Quality by Design HighlightsAnalytical Method Guidelines, Transfer,System Suitability, Traceability, andVariability Minimization By Satendra Kumar Vishwakarma, PhD
Declaration on OutlinesThe materials/ contents presented in the following slides , collected from various sources, reflect general information and minimum requirements for conducting analytical activities in a qualified laboratory system for regulatory submissions. General Outlines are not complete Reference GuidelinesThe readers are further requested to consult First Corporate Method Guidelines and then other appropriate Regulatory Web Sites for additional details and verification of outline contents. Ж♦Ж♦Ж♦Ж Thank You Ж♦Ж♦Ж♦Ж
Outlines of Presentation R&D Analytical CMC (Activity Classification and Responsibilities) Departmental Analytical Suitability Origin of Assay Method and Classifications Definition and Determination of Selectivity and Specificity International Validation Terms and Terminology Data Elements for Verification Methods for Cleaning Validation Chromatographic Adjustments and Changes in HPLC Technical Method Transfer Criteria & Concept International System Suitability Requirements Impurities/ Degradants in Drug Products/ Drug Substances Variability and Minimization by Quality by Design in Laboratory Quick Web Link References
Compliant Analytical CMC Activity Analytical Procedure & Method DevelopmentAPI, Excipient Pre-/ Post- Compatibility In-Process Specification QA &Evaluation & Formulation Studies Studies Safety Regulatory Control Support Support Support Evaluation ComplianceAPI, Product, & Packaging: Safety, Quality & Performance Testing Chemistry of Drug Molecule: Characterization of Reference & Raw Material and Control* Chemistry of Excipients: Characterization and Variation Control* for intended functions Chemistry of Drug Interaction: Preformulation/ Formulation Compatibility Drug Analysis: Method Development, Validation, Verification, and Transfer Stress Degradation and Stability Studies Identification/ Quantitation of Known and Unknown Impurities Acceptance Criteria/ Specification Development Method Life Cycle Management Bioequivalence: Verification of Product Quality and Integrity Studies Evaluation: Packaging, Drug Substances/ Drug Product Intrinsic Stability Testing Process Verification: Process Validation Batches Data Development Regulatory and Guidance: Compliance Data/ Reports and Maintenance* Worldwide Historical data on pharma products indicates that poor characterization and control on raw materials accounts to Long- term Manufacturing and Product Performance Issues.
State of Process Product AnalysisThe Old Way of Product / Substance Analysis – Lab:Off-line: Current Laboratory practices are destructive and non-destructive (regulatory disadvantage).The New Way of Product / Substance Analysis – PAT: At-line: In production area, analysis performed during production close to the manufacturing process. On-line: Analysis on diverted stream connected to process. In-line: Process stream disturbed. Non-invasive: Sensor not in contact with material, process not disturbed (regulatory advantages).Goals of both (Lab and PAT Way): Provide information about the sample of interest.Perspective different: Lab Way: Time dependence not critical for technical reasons. PAT Way: Typically used to control processes through feedback in real time or to diagnose and explain process anomalies.This dictates differences between the Two Ways with regard to Sampling and Rate of Data Collection
Process Product Quality Process Analysis – Sources of Error and Variability Current Quality By Lab Future Quality By Design Off-Line At-Line / By-Line In-Line / On-line Product Oriented Process Oriented Drug Release, Impurities Blending, Homogeneity, Filling, Granulation, Drying, Coating, Screening PAT Manual Sampling Manual Sampling Sample At InterfaceTransportation Sample Preparation Sample Preparation / Minimum Direct Analysis PreparationSlow Response Immediate Response Rapid ResponseQuality Not Controlled Rapid Quality Controlled Quality ControlledHigh Manufacturing Cost Low Manufacturing Cost Low Product Cost
Excipients in Product Quality Selection and Characterization Physicochemical Physicochemical Manufacturing Properties of Excipients Properties of Drug Process Requirement Physically Stable Polymorphic / Forms Direct compression (Polymorphic / Forms Hydrates Wet Granulation Hydrates) Heat & moisture sensitive Fluid Bed Coating/ Hygroscopic Poorly Soluble Granulation Chemically Stable Poorly absorbable Spray Drying Compatible with drug Poorly Stable in vivo Other novel Rheology Flow processes Direct Liquid Formulation Filtration & Fillings Route of Administration Desired Release Oral Excipients Choice in Characteristics Injection Dosage Forms Immediate release Pulmonary Sustained Release Transdermal Modified Release Buccal e.g. enteric Rectal/Vaginal Delivered Dose of Drug High Dose Low Dose
Dosage Form Development Chart Active Drug Suspension SolutionSuppositories Topicals Intrinsic Dissolution Dissociation Tonic Constant pKa pH Effect Co-solvents Adjustment pH? Intrinsic Salts Saturated Solubility Solubility IV Injection PEG 400 + 5% H2O + Glycerin OtherDelivery CapsuleSystem Solution Tonic Adjustment Excipient Compatibility Other Dosage Forms Stability Tablets
Analytical Quality-by-Design Molecular Properties and Impurities Identification • Spectroscopy, Hyphenated, Orthogonal Techniques (Process Tools) in DS/DP Impurities Identification. • Molecule Properties Identification and Characterization like Polymorphs and Polarity Screening by HPLC. • Application of Multiple or Suitable Detectors. Method • Selectivity/ Identification and Application of On-line Analyzers.Development • Application of Target Methods for Particular Impurities or Enantiomers. • Physiochemical Properties Identification of Formulation Components. • Phases Interaction and Evaluation at Rapid/ Accelerated Environmental Conditions. • Application of on-line Laboratory based Analyses and Chemometrics Knowledge.Formulation • Finger Print Mapping of Formulation Components.Development • Re-optimization of Methods against Re-optimized Formulations. • Monitor the identified Process Variable Parameters. • Control the Impurities by Controlling the Variable Parameters. Process • Direct Application of on-line Laboratory based Knowledge.Understanding • Integral to Product Specifications. • Integral to Process Controls. Control • Optimization for Ruggedness. Methods
Analytical Quality-by-Design FT-IR and HPLC ComparisonFeatures FT- IR HPLCSample Preparation Non-Destructive Pipetting, Crushing & DissolvingTime per Analysis Typically 30-90 seconds Typically 20-40 minutesSolvent Required No YesChemical Information Active Concentration/ Active Concentration/ Uniformity UniformityPhysical information Yes NoSurface Analysis Yes in reflectance mode NoMoisture Content Yes NoLow Concentration Impurities No YesQbR/ Regulatory Compliance Yes Yes/ No
Smart Analytical NIR Spectral Range Medium Long Short X-ray UV Cosmic Gamma IR Micro UHF Radio Vis Ultra violet Infrared Near Mid Far 1 400 750 2500 16000 1000000 nm Elemental Appearance Constituent Assay Functional Group Analysis Scan NIR spectrum range ≈ 780nm - 2526nm (12820-3959cm‾¹) non-invasively and non- intrusively. Scan in the range of 1100nm – 2300nm @ 2nm intervals. Spectra generated is average of 100 NIR scans
Departmental Analytical Suitability Regulatory Conditions form Method Development to Method Applicability Suitability of Analytical Instrument & Support System Current status of Qualification, Calibration, and approved documentation. Suitability of Required Materials Qualified reference standards, APIs, reagents, matrix/ placebo. Suitability of Analytical Chemist Approved status of qualification, training, and GLP-GMP experience. Suitability of Method Validation Documentation A well written analytical procedure and approved protocol with pre-established acceptance criteria. Suitability of Method/ Method Transfer Documentation A written protocol, defined responsibilities, identified & approved analytical procedure, statistical analysis, pre-defined acceptance criteria for each performance parameters, time frame with solutions stability time and suitability parameters. Suitability of Data, Method Audit, and Deficiency Documentation Chemist authorization, data audit trail & control, method audit trail, deviation/ Investigation, change control and records management.
