Guidance for Industry 

INDs for Phase 2 and Phase 3 

Studies
 
Chemistry, Manufacturing, and Controls
 
Information
 
U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER) 

May 2003
 
CMC 
 Guidance for Industry 

INDs for Phase 2 and Phase 3 

Studies
 
Chemistry, Manufacturing, and Controls
 
Information
 
Additional copies are available from:
 
Office of Training and Communications
 
Division of Drug Information (HFD-240)
 
Center for Drug Evaluation and Research (CDER)
 
5600 Fishers Lane, Rockville, MD 20857
 
(Tel) 301-827-4573
 
Internet at http://www.fda.gov/cder/guidance./index.htm
 
U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER) 

May 2003
 
CMC 
 Table of Contents 
I.  INTRODUCTION................................................................................................................. 1
 
II.  BACKGROUND ................................................................................................................... 2
 
A.  Current Requirements...................................................................................................................2
 
B.  General Principles..........................................................................................................................3
 
III.  PHASE 2 STUDIES .............................................................................................................. 6
 
A.  Drug Substance ..............................................................................................................................6
 
B.  Drug Product................................................................................................................................10
 
IV.  PHASE 3 STUDIES ............................................................................................................ 13
 
A.  Drug Substance ............................................................................................................................13
 
B.  Drug Product................................................................................................................................18
 
V.  PLACEBO ........................................................................................................................... 21
 
VI.  LABELING ......................................................................................................................... 22
 
VII.  ENVIRONMENTAL ASSESSMENTS......................................................................... 22 

RESOURCES .............................................................................................................................. 23
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry
INDs for Phase 2 and Phase 3 Studies
 
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. If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
I.  INTRODUCTION 
This guidance provides recommendations to sponsors of investigational new drug applications 
(INDs) on the chemistry, manufacturing, and controls (CMC) information that would be 
submitted for phase 2 and phase 3 studies conducted under INDs.2  This document applies to 
human drugs (as defined in the Federal Food, Drug, and Cosmetic Act).  The guidance does not 
apply to botanical drug products,3 protein drug products derived from natural sources or 
produced by the use of biotechnology, or other biologics. The goals of the guidance are to (1) 
ensure that sufficient data will be submitted to the Agency to assess the safety, as well as the 
quality of the proposed clinical studies from the CMC perspective, (2) expedite the entry of new 
drug products into the marketplace by clarifying the type, extent, and reporting of CMC 
information for phase 2 and phase 3 studies, and (3) facilitate drug discovery and development. 
The amount and depth of CMC information that would be submitted to the Agency depends, in 
large part, on the phase of the investigation, the testing proposed in humans, and whether the 
information is safety related.  This guidance identifies CMC information that would be presented 
in information amendments (i.e., CMC safety information) and annual reports (i.e., corroborating 
information). 
                                                
