CTD-Quality draft (Step2) ICH Guidance: Questions and Answers

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
5. Location Issues in Drug Product

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

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" o Table of Contents, listing the title of Procedure A, Procedure B, Procedure C
• Tab with "3.2.S.4.2 "Procedure A"; o Procedure A (i.e. document, page 1-n)
• Tab with "3.2.S.4.2 "Procedure B"; o Procedure B (i.e. document, page 1-n)
• Tab with "3.2.S.4.2 "Procedure C"; o 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. 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 Validation 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).

3.3 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

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5. Location Issues in Drug Product

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