Guidance for Industry

IND Meetings for Human Drugs

and Biologics

Chemistry, Manufacturing, and Controls Information

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

May 2001

CMC 
Guidance for Industry

IND Meetings for Human Drugs

and Biologics

Chemistry, Manufacturing, and Controls Information

Additional copies are available from:

Office of Training and Communication

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

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Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

or

 Office of Communication, Training and

Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research

 Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

 http://www.fda.gov/cber/guidelines.htm

Fax: 1-888-CBERFAX or 301-827-3844

Phone: the Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

May 2001

CMC 
TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. GENERAL ASPECTS....................................................................................................... 2

A. Purpose of Meeting................................................................................................ 2

B. Meeting Request.................................................................................................... 3

C. Information Package ............................................................................................. 3

D. Format of Meeting ................................................................................................. 3

1. Multidisciplinary Meeting......................................................................... 3

2. CMC-Specific Meeting .............................................................................. 3

E. Focus of Meeting.................................................................................................... 4

III. PRE-IND MEETING......................................................................................................... 4

A. Purpose ................................................................................................................... 4

B. Meeting Request, Information Package, and Format ......................................... 4

C. Focus of Meeting.................................................................................................... 4

IV. END-OF-PHASE 2 MEETING ........................................................................................ 5

A. Purpose ................................................................................................................... 5

B. Meeting Request, Information Package, and Format ......................................... 6

C. Focus of Meeting.................................................................................................... 6

1. All Drugs .................................................................................................... 6

2. rDNA Protein Biotechnology Drugs ......................................................... 7

3. Conventional Biologics.............................................................................. 8

D. Follow-up Meeting ................................................................................................. 8

V. PRE-NDA OR PRE-BLA MEETING.............................................................................. 8

A. Purpose ................................................................................................................... 8

B. Meeting Request, Information Package, and Format ......................................... 9

C. Focus of Meeting.................................................................................................... 9

REFERENCES............................................................................................................................. 10
1

GUIDANCE FOR INDUSTRY1

IND Meetings for Human Drugs and Biologics

Chemistry, Manufacturing, and Controls Information

I. INTRODUCTION

This document provides guidance to industry on formal meetings between sponsors of

investigational new drug applications (INDs) and the Center for Drug Evaluation and Research

(CDER) or Center for Biologics Evaluation and Research (CBER) on chemistry, manufacturing,

and controls (CMC) information. This guidance applies to INDs for human drugs and biologics

(referred to as drugs).2

This guidance covers three kinds of meetings that may be held between sponsors and the Agency: 

(1) pre-investigational new drug application (pre-IND), (2) end-of-phase 2 (EOP2), and (3) prenew drug application (pre-NDA) or pre-biologics license application (pre-BLA). These meetings

may be requested by the sponsor to address outstanding questions and scientific issues that arise

during the course of a clinical investigation, aid in the resolution of problems, and facilitate

evaluation of drugs. The meetings, which often coincide with critical points in the drug

development and/or regulatory process, are recommended, but are not mandatory. Additional

meetings may be requested at other times, if warranted. This guidance is intended to

 

1

This guidance has been prepared by the IND Reform Committee of the Chemistry, Manufacturing, and Controls

Coordinating Committee (CMCCC) in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for

Biologics Evaluation and Research (CBER) at the FDA. 

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The terms investigational new drug or drug as used in this guidance refer to the drug and/or biologic substance

and/or product.

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this

topic. It does not create or confer any rights for or on any person and does not operate to bind

FDA or the public. An alternative approach may be used if such approach satisfies the

requirements of the applicable statutes and regulations.
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assist in making these meetings more efficient and effective by providing information on the (1)

purpose, (2) meeting request, (3) information package, (4) format, and (5) focus of the meeting

when the meeting addresses CMC information.

General information about meetings can be found in the following documents:

! Section 119 of the Food and Drug Administration Modernization Act (Pub. L. 105-

115)

! Regulations applicable to meetings on investigational products in 21 CFR 312.47

! FDA guidance for industry on Formal Meetings with Sponsors and Applicants for

PDUFA Products (February 2000)

! FDA guidance for industry on Fast Track Drug Development Programs 

Designation, Development and Application Review (November 1998)

! FDA policies and procedures for formal meetings with external constituents

described in CDER's Manual of Policy and Procedures (MAPP 4512.1) and CBER

Standard Operating Procedures and Policies (SOPP) 8101.1

II. GENERAL ASPECTS

The general aspects of Pre-IND, EOP2, and Pre-NDA meetings provided in this guidance

summarize the information discussed in the formal meetings and fast track drug development

guidances listed in section I and supplement this information with respect to CMC.

