Guidance for Industry
M4: The CTD — Quality
Questions and Answers/
Location Issues
(PDF version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2004
ICH
Additional copies are available
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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. You can use an alternative approach if that 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 is one in a series of guidances that
provide recommendations for applicants preparing the Common
Technical Document for the Registration of Pharmaceuticals for Human
Use (CTD) for submission to the U.S. Food and Drug Administration
(FDA). The guidance for industry issued in November 2000 on
preparing the CTD was divided into four separate documents: (1)
M4: Organization of the CTD, (2) M4: The CTD — Quality, (3) M4: The
CTD — Efficacy, and (4) M4: The CTD — Safety. Since implementation
of these guidances, a number of questions regarding the CTD
documents have been submitted to the various ICH regions. The ICH
has developed a process for responding to questions submitted to the
ICH Web site. This guidance specifically addresses questions
related to quality. Other question and answer (Q & A) guidances
address general questions as well as questions related to safety and
efficacy. The questions and answers provided here reflect the
consensus of the ICH parties.
This document is intended to provide
additional guidance for the preparation of an application file in
the CTD-Q format (see section II: General Issues). It should be
read in conjunction with the CTD-Q guidance (Modules 2 and 3). The
document also addresses the relationship between linked CTD-Q
sections for certain parameters, such as polymorphism, impurities,
or particle size (see section III: Associated Information Located in
Different Sections). This document also clarifies location issues;
that is, it indicates in which CTD-Q section(s), requested
information should be placed (see section IV: Location Issues in
Drug Substance, section V: Location Issues in Drug Product, and
section VI: Location Issues in Appendices).
This document does not address the content of
an application file. For content questions, refer to the
appropriate FDA guidance documents on this matter.
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.
There can be a number of instances where
repeated sections can be considered appropriate. Whenever a section
is repeated, it should be made clear what the section refers to by
creating a distinguishing title in parentheses following the CTD-Q
heading, for example, 2.3.S Drug Substance (Name, Manufacturer A).
Drug Substance
When more than one drug substance is used in
a drug product, information should be presented separately as one
complete Drug Substance section followed by other complete Drug
Substance sections. In some cases, for a single drug substance, it
could be considered appropriate and logical to have information
presented in multiple Drug Substance sections. For example,
separate sections can be warranted when a single drug substance is
made at two different manufacturing sites with differences in the
manufacturing processes. However, despite these differences, it is
likely that these different processes will be described within the
same relevant subsection of 3.2.S. If, on the other hand, the
differences result in, for example, different specifications, then
adding an additional Drug Substance section is recommended (see also
regional guidance).
Drug Product
Depending upon regional requirements,
different drug product presentations (e.g., strengths, container
closure types and configurations, formulations) and/or manufacturing
schemes (e.g., aseptic and terminal sterilization) can be submitted
in the same application. In general, when a single application can
be submitted, information for each of the product presentations and
manufacturing schemes should be combined and presented together in
one Drug Product section, with information for each of the product
presentations and manufacturing schemes provided in the Appendices
and Regional Information sections, as warranted. For example, if
100 milligram (mg) tablets will be marketed in a bottle and a
unit-dose blister package, the information should be presented in
one Drug Product section. Where most of the quality information
would be identical for the two drug products, the data common to
both presentations should appear only once. The information that
differs between the two should be presented as separate documents
under the appropriate subsections (e.g., 3.2.P.7 Container Closure
System, 3.2.P.8 Stability).
In some cases, however, for product
presentations or manufacturing schemes that can be included in a
single application, it is considered more appropriate and logical to
have information presented separately. Information presented
separately means one complete Drug Product section followed by other
complete Drug Product sections. One such example is that
information on a drug product supplied with a reconstitution diluent
should be presented in separate Drug Product sections for the drug
product and the reconstitution diluent. These could be titled 3.2.P
(Drug Product) and 3.2.P (Diluent).
Excipients
If appropriate, where a novel, or
noncompendial nonnovel, excipient is proposed and a significant
amount of data is provided for the excipient, this information
should be provided in 3.2.A.3 Excipients, which follows the same
format and level of subsections as the Drug Substance section.
There should be a complete section of 3.2.A.3 Excipients for each
novel excipient or noncompendial nonnovel excipient.
Appendices
There can be occasions where it is
appropriate to repeat an Appendix. For example, where a sponsor
registers more than one manufacturing facility for the manufacture
of a biotech drug, the Appendix 3.2.A.1 should then be
repeated.
Regional Information
The content of the Regional Information
section (3.2.R) is not harmonized. In this section the documents,
their titling, and their order should be consistent with the
requirements of the relevant region.
