Method validation for drug substances and drug product _remodified_2014
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Method validation for drug substances and drug product _remodified_2014

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Method validation is the process of proving that an analytical method is acceptable for its intended purposes. ...

Method validation is the process of proving that an analytical method is acceptable for its intended purposes.

METHOD VALIDATION = ERROR ASSESSMENT

Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug substances and drug products

Validation: Prior Considerations Suitability of Instrument Status of Qualification and Calibration Suitability of Materials Status of Reference Standards, Reagents, Placebo Lots Suitability of Analyst Status of Training and Qualification Records Suitability of Documentation Written and approved standard test procedure and proper approved protocol with pre-established acceptance criteria

Compendial vs. Non-compendial Methods
Compendial methods-Verification
Regulatory analytical procedure in USP/NF
Non- compendial methods-Validation
Alternative analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure

Chromatographic Methods
Demonstrate Resolution
Impurities/Degradants Available
Spike with impurities/degradants
Show resolution and a lack of interference
Impurities/Degradants Not Available
Stress SamplesFor assay, Stressed and Unstressed Samples should be compared.

Ability of an analytical method to measure the analyte free from interference due to other components.

Selectivity describes the ability of an analytical method to differentiate various substances in a sample
Original term used in USP
Also Preferred by IUPAC and AOAC
Also used to characterize chromatographic columns
Degree of Bias (Used in USP)
The difference in assay results between the two groups
the sample containing added impurities, degradation products, related chemical compounds, placebo ingredients
Selectivity: For impurity test, impurity profiles should be compared.

Temperature (50-60℃)
Humidity (70-80%)
Acid Hydrolysis (0.1 N HCl)
Base Hydrolysis (0.1 N NaOH)
Oxidation (3-30%)
Light (UV/Vis/Fl)
Intent is to create 10 to 30 % Degradation
Change in the analytical procedure, drug substance, drug product, the changes, may necessitate revalidation of the analytical procedures.
“The degree of revalidation depends on the nature of the change.”
“FDA intends to provide guidance in the future on post-approval changes in analytical procedures.”

By Visual Inspection of plot of signals vs. analyte concentration
By Appropriate statistical methods
Linear Regression (y = mx + b)
Correlation Coefficient, y-intercept (b), slope (m)
Acceptance criteria: Linear regression r2 > 0.999

Requires a minimum of 6 concentration levels
Normally derived from Linearity studies.
Established by confirming that the method provides acceptable degree of linearity, accuracy, and precision.
Specific range dependent upon intended application of the procedure.

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Method validation for drug substances and drug product _remodified_2014 Method validation for drug substances and drug product _remodified_2014 Presentation Transcript

