# Common Technical Document---Quality

## Questions and Answers/Location Issues

## Washington D.C. -September 12, 2002

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This draft guidance, when finalized, will represent the Food and Drug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.

# Common Technical Document -- Quality

## Questions and Answers / Location Issues

## Washington D.C. -September 12, 2002

## Table of Contents

1.  **Introduction**

2.  **General Issues**

3.  **Multiple links between different sections**

4.  **Location Issues in Drug Substance: 3.2.S**

5.  **Location Issues in Drug Product: 3.2.P**

**1. Introduction**

This document is intended to give additional guidance for the
preparation of an application file in the CTD-Q format in the applicable
regions. (See under 2. General Issues.) It should be read in conjunction
with the CTD-Q (Modules 2 and 3). It also addresses the relationship
between linked sections for certain parameters like polymorphism,
particle size, etc. (See under 3. Multiple links between different
sections.) This document also clarifies location issues i.e. it
indicates, when information is requested, in which section it should be
addressed. (See under 4. Location Issues in Drug Substance and under 5.
Location Issues in Drug Product.)

This document does not address the content of an application file. Refer
to regional guidances.

**2. General Issues**

**2.1 Definition of a Quality Document**

In deciding whether one or more documents or files are appropriate, it
should be considered that once a particular approach has been adopted,
the same approach should be used throughout the life of the dossier.

Quality documents in either the paper or electronic dossier are defined
as follows:

**Module 2:**

A separate document should be provided for 2.3 Quality Overall Summary
Introduction.

For the following sections of the Quality Overall Summary, the applicant
can has the option to either submit one document with multiple
subheadings and subsection numbering, as defined in the M4Q guidance:

> 2.3.S Drug Substance
>
> 2.3.P Drug Product
>
> 2.3.A Appendices

or submit one document for each of the defined subheadings and
subsections, as follows: e.g.

2.3.S.1 General Information

> 2.3.S.2 Manufacture
>
> 2.3.S.3 Characterization
>
> 2.3.S.4 Control of Drug Substance
>
> 2.3.S.5 Reference Standards or Materials
>
> 2.3.S.6 Container Closure System
>
> 2.3.S.7 Stability
>
> 2.3.P.1 Description and Composition of the Drug Product
>
> 2.3.P.2 Pharmaceutical Development
>
> 2.3.P.3 Manufacture
>
> 2.3.P.4 Control of Excipients
>
> 2.3.P.5 Control of Drug Product
>
> 2.3.P.6 Reference Standards or Materials
>
> 2.3.P.7 Container Closure System
>
> 2.3.P.8 Stability
>
> 2.3.A.1 Facilities and Equipment
>
> 2.3.A.2 Adventitious Agents Safety Evaluation
>
> 2.3.A.3 Excipients

Similarly, the applicant has the option to submit one document or
multiple documents i.e. one document for each subsection, as defined
according to the appropriate regional guidance(s), under 2.3.R Regional
Information.

**Module 3:**

A separate document should be provided for each of the following
sections:

3.2.S.1.1 Nomenclature

> 3.2.S.1.2 Structure
>
> 3.2.S.1.3 General Properties
>
> 3.2.S.2.1 Manufacturer(s)
>
> 3.2.S.2.2 Description of Manufacturing Process and Process Controls
>
> 3.2.S.3.1 Elucidation of Structure and Other Characteristics
>
> 3.2.S.3.2 Impurities
>
> 3.2.S.4.1 Specification
>
> 3.2.S.4.4 Batch Analyses
>
> 3.2.S.4.5 Justification of Specification
>
> 3.2.S.6 Container Closure System
>
> 3.2.S.7.1 Stability Summary and Conclusions
>
> 3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
>
> 3.2.S.7.3 Stability Data
>
> 3.2.P.1 Description and Composition of the Drug Product
>
> 3.2.P.3.1 Manufacturer(s)
>
> 3.2.P.3.2 Batch Formula
>
> 3.2.P.3.3 Description of Manufacturing Process and Process Controls
>
> 3.2.P.3.4 Controls of Critical Steps and Intermediates
>
> 3.2.P.4.5 Excipients of Human or Animal Origin
>
> 3.2.P.4.6 Novel Excipients
>
> 3.2.P.5.1 Specification(s)
>
> 3.2.P.5.4 Batch Analyses
>
> 3.2.P.5.5 Characterisation of Impurities
>
> 3.2.P.5.6 Justification of Specifications
>
> 3.2.P.7 Container Closure System
>
> 3.2.P.8.1 Stability Summary and Conclusion
>
> 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
>
> 3.2.P.8.3 Stability Data

For the following sections, the applicant can submit for each section,
one document or multiple documents, e.g. one for each material, step,
validation study, study report, reference standard or material,
facility, or excipient, as the case may be:

> 3.2.S.2.3 Control of Materials
>
> 3.2.S.2.4 Controls of Critical Steps and Intermediates
>
> 3.2.S.2.5 Process Validation and/or Evaluation
>
> 3.2.S.2.6 Manufacturing Process Development
>
> 3.2.S.4.2 Analytical Procedures
>
> 3.2.S.4.3 Validation of Analytical Procedures
>
> 3.2.S.5 Reference Standards or Materials
>
> 3.2.P.2 Pharmaceutical Development
>
> 3.2.P.3.5 Process Validation and/or Evaluation
>
> 3.2.P.4.1 Specifications

3.2.P.4.2 Analytical Procedures

3.2.P.4.3 Validation of Analytical Procedures

> 3.2.P.4.4 Justification of Specifications
>
> 3.2.P.5.2 Analytical Procedures
>
> 3.2.P.5.3 Validation of Analytical Procedures
>
> 3.2.P.6 Reference Standards or Materials
>
> 3.2.A.1 Facilities and Equipment
>
> 3.2.A.2 Adventitious Agents Safety Evaluation
>
> 3.2.A.3 Excipients
>
> For the Pharmaceutical Development section, one document can be
> provided covering all subsections but an applicant can decide to
> submit several documents in which case, one document should be
> provided for each subsection, namely: 3.2.P.2.1, 3.2.P.2.2, 3.2.P.2.3,
> 3.2.P.2.4, 3.2.P.2.5, and 3.2.P.2.6.

The applicant can submit one document or multiple documents, i.e. one
document for each subsection, as defined according to the appropriate
regional guidance(s), under 3.2.R Regional Information.

Each copy of a literature reference should be submitted as an individual
document under 3.3 Literature References.

**2.2 Document Pagination and Segregation**

[]{.mark}

Every document should be numbered starting at page one, except for
individual literature references, where the existing journal page
numbering is sufficient. It is not considered necessary to display the
number as \'1 of n\' where n is the total number of pages in the
document.

(See **2.1.** **Definition of a Quality Document**.)

Additionally, all pages of a document should include a unique header or
footer which briefly identifies its subject matter. In a paper-based
drug submission, this same identifier should be used on a tab that
precedes the document, to facilitate finding that document within the
dossier.

If a section contains more than one document, a specific Table of
Contents for that section can be included to identify the chronology and
titles of the documents contained therein. e.g.

-   Tab with "3.2.S.4.2 Analytical Procedures"

    -   Table of Contents, listing the title of Procedure A, Procedure
        B, Procedure C

-   Tab with "3.2.S.4.2 "Procedure A";

    -   Procedure A (i.e. document, page 1-n)

-   Tab with "3.2.S.4.2 "Procedure B";

    -   Procedure B (i.e. document, page 1-n)

-   Tab with "3.2.S.4.2 "Procedure C";

    -   Procedure C (i.e. document, page 1-n)

If a section contains only a single document (e.g. 3.2.S.1.1
Nomenclature), only a tab identified by "3.2.S.1.1 Nomenclature" should
precede the document.

**2.3 Table of Contents Formatting**

**Module 2:**

The 2.1 CTD Table of Contents should go down to the third (e.g. 2.3.S)
or fourth (e.g. 2.3.S.1) level, depending on how a document is defined
for the Quality Overall Summary. (See **2.1** **Definition of a Quality
Document**.)

**Module 3:**

The Table of Contents provided under 3.1 should cover the high-level
section numbering, the associated section heading, and Volume number, in
the order that they appear in the drug submission. This Table of
Contents would be used to identify the contents of Module 3 as defined
in the M4Q guidance. It should go down to the fifth level only (e.g.
3.2.P.2.1). Note that additional subsections and subheadings are defined
in the M4Q guidance beyond this level (e.g. under 3.2.P.2) and this
formatting should be used within the dossier, despite not being stated
in the 3.1 Table of Contents. The lower level Table of Contents
described under **2.3** **Document Pagination and Segregation** should
be excluded from the 3.1 Table of Contents.

At the applicant's discretion, a Table of Contents can also be included
for a particular section that contains multiple documents, in order to
identify the chronology and the document subject matter. If there is a
desire to introduce additional headers or subsection numbering beyond
those which are defined in the M4Q guidance, these should only be
included within a document and should not created as a separate document
nor as a new subsection. In this case, a specific Table of Contents for
that document can be included to identify the chronology and titles of
the subsections contained therein. These documents and subsections
should not appear in the 3.1 Table of Contents.

