STANDARD OPERATING PROCEDURE

TITLE: QC LABORATORY INVESTIGATION OF OUT OF SPECIFICATION & SUSPECT RESULTS

SECTION: Laboratory Controls SOP NO: INV-001 DEPT: Quality Control
ORINGNATED BY: JULIE JIANG (QC CHEMIST) ISSUE DATE: 12/18/17 REVISION: 00
APPROVED BY: Manager: Farida SIGNATURE: Farida APPROVAL DATE: 01/11/18
EFFECTIVE DATE: 02/01/18

SCOPE: This procedure applies to both quantitative and qualitative analytical results generated for all
Finished Products, In-Process, Stability and Raw Materials analyzed by the QC Laboratory

PURPOSE: To define the process for conducting Laboratory investigation of Out of Specification (OOS)/
Out of Trend (OOT)/ Suspect results and reporting of laboratory data.

DEFINITION:
OOS result A final analytical result which is not within the defined and approved Product/Material
specifications.
OOT/Suspect A result obtained which is within specifications but not:
result A typical result for the test performed Supported by the result(s) from other test(s)
Examples:
A significant difference (>5%) between Assay result and the average of CU results
if performed using similar methodology.
● For Solid Dosage Form, if the dissolution result for one or more unit is greater than
115%
● For Oral Suspension, if the dissolution result for one or more unit is greater than 125%.

Root Cause The original, “true” or most fundamental cause of the deviation.
Laboratory An error created within laboratory and consisting of either Instrument Error (malfunction etc.),
Error Analyst Error, Methodology Error (mistake in the method or inadequate method) or Error due to
Environmental Factors.
Investigation A QA approved document that defines the test plan to be executed, the hypothesis to be
Protocol investigated, and the evaluation criteria. Any testing not defined in an SOP must be detailed in a
protocol.
Control A sample with a known value, which may be used in order to determine whether a laboratory
Sample error occurred during sample preparation.
Confirmatory Additional testing performed on the original sample composite according to a predefined
Testing procedure and acceptance criteria as per the current test method to verify initial results
Percent (Result A - Result B) / Result A x 100
Difference
Original Test Sample (for example solution or suspension) under investigation.
Sample
System Error caused by computer system/software issues. E.g. programming failure;
Related application is not working as intended without human intervention.

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BACKGROUND: The objective of the laboratory investigation is to determine the validity of the OOS/OOT/
Suspect result by determining:
a. If the proper methodology, instrumentation and calculations were used.
b. If there was an error introduced during the laboratory testing.

If there is objective evidence that a Laboratory error occurred, the initial OOS/OOT/Suspect
result will be invalidated. When there is no clear evidence that a Laboratory error occurred, a
Complete investigation will be performed by the Quality Assurance Group to determine the
cause of error in accordance with the QA Investigation Protocol.

REFERENCE DOCUMENTS:

1. FDA Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production, October 2016.
2. SOP: SN 0132;

RESPONSIBILITY: Analyst, Lab Supervisor, Investigation Supervisor, QC Manager, Compliance Manager,

QA Specialist, Site QA Manager

PROCEDURES:

1. NOTIFICATION OF OOS/OOT/SUSPECT RESULT(S):

1.1 Notify Supervisor and QC Lab Manager immediately if an OOS or OOT/Suspect test
result is obtained
1.2 All standard and sample preparations, glassware, reagents, as well as consumable
materials (disposable filters, syringes, chromatography vials) where appropriate, must be
retained and reserved to aid in the investigation.
1.3 If the error occurred before the start of the analysis, i.e., spilled sample, or observed
during/after the analysis, i.e., system suitability failure, an explanation will be written in
the workbook with signature and date immediately after noticing it, with verification by
laboratory management/supervisor before continuing the analysis