B. Multiple Containers (2.2)
When there are two containers (e.g., PVC
blister and PE bottle) for one drug product, the documents for the
drug product part in Module 3 should generally be common. In this
case, one set of documentation, 3.2.P.1 through 3.2.P.8, should be
provided. The information for the blister and the bottle should be
presented in the corresponding sections of the single drug product
part in Module 3 (e.g., 3.2.P.7, 3.2.P.8), divided by subsections
for each type of container and identified by the type of container.
Q: In the Common Technical
Document, under what section should bioanalytical methods and their associated validation reports be included?
A: In this context, bioanalytical
methods are understood to mean analytical procedures used in
clinical studies (human clinical
pharmacology/bioavailability/bioequivalence) and/or nonclinical
studies (nonhuman pharm/tox studies).
The description of analytical
procedures and associated validation reports should be
submitted in those modules where the corresponding studies are
described (i.e., in Module 4, section 4.2.2.1 for
analytical procedures and associated validation reports for nonclinical studies and in Module 5, section 5.3.1.4 for analytical
procedures and associated validation reports
used in clinical studies).
D. Drug Master Files (DMFs) (2.4)
Q: Can the Drug Master File use
the CTD format?
A: Since the DMF systems differ in the
three regions, ICH does not address this issue.
Consequently, the applicant should check with the relevant competent
authority in the region(s).
Q: If a drug substance is used
in the form of a preparation (e.g. a [commercially
available] vitamin trituration) in which module/section should the
excipient(s) included in the preparation be described?
Should the relevant information be given for example in
Section 3.2.S Drug Substance or in Section 3.2.P.4 Drug Product -
Control of Excipients?
A: If the drug substance is defined as
two or more materials, the manufacturing information would be
described in 3.2.S.2.2 and the control of the additional material(s)
(e.g., excipient(s)) would be described in 3.2.S.2.3.
Below, examples of multiple references in CTD-Q
are proposed for polymorphism, particle size, and impurities. They
indicate for some parameters that the information should not
necessarily be located in one section, but should be split into
different sections.
3.2.S.1.3 If called for, list the polymorphic form(s)
present in the proposed active as a characteristic of the drug
substance.
3.2.S.2.2 Description of Manufacturing Process and
Process Controls should indicate which polymorphic form is
synthesized.
3.2.S.3.1 Studies performed to identify the
potential polymorphic forms of the drug substance, including study
results. Total number of polymorphs should be listed here and those
intended to form the active should be summarized in 3.2.S.1.3.
3.2.S.4.1 Specification. If a polymorph is to be
defined or limited, it should be discussed here.
3.2.S.4.2
Analytical Procedures.
3.2.S.4.3
Validation of Analytical Procedures.
3.2.S.4.4
Results of batch analyses.
3.2.S.4.5 Justification of Specification (if
appropriate). Reasons why a particular limit on form is appropriate
(should also probably refer to 3.2.P.2).
3.2.P.2.1.1 and
3.2.P.2.2.3
Identifies the influence of polymorphism on the drug substance and
dosage form.
3.2.P.5.1 Specification. If polymorphs are to be
controlled in the drug product, they should appear here.
3.2.P.5.6
Justification of Specification (if called for).
3.2.S.2.2
Description of Manufacturing Process and Process Controls.
3.2.S.3.1 Studies performed to identify the particle
size distribution of the drug substance.
3.2.S.4.1
Specification.
3.2.S.4.2
Analytical Procedures.
3.2.S.4.3
Validation of Analytical Procedures.
3.2.S.4.4
Results of batch analyses.
3.2.S.4.5
Justification of Specification.
3.2.P.2.1.1 and
3.2.P.2.2.1
Identification of the influence of particle size on, for instance,
dissolution performance (consult
the ICH Q6A decision tree).
3.2.S.3.2 Here the discussion on impurities and
information on their qualification should take place (reference to
preclinical and clinical studies): e.g., absolute amount at which
the impurities can be considered as qualified.
3.2.S.4.1
Specification.
3.2.S.4.2
Analytical Procedures.
3.2.S.4.3
Validation of Analytical Procedures.
3.2.S.4.4 Results of batch analyses (all batches
including development, clinical, stability).
3.2.S.4.5
Justification of Specification.
3.2.P.5.1
Specification.
3.2.P.5.2
Analytical Procedures.
3.2.P.5.3
Validation of Analytical Procedures.
3.2.P.5.4 Results of batch analyses (all batches
including development, clinical, stability).
3.2.P.5.5 Characterization of Impurities (for those
impurities not already discussed under 3.2.S).
3.2.P.5.6
Justification of Specification.
Q: How does the CTD link
information on drug substance batch numbers, drug product
batch numbers, nonclinical and clinical study numbers, the levels of
impurities, history of formulation development, and any other
relevant information? Please clarify the assignment of this
information to the nonclinical and clinical sections.
