Question-based Review (QbR) at the Center for Veterinary Medicine

Dennis M. Bensley Jr., Ph.D. Director

Division of Manufacturing Technologies

FDA/OF/CVM/ONADE

FDA/PQRI Conference September 2014

Background on CMC Filing Requirements

QbR at CVM

QbR and eSubmitter

Advantages of QbR

Future QbR activities

General Outline

Section 512(b)(1) of the Federal Food, Drug, and Cosmetic (FFD&C) Act requires that animal drug applicants:

identify all of the components of the drug

provide the composition or formulation of the drug

provide a full description of the methods, facilities, and controls used in the manufacture, processing and packing of the drug

3

Federal Food, Drug, and Cosmetic Act

The Code of Federal Regulations (CFR), 21 CFR 514.1(b), provides additional information on CMC filing requirements

21 CFR 514.1(b)(4) and (5) were commonly used templates to format original CMC submissions

4

Code of Federal Regulations

• The QbR concept was pioneered at FDA by CDER’s Office of Generic Drugs (OGD)

• CVM adapted the QbR concept for CMC information filed in original generic and pioneer animal drug submissions

• CVM’s QbR process covers the submission of CMC information for Drug Substance, Drug Product, and Sterile Process Validation

5

QbR at FDA

• QbR at CVM was developed based on:

OGD’s QbR

Current filing requirements for (A)NADAs

Current CVM guidance documents

Input from CVM reviewers

Input from regulated industry

6

Development of QbR at CVM

• CVM has presented webinars to share the QbR concept with the regulated industry and the public

• Drug Substance, March 2010

• Drug Product, July 2010

• Sterile Process Validation, February 2011

• QbR is the basis of the eSubmitter template for the CMC Technical Section

7

QbR at CVM

When developed, no published QbR available from OGD, unlike Drug Substance/Drug Product document

Based roughly on Guidance for Industry for sterile process validation

Content level questions based on current review practices

Additional questions based on industry feedback

8

Sterile Process Validation QbR at CVM

• Sterile process validation QbR covers:

Terminal Sterilization

• Moist Steam

• Radiation

Aseptic Processing

Microbiological Methods

9

Sterile Process Validation QbR at CVM

10

QbR Format

Common Technical Document (CTD)

M4Q: The CTD Quality

Module 2 – CTD Summaries 2.3 Quality Overall Summary (QOS)

QbR is contained within this section

Module 3 – Quality 3.2 Body of Data

11

Section/Module 2 – CTD Summaries Overview of the CMC aspects of the submission

2.3.S (drug substance)

2.3.P (drug product)

Section/Module 3 – Quality Supporting data containing the details of the CMC submission

3.2.S (drug substance)

3.2.P (drug product)

Sterile process validation

Section 4 – Sterile Process

QbR Format

High-level question

Detailed question

Questions commonly asked by the sponsor

12

CVM’s QbR Format

• High-level question are the critical questions that should be answered to address product quality

– Detailed question are intended to clarify what information is needed to address the high level question

• Questions commonly asked by the sponsor provide additional explanation about the question and suggestions for formatting the response

13

CVM’s QbR Format

What are the manufacturing processes and controls and how do they ensure consistent production of the drug substance?

What are the filling procedures for the primary container-closure system?

Can a different manufacturing process/facility be used for the pilot batches?

14

Example Drug Substance: Manufacture

2.3.S.1 General Information

2.3.S.2 Manufacture

2.3.S.3 Characterization

2.3.S.4 Control of Drug Substance

2.3.S.5 Reference Standards

2.3.S.6 Container Closure System

2.3.S.7 Stability

15

2.3.S Drug Substance

16

2.3.P Drug Product

2.3.P.1 Description and Composition

2.3.P.2 Pharmaceutical Development Report

2.3.P.3 Manufacture

2.3.P.4 Control of Excipients

2.3.P.5 Control of Drug Product

2.3.P.6 Reference Standards and Materials

2.3.P.7 Container Closure System

2.3.P.8 Stability

17

Section 4 – Sterility

4.1 Moist Steam Sterilization

4.2 Radiation Sterilization

4.3 Aseptic Processing

4.4 Component Preparation

4.5 Microbiological Monitoring of the Environment

4.6 Microbiological Testing Controls and Stability

Considerations

4.7 Process Control Documentation

4.8 Microbiological Testing Controls

• All three sections of QbR document are present in the (J)INAD P MC Template for the eSubmitter

• Drug Substance (28 high level/detailed questions)

• Drug product (113 high level/detailed questions)

• Sterile Process Validation (164 high level/detailed questions)

• The questions you see in the eSubmitter are similar to published QBR documents

18

QbR and eSubmitter

An electronic question based system to create and submit information to ONADE

Used by sponsors to build and submit their correspondence

Submission is contained within a single ZIP file

Files attached can be XML, PDF, and SAS Xport file formats

19

What is eSubmitter?

– eSubmitter will be the sole electronic submission tool for ALL submissions to CVM-ONADE, including:

(J)INADs – all technical sections, protocols, etc.

(A)NADAs – Original, supplements, and MCSRs

VMFs – Original, supplements, and annual reports

GCs – User Fees waiver requests, etc.

20

What is eSubmitter?

Uses data capturing forms (question and answer, file attachment capability, etc.) to walk users through the process of compiling a complete and structured submission to FDA

Uses business rule logic (conditional statements) to require the submitter to complete sections based on previous responses

21

How does eSubmitter work?

eSubmitter Example

eSubmitter Example

• Paper submissions will continue to be accepted, and will be scanned to be reviewed electronically

• For additional information about eSubmitter visit: http://www.fda.gov/ForIndustry/FDAeSubmitter/default.htm

24

Using eSubmitter

Provides more transparency to applicants Provides focus for CVM reviewers Increase in one-cycle reviews Flexible process to provide guidance

Positive feedback from reviewers and sponsors

25

Advantages of QbR

0

20

40

60

80

CY'09 CY'10 CY'11 CY'12 CY'13

% One-cycle CMC review (INAD-P)

Continued modifications based on stakeholder and reviewer feedback; and new regulatory science

Expansion to non-CMC submissions:

Establish QbR process for bioequivalence submissions by end of FY’16 (see AGDUFA 2 re-authorization performance goals and procedures)

Future of QbR in CVM

Protecting both Human and Animal Health

THANK YOU!!