Furthermore, additional attachments or appendices should not be
incorporated into this formatting, except as a document under a section
where multiple documents might be provided. In this case, a
cross-reference should be made within the relevant section to the
attached or appended document. If there is a desire to append or attach
additional information to a section that is comprised of only one
document, this information should be incorporated within that document.

All Table of Contents title entries should either correspond to heading
names and section numbering as defined in the M4Q guidance or to
identifiers appearing on tabs (for a paper-based drug submission only),
preferably by their full title, which should easily identify any
abbreviated title which might be used on the corresponding tab. The
Table of Contents should not specify any page numbers.

Literature References should be listed in a Table of Contents specific
for this section.

**2.4 When can separate or repeated sections be appropriate?**

There can be a number of instances where repeated sections can be
appropriate. Whenever a section is repeated, it should be made clear
what the section refers to by creating a title in parentheses following
the CTD 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 it can
be appropriate and logical to have information presented separately for
a single drug substance. For example, separate sections can be warranted
when a single drug substance is made by two significantly different
manufacturers or manufacturing processes. However, it is more likely
that these different processes will be described within the relevant
sub-section of 3.2.S. If the different manufacturing processes also
refer to, for example, different specifications, then repeating the
whole of the drug substance section is recommended.

**Drug Product**

Depending on regional requirements, different product presentations
(e.g., strengths, container closure configurations, formulations) and/or
manufacturing schemes (e.g., aseptic and terminal sterilization) can be
submitted in the same dossier. In general, when a single dossier can be
submitted, information for each of the product presentations and
manufacturing schemes should be combined and presented together in one P
section with information provided in the Appendices, and Regional
Information sections for each of the product presentations and
manufacturing schemes, 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 P section. The majority of
the quality information would be identical for the two products. The
information that differs between the two would be presented together in
the appropriate subsections (e.g., P.7 Container Closure System, P.8
Stability), but would be physically or electronically separated within
the subsection.

However, there can be cases when it is more appropriate and logical to
have information presented separately for product presentations or
manufacturing schemes that can be included in a single dossier.
Information presented separately means one complete P section followed
by other complete P sections. One such example is that information on
the drug product and reconstitution diluent should be presented in
separate P sections for a drug product supplied with a reconstitution
diluent. These could be titled 3.2.P. (Drug Product) and 3.2.P.
(Diluent).

**Excipients**

If appropriate, where a novel or noncompendial non-novel excipient is
proposed, the guidance asks for an Appendix (3.2.A.3) that repeats the
format of the drug substance section. It is recommended that the
granularity of this Appendix should be the same as the granularity of
the drug substance section. In order to assist the construction of the
e-CTD, a Data Type Definition (DTD) will be created that replicates the
drug substance granularity. There should be a complete section for each
novel excipient.

**Appendices**

There can be occasions where it is appropriate to repeat an Appendix. An
example would be 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
harmonised. In this section the documents, their titling and their order
should be consistent with the requirements of the region.

**2.5 Multiple containers and multiple strengths**

*There are two containers (PVC blister and PE bottle) for one drug
product. The documents for the drug product part in Module 3 are
therefore common. Different documents would have to be presented in
sections 3.2.P.7 (container closure system) and 3.2.P.8 (stability).*

Should full document sets (P1-P8) for both PVC blister and PE bottle be
submitted? A similar question would apply for the documents in the case
of different package sizes (e.g., 25 tablets, 50 tablets and 1000
tablets in the same container)?

No duplication is necessary. One set of documentation 3.2.P.1 - 3.2.P.8
is needed per one drug product. The information for the blister and the
bottle should be presented in the corresponding sections and where
relevant (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.

**2.6 Bioanalytical Methods**

*In the Common Technical Document, under what section should
bioanalytical methods and their associated validation reports be
included?*

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.

**2.7 Drug Master Files**

*Can the Drug Master File use the CTD format?*

Since the DMF systems differ in the three regions, the ICH guidelines do
not address this issue. Consequently, the applicant should check with
the relevant competent authority in the regions.

**3. Multiple links between different sections**

Below, examples of multiple references in CTD-Q are proposed. It
indicates for some parameters that the information is not necessarily
located in one section but needs to be split into different sections.

## 3.1 Polymorphism 

*How is information on polymorphism submitted?*

> **3.2.S.1.3** If necessary, list the polymorphic form that is present
> in the proposed
>
> active (may be one or more) as characteristics of the drug substance.
>
> **3.2.S.2.2** Description of manufacturing process and process control
>
> Indicates which polymorphic form is synthesised.
>
> **3.2.S.3.1** Studies performed to identify the potential polymorphic
> forms of the
>
> drug substance. Total number of polymorphs should be listed here and
>
> those intended to form the active should be summarised in 3.2.S.1.3.
>
> **3.2.S.4.1** Specification. If polymorph(s) needs to be defined or
> limited, it will
>
> appear 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 analysis
>
> **3.2.S.4.5** Justification of specification (if needed). Reasons why
> a particular limit
>
> on form is appropriate (will also refer probably to 3.2.P.2)
>
> **3.3.P.5.1** Specification. If polymorphism needs to be controlled in
> the drug
>
> product, it will appear here.
>
> **3.2.P.5.6** Justification of specification (if needed).
>
> **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 Particle size**
>
> *How is information on the particle size for the drug substance
> submitted?*

**3.2.S.2.2** Description of manufacturing process and process control

**3.2.S.4.1.** Specification

**3.2.S.4.2** Analytical procedures

**3.2.S.4.3 V**alidation of analytical procedures

**3.2.S.4.4** Results of batch analysis

**3.2.S.4.5** Justification of specification

> **3.2.P.2.1.1 and 3.2.P.2.2.1**
>
> Identify the influence on particle size on for instance dissolution
>
> performance (Q6A decision tree).

3.  **New Location of Quality Information on Investigational
    Formulations**

*How does the CTD link information on drug substance batch numbers, drug
product batch numbers, nonclinical and clinical study numbers, the
levels of impurities, and history of formulation development? Please
clarify the assignment of this information to the nonclinical and
clinical sections.*

> The history of formulation development should be included in Module
> 3.2.P.2.2.1. A description of batches and the result of batches
> analyses for the drug product should be included in Module 3.2.P.5.4.
>
> The history of development for the drug substance should be included
> in Module 3.2.S.2.6. A description of batches and the result of
> batches analyses should be included in Module 3.2.S.4.4.
>
> This information can also be linked to impurity levels of batches
> described in 3.2.P.5.5 and 3.2.S.3.2.
>
> Appropriate references to Modules 4 and 5 for the nonclinical and
> clinical studies can also be made.