Assay Method Classifications Classification of Analytical Assay Methods & Methods to be ValidatedMethod Class Definition by Performance CharacteristicsClass 1 Analytical methods for Quantification (Identification) of major(Identity) components in drug substances (active ingredients), drug products (finished products), support vehicles (preservatives and excipients).Class 2 Analytical methods for Determination (Identification,(Detect & Quantification , Limit ) of known and unknown impurities inQuantitate) bulk drug substances (active ingredients), drug products (finished products), support vehicles (preservatives and excipients).Class 3 Analytical methods for Determination of Performance(Concentration) Characteristics – Drug Release ( e.g. Dissolution of Drug Products).Class 4 Identification tests – Physical, Chemical limit tests, FTIR, Chiral(Characteristics) Test, & Spectroscopy.
Evolution of Regulatory Method Stages of Continuous Verification & Validation of Pharmaceutical HPLC Method (from Drug Discovery to Early Drug Development to IND to NDA) Research & Method Development (RMD) TechnologyAnalytical Validation Formulation Development (FD) Mfg Method Early Drug TransferParameters (v) Development Pre-FD-Phase-1 FD-Phase-2 Final FD-Phase-3 & Submission RMD-1 RMD-2 RMD-3 RMD-4 RMD-5Accuracy … v v v vPrecision Injection Repeatability v v v v v Impurity Reproducibility … … v v v Assay Intermediate … v v v vSpecificity/ Forced Deg … v v v vDetection Limit … … v v vQuantitation Limit … v v v vLinearity v v v v vAnalytical Range v v v v vSolution Stability … … v v vRobustness … … v v v
Validation/ Verification Terminology Assay Parameters Basic Description of Analytical Performance Parameters Accuracy Evaluate the closeness of “Measured” value & „True‟ value. Imprecision Evaluate the variability in replicate measurements (intra- and inter-assay). Specificity Evaluate the ability of the method to measure all other (Selectivity)* components without reacting with other related substances. Analytical Range Establish analytical range of Active and Impurities over which the method shows acceptable performance. Reportable Range Establish range of reportable results over which the method is validated (may exceed analytical range when samples are diluted or concentrated). Sample Stability Evaluate stability of reference standard, impurity solution, and sample matrix under conditions that mimic the study conditions. Quality of Standards Evaluate the quality of calibrators/ standards. Calibration/ Standard Evaluate relationship between known quantities (concentration) of Curve reference standards in artificial or true matrix and measured instrument response. * See next slide for Definition and Significance of Specificity
Definition of Specificity/ SelectivitySpecificity (Selectivity)** The analytical performance and ability of a method to measure accurately and specifically the analyte in the presence of complex components (Active Ingredients, Degradation Products, Placebo Ingredients, Impurities) that may cause a degree of interference. This requires separation and characterization.Separation Resolution (Determination of separation between peaks), Plate Count (Determination of a systems efficiency), Tailing Factor (Calculation reference peak shape).Characterization (PDA/DAD) Peak Purity Test (angle and plots) is necessary to demonstrate that the analyte chromatographic peak is not attributed to more than one components.** See slide on “Stress or Forced Degradation” & its relation with Method Specificity
Determination of Specificity/ Selectivity Qualitative Identification Tests Demonstrate ability to select between compounds of closely related structure and confirm positive and negative results. Assay Demonstrate that the results are unaffected by spiked impurities or excipients. Impurities If the Impurities are Available Spike the drug product/ drug substance with impurities and demonstrate appropriate accuracy and precision. This demonstrate that assay is unaffected by the presence of spiked materials (impurities and/or excipients). Compare the results on unspiked assay samples. If the Impurities are Not Available** Compare test results to a second well-characterized procedure. For Assay, compare the two results. For Impurity Tests, compare impurity profiles Peak Purity Test ( by diode array detector or by mass spectrometer). Compare the results obtained under stress (forced degradation) conditions samples.** See slide on “Stress or Forced Degradation” & its relation with Method Specificity
Methods Under GuidelinesValidation of New Test Methods (Also known as Complete Method Validation) All New Non-compendial or Alternative Test methods will be evaluated as per ICH/FDA Critical Raw Material and Components Tests Process Validation and In-Process Tests All GMP Lot Release Tests 1. Potency and Purity 2. Stability Assays for Approved Products 3. Other Safety Tests including Sterility and PyrogenicityVerification of Pharmacopeia Methods (Also known as Partial Method Validation) All USP/EP Compendial Tests In-house Test Methods already used for Approved Products and Not further Modified System Suitability must be Demonstrated 1. Ensure Test System Working Properly when Run Performed 2. Needs Equipment Qualification and Periodic Calibration 3. Needs Demonstration of Analyst‟s Competence 4. Needs Reliable Reference Standards and Reagents 5. Test perform for specificity, intermediate Precision and sample solution stabilityQualification of Test Methods Comparability and Characterization Tests Stability Tests, Pre-NDA In-Process and Final Quality Tests during Development Some Clinical Test depending on Clinical Phase
International Analytical Methods Analytical Methods and their Analytical Performance CharacteristicsValidation Parameters FDA ICH USP EP JPAccuracy (Trueness) Yes Yes Yes * YesPrecision (Repeatability / Intra-Assay) Yes Yes Yes * YesPrecision (Reproducibility / Labs) Yes Yes Yes * YesPrecision (Intermediate / Ruggedness) Yes Yes Yes * YesSpecificity Yes Yes Yes * YesDetection Limit Yes Yes Yes * YesQuantitation Limit (= Detection + Concentration) Yes Yes Yes * YesLinearity Yes Yes Yes * YesAnalytical Range Yes Yes Yes * YesReportable Range Yes Yes Yes * YesRobustness Yes Yes Yes * YesAnalytical Solution Stability Yes Yes Yes * Yes Term Precision means 4Rs - Repeatability, Reproducibility, Ruggedness and Robustness
Data Elements for ValidationTable I: Data Elements required for Validation in a given Method ClassAnalytical Class 1 Class 2 Class 3 Class 4PerformanceCharacteristics Quantitative Limit TestsAccuracy Yes Yes MBR MBR NoPrecision Yes Yes No Yes NoSpecificity (Selectivity) Yes Yes Yes MBR YesDetection Limit No No Yes MBR NoQuantitation Limit No Yes No MBR NoLinearity Yes Yes No MBR NoRange Yes Yes MBR MBR NoRuggedness Yes Yes Yes Yes Yes MBR = May Be Required, depending upon nature of the specific tests