A: The history of development for the
drug substance should be included in 3.2.S.2.6. A
description of batches and the result of batch analyses should be
included in 3.2.S.4.4. The history of formulation
development should be included in 3.2.P.2.2.1. A description
(including a summary table) of batches and the results of batch
analyses for the drug product should be included in 3.2.P.5.4.
This information on the history of development and description of
batches can also be linked to the impurity levels of batches
described in 3.2.S.3.2 and 3.2.P.5.5.
Appropriate references to Modules
4 and 5 for the nonclinical and clinical studies can
also be made.
Q. Where would the information related to nonviral
adventitious agents be placed within Module 3.2?
A: The following guidance supersedes
the first sentence under 3.2.A.2 for nonviral
adventitious agents:
The detailed information
regarding the routine manufacturing control of adventitious
agents, such as bacteria, mycoplasma, and fungi,
typically using well-established (e.g., pharmacopoeial)
analytical procedures, should be provided in the appropriate
sections within Module 3.2.S and 3.2.P. If
well-established (e.g., pharmacopoeial) analytical
procedures are not used, more detailed information regarding the
analytical procedure(s) used should also be included in 3.2.S and
3.2.P.
With respect to other nonviral
adventitious agents, such as transmissible spongiform
encephalopathy agents and prions, the detailed information, should
be placed in 3.2.A.2.
CTD-Q Section 3.2.
S.1 General Information
S.1.1 Nomenclature
S 1.2 Structure
Q: Should drawings to show secondary and tertiary
structures and, if applicable, quaternary structures of proteins be
provided in 3.2.S.1.2?
A: Drawings to show secondary and tertiary structures and, if
applicable, quaternary structures should be provided in 3.2.S.3.1.
S.1.3 General Properties
Q: How much detailed information on the general properties
of the drug substance should be included in 3.2.S.1.3?
A: As stated in CTD-Q, a list of physicochemical and other
relevant properties of the drug substance, including biological
activity, should be included in 3.2.S.1.3. The information on
general properties should be provided only for the form of the drug
substance used in the drug product, not possible alternative forms
(e.g., polymorphs). More detailed information on the properties of
the drug substance, including possible alternative forms, should be
included in 3.2.S.3.1.
S.2 Manufacture
S.2.1 Manufacturers
S.2.2 Description of the Manufacturing
Process and Process Controls
Q: Should information on process controls be provided in
section 3.2.S.2.2 or 3.2.S.2.4?
A: All process controls should be identified in 3.2.S.2.2. For
critical controls, additional information should be provided in
3.2.S.2.4.
S.2.3 Control of Materials
Q1: Should the discussion and justification of starting
materials be included in 3.2.S.2.3?
A1: The discussion and justification of starting materials should
be included in 3.2.S.2.3.
Q2: Where should analytical procedures for materials
described in 3.2.S.2.3 be included?
A2: The analytical procedures for the control of materials (e.g.,
starting materials, reagents, raw materials, solvents) should be
presented in section 3.2.S.2.3. For materials of biological origin,
analytical procedures related to adventitious agent safety
evaluation, if applicable, should be presented in 3.2.A.2.
Q3: Since the addition of new headings is not an option,
where in the CTD should one locate (Quality Section) information
regarding a reagent used in the production of the drug substance
when the reagent is manufactured via recombinant DNA technology?
A3: The information should be located in 3.2.S.2.3: Control of
Materials.
S.2.4 Control of Critical Steps and
Intermediates
Q1: Should batch data for intermediates or critical steps be
included in 3.2.S.2.4?
A1: Batch data, together with analytical procedures and acceptance
criteria for intermediates or critical steps, would be presented in
3.2.S.2.4.
Q2: If release tests are performed on intermediates and at
critical steps instead of on drug substance, where would the
information on the analytical procedures and acceptance criteria be
presented in 3.2.S.4?
A2: Acceptance criteria should be referred to in 3.2.S.4.1, and
analytical procedures should be referred to in 3.2.S.4.2.
S.2.5 Process Validation and/or Evaluation
Q: Where should justification for reprocessing be
included?
A: If justification for reprocessing is warranted by a regional
authority, the information would be included as part of the
description of the manufacturing process in 3.2.S.2.2. If there are
critical controls associated with the reprocessing operation, the
critical controls should be included in 3.2.S.2.4. If validation
information is warranted, the validation information should be
included in 3.2.S.2.5.
S.2.6 Manufacturing Process Development
Q: Should bioavailability/bioequivalence study results
that demonstrate product comparability following process changes be
described in 3.2.S.2.6?
A: Reports of Bioavailability/Bioequivalence studies that
demonstrate comparability/equivalence after formulation or process
changes should be presented in Module 5. Cross-references to these
reports should be placed in section 3.2.S.2.6 (for drug substance
process changes), 3.2.P.2.2.1 (for drug product formulation changes)
or 3.2.P.2.3 (for drug product process changes). A brief summary of
the reports can be placed in these sections when considered
appropriate.
