Leedoyeon methodvalidation

What is AnalyticalMethod Validation ? 1

Validation 2

Validation Point Validation Protocol Monitoring, Calibration, Change Control, Qualification 3

Validation Process Validation  Prospective Validation  Ongoing Validation  Re-Validation: After change, Periodic,  Retrospective Validation Analytical Method Validation  Specificity, Linearity, Precision, Accuracy/Recovery, Ruggedness Cleaning Validation Utility System Validation Computer Validation 4

Validation Man Machine Material Method 5

Scope of Method Validation Product release methods Stability indicating methods In-Process testing methods Analytical methods for cleaning validation 6

Analytical Method Identity test Quantity test  UV extraction coefficient, HPLC, Capillary electrophoresis Purity test  SDS-PAGE, HPLC Biological activity & Potency  Cell-based bioassay, animal bioassay Stability test 7

What is Analytical Method Validation? The Proof of Method How much evidence is needed to convict? Provide the information of developed products 8

What is the purpose of Analytical Method Validation? Identification of Sources and Quantitation of Potential errors Determination if Method is Acceptable for Intended Use Establish Proof that a Method Can be Used for Decision Making Satisfy FDA Requirements 9

What are the Benefits of Analytical Method Validation? Regulatory Compliance Assurance that Test data from Methods are Reliable Establishment that Test Data are Reproducible, Accurate, Specificity…. 10

What is not Analytical Method Validation? Calibration The Process of Performing Tests on Individual System Components to Ensure Proper function System Suitability Test to verify the proper functioning of the operating system, i.e., the electronics, the equipment, the specimens and the analytical 11

HPLC Detector calibration  Wavelength Accuracy  Linear Range  Noise Level  Drift 12

Typical System Suitability Test  Minimum Resolution of 3.0 between the analyte peak and internal standard peaks  Relative Standard Deviation of replicate standard injections of not more than 2.0% 13

System Suitability Validation CalibrationPump InjectorDetector Data System Analyst Method Sample 14

Method Life Cycle ValidationDevelopment Optimization 15

Verification vs. Validation Compendial vs. Non-compendial Methods  Compendial methods-Verification  Non-compendial methods-Validation 16

Guideline for Method Validation USP Chapter <1225>  Validation of Compendial Methods ICH Guidelines  Q2A, Text on Validation of Analytical procedures (March 1995)  Q2B, Validation of Analytical Procedures: Methodology (May 1997) 17

Regulatory and Compliance Requirements Review Validation of an analytical method is the process by which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical USP 23 General applications Information <1225> 18

 The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 211.194(a)(2). 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Subpart I-Laboratory Controls 211.165 Testing and release for distribution (e) 19

 A statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. (If the method employed is in the current revision of the United States Pharmacopeia, National Formulary, Association of Official Analytical Chemists, Book of Methods,{2} or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice). The suitability of all testing methods used shall CFR verified under 21 be PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED actual conditions of use. PHARMACEUTICALS Subpart J-Records and Reports 20 211.194 Laboratory records (a) (2)

 FDA also Proposed to add a new subpart L to 211, entitled “Validation ”  Subpart L-Validation  Sec. 211.220 Process validation.  211.222 Methods validation.  The accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer shall be validated and documented . Such validation and documentation shall be accomplished in accordance with Sec. 211.194(a) 21 CFR PART 211 - CURRENT GOOD (2). MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Subpart L-Validation 21 211.222 Method validation

 Methods validation means establishing, through documented evidence, a high degree of assurance that an analytical method will consistently yield results that accurately reflect the quality characteristics of the product tested. 21 CFR PART 210 - CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS 210.3 Definitions (b) (25) 22

 The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose ICH Guideline for Industry Q2A, Text on Validation of Analytical Procedures March 1995 23

 In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: Specificity, Linearity, Range, Accuracy, and Precision. ICH Guideline for Industry Q2B, Validation of Analytical Procedures: Methodology 24

Published Validation Guidelines  1978 Current Good Manufacturing Practices (cGMPs)  1987 FDA Validation Guideline  1989 Supplement 9 to USP XXI  1994 FDA Reviewer Guidance  1995 ICH Validation Definitions  1997 ICH Validation Methodology  1999 Supplement 10 to USP 23  2000 FDA Draft Validation Guidance 25