Data Elements for Verification of DRUG SUBSTANCESTable II: Data Elements required for Verification of Drug Substances and ExcipientsAnalytical Class 1 Class 2 Class 3 Class 4Techniques Quantitative Limit TestsHPLC/GC Precision Precision Specificity - Specificity Specificity Detection - Quantitation -Spectrophotometric/ Precision Precision Specificity - SpecificityColorimetric Quantitation DetectionTitrimetric Precision Precision - - -TLC - Specificity Specificity - Specificity Quantitation DetectionElectrophoresis - Specificity Specificity - Specificity Quantitation Detection
Data Elements for Verification of DRUG PRODUCTSTable III: Data Elements required for Verification of Dosage Forms (Products)Analytical Class 1 Class 2 Class 3 Class 4Techniques Quantitative Limit TestsHPLC/GC Precision Precision Specificity Precision Specificity Specificity Specificity Detection Linearity Quantitation RangeSpectrophotometric/ Precision Precision Specificity Precision SpecificityColorimetric Specificity Quantitation Detection RangeTitrimetric Precision Precision - - - Linearity RangeTLC - Specificity Specificity - Specificity Quantitation DetectionElectrophoresis - Specificity Specificity - Specificity Quantitation Detection
International Validation Parameters Common Analytical Methods and their Assay Validation Parameters M E T H O D SValidation Parameters ID Impurities Cleaning Assay Specific(Analytical Characteristics) Test Quantitation LimitsAccuracy (Trueness) N Y N (Y) Y Y Y1Precision – Repeatability N Y N Y Y Y1Precision – Intermediate N Y3 N N Y3 Y1Precision – Reproducibility Y Y N Y Y Y1Specificity (Selectivity/ Sensitivity) Y2 Y Y Y Y YDetection Limit N N (Y) Y Y N NQuantitation Limit N Y N Y N NLinearity N Y N Y Y NRange N Y N (Y) Y Y NRobustness Y Y N N (Y) Y Y1Surface Recovery N N N Y N NStability Indicating N Y N N Y NSolution Stability (Standard/Sample) N Y Y Y Y YReference Standard Evaluation Y Y Y Y Y YN = Signifies that this characteristics is not normally evaluated. Y = Signifies that this characteristics is normallyevaluated. N(Y) = May be needed in some cases. 1 = May not be needed in some cases. 2 = Lack of specificity foran analytical procedure may be compensated for by addition of second analytical procedure. 3 = In cases wherereproducibility has been performed, intermediate precision is not needed.
Method Re/Validation Parameters Partial/ Revalidation Required by ICH Q2A under CircumstancesChanges in the synthesis of the drug substanceChanges in the composition of the finished productChanges in the analytical procedure or method is modified and modificationsare outside original scope of the method. (e.g. robustness)Change in analytical instrument conditions for which the method has beenvalidated (e.g. Instrument with different characteristics)* Revalidation is necessary, if ranges covered during validation of API-methodsare different from those of the FPP-methods (different test concentrations). Requirement for Revalidation of Analytical MethodsAccuracy Influence of formulation componentsPrecision Influence of formulation and sample preparationSpecificity Presence of new API(s) and impurities / degradants / formulation componentsLOD/LOQ Test concentrations of API(s) versus FPP)Range* Test concentrations of API(s) versus FPPRobustness Change of column material, column parameters, solvents
Methods for Cleaning ValidationProcedure Assay and Related Substances used in Stability Studies of API and FPPSpecificity Samples taken from a cleaning assessmentLinearity Response (from 50% of the cleaning limit to 10x this concentration; R2 ≥ 0.9900)Precision Repeatability Precision (RSD ≤ 5%) Intermediate Precision [Ruggedness (USP)] Reproducibility PrecisionLimits of Detection N(Y) Desirable to set in some casesLimit of Quantitation Acceptance CriteriaAccuracy or Rinsate (≥ 80%), Swabs (≥ 90%), and processRecovery surface (≥ 70%)Range Lowest level is at least 2x higher than LOQ
USP Adjustments/Changes in LCMultiple Adjustments / Changes? Regulation may require Additional-/Re-ValidationHPLC Parameters Specification CommentspH of Aq. Mobile Phase Within ± 0.2 units (value or range) …Buffer Salt Concentration ± 10% Provide pH variation is metRatio of Mobile Phase Components specified at 50% or Whichever is larger. Change in anyComponents less: ± 30% or ± 2% component can not exceed ± 10% Absolute, nor any reduced to Zero.UV-Visible Detector No deviations A validated procedure must be used to verifyWavelength that error in the detector wavelength setting is, at most, ± 3.0 nm.Column Length ± 70% …Column Inner Diameter ± 25% …Flow Rate ± 50% …Injection Volume Reduced as far as consistent with Increased to as much as 2X volume specified accepted Precision and Detection as long as there are no adverse Limits chromatographic effects.Particle Size Reduced by as much as 50% …Column Temperature ± 10% °C Recommended to improve control and reproducibility of RT (Login Required) http://www.uspnf.com/uspnf/pub/index?usp=31&nf=26&s=0
EP Adjustments/Changes in LCMultiple Adjustments / Changes? Regulation may require Additional-/Re-ValidationHPLC Parameters Specification and CommentspH of Aqueous part of May vary by ± 0.2 pH unless otherwise stated in the monograph, or ± 1.0 pH forMobile Phase neutral substances.Column Temperature Can be adjusted by ± 5 °C.Ratio of Mobile Phase The amount of minor solvent component can be adjusted by ± 30% relative (or ±Components 2% absolute).UV-Visible Detector No Adjustment is permitted.WavelengthBuffer Salt Concentration Concentration of salts in the buffer component of mobile phase: ± 10%.Flow Rate ± 50%Injection Volume May be decreased provided detection & repeatability are satisfactory.Stationary phase Column Length: ± 70%, Column Int. Diameter: ± 25%, Particle Size: max - 50%, no increase permitted. Flow Rate correction required.Gradient Elution Mobile Phase composition not permittedThe percentage variation of Ion Pair Reagent were not found in either USP or EP
Technical Method Transfer R&D Analytical Method Transfer to Regulated Quality Control Laboratory Procedure and Acceptance Criteria Driven Technical Protocol to fulfill proficiency/ reliability checks for Precision, Accuracy and Ruggedness parameters Do not change Validated Chromatographic Variable Parameters Ionic strength in mobile phase Solvent strength or ratio in mobile phase Final pH of mobile phase Temperature (column, vial, mobile phase) Flow rate (isocratic / gradient ratio and time) Sample diluent / extraction /sonication time Test solution stability Injection volume Specified analytical column (No equivalent terminology) Mode of detection or Wavelength of detection Measure Chromatographic Parameters Analytical system suitability parameters and injection frequency Response (area/amount) for repeatability & reproducibility Retention time Selectivity and/or resolution Method Transfer Acknowledgement/ Documentation/ Return with Feedback Document the acceptance criteria with pertinent observations/ Return to originating laboratory on failure for further optimization.