S.3 Characterization
S.3.1 Elucidation of Structure and Other
Characteristics
Q: Where should studies conducted to determine the
physicochemical characteristics of the drug substance be included?
A: Information on the studies conducted to determine the
physicochemical characteristics of the drug substance should be
included in 3.2.S.3.1. Only a list of the general properties of the
drug substance should be included in 3.2.S.1.3.
S.3.2 Impurities
Q1: Should structural characterization data and a summary of
the method of preparation of impurities be included in 3.2.S.3.2?
A1: This information should be included in 3.2.S.3.2.
Characterization of impurity reference standards should be provided
in 3.2.S.5. See also Q & A under III.C.
Q2: Where should chromatograms be provided for impurities?
A2: ICH Q3A identifies the chromatograms as part of the analytical
validation studies. Therefore, relevant chromatograms should be
included in 3.2.S.4.3.
Q3: Where should nonclinical and clinical data supporting
impurity levels be summarized?
A3: The qualified level of each impurity with cross-reference to the
supporting nonclinical/clinical studies should be included in
3.2.S.3.2.
Q4: Should data on impurities reported in batch analyses be
included in 3.2.S.3.2 or 3.2.S.4.4?
A4: Data on observed impurities for relevant batches (e.g.,
clinical, nonclinical, stability) should be provided in 3.2.S.3.2.
The data should be provided whether or not the impurity is included
in the specification. This information can be cross-referenced to
support other sections of the application as appropriate.
S.4 Control of Drug Substance
S.4.1 Specification
Q1: If there are different specifications for a drug
substance manufacturer and/or applicant, should they all be
provided in 3.2.S.4.1?
A1: When appropriate, more than one specification should be included
in 3.2.S.4.1.
Q2: If alternative analytical procedures are used to control
the drug substance, should they also be listed in the specification
(3.2.S.4.1)?
A2: Any analytical procedure used to
control the drug substance, and the associated
acceptance criteria, should be listed in the specification.
S.4.2 Analytical Procedures
Q1: Often an analytical procedure
changes during the development of the drug substance.
If this analytical procedure is submitted to support the dossier, in
which section should these analytical procedures be placed?
A1:
Information on historical analytical procedures used to generate
data included in the batch analyses should be included
in 3.2.S.4.4.
Q2: Should an analytical procedure that is only used for
stability studies be included in 3.2.S.4.2?
A2: Information on analytical procedures
that are used only for stability studies should be included in
3.2.S.7.3.
Q3: If the analytical methods for a
drug substance and drug product are identical, can these
methods and corresponding validation, if applicable, be described in
either 3.2.S or 3.2.P, with a corresponding reference
(e.g., a reference from 3.2.S to 3.2.P)?
A3: The analytical methods should be
placed in both the relevant sections of 3.2.S and 3.2.P
because the sample preparation, at least, will differ.
S.4.3 Validation of Analytical Procedures
Q: Where should chromatograms be
included?
A: Relevant chromatograms should be
included in 3.2.S.4.3.
S.4.4 Batch Analyses
Q1: Where should results from all
relevant batches be provided?
A1: Results from all relevant batches
(e.g., clinical, nonclinical, stability), including those
batches used to justify acceptance criteria should be
provided in 3.2.S.4.4.
Q2: If there are results from tests
that are not listed in the specifications, where should they be
provided?
A2: If results are submitted from tests
that are not listed in the specification, they should be
provided in 3.2.S.4.
Q3: Where should collated data for a
test from multiple batch analyses be presented?
A3: If collated data from batch analyses
are warranted, the data should be presented in
3.2.S.4.4.
S.4.5 Justification of Specification
Q1: Should justification for skip testing be
included in 3.2.S.4.5?
A1: If skip testing is considered
appropriate, the justification should be included in
3.2.S.4.5.
Q2: Rather than repeating
information, can a summary of data from other sections with a
cross-reference to the detailed information be provided to support
the justification of specification section of the
dossier?
A2: A summary of data from other sections
with a cross-reference to the detailed information can
be provided to support the justification of specification.
S.5 Reference Standards or Materials
Q1: Reference standards might be
available for the active moiety and impurities. Should
information on all reference standards be included in 3.2.S.5?
A1: If information is warranted for a
reference standard, the information should be included
in 3.2.S.5.
Q2: Where should characterization
data for a reference standard be placed in the CTD-Q?
A2: Characterization data for the
reference standard should be included in 3.2.S.5. Cross-reference to information in other sections (e.g.,
3.2.S.3.2) can be included as considered appropriate.
