Dgda - Directorate General of Drug Adminstration

DIRECTORATE GENERAL
OF DRUG ADMINSTRATION
(DGDA)
MINISTRY OF HEALTH & FAMILY WELFARE
GUIDELINE FOR THE SUBMISSION

OF BANGLADESH COMMON
TECHNICAL DOCUMENT:
MODULES 2 (QUALITY OVERALL
SUMMARY) and 3 (QUALITY)
This document provides instructions to applicants intending to submit applications for the registration of
medicines. These guidelines are governed by the Directorate General of Drug Administration’s (DGDA) current
thinking on safety, quality, and efficacy of medicines. The DGDA reserves the right to request additional
information to establish the safety, quality, and efficacy of a medicine in keeping with current knowledge at the
time of the evaluation of a medicine. The DGDA is committed to ensuring that all registered medicines are of
the required quality, safety, and efficacy. It is important that applicants adhere to the quality requirements in this
module to avoid delays in the processing and evaluation of applications.
Version 1 released for pilot implementation and comments

June 2015
GENERAL TABLE OF CONTENTS
Message from the Director General, Directorate General of Drug Administration ...... iii
Acronyms ...................................................................................................................iv
Module 2 Quality Overall Summary ............................................................................ 1
Module 2.1 Table of Contents .................................................................................... 1
Module 2.2 Background of the Quality Overall Summary ........................................... 2
Module 2.3 Body of Data of Quality Overall Summary ............................................... 5
Module 3 Quality ...................................................................................................... 10
Module 3.1 Table of Contents .................................................................................. 10
Module 3.2 Body of Data .......................................................................................... 11
Module 3.3 Literature References ............................................................................ 38
References ............................................................................................................... 39
ii
MESSAGE FROM THE DIRECTOR GENERAL, DIRECTORATE GENERAL OF
DRUG ADMINISTRATION
The Directorate General of Drug Administration (DGDA) of Bangladesh is changing

and improving its medicines registration system to ensure the safety and efficacy of
medicines as well as to strengthen the potential for the exportation of medicines. The
DGDA is therefore adopting the Common Technical Document (CTD) formats and
guidelines for the preparation of registration dossiers for pharmaceuticals that are
submitted with the application for registration.
The DGDA is also planning to implement PharmaDex to track registration

applications and to enhance its capacity to successfully manage the registration
process in a timely manner.
The Systems for Improved Access to Pharmaceuticals and Services (SIAPS)

Bangladesh office has been providing technical assistance to the DGDA under the
terms of cooperative agreement number AID-OAA-A-11-00021 in this regard. The
DGDA established a Taskforce Team to review the CTD modules and customize
modules 2 and 3 of these guidelines to the Bangladesh context. With the support of
SIAPS, the team was able to have a clear understanding of the process.
To adopt the CTD and implement PharmaDex, a series of workshops were

conducted for DGDA officials as well as other stakeholders.
It is hoped that the CTD will be adopted on a pilot basis within six months. Thanks
are offered to all members of the Taskforce Team and the SIAPS team for their
continuous support for the implementation of the CTD.
Major Gen Md. Jahangir Hossain Mollik

Director General, Directorate General of Drug Administration &
Licensing Authority of Drugs
iii
ACRONYMS
API active pharmaceutical ingredient

BCS Biopharmaceutical Classification System
BP British Pharmacopoeia
CoA certificate of analysis
CTD Common Technical Document
DGDA Directorate General of Drug Administration
DMF drug master file
EMA European Medicines Agency
EU European Union
FDC fixed-dose combination
FPP finished pharmaceutical product
FPRC Finished Product Release Control
GMP Good Manufacturing Practices
ICH International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use
INN international nonproprietary name
IPI inactive pharmaceutical ingredient
IR infrared
NCE new chemical entity
Ph Eur European Pharmacopoeia
PI prescribing information
PIL patient information leaflet
QOS Quality Overall Summary
SIAPS Systems for Improved Access to Pharmaceuticals and Services
USFDA United States Food and Drug Administration
USP United States Pharmacopoeia
VP validation protocol
VR validation report
WHO World Health Organization
iv
MODULE 2 QUALITY OVERALL SUMMARY
MODULE 2.1 TABLE OF CONTENTS
Module 2.2 Background of the Quality Overall Summary ........................................... 2