Evolution of Stability Indicating Method Implementation Re-validation Re-validation QC/ Stability Method Transfer Formulation Problem Problem Validation Pre-validation DOE for Qualification Optimization DOE for Development Screening Characterization Information Identification
Purity & Stability Indicating Method A stability method transfer must be Stability-Indicating Assay Method is a validated quantitative analytical procedure that can detect the changes with time the pertinent properties of the drug substance and drug product. A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities. A stability indicating methods are developed, optimized and adapted according to the ICH principles for forced degradation studies. A non-stability indicating analytical procedure can be used for release testing, then an analytical procedure capable of qualitatively and quantitatively monitoring the impurities, including degradation products, is required to complement it. Assay analytical procedures for stability studies should be purity and stability-indicating, unless scientifically justified.
Method Transfer Testing Criteria Method Transfer Testing Criteria involves either forVerification of Method (under actual conditions – Validation requirements),Qualification of Method (performing tests– Specification requirements) orComparison of Method (evaluation of test solutions – Confirmation requirements) Best Laboratory Practices/ Guidelines for Qualification Transfer CriteriaMethod Class Class 1 Class 2 Class 3 Class 4 Assay Performance ID Test Quantitative LimitParametersAccuracy Y Y N N NPrecision Y Y N Y NSpecificity Y, 1 Y1 Y, 2 N Y, 2Quantitation NR Y N N NLinearity Y Y N N N1 Tested with respect to Sample Diluent.2 Positive response for analyte presence. No response required for Blank.Y Verifying laboratory needs to perform tests.NR Not required.N Testing not suggested.
Method Transfer Testing Criteria Method Transfer Testing Criteria involves either forVerification of Method (under actual conditions – Validation requirements),Qualification of Method (performing tests– Specification requirements) orComparison of Method (evaluation of test solutions – Confirmation requirements) Best Laboratory Practices/ Current Validation / Revalidation Guidelines for Comparative Testing Criteria: Originating (O) & Receiving (R) LaboratoriesMethod Class Class 1 Class 2 Class 3 Class 4 Assay Performance ID Test Quantitative LimitComparative O R O R O R O R O RLaboratoryParametersAccuracy N N N N N NPrecision Y Y Y Y N (Y) N (Y)Specificity N Y N Y N Y Currently CurrentlyDetection N N N N N N Not Not Required RequiredQuantitation N N N Y N NLinearity N Y N Y N NRange N N N N N NResults Y Y N(Y)
Method Transfer Design Text Typical Method Transfer Experimental Design and Acceptance criteria ExampleMethod Type Chemists Product Acceptance Criteria CommentsAssay 2 3 Batches in A two one-sided t- Each chemist should use different Triplicate test with intersite instrument & columns, independent differences of ≤ 2% at preparations. System suitability 95% CI criteria must be met.Impurities and 2 3 Batches in For high levels, a two All samples age, homogeneityDegradation Duplicate one-sided t-test with packaging and storage should be the (Triplicate if intersite differences same. All system suitability criteria done of 10% at 95% CI. For must be met. The LOQ should be together low levels, criteria confirmed and chromatograms should with assay are based on the be compared with impurity profile. If absolute difference samples do not contain impurities of mean ±25% above reporting limit, then spiked sample are recommendedIdentification 1 3 Batches RT/ Spectral/ chemical resultsCleaning 1 Two spiked Spiked levels should All system suitability criteria must beValidation samples – not deviate from by met.. Cleaning is a limit test. Low and one above an amount 3 x the high samples to confirm both positive and one validated standard and negative information is required below limit/ deviation of method, spec or 10% of the spec, which ever is greater
Regulatory Analytical Suitability System Suitability Validation of Pump Module Injector Module Instrument Calibration & Computer System Validation Detector Module Temperature Module Chemist & Method Testing & Criteria
Regulatory System SuitabilityWhat‟s in System Suitability Criteria (Testing) System suitability testing is an integral part of many analytical procedures. The test concept constitute equipment, electronics, analytical operations, standards, and samples. System suitability criteria are Not The Same as method performance criteria. They usually provide a surrogate measure of the method performance criteria (Retention Characteristics, Resolution, Tailing, etc.) System suitability are limits to various tests and are designed to ensure the adequate performance of analytical procedure (Repeatability of Injections). System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated. System suitability requirements should met before samples are analyzed. System suitability must be performed for each study at the beginning and at the end by each analyst, preferably at the middle of standard loop. System Suitability may be needed to demonstrate / determine carryover and confirm reagent purity by injecting blank (diluent or matrix). Compliance with the system suitability criteria (sensitivity and selectivity) is required throughout the chromatographic procedure.
USP & ICH System SuitabilityUSP<1225>System Suitability Parameters RequirementsCapacity factor (K‟) : ≥ 2.0Peak Resolution (Rs) : > 2.0Symmetry/ Tailing Factor (T) : ≤ 2.0Theoretical Plates (N) : > 2000Repeatability (Reproducibility), RSD : ≤ 2.0% (n≥5)Repeatability (Reproducibility), RSD : ≥ 2.0% (n≥6)Separation Factor (Relative Retention): Set Retention Time WindowICH <Q2(R1)>Go to Respective PharmacopoeiasDefinition: Evaluation of equipment, electronic, analytical operations and samples as a whole.Determination: Repeatability, tailing factor (T), capacity factor (k‟), resolution (R), and theoretical Plates (N). USP is the only document that comes the closest to specific guidelines on System Suitability.
EP System Suitability CriteriaSuitability in terms of System Performance System Suitability Criteria are limits applied to various tests designed to ensure the adequate performance of analytical procedure. Compliance with the system suitability criteria is required throughout the chromatographic procedure.Suitability in terms of Selectivity Resolution of two closely eluting peaks (critical pair): preferably peaks of similar size or at least not saturating). Peak-to-valley ratio (incomplete separation, peaks of very different size) “Similarity” or “Concordance” with a chromatogram supplied. “Limit” Percent of individual impurity “System Suitability” Signal-to-noise minimum 3 for the peak due to impurity in reference solution.
ΣMethod = ∫Stability & SelectivityMethod Stability: System Suitability and Repeatiability Over Time Stability of Analytical Solutions Sample Solution Stability Impurity-spiked Sample Solution StabilityMethod Selectivity (Specificity & Sensitivity): The Sensitivity for an impurity can change depending on detector, lamp condition, mobile phase composition and purity, column efficiency, etc. Wavelength selection is often optimized for active ingredient but also should be considered of impurities. Wavelength sensitivity should be demonstrated during stress testing studies. Detection Limits (is estimated as 0.02% w/w by visual inspection of chromatogram) should be evaluated for all significant potential impurities and degradation products. Limit of Quantitation is estimated as 0.05% w/w and sample at this concentration included in linearity (0.05% to 0.5% w/w) and in accuracy. Significant impurities and degradation products include those that are specifically monitored as part of Release Testing and Stability Testing.Method Adaptability: Meets acceptance criteria of Specifications (limits), Robustness and Ruggedness performance characteristics of intended applicability of analytical method.