**4. Location Issues in Drug Substance**

+--------+---------------+---------------------------------------------+
| ## C   | **Issues /    | **Answers**                                 |
| TD-Q S | Questions**   |                                             |
| ection |               |                                             |
+========+===============+=============================================+
| **S 1. |               |                                             |
| G      |               |                                             |
| eneral |               |                                             |
| I      |               |                                             |
| nforma |               |                                             |
| tion** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    |               |                                             |
| 1.1    |               |                                             |
| No     |               |                                             |
| mencla |               |                                             |
| ture** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | Should        | Drawings to show secondary and tertiary     |
| 1.2    | drawings to   | structures and if applicable, quaternary    |
| Struc  | show          | structures should be provided in 3.2.S.3.1. |
| ture** | secondary and |                                             |
|        | tertiary      |                                             |
|        | structures    |                                             |
|        | and if        |                                             |
|        | applicable,   |                                             |
|        | quaternary    |                                             |
|        | structures of |                                             |
|        | proteins be   |                                             |
|        | provided in   |                                             |
|        | 3.2.S.1.2?    |                                             |
+--------+---------------+---------------------------------------------+
| **S    | How much      | As per CTD-Q, a list of physicochemical and |
| 1.3    | detailed      | other relevant properties (e.g., biological |
| G      | information   | activity) should be included in 3.2.S.1.3.  |
| eneral | on the        | The information on general properties       |
| Proper | general       | should be provided only for the form of the |
| ties** | properties of | drug substance used in the drug product,    |
|        | the drug      | not possible alternative forms (e.g.,       |
|        | substance     | polymorphs). More detailed information on   |
|        | should be     | the properties of the drug substance,       |
|        | included in   | including possible alternative forms,       |
|        | 3.2.S.1.3?    | should be included in 3.2.S.3.1.            |
+--------+---------------+---------------------------------------------+
| **S 2. |               |                                             |
| M      |               |                                             |
| anufac |               |                                             |
| ture** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    |               |                                             |
| 2.1    |               |                                             |
| Ma     |               |                                             |
| nufact |               |                                             |
| urer** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | Should        | All process controls should be identified   |
| 2.2    | information   | in 3.2.S.2.2. For critical controls,        |
| Descr  | on process    | additional information should be provided   |
| iption | controls be   | in 3.2.S.2.4.                               |
| of the | provided in   |                                             |
| M      | section       |                                             |
| anufac | 3.2.S.2.2 or  |                                             |
| turing | 3.2.S.2.4?    |                                             |
| p      |               |                                             |
| rocess |               |                                             |
| and    |               |                                             |
| P      |               |                                             |
| rocess |               |                                             |
| Cont   |               |                                             |
| rols** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  Should    | 1.  Yes. The discussion and justification   |
| 2.3    |     the       |     of starting materials should be         |
| C      |               |     included in 3.2.S.2.3.                  |
| ontrol |    discussion |                                             |
| of     |     and       | 2.  The analytical procedures for the       |
| Mater  |               |     control of materials (e.g., starting    |
| ials** | justification |     materials, reagents, raw materials,     |
|        |     of        |     solvents) should be presented in        |
|        |     starting  |     section S.2.3. For materials of         |
|        |     materials |     biological origin, analytical           |
|        |     be        |     procedures related to adventitious      |
|        |     included  |     agent safety evaluation should be       |
|        |     in        |     presented in 3.2.A.2, if applicable.    |
|        |               |                                             |
|        |    3.2.S.2.3? |                                             |
+--------+---------------+---------------------------------------------+
|        | 2.  Where     |                                             |
|        |     should    |                                             |
|        |               |                                             |
|        |    analytical |                                             |
|        |               |                                             |
|        |    procedures |                                             |
|        |     for       |                                             |
|        |     materials |                                             |
|        |     described |                                             |
|        |     in        |                                             |
|        |     3.2.S.2.3 |                                             |
|        |     be        |                                             |
|        |     included? |                                             |
+--------+---------------+---------------------------------------------+
| **S    | []{.mark}     | []{.mark}                                   |
| 2.4    |               |                                             |
| C      |               |                                             |
| ontrol |               |                                             |
| of     |               |                                             |
| Cr     |               |                                             |
| itical |               |                                             |
| Steps  |               |                                             |
| and    |               |                                             |
| Int    |               |                                             |
| ermedi |               |                                             |
| ates** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | Where should  | If justification for reprocessing is        |
| 2.5    | justification | warranted by a regional authority, the      |
| P      | for           | information would be included as part of    |
| rocess | reprocessing  | the description of the manufacturing        |
| Vali   | be included?  | process in 3.2.S.2.2. If there are critical |
| dation |               | controls associated with the reprocessing   |
| and /  |               | operation the critical controls should be   |
| or     |               | included in 3.2.S.2.4 and if validation     |
| evalua |               | information is warranted the validation     |
| tion** |               | information should be included in           |
|        |               | 3.2.S.2.5.                                  |
+--------+---------------+---------------------------------------------+
| **S    | Should        | Reports of Bioavailability / Bioequivalence |
| 2.6    | bi            | studies that demonstrate comparability      |
| M      | oavailability | after process changes should be presented   |
| anufac | /             | in Module 5. Cross references to these      |
| turing | b             | reports should be placed into section       |
| P      | ioequivalence | 3.2.P.2.2.1 in the case of a process change |
| rocess | study results | for the drug product manufacture or in      |
| D      | that          | 3.2.S.2.6 in the case of a process change   |
| evelop | demonstrate   | for the drug substance manufacturing. A     |
| ment** | product       | brief summary of the reports can be placed  |
|        | comparability | in these sections when considered           |
|        | following     | appropriate.                                |
|        | process       |                                             |
|        | changes, be   |                                             |
|        | described in  |                                             |
|        | 3.2.S.2.6 ?   |                                             |
+--------+---------------+---------------------------------------------+
| **S 3. |               |                                             |
| Charac |               |                                             |
| terisa |               |                                             |
| tion** |               |                                             |
+--------+---------------+---------------------------------------------+

