1. WAREHOUSE MANAGER
10.2. QA MANAGER
10.3. QA OFFICER
10.4. OPERATIONS
10.5. QC MANAGER
11. CHANGE CONTROL HISTORY
Change Control Version Effective Reason for Change
Date: