This presentation from the Institute of Validation Technology's 7th Annual Method Validation covers regulatory expectations for deviations and out-of-specification results and protocol exceptions, change control, handing investigations and CAPAs, and avoiding common pitfalls.

1. Handling Deviations &
Unexpected Results during
Method Validation
IVT – 7th Annual Method Validation at San Francisco
July 29th 2010
Upen Shah, B.S, MBA
Sr. Director, Quality Management
Amneal Pharmaceuticals 1
Handling Deviations & Unexpected Results during Method Validation
Elements of Method Validation documents & deviations
Regulatory expectations
Guidance documents of regulatory agencies
Protocol & report evaluations
FDA proposal for validation in cGMP
Handling OOS results and protocol exceptions
Review of protocols & compilation of data
Review reports - internal audits
Report findings and observations
Documenting OOS and protocol exceptions
Preparing for and documenting Change Control
Investigations & records
Factors contributing deviations followed by investigations
Notes from industry
Handling investigations & CAPA’s
Method transfer failures
Post validation failures & QC life
Avoiding common pitfalls 2
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2. Validation Deviations & OOS
What are analytical method validation &
deviations?
How are validations performed?
Protocols & Reports?
Identification & Evaluations of
deviations?
MV the Proof of Method?
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Guidance Documents for Industry
ICH
Q2A Text on Validation of Analytical
Procedures – March 1995
Q2B Validation of Analytical Procedures:
Methodology – Nov 1996
USP Chapter <1225>
Validation of Compendial Methods
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3. 21 CFR PART 211 –
CGMP for Finished Pharmaceuticals
Subpart J-Records and Reports
211.194 Laboratory records (a) (2)
method used in the testing
meet proper standards of Accuracy and
Reliability
Current revision of the USP/NF
AOAC or in other recognized Standard Ref.
An approved New Drug Application and
Suitability of methods under actual conditions
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Subpart I--Laboratory Controls
211.165 Testing and release for distribution
Accuracy, Sensitivity, Specificity, and
Reproducibility to be established and
documented.
Such validation and documentation
accomplished in accordance with
211.194(a)(2)
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4. FDA Proposed New subpart L to 211,
entitled “Validation”
Subpart L-Validation
211.222 Methods validation
The accuracy, sensitivity, specificity,
and reproducibility of test methods
used by a manufacturer shall be
validated and documented.
Such validation and documentation
shall be accomplished in accordance
with Sec. 211.194(a)(2).
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21 CFR PART 210 - CGMP
210.3 Definitions (b) (25)
Methods validation means establishing,
thorough documented evidence, a high
degree of assurance that an analytical
method will consistently yield results that
accurately reflect the quality characteristics of
the product tested.
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5. Guideline for Method Validation
1978 Current Good Manufacturing Practices (cGMPs)
1987 FDA Validation Guideline
1989 Supplement 9 to USP XXI
1994 FDA Reviewer Guidance
1995 ICH Validation Definitions
1997 ICH Validation Methodology
1999 Supplement 10 to USP 23
2000 FDA Draft Validation Guidance
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Objective of Method Validations?
To demonstrate suitability for its intended use
To design the experimental work
for evaluation of appropriate validation
characteristics simultaneously
To provide a sound, overall knowledge of the
capabilities of the analytical procedure for:
Specificity, Linearity, Range, Accuracy, and
Precision
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6. Protocol Details and
Evaluation for Deviations & OOS
Validation protocol –
A written plan – how, parameters &
characteristics, testing equipment &
instruments, and decision points for
acceptable test results
Deviations from a written protocol should be
identified & evaluated thoroughly upon
reviewing the data obtained during the
testing
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In a case “OOS” results obtained
meaning NOT meeting acceptance
criteria
The protocol exceptions –
To deal deviations & OOS results prior
to final method validation report
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7. Performance of Validation
Analytical method validation performance
should be meticulous
could be tedious
cost of not doing it right the first time?
Waste of time, money, and resources
The characteristics of the validations
should be well understood
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Why Validate a Method?
Fulfill FDA &/Or Other Regulatory
Requirements
Establish Proof of Method
Used for Decision Making
Critical Requirement in Risk Assessment
and Management:
establishment of product-specific
acceptance criteria & stability of APIs and
FPs
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8. Validation criteria
Analytical Method Validation
Specificity, Linearity, Precision,
Accuracy/Recovery, Ruggedness
What are the acceptance criteria of
each parameter?
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Verification vs. Validation
Compendial vs. Non-compendial Methods
Compendial methods-Verification
Non-compendial methods-Validation
Compendial Method Verification –
USP Chapter <1226>
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9. Which tests to Validate ?
Testing ID
Assay / Quantitation / Purity
/Dissolution / Content Uniformity
Could be HPLC, UV, GC etc.