  • Validationof AnalyticalValidationof Analytical Method for DrugMethod for Drug Substances & DrugProductsSubstances & DrugProducts Dr. R.Badmanaban., M.Pharm., M.D(A.M).,PhD., Associate Professor, Head of Dept - Pharmacognosy Shri Sarvajanik Pharmacy college - Mehsana-384001 www.sspcmsn.org Email: badu1977@gmail.com
  • Definition: Method validation is the process of proving that an analytical method is acceptable for its intended purposes. METHOD VALIDATION = ERROR ASSESSMENT  Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug substances and drug products
  • Analytical Method Body Full name Guidance on Eurachem Focus for Analytical Chemistry in Europe Method validation CITAC Cooperation of International Traceability in Analytical Chemistry Proficiency testing Quality Assurance EA European Cooperation for Accreditation Accreditation CEN European Committee for Normalization Standardization IUPAC International Union of Pure & Applied Chem. Method validation ISO International Standardization Organisation Standardisation AOAC ILAC Association of Official Analytical Chemists International Laboratory Accreditation Cooperat. Internal qual. Control Proficiency testing Accreditation FDA US Food and Drug Administration Method validation USP United States Pharmacopoeia Method validation ICH International Conference on Harmonization Method validation International regulatory bodies and their guidelines on different aspects of QA
  • Chromatography todayChromatography today More than sixty variants of the technique have been developed. HPLC, GC, SFC, and CE are the most frequently used. HPLC:  almost universal  wide range of equipment and columns is commercially available  well-understood separation mechanisms  sensitive, specific, selective, precise and robust, Rugged, accurate.  easy to maintain instrumentation  flexible in optimizing separations  More efficient than some of the separation techniques July 21, 2014 Shri Sarvajanik Pharmacy 4
  • Liquid Chromatography (HPLC) instrumentLiquid Chromatography (HPLC) instrument July 21, 2014 Shri Sarvajanik Pharmacy 5
  • The ChromatographicThe Chromatographic Process – TheoreticalProcess – Theoretical ConsiderationsConsiderations July 21, 2014 Shri Sarvajanik Pharmacy 6
  • Elution in Column ChromatographyElution in Column Chromatography July 21, 2014 Shri Sarvajanik Pharmacy 7 MobileMobile phasephase StationaryStationary phasephase tt00 tt11 tt22 tt44tt33
  • Intermolecular InteractionsIntermolecular Interactions July 21, 2014 Shri Sarvajanik Pharmacy 8
  • ChromatogramChromatogram July 21, 2014 Shri Sarvajanik Pharmacy 9
  • Retention RelationshipsRetention Relationships July 21, 2014 Shri Sarvajanik Pharmacy 10
  • 11 Validation (4M) Man Machine Material Method
  • Why Method Validation is Important ? Analytical Method
  • Why Method Validation is Important? 1. Develops confidence in using the method & Proof that Method is suitable for its intended purpose, The purpose of analytical measurement is to get consistent, reliable and accurate data. Incorrect measurement results can lead to tremendous costs. 2.2. Regulatory requirementRegulatory requirement, Equal importance for those working in a regulated and in an accredited environment.
  • When to be validated ? Analytical Method
  • When to be validated? Partial validation after development of method. Complete validation after manufacturing formula is finalized. Which methods are to be validated ? Compendia: Pharmacopoeia method Verification of suitability of method Non compendia methods: Laboratory developed methods. Pharmacopoeias methods used outside its scope.
  • Validation: Prior Considerations Suitability of Instrument Status of Qualification and Calibration Suitability of Materials Status of Reference Standards, Reagents, Placebo Lots Suitability of Analyst Status of Training and Qualification Records Suitability of Documentation Written and approved standard test procedure and proper approved protocol with pre-established acceptance criteria
  • Validation Activity Including the Complete Analytical Procedure Sampling Sample Preparation Analysis Data Evaluation Reporting
  • Validation Step Define the application, purpose and scope of the method. Analytes? Concentration? Develop a analytical method. Develop a validation protocol. Qualification of instrument. Qualify/train operator
  • Qualification of material. Perform pre-validation experiments. Adjust method parameters and/or acceptance criteria if necessary. Perform full validation experiments. Develop Procedures for executing the method in routine analysis. Document validation experiments and results in the validation report. Validation Step
  • Verification vs. Validation Compendial vs. Non-compendial Methods Compendial methods-Verification Regulatory analytical procedure in USP/NF Non- compendial methods-Validation Alternative analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure
  • Method Validation Method Transfer Method Development Approved BACKGROUND-LAB METHOD FLOW
  • ICH/USP Validation Requirements Precision Repeatability Intermediate Precision Reproducibility Limit of Detection Limit of Quantitation Robustness Specificity System suitability Linearity Range Accuracy
  • Validation Parameters Impurities Specificity Linearity and Range Accuracy Precision Robustness LOD & LOQs Dissolution Specificity Linearity and Range Accuracy Precision Robustness Assay / CU Specificity Linearity and Range Accuracy Precision Robustness