+--------+---------------+---------------------------------------------+
| **S    | Where should  | Information on the studies conducted to     |
| 3.1    | studies       | determine the physicochemical               |
| Eluci  | conducted to  | characteristics should be included in       |
| dation | determine the | 3.2.S.3.1. Only a list of the general       |
| of     | ph            | properties of the drug substance is         |
| Struc  | ysicochemical | included in 3.2.S.1.3.                      |
| ture** | ch            |                                             |
|        | aracteristics |                                             |
|        | be included?  |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  Should    | 1.  Yes. Such information should be         |
| 3.2    |               |     included in 3.2.S.3.2                   |
| Impuri |    structural |                                             |
| ties** |     cha       | 2.  ICH Q3A identifies the chromatograms as |
|        | racterisation |     part of the analytical validation       |
|        |     data and  |     studies. Therefore, relevant            |
|        |     a summary |     chromatograms should be included in     |
|        |     of the    |     3.2.S.4.3.                              |
|        |     method of |                                             |
|        |               | 3.  The qualified level of each impurity    |
|        |   preparation |     with cross-reference to the supporting  |
|        |     of        |     nonclinical/clinical studies should be  |
|        |               |     included in 3.2.S.3.2.                  |
|        |    impurities |                                             |
|        |     be        | 4.  Data on all observed impurities on      |
|        |     included  |     relevant batches (e.g., clinical,       |
|        |     in        |     nonclinical, stability) should be       |
|        |               |     provided in 3.2.S.4.4. The data should  |
|        |    3.2.S.3.2? |     be provided whether or not the impurity |
|        |               |     is included in the specification. This  |
|        | 2.  Where     |     information can be cross referenced to  |
|        |     should    |     support other sections of the dossier   |
|        |     relevant  |     as appropriate.                         |
|        |               |                                             |
|        | chromatograms |                                             |
|        |     be        |                                             |
|        |     provided  |                                             |
|        |     for       |                                             |
|        |               |                                             |
|        |   impurities? |                                             |
|        |               |                                             |
|        | 3.  Where     |                                             |
|        |     should    |                                             |
|        |               |                                             |
|        |   nonclinical |                                             |
|        |     and       |                                             |
|        |     clinical  |                                             |
|        |     data      |                                             |
|        |               |                                             |
|        |    supporting |                                             |
|        |     impurity  |                                             |
|        |     levels be |                                             |
|        |               |                                             |
|        |   summarised? |                                             |
|        |               |                                             |
|        | 4.  Should    |                                             |
|        |     data on   |                                             |
|        |               |                                             |
|        |    impurities |                                             |
|        |     reported  |                                             |
|        |     in batch  |                                             |
|        |     analyses  |                                             |
|        |     be        |                                             |
|        |     included  |                                             |
|        |     in        |                                             |
|        |     3.2.S.3.2 |                                             |
|        |     or        |                                             |
|        |               |                                             |
|        |    3.2.S.4.4? |                                             |
+--------+---------------+---------------------------------------------+
|        |               |                                             |
+--------+---------------+---------------------------------------------+
| **S 4. |               |                                             |
| C      |               |                                             |
| ontrol |               |                                             |
| of     |               |                                             |
| Drug   |               |                                             |
| Subst  |               |                                             |
| ance** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  If there  | 1.  When appropriate, more than one         |
| 4.1    |     are       |     specification sheet should be included  |
| Spec   |     different |     in 3.2.S.4.1.                           |
| ificat |               |                                             |
| ions** | specification | 2.  Any analytical procedure used to        |
|        |     sheets    |     control the drug substance, and the     |
|        |     for a     |     associated acceptance criteria, should  |
|        |     drug      |     be listed in the specification.         |
|        |     substance |                                             |
|        |               |                                             |
|        | manufacturer, |                                             |
|        |     drug      |                                             |
|        |     product   |                                             |
|        |               |                                             |
|        |  manufacturer |                                             |
|        |     and/or    |                                             |
|        |               |                                             |
|        |    applicant, |                                             |
|        |     should    |                                             |
|        |     they all  |                                             |
|        |     be        |                                             |
|        |     provided  |                                             |
|        |     in        |                                             |
|        |               |                                             |
|        |    3.2.S.4.1? |                                             |
|        |               |                                             |
|        | 2.  If        |                                             |
|        |               |                                             |
|        |    regulatory |                                             |
|        |     and       |                                             |
|        |               |                                             |
|        |   alternative |                                             |
|        |               |                                             |
|        |    analytical |                                             |
|        |               |                                             |
|        |    procedures |                                             |
|        |     are used  |                                             |
|        |     to        |                                             |
|        |     control   |                                             |
|        |     the drug  |                                             |
|        |     substance |                                             |
|        |     should    |                                             |
|        |     they both |                                             |
|        |     be listed |                                             |
|        |     in the    |                                             |
|        |               |                                             |
|        | specification |                                             |
|        |               |                                             |
|        |  (3.2.S.4.1)? |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  Often     | 1\. Information on historical analytical    |
| 4.2    |     times an  | procedures used to generate data included   |
| Anal   |               | in the batch analyses should be included in |
| ytical |    analytical | 3.2.S.4.4                                   |
| Proced |     procedure |                                             |
| ures** |     has       | 2\. No. Information on analytical           |
|        |     changed   | procedures that are used only for stability |
|        |     during    | studies should be included in 3.2.S.7.3.    |
|        |     the       |                                             |
|        |               |                                             |
|        |   development |                                             |
|        |     of the    |                                             |
|        |     drug      |                                             |
|        |               |                                             |
|        |    substance. |                                             |
|        |     If this   |                                             |
|        |               |                                             |
|        |    analytical |                                             |
|        |     procedure |                                             |
|        |     should be |                                             |
|        |     submitted |                                             |
|        |     to        |                                             |
|        |     support   |                                             |
|        |     the       |                                             |
|        |     dossier   |                                             |
|        |     in which  |                                             |
|        |     section   |                                             |
|        |     would     |                                             |
|        |     these     |                                             |
|        |               |                                             |
|        |    analytical |                                             |
|        |               |                                             |
|        |    procedures |                                             |
|        |     be        |                                             |
|        |     placed?   |                                             |
|        |               |                                             |
|        | 2.  Should an |                                             |
|        |               |                                             |
|        |    analytical |                                             |
|        |     procedure |                                             |
|        |     that is   |                                             |
|        |     only used |                                             |
|        |     for       |                                             |
|        |     stability |                                             |
|        |     studies   |                                             |
|        |     be        |                                             |
|        |     included  |                                             |
|        |     in        |                                             |
|        |               |                                             |
|        |    3.2.S.4.2? |                                             |
+--------+---------------+---------------------------------------------+
| **S    |               |                                             |
| 4.3    |               |                                             |
| Vali   |               |                                             |
| dation |               |                                             |
| of     |               |                                             |
| Anal   |               |                                             |
| ytical |               |                                             |
| Proced |               |                                             |
| ures** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  Should    | 1.  Results from all relevant batches       |
| 4.4    |     results   |     (e.g., clinical, nonclinical,           |
| Batch  |     from all  |     stability), which include those batches |
| Anal   |     batches   |     used to justify acceptance criteria,    |
| yses** |     be        |     should be provided in 3.2.S.4.4.        |
|        |     provided  |                                             |
|        |     in        | 2.  Yes, all data from relevant batches     |
|        |               |     should be reported in 3.2.S.4.4.        |
|        |    3.2.S.4.4? |                                             |
|        |               | 3.  If collated data from batch analyses is |
|        | 2.  Should    |     warranted, the data should be presented |
|        |     all tests |     in 3.2.S.4.4.                           |
|        |     performed |                                             |
|        |     be        |                                             |
|        |     reported  |                                             |
|        |     even if   |                                             |
|        |     not       |                                             |
|        |     included  |                                             |
|        |     in the    |                                             |
|        |     s         |                                             |
|        | pecification? |                                             |
|        |               |                                             |
|        | 3.  Where     |                                             |
|        |     should    |                                             |
|        |     collated  |                                             |
|        |     data for  |                                             |
|        |     a test    |                                             |
|        |     from      |                                             |
|        |     multiple  |                                             |
|        |     batch     |                                             |
|        |     analyses  |                                             |
|        |     be        |                                             |
|        |               |                                             |
|        |    presented? |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  Should    | 1.  Yes. If skip testing is appropriate,    |
| 4.5    |               |     the justification should be included in |
| J      | justification |     3.2.S.4.5                               |
| ustifi |     for skip  |                                             |
| cation |     testing   | 2.  Yes. A summary of data from other       |
| of     |     be        |     sections with a cross-reference to the  |
| Spe    |     included  |     detailed information can be provided to |
| cifica |     in        |     support the justification of            |
| tion** |               |     specification.                          |
|        |    3.2.S.4.5? |                                             |
|        |               |                                             |
|        | 2.  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   |                                             |
|        |     rather    |                                             |
|        |     than      |                                             |
|        |     repeating |                                             |
|        |               |                                             |
|        |  information? |                                             |
+--------+---------------+---------------------------------------------+
| **S 5  | 1.  Reference | 1.  If information is required for a        |
| Ref    |     standards |     reference standard, the information     |
| erence |     may be    |     should be included in 3.2.S.5.          |
| Sta    |     available |                                             |
| ndards |     for the   | 2.  Characterisation data for the reference |
| or     |     active    |     standard should be included in 3.2.S.5. |
| Mater  |     moiety    |     Cross reference to information in other |
| ials** |     and       |     sections (e.g., 3.2.S.3.2) can be       |
|        |               |     included as appropriate.                |
|        |   impurities. |                                             |
|        |     Should    |                                             |
|        |               |                                             |
|        |   information |                                             |
|        |     on all    |                                             |
|        |     reference |                                             |
|        |     standards |                                             |
|        |     be        |                                             |
|        |     included  |                                             |
|        |     in        |                                             |
|        |     3.2.S.5?  |                                             |
|        |               |                                             |
|        | 2.  Where     |                                             |
|        |     should    |                                             |
|        |     cha       |                                             |
|        | racterisation |                                             |
|        |     data for  |                                             |
|        |     a         |                                             |
|        |     reference |                                             |
|        |     standard  |                                             |
|        |     be placed |                                             |
|        |     in the    |                                             |
|        |     CTD-Q.    |                                             |
+--------+---------------+---------------------------------------------+
| **S 6  |               |                                             |
| Con    |               |                                             |
| tainer |               |                                             |
| C      |               |                                             |
| losure |               |                                             |
| Sy     |               |                                             |
| stem** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S 7. |               |                                             |
| Stabi  |               |                                             |
| lity** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    |               |                                             |
| 7.1    |               |                                             |
| Sta    |               |                                             |
| bility |               |                                             |
| S      |               |                                             |
| ummary |               |                                             |
| and    |               |                                             |
| C      |               |                                             |
| onclus |               |                                             |
| ions** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    |               |                                             |
| 7.2    |               |                                             |
| P      |               |                                             |
| ost-ap |               |                                             |
| proval |               |                                             |
| Sta    |               |                                             |
| bility |               |                                             |
| Pr     |               |                                             |
| otocol |               |                                             |
| and    |               |                                             |
| Sta    |               |                                             |
| bility |               |                                             |
| Commit |               |                                             |
| ment** |               |                                             |
+--------+---------------+---------------------------------------------+
| **S    | 1.  Should    | 1.  Yes. Stress studies should be located   |
| 7.3    |     stress    |     in 3.2.S.7.3. These data can be         |
| Sta    |     studies   |     referenced for validation of analytical |
| bility |     be        |     procedures as needed.                   |
| Data** |     located   |                                             |
|        |     in        | 2.  Information on historical analytical    |
|        |               |     procedures used to generate the         |
|        |    3.2.S.7.3? |     stability data included in 3.2.S.7.3.   |
|        |               |     should be included in 3.2.S.7.3.        |
|        | 2.  Should    |                                             |
|        |               | 3.  Yes data from supporting studies can be |
|        |   information |     included in 3.2.S.7.3, if appropriate   |
|        |     on any    |                                             |
|        |     changes   | 4.  Information on analytical procedures    |
|        |     in        |     unique to the stability program should  |
|        |               |     be included in 3.2.S.7.3.               |
|        |    analytical |                                             |
|        |               |                                             |
|        |    procedures |                                             |
|        |     over the  |                                             |
|        |     course of |                                             |
|        |               |                                             |
|        |    generating |                                             |
|        |     stability |                                             |
|        |     data be   |                                             |
|        |     included  |                                             |
|        |     in        |                                             |
|        |               |                                             |
|        |    3.2.S.7.3? |                                             |
|        |               |                                             |
|        | 3.  Can data  |                                             |
|        |     from      |                                             |
|        |               |                                             |
|        |    supporting |                                             |
|        |     studies   |                                             |
|        |     be        |                                             |
|        |     included  |                                             |
|        |     in        |                                             |
|        |     3.2.      |                                             |
|        | S.7.3QUESTION |                                             |
|        |     MARK      |                                             |
|        |               |                                             |
|        | 4.  Should    |                                             |
|        |               |                                             |
|        |   information |                                             |
|        |     on        |                                             |
|        |               |                                             |
|        |    analytical |                                             |
|        |               |                                             |
|        |    procedures |                                             |
|        |     unique to |                                             |
|        |     the       |                                             |
|        |     stability |                                             |
|        |     program   |                                             |
|        |     be        |                                             |
|        |     presented |                                             |
|        |     in        |                                             |
|        |               |                                             |
|        |    3.2.S.7.3? |                                             |
+--------+---------------+---------------------------------------------+
| **A    | If            | If drug substance and drug product          |
| Append | information   | information is included in the appendices   |
| ices** | for both the  | then the preferred presentation is DS first |
|        | drug          | and then DP within each section. For        |
|        | substance and | example A.1 (drug substance then drug       |
|        | the drug      | product) then A.2.                          |
|        | product       |                                             |
|        | should be     |                                             |
|        | included in   |                                             |
|        | an appendix   |                                             |
|        | A.1, how      |                                             |
|        | should it be  |                                             |
|        | presented?    |                                             |
+--------+---------------+---------------------------------------------+
| **R    |               |                                             |
| Re     |               |                                             |
| gional |               |                                             |
| I      |               |                                             |
| nforma |               |                                             |
| tion** |               |                                             |
+--------+---------------+---------------------------------------------+