2. PHASE I INVESTIGATION (Laboratory Bench Audit Investigation)

2.1. The supervisor performs the following steps no later than 24 hours after
notification.
2.1.1 Reviews the preliminary testing data to confirm that an OOS result was obtained.
Raw data obtained in the analysis to be examined by the supervisor, including
chromatograms and spectra and identify anomalous or suspect information.
2.1.2 The checklist must be completed by the analyst.
2.1.3 Interview the analyst and discuss the test method and critical analytical steps with
the analyst and confirm analyst knowledge of and performance of the correct
procedure
. 2.1.4 Confirm that appropriate and valid reference standards, solvents, reagents and other
solutions were used in the analysis.
2.1.5 Promptly examine all standard and sample solutions prepared during the analysis.
2.1.6 Verify instruments used were properly calibrated and meet established
performance specifications.
2.1.7 Confirm that all manual or automated calculations are correct.
2.1.8 Document any physical observations or anomalies which may support root cause
determination.
2.1.9 Confirm method validation and/or method transfer have been completed.
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2.2. Verification of original results:
2.2.1 Standard Verification: Reference standard must be verified against the secondary
reference standard stock bottle (when applicable) in Phase 1 investigations.
Reference standard may further be verified against the primary compendial reference
standard if available in Phase 2 investigations.
2.2.2 Re-Measurement: Whenever possible, the re-measurement should be performed for
each impacted lot/sample under the investigation.
a) Re-injection:Confirm the performance of the instruments by re-measuring the
OOS/Suspect original vial in triplicate. Re-measure a control
sample in triplicate whenever possible.
b) Re-filtration:Confirmation that no error was made during the mixing and
filtering of the original working sample solution, whenever
possible. The original working solution should be re-filtered, in
triplicate using a separate filter each time along with a control
sample if possible.
c) Re-dilution: Whenever possible, re-dilution is to be performed, in triplicate, to
determine if the analyst made a dilution error
d) Extraction: If suspected, further extraction of the active ingredient in the original
stock sample solution can be performed to determine whether it was
fully extracted during the original analysis.This can be achieved by
conducting additional shaking or sonication as appropriate, followed
by triplicate re-dilution whenever possible
e) Raw data: A separate page or book must be used to document investigation by
chemist, examples; re-preparation, re-dilution, etc.
2.2.3 Verification (Phase 1 Retest)
In situations where results cannot be verified due to degradation, GC Headspace
analysis or any other situation where the sample is consumed, then a single` retest will
be permitted to verify the initial results.
2.2.4 Where Original Results have been Verified:
When Standard Verification, Re-Measurement and Verification meet the criteria’ and
verifies the original results, proceed to Phase II for Confirmatory Testing, The original
results must be reported on the Certificate of Analysis.
2.2.5 Where Original Results have not been Verified:
2.2.5.1 Where Standard Verification, Re-Measurement and/or Verification exceed the
'% difference between results or mean criteria’, and an assignable cause is
found during Phase 1, proceed with retest
2.2.5.2 Where Standard Verification, Re-Measurement and Verification exceed the
'% difference between results or mean criteria’, but the exact root cause was
not identified. If no assignable cause is found during Phase 1, proceed with
Phase II investigation to identify the analytical root cause to aid in the
determination of effective CAPAs to prevent recurrence.

2.3 WHEN AN OBJECTIVE LABORATORY ERROR IS IDENTIFIED

2.3.1 If result invalidation is justified, the initial OOS/Suspect Result will be invalidated
and the analysis will be repeated following correction of the error as follows:
2.3.1.1 Perform the Retest on the original composite sample/original Stock solutions
which were used for the initial test.
2.3.1.2 Perform the retest using the same number of sample preparations as the initial
test.
2.3.1.3 Report only the retest result on the CofA and use this result to determine the
compliance with specifications.
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3 PHASE II INVESTIGATION
3.1 WHEN NO OBJECTIVE ERROR IS IDENTIFIED
The purpose of the Phase II investigation is to confirm the validity of the original Suspect
/OOT / OOS result or systematically eliminate possible laboratory errors which may have
caused the initial Suspect/OOT / OOS/ result. To this end Phase II investigations may be
initiated to perform either Hypothesis testing for Suspect/OOT / OOS results and or
Confirmatory testing for OOS results.
3.2. HYPOTHESIS TESTING
3.2.1 Prepare an Investigation Protocol (Hypothesis Testing Protocol) for additional testing
to be performed .The protocol is to be designed in consultation with the Lab Manager.
3.2.1.1 A new stock solution may be prepared from the original composite sample, if
applicable, to determine if the original stock solution was prepared correctly.
3.2.1.2 A new composite may be prepared from the original laboratory sample, if
applicable, to determine if the original composite was prepared correctly.
3.2.1.3 Either Confirmatory Testing or Retesting will be performed based on
the outcome of the Hypothesis Testing.

