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
5600 Fishers Lane
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 GUIDANCE FOR INDUSTRY1
IND Meetings for Human Drugs and Biologics
Chemistry, Manufacturing, and Controls Information
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.
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) pre-
new 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. 
2 The terms investigational new drug or drug as used in this guidance refer to the drug and/or biologic substance
and/or product.
1 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 (cid:31)
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 pre-
BLA 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.).
2 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.
3 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
4 !  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
5 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 sponsors 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)
6 !  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:
7 !  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.
8 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
9 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).  
10