5.  **Location Issues in Drug Product**

+----------+---------------+-------------------------------------------+
| > **CTD- | > **Issues /  | > **Answers**                             |
| > Q      | > Questions** |                                           |
| > S      |               |                                           |
| ection** |               |                                           |
+==========+===============+===========================================+
| > **P 1  | > 1\. Where   | 1.  All drug product components should be |
| > Des    | > should      |     listed in 3.2.P.1. The composition    |
| cription | > information |     (e.g. components of the capsule       |
| > and    | > related to  |     shell, components of inks) should be  |
| > Com    | > the         |     included in 3.2. P.1 also. In some    |
| position | > composition |     regions the qualitative composition   |
| > of     | > of inks     |     of proprietary components can be      |
| > DP**   | > used on the |     replaced with reference to            |
|          | > drug        |     appropriate DMFs.                     |
|          | > product be  |                                           |
|          | > placed?     | 2.  If the diluent is co-packaged with    |
|          | >             |     the drug product, the information on  |
|          | > 2\. Where   |     the diluent should be placed in a     |
|          | > should      |     separate P section. If not            |
|          | > information |     co-packaged, the compatibility of the |
|          | > on          |     diluent with the drug product should  |
|          | > r           |     be discussed in 3.2.P.2.6.            |
|          | econstitution |                                           |
|          | > diluents be | 3.  Yes the use of an overfill should     |
|          | > included?   |     indicated in 3.2.P.1. The rationale   |
|          | >             |     for an overfill should be included in |
|          | > 3\. Should  |     3.2. P.2.2.1 (Formulation             |
|          | > an overfill |     Development).                         |
|          | > be          |                                           |
|          | > indicated   | 4.  As needed additional information can  |
|          | > in 3.2.P.1? |     be included to adequately describe    |
|          | >             |     the composition of the drug product   |
|          | > 4 Can       |     such as (1) total weight, volume,     |
|          | > information |     etc. of unit, (2) tracers or          |
|          | > on the      |     markers, (3) composition statement    |
|          | > composition |     for (purchased) mixtures, and (4)     |
|          | > of drug     |     capsule shells.                       |
|          | > product,    |                                           |
|          | > other than  |                                           |
|          | > what is     |                                           |
|          | > listed in   |                                           |
|          | > CTD-Q, be   |                                           |
|          | > included in |                                           |
|          | > 3.2.P.1?    |                                           |
+----------+---------------+-------------------------------------------+
| > **P 2  |               |                                           |
| > Pharma |               |                                           |
| ceutical |               |                                           |
| > Devel  |               |                                           |
| opment** |               |                                           |
+----------+---------------+-------------------------------------------+
| ## P 2   | 1.  Where     | 1.  There should be a separate P section  |
| .1 Compo |     should    |     for co-packaged diluents. Choice and  |
| sition o |               |     development of co-packaged diluents   |
| f the DP |   information |     should be included I n3.2. P.2.2.1).  |
|          |     on the    |                                           |
| > **P    |               | 2.  Drug substance stability data should  |
| > 2.1.1  |   development |     be included in 3.2.S.7 and            |
| > Drug   |     of        |     cross-referenced as needed in3.2. P.2 |
| > Sub    |               |     as appropriate. Discussion of key     |
| stance** |   co-packaged |     drug substance physicochemical        |
| >        |     diluents  |     characteristics that can influence    |
| > **P    |     be placed |     manufacturability of the drug product |
| > 2.1.2  |     ?         |     should be included in 3.2.P.2.1.1).   |
| > Exci   |               |                                           |
| pients** | 2.  Where     | 3.  Discussion of effect of modification  |
|          |     should a  |     of active moiety (e.g., salt) on key  |
|          |               |     drug substance physicochemical        |
|          |    discussion |     characteristics be provided should be |
|          |     of the    |     included in3.2.P.2.1.1 .              |
|          |     drug      |                                           |
|          |     substance | 4.  Data from studies on drug product to  |
|          |     stability |     evaluate the potential effect of key  |
|          |     or key    |     drug substance physicochemical        |
|          |     ph        |     characteristics should be provided in |
|          | ysicochemical |     3.2.P.2.1.1 \[e.g., Q6A Decision      |
|          |     ch        |     Trees 3 and 4 (Part 2)\]              |
|          | aracteristics |                                           |
|          |     which     | 5.  Justification for using an excipient  |
|          |     might     |     if there is evidence of               |
|          |     influence |     incompatibility should be included in |
|          |     the       |     3.2.P.2.1.1                           |
|          |               |                                           |
|          | manufacturing | 6.  Discussion of excipients that can     |
|          |     process   |     influence manufacturability of drug   |
|          |     of the    |     product should be included in         |
|          |     drug      |     3.2.P.2.1.2.                          |
|          |     product   |                                           |
|          |     be        | 7.  Discussion of ability of functional   |
|          |     provided? |     excipients to perform though          |
|          |               |     shelf-life (e.g., antioxidants,       |
|          | 3.  Where     |     penetration enhancers) should be      |
|          |     should a  |     included in 3.2. P.2.1.2.             |
|          |               |                                           |
|          |    discussion |                                           |
|          |     of the    |                                           |
|          |     effect of |                                           |
|          |               |                                           |
|          |  modification |                                           |
|          |     of active |                                           |
|          |     moiety    |                                           |
|          |     (e.g.,    |                                           |
|          |     salt) on  |                                           |
|          |     key drug  |                                           |
|          |     substance |                                           |
|          |     ph        |                                           |
|          | ysicochemical |                                           |
|          |     ch        |                                           |
|          | aracteristics |                                           |
|          |     be        |                                           |
|          |     provided? |                                           |
|          |               |                                           |
|          | 4.  Where     |                                           |
|          |     should    |                                           |
|          |     data from |                                           |
|          |     studies   |                                           |
|          |     on drug   |                                           |
|          |     product   |                                           |
|          |     to        |                                           |
|          |     evaluate  |                                           |
|          |     the       |                                           |
|          |     potential |                                           |
|          |     effect of |                                           |
|          |     key drug  |                                           |
|          |     substance |                                           |
|          |     ph        |                                           |
|          | ysicochemical |                                           |
|          |     ch        |                                           |
|          | aracteristics |                                           |
|          |     be        |                                           |
|          |     provided? |                                           |
|          |               |                                           |
|          | 5.  Should    |                                           |
|          |               |                                           |
|          | justification |                                           |
|          |     for using |                                           |
|          |     an        |                                           |
|          |     excipient |                                           |
|          |     if there  |                                           |
|          |     is        |                                           |
|          |     evidence  |                                           |
|          |     of        |                                           |
|          |     in        |                                           |
|          | compatibility |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |   3.2.P.2.1.1 |                                           |
|          |     or        |                                           |
|          |               |                                           |
|          |  3.2.P.2.1.2? |                                           |
|          |               |                                           |
|          | 6.  Where     |                                           |
|          |     should a  |                                           |
|          |               |                                           |
|          |    discussion |                                           |
|          |     of an     |                                           |
|          |               |                                           |
|          |    excipients |                                           |
|          |     influence |                                           |
|          |     on the    |                                           |
|          |     manu      |                                           |
|          | facturability |                                           |
|          |     of the    |                                           |
|          |     drug      |                                           |
|          |     product   |                                           |
|          |     be        |                                           |
|          |     included? |                                           |
|          |               |                                           |
|          | 7.  Where     |                                           |
|          |     should a  |                                           |
|          |               |                                           |
|          |    discussion |                                           |
|          |     of the    |                                           |
|          |     ability   |                                           |
|          |     of a      |                                           |
|          |               |                                           |
|          |    functional |                                           |
|          |     excipient |                                           |
|          |     to        |                                           |
|          |     perform   |                                           |
|          |     through   |                                           |
|          |     shelf     |                                           |
|          |     life be   |                                           |
|          |     included? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | > 1\. Where   | > 1\. Tables describing different         |
| > 2.2    | > should      | > development formulations should be      |
| > Des    | > tables that | > included in3.2.P.2.2.1 .                |
| cription | > describe    |                                           |
| > of the | > the         |                                           |
| > Mfg    | > composition |                                           |
| >        | > of          |                                           |
|  Process | >             |                                           |
| > and    |  formulations |                                           |
| >        | > used in     |                                           |
|  Process | > development |                                           |
| > Co     | > studies be  |                                           |
| ntrols** | > included?   |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Where     | 1.  Summarised information on the IVIV    |
| > 2.2.1  |     should    |     correlation should be included in     |
| > For    |               |     3.2.P.2.2.1 with inclusion of a cross |
| mulation |   information |     reference the studies in Module 5.    |
| > Devel  |     on IVIV   |                                           |
| opment** |               | 2.  Cross-referencing to both Modules 2   |
|          |   correlation |     and 5 ,can be included to facilitate  |
|          |     be        |     the review process.                   |
|          |     included  |                                           |
|          |     in CTD-Q? | 3.  The rationale/justification for       |
|          |               |     tablet scoring should be provided in  |
|          | 2.  Can       |     3.2.P.2.2.1.                          |
|          |     cr        |                                           |
|          | oss-reference | 4.  Description of release mechanism in   |
|          |     be made   |     the dosage form for controlled        |
|          |     to        |     release drug products should be       |
|          |     b         |     included in section 3.2.P.2.2.1.      |
|          | ioequivalence |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     in other  |                                           |
|          |     Modules?  |                                           |
|          |               |                                           |
|          | 3.  Where     |                                           |
|          |     should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |     to        |                                           |
|          |     justify a |                                           |
|          |     tablet    |                                           |
|          |     score?    |                                           |
|          |               |                                           |
|          | 4.  Should    |                                           |
|          |     the       |                                           |
|          |     release   |                                           |
|          |     mechanism |                                           |
|          |     of the    |                                           |
|          |     dosage    |                                           |
|          |     form for  |                                           |
|          |               |                                           |