Organic Impurity and DegradantSpecified Impurity An impurity that is individually listed and qualified in product with a specific acceptance criterion (can be identified or unidentified).Impurity Definition (API Impurities) An impurity is any substance that is in the Drug Substance…….. that is not that Chemical Entity.Conclusion: It may be: Known, Unknown, Specified, or Unspecified.Degradant Definition (FPP Impurities) A degradant is an Impurity resulting from a Chemical Change of the Drug Substance brought on by Manufacturing or Storage of a Drug Product.Conclusion: It may be: Known, Unknown, Specified, or Unspecified.Reference Identification Procedure (API & FPP) An analytical procedure to differentiate and separate potential impurities from matrix under a given conditions and specification.Conclusion: It may be: Specificity, Sensitivity, Stability and Purity.Quick Link: http://www.fda.gov/cber/gdlns/ichq3a.htm#att1 http://188.8.131.52/cder/guidance/2452fnl.htm#ATTACHMENT%20I
Stress or Forced Degradation Method Specificity through Forced Degradation ActivitiesICH Q2 (R1)Stress studies (e.g. products of acid and base hydrolysis, thermal degradation,photolysis, oxidation) for the drug substance and for the active ingredient in thedrug product should be provided to demonstrate the specificity of the assay andanalytical procedures for Impurities.Goals To understand the drug substance stability. To establish degradation pathways. To validate the stability indicating power of the analytical procedures used. To support the severe conditions that may be encountered during distribution.To generate typical degradation products which may be expected on stability at sufficient levels to allow identification. To avoid secondary degradation. To get the target range is 5-20 % loss of active as judged by assay relative to an un-degraded sample. To look for purity and mass balance.
Stress or Forced DegradationStress Testing – Forced Degradation (API)Stress studies elucidate intrinsic stability of the API and is part of thedevelopment strategy and is normally carried out under more severeconditions than those used for accelerated testing.Stress Testing – Forced Degradation (FPP)Studies undertaken to assess the effect of severe conditions on the FPP.Such studies include photostability testing and compatibility testing on APIswith each other in FDCs and API(s) with excipients during formulationdevelopment. ICH Guidelines on Stress Testing http://www.ich.org/cache/compo/276-254-1.html Reference Subject Title ICH Q1A(R2) Stability Testing of New Drug Substances and Products ICH Q1B Stability Testing: Photostability Testing of New Drug Substances and Products ICH Q2(R2) Validation of Analytical Procedures: Text and Methodology ICH Q3A(R2) Impurities in New Drug Substances ICH Q3B(R2) Impurities in New Drug Products
Impurities / Degradants From Stress Stress conditions for Exploratory and Drug Substance/ Impurity Peak Purity Definitive studies* Product, %** Identification*** Match**** Control Y Y Y 0.1 M HCl/ Temp/ Hrs Y Y Y 0.1M NaOH/ Temp/ Hrs Y Y Y 3% H2O2 / Temp/ Hrs Y Y Y Humidity/ % RH/ Temp/Days Y Y Y UV (Short and Long wavelength / Temp/ Y Y Y Days Light/ Lux/ Days Y Y Y Thermal/ Temp/ Hrs+ Y Y Y Transitional ion, Fe / Cu (Optional) … … … Visit ICH Guidelines Website for Stress Stability Section for further Information * Variable environmental conditions may be needed based on stability of molecule. ** Desirable to achieve realistic impurities/ degradation level 10 % to 30 % (NMT 50%) based on active component mass balance. *** Desirable to monitor impurity/ degradants at various wavelengths. **** Drug Peak Purity Match is highly desirable (to indicate Peak Purity Indicating Method). + Induced temperature should be below the melting point by 10°C to 20°C.
Source of Impurities / DegradantsPotential Impurities (degradants) Source: May be affecting Drug Stability Impurities in starting materials Products of over reaction or decomposition Products of incomplete reaction and synthesis precursors Impurities from the solvents of the reaction Impurities from catalysts Products of side reactions (synthesis by-products) Degradation products (metabolites) Residual solvents Inorganic impurities Impurities in excipients or reaction products of API with excipient(s) in formulation Process Related impurities (e.g. Thermal Sterilization, Oxidative Environment) Reaction products of API / Drug Product with immediate container / closure system Enantiomeric forms as impurities* Polymorph forms as impurities* *(basically these are not impurities)
Impurities: Identification & CharacterizationImpurities Identification: (Not exhaustive List) Organic Impurity Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not more than () the figure in the identification threshold [ICH Q3A/B(R)] Total impurities (including extractable and leachable impurities) Residual Solvents (By GC/GC-MS: Not covered in this presentation) Inorganic Impurities (By compendial methods: Not covered in this presentation)Impurities Characterization:Impurity ID Chemical Name Molecular Structure Source/ OriginImpurity A Chemical Name A Structure A Degradation and process impurityImpurity B Chemical Name B Structure B Process impurityImpurity C Unknown Structure unknown Process impurity (levels do not (RRT by HPLC) increase on stability / forced stress testing) Summarize all potential and actual impurities arising from the synthesis. Identify impurities by Names, Structures, or RRT/HPLC. Specify impurities as process impurities and/or degradants
Impurities: Acceptance CriteriaRelease and Stability Specifications: Justification are based on Pharmaceutical Development Studies Data Analytical Data from Batches Compendial Specifications (USP/EP Monographs) Scientific Literature including EP, JP, etc Safety Data on QualificationImpurity specifications: Justification are based on ICH Q3B and ANDA Guidance: Impurities in Drug Products Level of Impurity observed in an FDA-Approved Drug Product (RLD), batch analysis of the RLD close to expiry should be included Significant Metabolite of Drug Substance Scientific Literature including EP, JP, etc Toxicology Studies Compendial Specifications (Unspecified Impurities can not be justified based on USP specifications) Negotiation with FDA
Defining Impurities Safety: DS/ DP ICH Q3A/B (R2) Threshold Terminology Listing, Reporting, Identification and Qualification of Degradation Products / Drug Substances. Threshold for degradation products are expressed either Threshold as % of drug substance or Total Daily Intake (TDI) of the Drug Product. Reporting A limit above (>) which a degradation product should be Threshold reported. A limit above (>) which a degradation product should be Identification identified. Threshold Achieving of the structural characterization or qualitative parameter e.g. retention time in HPLC. A limit above (>) which a Impurity/ degradation product Qualification found to be toxicologically qualified. Threshold Process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile. See Next Decision Tree for Threshold Safety Studies
Start HereDecrease impuritylevel below threshold Yes Above threshold? No Qualified Decision Tree for Yes No Threshold Structure elucidated? Safety Studies Yes Yes Toxicity documented and sufficient? No Yes Yes Related to others Acceptable with known toxicity? Justification? No No Qualified Consider patient population and duration of use Consider need for: 1. Genotoxicity studies (point mutation, chromosomal aberration) 2. General toxicity studies (one species, min 14 days, max 90 days 3. Other specific toxicity end point as appropriate Consider additional Yes No testing or removal of Adverse Effects? Qualified impurity
Acceptance Criteria: Drug Substances Drug Substances Acceptance Criteria : ICH Q3A (R2) Determine the Maximum Daily Dose (MDD) Use MDD to calculate the ICH Thresholds for drug related impurities [ICH Q3A (R2)] Maximum Daily Reporting Identification Qualification Dose (MDD) 1 Threshold (RT) 2,3 Threshold (IT) 3 Threshold (QT) 3,* ≤ 2g/day 0.05% 0.10% or 1mg per day 0.15% or 1mg per day intake intake (whichever is lower) (whichever is lower) ≥ 2g/day 0.03% 0.05% 0.05%1 The amount of drug substance, in the form of dose, administered per day.2 Higher reporting thresholds should be scientifically justified.3 Lower thresholds can be appropriate if the impurity is unusually toxic…………. That means Impurities below this level need not to be identified but Identification is recommended, if it is acute toxic in nature.* Impurities exceeding ICH Qualification Thresholds (QT)...... Try first if it is possible to reduce the Level....If not possible, then Qualify – a process of evaluation of data which establishes the Biological Safety of an individual impurity or an impurity profile.............. That means In all cases impurity At ICH Qualification Threshold must be QUALIFIED.4 Ensure the Analytical Method is adequate to determine LOQ is equal or below RT.5 Establish limits for “Individual Unspecified Impurity” to equal or below the IT.6 Establish limits for each “Identified and/or Specified Impurity” to equal or below the QT.