1 This guidance has been prepared by IND Reform Committee of the Chemistry, Manufacturing, and Controls 
Coordinating Committee (CMCCC) in the Center for Drug Evaluation and Research (CDER) at the FDA. 
2 Recommendations are provided in other guidances for CMC  issues relating to pre-IND, end-of-phase 2 (EOP2), 
and pre-new drug application (NDA) meetings (e.g., guidance for industry on IND Meetings for Human Drugs and 
Biologics; Chemistry, Manufacturing, and Controls Information), and pre-new drug application (NDA) rolling 
submissions (guidance for industry on Fast Track Drug Development Programs  Designation, Development, and 
Application Review). 
3 Information on INDs for botanical drug products will be provided in FDAs forthcoming guidance for industry on 
Botanical Drug Products (draft published August 2000; 65 FR 49247). 
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  Contains Nonbinding Recommendations 
The recommendations in this guidance are intended to provide regulatory relief for IND sponsors 
by providing greater flexibility in the collecting and reporting of data and by avoiding redundant 
submissions.  Four areas of regulatory relief are as follows: 
	   Certain information that traditionally has been submitted in information amendments would 
be identified as corroborating information (see section II.B.2) and can be submitted in an 
annual report. 
	   The limited phase 2 corroborating information recommended in section III need not be 
submitted before initiation of phase 2 studies and can be generated during phase 2 drug 
development. 
	   The phase 3 corroborating information recommended in section IV need not be submitted 
before the initiation of phase 3 studies and can be generated during phase 3 drug 
development. 
	   The corroborating information and a summary of CMC safety information submitted during a 
subject-reporting period would be included in the annual report.  Therefore, there should be 
no need for general CMC updates at the end of phase 1 or phase 2. 
Although applicable to INDs that are sponsored by both commercial establishments and 
individual investigators, the guidance's greater value and relevance will be for commercial INDs. 
For phase 1 submissions, sponsors can refer to the guidance for industry on Content and Format 
of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-
Characterized, Therapeutic, Biotechnology-derived Products (phase 1 guidance). 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
II.  BACKGROUND 
A.  Current Requirements 
Under current regulations in the United States, use of a human drug product not previously 
authorized for marketing in the United States requires the submission of an IND to the Agency. 
FDAs regulations at 21 CFR 312.22 and 312.23, respectively, contain the general principles 
underlying the IND submission and the general requirements for content and format.  Section 
312.23(a)(7)(i) requires that an IND for each phase of investigation include sufficient CMC 
information to ensure the proper identity, strength or potency, quality, and purity of the drug 
substance and drug product. The type of information submitted will depend on the phase of the 
investigation, the extent of the human study, the duration of the investigation, the nature and 
source of the drug substance, and the drug product dosage form. 
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  Contains Nonbinding Recommendations 
As clinical development of the drug product proceeds, sponsors can discuss with the Agency the 
type of CMC information that would be submitted to support the use of the drug in all 
investigational phases. The Agency encourages sponsors to meet with the CMC review team, if 
appropriate, before the initiation of or during phase 3 clinical trials to discuss issues and 
protocols that might affect the approvability of the NDA.  The Agency will grant CMC-specific 
meetings when justified (see CDERs guidance on IND Meetings for Human Drugs and 
Biologics; Chemistry, Manufacturing, and Controls Information). 
B.  General Principles 
This guidance provides recommendations on CMC safety information and the limited 
corroborating information that should be submitted to support phase 2 and phase 3 studies.  The 
scope of the guidance covers many different types of drug substances and drug products. 
Therefore, every recommendation may not be applicable to a particular drug substance or drug 
product. CMC safety information and corroborating information should be submitted in 
information amendments (21 CFR 312.31) and annual reports (21 CFR 312.33), respectively. 
Under  312.33 annual reports must be submitted during the ongoing development of the drug. 
With respect to CMC information, each annual report to the IND should include a summary of 
CMC safety information submitted in information amendments during the past year (i.e., subject-
reporting period) and, when applicable, corroborating information.  The annual report should 
also include updates of corroborating information  or corrections to information previously 
provided to the IND that cannot be considered significant enough to warrant an information 
amendment. 
FDA recommends that the sponsor carefully document its drug development program.  This 
more-detailed information is often used to establish correlations between data generated during 
IND studies and the to-be-marketed product and to support other aspects of the NDA (e.g., 
process controls, justification of specifications) even when the submission of this information 
was not warranted during the IND studies. 
1.  CMC Safety Information 
CMC safety information should be submitted to support the safe use of the drug.  FDA 
reviews the safety information to determine whether a clinical hold on the IND is 
warranted. A summary of CMC safety information submitted during a subject-reporting 
period should be included in the annual report. 
CMC safety information, as recommended in this guidance, and any other CMC information 
available to the sponsor that relates to the safe use of drug  should be submitted in 
information amendments as follows: 
	   The CMC safety information identified in section III (Phase 2 Studies) should be 
submitted before initiation of the phase 2 studies.  This information can be submitted 
during phase 1 or before the initiation of phase 2 studies. 
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  Contains Nonbinding Recommendations 
	   The CMC safety information identified in section IV (Phase 3 Studies) should be 
submitted before initiation of the phase 3 studies.  This information can be submitted 
during phase 1 or phase 2 or before the initiation of phase 3 studies. 
	   When new information becomes available that relates to the safe use of the drug or 
when there are changes in previously submitted CMC safety information, the 
information should be submitted during IND clinical trials in an information 
amendment as the information becomes available. 
FDA recommends that the sponsor carefully assess any changes in the drug substance 
and drug product manufacturing process or drug product formulation at any phase of 
clinical development to determine if the changes can directly or indirectly affect the 
safety of the product. For changes with a significant potential to affect the safety of the 
product (see examples below), an information amendment should be submitted that 
describes the changes and contains relevant information at a level of detail sufficient for 
an adequate review and assessment.  When appropriate, this information should include 
data from tests on the drug substance and/or drug product produced from the previous 
manufacturing process and the changed manufacturing process to evaluate product 
equivalency, quality, and safety. In addition, when analytical data from tests on the drug 
substance and/or drug product demonstrate that the materials manufactured before and 
after are not comparable, sponsors should perform additional qualification and/or 
bridging studies to support the safety and bioavailability  of the material to be used in the 
proposed trials and, when applicable, to support the quality of the trials. 
The CMC safety concerns identified in the phase 1 guidance are equally applicable to 
phase 2 and phase 3. 
CMC modifications throughout the IND process that can affect safety include, but are not 
limited to, a change in: 
	   the synthetic pathway used to manufacture the drug substance 
-- material change in one of the bond forming steps 
-- change in a solvent used for the last reaction and/or crystallization step 
-- change resulting in a different impurity profile 
	   the manufacturing process that can affect the quality of a drug substance produced by 
fermentation or derived from a natural source (plant, animal, or human) 
	   the manufacturing process that can directly or indirectly affect viral or impurity 
clearance for a drug substance produced by fermentation or derived from a natural 
source 
	   the manufacturing method from one manufacturing method (chemical synthesis, 
fermentation, or derivation from a natural source) to another 
	   source material (e.g., plant to animal, species, part used) or country of origin for a 
drug substance derived from a natural source 
	   species and/or strain of microorganism for a drug substance produced by fermentation 
	   certain aspects of specifications (see sections III.A.4, III.B.4, IV.A.4, and IV.B.4) 
4
  Contains Nonbinding Recommendations 
	   the method of sterilization of the drug substance or drug product 
	   the route of administration 
	   the composition and/or dosage form of the drug product 
	   the drug product manufacturing process that can affect product quality 
	   the drug product container closure system that can affect product quality (e.g., 
metering capability, dose delivery) 
2.  Corroborating Information 
Corroborating information is used to assess the scientific quality of the drug substance 
and drug product used in the clinical investigations to ensure that the clinical 
investigations will yield reliable and interpretable data and to corroborate the quality and 
safety of clinical materials used in earlier investigational phases.4  Corroborating 
information is less likely to affect the safe use of the drug but should be submitted to 
ensure the proper identity, strength or potency, quality, and purity of the investigational 
drug (21 CFR 312.23(a)(7)(i)). 
Corroborating information should be submitted in annual reports.  In general, the 
corroborating information should focus on summaries and analyses of data rather than 
extensive compilations of data.  However, there are some exceptions when compilations 
of data should be submitted (e.g., stability data).  Occasionally, CDER may request more 
detailed corroborating information when warranted to assess the scientific quality of the 
investigations. 
Submission of corroborating information in annual reports should occur as follows: 
	   Corroborating information specified in section III (Phase 2 Studies) that is generated 
during phase 1 need not be submitted until the first annual report  after initiation of 
phase 2 studies. However, a sponsor can choose to submit the information in annual 
reports during phase 1 studies. 
	   Corroborating information specified in section III (Phase 2 Studies) that is generated 
during phase 2 studies should be submitted in the next annual report after the 
information becomes available.  Corroborating information specified in section III 
need not be submitted before initiating phase 2 clinical trials. 
	   Corroborating information specified in section IV (Phase 3 Studies) that is generated 
earlier during phase 1 and phase 2 need not be submitted until the first annual report 
after initiation of phase 3 studies.  However, a sponsor can choose to submit the 
information in annual reports during phase 1 and phase 2 studies. 
                                                