|          |    controlled |                                           |
|          |     release   |                                           |
|          |     drug      |                                           |
|          |     products  |                                           |
|          |     be        |                                           |
|          |     described |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |  3.2.P.2.2.1? |                                           |
+----------+---------------+-------------------------------------------+
| ##       | 1.  1\. Where | 1.  Justification for overages should be  |
| P 2.2.2  |     should    |     included in 3.2.P.2.2.2.              |
| Overages |     overages  |                                           |
|          |     be        |                                           |
|          |               |                                           |
|          |    justified? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Where     | 1.  A summary of dissolution development  |
| > 2.2.3  |     should    |     should be included in 3.2.P.2.2.3     |
| >        |     any       |     with cross reference to studies in    |
|  Physico |               |     Module 5 as appropriate. The          |
| chemical |    discussion |     justification for the dissolution     |
| > and    |     on        |     test should be included in 3.2.P 5.6. |
| > Bi     |               |                                           |
| ological |   dissolution | 2.  Discussion of key drug product        |
| > Prop   |               |     physicochemical or biological         |
| erties** |   development |     characteristics that can influence    |
|          |     be        |     manufacturability of the drug product |
|          |     included? |     should be included in 3.2.P.2.2.3.    |
|          |               |                                           |
|          | 2.  Where     | 3.  Data from studies on drug product to  |
|          |     should a  |     evaluate the appropriateness of the   |
|          |               |     drug product acceptance criteria for  |
|          |    discussion |     physicochemical/biological properties |
|          |     of the    |     should be included in 3.2.P.2.2.3     |
|          |     key drug  |     \[e.g., Q6A Decision Trees 4 (Part 3) |
|          |     product   |     and 7 (Part1)\].                      |
|          |     ph        |                                           |
|          | ysicochemical |                                           |
|          |     or        |                                           |
|          |               |                                           |
|          |    biological |                                           |
|          |     ch        |                                           |
|          | aracteristics |                                           |
|          |     which     |                                           |
|          |     might     |                                           |
|          |     influence |                                           |
|          |     the       |                                           |
|          |               |                                           |
|          | manufacturing |                                           |
|          |     process   |                                           |
|          |     of the    |                                           |
|          |     drug      |                                           |
|          |     product   |                                           |
|          |     be        |                                           |
|          |     provided? |                                           |
|          |               |                                           |
|          | 3.  Where     |                                           |
|          |     should    |                                           |
|          |     data from |                                           |
|          |     studies   |                                           |
|          |     on the    |                                           |
|          |     potential |                                           |
|          |     effects   |                                           |
|          |     of key    |                                           |
|          |     drug      |                                           |
|          |     substance |                                           |
|          |     p         |                                           |
|          | hysiochemical |                                           |
|          |     ch        |                                           |
|          | aracteristics |                                           |
|          |     on the    |                                           |
|          |               |                                           |
|          |   performance |                                           |
|          |     of the    |                                           |
|          |     drug      |                                           |
|          |     product   |                                           |
|          |     be        |                                           |
|          |     provided? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Where     | 1.  If required, justification would be   |
| > 2.3    |     should    |     included in 3.2.P.2.3                 |
| > Manuf  |     the       |                                           |
| acturing |               | 2.  Information on clinical formulations  |
| >        | justification |     would be included in 3.2.P.2.2.1 .    |
|  Process |     of        |     Information on the differences in the |
| > Devel  |               |     manufacturing process among           |
| opment** | sterilisation |     supporting batches (e.g., clinical,   |
|          |     be        |     stability) and the proposed           |
|          |     provided? |     production process should be included |
|          |               |     in3.2. P.2.3.                         |
|          | 2.  What      |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on        |                                           |
|          |     clinical  |                                           |
|          |     trial     |                                           |
|          |               |                                           |
|          |  formulations |                                           |
|          |     should be |                                           |
|          |     included  |                                           |
|          |     in3.2.    |                                           |
|          |     P.2.3?    |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Should    | 1.  Yes, information on both are included |
| > 2.4    |               |     in 3.2.P.2.4. When warranted,         |
| > C      |   information |     leachables should be included in      |
| ontainer |     on        |     3.2.P.5.5 and 3.2.P.5.1 . Also,       |
| >        |     container |     leachables might be confirmed through |
|  Closure |     closure   |     shelf-life as part of the formal      |
| >        |     system    |     stability studies and the results     |
| System** |               |     would be reported in3.2.P.8.3.        |
|          |    leachables |                                           |
|          |     and       | 2.  Information on performance of the     |
|          |               |     container closure system should be    |
|          |  extractables |     included in3.2. P.2.4 (e.g., priming  |
|          |     be        |     and repriming studies for metered     |
|          |     included  |     dose inhalers).                       |
|          |     in        |                                           |
|          |               | 3.  Information on cleaning of metered    |
|          |   3.2.P.2.4?. |     dose inhalers should be included      |
|          |               |     in3.2.P.2.4.                          |
|          | 2.  Where     |                                           |
|          |     should    | 4.  Suitability of the container closure  |
|          |               |     system to protect from light (e.g.,   |
|          |   performance |     light transmission data) should be    |
|          |     ch        |     discussed in 3.2.P.2.4.               |
|          | aracteristics |     Photostability data is provided in    |
|          |     of a      |     3.2.P.8.3 (defined as stress study in |
|          |     container |     Q1A/B).                               |
|          |     closure   |                                           |
|          |     be        |                                           |
|          |     provided? |                                           |
|          |               |                                           |
|          | 3.  Where     |                                           |
|          |     should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on        |                                           |
|          |     studies   |                                           |
|          |     relating  |                                           |
|          |     to        |                                           |
|          |     cleaning  |                                           |
|          |     of        |                                           |
|          |     metered   |                                           |
|          |     dose      |                                           |
|          |     inhalers  |                                           |
|          |     be        |                                           |
|          |     included? |                                           |
|          |               |                                           |
|          | 4.  Where     |                                           |
|          |     should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on the    |                                           |
|          |     light     |                                           |
|          |               |                                           |
|          |    protection |                                           |
|          |     ch        |                                           |
|          | aracteristics |                                           |
|          |     of the    |                                           |
|          |     container |                                           |
|          |     closure   |                                           |
|          |     be        |                                           |
|          |     provided? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Should    | 1.  Yes. Discussions relating to Decision |
| > 2.5    |               |     Tree 6 (non-sterile drug substance    |
| >        |    discussion |     and excipients) and Decision Tree 8   |
|  Microbi |     of        |     (non-sterile solid) should be         |
| ological |     Decision  |     provided in3.2.P.2.5.                 |
| > Attr   |     Tree 6    |                                           |
| ibutes** |     from Q6A  |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |     in        |                                           |
|          |     3.2.P.2.5 |                                           |
|          |     ?         |                                           |
+----------+---------------+-------------------------------------------+
| ## P 2   | 1.  Where     | > 1\. Information on the compatibility of |
| .6 Compa |     should    | > reconstitution diluents to support      |
| tibility |     data from | > claims in the label is included in3.3.  |
|          |               | > P.2.6. Data from constitution or        |
|          |  constitution | > dilution studies performed as part of   |
|          |     or        | > the formal stability studies to confirm |
|          |     dilution  | > product quality through shelf life are  |
|          |     studies   | > reported in 3.2.P.8.3.                  |
|          |     performed |                                           |
|          |     as part   | 2.  Compatibility with co-administered    |
|          |     of the    |     drugs should be included in 3.2.P.2.6 |
|          |     formal    |                                           |
|          |     stability | > 3\. Yes.                                |
|          |     studies   |                                           |
|          |     to        |                                           |
|          |     confirm   |                                           |
|          |     product   |                                           |
|          |     quality   |                                           |
|          |     through   |                                           |
|          |     shelf     |                                           |
|          |     life be   |                                           |
|          |     provided  |                                           |
|          |     ?         |                                           |
|          |               |                                           |
|          | 2.  Should    |                                           |
|          |               |                                           |
|          | compatibility |                                           |
|          |     of        |                                           |
|          |     co        |                                           |
|          | -administered |                                           |
|          |     drugs be  |                                           |
|          |     provided  |                                           |
|          |               |                                           |
|          |  in3.2.P.2.6? |                                           |
|          |               |                                           |
|          | 3.  Should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on        |                                           |
|          |               |                                           |
|          |  incompatible |                                           |
|          |     diluents  |                                           |
|          |     be        |                                           |
|          |     provided  |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |    3.2.P.2.6? |                                           |
+----------+---------------+-------------------------------------------+
| > **P 3  |               |                                           |
| > Manuf  |               |                                           |
| acture** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 3.1    |               |                                           |
| > M      |               |                                           |
| anufactu |               |                                           |
| rer(s)** |               |                                           |
+----------+---------------+-------------------------------------------+
| ## P 3   | 1.  Are       | 1.  Yes, overages are included in the     |
| .2 Batch |     overages  |     batch fomula in section 3.2.P.3.2     |
|  formula |     included  |                                           |
|          |     in 3.2.P  |                                           |
|          |     3.2 ?     |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Where     | 1.  Reprocessing should be included as    |
| > 3.3    |     should    |     part of the description of the        |
| > Des    |               |     manufacturing process in 3.2.P.3.3.   |
| cription |  reprocessing |     If there are critical controls        |
| > of the |     be        |     associated with the reprocessing      |
| > Manu   |               |     operation the critical controls       |
| facturin |    described? |     should be included in 3.2.P.3.4 and   |
| gProcess |               |     if validation information is          |
| > and    | 2.  Should    |     warranted the validation information  |
| > Co     |     critical  |     should be included in 3.2.P.3.5.      |
| ntrols** |     steps and |                                           |
|          |               | 2.  All process controls should be        |