ICH Q3A(R2) Is impurity greater Start Here than identification threshold? Yes No No action Any Yes Structure Yes known human Reduce to identified? relevant risks? safe level No No Reduceto not more than Yes No further Greater No() identification action threshold? than qualification No action threshold? Yes No Yes Is the impurity observed in an approved Reduce drug substance and at a similar level No to not more than Yes or is it adequately () qualification No action qualified by other threshold? approaches? No Consider patient population and duration of use and Decision Tree for Identification consider conducting: Genotoxicity studies (point mutation, chromosomal aberration)a and Qualification of Impurities in General toxicity studies (one species, usually 14 to 90 days)b Drug Substances (ICH Q3A(R2) Other specific toxicity endpoints, as appropriate Any No Quick Link for more details: Reduce to Yes safe level clinically relevant Qualified http://www.emea.europa.eu/pdfs/human/ich/273799en.pdf adverse effects?
DS: Identification & Qualification/1Reporting Example 1 for 0.5 g Maximum Daily DoseReporting threshold = 0.05%, Identification threshold = 0.10%, andQualification threshold = 0.15% Reporting Impurity Results for Identification and Qualification of Drug Substances"Raw" Reported Result Calculated Total ActionResult (%) Reporting Daily Intake (TDI) Identification Qualification(%) Threshold (mg) of impurity (Threshold (Threshold = 0.05% (rounded result in 0.10% 0.15% mg) exceeded?) exceeded?)0.044 Not Reported 0.2 None None0.0963 0.10 0.5 None None0.12 0.12 + 0.6 Yes None +0.1649 0.16 + 0.8 Yes Yes ++ After identification, if the response factor is determined to differ significantly from the originalassumptions, it may be appropriate to re-measure the actual amount of the impurity present andreevaluate against the qualification threshold (See Acceptance Criteria: Drug Substances Slide).
DS: Identification & Qualification/2Reporting Example 2 for 0.8 g Maximum Daily DoseReporting threshold = 0.05%, Identification threshold = 0.10%, andQualification threshold = 1.0 mg TDI Reporting Impurity Results for Identification and Qualification of Drug Substances"Raw" Reported Result Calculated Total ActionResult (%) Reporting Daily Intake (TDI) Identification Qualification(%) Threshold (mg) of impurity (Threshold 0.10% (Threshold 1.0 mg = 0.05% (rounded result in mg) exceeded?) TDI exceeded?)0.066 0.07 0.6 None None0.124 0.12 1.0 Yes None +, *0.143 0.14 1.1 Yes Yes ++ See Identification & Qualification/1Slide* To verify if a threshold is exceeded, a reported result has to be evaluated against thethresholds as follows: when the threshold is described in %, the reported result rounded to thesame decimal place as the threshold should be compared directly to the threshold. When thethreshold is described in TDI, the reported result should be converted to TDI, rounded to thesame decimal place as the threshold and compared to the threshold. For example the amount ofimpurity at 0.12% level corresponds to a TDI of 0.96 mg (absolute amount) which is thenrounded up to 1.0 mg; so the qualification threshold expressed in TDI (1.0 mg) is not exceeded.
Acceptance Criteria: Drug Products Identify Impurity Identified Unidentified Impurity Impurity Unspecified Impurity has limited acceptance Determine (ICH Q3B – see next slide) Specified Impurity Maximum Daily Dose (MDD) Reporting Threshold (RT) Degradation Product Identification Threshold (IT) (Degradation Impurity) Qualification Threshold (QT) Unspecified Impurity Ensure Analytical Method is Adequate, LOQ is < Reporting Threshold Establish Limits for “Individual Unspecified Impurity” < Identification Threshold Limits for “Specified Identified Impurity” < Qualification Threshold Limits for “Specified Unidentified Impurity” < Qualification Threshold Total Impurities Qualify / Identify Any impurity if a limit is greater than Qualification / Identification Threshold
Is Degradation Start Here Product greater than identification threshold? ICH Q3B(R2) Yes No No action Any Yes Structure Yes known human Reduce to identified? relevant risks? safe level No No Reduceto not more than Yes No further Greater No() identification action threshold? than qualification No action threshold? Yes No Yes Is the degradation observed in an approved Reduce drug product and at a similar level or No to not more than Yes is it adequately () qualification No action qualified by other threshold? approaches? No Consider patient population and duration of use and Decision Tree for Identification consider conducting: Genotoxicity studies (point mutation, chromosomal aberration)a and Qualification of Degradants General toxicity studies (one species, usually 14 to 90 days)b in Drug Product (ICH Q3B(R2) Other specific toxicity endpoints, as appropriate Reduce to Yes Any No Quick Link for more details: clinically relevant Qualified safe level adverse effects? http://www.emea.europa.eu/pdfs/human/ich/273899en.pdf
Acceptance Criteria: Drug Products Drug Substances Acceptance Criteria : ICH Q3B (R2) Determine the Maximum Daily Dose (MDD) Use MDD to calculate the ICH Thresholds for drug related impurities [ICH Q3B (R2)] Reporting Thresholds (RT)Maximum Daily Dose (MDD) of API in Drug Product 1 Threshold Limit Based on TDI 2, 3≤1 g 0.1% TDI>1g 0.05% TDI Identification Thresholds (IT)Maximum Daily Dose of API in Drug Product 1 Threshold Limit Based on TDI 2, 3< 1 mg 1.0% TDI or 5 μg, whichever is lower1 mg – 10 mg 0.5% TDI or 20 μg, whichever is lower> 10 mg – 2 g 0.2% TDI or 2 mg, whichever is lower>2g 0.10% TDI Qualification Thresholds (QT)Maximum Daily Dose of API in Drug Product 1 Threshold Limit Based on TDI 2, 3< 10 mg 1.0% TDI or 50 μg, whichever is lower10 mg – 100 mg 0.5% TDI or 200 μg, whichever is lower> 100 mg – 2 g 0.2% TDI or 3 mg, whichever is lower>2g 0.15%1 The amount of drug substance, in the form of dose, administered per day.2 Higher reporting thresholds should be scientifically justified.3 Threshold for degradation products are expressed either as a percentage of drug substance or as Total DailyIntake (TDI) of the degradation product. Lower thresholds can be appropriate if the impurity is unusually toxic.
