Questions and Answers on Quality Related Controlled Correspondence Guidance for Industry: Guidance for Industry

Description

This questions and answers (Q&A) guidance provides FDA’s current thinking on quality-related scientific and regulatory topics that appear frequently in controlled correspondence submissions. The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract.This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA guidance documents, including this guidance, should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Generic Drug

Subject of GDUFA and related meeting processes.

Combination Product

Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.

Solid Oral Dosage Form

Example of risk assessment for manufacturing process

RLD

Reference Listed Drug used as the basis for an ANDA submission.

Ophthalmic drug product

Generic ophthalmic drug products and their cap colors

Stakeholders

3

Manufacturer

Entity responsible for submitting NDINs

reference standard

FDA designated standard for bioequivalence studies

reference listed drug

RLD used as a comparator for generic products

Regulatory Context

Regulatory Activities

3

Controlled Correspondence

Process by which generic drug manufacturers request information from FDA; Mechanism for requesting information on generic drug development; A mechanism to facilitate generic drug development by requesting FDA comment on specific questions.; Mechanism for requestors to seek evaluation of inactive ingredients and formulations; Primary mechanism for seeking regulatory and scientific advice from FDA regarding generic drug development.; A submission to FDA for information related to generic drug deve

ANDA

Abbreviated New Drug Application

505(b)(2) Application

Alternative submission pathway to ANDA

Document Types

1

Type II Drug Master File

OPQ reviews controlled correspondence inquiries related to Type II drug master files

Attributes

2

Dose Proportional

active and inactive ingredients are in the same proportion between the different strengths

Cap color

Physical property of ophthalmic drug packaging

Technical Details

Substances

1

Drug Substance

Postapproval changes to drug substances; the active pharmaceutical ingredient being modified; Evaluation of physical properties for drug substance; Active ingredient intended to furnish pharmacological activity; The molecule or ion responsible for the physiological or pharmacological action.; The active pharmaceutical ingredient subject to postapproval changes

Testing Methods

6

Stability Testing

Testing used to justify leveraging data across products

in-vivo bioequivalence studies

studies required for generic drug approval

split tablet testing

testing performed to evaluate functional scoring

Endotoxin Testing

Product-specific sterile process validation question

Dissolution method

Analytical procedure for drug release testing

Bacterial endotoxins test

Testing for pyrogens in finished drug products

Processes

5

Bracketing

Alternative approach to stability protocol design; A reduced stability design testing only extremes of certain factors.; An example of a bracketing design is given in Table A1-1; If a bracketing design is utilised

Matrixing

Alternative approach to stability protocol design; A science- and risk-based reduced stability design strategy.; Matrixing is the design of a stability schedule such that a selected subset of samples is tested; The use of a matrixing design

Sterilization

Required for contaminated equipment and media before disposal

Lyophilization

Physical modification that does not result in chemical alteration.; A process that does not typically chemically alter an ingredient

blow-fill-seal technology

packaging technology for drug products

Clinical Concepts

2

Bioequivalence

Studies needed if comparative dissolution similarity is not achieved

Pediatric patients

Guidance does not address the development of drugs for the prevention of PONV in pediatric patients.

Standards & References

External Standards

4

USP General Chapter <711>

Standard for Dissolution testing requirements

USP General Chapter <724>

United States Pharmacopeia standard for Drug Release

USP General Chapter <1092>

The Dissolution Procedure: Development and Validation

USP General Chapter <85>

Bacterial endotoxins testing standard; Endotoxin limits for subcutaneous administration

Specifications

1

Acceptance criterion

Specific limits used to define specified or unspecified impurities.

ICH References (2)

ICH M9

Biopharmaceutics Classification System-Based Biowaivers

ICH Q1A(R2)

Stability Testing of New Drug Substances and Products

Related CFR Sections (2)

21CFR211.170§ 211.170 Reserve samples.
(a) An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its establishedRead full regulation →
21CFR211.166§ 211.166 Stability testing.
(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to conduct at least one test to verify the identity of each component

12

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

12

Failure to establish and follow an adequate written testing program designed to assess stability

10

Failure to establish adequate written procedures for production and process control

9

Quality control unit failed to exercise its responsibility

8

Failure to conduct adequate finished drug product testing

7

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

5

Failure to establish an adequate stability testing program

5

Failure to test samples of each component for identity and conformity

5

Failure to establish and follow an adequate written testing program designed to assess stability characteristics

5