Module 2.3 Body of Data of Quality Overall Summary ............................................... 5
2.3.S Active Pharmaceutical Ingredient (API) [Name, Manufacturer] ..................... 5
2.3.S.1 General Information [Name, Manufacturer] ............................................ 5
2.3.S.2 Manufacture [Name, Manufacturer] ........................................................ 5
2.3.S.3 Characterization [Name, Manufacturer] .................................................. 5
2.3.S.4 Control of Active Pharmaceutical Ingredient [Name, Manufacturer] ....... 6
2.3.S.5 Reference Standards or Materials [Name, Manufacturer] ...................... 6
2.3.S.6 Container Closure System [Name, Manufacturer] .................................. 6
2.3.S.7 Stability [Name, Manufacturer] ............................................................... 7
2.3.P Pharmaceutical Product [Name, Dosage Form] ......................................... 7
2.3.P.1 Description and Composition of the Pharmaceutical Product ................. 7
2.3.P.2 Pharmaceutical Development [Name, Dosage Form] ............................. 7
2.3.P.3 Manufacture [Name, Dosage Form] ....................................................... 7
2.3.P.4 Control of Inactive Pharmaceutical Ingredients (Excipients) [Name,
Dosage Form] ...................................................................................................... 8
2.3.P.5 Control of Pharmaceutical Product [Name, Dosage Form] ..................... 8
2.3.P.6 Reference Standards or Materials [Name, Dosage Form] ...................... 8
2.3.P.7 Container Closure System [Name, Dosage Form] .................................. 8
2.3.P.8 Stability [Name, Dosage Form] ............................................................... 8
2.3.A Appendices ................................................................................................ 9
2.3.A.1 Facilities and Equipment......................................................................... 9
2.3.A.2 Adventitious Agents Safety Evaluation ................................................... 9
2.3.A.3 Novel Excipients ..................................................................................... 9
2.3.R Regional Information .................................................................................. 9
3.2.P.8 Stability (Name, Dosage Form) ............................................................ 34
1
MODULE 2.2 BACKGROUND OF THE QUALITY OVERALL SUMMARY
The Quality Overall Summary (QOS) is a summary that follows the scope and the
outline of the Body of Data in module 3 (Quality) of the dossier, which contains the
chemical, pharmaceutical, and biological data relevant to the application. The QOS
should contain the summary data of what is already provided in module 3 or in
other parts of the Common Technical Document (CTD). The QOS should include
sufficient information from each section of module 3 to provide the quality reviewer
with an overview of the quality of the product. The QOS should also emphasize
critical key parameters of the medicine and provide, for instance, justification in
cases where guidelines were not followed. The QOS should include a discussion
of key issues that integrate information from sections in module 3 and supporting
information from other modules, including cross-referencing to volume(s) and page
number(s) in other module(s).
This QOS should normally not exceed 40 pages of text, excluding tables and
figures. For biotech products and products manufactured using more complex
processes, the document may be longer, but normally should not exceed 80 pages
of text, excluding tables and figures. For a sample template of the QOS, refer to
WHO Quality Overall Summary - Product Dossier (QOS-PD), 2014-12-11.1
Although, the CTD is organized by modules, the guidance providing

recommendations for applicants on preparing the CTD is organized by topic: quality,
safety, and efficacy. As a result, guidance discussed in module 2 is divided into three
sections:
 Guidance on the quality section of the CTD (module 2, Quality Overall

Summary [QOS], and module 3) may be found in the ICH M4Q: The CTD —
Quality.
 Guidance on the safety section of the CTD (module 2, the Nonclinical
Overview and the Nonclinical Written and Tabulated Summaries, and module
4) may be found in the ICH M4S: The CTD — Safety.2
 Guidance on the efficacy section of the CTD (module 2, the Clinical Overview
and the Clinical Summary, and module 5) may be found in the ICH guideline
M4E: The CTD — Efficacy.2
The Bangladesh CTD guidelines are intended to be used along with other
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) requirements for the
registration of pharmaceuticals for human use. For general information about the
CTD, as well as specific information about module 1, see the Guideline for the
1
http://apps.who.int/prequal/ (go to A-Z Listings of Documents).
2
Module 2.2 Background of the Quality Overall Summary
Submission of Bangladesh CTD: General Guidelines and Module 1. For information

on safety and efficacy, refer to the ICH M4S and M4E guidelines.2
The CTD guidelines, together with the other DGDA guidelines available on its
website, provide detailed information about the contents of an application. These
guidelines apply to applications to register medicines and all related variations.
Applicants should not modify the overall organization of the CTD. If not contained in
the bulk of the documentation, any additional data should be included as addenda to
the relevant part, together with additional expert comment that may be provided as a
supplement to, or incorporated into, the relevant summary, overall summary, or
overview.
Module 1 - Administrative Information and Prescribing Information
Relevant administrative documentation and the proposed label for use in