4 Although FDAs review of phase 1 submissions will focus on assessing the safety of phase 1 investigations, 
FDAs review of phases 2 and 3 submissions will include an assessment of the scientific quality of the clinical 
investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for 
market approvals (21 CFR 312.22(a)). 
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  Contains Nonbinding Recommendations 
	   Corroborating information specified in section IV (Phase 3 Studies) that is generated 
during phase 3 studies should be submitted in the next annual report after the 
information becomes available.  Corroborating information specified in section IV 
need not be submitted before initiating phase 3 clinical trials. 
III.  PHASE 2 STUDIES 
The CMC information provided to support the phase 2 studies should focus on additional CMC 
information to maintain the continued safety of the patients enrolled in these studies. 
Corroborating information should be provided to ensure that the clinical investigations will yield 
reliable and interpretable data. During or before phase 2, CMC safety information that has 
previously been submitted to the IND may have changed and consequently must be updated as 
required under 21 CFR 312.31.5  For information amendments submitted to the IND during 
ongoing development, the emphasis should be on reporting significant changes that can have a 
safety-related impact. These include, but are not limited to, those changes specified in section 
II.B.1. In cases where studies begin with phase 2 clinical studies, CMC safety information 
should be submitted before initiation of the phase 2 studies as specified in the phase 1 guidance 
and in this section. 
The information recommended in sections III.A and III.B is considered CMC safety information 
that should be submitted in an information amendment before initiation of phase 2 studies, 
except where particular information is identified for submission in an annual report (i.e., 
corroborating information).  Information that is considered corroborating information that can be 
submitted in an annual report is indicated in sections III.A.5, 6, and 7 and III.B.5 and 6. 
Sponsors can reference an official compendium or other FDA recognized standard reference 
(e.g., AOAC International Book of Methods) to provide certain recommended CMC information 
(e.g., general methods, monograph standard) for an investigational drug substance or drug 
product, when applicable.6  Reference to drug master files (DMFs) or other existing INDs or 
NDAs, with an authorization letter from the holder, sponsor, or applicant, can also be used to 
provide CMC information in support of the IND submission (21 CFR 312.23(b)). 
A.  Drug Substance 
1.  General Information 
The Agency recommends that sponsors provide updates on the brief description of the 
drug substance, which was provided to support the phase 1 studies, and a more detailed 
description of the configuration and chemical structure for complex organic compounds 
(e.g., paclitaxel, polyketides). This information will be helpful in predicting the structure 
                                                
