Analytical Procedures and Methods Validation for Drugs and Biologics

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1 Final Guidance for Industry Analytical Procedures and Methods Validation for Drugs and Biologics Analytical procedures and Method Validation June 21, 2016 Lokesh Bhattacharyya Chief, LACBRP/DBSQC OCBQ/CBER/FDA 1

2 New Guidance for Industry: Background The final guidance was issued in July 2015 Supersedes the 2000 draft guidance for industry on Analytical Procedures and Methods Validation Replaces the 1987 FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation Compliments ICH Q2(R1) Validation of Analytical Procedures. Provides recommendation on what an applicant should submit for analytical procedures and methods validation 2

3 New Guidance for Industry: Background The draft guidance was issued in February 2014 for public comment We received 650+ comments thanks for your comments Comments were reviewed and some revisions made to the guidance based on the comments 3

4 Scope Applies to : New Drug Applications (NDAs) Abbreviated New Drug Applications (ANDAs) Biologics License Applications (BLAs) Supplements OTC monograph products 4

5 Contents I. Introduction II. Background III. Analytical Methods Development IV. Content of Analytical Procedures V. Reference Standards and Materials VI. Analytical Method Validation VII. Statistical Analysis and Models VIII. Life Cycle Management IX. FDA Methods Verification X. References 5

6 Analytical Method Development Recommends Submission of data to indicate mechanistic understanding of the basic methodology Evaluation of specificity, linearity, range, accuracy, precision, LOQ/LOD (if applicable) and robustness May submit data obtained during method development in support of method validation Emphasis on robustness study Role of robustness studies to acquire in-depth knowledge of methods Effects of method parameters on method performance Multivariate DOE experimental design Understand sources of variation and their impacts on method performance Risk assessment 6

7 Content of Analytical Procedures FDA recognized sources may be referenced if procedures are described in detail by the source and not modified (standard methods) USP/NF, AOAC Identify/describe changes from the method as published Principle/Scope Basic Principles of test methodology mechanism of operation Sample type drug substance, active, excipient, impurities Target analyte Equipment and accessories Mechanism of action (for specialized equipment, e.g., coagulation determined by increase in viscosity from pendular oscillatory motion) 7

8 Content of Analytical Procedures Operating Parameters Optimal settings and ranges critical to the analysis (supported by robustness data) Details of column conditioning, warm-up time (as appropriate) Scan/injection/performance sequence Reagents/Standards Grade (quality), source, state of purity, concentration, storage conditions, shelf life, Direction of safe use Sample Preparation Procedures Composition and other description of the diluent (e.g., ph) Replicate analyses Storage conditions and solution stability 8

9 Content of Analytical Procedures Standards and Control Solution Preparations Appropriate description and source Stability and storage conditions Procedure Allow a competent analyst to reproduce the procedure in the same manner as performed by the manufacturer Permit evaluation of the method performance (system suitability/ assay validity criteria) Permit evaluation of results 9

10 Content of Analytical Procedures System Suitability Criteria Ensure system (equipment, electronics, analytical operations) will function correctly Criteria applicable to standards/controls Peak tailing, peak resolution RSD of replicate measurements Linearity of standard curve Assay validity Criteria Ensure the assay/test results are valid Dilution parallelism between standard and samples (critical for biological assays) RSD of replicate measurements of samples 10

11 Content of Analytical Procedures Calculations Equations Include representative calculations, justification for correction factors Data Reporting Format to report results (including significant figures) Consistent with instrumental capabilities and product specification (significant figures, rounding) American Society for Testing and Materials (ASTM) E29 Include units (not just numbers) Other critical information, e.g., RT or RRT of peaks for chromatographic methods 11

12 Reference Standards Selection of appropriate standard is critical Same chemical entity as analyte, to the extent possible Plasma-derived FVIII shows poor results when a Recombinant FVIII is used as standard (Conclusion from 2013 WHO sponsored collaborative study) Comparable physical response for standards used in the measurements of physical properties (e.g., particle size) Primary standard standards from an authoritative source to the extent possible USP, EP, NIST, CBER, WHO For biological methods, reference standards available from CBER should be used, where applicable 12