S.6 Container Closure System
S.7 Stability
S.7.1 Stability Summary and Conclusions
S.7.2 Postapproval Stability Protocol and
Stability Commitment
S.7.3 Stability Data
Q1: Should stress studies be located
in 3.2.S.7.3?
A1: Stress studies should be located in
3.2.S.7.3. These data can be referenced for validation
of analytical procedures as considered appropriate.
Q2: Should information on any
changes in analytical procedures over the course of
generating stability data be included in 3.2.S.7.3?
A2: Information on historical
analytical procedures used to generate the stability data should be
included in 3.2.S.7.3.
Q3: Can data from supporting studies
be included in 3.2.S.7.3?
A3: Data from supporting studies can be
included in 3.2.S.7.3, if considered appropriate.
Q4: Should information on analytical
procedures unique to the stability program be presented
in 3.2.S.7.3?
A4: Information on analytical procedures
unique to the stability program should be included in
3.2.S.7.3.
CTD-Q Section 3.2
P.1 Description and Composition of the Drug
Product
Q1: Where should information related
to the composition of inks used on the drug product be
placed?
A1: All drug product components
should be listed in 3.2.P.1. The composition (e.g.,
components of the capsule shell, components of inks) should also be
included in 3.2.P.1. In some regions, the qualitative
composition of proprietary components can be replaced
with reference to appropriate DMFs.
Q2: Where should information on
reconstitution diluents be included?
A2: If the diluent is
co-packaged with the drug product, the information on the diluent should be placed in a separate Drug Product section.
The compatibility of the drug product with reconstitution
diluents should be discussed in 3.2.P.2.6.
Q3: Should an over-fill be indicated
in 3.2.P.1?
A3: The use of an over-fill
should be indicated in 3.2.P.1. The rationale for an overfill
should be included in 3.2.P.2.2.1.
Q4: Can information on the
composition of a drug product, other than what is listed
in the CTD-Q guidance, be included in 3.2.P.1?
A4: When called for, additional
information can be included to adequately describe the
composition of the drug product, for example, (1) total weight,
volume, etc., of unit, (2) tracers or markers, (3)
composition statement for (purchased) mixtures, and (4)
capsule shells.
P.2 Pharmaceutical Development
P.2.1 Components of the Drug Product
Q1: Where should information on the
development of co-packaged diluents be placed?
A1: There should be a separate Drug
Product (Diluent) section for co-packaged diluents. Choice and
development of co-packaged diluents should be included in
3.2.P.2.2.1 and 3.2.P.2.6.
P.2.1.1 Drug Substance
Q1: Where should a discussion of the
drug substance stability or key physicochemical
characteristics that might influence the manufacturing process of
the drug product be provided?
A1: Drug substance stability data should
be included in 3.2.S.7 and cross-referenced as needed in
3.2.P.2 as appropriate. Discussion of key drug substance
physicochemical characteristics that can influence
manufacturability of the drug product should be included
in 3.2.P.2.1.1.
Q2: Where should a discussion of the
effect of modification of active moiety (e.g., salt) on
key drug substance physicochemical characteristics be provided?
A2: Discussion of effect of modification
of active moiety (e.g., salt) on key drug substance
physicochemical characteristics should be included in 3.2.P.2.1.1.
Q3: Where should data from studies
on drug product to evaluate the potential effect of key
drug substance physicochemical characteristics be provided?
A3: Data from studies on drug product to
evaluate the potential effect of key drug substance
physicochemical characteristics should be provided in 3.2.P.2.1.1
(see ICH Q6A Decision Trees 3 and 4 (Part 2)).
P.2.1.2 Excipients
Q1: Should justification for using
an excipient if there is evidence of incompatibility be
included in 3.2.P.2.1.1 or 3.2.P.2.1.2?
A1: Justification for using an excipient
if there is evidence of incompatibility should be
included in 3.2.P.2.1.1.
Q2: Where should a discussion of an
excipient’s influence on the manufacturability of the
drug product be included?
A2: Discussion of excipients that can
influence the manufacturability of the drug product
should be included in 3.2.P.2.1.2.
Q3: Where should a discussion of the
ability of a functional excipient to perform through
shelf-life be included?
A3: Discussion of the ability of
functional excipients (e.g., antioxidants, penetration
enhancers) to perform through shelf-life should be included in
3.2.P.2.1.2. The effectiveness of antimicrobial
preservatives should be discussed in 3.2.P.2.5.
P.2.2 Drug Product
Q: Where should tables that
describe the composition of formulations used in development studies be included?
A: Tables describing different
development formulations should be included in
3.2.P.2.2.1.
P.2.2.1 Formulation Development
Q1: Where should information on
IV-IV correlation be included in CTD-Q?