5 Throughout section III, the guidance indicates that updates of or changes in CMC safety information from that 
provided for phase 1 should be submitted.  This statement refers to updates that are warranted because changes are 
being made for materials intended for phase 2 studies.  If changes relate to materials used in phase 1 studies, the 
changes should have been reported during the phase 1 studies. 
6 Official compendium is defined in section 201(j) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(j)). 
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  Contains Nonbinding Recommendations 
of possible metabolites.  For peptides, characterization should include data on the amino 
acid sequence, and when relevant, peptide map.  For DNA products, characterization 
should include nucleic acid sequence, DNA melting point, and side chain modifications 
when applicable. 
2.  Manufacture 
a.  Manufacturers 
The addition, deletion, or change of any manufacturer of the drug substance from 
that specified during phase 1 should be reported. 
b.  Description of Manufacturing Process and Process Controls 
An updated flow diagram for the synthesis or manufacturing process should be 
provided, if applicable. This information can be a general description.  However, 
the flow diagram should contain the chemical structures and configurations, 
including stereochemical information of the starting materials, intermediates 
(either in situ  or isolated), and, when feasible, significant side products. 
Reagents, solvents and auxiliary materials, equipment (e.g., fermenters, columns), 
and provisions for monitoring and controlling critical conditions should be 
identified. Furthermore, a manufacturing step should be described in more detail 
if it is unique or critical to the synthetic or manufacturing process.  For example, 
for fermentation and natural source drug substances, identification of model 
number or manufacturer of the fermenter is not warranted, but process controls 
that ensure performance of safety-related manufacturing steps (e.g., viral or 
impurity clearance) should be clearly described. 
The general description of the synthetic and manufacturing process (e.g., 
fermentation, purification) provided to support the phase 1 studies should be 
updated from a safety perspective if changes or modifications have been 
introduced. Reprocessing procedures and controls need not be described except 
for natural source drug substances when the steps affect safety (e.g., virus or 
impurity clearance). 
For sterile drug substances, updates on the manufacturing process from that 
provided for phase 1 studies should be submitted.  The phase 2 information 
should include changes in the drug substance sterilization process (e.g., terminal 
sterilization to aseptic processing). Information related to the validation of the 
sterilization process need not be submitted at this time. 
c.  Control of Materials 
The structures of the proposed starting materials should be provided if they have 
not been previously submitted.  The source, analytical procedures, and test results 
for the starting materials should be submitted upon request.  A list of any new 
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  Contains Nonbinding Recommendations 
reagents, solvents, auxiliary materials, or biological raw materials should be 
provided. For critical, complex materials (e.g., monoclonal antibodies configured 
in affinity matrices), a full description of the manufacturing process and 
acceptance criteria for the material should be provided. 
For fermentation products or natural substances extracted from plant, human, or 
animal sources, the following information would have been provided in phase 1: 
(1) origin (e.g., country), source (e.g., pancreas), and taxonomy (e.g., family, 
genus, species, variety) of the starting materials or strain of the microorganism; 
(2) details of appropriate screening procedures for adventitious agents, if relevant; 
and (3) information to support the safe  use of any materials of microbial, plant, 
human, or animal origin (e.g., certification, screening, testing).  Any updates to 
the information submitted in phase 1 and any new information to support the 
safety of materials of human or animal origin should be provided. 
d.  Controls of Critical Steps and Intermediates 
To the extent possible in phase 2, sponsors should provide information on 
controls of critical steps and intermediates and tentative acceptance criteria to 
ensure that the manufacturing process is controlled at predetermined points. 
Although controls of critical steps and intermediates can still be in development, 
information on controls for monitoring adventitious agents should be provided for 
fermentation and natural source (human or animal) drug substances, as 
appropriate. 
3.  Characterization 
Evidence to reasonably support the proposed chemical structure of the drug substance 
should be provided. Data on particle size distribution and other physical properties (e.g., 
polymorphic or solid state form) should be generated so that relevant correlations can be 
established between data generated during early and late drug development.   Data on the 
particle size distribution and/or physical properties should be submitted, when 
appropriate (e.g., inhalation, suspension, modified release solid dosage forms). 
4.  Control of Drug Substance 
A specification sheet is a list of tests, analytical procedures, and acceptance criteria (i.e., 
numerical limits, ranges, or other criteria for the tests described).  Critical quality 
attributes include, but are not limited to, identity, purity, quality, potency or strength, and 
impurities.  During the clinical investigation process, the sponsor would establish 
tentative acceptance criteria that are continually refined based on data obtained from 
analysis of batches of drug substance and new information that becomes available.  In the 
course of product development, the analytical technology or methodology often evolves 
parallel to the clinical investigations. In setting subsequent acceptance criteria, relevant 
correlations should be established between data generated during early and late drug 
development. 
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  Contains Nonbinding Recommendations 
Any change in the tentative specification, including the tentative acceptance criteria, 
should be reported. This includes changes in the sponsors drug substance specification 
and, if different, drug product manufacturers acceptance testing for the drug substance. 
Test results and analytical data (e.g., infrared spectra, chromatograms) from batch release 
of representative clinical trial materials should be provided initially and when any change 
is made in the specification. 
The analytical procedure (e.g., high-pressure liquid chromatography) used to perform a 
test and to support the tentative acceptance criteria should be briefly described and 
changes reported when the changes are such that an update of the brief description is 
warranted. A complete description of analytical procedures and appropriate validation 
data should be available for the analytical procedures that are not from an FDA-
recognized standard reference (e.g., official compendium, AOAC International Book of 
Methods), and this information should be submitted upon request. 
New impurities (e.g., from a change in synthetic pathway) should be qualified, 
quantified, and reported, as appropriate. Procedures to evaluate impurities to support an 
NDA (e.g., recommended identification levels) may not be practical at this point in drug 
development.  Suitable limits should be established based on manufacturing experience, 
stability data, and safety considerations. 
5.  Reference Standards or Materials 
Where a recognized national or international standard (such as a standard from the World 
Health Organization (WHO)) is available, the manufacturers reference material and/or 
working standard should be qualified against this standard. A national or international 
reference standard may not be available because many INDs will be for new molecular 
entities. In this case, the sponsor can select a batch of drug substance to be used as a 
reference material, against which initial clinical batches would be tested before their 
release. Preferably, the sponsor would establish a working standard even at the initial 
stage of drug development.  For the purpose of this guidance, a working standard  is a 
reference material that has been further characterized beyond the standard batch release 
tests. The protocol for establishing the working standard should be submitted in an 
information amendment.  However, the results from the testing to establish the working 
standard can be reported in an annual report. 
When a reference material is fully characterized, it would become the manufacturers 
primary reference material.  The manufacturer can continue to establish new working 
standards that are qualified against that primary reference material. 
6.  Container Closure System 
The container closure system is defined as the sum of packaging components that 
together contain and protect the drug substance.  A brief description of the container 
closure system (also referred to as the packaging system) and any subsequent changes 
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  Contains Nonbinding Recommendations 
should be provided in an annual report. 
7.  Stability 
A description of the stability program to support the drug substance under clinical 
investigation in phase 2  should be submitted that includes a list of tests, analytical 
procedures, acceptance criteria, test time points for each of the tests, storage conditions, 
and the duration of the study. 
Any available stability data for the clinical material used in the phase 1 study that were 
not reported during phase 1 should be provided in an information amendment.  Stability 
data from representative clinical trial materials used in phase 2 should be provided in 
annual reports as the data become available. 
If degradation of the drug substance occurs during manufacture or storage, this change 
should be considered when establishing acceptance criteria and monitoring quality. 
Because of the inherent complexity of many drug substances, there may be no single 
stability-indicating assay or parameter that profiles all the stability characteristics of the 
drug substance. Consequently, the manufacturer should consider the development of 
stability-indicating analytical procedures that will detect significant changes in the 
quality of the drug substance.  The nature of the particular drug substance will determine 
which tests should be included in the stability program.  Performance of stability stress 
studies with the drug substance early in drug development is encouraged, as these studies 
provide information crucial to the selection of stability indicating analytical procedures 
for real time studies. 
B.  Drug Product 
1.  Description and Composition of the Drug Product 
Any changes from the information specified for phase 1 (i.e., table listing of all 
components) should be provided.  All components used in the manufacture of the drug 
product, regardless of whether or not they appear in the finished drug product, should be 
identified by their established names and a reference to a quality standard (e.g., United 
States Pharmacopeia (USP), National Formulary (NF)) included. The quantitative 
composition on a per unit basis (e.g., milligram (mg)/milliliter (mL), mg/tablet) should be 
provided. However, quantitative values need not be reported for components that are 
removed during manufacturing and do not appear in the final drug product. 
2.  Manufacture 
a.  Manufacturers 
The addition, deletion, or change of any manufacturer of the drug product from 
that specified during phase 1 should be reported. 
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  Contains Nonbinding Recommendations 
b.  Batch Formula 
A representative batch formula should be provided if not already submitted. 
Quantitative information should be reported for all components in the batch 
formula whether or not the component appears in the final drug product. 
c.  Description of Manufacturing Process and Process Controls 
An updated flow diagram and a brief step-by-step description of the 
manufacturing process should be provided. The description can focus on the unit 
operation (e.g., blending) rather than the individual manufacturing steps of the 
unit operation. Information, such as the following, need not be provided in either 
the flow diagram or description:  (1) equipment used (e.g., V-blender);  (2) the 
packaging and labeling process; (3) controls, except for sterile products (e.g., 
injectables, implants, ophthalmics) or atypical dosage forms (e.g., metered dose 
inhalation (MDI), liposomal encapsulation, implants, injectable microspheres); 
and (4) information on reprocessing procedures and controls, unless it is safety 
related. Where the qualitative formulation does not change, a single description 
of the manufacture of different strength unit doses can be provided. 
For sterile products, updates on the manufacturing process from that provided for 
phase 1 studies should be submitted.  The phase 2 information should include 
changes in the drug product sterilization process (e.g., terminal sterilization to 
aseptic processing). Information related to the validation of the sterilization 
process need not be submitted at this time. 
3.  Control of Excipients 
For compendial excipients, references to quality standards (e.g., USP, NF) should be 
provided if changed from phase 1. 
For noncompendial excipients, a specification sheet should be provided that identifies the 
tests and acceptance criteria and indicates the types of analytical procedure (e.g., HPLC) 
used. A complete description of the analytical procedures should be submitted upon 
request. A brief description of the manufacture and control of these components or an 
appropriate reference should be provided (e.g., DMF, NDA). Information for excipients 
not used in previously approved drug products in the United States (e.g., novel 
excipients) should be equivalent to that submitted for drug substances. 
4.  Control of Drug Product 
Physicochemical tests (e.g., identity, assay, content uniformity, degradants, impurities, 
dissolution, viscosity, particle size), biological (e.g., potency), and microbiological tests 
(e.g., sterility and pyrogens or bacterial endotoxins for sterile products, antimicrobial 
preservative for multiple-dose sterile and nonsterile dosage forms, and microbial limits 
for nonsterile dosage forms) that have been added or deleted from the specification 
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should be reported. Data on the particle size distribution and/or polymorphic form  of the 
drug substance used in clinical trial materials should be included, when appropriate (e.g., 
inhalation, suspension, modified release solid dosage forms) so that relevant correlations 
can be established between data generated during early and late drug development and in 
vivo product performance.  Relaxation of acceptance criteria or any change that affects 
safety should be reported. Test results and analytical data (e.g., chromatograms) from 
batch release of representative clinical trial materials should be provided initially and 
when any changes are made in the specification. 
The analytical procedure (e.g., HPLC) used to perform a test should be briefly described 
and changes reported when the change is such that an update of the brief description is 
warranted. A complete description of analytical procedures and appropriate validation 
data should be available for analytical procedures that are not from an FDA-recognized 
standard reference (e.g., official compendium, AOAC International Book of Methods), 
and this information should be submitted upon request. 
Data updates on the degradation profile should be provided so safety assessments can be 
made. 
5.  Container Closure System 
The container closure system is defined as the sum of packaging components that 
together contain and protect the drug product. A brief description of the container 
closure system (also referred to as packaging system) should be provided in an 
information amendment.  When changes are made in the container closure system, 
information should be submitted in an information amendment if there can be an effect 
on product quality. Otherwise, the changes can be reported in an annual report. 
Additional information may be requested for atypical delivery systems (e.g., MDIs, 
disposable injection devices). 
6.  Stability 
A description of the stability program to support phase 2 clinical studies should be 
submitted that includes a list of the tests, analytical procedures, acceptance criteria, test 
time points for each of the tests, storage conditions,  and the duration of the study, which 
should be long enough to cover the expected duration of the clinical studies. 
Any stability data for the clinical material used in the phase 1 study that were not 
reported during phase 1 should be provided in an information amendment.  The stability 
of reconstituted products should be studied and data submitted if not already provided or 
when there are formulation or diluent changes.  Stability data from representative clinical 
trial materials used in phase 2 should be provided in annual reports as the data become 
available. 
If degradation of the drug product occurs during manufacture or storage, this change 
should be considered when establishing acceptance criteria and monitoring quality. 
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Because of the inherent complexity of many dosage forms, there may be no single 
stability-indicating assay or parameter that profiles all the stability characteristics of the 
drug product. Consequently, the manufacturer should consider the development of 
stability-indicating analytical procedures that will detect significant changes in the 
quality of the drug product. The nature of the particular drug product will determine 
which tests should be included in the stability program. 
IV.   PHASE 3 STUDIES 
CMC development continues in parallel with the clinical development during phase 3 studies. 
The CMC safety information provided to support phase 3 studies should focus on the 
information that is warranted in maintaining the continued safety of the patients enrolled in these 
studies. For information amendments submitted to the IND during ongoing development, the 
emphasis should be on reporting significant changes that can have a safety-related impact. 
During or before phase 3, CMC safety information that has previously been submitted to the 
IND may have changed and, consequently, should be updated as required under  312.31.7 
These changes include, but are not limited to, those specified in section II.B.1.  The 
corroborating information should be provided in the annual report  to ensure that the clinical 
investigations will yield reliable and interpretable data. 
Sponsors can reference an official compendium or other FDA-recognized standard reference 
(e.g., AOAC International Book of Methods) to provide certain recommended CMC information 
(e.g., general methods, monograph standard) for an investigational drug substance or drug 
product, when applicable. Reference to DMFs or other existing INDs or NDAs, with an 
authorization letter from the holder, sponsor or applicant, can also be used to provide CMC 
information in support of the IND submission (21 CFR 312.23(b)). 
Before the phase 3 studies, the sponsor can have an end-of-phase-2 meeting, or during the phase 
3 studies, a CMC specific end-of-phase-2 meeting, with the Agency.  As part of the preparation 
for that meeting, a background document is often provided that can be a valuable information 
amendment to the IND.  The document would include updates to describe the materials already 
used and/or to be used in phase 3 studies, as well as put the studies performed to date in context 
with the prospective strategy for the ultimate NDA. 
A.  Drug Substance 
1.  General Information 
General descriptive information on the physical, chemical, and biological characteristics 
of the drug substance should be provided in an annual report. This information, if not 
                                                