  • Specificity/Selectivity Ability of an analytical method to measure the analyte free from interference due to other components. Selectivity Bias
  • Specificity: ICH/USP The ability to measure accurately and specifically the analyte in the presence of components that may be expected to be present in the matrix The degree of interference Active Ingredients Excipients Impurities (synthetic precursors, enantiomers) Degradation Products Placebo Ingredients
  • Analytical Method
  • Continue.... . Combination of 2 or more analytical procedures may be required to achieve necessary level of discrimination . Stability indicating analytical methods should always be specific. . Analysts should ascertain whether the peaks within a sample chromatogram are pure or consist of more than one compound. Therefore should know how many compounds are in the sample or use procedures to detect peak purity Analytical Method
  • Specificity: Impurities Assay Chromatographic Methods Demonstrate Resolution Impurities/Degradants Available Spike with impurities/degradants Show resolution and a lack of interference Impurities/Degradants Not Available Stress Samples For assay, Stressed and Unstressed Samples should be compared. 29 2009
  • Selectivity Ability of an analytical method to measure the analyte free from interference due to other components. Selectivity describes the ability of an analytical method to differentiate various substances in a sample Original term used in USP Also Preferred by IUPAC and AOAC Also used to characterize chromatographic columns Degree of Bias (Used in USP) The difference in assay results between the two groups - the sample containing added impurities, degradation products, related chemical compounds, placebo ingredients Selectivity: For impurity test, impurity profiles should be compared. 30 2009
  • Analytical Method
  • Forced Degradation Studies Temperature (50-60℃) Humidity (70-80%) Acid Hydrolysis (0.1 N HCl) Base Hydrolysis (0.1 N NaOH) Oxidation (3-30%) Light (UV/Vis/Fl) Intent is to create 10 to 30 % Degradation 32 2009
  • Analytical Method
  • Linearity Ability of an assay to elicit a direct and proportional response to changes in analyte concentration. 34 2009
  • Linearity Should be Evaluated By Visual Inspection of plot of signals vs. analyte concentration By Appropriate statistical methods Linear Regression (y = mx + b) Correlation Coefficient, y-intercept (b), slope (m) Acceptance criteria: Linear regression r2 > 0.999 Requires a minimum of 6 concentration 35 2009
  • Range The interval between the upper and lower concentrations of analyte in the sample that have been demonstrate to have a suitable level of precision, accuracy, and linearity.
  • Range Normally derived from Linearity studies. Established by confirming that the method provides acceptable degree of linearity, accuracy, and precision. Specific range dependent upon intended application of the procedure.
  • Range Acceptable range having linearity, accuracy, precision. For Drug Substance & Drug product Assay 80 to 120% of test Concentration For Content Uniformity Assay 70 to 130% of test Concentration For Dissolution Test Method +/- 20% over entire Specification Range 38 2009
  • Accuracy Closeness of the test results obtained by the method to the true value.
  • Accuracy Should be established across specified range of analytical procedure. Should be assessed using a minimum of 3 concentration levels, each in triplicate (total of 9 determinations) Should be reported as: Percent recovery of known amount added or The difference between the mean assay result and the accepted value 40 2009
  • Accuracy Data Set (1 of 3) 41 2009
  • Precision The closeness of agreement (degree of scatter) between a series of measurements obtained from multiple samplings of the same homogeneous sample. Should be investigated using homogeneous, authentic StrikeStrike StrikeStrike StrikeStrike StrikStrik ee StrikeStrike StrikeStrike BallBall BallBall BallBall BallBall BallBall BalBal llBallBall BallBall
  • Accuracy Vs Precision Inaccurate & imprecise Inaccurate but precise Accurate but imprecise
  • Precision… Considered at 3 Levels Repeatability Intermediate Precision Reproducibility
  • Repeatability Express the precision under the same operating conditions over a short interval of time. Also referred to as Intra-assay precision
  • Intermediate Precision Express within-laboratory variations. Expressed in terms of standard deviation, relative standard deviation (coefficient of variation) and confidence interval. Known as part of Ruggedness in USP (Different Analysts, Different Laboratories, Different Instruments, Different Depends on the circumstances under which the procedure is intended to be used.
  • Repeatability & Intermediate Precision Day 1 Day 2 100.6 99.5 100.8 99.9 100.1 98.9 100.3 99.2 100.5 99.7 100.4 99.6 47 Grand Mean = 100.0 RSD = 0.59% Mean = 100.5 RSD = 0.24% Mean = 99.5 RSD = 0.36% 2009
  • Definition: Ability to reproduce data within the predefined precision Determination: SD, RSD and confidence interval Repeatability test at two different labs. Reproducibili ty
  • Reproducibility Study Lab 1 Lab 2 Lab 3 Day 1 Day 2 Day 1 Day 2 Day 1 Day 2 Analys t1 Analyst 2 Analyst 1 Analyst 2 Analyst 1 Analyst 2 3 Preps 3 Preps 3 Preps 3 Preps 3 Preps 3 Preps
  • Lowest amount of analyte in a sample that can be detected but not necessarily quantitated. Estimated by Signal to Noise Ratio of 3:1. Detection Limit (DL) Lowest amount of analyte in a sample that can be quantified with suitable accuracy and precision. Estimated by Signal to Noise Ratio of 10:1. Quantitation Limit (QL)