Biological activity
Testing product Stability
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Which Methods to Validate?
In-Process testing methods
Product Release methods
Stability indicating methods
Analytical methods for
Cleaning Validation / Verifications
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10. Contributing Factors of Deviations
Man ( Human factor )
Method ( Procedures )
Machine ( Lab Equip./ Instruments )
Material ( Chemicals & Reagents )
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FDA Validation Parameters
1987 FDA Guidelines
Accuracy
Precision
Linearity & Range
Specificity & LOD / LOQ
Recovery
Ruggedness
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11. ICH/USP Validation Parameters
ICH USP
Specificity Specificity
Linearity Linearity and Range
Range Accuracy
Accuracy Precision
Precision Limit of Detection
Repeatability Limit of Quantitation
Intermediate Ruggedness
Precision Robustness
Reproducibility
Limit of Detection
Limit of Quantitation
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Analytical MV Overview
GMP Consideration
Validation SOP / Protocols
Training
Specifications / Acceptance criteria
Sample preparation Ref. Standards
Instrument Qualification and
Calibrations & Maintenance
Validation Reports
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12. SOAR - GAS PRICES!!
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Validation SOP & Protocols
Procedure that describes:
methods requiring validation?
responsibility for performing validation?
How much?
How documented?
Protocol:
Needed in absence of a detailed SOP
A specific procedure for a type of method under
validation
Plans, “Specifications” = acceptance criteria
Data compilation & Final Report
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13. Data Review & Deviations
Compilation and data Review
Regulatory and Compliance
Requirements Review
Experimental data
compiled, reviewed &
a final Report is prepared
Deviations, OOS & Exceptions
Must be noted & investigated
Any Deviations / Failures need to be
identified
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Extensive Investigation ?
Rigorous OOS procedures – When applicable?
How Deviations issued?
Investigations? Reported?& True error?
E.g : One data point of the standard curve of a
linearity test is inconsistent with the other
points (i.e., OOS because it fails acceptance
criteria)
E.g: Dilution by analyst. This should not be
ignored to ensure someone doesn't use
inappropriate procedures -- such as testing into
compliance.
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14. Root cause may be revealed
e.g trends, such as a high error rate
associated with particular analyst or a
recurring instrument problem
CAPA considered - Analyst training or
Instrument maintenance & calibration
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Case of Extensive
Investigation NOT required
Example
Coeluted peaks – during specificity
experiment ( e.g forced degradation,
placebo/ matrix evaluation, analysis of
known degradants/impurities )
The separation modified and the
validation restarted
No extensive Investigation required
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15. Barr decision - QC release of drug substance
and products & testing of in-process samples
Only validated release testing considered
Applicability to unvalidated methods?
US v. Barr did not deal with method
development/validation?
Validation protocol criteria?
Based on experience gained in developing a new
analytical method
Analyst's best guess at what to expect following a
limited amount of experience with a new method
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When the results obtained do not
comply:
investigation needs to be performed
to determine
whether method development
done was sufficient? OR
whether the criterion was simply
too tight?
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16. Deviation & OOS Handling Notes
Method validation - a recursive process
Non-complying results means various
possibilities:
method improvement OR
Criterion to be changed with proper
justification
Based on these, changes may be made
through Change Control procedure,
when required
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No system allows a company to openly deal with
validation failures
Notes to be made:
ICH Q8–10 guidelines and the US FDA (OOS)
guidance document provide regulatory
flexibility
Current industry practice is that risks be
managed -
to the extent of validation studies executed
but not so much by actually using risk-based acceptance
criteria
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17. Common Pitfalls:
Calibration failure
In which Performing Tests on System Components to
Ensure Proper Functioning
If the instrument is not calibrated, tests are invalid
System Suitability failure
S.S Tests to verify the proper functioning of the operating
system
If the system is not suitable, the tests are invalid
Untrained analyst & or reviewer
Data obtained are not to be considered
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FDA – OOS Guidance document
Very systematic approach for OOS investigation
Identifying & assessing the deviation/OOS result,
Investigating - Lab phase
Retesting, Resampling and full scale investigation
Averaging, Outlier test
Conclusion & CAPA
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18. Method Transfer Failures
Validated method when need to be transferred to
QC routine lab or other site
Concept of “abbreviated” or “limited”
validation
Identify the failures
To verify the validation and transfer protocols
Very systematic approach for investigation
Treat failures as an OOS or OOT
Explainable / logical OOS
Unexplainable / illogical OOS
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Post Validation Failures & QC Life
QC daily routine worker - mostly not
exposed to Validation
QC method training
an overview of the basis of the method
the critical steps and materials
the behavior of the method as reviewed
in the method validation report – for
their usefulness in QC
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19. FDA references
to use of the method validation along
with historical trending data by QC
to ensure that the test method is
behaving as intended
Why are these important?
What are the implications?
