Purpose
To lay down the procedure for identification,
investigation and evaluation of Out of
Specification (OOS) results.
Procedure
Definition of OOS:
The term OOS results include all test results that fall
outside the specifications or acceptance criteria established for Finished
Products, Stability Study, Raw Materials and Packing Materials.
Out of Specification (OOS) means the test result that
falls outside the specifications or acceptance criteria which has been
specified in the official compendium monographs or the finished product
specification in registration dossiers, filed applications, drug master files,
approved marketing submissions, or internal acceptance criteria.
OOS procedure is not applicable for data generation of
analytical method and analyst qualification of new analyst.
Causes of OOS test result:
OOS results shall describe all suspected test result
that fall outside the specification against which it has been tested. An OOS
results can be due to:
Obvious causes: These include those clear and obvious errors
which are generated due to external circumstances or those that the analyst has
detected prior to generating data such as spilling sample, power failure, equipment
failure, incomplete transfer of a sample, incorrect instrument parameters, use
of non-calibrated instruments or apparatus, use of contaminated apparatus and glassware’s,
improper handling and storage of sample etc.
Analyst shall not knowingly continue an analysis they
expect to invalidate at a later time for an obvious cause (Analysis shall not
be completed for the purpose of seeing what results can be obtained when obvious
errors are known).
These shall be investigated through preliminary
laboratory investigation.
Assignable Cause: An assignable cause is an identifiable,
specific cause of variation in an analysis or measurement. A cause of variation
that is not random and does not occur by chance is “Assignable”. Some of the
common Laboratory error during analysis are as follows, but not limited to:
Error
in the method of analysis
Error
in specification
Error
in calculation
Wrong
transcription of data
Use of
invalid incorrect working standard
Lack of
training or knowledge
Use of
expired or old chemicals, reagents or solvents
Software
error
Error
in sampling procedure
Inadequate
transfer of analyst / solution / wrong weighing
Dilution
Stability
Non -Assignable Cause: In such cases, additional data must be
generated to assess whether the initial atypical result is a statistical
outlier. Non Assignable Causes for OOS
results may include, but not limited to:
Non-process
related or operator error
Process
related or manufacturing errors
Deviation
from the validated process
Quality
of intermediate, raw materials used
In-Process
control during manufacturing
Identifying and assessing
the OOS
OOS shall be reported within 24 hours / one working
day.
Analyst shall raise the request for OOS investigation
form to QA department. QA personnel shall issue the OOS investigation form for investigation of OOS
in Quality Control.
Quality Assurance department shall allocate the unique
identification numbering the
Phase-I (a) Investigation:
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| OOS investigation flowchart |
Preliminary laboratory investigation shall be concluded
within 48 hrs. from the date of generation of OOS. Any deviation from this
shall be justified and documented along with the OOS investigation form.
Phase I(a) I(b) up to re-measurement should be
completed at least within 3 working days, based on solution stability which we
perform in the AMV.
The investigation should be thorough, timely, unbiased,
well documented and scientifically defensible.
Phase-Ia investigation is to determine whether has been
a clear obvious error due to external circumstances such as power failure or
those that the analyst has detected prior to generating data such as spilling
sample that will neglect the requirement of a phase-II investigation.
Some examples of obvious error in Phase-I(a) (But not
limited to):
Calculation
error- Analyst and Designee to review and correct.
Equipment
Failure- Analyst & Designee to review and correct.
Testing Error- Spilling
of sample solution, incomplete transfer of sample, then analyst must document
parameters immediately.
Incorrect instrument Parameter-
Setting the detector at the wrong wavelength, analyst and Designee document the
event, annotate “incorrect instrument parameter” analysis to be repeated.
Enter the findings based on
investigation and discussion with analyst, in “Out of Specification
investigation form” and write the remark based on outcome of discussion with
analyst.
If no obvious error was identified and none of above
conditions was met, then phase-Ib investigation must take place.
Phase-I (b) Investigation:
If no obvious error is identified analyst and
supervisor should initiate phase Ib investigation as per the checklist.
This
should include.
Correct
methodology followed.
Test preparations.
Correct
sampling procedure followed.
Proper
calibrated instruments/ equipment’s are used.
Equipment
and other log entries are available.
Appropriate
standards are being used.
Correct
glassware used.
System
suitability conditions are followed.
If assignable cause is identified during investigation
done by analyst and supervisor, invalid the initial test data.
On completion of analyst and supervisor investigation,
re-measurement can start once the hypothesis plan is documented and is only
support the investigation testing.
If hypothesis is proven, repeat the analysis in
triplicate by the same analyst. If same analyst is not available, second
analyst with equal qualification can perform the analysis.
Record the results. Generate the CAPA and close the
investigation.
If no assignable cause or evidence of error is
identified, Phase-II investigation is to be started as per the checklist.
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| OOS investigation flowchart |
Phase-II Investigation (Manufacturing):
In case no assignable cause to the OOS test result is
established, the QC- Designee / Manager shall refer the matter to QA &
production department for investigation of manufacturing process within 2
working days.
QA department should be raised deviation and log in to
the deviation logbook as per the SOP of “Handling of Deviation” PAL/QAD/O/008.
QA & production departments shall jointly
investigate the manufacturing & packing process to identify any possible
root cause. Other applicable departments such as engineering, warehouse, ARD,
FRD shall be in involved if necessary.
