FDA 483’s in the LabFDA 483’s in the Lab
Current IssuesCurrent Issues
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues
483 Observation Rates
for ALL Systems
Recent FDA Documents: 216 inspections: 2,221 observations
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues
LABORATORY System
483 Observation Rates: 216 inspections; 477 observations
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues
71 Observations
Contract LaboratoriesContract Laboratories
Laboratory
53%
Material
6%
Other
4%
Production
1%
Quality
21%
Packaging/Label.
1%
Facilities/Equip.
14%
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues
%Citations by System
26 warning letters over a three year period
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues
Warning Letter Summary
• 26 Warning Letters issued
• Quality or Production or Laboratory
cited in every letter, 26 of 26
• Quality cited in 20 of 26
• Production cited in 18 of 26
• Laboratory cited in 17 of 26
• Quality & Production & Laboratory cited in
10 of 26
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s and Warning LettersFDA 483s and Warning Letters
Warning Letter A (Drug Product Manufacturer)Warning Letter A (Drug Product Manufacturer)
Failure to conductFailure to conduct performance qualificationperformance qualification on the laboratory instruments (HPLCon the laboratory instruments (HPLC
and GC) that are used to analyze raw materials and finished products.and GC) that are used to analyze raw materials and finished products.
Failure toFailure to validatevalidate software programs used to run HPLC equipment. Software usedsoftware programs used to run HPLC equipment. Software used
doesn’t secure data from alterations, loss, or erasures and allow for overwriting ofdoesn’t secure data from alterations, loss, or erasures and allow for overwriting of
original data.original data.
Warning Letter B (Drug Product Manufacturer)Warning Letter B (Drug Product Manufacturer)
Failure toFailure to calibrate HPLCcalibrate HPLC used for testing in-process lots.used for testing in-process lots.
Performance qualifications didn’t include critical chromatographic specificationsPerformance qualifications didn’t include critical chromatographic specifications
No SOP requiringNo SOP requiring calibrationcalibration of laboratory equipment.of laboratory equipment.
Warning Letter C (Drug Product Manufacturer)Warning Letter C (Drug Product Manufacturer)
Failure to establish SOPs orFailure to establish SOPs or document the performance qualificationsdocument the performance qualifications andand
maintenance of analytical equipment used in the testing and release of drugmaintenance of analytical equipment used in the testing and release of drug
product.product.
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20132013

FDA 483s and Warning LettersFDA 483s and Warning Letters
Warning Letter D (Drug Product Manufacturer)Warning Letter D (Drug Product Manufacturer)
Failure toFailure to validatevalidate the Dissolution Test Method used to test the drug product.the Dissolution Test Method used to test the drug product.
There is no assurance thatThere is no assurance that qualification or maintenance of laboratory equipmentqualification or maintenance of laboratory equipment
can consistently produce valid and accurate analytical results because ofcan consistently produce valid and accurate analytical results because of
numerous instrument malfunction.numerous instrument malfunction.
Warning Letter E (Contract laboratory)Warning Letter E (Contract laboratory)
No established procedure for theNo established procedure for the qualification of analytical instrumentsqualification of analytical instruments for drugfor drug
testing, when purchased and installed in this laboratory.testing, when purchased and installed in this laboratory.
483 Observations A (Drug Product Manufacturer)483 Observations A (Drug Product Manufacturer)
Several major laboratory instruments (HPLC, AA/AE/GC, etc,..)Several major laboratory instruments (HPLC, AA/AE/GC, etc,..) have not beenhave not been
qualified (installational, operational and performance qualificationqualified (installational, operational and performance qualification).).
System suitability tests are not performedSystem suitability tests are not performed for several methods.for several methods.
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA 483s and Warning LettersFDA 483s and Warning Letters
483 Observations B (Contract Test Laboratory)483 Observations B (Contract Test Laboratory)
RoutineRoutine calibrationcalibration, inspection, and checking of equipment is not performed, inspection, and checking of equipment is not performed
according to a written program designed to assure proper performance.according to a written program designed to assure proper performance.
Major laboratory equipment have not beenMajor laboratory equipment have not been qualified (installation, operational andqualified (installation, operational and
performance qualificationperformance qualification).).
483 Observations C (Contract Test Laboratory)483 Observations C (Contract Test Laboratory)
No performance qualificationNo performance qualification conducted on several instruments (HPLC, UV/VISconducted on several instruments (HPLC, UV/VIS
and AA Spectrometer).and AA Spectrometer).
GMP vs non-GMP laboratory studies.GMP vs non-GMP laboratory studies.
483 Observations A (Drug Product Manufacturer)483 Observations A (Drug Product Manufacturer)
For HPLC instrumentation used for drug product testing, there was noFor HPLC instrumentation used for drug product testing, there was no
documentation available which was approved by appropriate personnel showingdocumentation available which was approved by appropriate personnel showing
that HPLC was fully qualified. This includes lack ofthat HPLC was fully qualified. This includes lack of written and approvedwritten and approved
installation and operational qualification documentationsinstallation and operational qualification documentations..
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA’s ExpectationsFDA’s Expectations
ICH-Q2A Guideline for Industry – Text on Validation ofICH-Q2A Guideline for Industry – Text on Validation of
Analytical ProceduresAnalytical Procedures
ICH-Q2B Guideline for Industry – Validation ofICH-Q2B Guideline for Industry – Validation of
Analytical Procedures: MethodologyAnalytical Procedures: Methodology
FDA Guidance for Industry – Analytical Procedures andFDA Guidance for Industry – Analytical Procedures and
Methods Validation Chemistry, Manufacturing andMethods Validation Chemistry, Manufacturing and
Controls DocumentationControls Documentation
Reviewer Guidance Validation of ChromatographicReviewer Guidance Validation of Chromatographic
Methods Nov.’94Methods Nov.’94
U.S. Pharmacopeia/National Formulary (Chapters <621>U.S. Pharmacopeia/National Formulary (Chapters <621>
and <1225> )and <1225> )
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20132013

