Guide for the Quality Module 3- Part S - Drug Substance
Guide for the Quality Module 3 - Part S
Drug Substance
Prepared by the Technical Subcommittee’s experts under the supervision of
Dr. Rita Karam, Head of Quality Assurance of Pharmaceutical Products
-1-
Guide for the Quality Module 3- Part S - Drug Substance
Chemical, Pharmaceutical and biological information for medical products containing chemical and/or biological
active substances
INTRODUCTION
The Quality guideline provides a harmonized structure and format for presenting CMC
(Chemistry, Manufacturing and Controls) information in a registration application based on
Good Manufacturing Practice (GMP) risk management. It defines criteria for the validation of
the two most common types of analytical procedures: qualitative and quantitative tests for
active substance and impurities (organic and inorganic impurities and residual solvents) in
Active Pharmaceutical Ingredient-API.
The Quality module for the drug substance defining the validation parameters needed for a
variety of analytical methods of control and describing characteristics to be considered for the
validation of analytical procedures are included in a marketing authorization application
(MAA).
This document is intended to provide a global policy and guidance for the preparation of the
Quality module of Drug Substance for an application file that meet with the requirement of
Ministry of Public Health in Lebanon.
Drawing upon the reviewed files, we are including a rubric on the answers of the Frequently
Asked Questions (FAQ) that had been received from several manufacturers.
The document must be presented in pdf form and not in the form of pictures such as scan,
paint, jpeg, etc.
The manufacturer should provide all information for the different sections including the closed
part of the DMF
INFORMATION AND REQUIREMENTS
As defined in the scope of the ICH Guidelines, information and requirements described below
are intended to facilitate the handling and assessment of submissions.
When more than one drug substance is used in a drug product, information should be presented
separately as one complete Drug Substance section.
The activities and outputs which need to be addressed for the registration file include:
Section Title Requirements Answer to FAQ
-2-
Guide for the Quality Module 3- Part S - Drug Substance
Table of content A Table of Contents for the filed application should
3.1.
of module 3 be provided
3.2. Body of Data Indicates where the information should be located
3.2.S Drug Substance
General
3.2.S.1 Name, Manufacturer
Information
- Chemical Abstracts Service (CAS) registry
number
3.2.S.1.1 Nomenclature - Recommended International
Nonproprietary Name (INN)
- Chemical name (s)
The structural formula, including relative and
absolute stereochemistry, the molecular formula,
3.2.S.1.2 Structure
the relative molecular mass and chirality should all
be provided
Q1. How much detailed
information on the general
properties of the drug substance
should be included in 3.2.S.1.3?
A1. A list of physicochemical and
other relevant properties of the
drug substance, including
A list should be provided of physicochemical and biological activity, should be
other relevant properties of the drug substance: pH / included in 3.2.S.1.3. The
General
3.2.S.1.3 pKa, melting point, solubility, Hygroscopicity, information on general properties
Properties
physical form, crystalline form, etc. List the should be provided only for the
polymorphic form(s) present in the proposed active. form of the drug substance used in
the drug product, not possible
alternative forms (e.g.,
polymorphs). More detailed
information on the properties of
the drug substance, including
possible alternative forms, should
be included in 3.2.S.3.1.
3.2.S.2 Manufacture
The name, address, and responsibility of each
Manufacturer(s)
manufacturer, including contractors, and each
3.2.S.2.1 (name,
proposed production site or facility involved in
manufacturer)
manufacturing and testing should be provided
A flow diagram of the synthetic process (es) and a
sequential procedural narrative of the Q1. Should information on process
manufacturing process should be submitted. controls be provided in section
Description of
-The narrative should include quantities of raw 3.2.S.2.2 or 3.2.S.2.4?
Manufacturing
3.2.S.2.2 materials, solvents, catalysts and reagents reflecting A1. All process controls should be
Process and
the representative batch scale for commercial identified in 3.2.S.2.2. For critical
Process Controls
manufacture, identification of critical steps, process controls, additional information
controls, equipment and operating conditions (e.g., should be provided in 3.2.S.2.4.
temperature, pressure, pH, time)
-3-
Guide for the Quality Module 3- Part S - Drug Substance
Information on the quality and control of Materials Q1. Where should analytical
used in the manufacture of the drug substance (e.g., procedures for materials described
raw materials, starting materials, solvents, reagents, in 3.2.S.2.3 be included?
Control of catalysts) should be listed identifying where each A1. The analytical procedures for
3.2.S.2.3
Materials material is used in the process. the control of materials (e.g.,
-For biologically-sourced materials, this should starting materials, reagents, raw
include information regarding the source, materials, solvents) should be
manufacture, and characterization. presented in section 3.2.S.2.3.
Q1. Should batch data for
intermediates or critical steps be
Controls of Tests and acceptance criteria (with justification included in 3.2.S.2.4?
Critical Steps including experimental data) performed at critical A1. Batch data, together with
3.2.S.2.4
and steps identified in 3.2.S.2.2 of the manufacturing analytical procedures and
Intermediates process should be provided acceptance criteria for
intermediates or critical steps,
would be presented in 3.2.S.2.4.
Process validation and/or evaluation studies for
Q1. Where should justification for
aseptic processing and sterilization should be
reprocessing be included?
included. The aseptic process may be recorded
A1. If justification for reprocessing
through a comprehensive documentation :
is warranted by a regional
- Suitable testing facilities, equipment,
authority, the information would
instruments and methodology (properly
be included as part of the
Process installed, qualified and maintained) should
description of the manufacturing
Validation be available
3.2.S.2.5 process in 3.2.S.2.2. If there are
and/or - Suitable clean room facilities should be
critical controls associated with
Evaluation available, in terms both of the "local" and
the reprocessing operation, the
"background “environments. Assurance
critical controls should be included
that the Clean Room environment is as
in 3.2.S.2.4. If validation
specified should be secured through the
information is warranted, the
implementation of a program of retesting,
validation information should be
in-process control and monitoring
included in 3.2.S.2.5.
