Out of Specification OOS Test Results

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Out of Specification (OOS) Test Results

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• 2003? 8? 25?

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OOS (Out of Specification)

• The failure of a batch or any of its components
  to meet any of its specifications
• OOS indicates non-compliance with specifications

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Outliers

• Statistically invalid individual test result
• Can be eliminated

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OOS General Principles

• How should we handle OOS results?
• OOS cannot be ignored or discounted without basis
• When does testing stop (accept the result)
• First test failure?
• Second test failure? Tenth test failure?

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Barr Decision (1993)

• cGMP regulations are vague about exactly how to
  handle OOS
• 1993? Barr Laboratories, Inc
• United States District Court for the District of
  New Jersey
• Jurdge Wolin made it clear
• what is acceptable and
• what is not acceptable in handling OOS

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• What does the cGMP Regulation say about Handling
  OOS Results?

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cGMP Part 211.192

• The failure of a batch or any of its components
  to meet any of its specifications shall be
  thoroughly investigated
• The investigation shall extend to other batches
  of the same drug product and other drug products
  that may have been associated with the specific
  failure of discrepancy

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cGMP Part 211.194

• A written record of the investigation shall
  include the conclusions and follow-up
• A complete record of all data secured in the
  course of each test
• Complete records shall be maintained of all
  stability testing performed

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Barr Decision

• Failure investigation is central
• Failure investigation
• Immediate
• Timely follow-up
• Appropriate resolution
• Documented

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FDA Interpretation of investigation results

• Batch acceptance or rejection must be based on
  scientific justification
• Overall body of data must be considered in
  judging the batch

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Essence of Barr Labs Decision

• Include all suspect results that fall outside
  established specifications
• Drug testing
• Drug companies must
• Validate their processes and
• Ensure the quality of the batch for release
• Out-of-Specification
• Better word than failure for non-passing results

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Essence of Barr Labs Decision (continued)

• Failure investigation Elements include
• Reason for investigation
• Summation of process sequences
• List of other batches and results
• All comments and signatures

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Key Points Essence of Barr Labs Decision

• Release of batch
• Testing must show satisfactory conformance to
  specifications, including ID/Strength of each
  active ingredient
• Context and history of product and batches inform
  the final conclusion

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Averaging

• Assay results should never be averaged because
  averaging hides individual variability
• e.g. 89, 89, 92 (x90)
• Individual content uniformity tests should not be
  averaged to obtain passing value
• Microbiology averaging is acceptable due to
  biological variability

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Averaging (continued)

• Relying on the average of OOS results and in-spec
  results is usually misleading and unacceptable
• Should not be used to hide variation in
  individual test results
• As a general rule, avoid averaging
• Preferred only when it is originally designed as
  part of test

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Averaging of Results FDA

• Caution with product release at either end of
  limits

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Avoid Testing into Compliance

• Retesting Additional test should be for the same
  sample, only after a failure investigation is
  underway
• Testing into compliance is not acceptable
• Retest only by predetermined written SOP

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Retesting

• In accordance with SOPs
• Re-test done by a second analyst
• Number of retests predetermined
• Results substitute for original
• Investigation ? Remove all bias ? Retest
• If the retest is pass, it is pass.

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Resampling Controversial

• Cannot be relied upon when testing and retesting
  have failed
• Appropriate for USP content uniformity and
  dissolution testing and for limited circumstances
  when initial sample is unrepresentative
• Never do resampling

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Resampling

• Never do resampling
• Justification for resampling
• Not representative of batch
• Sample preparation error
• Sample consumed in analysis
• Only for homogeneous material

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Reprocessing/Reworking

• Reprocessing
• Repeat of the validated process
• Reworking
• Repeat of the unvalidated process

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Reprocessing/Reworking (continued)

• cGMP is vague in allowing reprocessing and
  reworking
• cGMP allows reworking if the batches conform to
  all established standards, specifications and
  characteristics at CFR211.115

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OOS Investigations FDA Expectations

• Written SOPs
• Responsibility
• Methodology Handling of OOS
• Results
• Documentation

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Is the First Result Real?

• Are the first results true and accurate?
• Validated methods?
• Changes in validated methods?
• Qualified and calibrated laboratory equipment?
• Correct instrumentation parameters?
• Correct sample and standard weights?
• Reference standards dried properly?

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Lab Error Evaluation

• System suitability before and during run?
• Incomplete
• Dissolution of active?
• Dilution, shaking, extraction times?
• Proper
• Glassware/solution storage?
• Trained personnel?
• Documentation problems?
• Transcription errors?

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Qualification

• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)
• Maintenance Procedures (MP)

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Installation Qualification (IQ)

• Verify receipt of software and hardware product
• Identify all component of software and hardware
  product
• Connect
• Fluid
• Electrical power
• Communications
• Document

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Operational Qualification (OQ)

• Verify equipment performance (each component, in
  case of HPLC)
• Pump
• Flow rate accuracy test
• Gradient proportioning valve test
• Auto sampler
• Injection accuracy test
• Heater/cooler test
• Column heater test

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Operational Qualification (OQ, continued)

• Detector
• Wavelength accuracy test
• Linearity test
• Software
• Internal or external standard and unknown samples
• Actual vs. expected output testing

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Performance Qualification (PQ)

• Documented verification of system (hardware
  software) performance
• Verify total system control integrity
• Analytical system
• Reproducibility test
• Peak area
• Peak height
• Retention time
• Injection linearity test (5, 10, 20, 50 ?l)