Today ’s Validation Requirements ICH/USP GMPs (legal) FDA 26

GMP Validation Parameters  Accuracy  Specificity  Sensitivity  Reproducibility 21 CFR 211.165 (e) 27

FDA Validation Parameters  Accuracy  Precision  Linearity (& Range)  Specificity (& Determination Limit)  Recovery  Ruggedness 1987 FDA Guidelines 28

ICH/USP ValidationRequirements & Parameters USP ICH Specificity  Specificity Linearity and Range  Linearity Accuracy  Range Precision  Accuracy Limit of Detection  Precision Limit of Quantitation  Repeatability Ruggedness  Intermediate Robustness Precision  Reproducibility  Limit of Detection 29  Limit of Quantitation

USP Data Elements Required For Assay Validation Analytical Assay Category 2 Assay Assay Performance Quantitativ Category Category 1 Limit Tests Parameter e 3 Accuracy Yes Yes * * Precision Yes Yes No Yes Specificity Yes Yes Yes * LOD No No Yes * LOQ No Yes No * Linearity Yes Yes No * Range Yes Yes * * Ruggedness Yes Yes Yes Yes* May be required, depending on the nature of the specific test. 30

USP Categories Category 1: Quantitation of major components or active ingredients Category 2: Determination of impurities or degradation products Category 3: Determination of performance characteristics 31

ICH Validation Characteristics vs. Type of Analytical Procedure Type of Impurity testing Analytical Identificati Quantitativ Assay on Limit Tests Procedure eAccuracy No Yes No YesPrecision No Yes No YesRepeatability Interm. No Yes No YesPrec.Specificity Yes Yes Yes YesLOD No No Yes NoLOQ No Yes No NoLinearity No Yes No YesRange No Yes No Yes 32

How do we go about performing an ICH Assay Method Validation? Must Know and understand what it is Must understand method validation terms Must design an experimental approach 33

Method Validation Overview  GMP/GLP Consideration  Validation SOP  Validation Protocols  Validation Specifications  Validation Samples  Validation Standards  Reference Standards  Instrument Qualification and maintenance  Training 34

How do we Know the expectations of the FDA? FDA Form 483 FDA Warning Letters Personal Experiences 35

483 Observations There was no 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 36

483 Observations Stress studies conducted as part of method validation do not target a minimum amount of degradation. … a standard period of two hours as commonly used for stress studies with no justification… Spreadsheets used to calculate linearity, percent recovery, and final assay results for the cleaning validation of …were not validated and the data transcribed from chromatographs to the spreadsheets were 37

FDA Waning Letter On addition to the example of modifying both compendial methods and customer supplied methods, we also observed the use of unvalidated in-house methods as well as unvalidated modifications to 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 38

FDA Waning Letter Change control procedures in the laboratory failed to document test method changes to assure accurate, reliable, and reproducible results. The test method did not state whether a helix was to be used during dissolution testing. A … was reportedly used during method development, validation and daily method runs, but there is no documentation of a … being used in any of the documents. There is no assurance that qualification or maintenance of the laboratory equipment can consistently produce valid and accurate analytical results in that numerous examples of test data were invalidated due to instrument malfunction. 39

FDA Warning Letter Attempts to corroborate data in the validation report with supporting raw data in the laboratory were difficult and frustrating for the FDA personnel conducting the inspection. OOS accuracy results reported by analyst 3 were never submitted in the final report. Repeat analysis performed in a different system passed specifications and these results were submitted in the report. Raw data and calculations were not checked by a 40 second responsible individuals required by your

FDA Warning Letter The process validation samples were assays using an HPLC method that had not been validated. The method validation used for both products … did not include a protocol that included specification and acceptance criteria. … The method validation was not reviewed and approved until during the current inspection. Lots of both products were released for distribution prior to completion of the method validation. (August 2001) Method validation for the product Sennosides is inadequate in that the data does not assess all variables, such as different mobile phase concentrations and analytes, to demonstrate that the 41 method can sustain variance. (November 2001)

FDA Systems Based Inspection: Laboratory System Feb – July 2002: 212 Inspections (US), 477 Observations Method Validation Training/Qual. 13% 4% Controls. General Stability Program 35% 21% Inadequate Records 27%* Reference: Albinus D’ Sa, FDA, CDER Office of Compliance, from AAPS, Nov. 2002 42presentation.