A description and discussion should be provided of
the significant changes made to the manufacturing
Manufacturing
process and/or manufacturing site of the drug
3.2.S.2.6 Process
substance
Development
-Reference should be made to the drug substance
data provided in section 3.2.S.4.4.
3.2. S.3. Characterization
Q1. Where should the list of
Confirmation of structure based on synthetic route
Elucidation of polymorphs be included?
and spectral analyses should be provided.
Structure and A1. Total number of polymorphs
3.2.S.3.1 Information such as the potential for isomerism, the
other should be listed here and those
identification of stereochemistry, or the potential
Characteristics intended to form the active should
for forming polymorphs should also be included.
be summarized in 3.2.S.1.3.
Information on impurities should be provided Q1. Should structural
include classification and identification of characterization data and a
impurities, report generation, listing of impurities in summary of the method of
3.2.S.3.2 Impurities
specifications, and a brief discussion of analytical preparation of impurities be
procedures. included in 3.2.S.3.2?
- Organic impurities (process- and drug- A1. This information should be
-4-
Guide for the Quality Module 3- Part S - Drug Substance
related) included in 3.2.S.3.2.
- Inorganic impurities Characterization of impurity
- Residual solvents reference standards should be
provided in 3.2.S.5.
Q2. Where chromatograms should
be provided for impurities?
A2. ICH Q3A identifies the
chromatograms as part of the
analytical validation studies.
Therefore, relevant
chromatograms should be included
in 3.2.S.4.3.
Q3. Should data on impurities
reported in batch analyses be
included in 3.2.S.3.2 or 3.2.S.4.4?
A3. Data on observed impurities
for relevant batches should be
provided in 3.2.S.3.2.
Control of Drug
3.2.S.4
Substance
Q1. If alternative analytical
procedures are used to control the
A specification is defined as a list of tests, references
to analytical procedures, and appropriate acceptancedrug substance, should they also be
listed in the specification
criteria, which are numerical limits, ranges, or other
3.2.S.4.1 Specification criteria for the tests described. A1. Any analytical procedure used
- A copy of monograph should be provided to control the drug substance, and
including : Description, identification, the associated acceptance criteria,
assay and impurities should be listed in the
specification.
Q1. Should an analytical procedure
that is only used for stability
studies be included in 3.2.S.4.2?
A1. Information on analytical
procedures that are used only for
The analytical procedures used for testing the drug stability studies should be included
substance should be provided. in 3.2.S.7
The discussion of the validation of analytical
procedures is directed to the four most common Q2. If the analytical methods for a
Analytical types of analytical procedures: drug substance and drug product
3.2.S.4.2
Procedures - Identification tests; are identical, can these methods
- Quantitative tests for impurities' content; and corresponding validation, if
- Limit tests for the control of impurities; applicable, be described in either
- Quantitative tests of the active moiety in samples 3.2.S or 3.2.P, with a
of drug substance corresponding reference (e.g., a
reference from 3.2.S to 3.2.P)?
A2. The analytical methods should
be placed in both the relevant
sections of 3.2.S and 3.2.P because
the sample preparation, at least,
-5-
Guide for the Quality Module 3- Part S - Drug Substance
will differ.
Validation of Analytical validation information, including
3.2.S.4.3 Analytical experimental data for the analytical procedures used
Procedures for testing the drug substance, should be provided.
Description of batches and results of batch analyses Q1. Where collated data for a test
should be provided. from multiple batch analyses
All residual solvents should be removed to the should be presented?
3.2.S.4.4 Batch Analyses
extent possible to meet product specifications, good A1. If collated data from batch
manufacturing practices, or other quality-based analyses is warranted, the data
requirements. should be presented in 3.2.S.4.4.
Justification for the drug substance specification
should be provided
Justification of - A summary of data from other sections
3.2.S.4.5
Specification with a cross-reference to the detailed
information can be provided to support the
justification of specification.
A reference standard, or reference material, is a
substance prepared for use as the standard in an
Reference
assay, identification, or purity test.
3.2.S.5 Standards or
- All analytical results of reference standard,
Materials
or reference material used as reference
substance should be provided
A description of the container closure system(s)
should be provided, including the identity of
materials of construction of each packaging
component, and their specifications.
- The suitability should be briefly discussed
Container with respect to, for example, choice of
3.2.S.6
Closure System 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.
Results of the stability studies should be presented
in an appropriate format such as tabular, graphical,
or narrative.
- Conclusions with respect to storage
conditions and retest date or shelf-life, as
appropriate should be provided.
- Post-approval Stability Protocol and
3.2.S.7 Stability
Stability Commitment should be provided
Study Storage Minimum time
condition period covered
by
data at
submission
-6-
Guide for the Quality Module 3- Part S - Drug Substance
25°C ± 2°C/60%
RH ± 5% RH or
Long term* 12 months
30°C ± 2°C/65%
RH ± 5% RH
30°C ± 2°C/65%
Intermediate** 6 months
RH ± 5% RH
40°C ± 2°C/75%
Accelerated 6 months
RH ± 5% RH
*It is up to the applicant to decide whether long
term stability studies are performed at 25 ± 2°C/60%
RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.
**If 30°C ± 2°C/65% RH ± 5% RH is the long-term
condition, there is no intermediate condition.
Reference:
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH), 2002, Common Technical Document, Quality Guidelines (M4Q (R1)
-7-