13 Reference Standards Secondary standard standard from other sources including, in-house standard Characterized by routine and beyond routine testing (ICH Q6A), including orthogonal methods Characterization of impurities or matrix components critical Qualified against a suitable primary standard not against a previous lot of the secondary standard to prevent drift Correlation with the standard used with clinical material should be clearly established Biological products reference standard Details of characterization and qualification information should be in BLA/supplement Refers to ICH Q6A and Q6B for additional details 13

14 Method Validation Noncompendial: Follow ICH Q2(R1) Assess validation characteristics as appropriate Specificity, Linearity, Accuracy, Precision (repeatability and intermediate precision), Quantitation Limit, Detection Limit Reproducibility: if necessary (interlaboratory evaluation) Stability indicating assays Specificity is critical Analyze in the presence of all actual and potential degradants Samples subjected to stress conditions (heat, humidity, light) Compendial: Verify suitability under actual conditions of use Using actual drug substance/excipient/drug product USP General Chapter <1226> 14

15 Method Validation Include in the validation report: Details of methodology Equipment: description of system set up (column, detector, setting etc.) and operating conditions Critical Reagents: complete description, preparation/dilution procedure, stability Samples: complete descriptions and compositions, preparation methods, details of spiking (what, to what) Details of calculation for the assessment of validation characteristics Linearity, distribution of residuals, spike recovery, LOQ, LOD Details of statistical analysis Details of chemometric and/or multivariate models Do not simply refer to a software that is not informative Experimental verification of LOQ or LOD (where appropriate) 15

16 Lifecycle Management When should a method be changed? Trend analysis to evaluate method performance suggests method is not optimal System Suitability criteria difficult to meet New product knowledge Change in product formulation or manufacturing Availability of a new technology Particularly when the approved method is no longer optimal When would a comparability report be needed? Alternative analytical procedure Transfer of an analytical method 16

17 Alternative Analytical Procedures Alternative to FDA-approved analytical procedure Alternative to compendial methods Full or partial validation may be necessary depending upon the nature and extent of the change Post-marketing change Submit as directed by 21 CFR (NDA, ANDA) or (BLA) Conduct a comparability study to demonstrate: New method together with additional control measures is equal or superior to the original method for the intended purpose New method is not more susceptible to matrix effects 17

18 FDA Methods Verification FDA laboratory may determine whether a procedure is acceptable for QC and regulatory purposes In-support testing - part of the review process FDA laboratory will send request for samples, standards and in-house reagents (not available commercially) Laboratory results and comments forwarded to the product quality reviewer Compliance with system suitability and assay validity criteria Compliance with proposed specifications Performance related issues FDA labs work with the sponsor to resolve any issue with assay performance or lack of compliance 18

19 Frequent Comments from Reviewers Incomplete description of method, calculations, and System Suitability / Assay Validity Criteria Sample preparation Missing stability (hold time) information for prepared samples or standards Load not specified: column or detector over load problems No or insufficient system suitability/assay validity requirement No calculation: reference to a software Method LOQ is above the proposed specification limit, yet results are provided as numbers Method Validation not performed citing that the method is compendial There is no USP-NF monograph for the article No method in USP-NF or USP-NF procedure is substantially altered 19

20 Frequent Comments from Reviewers Incomplete or inappropriate method validation Incorrect choice of test category Method validation using standard only actual product not used Linearity from a linear plot of measured vs nominal/expected Conclusions regarding validation characteristics are made based on a related study, which is not included in the submission No method verification for a compendial method citing that it is verified for another article Accuracy inferred not evaluated LOQ/LOD estimated, not experimentally verified Critical test parameters are not evaluated during robustness Failure to include different columns, reagent lots, analysts, etc., for intermediate precision 20

21 Thank you We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at: Information/Guidances/default.htm 21

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