FDA’s ExpectationsFDA’s Expectations
Each NDA and ANDA must include the analytical procedures necessary toEach NDA and ANDA must include the analytical procedures necessary to
ensure the identity, strength, quality, purity, and potency of the drugensure the identity, strength, quality, purity, and potency of the drug
substance and drug product, including bioavailability of the drug product (21substance and drug product, including bioavailability of the drug product (21
CFR 314.50(d)(1) and 314.94(a)(9)(i)).CFR 314.50(d)(1) and 314.94(a)(9)(i)). Data must be available to establish thatData must be available to establish that
the analytical procedures used in testing meet proper standards of accuracythe analytical procedures used in testing meet proper standards of accuracy
and reliability (21 CFR 211.165(e) and 211.194(a)(2)).and reliability (21 CFR 211.165(e) and 211.194(a)(2)).
All analytical procedures are of equal importance from a validationAll analytical procedures are of equal importance from a validation
perspective. In general,perspective. In general, validated analytical procedures should be usedvalidated analytical procedures should be used,,
irrespective of whether they are for in-process, release, acceptance, orirrespective of whether they are for in-process, release, acceptance, or
stability testing. Each quantitative analytical procedure should be designedstability testing. Each quantitative analytical procedure should be designed
to minimize assay variation.to minimize assay variation.
ValidationValidation should not be a one-timeshould not be a one-time situation to fulfill agency filingsituation to fulfill agency filing
requirement.requirement.
Applicants should submit information on the validation characteristics ofApplicants should submit information on the validation characteristics of
their proposed analytical procedures (see ICHtheir proposed analytical procedures (see ICH Q2AQ2A and ICHand ICH Q2BQ2B). Although). Although
not all of the validation characteristics are needed for all types of tests (seenot all of the validation characteristics are needed for all types of tests (see
section VII.A.3),section VII.A.3), typical validation characteristics are: Accuracy, Precisiontypical validation characteristics are: Accuracy, Precision
(repeatability and intermediate precision), Specificity, Detection limit,(repeatability and intermediate precision), Specificity, Detection limit,
Quantitation limit, Linearity, Range, and RobustnessQuantitation limit, Linearity, Range, and Robustness
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

FDA’s ExpectationsFDA’s Expectations
All chromatographic analytical proceduresAll chromatographic analytical procedures should include system suitabilityshould include system suitability
testingtesting and criteria. Parameters typically used in system suitabilityand criteria. Parameters typically used in system suitability
evaluations are defined and discussed in the CDER Reviewer Guidance onevaluations are defined and discussed in the CDER Reviewer Guidance on
Validation of Chromatographic MethodsValidation of Chromatographic Methods (November 1994).(November 1994).
A listing of all equipment (e.g., instrument type, detector, column type,A listing of all equipment (e.g., instrument type, detector, column type,
dimensions) should be included, as well as a list of equipment parametersdimensions) should be included, as well as a list of equipment parameters
(e.g., flow rate, temperatures, run time, wavelength settings).(e.g., flow rate, temperatures, run time, wavelength settings).
VALIDATION OF COMPENDIAL METHODSVALIDATION OF COMPENDIAL METHODS
– Compendial procedures vary from highly exacting analyticalCompendial procedures vary from highly exacting analytical
determinations to subjective evaluation of attributesdeterminations to subjective evaluation of attributes
– Performance characteristics meet the requirements for the intendedPerformance characteristics meet the requirements for the intended
analytical applicationsanalytical applications
– Equipment, electronics, analytical operations, and samples to beEquipment, electronics, analytical operations, and samples to be
analyzed constitute an integral system that can be evaluated as suchanalyzed constitute an integral system that can be evaluated as such
System suitability tests verify that the resolution and reproducibility of theSystem suitability tests verify that the resolution and reproducibility of the
chromatographic system are adequate for the analysis to be done.chromatographic system are adequate for the analysis to be done.
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

ConclusionsConclusions
Do your homework prior to method development and instrument’sDo your homework prior to method development and instrument’s
purchase:purchase: Method validation and instrument qualification shouldMethod validation and instrument qualification should
focus on suitability for intended usefocus on suitability for intended use
Installation Qualification should clearly identify calibration,Installation Qualification should clearly identify calibration,
maintenance, SOP and training needsmaintenance, SOP and training needs
Operational Qualification should ensure proper function of allOperational Qualification should ensure proper function of all
system componentssystem components
Performance Qualification should ensure suitability of “entire”Performance Qualification should ensure suitability of “entire”
HPLC systemHPLC system
Develop and validate methods using appropriate system suitabilityDevelop and validate methods using appropriate system suitability
teststests
SST failures? Go back to PQ (holistic), if necessary OQ (modular)toSST failures? Go back to PQ (holistic), if necessary OQ (modular)to
identify problems, initiate repairs, etc.identify problems, initiate repairs, etc.
Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.
20132013

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Call us at 513-860-3512Call us at 513-860-3512
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FDAWarningLetterTeam@Compliance-Insight.comFDAWarningLetterTeam@Compliance-Insight.com
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