7 Throughout section IV, the guidance indicates that updates of or changes in CMC safety information from that 
provided for phase 1 or phase 2 should be submitted.  This statement refers to updates that would be warranted 
because changes are being made for materials intended for phase 3 studies.  If changes relate to materials used 
during phase 1 or phase 2 studies, the changes should have been reported, as warranted, during those studies. 
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previously submitted, can include (1) neutralization equivalents; (2) solubility properties, 
partition coefficient, dissociation constant (pKa), and isoelectric point (pI); (3) 
hygroscopicity; (4) crystal properties and morphology determined by thermal analysis 
(e.g., DSC, TGA),8 powder X-ray diffraction and microscopy; (5) particle size and 
surface area; (6) melting point and boiling point; (7) optical rotation; (8) stereochemistry; 
and (9) biological activities, if applicable. 
2.  Manufacturer 
a.  Manufacturers 
A list of all firms associated with the manufacture of the drug substance should be 
provided in an information amendment, including contract facilities used for 
manufacturing and/or testing (e.g., stability studies, quality control release 
testing). 
b.  Description of Manufacturing Process and Process Controls 
An updated flow diagram should be provided in an information amendment when 
changes occur. A general step-by-step description of the synthesis and 
manufacturing processes, including the final isolation of the drug substance, 
should be provided in an annual report. Examples of relevant information that 
should be included in the description are as follows: (1) batch size (range); (2) 
relative ratios of reagents, solvents, and auxiliary materials; (3) process controls 
(brief description of the analytical procedures) and general operating conditions 
(time, temperature); (4) controls of critical steps and intermediates; (5) control of 
crystalline forms; and (6) literature references for any novel reactions or complex 
mechanisms.  Reprocessing procedures and pertinent controls should be described 
in an annual report, except when reprocessing steps for fermentation or natural 
source drug substances are likely to affect safety (e.g., virus or impurity 
clearance). In this case, new or updates of previously submitted reprocessing 
information should be provided in an information amendment. 
For sterile drug substances, updates on information from that provided in phase 1 
and phase 2 should be submitted in an information amendment.  The information 
should include a description of changes in the drug substance sterilization process 
(e.g., terminal sterilization to aseptic processing).  Information related to the 
validation of the sterilization process need not be submitted at this time but 
should be submitted at the time of an NDA filing (see FDA guidance  Submission 
Documentation for Sterilization Process Validation in Applications for Human 
and Veterinary Drug Products). 
c.  Control of Materials 
                                                