Bangladesh should be submitted in module 1 of the CTD dossier. This module
should be divided into the relevant sections, as described in Part B of module 1.
Module 2 - Summary of the Dossier
Module 2 of the CTD dossier contains the summaries and overviews for the quality,
nonclinical, and clinical sections of the dossier (refer to ICH guidelines M4Q, M4S,
and M4E).2 The module begins with a general introduction to the medicine, including
its pharmacological class, mode of action, and proposed clinical use. The summary
of quality information should be provided according to the World Health
Organization’s (WHO) Quality Overall Summary–product dossier (QOS-PD)
template.
Module 3 - Quality
Module 3 of the dossier contains the chemical, pharmaceutical, and biological data
relevant to the application. This information should be structured as described in the
Bangladesh CTD Module 2 (Quality Overall Summary) and 3 (Quality) guidelines.
Also, refer to the ICH Guidelines M4Q (M4Q (R1): QUALITY Module 2: Quality
Overall Summary (QOS) and Module 3: Quality.3
Module 4 - Nonclinical Study Reports
Module 4 of the dossier contains the nonclinical (pharmacotoxicological) data

relevant to the application. Exemptions apply to multisource (generic) products.
2
http://www.ich.org/products/ctd.html.
3
http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html.
3
CTD General Guidelines Module 2
Module 5 - Clinical Study Reports
Module 5 of the dossier contains the clinical data relevant to the application. In
most circumstances, the clinical studies included in module 5 of the dossier will be
international studies used to establish the pharmacodynamics, pharmacokinetics,
safety, and efficacy of the medicine across an international patient population.
However, where there is evidence to suggest that the pharmacokinetics or
pharmacodynamics of the product may vary across the populations that will use the
medicine in Bangladesh, the applicant should consider submitting studies relevant
to those target populations. These reports should be presented in the order
described in the Bangladesh CTD Module 2 (Clinical Overview), Guideline for Good
Clinical Practice (GCP) for Trials on Pharmaceutical Products, Bangladesh:
Annexure 3, and CTD Module 5 (Bioequivalence Studies) guidelines. Also, refer to
the ICH guidelines M4E (M4E (R1): Efficacy and Module 2: Clinical Overview and
Clinical Summary Module 5 Clinical Study Reports.2
In cases concerning well-known active pharmaceutical ingredients, the DGDA may

grant exemption from the submission of bioequivalence study reports in module 5.
Schematic of the Organization of the ICH CTD
4
MODULE 2.3 BODY OF DATA OF QUALITY OVERALL SUMMARY
2.3.S Active Pharmaceutical Ingredient (API) [Name, Manufacturer]
2.3.S.1 General Information [Name, Manufacturer]
Information from section 3.2.S.1 of module 3 should be included here.
2.3.S.2 Manufacture [Name, Manufacturer]
Information from section 3.2.S.2 of module 3 should be included here.
 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
materials of appropriate quality.
 A flow diagram, as provided in section 3.2.S.2.2 of module 3, should be
imported directly to this section.
 A description of the source and starting material and raw materials of
biological origin used in the manufacture of the API, as described in section
3.2.S.2.3 of module 3.
 A discussion of the selection and justification for critical manufacturing steps,
process controls, and acceptance criteria. Highlight critical process
intermediates, as described in section 3.2.S.2.4 of module 3.
 A description of process validation and/or evaluation, as described in section
3.2.S.2.5 of module 3.
 A brief summary of major manufacturing changes made throughout the
development process and conclusions from the assessment used to evaluate
product consistency, as described in section 3.2.S.2.6 of module 3. The QOS
should also cross-reference the nonclinical and clinical studies that used
batches affected by these manufacturing changes. For more information, also
refer to the ICH guidelines M4S and M4E sections of the application.
2.3.S.3 Characterization [Name, Manufacturer]
For New Chemical Entities (NCE):
A summary of the interpretation of evidence of structure and isomerism, as described