The investigation shall include but not limited to:
To
check any deviation from manufacturing procedure or equipment operation
procedure or environment monitoring parameter & yield at different stages
etc.
Review
of trend of result of starting material, stability data & impact of the
trend on related attributes etc.
Review
of trend data of past batches in last 12 months.
Interview
with personal involved
During review, if any assignable cause is identified as
manufacturing errors, OOS test results shall be considering as valid. Decision
for the approval or rejection of the batch shall be taken by QA-Head and based
on review of additional relevant data such as stability data, method validation
report etc. & further CAPA shall be proposed.
Head-QC discontinues the further stages of
investigation.
Phase-II Investigation (Quality Control):
If no assignable cause is identified during phase I(b)
investigation, hypothesis testing should be started.
Hypothesis testing performed to help confirm or
discount a possible root cause i. e. what might have happened that can be
tested. It may include:
Sample
preparation.
Sonication/Extraction.
Potential
equipment failure.
Multiple
hypothesis can be explored.
This hypothesis testing may continue from the
re-measurement of the original preparation.
During hypothesis testing can include additional
testing preformed using a predefined testing plan to include retest performed
by an analyst other than one who performed the original test. A second analyst
performed a retest should be at least an experienced and qualified in the
method as the original analyst.
Based on the hypothesis re-testing by using initial
sample can be performed by second analyst as per predefined.
If any assignable cause is identified invalid original
results and retest the sample. Report the re-test results. Performed impact
assessment and proposed the CAPA.
If investigation determines analyst error all analysis
using the same technique performed by the concerned analyst should be reviewed.
If no assignable caused is identified based on sound
scientific justification re-sampling can be done.
Resampling should be done in case of:
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.
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.
Impact assessment on the batches sampled by previous sampling techniques
is to be done.
It involves the collecting a new sample from the batch
It will occur when the original sample was not truly representative of the
batch or there was a documented/traceable lab error in its preparation.
Analyst to present analysis by using re-sampled
material, if show falling results, confirm the OOS.
If analysis perform of using resampled material is
passing the test, repeat the analysis for 05 times. If all results are passing,
then take the average of all results and release the batch. Any one result is
not within the limit, the OOS results shall be treated as valid and decision
for disposition of material shall be taken by QA Head.
Phase III Investigation:
Extended / Failure Investigation: QA
shall review the completed manufacturing & combined laboratory
investigation to perform the impact assessment on other batches, ongoing
stability studies, validated process, and trend data of previous batches,
testing procedure and method validation.
The conclusion of investigation shall be evaluated
& documented along with appropriate corrective action & preventive
action based on above complete review.
The batch quality shall be determined & disposition
decision shall be taken by QA Head.
The OOS investigation shall be completed within 30
working days of initial OOS occurrence. In case, an interim report shall be
issued by QA & that shall describe details, reason for extension &
timeline for completion & shall be approved by Head-QA/ Designee.
The extension for given timeline shall be allowed only
two time & unless same be failed, the risk assessment shall be performed.
The data associated with initial OOS like STP,
protocol, chromatogram, calculation sheet etc. shall be invalidated after
evaluation by QC-Head.
Trending of OOS test result shall be performed
quarterly, category wise like analyst error, instrument error, method /
specification error, material / product error etc. the same shall be reviewed
as a part of APQR & Management
review.
OOS in case of Stability Sample:
OOS results in case of stability sample shall be
investigated preliminary for Phase-I investigation where following points shall
be taken into consideration as (but not limited to).
Trend
of the product.
Nature
of the product.
History
of the failure.
Expected
failure
Comparison
between other strength & peaks
Comparison
between similar manufacturing formula
Pack
integrity
On investigation, the reanalysis result if found not
within the specification, the OOS result shall be treated as valid. The Head-QC
/ Designee shall discuss with Head-QA. The QA & QC shall investigate the
case jointly for storage condition of sample in the stability chamber for:
Any
deviation in the maintaining of temperature & humidity.
Location
of sample in the chamber.
Any
damage to pack.
If there is assignable cause noticed shall be corrected
with proper corrective action & preventive action & further impact
analysis shall be performed.
If there is no assignable cause identified for storage,
the Head-QC / Designee may authorize for retest on the original sample by
second analyst in duplicate.
In case, the test result is not within the
specification, the OOS result shall stand valid & further stability study
shall be continued for next station. If the result of the next station sample
is also found failing with respect to the test for which OOS reported.
The decision for stability study discontinued shall be
taken in consultation with QA.
Note - The OOS investigation shall not be
performed for stability interval beyond shelf life, the same data shall be
monitored for data generation purpose only.
OOS in case of Raw Materials and Packing Materials
If the results are not within limit, the OOS results
shall be treated as valid & decision for disposition of material shall be
taken by Head-QA.
OOS result in case of raw material shall be
investigated preliminary for Phase-I investigation.
Head-QC may allow for retest on original portion by the
second analyst in triplicate.
If the results are not within limit, the OOS results
shall be treated as valid & decision for disposition of material shall be
taken by QA-Head.
The communication about failure of raw material &
packing material shall be shared with the Warehouse, QA, Purchase department,
Vendor & Customer.
If OOS observed at Outside laboratory, then
investigation shall be started from Phase-II.