8 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). 
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In addition to the information provided during phase 1 and phase 2, analytical 
procedures and acceptance criteria for assessing the quality of starting materials 
should be provided in an information amendment.  Furthermore, a list of any new 
reagents, solvents, auxiliary materials, or biological raw materials should be 
provided in an information amendment.  For critical, complex materials  (e.g., 
monoclonal antibodies configured in affinity matrices), changes to the description 
of the manufacturing process and acceptance criteria should also be provided in 
an information amendment. 
In an annual report, a table listing all reagents, solvents, and catalysts should be 
submitted that includes (1) a reference to a quality standard for each material used 
and (2) the specific identity test performed upon receipt of the material.  When 
warranted, a more comprehensive list of tests and acceptance criteria should be 
submitted in an annual report for special reagents (e.g., reagents for kinetic 
resolution, sera, enzymes, or proteins). 
Information should be provided in an information amendment to (1) update the 
information submitted in phase 1 and phase 2 regarding the origin of fermentation 
products or natural substances extracted from plant, human, or animal sources and 
(2) provide any new information to support the safety of materials of human or 
animal origin. 
d.  Controls of Critical Steps and Intermediates 
Controls at critical steps in the synthesis or manufacturing process that ensure 
reaction completion, identity, purity or proper cell growth, and changes in critical 
controls reported during phase 2, should be described in an information 
amendment.  For fermentation and natural source drug substances, changes to 
process controls that ensure performance of safety-related manufacturing steps 
(e.g., viral or impurity clearance) should be clearly described.  Changes in 
controls for monitoring adventitious agents should be provided for fermentation 
and natural source drug substances, as appropriate. 
For isolated intermediates that are controlled, the analytical procedures and 
tentative acceptance criteria should be described in an annual report. Tentative 
acceptance criteria can be used to allow for flexibility in the development process 
but should fulfill the primary purpose of quality control.  The description of the 
analytical procedures can be brief, and appropriate validation information should 
be submitted upon request. 
3.  Characterization 
Updates on the information previously provided during phase 2 should be provided in 
information amendments.  The information amendment should include evidence to 
support the elucidation and characterization of the structure, which augments the 
information provided in phase 2.  This information can include elemental analysis, 
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conformational analysis, molecular weight determination, spectra from IR, NMR (1H & 
13C), UV, MS, optical activity, and if available, single crystal X-ray diffraction data, if 
not previously provided.9 
Analytical procedures used to characterize the primary reference material should also be 
provided in an information amendment.  (See section IV.A.5) 
4.  Control of Drug Substance 
A detailed listing of all the tests performed on the drug substance (e.g., description, 
identity, assay, impurities, residual solvents) and the tentative acceptance criteria should 
be provided in an information amendment.  A list should be provided for the testing 
performed by the sponsor and, if different, the drug product manufacturer.  Test results 
and analytical data (e.g., infrared spectra, chromatograms) from batch release of 
representative clinical trial materials should also be provided in an information 
amendment initially and when any changes are made in the specification. 
Information on the analytical procedures should be provided in an annual report.  A 
general description of the analytical procedures should be provided that includes a 
citation to an official compendium, other FDA-recognized standard reference, or the 
sponsors standard test procedure number, as appropriate.  A description of analytical 
procedures with appropriate validation information should be provided for the analytical 
procedures that are not from an FDA-recognized standard reference (e.g., official 
compendium, AOAC International Book of Methods). 
New impurities (e.g., from a change in synthetic pathway) should be identified, qualified, 
quantified, and reported, as appropriate. Procedures to evaluate impurities to support an 
NDA (e.g., recommended identification levels) may not be practical at this point in drug 
development.  Suitable limits should be established based on manufacturing experience, 
available stability data, and safety considerations. 
Suitable microbial limits should be established for nonsterile products that have potential 
to support microbial growth, if not previously submitted.  These limits or changes in 
previously reported limits should be reported in an information amendment. 
5.  Reference Standards or Materials 
If a national or international standard is not yet available, the sponsor should establish its 
own primary reference material during phase 3 studies.  The manufacturer can continue 
to use the working standard from phase 2 or can establish a new working standard for lot 
release. The synthesis and purification of the primary reference material and/or working 
standard should be described in an information amendment if it differs from that of the 
investigational drug substance. The analytical procedures for and results from qualifying 
                                                
9 Infrared spectrometry (IR), nuclear magnetic resonance spectrometry (NMR), ultraviolet spectrometry (UV), and 
mass spectrometry (MS). 
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the working standard against the primary reference material should be provided in an 
annual report. 
Where a recognized national or international standard is available and appropriate, the 
manufacturers reference material and/or working standard should be qualified against 
this standard, and the results provided in an annual report. 
6.  Container Closure System 
Any changes in the container closure system used to transport and/or store the bulk drug 
substance should be described in an annual report. 
7.  Stability 
Changes in the drug substance stability program from that described for phase 2 (see 
section III.A.7) should be provided in an information amendment.  Furthermore, the 
stability program should be updated to include descriptions of the stress and accelerated 
studies, if not previously described in phase 2.   A container closure system that simulates 
the container closure system used to transport and/or store the bulk material can be used 
for the drug substance stability studies.  Tests unique to the drug substance stability 
program (i.e., tests not included in section IV.A.4) should be defined and described. 
Any stability data for the clinical material used in the phase 2 studies that were not 
reported during phase 2 should be provided in an information amendment.  Stability data 
for representative  clinical  trial  materials used in phase 3 should be provided in annual 
reports in tabular format  as the data become available.  The submitted stability 
information should include the lot number, manufacturer, manufacturing site, and the 
date of manufacture of the drug substance. 
If not performed earlier, stress studies should be conducted during phase 3 to demonstrate 
the inherent stability of the drug substance, potential degradation pathways, and the 
capability and suitability of the proposed analytical procedures. The stress studies should 
assess the stability of the drug substance in different pH solutions, in the presence of 
oxygen and light, and at elevated temperatures and humidity levels.  These one-time 
stress studies on a single batch are not considered part of the formal stability program. 
The results should be summarized and submitted in an annual report. 
To ensure appropriate stability data are generated for filing at the NDA stage, a stability 
protocol that will be used for the formal stability studies should be developed.10  The 
analytical procedures should be referenced to the drug substance specification section of 
the IND or an official compendium, if possible.  Tests unique to the stability protocol 
should be defined and described. It is helpful if the stability protocol is submitted in an 
                                                