A. Purpose of Meeting

The purpose of meetings between sponsors and CDER or CBER on CMC information

varies with the phase of the investigational study. For pre-IND meetings, the purpose is to

discuss CMC issues as they relate to the safety of an investigational new drug proposed for

use in initial clinical studies. The purpose of EOP2 meetings is to evaluate CMC plans

and protocols to ensure that meaningful data will be generated during phase 3 studies to

support a planned marketing application. Safety issues, nevertheless, will remain an

important consideration during all phases of the study. The purpose of pre-NDA or preBLA meetings is to discuss filing and format issues. Under certain circumstances, other

types of meetings may be appropriate, such as end-of-phase 1 (EOP1) meetings for fast

track drugs or meetings to discuss new protocols or changes during phase 3 studies that

affect previously agreed upon strategies (see IV.D.).
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B. Meeting Request

For general information on procedures for written meeting requests, sponsors should refer

to the regulations, guidances, and policies and procedures listed in section I. The request

should contain a list of the specific objectives and/or desired outcomes of the meeting,

including a draft list of CMC-related questions. 

C. Information Package

Sponsors should prepare an information package that includes a brief summary of the

relevant CMC information, the developmental status, and the plan and time line for future

development of the drug. The CMC-related questions should be presented in the

information package in final form, grouped together and identified. The questions should

be as specific, comprehensive, and precise as possible to identify the critical issues. The

questions should be presented in the same relative subject matter order as a typical CMC

section of an application or as otherwise appropriate to aid in the review of the

information. Sufficient CMC background information on the drug should be provided by

the sponsor in the information package to allow the Agency to address the specific

questions. Sponsors should coordinate the agenda and the content of the information

package to expedite review of the material and discussion at the meeting. Where data

presentation is appropriate, sponsors should present a summary of the data (e.g., tables,

charts, graphs).

D. Format of Meeting

1. Multidisciplinary Meeting

Usually the format of meetings prior to and during the IND stage is

multidisciplinary, involving Agency personnel in clinical, pharmacology,

pharmacokinetics, chemistry, microbiology, statistics, and other disciplines. 

Sufficient time should be allotted during multidisciplinary meetings to discuss

CMC issues. Of particular importance are CMC-related issues that affect other

disciplines. The sponsor can provide a brief introductory presentation of CMC

information; however, the majority of the meeting time allotted to CMC should be

used to discuss specific CMC issues. Appropriate technical experts (e.g.,

chemists, microbiologists, biologists) representing the sponsor and the Agency

should be present during all discussions of CMC-related issues.

2. CMC-Specific Meeting

Under appropriate circumstances, a separate CMC-specific meeting can be held in

addition to, or as an alternative to, the multidisciplinary format. For example, a

CMC-specific meeting is encouraged to discuss CMC issues that are too extensive

or detailed to be adequately addressed in a multidisciplinary meeting, or are

otherwise beyond the scope of a multidisciplinary meeting.
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E. Focus of Meeting

Meetings should focus primarily on addressing the specific questions listed in the

information package. The Agency may also wish to discuss relevant questions on safety

issues or various scientific and/or regulatory aspects of the drug (see sections III, IV and

V). These can arise from Agency guidance documents, the reviewing division's

experience, the manufacturing industry's experience, or scientific literature. The actual

questions, issues, and/or problems discussed at a given meeting will be specific to the

sponsor, drug, route of synthesis or isolation, dosage form, formulation, stability, route of

administration, dosing frequency, or duration. 

The following sections provide specific guidance and more detailed information on each of

the three basic types of meetings, pre-IND, EOP2 and pre-NDA or pre-BLA, as well as

examples of the CMC issues typically addressed in each of these meetings. 

III. PRE-IND MEETING

A. Purpose of Meeting

With respect to CMC information, the purpose of pre-IND meetings for phase 1/phase 2 is

to discuss safety issues related to the proper identification, strength, quality, purity, or

potency of the investigational drug, as well as to identify potential clinical hold issues. 

Meetings at the pre-IND stage regarding CMC information are often unnecessary when the

project is straightforward.

B. Meeting Request, Information Package, and Format

See section II above for general aspects regarding the meeting request, information

package, and format for the meeting. 

