Analytical Procedures and Methods Validation for Drugs and Biologics

Description

This guidance supersedes the draft of the same name that published on February 19, 2014 (79 FR 9467) and replaces the 2000 draft guidance for industry on Analytical Procedures and Methods Validation and the 1987 Guidelines for Submitting Samples and Analytical Data for Methods Validation. It provides recommendations on how you, the applicant, can submit analytical procedures and methods validation data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

1

drug products

Products distributed in the United States subject to DSCSA

Regulatory Context

Regulatory Activities

4

NDA

New Drug Application

ANDA

Abbreviated New Drug Application

BLA

Biologics License Application

IND

Investigational New Drug submissions

Document Types

5

Type II drug master files

Principles apply to drug substances and products covered in Type II DMFs

Material Safety Data Sheets

Documents FDA does not intend to enforce submission for if unaltered

Annual report

Submission of long-term stability data

Verification protocol

Includes methodology and acceptance criteria

Certificate of Analysis

Document indicating analytical results of testing; record relied on to control L. monocytogenes in ingredients; document provided for a food prior to or upon receipt of the food; COA documentation

Attributes

5

potency

Key search term and scientific factor for evaluation.

LOQ

Limit of Quantitation for analytical methods

LOD

Limit of Detection for analytical methods

Robustness

Evaluation of robustness and parameter ranges of analytical procedures; Development of a robust multivariate analytical procedure includes scientifically justified sample selection; Capacity of an analytical procedure to meet performance criteria during normal use.; Assessed using retention time models; Performance characteristic to be validated

Specificity

Ability to detect intended mechanism of action without interference; Performance characteristic to be validated

Technical Details

Substances

5

drug substances

documentation of identity, strength, quality, purity, and potency

Synthetic Peptide Substances

Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances

Drug product

assaying for the active or other selected component(s)

Drug substance

quantitative measurement of the major component(s) in the drug substance; changes in the synthesis of the drug substance

Reference Standard

blank biological matrix is spiked with the analyte(s) of interest using solutions of reference standard(s); Used to make stock solutions; stability defined by expiration or retest date; The reference standard should be well characterized and documented; Material used as a basis for comparison in the assay.; A well-characterized substance of known purity and identity used to prepare calibration and quality control samples.

Testing Methods

7

bioassays

based on animal challenge models

Chromatographic Methods

Quantitative analysis method within scope; Acceptance criteria for ISR in chromatographic methods

Linear regression

Used to measure linearity

ANOVA

Analysis of variance for % TBWL

immunoassays

unique features for development and validation

System Suitability

Determination of instrument performance by analysis of a set of reference standards

Stability-Indicating Test

Quantitative procedure detecting changes in quality attributes during storage.

Processes

6

Analytical Methods Transfer Studies

Life cycle management of analytical procedures

Revalidation

Demonstration that an analytical procedure is still fit for purpose after a change.

Analytical method comparability study

Demonstrating equivalence of two test methods

Robustness evaluation

Conducted during method development or validation

Analytical Method Validation

Process of demonstrating suitability for intended purpose.

Method Development

General principle discussed in section 2.1; Initial phase before validation

Standards & References

External Standards

8

USP General Chapter <1226>

Verification of analytical procedures; A verification of USP General Chapter <1226> procedures

USP General Chapter <1225>

Validation of Compendial Procedures

USP General Chapter <621>

Requirements for system suitability tests in chromatography.

ASTM E2935

Standard Practice for Conducting Equivalence Testing; Standard Practice for Conducting Equivalence Testing in Laboratory Applications

USP General Chapter <1224>

Transfer of Analytical Procedures

USP/NF

Compendial excipients should comply with USP/NF monographs

ASTM E29

Standard practice for using significant digits in test data.; Standard Practice for Using Significant Digits in Test Data

AOAC International

Use of a method published by an authoritative source such as AOAC International

Specifications

1

Acceptance Criteria

limits for solid state form and particle size; Tightening acceptance criteria; Numerical limits or ranges for tests

ICH References (6)

ICH Q3A(R2)

Impurities in New Drug Substances

ICH Q1A(R2)

Stability Testing of New Drug Substances and Products

ICH Q2(R1)

Validation of Analytical Procedures: Text and Methodology

ICH M2

Electronic Common Technical Document Specification.

ICH Q6B

Specifications for biotechnological/biological products; Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

ICH Q7

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; Reworking needs more evaluation and testing according to ICH Q7; Good manufacturing practice for API starting materials; Referenced regarding the definition of intermediates.

Related CFR Sections (9)

21CFR312.23§ 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:Read full regulation →
21CFR314.50§ 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA for a new chemical enRead full regulation →
21CFR314.94§ 314.94 Content and format of an ANDA.
ANDAs are required to be submitted in the form and contain the information required under this section. Three copies of the ANDA are required, an archival copy, a review copy, and a field copy. FDA will maintain guidance documents on the format and content of ANDAs to assist applicants in their prepRead full regulation →
21CFR601.2§ 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing aRead full regulation →
21CFR211.165§ 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on sRead full regulation →
21CFR211.194§ 211.194 Laboratory records.
(a) Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays, as follows:Read full regulation →
21CFR314.70§ 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA.Read full regulation →
21CFR601.12§ 601.12 Changes to an approved application.
(a) General.Read full regulation →
21CFR610.9§ 610.9 Equivalent methods and processes.
Modification of any particular test method or manufacturing process or the conditions under which it is conducted as required in this part or in the additional standards for specific biological products in parts 620 through 680 of this chapter shall be permitted only under the following conditions:Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods

7

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

4

Failure to establish adequate written procedures for production and process control

3

Failure to exercise appropriate controls over computer or related systems

2

Failure to establish the accuracy, sensitivity, specificity, and reproducibility of test methods

1

Failure to ensure returned drugs meet appropriate standards

1

Failure to establish an adequate quality control unit

1

Failure to exercise appropriate controls over computer systems

1

Failure to follow a written testing program designed to assess stability characteristics

1

Quality control unit failed to approve or reject all procedures or specifications