10 Applicants should refer to the forthcoming guidance Stability Testing of Drug Substances and Drug Products, 
when finalized, for information on stability protocols for formal stability studies.  In June 1998 (63 FR 31224), the 
Agency made available a draft version of this guidance. 
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information amendment before or during phase 3 studies and is discussed at the end-of-
phase-2 meeting. 
B.  Drug Product 
1.  Description and Composition of the Drug Product 
The sponsor should provide updated information regarding the components and 
composition in an information amendment if different from that reported in phase 1 
and/or phase 2. The formulation for certain drug products delivered by devices (e.g., 
MDIs, dry powder inhalation (DPIs), and nasal sprays) should be similar to that intended 
for the marketed drug product. 
2.  Manufacture 
a.  Manufacturers 
A listing of all firms associated with the manufacture of the drug product should 
be provided in an information amendment, including any contract facilities used 
for manufacturing and/or testing (e.g., stability studies, packaging, labeling, 
quality control release testing). 
b.  Batch Formula 
The sponsor should provide updated representative batch formula in an 
information amendment if different from that used in phase 1 and/or phase 2. 
c.  Description of Manufacturing Process and Process Controls 
Changes in the manufacturing method for the drug product should be provided. 
An updated flow diagram and description of the manufacturing process 
(excluding packaging and labeling) should be provided in an information 
amendment.  The description should indicate how the material is being processed 
and can be general enough to allow for flexibility in development.   Reprocessing 
procedures and pertinent controls should be described in an information 
amendment, if applicable.  A brief description of the packaging and labeling 
process for clinical supplies should be provided in an annual report. 
For sterile products, updates on information from that provided for phase 1 and 
phase 2 should be submitted in an information amendment.  The information 
should include a description of changes in the drug product sterilization process 
(e.g., terminal sterilization to aseptic processing).  Information related to the 
validation of the sterilization process need not be submitted at this time but 
should be submitted at the time of an NDA filing (see FDA guidance for industry 
Submission Documentation for Sterilization Process Validation in Applications 
for Human and Veterinary Drug Products). 
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3.  Control of Excipients 
Updates on compendial excipient information previously provided should be submitted in 
information amendments.  In certain cases, testing in addition to that specified in a 
compendium (e.g., functionality) can be useful and should be proposed. 
For a noncompendial excipient, updates and a full description of the characterization, 
manufacture, control, analytical procedures, and acceptance criteria should be provided 
in an information amendment.  Alternatively, a reference with authorization to a DMF 
can be provided. Information for excipients not used in previously approved drug 
products in the United States (e.g., novel excipients) should be equivalent to that 
submitted for new drug substances. 
4.  Control of Drug Product 
A detailed listing of all the tests performed on the drug product and the tentative 
acceptance criteria should be provided in an information amendment. A summary table of 
test results and analytical data (e.g., chromatograms) from batch release of representative 
clinical trial materials should be provided in an information amendment initially and 
when any changes are made in the specification.  Data on the particle size distribution 
and/or polymorphic form of the drug substance used in clinical trial materials should be 
included, when appropriate (e.g., inhalation, suspension, modified release solid dosage 
forms), so that relevant correlations can be established between data generated during 
early and late drug development and in vivo product performance. 
A general description of the analytical procedures used should be provided in an annual 
report  that includes a citation to an official compendium, other FDA-recognized standard 
reference, or the sponsors standard test procedure number, as appropriate.  A description 
of the analytical procedure with appropriate validation information should be provided 
for analytical procedures that are not from an FDA-recognized standard reference (e.g., 
official compendium, AOAC International Book of Methods). 
Data updates on the degradation profile should be provided in an information amendment 
so safety assessments can be made.  Degradation products should be identified, qualified, 
quantified, and reported, as appropriate. Evaluation procedures to support an NDAs 
degradants (e.g., recommended identification levels) may not be practical at this point in 
drug development.  Suitable limits should be established based on manufacturing 
experience, stability data, and safety considerations. 
For sterile-preserved products in multiple-dose containers or nonsterile-preserved 
products, a citation to the USP Antimicrobial Preservative-Effectiveness Test (APET) or 
a description of an equivalent procedure with the associated test validation information 
should be provided in an information amendment.  This test should be performed at the 
lowest specified concentration of antimicrobial preservative specified for the drug 
product at release or at the end of the expiration dating period, whichever is less. The 
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efficacy of preservative systems is evaluated based on their effect on inoculated 
microorganisms. 
A dissolution testing program for oral immediate release dosage forms (e.g., tablets, 
capsules, suspensions) and a drug release program for modified release dosage forms 
(e.g., modified release tablets, capsules, suspensions, transdermal drug delivery systems) 
should be developed. Dissolution or drug release characteristics of a drug product, 
particularly the selection of the medium, are generally based on the pH solubility profile 
and pKa of the drug substance. Dissolution or drug release profiling should be performed 
in physiologically relevant media with reasonable speeds of rotation (e.g., basket at 50 or 
100 rotations per minute (rpm), paddle at 50 rpm).  The dissolution or drug release 
program at phase 3 should bring commonality to both the methodology and the proposed 
acceptance criteria by taking into consideration the results of dissolution or drug release 
testing of clinical, bioavailability, and bioequivalence batches (e.g., clinically studied 
formulations versus the to-be-marketed formulation) and relevant stability batches.  The 
overall aim is to set in vitro dissolution or drug release acceptance criteria that ensure 
batch-to-batch and unit-to-unit consistency, post-NDA approval. The sponsor is 
encouraged to obtain concurrence on choice of apparatus, medium, rotation speed, and 
sampling time points from the Agency before the primary stability studies are initiated. 
Discussions with the Agency (e.g., at the end-of phase-2 meeting) can also include plans 
for establishing an in vivo-in vitro correlation (IVIVC) and characterizing the drug 
substance using the Biopharmaceutics Classification System (BCS). 
5.  Container Closure System 
An update of the description of the container closure system should be provided in an 
information amendment if it differs from that reported during phase 2.  When changes are 
made in the container closure system during phase 3 studies, information should be 
submitted in an information amendment if there can be an effect on product quality. 
Otherwise, the changes can be reported in an annual report. 
For packaging components with compendial standards (e.g., glass, polyethylene 
containers), compliance with the appropriate compendial standards should be stated.  If 
the sponsor refers to information in a Type III DMF, an authorization letter from the 
DMF holder should be provided. Additional information may be requested for atypical 
delivery systems (e.g., MDIs, disposable injection devices).  The container closure 
system of certain drug products delivered by devices (e.g., MDIs, DPIs, nasal sprays) 
should be similar to that intended for the marketed drug product.  A sponsor can consult 
with the appropriate CMC review team for additional guidance if it has any questions. 
6.  Stability 
A stability program should be designed to monitor the chemical, physical, biological, or 
microbiological (if applicable) stability of the drug product throughout the clinical testing 
program.  Changes in the drug product stability program from that described for phase 2 
(see section III.B.7) should be provided in an information amendment.   A brief 
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description should be provided in an information amendment for each of the attributes 
being investigated in the stability program (i.e., long-term and accelerated), 
demonstrating that the appropriate controls and storage conditions are in place to ensure 
the quality of the product used in clinical trials. Furthermore, tests unique to the drug 
product stability program (i.e., tests not included in section IV.B.4) should be adequately 
defined and described. 
Any stability data for the clinical material used in the phase 2 studies that were not 
reported during phase 2 should be provided in an information amendment.  Stability data 
for representative clinical material used in phase 3 should be provided in annual reports 
in tabular format as the data become available.  The submitted information should 
include the batch number, manufacturing site, date of manufacture of the drug product, 
and relevant information on the drug substance (e.g., lot number, manufacturer) used to 
manufacture the drug product.  The analytical results for each test should be reported. 
Representative chromatograms should be provided in the annual report, if applicable. 
For certain drug products, one-time stress testing can be warranted to assess the potential 
for changes in the physical (e.g., phase separation, precipitation, aggregation, changes in 
particular size distribution) and/or chemical (e.g., degradation and/or interaction of 
components) characteristics of the drug product.  The studies could include testing to 
assess the effect of high temperature, humidity, oxidation, photolysis and/or thermal 
cycling. The relevant data should be provided in an annual report. 
To ensure appropriate stability data are generated for filing at the NDA stage, a stability 
protocol that will be used for the formal stability studies should be developed.11  The 
analytical procedures should be referenced to the control of drug product section of the 
IND or an official compendium, if possible.  Tests unique to the stability protocol should 
be defined and described.  It is helpful if the stability protocol is submitted in an 
information amendment before or during phase 3 studies and is discussed at the end-of-
phase-2 meeting, especially for those protocols including bracketing and matrixing 
approaches. 
V.  PLACEBO 
A brief, general description of the composition, manufacture, and control of the placebo 
provided during phase 1 should be updated or provided for phase 2 and/or phase 3 if the placebo 
is being used for the first time.  This information and any updates to this information should be 
provided in an information amendment.  When placebos are used in clinical trials, the placebo 
clinical study materials should be tested to demonstrate the absence of the drug substance.  The 
results from the placebo testing should be submitted in an annual report. 
                                                