C. Focus of Meeting

The pre-IND meeting should focus on the specific questions related to the planned clinical

trials. The meeting should also include a discussion of various scientific and regulatory

aspects of the drug as they relate to safety and/or potential clinical hold issues. Examples

of the CMC issues that could be discussed in pre-IND meetings include, but are not limited

to:

! Physical, chemical, and/or biological characteristics 

! Manufacturers

! Source and method of preparation

! Removal of toxic reagents
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! Quality controls (e.g., identity, assay, purity, impurities profile)

! Formulation

! Sterility (e.g., sterilization process, release sterility and endotoxin testing, if

applicable)

! Linkage of pharmacological and/or toxicity batches to clinical trial batches

! Stability information

The discussion of safety issues for conventional synthetic drugs is typically brief. For

certain types of drugs, such as biotechnological drugs, biological drugs, natural products,

complex dosage forms, and drug-device combinations, it may be appropriate to discuss the

CMC information in more detail. Examples where detailed discussion may be appropriate

include, but are not limited to:

! Drugs from human sources (e.g., appropriate donor screening procedures for

tissues, blood, or other fluids; removal or inactivation of adventitious agents (e.g.,

viruses, bacteria, fungi, mycoplasma))

! Drugs from animal sources (e.g., removal or inactivation of adventitious agents,

transmissible spongiform encephalopathy (TSE)-free certification)

! Biotechnology drugs, particularly rDNA proteins from cell line sources (e.g.,

adequacy of characterization of cell banks, potential contamination of cell lines,

removal or inactivation of adventitious agents, potential antigenicity of the product)

! Botanical drugs (e.g., raw material source, absence of adulteration)

! Reagents from animal or cell line sources (same considerations as for drugs

derived from animal cell or cell line sources)

! Novel excipients

! Novel dosage forms (e.g., characteristics, potential for overly rapid release of

dose, if applicable)

! Drug-device delivery systems (e.g., demonstration of device and its characteristics,

potential for overly rapid release of dose, particle size distribution considerations,

where applicable)

IV. END-OF-PHASE 2 MEETING

A. Purpose of Meeting
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The purpose of the EOP2 meeting, with respect to CMC information, is to provide an

opportunity for the sponsor and reviewing division to (1) evaluate the results of the drug

development program to date; (2) discuss the sponsor’s plans and protocols relative to

regulations, guidances, and Agency policy; (3) identify safety issues, scientific issues,

and/or potential problems and resolve these, if possible, prior to initiation of phase 3

studies; and (4) identify additional information important to support a marketing

application. The CMC portion of the EOP2 meeting is a critical interaction between the

sponsor and the chemistry review team to ensure that meaningful data will be generated

during phase 3 studies. The goal is to identify potential impediments to further progress at

an early stage, thus reducing the number of review cycles for the proposed marketing

application. Although the EOP2 meeting is important for all drugs, it is particularly

important for new molecular entities, biotechnology drugs, biological drugs, natural

products, complex dosage forms, and/or drug-device delivery systems.

B. Meeting Request, Information Package, and Format

See section II for general aspects of the meeting request, information package, and format

for the meeting. A multidisciplinary or separate CMC-specific EOP2 meeting can be held.

 If a CMC-specific meeting is held, it is preferred that it be scheduled to take place

immediately prior to or after the meeting on clinical issues. Under appropriate

circumstances, such CMC-specific meetings can occur during phase 3 trials, but prior to

phase 3-associated scale-up and manufacturing changes.

C. Focus of Meeting

The EOP2 meeting should focus on the CMC-specific questions on the planned phase 3

studies. Typically the meeting will also include a discussion identifying additional

information to support a marketing application. Examples of the CMC issues that can be

addressed in EOP2 meetings include, but are not limited to: 

1. All Drugs 

! Unique physicochemical (e.g., polymorphic forms, enantiomers) and

biological properties

! Adequacy of physicochemical characterization studies

! Starting material designation

! Coordination of all activities, including full cooperation of DMF holders

and other contractors and suppliers in support of the planned NDA or BLA

! Qualification of impurities (update from phase 1/phase 2)
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! Removal or inactivation of adventitious agents (update from phase 1/phase

2, where applicable)

! Approach to specifications (i.e., tests, analytical procedures, and

acceptance criteria)

! Coordination between sponsor and Agency chemists and

pharmacokineticists to establish proper dissolution test procedures

(particularly because dissolution testing will be included in the stability

protocols, where applicable)

