Compilation of API drug master file with reference to ICH M4 Q (R1) guideline

Compilation of API drug master file with reference to ICH M4 Q (R1) guideline

This article is a summary of contents that should be part of API drug master file. Contents are referenced from ICH M4 Q (R1) guideline. Since this article is based on ICH guidelines, no changes have been made to content of guidelines and most of the data is included in as is form from the guideline. The information which is included in as is form is represented by “#” symbol at the end of respective title.

Module 2: Quality overall summary (QOS).

As the name suggests, this module should contain section wise summary of information which is presented in module 3.

Information that should be part of QOS:

• ü Sufficient information from each section to provide the quality reviewer with an overview of module 3.
• ü Should emphasize on critical key parameters of the product.
• ü  In case, any guideline is not followed in module 3, justification of the same should be included.

 Information that should NOT be part of QOS:

• Ø  Information, data or justification that was not already included in Module 3 or in other parts of the CTD.
• Ø  QOS normally should not exceed 40 pages of text, excluding tables and figures.

Below is a brief description summary of contents that should be included in quality over all summary (QOS).

Section number	Section name
2.3.S.1	General information
2.3.S.2	Manufacturer
2.3.S.3	Characterisation
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

Section 2.3.S.1           General information

• Summarized (but not complete) Information included in section 3.2.S.1 should be presented.

Section 2.3.S.2           Manufacturer #

•  Information on the manufacturer;
•  A brief description of the manufacturing process (including, for example, reference to starting materials, critical steps, and reprocessing) and the controls that are intended to result in the routine and consistent production of material(s) of appropriate quality;
• A flow diagram, as provided in 3.2.S.2.2;
• A description of the source and Starting Material and raw materials of biological origin used in the manufacture of the drug substance, as described in 3.2.S.2.3;
• A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Highlight critical process intermediates, as described in 3.2.S.2.4;
• A description of process validation and/or evaluation, as described in 3.2.S.2.5.
• A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency, as described in 3.2.S.2.6. The QOS should also cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes, as provided in the CTD-S and CTD-E modules of the dossier.

Section 2.3.S.3           Characterisation 

• A summary of the interpretation of evidence of structure and isomerism, as described in 3.2.S.3.1 and 3.2.S.3.2 should be included.

Section 2.3.S.4           Control of Drug Substance

• Brief summary of information included in section 3.2.S.4.1 specification should be included. This can be in tabular format.
• Similarly, summarized information on section 3.2.S.4.2 and 3.2.S.4.3 should be included.
• For batch analysis, tabulated summary of section 3.2.S.4.4 should be presented. E.g.:

Parameters	Specification	Batch 001	Batch 002	Batch 003
Description	Abc
Solubility	Xyz

Section 2.3.S.5           Reference Standards or Materials #

• Information from 3.2.S.5 (tabulated presentation, where appropriate) should be included.

Section 2.3.S.6           Container closure system #

• A brief description and discussion of the information, from 3.2.S.6 should be included.

Section 2.3.S.7           Stability #

This section should include a summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions, the proposed storage conditions, retest date or shelf-life, where relevant, as described in 3.2.S.7.1.

The post-approval stability protocol, as described in 3.2.S.7.2, should be included.

A tabulated summary of the stability results from 3.2.S.7.3, with graphical representation

where appropriate, should be provided.

Module 3.2.S Drug Substance

Section number	Section name	Reference ICH Guidelines
3.2.S.1	General information
3.2.S.1.1	Nomenclature
3.2.S.1.2	Structure
3.2.S.1.3	General properties	Q6A and Q6B
3.2.S.2	Manufacturer
3.2.S.2.1	Manufacturer(s)
3.2.S.2.2	Description of manufacturing process and process controls
3.2.S.2.3	Control of materials	Q6A and Q6B
3.2.S.2.4	Control of critical steps and intermediates	Q6A and Q6B
3.2.S.2.5	Process validation and evaluation
3.2.S.2.6	Manufacturing process development	Q3A
3.2.S.3	Characterisation
3.2.S.3.1	Elucidation of structure and other characteristics	Q6A
3.2.S.3.2	Impurities	Q3A, Q3C, Q5C, Q6A, and Q6B
3.2.S.4	Control of drug substance
3.2.S.4.1	Specification	Q6A and Q6B
3.2.S.4.2	Analytical procedures	Q2A and Q6B
3.2.S.4.3	Validation of analytical procedures	Q2A, Q2B, and Q6B
3.2.S.4.4	Batch analysis	Q3A, Q3C, Q6A, and Q6B
3.2.S.4.5	Justification of specification	Q3A, Q3C, Q6A, and Q6B
3.2.S.5	Reference standards or materials	Q6A and Q6B
3.2.S.6	Container closure system
3.2.S.7	Stability
3.2.S.7.1	Stability summary and  conclusions	Q1A, Q1B, and Q5C
3.2.S.7.2	Post approval stability protocol and stability commitment	Q1A and Q5C
3.2.S.7.3	Stability data	Q1A, Q1B, Q2A, Q2B, and Q5C

3.1. TABLE OF CONTENTS OF MODULE 3

A Table of Contents for the filed application should be provided.

