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Training Program on
Out-of-Specifications & Laboratory Incident
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Out-of-Specifications & Laboratory Incident
Introduction: Out-of-specifications & Laboratory incident
“Test results does not comply with the pre-determined acceptance criteria then
it is called Out of Specification(OOS)”
Any unaccepted event happened during analysis is called laboratory incident
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Out-of-Specifications & Laboratory Incident
Out-of-specifications & Laboratory incident: Applicable Guidelines
ICH HARMONISED TRIPARTITE GUIDELINE
GOOD MANUFACTURING PRACTICE GUIDE FOR
ACTIVE PHARMACEUTICAL INGREDIENTS
Q7
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Out-of-Specifications & Laboratory Incident
Out-of-specifications & Laboratory incident: Regulatory Prospective
ICH Q7
A
t Coral Drugs Pvt Ltd
Section 6.61
Complete records should be maintained for out
-of-
specifications (OOS) investigations.
For
any out of specification results, investigation is
performed and each step of investigation is
documented. (Section 6.2 & 6.15)
SOP# CDPL/SOP/QA/013/10
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Out-of-Specifications & Laboratory Incident
ICH Q7
A
t Coral Drugs Pvt Ltd
Section 6.72
All deviation, investigation, and OOS reports should
be reviewed as part of the batch record review
before the batch is released.
During Batch record review, deviation and OOS
related to batch are reviewed through checklist
(Format# CDPL/FR/QA/202)
SOP# CDPL/SOP/QA/017/05
Out-of-specifications & Laboratory incident: Regulatory Prospective
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Out-of-Specifications & Laboratory Incident
ICH Q7
A
t Coral Drugs Pvt Ltd
Section 8.36
Out
-of-specification (OOS) investigations are not
normally needed for in
-process tests that are
performed for the purpose of monitoring and/or
adjusting the process.
Out
-of-specification (OOS) investigation are
performed for raw/packing material, intermediate,
Finished products and stability samples.(Section 2)
SOP# CDPL/SOP/QA/013/10
Out-of-specifications & Laboratory incident: Regulatory Prospective
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Out-of-Specifications & Laboratory Incident
ICH Q7
A
t Coral Drugs Pvt Ltd
Section 11.15
Any out
-of-specifications result obtained should be
investigated and documented according to a
procedure. This procedure should require analysis of
the data, assessment of whether a significant problem
exists, allocation of the tasks for corrective actions,
and conclusions. Any resampling and/or retesting
after OOS results should be performed according to a
documented procedure.
Any out
-of-specifications results are handled with
SOP for Out of specification. (SOP #CDPL/SOP/QA/
013/10). Three phase investigation is carried out as
per the requirement.
Root cause is identified and corrective and preventive
action is determined. (Section 6.2 & 6.57)
SOP# CDPL/SOP/QA/013/10
Out-of-specifications & Laboratory incident: Regulatory Prospective
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Out-of-Specifications & Laboratory Incident
Let us Discuss….!!!
Out-of-specifications & Laboratory incident in
Details….!!!
(SOP#CDPL/SOP/QA/013)
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Out-of-Specifications & Laboratory Incident
• Phase I- Laboratory investigation
• Phase II- Sampling Investigation
• Phase III- Manufacturing process investigation.
OOS test results are investigated and identified in three phases:-
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Out-of-Specifications & Laboratory Incident
• Include initial assessment to check the accuracy of data.
Responsibility of Analyst Responsibility of supervisor
Phase-I Investigation-
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Out-of-Specifications & Laboratory Incident
• Identify all OOS and report immediately to supervisor / In-charge QC.
• Preserve all solution an sample.
• Document each step of investigation
• Follow checklist during investigation.
• Find out the problems that could occur during the testing process.
• Verify that calibrated instruments were being used during testing.
Responsibility of Analyst
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Out-of-Specifications & Laboratory Incident
• An immediate assessment could include re-examination of the actual solutions, test units, and glassware
used in the original measurements and preparations.
• Supervisor investigate the OOS covering following guidelines.
• Test method should be discussed with analyst.
• Examine raw data obtained in the analysis, including chromatograms and spectra and identity anomalous
and suspect information
• Calculation done for converting raw data into final finished data should be checked.
• Confirm the performance of instruments.
• Quality of standards, solvents, reagents and other solutions used in analysis.
• Evaluate the performance of the test method to ensure that it is performing according to the standard
expected based on method validation data and historical data.
• Preserve records of investigation.
Responsibility of Supervisor
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Out-of-Specifications & Laboratory Incident
Phase -1 investigation is to determine whether there has been a clear obvious
errors due to external circumstances such as calculation error, testing error or incorrect instrument
parameter. These are called Laboratory error.