A1: Summarized information on the in
vivo-in vitro (IV-IV) correlation should be included in
3.2.P.2.2.1 with a cross-reference to the studies in Module 5.
Q2: Can cross-reference be made to
bioequivalence information in other modules?
A2: Cross-referencing to both Modules 2
and 5 can be included to facilitate the review process.
Q3: Where should information to
justify a scoring of tablets be included?
A3: The rationale/justification for
scoring of tablets should be provided in 3.2.P.2.2.1.
Q4: Should the release mechanism of
the dosage form for controlled release drug products be
described in 3.2.P.2.2.1?
A4: Description of the release mechanism
in the dosage form for controlled release drug products
should be included in 3.2.P.2.2.1.
P.2.2.2 Overages
Q: Where should overages be
justified?
A: Justification for overages should be
included in 3.2.P.2.2.2.
P.2.2.3 Physicochemical and Biological
Properties
Q1: Where should any discussion on
dissolution development be included?
A1: A summary of dissolution development
should be included in 3.2.P.2.2.3, with cross-reference
to studies in Module 5, as considered appropriate. The
justification for the dissolution test should be
included in 3.2.P.5.6.
Q2: Where should a discussion of the
key drug product physicochemical or biological
characteristics that might influence the manufacturing process of
the drug product be provided?
A2: A discussion of key drug product
physicochemical or biological characteristics that can
influence manufacturability of the drug product should be included
in 3.2.P.2.2.3.
Q3: Where should data from studies
on the potential effects of key drug substance
physiochemical characteristics on the performance of the drug
product be provided?
A3: Data from studies on drug product to
evaluate the appropriateness of the drug product
acceptance criteria for physicochemical/biological properties should
be included in 3.2.P.2.2.3 (see ICH Q6A Decision Trees 4
(Part 3) and 7 (Part 1)).
P.2.3 Manufacturing Process Development
Q1: Where should justification of
sterilization be provided?
A1: When called for, justification of
sterilization should be included in 3.2.P.2.3.
Q2: What information on clinical
trial formulations should be included in 3.2.P.2.3?
A2: Information on clinical trial
formulations should be included in 3.2.P.2.2.1. Information on the differences in the manufacturing process among
supporting batches (e.g., clinical, stability) and the
proposed production process should be included in
3.2.P.2.3.
P.2.4 Container Closure System
Q1: Should information on container
closure system leachables and extractables be included
in 3.2.P.2.4?
A1: Information on both should be included
in 3.2.P.2.4. When warranted, information on leachables
should also be included in 3.2.P.5.1 and 3.2.P.5.5. Also, if
leachables are confirmed through shelf-life as part of
the formal stability studies, the results would be reported in 3.2.P.8.3.
Q2: Where should performance
characteristics of a container closure be provided?
A2: Information on performance of the
container closure system should be included in 3.2.P.2.4
(e.g., priming and re-priming studies for metered dose inhalers).
Q3: Where should information on
studies relating to cleaning of metered dose inhalers be
included?
A3: Information on cleaning of metered
dose inhalers should be included in 3.2.P.2.4.
Q4: Where should
information on the light protection characteristics of the container
closure be provided?
A4: Suitability of the container closure
system to protect from light (e.g., light transmission
data) should be discussed in 3.2.P.2.4. Photostability data should
be provided in 3.2.P.8.3 (defined as a stress study in
Q1A/Q1B).
P.2.5 Microbiological Attributes
Q: Should discussion of Decision
Tree #6 from ICH Q6A be included in 3.2.P.2.5?
A: Discussions relating to ICH Q6A
Decision Tree #6 (nonsterile drug substance and excipients) and Decision Tree #8 (nonsterile solid) should be
provided in 3.2.P.2.5.
P.2.6 Compatibility
Q1: Where should data from
constitution or dilution studies performed as part of the formal stability studies to confirm product quality
through shelf-life be provided?
A1: Information on the compatibility of
reconstitution diluents to support claims on the label
should be included in 3.2.P.2.6. Data from constitution or dilution
studies that are performed as part of the formal stability
studies to confirm product quality through shelf-life should be
reported in 3.2.P.8.3.
Q2: Should compatibility of
co-administered drugs be provided in 3.2.P.2.6?
A2: Compatibility with co-administered
drugs should be included in 3.2.P.2.6.
Q3: Should information on
incompatible diluents be provided in 3.2.P.2.6?
A3: Information on incompatible diluents
should be provided in 3.2.P.2.6.
P.3 Manufacture
P.3.1 Manufacturer(s)
P.3.2 Batch Formula
Q: Should overages be included in
3.2.P.3.2?
A: Overages should be included in the
batch fomula in 3.2.P.3.2.
P.3.3 Description of Manufacturing Process and Process
Controls
Q1: Where should reprocessing be
described?