  • LOD, LOQ and SNR Limit of Quantitation (LOQ( Limit of Detection (LOD( Signal to Noise Ratio (SNR( noise Peak A LOD Peak B LOQ Baseline
  • S = slope of calibration curve s = standard deviation of blank readings or standard deviation of regression line Validated by assaying samples at DL or QL 52 DL =DL = 3.3s3.3s QL =QL = 10s10s SS SS LOD and LOQ Estimated by 2009
  • 53 Ybl LOD LOQ Statistical estimate of LOD & LOQ LOD = 3.3 Sbl / b LOQ = 10 Sbl / b Y = b X + a 2009
  • Analytical Method
  • Definition: Capacity to remain unaffected by small & deliberate variations in method parameters Determination: Comparison results under differing conditions with precision under normal conditions Variations may include: stability of analytical solution, variation of pH in a mobile phase, different column (lot/supplier), temperature, flow rate. Robustnes s
  • Robustness Variations All Assays HPLC Assays GC Assays -Sample Prep Manipulation -Extraction Time -Mobile Phase Composition -Different Columns -Temperature -Flow Rate -Different Columns -Temperature -Flow Rate
  • Ruggedness Degree of reproducibility of test results under a variety of conditions Different Laboratories Different Analysts Different Instruments Different Reagents Different Days Etc. Expressed as %RSD 57 2009
  • Solutes may readily decompose prior to chromatographic investigations e.g. during sample preparation, extraction, cleanup, phase transfer or storage of prepared vials (refrigerators or automatic sampler). Method development should investigate the stability of the Analytes AND standards. Stability of analytical solution Solution stability • Stability of the samples being analyzed in a sample solution. e.g. 1 – 48 hours using a single solution. • should be determined by replicate analysis of the sample solution.
  • The checking of a system, before or during analysis of unknowns, to ensure system performance. “No sample analysis is acceptable unless the requirements for system suitability have been met.” (USP Chapter 621) Plate Count, Tailing, Resolution Determination of reproducibility (%RSD) For %RSD < 2.0%, Five replicates System Suitability "Sample“ - A mixture of main components and expected by-products utilized to determine system suitability “Whenever There is a Significant change in Equipment or Reagents SYSTEM SUITABILITY
  • Confuse of Precision Terms  Repeatabili ty  Intermediat e Precision  Reproducibilit y  Ruggedness  Robustness
  • Precision Terms Instrument Precision Repeatability Intermediate Precision Reproducibility Ruggedness Robustness - 6 Standard Injections - One Analysis (6 preps) - Two Analyses - Two different Lab. - Many Variables
  • Change in the analytical procedure, drug substance, drug product, the changes, may necessitate revalidation of the analytical procedures. “The degree of revalidation depends on the nature of the change.” “FDA intends to provide guidance in the future on post- approval changes in analytical procedures.”Revalidation should accompany formulation changes (new samples with new compounds or new matrices) manufacturing batch changes new analysts with different skills, new instruments with different characteristics, new location with different environmental conditions, new chemicals and/or reference standards and modification of analytical parameters. Revalidation
  • Validation Report Objective and scope of the method (applicability, type). Summary of methodology. Type of compounds and matrix. All chemicals, reagents, reference standards, QC samples with purity, grade, their source or detailed instructions on their preparation. Procedures for quality checks of standards and chemicals used. Method parameters. Critical parameters taken from robustness testing. Listing of equipment and its functional and performance requirements, e.g., cell dimensions, baseline noise and column temperature range. Detailed conditions on conduct of experiments, including sample preparation  Statistical procedures and representative calculations.  Procedures for QC in routine analyses, e.g., system suitability tests.  Representative plots, e.g., chromatograms, spectra and calibration curves.  Method acceptance limit performance data and expected uncertainty of measurement results. Criteria for revalidation. The person's) who developed and validated the method. References (if any).
  • Analytical Method
  • How do we Know the expectations of the FDA? FDA Form 483 FDA Warning Letters Personal Experiences 65 2009
  • 483 Observations There was inadequate 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 66 2009
  • FDA Warning Letter On addition to an example of modifying both compendia methods and customer supplied methods, we also observed the use of invalidated in-house methods 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. (June 2009) 67 2009
  • General requirements Qualified and calibrated instruments Documented methods Reliable reference standards Qualified analysts Sample integrity Change control (e.g., synthesis,) Analytical methods should be used within GMP and GLP environments, and must be developed using the protocols and acceptance criteria set out in the ICH guidelines Q2 (R1)
  • Analytical Method
  • Related Site www.fda.gov www.fda.gov/cder/ www.waters.com www.usp.org www.ich.org www.aoac.org www.pharmweb.net 70 2009
  • Thank you