DP: Identification & Qualification/1Reporting Example 1 for 50 mg Maximum Daily DoseReporting threshold = 0.1%, Identification threshold = 0.2%, andQualification threshold = 200 ugReporting Degradation Results for Identification and Qualification of Drug Products"Raw" Reported Result Total Daily Intake ActionResult (%) Reporting (TDI) of the Identification Qualification(%) Threshold Degradation (Threshold (Threshold = 0.1% Product (rounded 0.2% 200 ug TDI result in ug) exceeded?) exceeded?)0.04 Not Reported 20 None None0.2143 0.2 100 None None0.349 0.3+ 150 Yes None +0.550 0.6+ 300 Yes Yes ++ After identification, if the response factor is determined to differ significantly from the originalassumptions, it may be appropriate to re-measure the actual amount of the degradation product presentand re-evaluate against the qualification threshold (See Acceptance Criteria: Drug Product Slide). Quick Link for more details: http://www.emea.europa.eu/pdfs/human/ich/273899en.pdf
DP: Identification & Qualification/2Reporting Example 1 for 1.9 g Maximum Daily DoseReporting threshold = 0.05%, Identification threshold = 2 mg, andQualification threshold = 3 mg Reporting Degradation Results for Identification and Qualification of Drug Products"Raw" Reported Result (%) Total Daily Intake ActionResult (%) Reporting Threshold (TDI) of Degradation Identification Qualification = 0.05% Product (rounded (Threshold 2 mg (Threshold 3 mg result in mg) TDI exceeded?) TDI exceeded?)0.049 Not Reported 1 None None0.079 0.08 2 None None0.183 0.18 + 3 Yes None +, *0.192 0.19 + 4 Yes Yes ++ See Identification & Qualification/1Slide* To verify if a threshold is exceeded, a reported result has to be evaluated against the thresholds asfollows: when threshold is described in %, reported result rounded to the same decimal place as thethreshold should be compared directly to the threshold. When threshold is described in TDI, the reportedresult should be converted to TDI, rounded to the same decimal place as threshold and compared to thethreshold . For Example an amount of 0.18% degradation level corresponds to a TDI of 3.4 mg impurity(absolute amount) which is then rounded down to 3 mg; so the qualification threshold expressed in TDI (3mg) is not exceeded. Quick Link for more derails: http://www.emea.europa.eu/pdfs/human/ich/273899en.pdf
Acceptance Criteria: Drug Products Example for Justification of Impurity Limits Name Current RLD Lot Proposed Proposed Justification Lot Release Stability Limits Limits Impurity A 0.80% 2.5% NMT 1.5% NMT 2.5% Metabolite Impurity E 0.40% 1.0% NMT 1.0% NMT 1.0% Equivalent to RLD Any < 0.07% < 0.05% NMT 0.20% NMT ICH Q3B Unknown 0.20% Identification Impurity Threshold ++ Total 1.3% 3.6% NMT 2.5% NMT 3.5% Below RLD Impurities + + Process-related impurities B, C, D, and F are excluded from the calculation of impurities in the drug product. ++ The maximum daily dose of RLD is 64 mg/day and recommended Identification Threshold is 0.2% or 2 mg TDI (Therapeutic Daily Intake/ Total Daily Intake) and Qualification Threshold is 0.5% or 200μg TDI.
Acceptance Criteria: Drug Products Testing should be conducted on various samples of marketed drug product over the span of its shelf life (one sample near its expiration date) Individual Unspecified Impurities in the drug product at release and for stability should not exceed ICH Q3B “IT” based on MDD. The acceptance criteria for Individual Specified Impurities for release and stability should be the same as the drug substance unless the impurities are shown to increase during manufacture or over time. Any impurities that increase over time and are allowed > QT will need to be qualified for safety. If the accelerated stability data fail tightened limits full term long term data should be provided. Example: MDD (Maximum Daily Dose) for the DP is 24 mg Drug Product QT = 0.5% Impurity A: NMT 0.15% (drug substance) NMT 0.8% (drug product release) NMT 1.0% (shelf-life).
Minimization Variability, Traceability and UncertaintyObjectives of Measurement in Health Care Industries1. To Ascertain: The Quality of a Product and the Control of Process2. To Demonstrate: Potency of Product, Compliance with Specifications, and Conformity with Regulations.3. To Fulfill Requirements: Pharmacopoeias and GuidelinesGoals of Determination of a Parameters1. Testing: 2. Measurement Test Results in Arbitrary Units Analytical Results in SI units Method Dependent Method independent Accepted Method Traceability Reproducibility Uncertainty
Variability & MinimizationNo Matter What….Corporate must shows that Analytical Instrument is Qualified Computer System and Software is Validated Audit Trail and Data Access is Limited Data Storage (Electronic and Paper) and Traceability Method is Validated & Purity-Stability Profile Indicator SOP is Adequately Defined and ApprovedPotency Assays for Generic Pharmaceutical Method Feasibility Method DOE and Development Method Verification for Variables Method Validation Method Transfer for Re/Verification of Variables Additional Validation / Revalidation Monitor / Access Method Life CycleQuality Measurements via Technical Communication & Evaluation Evaluate potential uncertainty of quantitative and qualitative results and variables Reduce variables as much as possibleIdentified and optimize key variables using cause and effects diagram
Variability & Traceability in HPLCPotential Source of Method Variability: Ishikawa Diagnostic MethodologyEnvironment Materials Method Lab temperature Stability and Purity Ruggedness Lab humidity Storage and Handling Complexicity of SOP / Protocols Light exposure Sampling of test materials Suitability of mobile phase Air borne contamination Standard contamination Accuracy of preparation of standards Laboratory layout Sample contamination Accuracy of preparation of samples Glassware contamination Matrix interference Wrong glassware selection P R Wrong reagents selection R E O S »»»»»»»» Root Cause & Effect F r a m e W o r k Analysis »»»»»»»» B U L L E T Training Time since certification Column degradation, M S Failure to understand protocol Time since sampling / dilution temperature fluctuations Work precision and accuracy Repeatability interference UV detector lamp with Individual interpretation of SOP Noisy baseline, carryovers variable performance, air bubbles Lack of Communication Density difference in solutions Pump, flow rate, blockage, leakage, Poor housekeeping Improper correction factor entry trapped air, improper mixing, Injector reproducibility People Measurement LC EquipmentDevelop Yourself - Knowledge Based Methods and Tools from ICH Q9 Quality Risk Management
Assay & Imp: Variability & Traceability Potential Source of Variability in Assay and Impurities MethodEnvironment Materials Method Lab temperature-N Reagents-source , grade, lot-N Diluent and Mobile Phase Lab humidity-N Column and Vials-N Standard/ Sample Prep / Light exposure-N Volumetric glasswares-N Resolution Prep/ Sensitivity Check Air borne contamination-N Transfer Pipettes-N Runtime/ re-equilibration-X Filters & Syringe-N Filtrate discard volume-X Filtrate & glasswares-N Pipette Techniques-N Weighing boat for Buffer-N Weighing Techniques-N A Product Type-N P S Reference Material-C R S O A »»»»»»»» Root Cause & Effect F r a m e W o r k Analysis »»»»»»»» B Y L & E I Weighing Techniques -C Impurity calculation-C HPLC Parameters-N M M P Integration Techniques-C Data Reporting-C Sonication Time-N Equilibration Techniques-C Suppress Integration Time-C Mechanical Shaker Action-N Variation in Extraction-C Noisy Baseline-C Physical Balance Environment-N Incorrect flask/Pipettes-C Software Quality-C Balance Accuracy-C Improper Correction Factor –C pH Meter Accuracy/Calibration-C Sampling Rate-X Run Time/ Equilibrium Time-X People Measurement Equipment N= Noise factor for Ruggedness, C= Control, eXperimental parameters for Robustness
Federal CFR Guidance Most Frequent referred Code of Federal Regulations http://www.gpoaccess.gov/cfr/index.html http://www.betterchem.com/title21.htm: Analytical Method Validation21CFR 211.165 21 CFR 211.165accuracy, sensitivity, specificity and reproducibility of test method employed The (a) 3 :(e) by the firm shall be established and documented. Such validation and document may be accomplished in accordance with § 211.194 (a) (2). Stability Indicating Analytical Method21 CFR 211.166 There shall be a written testing program designed to assess the stability(a) (3) characteristics of drug products. The results of stability testing shall be used in determining appropriate storage conditions and expiration dates Regulatory Guidance on Method Transfer Methods used in the testing of the sample meet proper standards of accuracy21 CFR 211.194 and reliability as applied to product tested.(a) (2) The suitability of all testing methods used shall be verified under actual conditions of use. Regulatory Guidance on GLP21 CFR 58.190 All protocol, raw data documentation, generated reports shall be retained,(a, b, c, d) archives, individual shall be indentified to archives. etc.21 CFR 211.160 Laboratory Control Systems(a, b) Deviations from test procedure and written specifications.