A1: Reprocessing should be included as
part of the description of the manufacturing process in
3.2.P.3.3. If there are critical controls associated with the
reprocessing operation, the critical controls should be included in
3.2.P.3.4. If validation information is warranted, the
validation information should be included in 3.2.P.3.5.
Q2: Should critical steps and
intermediates be identified in P.3.3?
A2: All process controls should
be identified in 3.2.P.3.3. For critical controls, additional
information should be provided in 3.2.P.3.4.
Q3: Should an over-fill be
identified in 3.2.P.3.3?
A3: An over-fill should be identified in
3.2.P.3.3.
Q4: Should a statement regarding
manipulation of ruminant-derived materials in the drug
product manufacturing facility be included in 3.2.P.3.3?
A4: A statement regarding manipulation of
ruminant-derived materials in the drug product
manufacturing facility should be included here (3.2.P.3.3). If a
potential for cross-contamination with adventitious
agents exists, additional information should be provided in
3.2.A.1 and 3.2.A.2.
P.3.4 Controls of Critical Steps and
Intermediates
Q1: Should the detailed information
on critical steps and intermediates that have been
identified in 3.2.P.3.3 be included in 3.2.P.3.4?
A1: Detailed information should be
provided in 3.2.P.3.4 for critical steps and all
intermediates that are controlled.
Q2: Should critical process control
values from relevant batches be included in 3.2.P.3.4 to
support numeric ranges, limits, etc., for the critical process
controls?
A2: Critical process control values from
relevant batches to support numeric ranges, limits,
etc., for critical process controls should be included in 3.2.P.3.4.
Q3: Where should information on the
analytical procedures for an in-process material test
performed in lieu of a finished product test be included?
A3: In 3.2.P.3.4, the same information
should be provided for an in-process material test
performed in lieu of a finished product test as that submitted for a
finished product test (analytical procedure, methods
validation information).
Q4: If a process test were to
replace an end-product test, where would it be mentioned in
the specification?
A4: If a process test takes the place of
an end-product test, it should be listed in the
specification (3.2.P.5.1) and specified as a process test (see ICH
Q6A).
P.3.5 Process Validation and/or Evaluation
P.4 Control of Excipients
Q: If a significant amount of data
for an excipient (e.g., a novel excipient or a noncompendial nonnovel excipient) needs to be provided, where would
it be placed?
A: This information should be included
in 3.2.A.3 Excipients, if required. If only a minimal
amount of information was necessary for these excipients (e.g.,
pharmacopoeial), this information should be provided in
3.2.P.4.1 and/or 3.2.P.2.1.2.
P.4.1 Specifications
P.4.2 Analytical Procedures
P.4.3 Validation of Analytical Procedures
P.4.4 Justification of Specifications
Q1: Where should certificates of
analysis or batch data for excipients be included?
A1: Certificates of analysis or batch data
for excipients should be included in 3.2.P.4.4.
Q2: Can a summary of data from other
sections with a cross-reference to the detailed
information be provided, rather than repeating this information to
support the Justification of Specifications section of
the dossier?
A2: A summary of data from other sections
with a cross-reference to the detailed information can
be provided to support the justification of specification.
P.4.5 Excipients of Human or Animal Origin
Q: Where should information on
excipients of human or animal origin be located?
A: Information on excipients of human or
animal origin should be included in 3.2.P.4.5. Information on
adventitious agent safety evaluation should be included in
3.2.A.2. For the location of certifications relating to TSE/BSE,
see region specific guidance.
P.4.6 Novel Excipients
P.5 Control of Drug Product
P.5.1 Specification(s)
Q1: Where should release and
shelf-life specifications be
located?
A1: Both specifications should be included
in 3.2.P.5.1. (See also question for 3.2.P.8.1)
Q2: If alternative analytical
procedures are used to control the drug product, should
they be listed in the specification (3.2.P.5.1) also?
A2: Any analytical procedure used to
control the drug product, and the associated acceptance
criteria, should be listed in the specification.
P.5.2 Analytical Procedures
Q1: Often an analytical procedure changes during the
development of the drug product. If this analytical procedure is
submitted to support the dossier, in which section should it be
placed?
A1: Information on historical
analytical procedures used to generate data included in the Batch
Analyses section should be included in 3.2.P.5.4.
Q2: Should an analytical procedure
that is only used for stability studies be included in
3.2.P.5.2?
A2: Information on analytical procedures
that are used only for stability studies should be included in
3.2.P.8.3.
Q3: If the analytical methods for a
drug substance and drug product are identical, can these
methods and corresponding validation, if applicable, be described in
either 3.2.S or 3.2.P, with a corresponding reference (e.g., a
reference from 3.2.S to 3.2.P)?
A3: The analytical methods should be
placed in both the relevant sections of 3.2.S and 3.2.P
because the sample preparation, at least, will usually differ.