3.2. BODY OF DATA

3.2.S DRUG SUBSTANCE

3.2.S.1 General Information (name, manufacturer) #

3.2.S.1.1 Nomenclature

Information on the nomenclature of the drug substance should be provided.  For example:

• Recommended International Non-proprietary Name (INN);
• Compendial name if relevant;
• Chemical name(s);
• Company or laboratory code;
• Other non-proprietary name(s), e.g., national name, United States Adopted Name (USAN), Japanese Accepted Name (JAN); British Approved Name (BAN), and
• Chemical Abstracts Service (CAS) registry number.

3.2.S.1.3 General Properties

A list should be provided of physicochemical and other relevant properties of the drug substance, including biological activity for Biotech.

Reference ICH Guidelines:  Q6A and Q6B

Examples that should be included are description, solubility profile, pH values, melting point, boiling point, polymorphism, isomerism etc.

3.2.S.2 Manufacture #

3.2.S.2.1 Manufacturer(s)

The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

3.2.S.2.2 Description of Manufacturing Process and Process Controls

The description of the drug substance manufacturing process represents the applicant’s commitment for the manufacture of the drug substance.  Information should be provided to adequately describe the manufacturing process and process controls.

A flow diagram of the synthetic process(es) should be provided that includes molecular formulae, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and drug substance reflecting stereochemistry, and identifies operating conditions and solvents.

A sequential procedural narrative of the manufacturing process should be submitted.  The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g., temperature, pressure, pH, time).

Alternate processes should be explained and described with the same level of detail as the primary process.  Reprocessing steps should be identified and justified.  Any data to support this justification should be either referenced or filed in 3.2.S.2.5.

3.2.S.2.3 Control of Materials #

Materials used in the manufacture of the drug substance (e.g., raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process.  Information on the quality and control of these materials should be provided.

3.2.S.2.4 Controls of Critical Steps and Intermediates #

Critical Steps:  Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.

Intermediates:  Information on the quality and control of intermediates isolated during the process should be provided. All in-process specifications, intermediate specifications and its certificate of analysis should be included in this section.

Reference ICH Guidelines:  Q6A and Q6B 

3.2.S.2.5 Process Validation and/or Evaluation #

Process validation and/or evaluation studies for aseptic processing and sterilisation should be included. A process validation report should be attached in this section of drug master file.

3.2.S.2.6 Manufacturing Process Development #

A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the drug substance used in producing nonclinical, clinical, scale-up, pilot, and, if available, production scale batches. Reference should be made to the drug substance data provided in section 3.2.S.4.4.

Reference ICH Guideline: Q3A

3.2.S.3 Characterisation #

3.2.S.3.1 Elucidation of Structure and other Characteristics

Confirmation of structure based on e.g., synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.

3.2.S.3.2 Impurities

This section is most important part of drug master file. This part can also be termed as “heart of drug master file” and can prove to be the toughest part for compilation of drug master file. All possible impurities should be identified, listed and described. A discussion should be included for control of impurities. Below is example for listing of impurities in tabular form:

Sr. No.	impurity name & structure	Type of impurity/ source of impurity
01.	Abc	Process related impurity
02.	Xyz	Degradation impurity

Reference ICH Guidelines:  Q3A, Q3C, Q5C, Q6A, and Q6B

3.2.S.4 Control of Drug Substance #

3.2.S.4.1 Specification

The specification for the drug substance should be provided.

Reference ICH Guidelines: Q6A and Q6B

3.2.S.4.2 Analytical Procedures #

The analytical procedures used for testing the drug substance should be provided.

Reference ICH Guidelines: Q2A and Q6B

3.2.S.4.3 Validation of Analytical Procedures #

Analytical validation information, including experimental data for the analytical procedures used for testing the drug substance, should be provided.

Reference ICH Guidelines: Q2A, Q2B, and Q6B

3.2.S.4.4 Batch Analyses #

Description of batches and results of batch analyses should be provided.

Reference ICH Guidelines: Q3A, Q3C, Q6A, and Q6B

3.2.S.4.5 Justification of Specification #

Justification for the drug substance specification should be provided.

Reference ICH Guidelines: Q3A, Q3C, Q6A and Q6B

3.2.S.5 Reference Standards or Materials #

Information on the reference standards or reference materials used for testing of the drug substance should be provided.

Reference ICH Guidelines: Q6A and Q6B

3.2.S.6 Container Closure System #

A description of the container closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). Non-compendial methods (with validation) should be included, where appropriate.

The suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the drug substance, including sorption to container and leaching, and/or safety of materials of construction.

3.2.S.7 Stability #

3.2.S.7.1 Stability Summary and Conclusions

The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.

Reference ICH Guidelines:  Q1A, Q1B, and Q5C

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment

The post-approval stability protocol and stability commitment should be provided.

Reference ICH Guidelines:  Q1A and Q5C

3.2.S.7.3 Stability Data

Results of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.

Reference ICH Guidelines:  Q1A, Q1B, Q2A, Q2B, and Q5C