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Method trending files to be reviewed
on a routine basis by the Quality group
with reference to the validation
parameters
the capability of the method to
monitor?
Method still behaving as intended
when the specifications were set?
has there been a drift?
to what could this be attributed?
and how can it be addressed? 38
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20. FDA Form 483 Observations,
Warning Letters & EIR’s
483 Observations
There was no adequate method validation
specificity data to demonstrate that each
method was capable of distinguishing the active
ingredient from its impurities and degradation
products.
Specificity studies did not include the minimum
stress conditions of acid and base hydrolysis,
oxidation, thermal degradation and photolysis,
degradation schematic for the active ingredient
that identifies the major degradation products
was not included for each product.
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Stress studies conducted as part of method
validation do not target a minimum amount
of degradation. … a standard period of two
hours as commonly used for stress studies
with no justification…
Spreadsheets used to calculate linearity,
percent recovery, and final assay results for
the cleaning validation of …were not
validated and the data transcribed from
chromatographs to the spreadsheets were
not checked for accuracy.
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21. Warning letters & EIR’s
A statement indicating that the method has not
been validated in the particular formulation was
included in the certificate of analysis for…use of
this statement does not absolve…from using valid,
accurate and reproducible methods.
There is no assurance that qualification or
maintenance of the laboratory equipment can
consistently produce valid and accurate analytical
results in that numerous examples of test data were
invalidated due to instrument malfunction.
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Change control procedures in the laboratory
failed to document test method changes to
assure accurate, reliable, and reproducible
results. The test method did not state
whether a helix was to be used during
dissolution testing. A … was reportedly used
during method development, validation and
daily method runs, but there is no
documentation of a … being used in any of
the documents.
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22. Attempts to corroborate data in the validation
report with supporting raw data in the laboratory
were difficult and frustrating for the FDA
personnel conducting the inspection.
OOS accuracy results reported by analyst 3 were
never submitted in the final report. Repeat analysis
performed in a different system passed
specifications and these results were submitted in
the report.
Raw data and calculations were not checked by a
second responsible individuals required by your
procedures. Inaccurate calculations were noted in
the report.
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The process validation samples were
assayed using an HPLC method that had
not been validated. The method validation
used for both products … did not include a
protocol that included specification and
acceptance criteria. … The method
validation was not reviewed and approved
until during the current inspection. Lots of
both products were released for distribution
prior to completion of the method
validation.
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23. Compendial methods not verified, no system
suitability testing performed .
Insufficient documentation of method
validation, inadequate documentation of
laboratory equipment calibration,
Method validation documentation did not
include appropriate data to verify that the
analytical method produced accurate and
reliable data
Laboratory equipment calibration was not
adequately documented.
45
Failure to validate changed USP standard
methods, missing validation for stability
indicating methods, insufficient
documentation of test methods, insufficient
documentation of changes, no follow-up of
OOS situations, failure to release products
that do not meet USP requirements,
incomplete batch records
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24. Inadequate validation of the analytical
method for detecting residual solvents in
xxxx in that an unknown xxxx was
determined above the limit
Accuracy of the test for xxxx was determined
at a higher concentration than the limit
Linearity and limits of detection were
determined above the limit of the test
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Extraneous HPLC peaks continuously
explained to be autoinjector contamination,
no further investigation
Missing acceptance criteria for validation
testing
Failure to effectively train employees in
laboratory operations to assure that original
records are accurate, complete and in
compliance with established specifications.
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25. FDA Systems Based Inspection:
Laboratory System
- 477 Observations in a typical year
Controls & General – 35%
Inadequate Records – 27%
Stability Program – 21%
Method Validation – 13%
&Training & Qualification – 4
Source – FDA, CDER Office of Compliance
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Most Common GMP Deficiencies by System
Domestic Inspections by FDA
Quality -47%
Laboratory -19%
Production – 11%
Facility & Equipment – 8%
Materials – 6%
Packaging & Labeling – 0%
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26. Important Check Points:
Check whether any failures occurred in the past for
similar methods?
Review all the developmental work notebooks, data for
such occurrences – Interview the Devp. Chemist/
Analysts
Review the protocols again – to find out the
justifications for acceptance criteria.
Verify all the critical characteristics for OOS &
deviations.
Where do we stand with Regulatory agency for OOS
dealing?
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References
• ‘Analytical Methods Validation for FDA Compliance’
Guideline for submitting samples and analytical data for
methods validation (Feb. 1987)
• ICH Q2A
• ICH Q2B
• 21 Code of Federal Registrations Part 210 and 211
• USP – Current <1225>
• FDA 483’s & Warning Letters
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27. QUESTIONS????
THANK YOU
upen@amneal.com
Branchburg Facility
131 Chambersbrook Road
Branchburg, NJ 08876
908.231.1911
www.amneal.com 53
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