Transcript Slide 1

Out of Specification
and Atypical Test
Results
Contents
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Objective
Definitions and terminology
General investigation principles
Investigation stages
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Initial Laboratory Investigation
Full-Scale OOS Investigation
Additional Laboratory Testing
Review of Production
• Importance of corrective and preventive
actions
Process overview
Manufacturing of batch
Sampling
Analysis of sample
Evaluation of results
Cause for an investigation
Manufacturing of batch
Sampling
Analysis of
sample
Out of Specification
arises:
Production
error?
Analytical
(lab)
error?
Investigation
Evaluation of results
Root cause
assigned?
Corrective
and
Preventive
Action?
References
 FDA Guidance for Industry : Investigating Out-of-Specification
(OOS)Test Results for Pharmaceutical Production, October
2006 : Contains Nonbinding Recommendations
 USP– NF General Chapter <1010> Analytical Data –
Interpretation and treatment
 ICH Q7A Note for Guidance on Good Manufacturing Practice
for Active Pharmaceutical Ingredients, November 2000
 EU Guidelines to GMP Part I Chapter 6 Quality Control Section
6.32.
Definitions and Terminology (1)
• Out of Specification (OOS) Result
– Reportable result that falls outside established specifications or acceptance
criteria.
– Do not include situations where Control test is not continued due to violations of
system suitability tests (SST) limits
– Identification of gross operator-errors during a run: e.g. wrong instrument
settings
– Such deviation cases should be tracked in order to apply CAPA if appropriate
• Reportable Result
– Result that must be compared to a particular acceptance criterion.
– May be “an average value, an individual measurement, or something else”, as
defined in the control test [USP]
Definitions and Terminology (2)
•
Established Specifications or Acceptance criteria:
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Atypical Test Result or Out of Trend / expectation, suspect, …
– Approved specifications or acceptance criteria (e.g. limits) with respect to the final
result (reportable result) in order to evaluate the quality of a product or sample.
– May be official (part of a regulatory file) or internal (e.g. additional or alternative
control tests)
These do not apply to:
– Acceptance criteria during the course of analysis (before the reportable result) such as
system suitability tests (SST), warning limits, in-process control limits for process
adjustments
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Result within specification
Result different from those usually obtained or expected
Same general investigation principles as OOS results
Site Quality Control Manager must determine extent and depth of any
investigation
Definitions and Terminology (3)
• Re-analysis
– Analysis of retained sample preparations
– Repeating some part of the testing, e.g.
 re-measurement
 re-injection
 redilution of sample and standard preparations
 Further extraction
• Fresh analysis
– Performing the testing as normal (New execution of the control
test)
– As described in the control test
– Only allowed if initial results could be invalidated
Definitions and Terminology (4)
• Retest :
– New preparation and analysis of a portion of the original sample
– Part of a full-scale OOS investigation
– Using a predefined procedure/plan with a MAXIMUM number of
retests,
– Used to verify/ reject the possibility of laboratory errors
• Control Sample :
– A sample of material that has previously been tested and approved or
well characterised.
• Re-sampling :
– Collecting and analyzing a new sample from the product
– Must have a documented rationale for re-sampling, (e.g. original
sample not representative or compromised/contaminated)
– Used for confirmation of product failure
Presentation Scope
• Applicable to QC laboratories, Manufacturing
sites and Affiliates
• All GMP relevant laboratory testing including
inprocess controls
– Where approved specification or acceptance limits are
established.
Note: Compendial tests
Where interpretation and handling of test results are described,
those procedures are to be followed.