in section 3.2.S.3.1 of module 3, should be included.
When the API is chiral, please specify whether specific stereoisomers or a mixture of
stereoisomers were used in the nonclinical and clinical studies. Information should
5
also be given as to the stereoisomer of the API that is to be used in the final product
intended for marketing.
For Biotech:
A description of the desired product and product-related substances and a summary

of general properties, characteristic features, and characterization data (for example,
primary and higher order structure and biological activity), as described in section
3.2.S.3.1 of module 3, should be included.
For NCE and Biotech:
The QOS should summarize the data on potential and actual impurities arising from
the synthesis, manufacture, and/or degradation, and should summarize the basis for
setting the acceptance criteria for individual and total impurities. The QOS should
also summarize the impurity levels in batches of the API used in the nonclinical
studies, in the clinical trials, and in typical batches manufactured by the proposed
commercial process. The QOS should state how the proposed impurity limits are
qualified.
A tabulated summary of the data provided in section 3.2.S.3.2 of module 3, with

graphic representation, where appropriate, should be imported directly to this
section.
2.3.S.4 Control of Active Pharmaceutical Ingredient [Name, Manufacturer]
A brief summary of the justification for the specifications, the analytical procedures,
and validation should be included.
Specifications from section 3.2.S.4.1 of module 3 should be imported directly to this

section.
A tabulated summary of the batch analyses from section 3.2.S.4.4 of module 3, with
section.
2.3.S.5 Reference Standards or Materials [Name, Manufacturer]
Information from section 3.2.S.5 of module 3 (tabulated presentation, where

appropriate) should be included.
2.3.S.6 Container Closure System [Name, Manufacturer]
A brief description and discussion of the information from section 3.2.S.6 of module 3
should be included.
6
Module 2.3 Body of Data of Quality Overall Summary
2.3.S.7 Stability [Name, Manufacturer]
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, and the retest date or shelf life, where relevant, as
described in section 3.2.S.7.1 of module 3.
The post-approval stability protocol, as described in section 3.2.S.7.2 of module 3,

should be included.
A tabulated summary of the stability results from section 3.2.S.7.3 of module 3, with
section.
Note: A separate section 2.3.S should be provided for each API. For example, for a
second substance, the sections would be labeled 2.3.S [name 2, manufacturer]. For
a substance coming from another manufacturer, the sections would be labeled 2.3.S
[name, manufacturer 2].
2.3.P Pharmaceutical Product [Name, Dosage Form]
2.3.P.1 Description and Composition of the Pharmaceutical Product
Information from section 3.2.P.1 of module 3 should be provided.
The description and composition of the pharmaceutical product from section 3.2.P.1
of module 3 should be imported directly to this section.
2.3.P.2 Pharmaceutical Development [Name, Dosage Form]
A discussion of the information and data from section 3.2.P.2 of module 3 should be
presented. A tabulated summary of the composition of the formulations used in
clinical trials and a presentation of dissolution profiles should be imported directly to
this section, where relevant.
2.3.P.3 Manufacture [Name, Dosage Form]
Information from section 3.2.P.3 of module 3 should be included here.
 Information on the manufacturer.

 A brief description of the manufacturing process and the controls that are
intended to result in the routine and consistent production of a product of
appropriate quality.
7
 A flow diagram, as provided in section 3.2.P.3.3 of module 3, should be

imported directly to this section.
 A brief description of the process validation and/or evaluation, as described in
section 3.2.P.3.5 of module 3, should be provided.
2.3.P.4 Control of Inactive Pharmaceutical Ingredients (Excipients)