Quick International References ICH Quick Link: Http://www.emea.europa.eu/htms/human/ich/ichquality.htmAnalytical Validation:ICH Topic Q 2 (R1) Validation of Analytical Procedures: Text andMethodologyhttp://www.emea.europa.eu/pdfs/human/ich/038195en.pdfImpurities:ICH Topic Q 3 A (R2) Impurities in new Drug Substanceshttp://www.emea.europa.eu/pdfs/human/ich/273799en.pdfICH Topic Q 3 B (R2) Impurities in New Drug Productshttp://www.emea.europa.eu/pdfs/human/ich/273899en.pdfICH Topic Q 3 C (R3) Impurities in Residual Solventshttp://www.emea.europa.eu/pdfs/human/ich/028395en.pdfSpecifications:ICH Topic Q 6 A Specifications: Test Procedures and Acceptance Criteriafor New Drug Substances and New Drug Products: Chemical Substanceshttp://www.emea.europa.eu/pdfs/human/ich/036796en.pdfICH Q6A Decision Treeshttp://www.ich.org/LOB/media/MEDIA431.pdf
Quick International References ICH Quick Link: Http://www.emea.europa.eu/htms/human/ich/ichquality.htmStability:ICH Topic Q 1 A (R2) Stability Testing of new Drug Substances andProductshttp://www.emea.europa.eu/pdfs/human/ich/273699en.pdfICH Topic Q1B Photostability Testing of New Active Substances andMedicinal Productshttp://www.emea.europa.eu/pdfs/human/ich/027995en.pdfICH Topic Q1C Stability Testing: Requirements for New Dosage Formshttp://www.emea.europa.eu/pdfs/human/ich/028095en.pdfICH Topic Q 1 D Bracketing and Matrixing designs for Stability Testing ofDrug Substances and Drug Productshttp://www.emea.europa.eu/pdfs/human/ich/410400en.pdfICH Topic Q 1 E Evaluation of Stability Datahttp://www.emea.europa.eu/pdfs/human/ich/042002en.pdfICH Topic Q 1 F Stability Data Package for Registration Applicationsin Climatic Zones III and IVhttp://www.emea.europa.eu/pdfs/human/ich/042102en.pdf
Quick International References ICH Quick Link: Http://www.emea.europa.eu/htms/human/ich/ichquality.htmRegulatory Acceptance:ICH Topic Q 4 B Regulatory Acceptance of Analytical Procedures and/orAcceptance Criteria (RAAPAC)http://www.emea.europa.eu/pdfs/human/ich/22200706en.pdfICH Topic Q 4 B Annex Annex to Regulatory Acceptance of AnalyticalProcedures and/or Acceptance Criteria (RAAPAC)http://www.emea.europa.eu/pdfs/human/ich/22206306en.pdfPharmaceutical Development:ICH Topic Q 8 Pharmaceutical Developmenthttp://www.emea.europa.eu/pdfs/human/ich/16706804en.pdfICH Topic Q 8 Annex Pharmaceutical Developmenthttp://www.emea.europa.eu/pdfs/human/ich/51881907en.pdfICH Q9 document on Quality Risk Managementhttp://www.emea.europa.eu/Inspections/docs/ICHQ9Step4QRM.pdfICH Topic Q 10 Pharmaceutical Quality Systemhttp://www.emea.europa.eu/pdfs/human/ich/21473207en.pdf
Quick International References USA Guidelines LinksCDER Master Index Pagehttp://www.fda.gov/cder/guidance/index.htmAnalytical Procedures and Methods Validation Chemistry, Manufacturing,and Controls Documentationhttp://www.fda.gov/cder/guidance/2396dft.htmReviewer Guidance Validation of Chromatographic Methodshttp://www.fda.gov/Cder/guidance/cmc3.pdfGuidance for Industry, Bioanalytical Method Validationhttp://www.fda.gov/cder/guidance/4252fnl.pdfNational Archives and Records Administration (CFR)http://www.gpoaccess.gov/cfr/index.htmlUSP<1225> Validation of Compendial Procedures * Login Requiredhttp://www.uspnf.com/uspnf/pub/index?usp=30&nf=25&s=2USP<1226> Verification of Compendial Procedures * Login Requiredhttp://www.uspnf.com/uspnf/pub/index?usp=30&nf=25&s=2
Quick International References CTD and eCTD Informational LinksM4: Organization of the CTDhttp://www.fda.gov/cder/guidance/4539O.PDFeCTD Submissionshttp://www.fda.gov/cder/guidance/7087rev.pdfDrug Substancehttp://www.fda.gov/cder/guidance/3969DFT.pdfDrug Producthttp://www.fda.gov/cder/guidance/1215dft.pdfQ8: Pharmaceutical Developmentwww.fda.gov/cder/guidance/6746fnl.pdfCTD-Efficacyhttp://www.fda.gov/cder/guidance/4539E.pdfCTD-Qualityhttp://www.fda.gov/cder/guidance/4539Q.PDFQbR-Quality Overall Summary Outlinehttp://www.fda.gov/cder/ogd/