|          | intermediates |     identified in 3.2.P.3.3. For critical |
|          |     be        |     controls, additional information      |
|          |               |     should be provided in 3.2.P.3.4.      |
|          |    identified |                                           |
|          |     in P.3.3? | 3.  Yes, the overfill should be           |
|          |               |     identified in 3.2.P.3.3.              |
|          | 3.  Should an |                                           |
|          |     overfill  | 4.  A statement regarding manipulation of |
|          |     be        |     ruminant-derived materials in drug    |
|          |               |     product manufacturing facility should |
|          |    identified |     be included here.. If potential for   |
|          |     in3.2. P  |     cross contamination with adventitious |
|          |     3.3 ?     |     agents exist, additional information  |
|          |               |     provided in 3.2.A.1 and or3.2.A.2.    |
|          | 4.  Should a  |                                           |
|          |     statement |                                           |
|          |     regarding |                                           |
|          |               |                                           |
|          |  manipulation |                                           |
|          |     of        |                                           |
|          |     rum       |                                           |
|          | inant-derived |                                           |
|          |     materials |                                           |
|          |     in drug   |                                           |
|          |     product   |                                           |
|          |               |                                           |
|          | manufacturing |                                           |
|          |     facility  |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |    3.2.P.3.3. |                                           |
|          |     ?         |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Is the    | 1.  Yes detailed information should be    |
| > 3.4    |     detailed  |     provided in 3.2. P.3.4 for critical   |
| >        |               |     steps and all intermediates that are  |
|  Control |   information |     controlled.                           |
| > of     |     on        |                                           |
| >        |     critical  | 2.  Yes. Critical process control values  |
| Critical |     steps and |     from relevant batches to support      |
| > Steps  |               |     numeric ranges, limits, etc for       |
| > and    | intermediates |     critical process controls should be   |
| >        |     that have |     included in3.2. P.3.4                 |
|  Interme |     been      |                                           |
| diates** |               | 3.  In3.2. P.3.4, the same information    |
|          |    identified |     should be provided for an in-process  |
|          |               |     material test performed in lieu of a  |
|          |   in3.2.P.3.3 |     finished product test as that         |
|          |     included  |     submitted for a finished product test |
|          |     in 3.2.P  |     (analytical procedure, methods        |
|          |     3.4?      |     validation information).              |
|          |               |                                           |
|          | 2.  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?. |                                           |
|          |               |                                           |
|          | 3.  Where     |                                           |
|          |     should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on the    |                                           |
|          |               |                                           |
|          |    analytical |                                           |
|          |               |                                           |
|          |    procedures |                                           |
|          |     for an    |                                           |
|          |               |                                           |
|          |    in-process |                                           |
|          |     material  |                                           |
|          |     test      |                                           |
|          |     performed |                                           |
|          |     in lieu   |                                           |
|          |     of a      |                                           |
|          |     finished  |                                           |
|          |     product   |                                           |
|          |     test?     |                                           |
|          |               |                                           |
|          | 4.            |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 3.5    |               |                                           |
| >        |               |                                           |
|  Process |               |                                           |
| > Va     |               |                                           |
| lidation |               |                                           |
| > and/or |               |                                           |
| > Eval   |               |                                           |
| uation** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P 4  | 1.  Where     | 1.  For noncompendial, nonnovel           |
| >        |     would     |     excipients additional scientific data |
|  Control |               |     can be included in3.2.A.3.            |
| > of     |    additional |                                           |
| > Exci   |               |                                           |
| pients** |    scientific |                                           |
|          |     data for  |                                           |
|          |     n         |                                           |
|          | oncompendial, |                                           |
|          |     nonnovel  |                                           |
|          |               |                                           |
|          |    excipients |                                           |
|          |     be        |                                           |
|          |     placed?   |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 4.1    |               |                                           |
| >        |               |                                           |
| Specific |               |                                           |
| ations** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 4.2    |               |                                           |
| > An     |               |                                           |
| alytical |               |                                           |
| > Proc   |               |                                           |
| edures** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 4.3    |               |                                           |
| > Va     |               |                                           |
| lidation |               |                                           |
| > of     |               |                                           |
| > An     |               |                                           |
| alytical |               |                                           |
| > Proc   |               |                                           |
| edures** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Where     | 1.  Certificates of analysis or batch     |
| > 4.4    |     should    |     data for excipients should be         |
| > Justi  |               |     included in3.2. P.4.4.                |
| fication |  certificates |                                           |
| > of     |     of        | 2.  Yes. A summary of data from other     |
| >        |     analysis  |     sections with a cross-reference to    |
| Specific |     or batch  |     the detailed information can be       |
| ations** |     data for  |     provided to support the justification |
|          |               |     of specification..                    |
|          |    excipients |                                           |
|          |     be        |                                           |
|          |     included? |                                           |
|          |               |                                           |
|          | 2.  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   |                                           |
|          |     rather    |                                           |
|          |     than      |                                           |
|          |     repeating |                                           |
|          |     this      |                                           |
|          |               |                                           |
|          |  information? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Where     | 1.  Information on excipients of human or |
| > 4.5    |     should    |     animal origin in 3.2.P.4.5.           |
| > Ex     |               |     Information on adventitious agent     |
| cipients |   information |     safety evaluation should be included  |
| > of     |     on        |     in 3.2.A.2. For location of           |
| > Human  |               |     certifications relating to TSE/BSE    |
| > or     |    excipients |     see region specific guidance.         |
| > Animal |     of human  |                                           |
| >        |     or animal |                                           |
| Origin** |     origin be |                                           |
|          |     located?  |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 4.6    |               |                                           |
| > Novel  |               |                                           |
| > Exci   |               |                                           |
| pients** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P 5  |               |                                           |
| >        |               |                                           |
|  Control |               |                                           |
| > of     |               |                                           |
| > Drug   |               |                                           |
| > P      |               |                                           |
| roduct** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  where     | 1.  Both specifications are included      |
| > 5.1    |     should    |     in3.2.P.5.1 (see also question for    |
| > Sp     |     release   |     3.2.P.8.1).                           |
| ecificat |     and       |                                           |
| ion(s)** |               | 2.  Yes. An in-process test that can take |
|          |    shelf-life |     the place of an end-product test      |
|          |     s         |     should be listed in the               |
|          | pecifications |     specification.                        |
|          |     be        |                                           |
|          |     located?  | 3.  Any analytical procedure used to      |
|          |               |     control the drug product, and the     |
|          | 2.  Should an |     associated acceptance criteria,       |
|          |     in        |     should be listed in the               |
|          |     process   |     specification.                        |
|          |     test      |                                           |
|          |     which can |                                           |
|          |     take the  |                                           |
|          |     place of  |                                           |
|          |     an        |                                           |
|          |               |                                           |
|          |   end-product |                                           |
|          |     test be   |                                           |
|          |     included  |                                           |
|          |     in the    |                                           |
|          |     s         |                                           |
|          | pecification. |                                           |
|          |     ?         |                                           |
|          |               |                                           |
|          | 3.  If        |                                           |
|          |               |                                           |
|          |    regulatory |                                           |
|          |     and       |                                           |
|          |               |                                           |
|          |   alternative |                                           |
|          |               |                                           |
|          |    analytical |                                           |
|          |               |                                           |
|          |    procedures |                                           |
|          |     are used  |                                           |
|          |     to        |                                           |
|          |     control   |                                           |
|          |     the drug  |                                           |
|          |     product   |                                           |
|          |     should    |                                           |
|          |     they both |                                           |
|          |     be listed |                                           |
|          |     in the    |                                           |
|          |               |                                           |
|          | specification |                                           |
|          |               |                                           |
|          |  (3.2.P.5.1)? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Often     | 1.  Information on historical analytical  |
| > 5.2    |     times an  |     procedures used to generate data      |
| > An     |               |     included in the batch analyses        |
| alytical |    analytical |     section should be included in         |
| > Proc   |     procedure |     3.2.P.5.4                             |
| edures** |     has       |                                           |
|          |     changed   | 2.  No. Information on analytical         |
|          |     during    |     procedures that are used only for     |
|          |     the       |     stability studies should be included  |
|          |               |     in 3.2.P.8.3.                         |
|          |   development |                                           |
|          |     of the    |                                           |
|          |     drug      |                                           |
|          |     product.  |                                           |
|          |     If this   |                                           |
|          |               |                                           |
|          |    analytical |                                           |
|          |     procedure |                                           |
|          |     should be |                                           |
|          |     submitted |                                           |
|          |     to        |                                           |
|          |     support   |                                           |
|          |     the       |                                           |
|          |     dossier,  |                                           |
|          |     in which  |                                           |
|          |     section   |                                           |
|          |     would     |                                           |
|          |     these     |                                           |
|          |               |                                           |
|          |    analytical |                                           |