GMP/GLP Aspects of Validation 21 CFR Part 58  Good Laboratory practice for Nonclinical Laboratory Studies 21 CFR Part 211  Current Good Manufacturing Practice for Finished Pharmaceuticals 43

21CFR 58.63 Equipment will be inspected, cleaned, and maintained SOPs will be in place to describe methods, materials, and schedules for maintenance Written records will be maintained of inspections, maintenance, testing, and calibration 44

21 CFR 211.160 and 165 Instruments, gauges, and recording devices will be calibrated at suitable intervals in accordance with an established written program. The accuracy, sensitivity, specificity, and reproducibility of methods will be established and documented. 45

21 CFR 211.194 Laboratory records- data is required to establish accuracy and reliability of test methods. USP, NF, AOAC methods that are used must be referenced. The suitability of all test methods must be verified under actual conditions of use. 46

Validation SOP What is it? - It is your laboratory’s documented procedure/philosophy that describes:  What methods require validation  Who is responsible for performing validation  How much validation will be done for different methods  How the validation process will be 47

Validation SOP Why do you need it?  483 findings indicates that it is expected  For consistency between methods, operators, and projects 48

Validation SOP Two options  A very detailed SOP which covers everything you need to plan, execute, report, and approve validation studies for all types of analytical methods or  A very general SOP for guidance, with separate detailed protocols for each different type of 49

Validation SOP Content - Purpose  This document describes the procedures for validating analytical methods in the XYZ Pharmaceutical Company - Scope  This document applies to all analytical methods used for release and stability testing - Responsibilities  State who will - Prepare the validation protocol/guideline - Review and approve the protocol - Prepare the validation report 50 - Review and approve the validation report

- Definitions  Define any unique of ambiguous terms used within your company - Compendial, selectivity/specificity, evaluation criteria, etc.- Validation of non-compendial methods  Noncompendial methods will be evaluated according to the current ICH/FDA guidelines- Validation of compendial methods  Compendial methods used for their intended compendial material will be tested for sepcificity, intermediate precision, and stability. 51

- Revalidation of methods  state your process for - Updating validation for older products - Revalidating when changes in synthesis, formulation, or analytical procedure occur- Validation reports  state who is responsible for writing, reviewing, approving, and archiving 52

Validation Protocol It is a description of…  How specific validation studies will be performed for a given type of method  How results will be evaluated for acceptability It is an opportunity to document your customer’s needs, and their acceptance of your plan 53

Validation Protocol Example content:  Linearity-standard solutions will be prepared and analyzed at 5 levels over the range of 80 to 120% of the target concentration. This will be performed in triplicate.  Repeatability precision-a homogeneous sample will be analyzed 6 times. 54

Validation Specification How good to my validation results need to be?  Agree on the acceptance criteria (specifications) before beginning the validation.  Acceptance criteria should be based on - The intended use of the method 55

Validation Specification Examples  Linearity-standard curves will have correlation coefficients ≥ 0.99 and y- intercept values less than 2% of the target level response.  Repeatability precision-the test results will have a RSD ≤ 2%. 56

Validation Samples Key problem (If working with new chemical entitles):  Having sufficient material to develop an analytical method and perform validation studies early in the development of a drug 57

Validation Samples For Bulk Pharmaceuticals the validation samples should be representative of the synthetic process  Scale  Starting materials  Solvents  Product morphology 58

Validation Samples For Drug Products the validation samples should be representative of the manufacturing process  Scale  Source of formulation components  Materials/Surfaces contacted  Container closure system 59

Reference Standards ICH states that “Well characterized reference materials, with documented purity, should be used throughout the validation study.” 60

Instrument Qualification and Maintenance Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Maintenance Log Books 61

References ‘Analytical Methods Validation for FDA Compliance ’ 교육교재 The Center for Professional Advancement 2003. 3.12-14. Guideline for submitting samples and analytical data for kethods validation (Feb. 1987) ICH Q2A ICH Q2B 21 Code of Federal Registrations Part 210 and 211 Michael E. Swatrz and Ira S. Krull, Analytical method development and validation. Mrcel Dekker, Inc. New York, 1997. USP 23 <1225> http:// www.suregmp.com http://www.biosupport.com http://www.waters.com 62

Leedoyeon methodvalidation

by Shafiqul Islam

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