11 Applicants should refer to the forthcoming guidance Stability Testing of Drug Substances and Drug Products, 
when finalized, for information on stability protocols for formal stability studies.  In June 1998 (63 FR 31224), the 
Agency made available a draft version of this guidance. 
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VI.  LABELING 
Updates of the information provided for phase 1 should be submitted in information amendments 
during phase 2 and phase 3. 
VII.  ENVIRONMENTAL ASSESSMENTS 
Updates on information already submitted and on whether a claim for a previous categorical 
exclusion has changed should be provided in information amendments for phase 2 and phase 3 
(see FDA guidance for industry on Environmental Assessment of Human Drug and Biologics 
Applications). 
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RESOURCES 

FDA continues to update existing and publish new guidance documents.  An applicant 
should ensure that it is using current guidance when preparing a submission. CDER 
guidances are available on the Internet at http://www.fda.gov/cder/guidance/index.htm. 
ICH Guidances 
Although not intended to be applicable to IND applications, the International Conference on 
Harmonization (ICH) documents below can serve as valuable resources in guiding the course of 
product development. 
ICH Q1A Stability Testing of New Drug Substances and Products 
ICH Q1B Photostability Testing of New Substances and Products 
ICH Q1C Stability Testing for New Dosage Forms 
ICH Q2A  Validation of Analytical Procedures 
ICH Q2B Validation of Analytical Procedures: Methodology 
ICH Q3A Impurities in New Drug Substances 
ICH Q3B Impurities in New Drug Products 
ICH Q3C Impurities: Residual Solvents 
ICH Q5A Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human 
or Animal Origin 
 
ICH Q5B Quality of Biotechnological Products: Analysis of the Expression Construct in Cells 
Used for Production of r-DNA Derived Protein Products 
ICH Q5D Quality of Biotechnological/Biological Products:  Derivation and Characterization of 
Cell Substrates Used for Production of Biotechnological/Biological Products 
ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances 
and New Drug Products: Chemical Substances 
ICH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 
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  Contains Nonbinding Recommendations 
FDA Guidances for Industry 
Draft FDA guidances are cited for completeness of information and are not for implementation 
until finalized. 
Analytical Procedures and Methods Validation  Chemistry, Manufacturing, and Controls 
Documentation, Draft. The Agency published this draft guidance in the Federal Register on 
August 30, 2000 (65 FR 52776). 
Botanical Drug Products, Draft. The Agency published this draft guidance in the Federal 
Register on August 11, 2000 (65 FR 49247). 
Container Closure Systems for Packaging Human Drugs and Biologics 
Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of 
Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products 
Drug Product: Chemistry, Manufacturing, and Controls Information, Draft. The Agency 
published this draft guidance in the Federal Register on January 28, 2003 (68 FR 4219). 
Drug Substance: Chemistry, Manufacturing, and Controls Information (forthcoming  guidance) 
Environmental Assessment of Human Drug and Biologics Applications 
Fast Track Drug Development Programs Designation, Development, and Applications Review 
IND Meetings for Human Drugs and Biologics  Chemistry, Manufacturing, and Controls 
Information 
Monoclonal Antibody Used as Reagents in Drug Manufacturing 
Stability Testing of Drug Substances and Drug Products, Draft. The Agency published this draft 
guidance in the Federal Register on June 8, 1998 (63 FR 31224). 
Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide 
Substances 
Submission Documentation for Sterilization Process Validation in Applications for Human and 
Veterinary Drug Products 
24