|          |               |                                           |
|          |    procedures |                                           |
|          |     be        |                                           |
|          |     placed?   |                                           |
|          |               |                                           |
|          | 2.  Should an |                                           |
|          |               |                                           |
|          |    analytical |                                           |
|          |     procedure |                                           |
|          |     that is   |                                           |
|          |     only used |                                           |
|          |     for       |                                           |
|          |     stability |                                           |
|          |     studies   |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |               |                                           |
|          |  in3.2.P.5.2? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 5.3    |               |                                           |
| > Va     |               |                                           |
| lidation |               |                                           |
| > of     |               |                                           |
| > An     |               |                                           |
| alytical |               |                                           |
| > Proc   |               |                                           |
| edures** |               |                                           |
+----------+---------------+-------------------------------------------+
| ## P 5.  | 1.  Should    | 1.  Results from all relevant batches     |
| 4 Batch  |     results   |     (e.g., clinical, nonclinical,         |
| analysis |     from all  |     stability), including those batches   |
|          |     batches   |     used to justify acceptance criteria,  |
|          |     be        |     should be provided in 3.2.P.5.4.      |
|          |     provided  |     Information describing the batches    |
|          |     in        |     should also be included in 3.2.P.5.4  |
|          |               |                                           |
|          |    3.2.P.5.4? | 2.  Yes all data from relevant batches    |
|          |     Should    |     should be reported in P.5.4.          |
|          |     the       |                                           |
|          |               | 3.  If collated data from batch analyses  |
|          |   description |     is warranted, the data should be      |
|          |     of the    |     presented here.                       |
|          |     batches   |                                           |
|          |     (e.g.,    |                                           |
|          |     batch     |                                           |
|          |     number,   |                                           |
|          |               |                                           |
|          | manufacturing |                                           |
|          |     site,     |                                           |
|          |     use) be   |                                           |
|          |     included  |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |   3,.2.P.5.4? |                                           |
|          |               |                                           |
|          | 2.  Should    |                                           |
|          |     all tests |                                           |
|          |     performed |                                           |
|          |     be        |                                           |
|          |     reported  |                                           |
|          |     even if   |                                           |
|          |     not       |                                           |
|          |     included  |                                           |
|          |     in the    |                                           |
|          |     s         |                                           |
|          | pecification? |                                           |
|          |               |                                           |
|          | 3.  Where     |                                           |
|          |     should    |                                           |
|          |     collated  |                                           |
|          |     data for  |                                           |
|          |     a test    |                                           |
|          |     from      |                                           |
|          |     multiple  |                                           |
|          |     batch     |                                           |
|          |     analyses  |                                           |
|          |     be        |                                           |
|          |               |                                           |
|          |    presented? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | > Should all  | 1.  Yes, all observed impurities should   |
| > 5.5    | > observed    |     be listed. Justification for not      |
| >        | > impurities  |     including an observed impurity in the |
| Characte | > be listed   |     specification should be included      |
| risation | > in          |     in3.2.P.5.6.                          |
| > of     | > 3.2.P.5.5   |                                           |
| > Impu   | > even if     |                                           |
| rities** | > they are    |                                           |
|          | > not         |                                           |
|          | > included in |                                           |
|          | > the drug    |                                           |
|          | > product     |                                           |
|          | > s           |                                           |
|          | pecification? |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Should    | 1.  Yes. If skip testing is appropriate,  |
| > 5.6    |               |     the justification should be included  |
| > Justi  | justification |     in 3.2.P.5.6                          |
| fication |     for skip  |                                           |
| > of     |     testing   | 2.  Yes. A summary of data from other     |
| > Sp     |     be        |     sections with a cross-reference to    |
| ecificat |     included  |     the detailed information can be       |
| ion(s)** |     in        |     provided to support the justification |
|          |               |     of specification.                     |
|          |    3.2.P.5.6? |                                           |
|          |               |                                           |
|          | 2.  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? |                                           |
+----------+---------------+-------------------------------------------+
| > **P 6  | 1.  Reference | 1.  If information is required for a      |
| > R      |     standards |     reference standard, the information   |
| eference |     may be    |     should be included in 3.2.P.6.        |
| > S      |     available |                                           |
| tandards |     for the   | 2.  Characterisation data for the         |
| > or     |     active    |     reference standard should be included |
| > Mat    |     moiety    |     in 3.2.P.6. Cross reference to        |
| erials** |     and       |     information in other sections can be  |
|          |               |     included as appropriate.              |
|          |   impurities. |                                           |
|          |     Should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on all    |                                           |
|          |     reference |                                           |
|          |     standards |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |               |                                           |
|          |    in3.2.P.6? |                                           |
|          |               |                                           |
|          | 2.  2\. Where |                                           |
|          |     should    |                                           |
|          |     cha       |                                           |
|          | racterisation |                                           |
|          |     data for  |                                           |
|          |     a         |                                           |
|          |     reference |                                           |
|          |     standard  |                                           |
|          |     be placed |                                           |
|          |     in the    |                                           |
|          |     CTD-Q.    |                                           |
+----------+---------------+-------------------------------------------+
| > **P 7  |               |                                           |
| > C      |               |                                           |
| ontainer |               |                                           |
| >        |               |                                           |
|  Closure |               |                                           |
| >        |               |                                           |
| System** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P 8  |               |                                           |
| > Sta    |               |                                           |
| bility** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P8.1 | 1.  Should    | 1.  Shelf-life specifications should be   |
| > S      |               |     indicated here and as appropriate in  |
| tability |    shelf-life |     3.2.P.8.3.                            |
| >        |     s         |                                           |
|  Summary | pecifications |                                           |
| > and    |     be        |                                           |
| > Conc   |     repeated  |                                           |
| lusion** |     under     |                                           |
|          |     this      |                                           |
|          |     section?  |                                           |
+----------+---------------+-------------------------------------------+
| > **P    |               |                                           |
| > 8.2 No |               |                                           |
| > format |               |                                           |
| > co     |               |                                           |
| mments** |               |                                           |
+----------+---------------+-------------------------------------------+
| > **P    | 1.  Should    | 1.  Yes. Stress studies should be located |
| > 8.3    |     stress    |     in 3.2.P.8.3. These data can be       |
| > S      |     studies   |     referenced for validation of          |
| tability |     be        |     analytical procedures as needed.      |
| > Data** |     located   |                                           |
|          |     in        | 2.  Information on historical analytical  |
|          |               |     procedures used to generate the       |
|          |    3.2.P.8.3? |     stability data included in 3.2.P.8.3  |
|          |               |     should also be included in 3.2.P.8.3. |
|          | 2.  Should    |                                           |
|          |               | 3.  Yes, data from supporting studies can |
|          |   information |     be included in 3.2.P.8.3, if          |
|          |     on any    |     appropriate.                          |
|          |     changes   |                                           |
|          |     in        | 4.  Yes, information on analytical        |
|          |               |     procedures unique to the stability    |
|          |    analytical |     program should be included in         |
|          |               |     3.2.P.8.3.                            |
|          |    procedures |                                           |
|          |     over the  | 5.  The detailed statistical analysis     |
|          |     course of |     report, if included, should go in     |
|          |               |     3.2.P.8.3, but a summary or           |
|          |    generating |     conclusions of the statistical        |
|          |     stability |     analysis should go in3.2.P.8.1.       |
|          |     data be   |                                           |
|          |     included  |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |    3.2.P.8.3? |                                           |
|          |               |                                           |
|          | 3.  Can data  |                                           |
|          |     from      |                                           |
|          |               |                                           |
|          |    supporting |                                           |
|          |     studies   |                                           |
|          |     be        |                                           |
|          |     included  |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |    3.2.P.8.3? |                                           |
|          |               |                                           |
|          | 4.  Should    |                                           |
|          |               |                                           |
|          |   information |                                           |
|          |     on        |                                           |
|          |               |                                           |
|          |    analytical |                                           |
|          |               |                                           |
|          |    procedures |                                           |
|          |     unique to |                                           |
|          |     the       |                                           |
|          |     stability |                                           |
|          |     program   |                                           |
|          |     be        |                                           |
|          |     presented |                                           |
|          |     in        |                                           |
|          |               |                                           |
|          |    3.2.P.8.3? |                                           |
|          |               |                                           |
|          | 5.  Where     |                                           |
|          |     should    |                                           |
|          |     the       |                                           |
|          |               |                                           |
|          |   statistical |                                           |
|          |     analysis  |                                           |
|          |     of the    |                                           |
|          |     stability |                                           |
|          |     data be   |                                           |
|          |     included? |                                           |
+----------+---------------+-------------------------------------------+

  -------------- ------------------------ ----------------------------------
  **A            1.If information for     1.If drug substance and drug
  Appendices**   both the drug substance  product information is included in
                 and the drug product     the appendices then the preferred
                 should be included in an presentation is DS first and then
                 appendix 3.2.A.1 of a    DP within each section. For
                 paper submission, how    example3.2. A.1 (drug substance
                 should it be presented?  then drug product) then 3.2.A.2.

  -------------- ------------------------ ----------------------------------