Principles of Investigation (1)
•
All OOS or atypical test results must be thoroughly investigated and
documented
– Includes identification of root cause
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OOS or Atypical test results are only allowed to be invalidated if a
laboratory error can be assigned
– Demonstrated or indicated with high probability and/or a product failure definitely
excluded
– Supporting information and/or data
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Timely initiation (e.g. 2 business days) and completion (e.g. 20 business
days)
– Otherwise written rationale
– Sterile products: a parallel investigation in the manufacturing area must be initiated
immediately
– A risk assessment and notification in case of confirmed OOS for product already on
the market or for a risk that could affect other batches or products on the market
Principles of Investigation (2)
• Consider:
– Problem has occurred previously (historical data)
– Possibility that other batches or products are affected
• Corrective actions must be defined as a conclusion of the
investigation and followed through to prevent reoccurence
• A system must be in place for the tracking of OOS results
• Investigation phases
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Initial Laboratory Investigation
Full-Scale OOS Investigation
Additional Laboratory Testing
Review of Production
Responsibilities (1)
• Analyst
– Achieves accurate analytical results
– Should not use systems that do not meet system suitability
requirements (SST); or in such case during analysis identifies data
collected during suspect time period (e.g. reference standard injection
runs in a chromatographic system)
– Should not continue test in case of obvious error (spilling of a sample
solution, incorrect dilution etc.)
– Immediately reports the OOS to his/her supervisor
– Retains the original test solutions, materials and source data
– Participates in the investigation
Responsibilities (2)
• Supervisor / QC Manager
– Conducts an objective and timely investigation
– Informs Site Quality Manager (immediately in the case of a sterile
product)
– Decides upon investigation of atypical results
• Site Quality Manager
– Ensures specific site procedures and systems exist
– Ensures appropriate training given
– Makes batch related decisions when an OOS or atypical result is
confirmed
– Informs all relevant departments
– Assuring that corrective actions are taken to prevent reoccurrence
– For sterile products, promptly initiates parallel investigation in
laboratory AND manufacturing area.
Initial Laboratory Investigation
OOS/OOT results identified by Analyst.
Supervisor informed immediately
INITIAL LABORATORY INVESTIGATION
Assess whether the test procedure was followed correctly
(calculation; sampling; sample preparation; equipment
functionality& qualification; training etc)
Laboratory Error
Identified?
YES
See slide 18
(Lab error IS identified)
NO
Full scale OOS investigation
required
(See slide 20 )
Initial Laboratory Investigation:
examples (1)
• Method discussed between analyst and supervisor : confirm analyst
knowledge of and performance of the correct procedure
• Verification of calculations
• Review of samples for correct labelling and identification
• Verification of correct laboratory test methods
• Examination for proper documentation
• Review of chromatograms, spectra, data and calculations
• Review of reagents, media, diluents, controls and standards
• Examination of the instruments and laboratory systems
(qualification, calibration, maintenance)
• Review other samples run concomitantly (if any)
Initial Laboratory Investigation:
examples (2)
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Verification of analyst’s training history
Inspection of prepared sample
Reanalysis/Redilution of test samples (if stable)
Supervisor fully document and preserve records of the Initial
Assessment
 Everything except new sample preparation
Laboratory Error is Identified
(Initial Lab investigation- slide 15)
Laboratory error IS identified
Invalidate original
test results
Consider Implication on
other analytical
tests/products
Fresh analysis
Evaluation if
positive
New Evaluation
Conclusion
CAPA plan
Implement CAPA
action plan and
follow through
Categorising Errors
Error type:
Description:
Transcription Error
Wrong interpretation or calculation
Identifiable Analytical
Error
• Non-adherence to control test instructions
(wrong materials, dilutions, instrument settings
etc.)
• Equipment malfunctions
Anticipated OOS
E.g. stability, accelerated conditions or beyond
shelf-life
Consider Actions for improvement of processes/
prevention of errors – e.g. training analysts;
instrument re-qualification, update to procedures.
Full scale OOS Investigation
Laboratory error is NOT identified
(from slide 15):
Full Scale OOS investigation
Review of Production
(slide 22)
Additional
Laboratory testing
Areas to review will include:
Full Laboratory investigation
• Batch Dossier Evaluation
• Equipment: Validation,
Qualification, Calibration
• Training of Personnel
• Risk Management Evaluation
Follow Company protocols on:
•Re-testing
•Re-sampling
OOS Confirmed?
(See slide 21)
NO
Deviation explaining
OOS confirmed?
YES
Batch Failure Investigation
(See slide 21)
OOS Confirmed?
YES
(Additional Laboratory testing, slide 20)
NO
OOS Confirmed?
YES
Batch Failure
Investigation
Evaluate rejection of batch
•Risk Assessment
•Quality Alert Notification
Impact on Other
Products?
Document.