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Maintenance Procedures (MP)

• Periodic procedures
• To minimize the risk of losing raw data and
  analytical results
• Inspection/replacement of normal wear and
  maintenance items
• File back-up and recovery
• Data archival and retrieval
• Security
• Lan administration

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System Suitability Test

• H/W, S/W and analysis checks to provide assurance
  of system integrity
• Before, during and following analysis of unknown
  samples
• System precision
• Separation parameters
• System suitability testing alone is not
  sufficient, qualification is still required

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Precision (Repeatability)

• Retention time (RT)
• Area
• Height
• RSD ? 1 for N ? 5

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Separation Parameters

• Tailing factor (T)
• T W/2f
• W width of the peak determined at 5 from the
  baseline of the peak height
• f Distance between peak maximum and peak front
  at W
• T ? 2

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Separation Parameters (continued)

• Theoretical plate number (N)
• N 16 (tR/tW)2
• tR Retention time of the analyte
• tW Peak width measured at the baseline

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Analytical Methods

• Validation or verification
• Finished dose form
• API
• Intermediates
• Ruggedness and robustness
• Transferability
• Person-to-person
• Equipment-to-equipment
• Site-to-site

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Chromatography

• Chromatography
• HPLC
• GC
• TLC
• Inspection
• Column (Medium)
• Mobile phase (pH, buffer, etc.)
• Expiration date (change with time)
• Detector (wavelength)
• Flow rate
• Injection volume
• Cleaning and regeneration

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Chromatography Inspection

• Identification of equipment and materials
• Status
• Reagent mfg by
• Mfg date expiration date
• Cautionary statements on label
• Expiration date
• RH (relative humidity)
• Light
• Temperature
• Cleaning
• Lab, table, equipment

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Chromatography Impurities

• 0.1 individual impurities
• Identify known impurities
• 1 total
• Impurity profile

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HPLC Consistency

• Peak areas
• Retention times
• Unusual peak shapes
• Poor chromatography
• Unexplained peaks
• Shoulders
• Poor separation
• Qualification/System suitability

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UV/Vis Spectrophotometers

• No filters (UV region 200 to 380 nm)
• Internal calibration only
• Old-outdated standard spectra
• Generally poor quality spectra
• No baseline
• Point readings
• Scanning

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IR Spectrophotometers

• Reference standard missing
• Polystyrene film
• Old standard spectra library
• Poor quality spectra
• Follow SOP for fingerprint scan
• Poor peak comparison for fingerprint region
• Fast vs slow scan speed (follow specification)
• Varying scan speeds - problem

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Balances

• Equipment not identified
• Not checked or calibrated each day of use
• Linearity test
• Zero plus 2 weight points (3 points)
• Weights missing
• No periodic checks by manufacturer
• Faulty room design
• Air flow directly onto balance
• Table stability

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pH Meters

• Buffer
• No in-house manufacturing record for buffer
• One point calibration?
• Linearity
• Lot number missing
• Temperature compensating check?

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Stability Test

• Temperature recording
• Controlled temperature vs monitored
• Actual product packaging
• Method validation missing?
• Stability indicating methods
• Impurities
• Protocol discrepancies
• Missing time points
• Late time points

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OOS Investigations FDA Focus

• Pre-established protocol for investigating OOS
  results
• Summary of specific investigation steps
• Evaluation of other batches
• Conclusion and follow-up
• Action necessary to prevent similar recurrences

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OOS Investigations FDA Focus (continued)

• Timely investigation must be performed within 30
  business days
• Investigate before retest
• Well documented
• Scientifically sound

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Investigations

• If the investigation has an attributable cause,
  then corrective action must be instituted
• Cause Incomplete capsule dissolution
• Corrective action A 15 minute sonication step
  will be added to the assay prep procedure

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Expectation of FDA

• OOS results will be generated
• Comprehensive, honest approach to investigation
  of OOS results
• Evaluation using scientifically valid principles
• Learn from the experience
• Permanent solution to the problem

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Documentation

• Document reasons for investigation
• Report the set of events that may have caused the
  problem
• Report results (actual or probable cause)
• Review of other batches and products
• Document corrective action

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Warning Letters

• In FY 1997, about 30 of GMP Warning Letters sent
  to firms referenced deficient OOS failure
  investigations
• Failure to conduct an investigation
• Inadequate follow-up

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Inspectional Observations on FDA 483s

• Laboratory Investigations for OOS Results, SOP
  xxx does not specify the number of retests which
  can be performed.
• For lot xxxx, the product was retested 6 times
  by 3 different analysts

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Inspectional Observations on FDA 483s (continued)

• 22 out of 37 failure investigation reports
  reviewed did not include corrective actions.
• There is no procedure in place to assure that
  corrective actions are actually made
• For report xxxx, 14 months had elapsed before
  the corrective action was actually implemented

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Inspectional Observations on FDA 483s (continued)

• The laboratory does not have procedures in place
  for tracking and trending laboratory
  investigations.
• The investigations do not include
• The corrective actions necessary, nor do they
  include a review of batches with similar OOS
  results, or other products affected

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Inspectional Observations on FDA 483s (continued)

• The firm does not conduct failure investigations
  for every product failure
• During the failure investigation, it was
  determined that the analytical method used was
  not stability indicating, and therefore the
  analytical results were not valid.
• No follow-up, changes or corrective actions were
  instituted regarding the analytical method.

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FDA Out of Specifications Guidance

• Draft issued in September 1998