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Final Guidance for Industry

Analytical Procedures and Methods Validation for Drugs and Biologics

IVT‘s AnAlyTIcAl procedures And Method Validation Conference

December 8, 2015

Lokesh Bhattacharyya

Chief, LACBRP/DBSQC

OCBQ/CBER/FDA

New Guidance for Industry: Background

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■ 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■ Supersedes the 2000 draft guidance for industry on Analytical Procedures and Methods Validation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

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■ The draft guidance was issued in February 2014 for public comment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

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Scope

Applies to :

New Drug Applications (NDAs)

Abbreviated New Drug Applications (ANDAs)

Biologics License Applications (BLAs)

Supplements

OTC monograph products

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

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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 development data in support of method validation

Emphasis on robustness study

– Role of robustness studies in method validation

– Effects of method parameters on method performance

• Multivariate DOE experimental design

• Understand sources of variation and their impacts on method performance

• Risk assessment

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Content of Analytical Procedures

FDA recognized sources may be referenced if procedure is 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)

Content of Analytical Procedures

Operating Parameters

– Optimal settings and ranges critical to the analysis

– 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

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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:

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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 (mostly for biological assays)

• RSD of replicate measurements of samples

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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

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Reference Standards

Selection of appropriate standard is critical

‒ Same chemical entity as analyte, to the extent possible

• Highly purified recombinant FVIII standard shows poor results when used as standard for plasma-derive FVIII product – non-identical structures (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

‒ Where applicable, reference standards available from CBER should be used (for biological methods)

Reference Standards

Secondary standard – standard from other sources; 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/annual reports

Refers to ICH Q6A and Q6B for additional details 13

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: interlaboratory evaluation

Stability indicating assays

− Specificity

• 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>

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Method Validation

Include in the validation report:

− Details of methodology

• Equipment: description of system set up (column, detector, response including units) 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

− Experimental verification of LOQ or LOD (where appropriate) 15

Lifecycle Management

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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

Alternative Analytical Procedures

Alternative to regulation methods

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 in 21 CFR 314.70 (NDA, ANDA) or 601.12 (BLA)

Conduct a comparability study to demonstrate:

− New method coupled 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

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FDA Methods Verification

FDA laboratory may determine whether a procedure is acceptable for QC and regulatory purposes

− Part of the review process (in-support testing)

FDA laboratory will send request for samples, standards and in-house reagents (not available commercially)

Laboratory results and comments will be 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

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 minimal system suitability/Assay validity requirement

– No calculation: reference to a software

Method LOQ is above the proposed specification limit

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

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

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:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatory

Information/Guidances/default.htm

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