P.5.3 Validation of Analytical Procedures
P.5.4 Batch Analyses
Q1: Should results from all batches
be provided in 3.2.P.5.4? Should the description of the batches
(e.g., batch number, manufacturing site, use) be included in
3.2.P.5.4?
A1: Results from all relevant batches
(e.g., clinical, nonclinical, stability), including those batches used to justify acceptance criteria, should be
provided in 3.2.P.5.4. Information describing the batches
should also be included in 3.2.P.5.4.
Q2: If there are results from tests
that are not listed in the specifications, where should
they be provided?
A2: If results are submitted from tests
that are not listed in the specification, they should be
provided in 3.2.P.5.4.
Q3: Where should collated data for a
test from multiple batch analyses be presented?
A3: If collated data from batch analyses
are warranted, the data should be presented in
3.2.P.5.4.
P.5.5 Characterization of Impurities
Q1: Should all observed impurities
be listed in 3.2.P.5.5 even if they are not included in the
drug product specification?
A1: All observed impurities should be
listed. Justification for not including an observed impurity in the
specification should be included in 3.2.P.5.6.
P.5.6 Justification of Specification(s)
Q1: Should justification for skip
testing be included in 3.2.P.5.6?
A1: If skip testing is considered
appropriate, the justification should be included in
3.2.P.5.6.
Q2: Can a summary of data from other
sections with a cross-reference to the detailed
information be provided to support the justification of the
specification rather than repeating information?
A2: A summary of data from other sections
with a cross-reference to the detailed information can
be provided to support the justification of specification.
P.6 Reference Standards or Materials
Q: Reference standards might be
available for the active moiety and impurities. Should
information on all reference standards be included in 3.2.P.6?
A: Where considered appropriate, a
reference standard cited in 3.2.S.5 can be cross-referenced in 3.2.P.6. Information on all other reference
standards should be included in 3.2.P.6.
P.7 Container Closure System
P.8 Stability
P.8.1 Stability Summary and Conclusion
Q1: Should the shelf-life
specification be repeated
under this section?
A1: The shelf-life
specification should be
indicated in 3.2.P.8.1.
Q2: Where should the design and
justification for a reduced stability design (e.g.,bracketing or matrixing) be discussed?
A2: The design and justification for a
reduced stability design should be included in
3.2.P.8.3.
P.8.2 Postapproval Stability Protocol and
Stability Commitment
P.8.3 Stability Data
Q1:
Should stress studies be located in 3.2.P.8.3?
A1: Stress studies should be located in
3.2.P.8.3. These data can be referenced for validation
of analytical procedures as considered appropriate.
Q2: Should information on any
changes in analytical procedures over the course of generating stability data be included in 3.2.P.8.3?
A2: Information on historical analytical
procedures used to generate the stability data should also be
included in 3.2.P.8.3.
Q3: Can data from supporting studies
be included in 3.2.P.8.3?
A3: Data from supporting studies can be
included in 3.2.P.8.3, if considered appropriate.
Q4: Should information on analytical
procedures unique to the stability program be presented
in 3.2.P.8.3?
Information on analytical
procedures unique to the stability program should be
included in 3.2.P.8.3
Q5: Where should the statistical
analysis of the stability data be included?
A5: The detailed statistical analysis
report, if included, should go in 3.2.P.8.3, and a
summary or conclusions of the statistical analysis should go in
3.2.P.8.1.
CTD-Q Section 3.2.
A. Appendices
Q1: If
information for both the drug substance and the drug product should
be included in an appendix (e.g., 3.2.A.1), how should
it be presented?
A1: If drug substance and drug product
information is included in the appendices, then the preferred
presentation is drug substance first and then drug product within
each section, for example, 3.2.A.1 (Drug Substance, then Drug
Product), then 3.2.A.2 (Drug Substance, then Drug Product),
then 3.2.A.3 (Drug Substance, if applicable, then Drug Product).
Q2: Should 3.2.A.3 be retitled from
Novel Excipients to Excipients to include noncompendial,
nonnovel excipients?
A2: At ICH, the
title of 3.2.A.3 was changed to Excipients (see 3.2.P.4) to include noncompendial nonnovel excipients.
This guidance was developed
within the M4 CTD-Quality Implementation Working Group of the
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
and has been subject to consultation by the regulatory parties,
in accordance with the ICH process. This document has been
endorsed by the ICH Steering Committee at Step 4 of the
ICH process, July 18, 2003. At Step 4 of the process,
the final draft is recommended for adoption to the regulatory
bodies of the European Union, Japan, and the United States.
Arabic numbers reflect the
organizational breakdown in the document endorsed by the ICH
Steering Committee at Step 4 of the ICH process.
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Date created: June 8, 2004 |