! Link between formulations and dosage forms used in preclinical, clinical,

pharmacokinetic/pharmacodynamic studies, and formulations planned for

the NDA or BLA

! Specific considerations for container/closure system components for

specialized delivery systems such as metered dose inhalers (MDIs), dry

powder inhalers (DPIs), disposable pen injectors, transdermal patches, or

other novel dosage forms

! Approach to sterilization process validation and/or container closure

challenge testing, where applicable

! Devices (e.g., pumps, valves, cartridge injectors, actuators), where

applicable

! Appropriateness of the stability protocols to support phase 3 studies and the

planned NDA or BLA

! Major CMC changes, including site changes, anticipated from phase 2

through the proposed NDA or BLA, ramifications of such changes, and

appropriateness of planned comparability and/or bridging studies, if

applicable

! Environmental impact considerations, if pertinent

! Identification of any other CMC issues, including manufacturing site, which

pose novel policy issues or concerns, or any other questions, issues or

problems that should be brought to the attention of the Agency or sponsor

2. rDNA Protein Biotechnology Drugs

In addition to the items listed in section IV.C.1, CMC issues that can be addressed

in EOP2 meetings for rDNA protein biotechnology drugs include, but are not

limited to:
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! Adequacy of physicochemical and biological characterization (e.g., peptide

map, amino acid sequence, disulfide linkages, higher order structure,

glycosylation sites and structures, other post-translational modifications,

and plans for completion, if still incomplete)

! Bioassay (e.g., appropriateness of method, specificity, precision)

! Adequacy of cell bank characterization (e.g., update from phase 1/phase 2,

plans for completion, if still incomplete)

! Removal of product- and process-related impurities (e.g., misfolded

proteins, aggregates, host cell proteins, nucleic acid)

! Bioactivity of product-related substances and product-related impurities

relative to desired product

3. Conventional Biologics

In addition to the items listed in section IV.C.1-2, CMC issues that could be

addressed in EOP2 meetings for conventional biologics (e.g., nonrecombinant

vaccines and blood products) include, but are not limited to:

! Coordination of facility design

! Process validation considerations

! Potency assay

D. Follow-up Meeting

In the event that new issues arise during phase 3 studies that affect the drug development

program, a follow-up meeting may be warranted. The meeting can be used to address

major changes in plans from those previously discussed in the EOP2 meeting or resolve

potential problems and/or refuse-to-file issues. 

V. PRE-NDA OR PRE-BLA MEETING

A. Purpose of Meeting

The purpose of the pre-NDA or pre-BLA meeting is to discuss filing and format issues. 

The CMC portion of the pre-NDA or pre-BLA meeting is a critical interaction between the

CMC review team and the sponsor to ensure the submission of a well-organized and

complete NDA or BLA.
9

B. Meeting Request, Information Package, and Format

See section II for general guidance on the meeting request, information package, and format

for the meeting. A pre-NDA or pre-BLA meeting should be held about 6 months prior to

the planned NDA or BLA submission date.

C. Focus of Meeting

The pre-NDA or pre-BLA meeting should focus on addressing the specific questions

related to filing and format issues. Typically the meeting also includes a discussion to

identify problems that can cause a refuse-to-file recommendation or hinder the review

process. Examples of CMC issues that could be addressed in pre-NDA or pre-BLA

meetings include, but are not limited to: 

! Discussion of the format of the proposed NDA or BLA submission, including

whether an electronic submission will be provided

! Confirmation that all outstanding issues discussed at the EOP2 meeting or raised

subsequently will be adequately addressed in the proposed NDA or BLA

! Assurance that all activities in support of the proposed NDA or BLA have been

coordinated, including the full and timely cooperation of DMF holders or other

contractors and suppliers

! Discussion of the relationship between the manufacturing, formulation, and

packaging of the drug product used in the phase 3 studies and the final drug product

intended for marketing, and assurance that any comparability or bridging studies

agreed upon at the EOP2 meeting have been appropriately completed

! Assurance that the submission will contain adequate stability data in accordance

with stability protocols agreed upon at the EOP2 meeting

! Confirmation that all facilities (e.g., manufacturing, testing, packaging) will be

ready for inspection by the time of the NDA or BLA submission

! Identification of any other issues, potential problems, or regulatory issues that

should be brought to the attention of the Agency or sponsor
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REFERENCES

FDA guidance for industry on Content and Format of Phase I Investigational New Drug

Applications (INDs) for Phase I Studies of Drugs, Including Well-Characterized, Therapeutic,

Biotechnology-Derived Products (November 1995).

FDA, CDER Manual of Policies and Procedures (MAPP) 4512.1, Training and

Communications, Formal Meetings between CDER and External Constituents, March 1996

(http://www.fda.gov/cder).

FDA, Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants,

CBER Standard Operating Procedures and Policies (SOPP) 8101.1 (http://www.fda.gov/cber).

FDA guidance for industry on Formal Meetings with Sponsors and Applicants for PDUFA

Products (February 2000).

FDA guidance for industry on Fast Track Drug Development Programs: Designation,

Development and Application Review (November 1998). 

FDA guidance for industry on CMC Content and Format of Investigational New Drug

Applications (INDs) for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic

Biotechnology-Derived Products (Draft, February 1999).