Phase -1 Investigation (Laboratory Investigation)
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Out-of-Specifications & Laboratory Incident
• Calculation error –
Analyst and supervisor to review, raw data and calculations.
• Testing errors –
for example, spilling of the sample solution, incomplete transfer of a sample;
Glassware and vials contamination , chemical Reagent used after expiry date
Mobile phase contamination.
• Incorrect Instrument Parameters –
for example setting the detector at the wrong wavelength.
• If no assignable cause found in laboratory, Phase II investigation is conducted
Phase-1 Investigation (Obvious Error)
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Out-of-Specifications & Laboratory Incident
Retesting-
If insufficient quantity of the original sample remains to perform all further testing then the procedure
for obtaining a resample must be discussed and agreed by QA. The process of obtaining the resample
should be recorded within the laboratory investigation.
Performed on the original sample not a different sample.
The decision to retest should be based on sound scientific judgment. The test plan must be approved
before re-testing occurs.
Should be performed by 2nd analyst if possible.
The second analyst should be at least as experienced and qualified in the method as the original
analyst.
Phase-II Investigation (Sampling or Non process related Investigation)
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Out-of-Specifications & Laboratory Incident
• Re-sampling shall be performed after proper justification and authorization from Quality Assurance Head.
• Re-sampling should be performed by the same qualified methods that were used for the initial sample.
However, if the investigation determines that the initial sampling method was in error, a new accurate
sampling method shall be developed, qualified and documented.
• It involves the collecting a new sample from the batch.
• Will occur when the original sample was not truly representative of the batch or there was a
documented/traceable lab error in its preparation.
• Evidence indicates that the sample is compromised or invalid.
Sound scientific justification must be employed if re-sampling is to occur.
Re-sampling
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Out-of-Specifications & Laboratory Incident
• Also called full-scale or process related OOS investigation.
• Investigation consist of production process review and/or additional laboratory
work.
Review of production
• The investigation is conducted by quality assurance Dept. involving all concerned
departments, including manufacturing, process development and engineering.
• In cases where manufacturing occurs off-side, all sites potentially involved are
included in investigation.
• Records and documentation of the manufacturing process are reviewed as per
checklist to determine the root cause of the OOS results.
• Investigation results shall include
oProbable Root cause.
oCorrective action
oRemedial action .
oPreventive action.
Phase III Investigation (Manufacturing Investigation)
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Out-of-Specifications & Laboratory Incident
• The root cause are determined applying suitable method such as Fish bone or 5 why etc. following SOP
# CDPL/SOP/QA/033.
• The investigation report is reviewed and concluded for assignable or most probable cause of the OOS
and CAPA suggested by Head of production.
• If OOS investigation confirm the OOS results and is successful in identifying its root cause, the OOS
investigation may be terminated and the product is rejected.
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Out-of-Specifications & Laboratory Incident
• Investigation report is finally reviewed by Quality Assurance.
• Quality Assurance head decide final disposition of batch.
• Out of specification closure report contain summery of investigation performed and a
detailed conclusion.
Closure of investigation
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Out-of-Specifications & Laboratory Incident
• Phase-I Within 7 working day
• Phase-II Within 3 working day
• Phase-III Within 20 working day
Time Frame for Completion of Investigation
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Out-of-Specifications & Laboratory Incident
Record the Laboratory incidents in case of unexpected problems faced during the analysis or in the lab. The
details are given below.
In case of power failure (UPS)
In case of system suitability and theoretical plates not meeting the requirements (out of specification limit).
In case of instrument out of calibration.
In case of stability chamber out of order.
In case of glassware breakage during the dilution.
In case of cylinder leakage or gas cylinder change during GC analysis.
In case of any unknown peak observed during the analysis.
In case of failure in relative standard deviation after bracketing.
Sample injection could not started on system due to any technical reason.
Data acquisition is stopped by analyst due to any reason.
Any unexpected problem in the instrument during analysis like pressure problem, leakage and others shall be
noticed & immediately informed to the supervisor.
Laboratory Incident
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Out-of-Specifications & Laboratory Incident
• Power outage –
Analyst and supervisor document the event, annotate “power failure; analysis to be repeated” on all
associated analytical documentation.
• Equipment failure –
Analyst and supervisor document the event, annotate “equipment failure; analysis to be repeated”
cross reference the maintenance record.
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Out-of-Specifications & Laboratory Incident
Investigation for Laboratory Incident
• All Laboratory Incident should document properly with Description.
• Informed the supervisor and QA immediately and Documents the prompt action taken after incident as
suggested by Supervisor.
• Investigate the incident properly to find out the root cause.
• CAPA shall be taken as per based on root cause.
• Documents the implementation status of the incident batch.
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Out-of-Specifications & Laboratory Incident