3.3 CONFIRMATORY TESTING

3.3.1 Where the criteria (Verification of Results) have been met, and no objective lab
error or possible analytical root cause has been identified, Confirmatory Testing will
be performed on OOS results for Commercial and Stability testing that are believed
to be analytically valid.
3.3.2 Where possible, Confirmatory Testing by a new analyst should be performed on a
new grind, from the original lab sample/composite sample. specification and the
acceptance criteria for Confirmatory Testing have been met.

3.4. CONFIRMATORY TESTING MEETS ACCEPTANCE CRITERIA

For tests that meet the Confirmatory Testing acceptance criteria, the original results are
confirmed and a manufacturing investigation will begin

3.5. CONFIRMATORY TESTING DOES NOT MEET ACCEPTANCE CRITERIA

For tests that do not meet the Confirmatory Testing acceptance criteria, further investigation
will be undertaken. In situations where the predefined acceptance criteria for confirmatory
testing are met but the results generated are still suspect, further investigation should be
undertaken based on sound scientific rationale by the Investigation Stream Group.

3.6. OUTCOME OF PHASE II INVESTIGATION

3.6.1 Additional investigation testing conducted as per Phase II should conclude with one
of three possibilities:
3.6.1.1 The original result is valid and verified by Confirmatory Testing, (no further
testing is required).
3.6.1.2 The original result is invalid due to an assignable cause (Retesting required).
3.6.1.3 The original result is invalid due to an unassignable cause (an unidentified
laboratory error) (Retesting required).

4. RETEST PROCEDURE
4.1 For investigations which determined the OOS / suspect result is invalid but did not
conclusively determine an assignable cause, but meet the criteria for result invalidation,
perform the retest with a documented re-test plan to include the following:
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 Reason for the retest , Number of tests to be performed, Two (2) analysts who will
perform the retesting, Details of sample used for retesting
4.2 For investigations which did find an assignable root cause, retesting should be
performed,
with one analyst only.
4.3 Retesting will be performed on the same laboratory sample which was used for the initial
test, A Replacement Sample may be obtained only when there is not enough original
remaining to perform the required test.

5. INITIATING A DEVIATION REPORT FOR A PHASE II INVESTIGATION

Upon notification of the initiation of a Phase II investigation in the lab, QA Specialist
assigned to review Phase II
5.1 IMPACT ASSESSMENT
If during the investigation it has been identified that an objective reason for the
OOS/OOT/Suspect is a result of an equipment, system, reagent / solution, procedure, etc.,
an evaluation / assessment must be initiated to determine if previously analyzed samples /
material (where applicable) are affected.

5.2 ROOT CAUSE

The following related field values are root causes
● Human Related
● Inconclusive
● Material Related – API / Excipient
● Analytical Method Related
● Computer System Related
● Laboratory Procedure Related

5.3 OVERALL CONCLUSION

The overall conclusion must state the following:
Invalidated results and reason
Results to be reported on the Certificate of Analysis
Lots which are to be rejected or released
Corrective action that will be taken by the laboratory to prevent similar investigations in
the future Other samples affected / reviewed and the conclusion

5.4 CAPA DOCUMENTATION

5.4.1 In the event an investigation indicates a preventative action (e.g. chemist

retraining,method revision, filter study) then a CAPA record will be initiated in
an appropriate computer system
5.4.2 A CAPA or a justification for excluding a CAPA must be present in each
investigation.
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