If yes, further
evaluation required
Investigation
report
Lab error
identified?
NO
Take all results into
consideration
See slide
18, above.
Review of Production
• Involvement required of all departments that could be implicated:
Manufacturing, Process Development, Maintenance, Engineering,
Sub-contractor
• Timely, thorough, well-documented review
• Review of: batch dossier, equipment (qualification, calibration),
personnel training and risk management evaluation, etc.
• Once Root cause is identified and CAPA plan implemented: OOS
investigation may be terminated
Additional Laboratory testing;
retesting; Maximum number; design
• Variables : number specified in advance, analyst, control samples …
• Must be defined before testing
• Case-by case decision, e.g. depending on
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Possible cause of the OOS (analyst, equipment, sample …)
Level of confidence required
Analytical variability
“Extent” of OOS
Additional Laboratory testing:
Resampling
• Resampling to be carried out:
– in accordance with predetermined procedures and sampling strategies
– where it is identified that the original sample was improperly prepared and not
representative of batch quality
• Use same sampling method unless it is demonstrated as inadequate
Reporting Testing results: Averaging
General Considerations
• Mean
 Estimate of the true value
 Reliability increases with the number of determinations
 However: may hide (unacceptable) variability
• Reportable results and acceptance limits
 Correlated
 Evaluation of single results requires wider limits due to the broader distribution
 If the mean is defined as reportable result, the variability should be checked
(standard deviation or range)
Reporting Testing results:
Appropriate and Inappropriate Uses of Averaging
Appropriate
• When sample assumed homogeneous and if the written and approved
test method specify that the average of multiple replicates (assays) is
considered one test and represents one reportable result
Inappropriate
• When testing is intended to measure variability of a product (blend
uniformity, content uniformity)
• In case of additional testing during OOS investigation because
variability is hidden
– Specifically when some results are OOS and other within specifications
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Provide all individual results to quality management responsible for
approving or rejecting the product
Reporting Testing results:
Outlier Tests
• Outlier result, Definition: A value obtained, on rare occasions,
markedly different from the others in a series, with a validated
method
• Outlier testing: statistical procedure for identifying from an array
those data that are extreme:
– SOP is mandatory (includes minimum number of results required, to obtain
a statistically significant assessment)
• Used when it is not possible to reveal the root cause of OOS/
deviation
• May be used as investigative tool
• Should not be used as sole criteria to invalidate data
Concluding the Investigation
• Results evaluated, batch quality determined,
release/rejection: decision by Quality Management
• OOS cause revealed:
– Suspect result invalidated and not used
– OOS confirmed and is caused by factor affecting batch quality
– OOS result used to evaluate quality of lot
• OOS Cause not revealed:
– Inconclusive investigation
– OOS not confirmed
– OOS result given full consideration for batch decision
Reporting and Documentation
• OOS report should include the following:
 Chronology of the investigation
 Full description of the initial laboratory investigation including an
analysis of all data derived from all testing
 Batches or products involved
 Justification for invalidating any data
 Conclusion including conformity of final results and batch
 disposition
 Corrective and preventive actions taken to prevent the OOS
 from occurring again
• Uniquely numbered to permit tracking
• Maintained in a controlled and retrievable manner
OOS Investigations
• Clear definition of the reportable result
• Thorough, timely, well documented, scientifically justified
with no preconceived assumptions
– Clear and methodical escalation
• Objective to assign a cause
– Product failure
– Laboratory (analytical) error
• Corrective actions to prevent reoccurrence
• Atypical results: chance to increase data quality
– E.g. in stability studies
Examples: Identification of
Analytical Errors
Examples of Errors
Solutions
One injection OOS,
reanalysis/reinjection ok
Instrument failure (consider
maintenance, repair, qualification)
All injections of one sample
preparation OOS, redilution ok
Dilution error (consider training,
clarification of control test)
One sample preparation OOS,
retesting 2nd analyst ok
Analyst error (consider training,
clarification of control test)
Results near limit, one result just OOS; Reportable result? May indicate
1 out of 4 retests also OOS
unsuitable specification limits (too
tight for the analytical variability)
All sample preparations OOS, retesting Sampling error or batch failure
OOS, control samples ok
Thank You
Any Questions