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
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.
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.
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,
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).
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
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. FDA’s
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.
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 CDER’s
guidance on IND Meetings for Human Drugs and Biologics;
Chemistry, Manufacturing, and Controls Information).
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.
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.
·
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 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)
·
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)
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.
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.
·
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.
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.
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.
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)).
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 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.
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 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.
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).
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.
Any change in the
tentative specification, including the tentative acceptance
criteria, should be reported. This includes changes in the
sponsor’s drug substance specification and, if different, drug
product manufacturer’s 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.
Where a recognized
national or international standard (such as a standard from the
World Health Organization (WHO)) is available, the manufacturer’s
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
manufacturer’s primary reference material. The manufacturer can
continue to establish new working standards that are qualified
against that primary reference material.
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 should be
provided in an annual report.
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.
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.
a. Manufacturers
The addition,
deletion, or change of any manufacturer of the drug product from
that specified during phase 1 should be reported.
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.
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.
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 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.
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).
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. 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.
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.
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.
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 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),
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.
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
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.
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,
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.
Analytical
procedures used to characterize the primary reference material
should also be provided in an information amendment.
(See section IV.A.5)
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 sponsor’s 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.
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 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 manufacturer’s reference material and/or working standard
should be qualified against this standard, and the results
provided in an annual report.
Any changes
in the container closure system used to transport and/or store the
bulk drug substance should be described in an annual report.
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.
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 information amendment before or during
phase 3 studies and is discussed at the end-of-phase-2 meeting.
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.
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).
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.
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
sponsor’s 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 NDA’s 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 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).
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.
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 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.
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.
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.
Updates of the information provided for phase
1 should be submitted in information amendments during phase 2 and
phase 3.
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).
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
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
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