[Name, Dosage Form]
A brief summary of the quality of excipients, as described in section 3.2.P.4 of

module 3, should be included here.
2.3.P.5 Control of Pharmaceutical Product [Name, Dosage Form]
A brief summary of the justification for the specifications, a summary of the analytical
procedures and validation, and characterization of impurities should be provided.
Specifications from section 3.2.P.5.1 of module 3 should be imported directly to this

section.
A tabulated summary of the batch analyses provided under section 3.2.P.5.4 of

module 3, with graphic representation, where appropriate, should be imported
directly to this section.
2.3.P.6 Reference Standards or Materials [Name, Dosage Form]
Information from section 3.2.P.6 of module 3 (tabulated presentation, where

appropriate) should be included here.
2.3.P.7 Container Closure System [Name, Dosage Form]
A brief description and discussion of the information in section 3.2.P.7 of module 3

should be included here.
2.3.P.8 Stability [Name, Dosage Form]
A summary of the studies undertaken (conditions, batches, analytical procedures)

and a brief discussion of the results and conclusions of the stability studies and
analysis of data should be included. Conclusions regarding storage conditions and
shelf life (and in-use storage conditions and shelf life, if applicable), should be given.
A tabulated summary of the stability results from section 3.2.P.8.1 of module 3, with
section.
The post-approval stability protocol, as described in section 3.2.P.8.2 of module 3,

should be provided.
8
Module 2.3 Body of Data of Quality Overall Summary
Note: A separate section 2.3.P should be provided for each dosage form. For
example, for a second dosage form, the sections would be labeled 2.3.P [name,
dosage form 2].
2.3.A Appendices
2.3.A.1 Facilities and Equipment
For Biotech:
A summary of facility information described under Appendix 3.2.A.1 of module 3,

Facilities and Equipment, should be included here.
2.3.A.2 Adventitious Agents Safety Evaluation
A discussion of measures implemented to control endogenous and adventitious

agents in production should be included.
A tabulated summary of the reduction factors for viral clearance from Appendix
3.2.A.2 of module 3, Adventitious Agents Safety Evaluation section of module 3,
should be imported directly to this section.
2.3.A.3 Novel Excipients
A brief discussion of information described under section 3.2.A.3 of module 3 should

be included.
2.3.R Regional Information
A brief description of information specific to the region, as provided under section

3.2.R Regional Information, should be included, where appropriate.
9
MODULE 3 QUALITY
MODULE 3.1 TABLE OF CONTENTS
Module 3.2 Body of Data .......................................................................................... 11

3.2.S Active Pharmaceutical Ingredient (Name, Manufacturer) ......................... 11
3.2.S.1 General Information (Name, Manufacturer) .......................................... 12
3.2.S.2 Manufacture (Name, Manufacturer) ...................................................... 12
3.2.S.3 Characterization (Name, Manufacturer)................................................ 14
3.2.S.4 Control of Active Pharmaceutical Ingredient (Name, Manufacturer) ..... 15
3.2.S.5 Reference Standards or Materials (Name, Manufacturer) .................... 16
3.2.S.6 Container Closure System (Name, Manufacturer) ................................ 16
3.2.S.7 Stability (Name, Manufacturer) ............................................................. 16
3.2.P Pharmaceutical Product (Name, Dosage Form) ...................................... 17
3.2.P.1 Description and Composition of the Pharmaceutical Product (Name,
Dosage Form) .................................................................................................... 17
3.2.P.2 Pharmaceutical Development (Name, Dosage Form) .......................... 21
3.2.P.3 Manufacture (Name, Dosage Form) ..................................................... 24
3.2.P.4 Control of Inactive Pharmaceutical Ingredients (Name, Dosage Form) 26
3.2.P.5 Control of Pharmaceutical Product (Name, Dosage Form)................... 29
3.2.P.6 Reference Standards or Materials (Name, Dosage Form).................... 33
3.2.P.7 Container Closure System (Name, Dosage Form) ............................... 33
3.2.A Appendices .............................................................................................. 35
3.2.A.1 Facilities and Equipment (Name, Manufacturer) ................................... 35
3.2.A.2 Adventitious Agents Safety Evaluation (Name, Dosage Form,
Manufacturer) .................................................................................................... 35
3.2.A.3 Novel Excipients ................................................................................... 37
3.2.R Regional Information ................................................................................ 37
Module 3.3 Literature References ............................................................................ 38
10
MODULE 3.2 BODY OF DATA
3.2.S Active Pharmaceutical Ingredient (Name, Manufacturer)
Neither the complete nor the open part of the drug master file (DMF) should be sent
directly to the DGDA.
The information should be submitted in the dossier under the headings provided
below.
The documentation must comply with the WHO Good Manufacturing Practices4 that
has been adopted by the DGDA.
Starting materials for in situ API preparation are treated as APIs.
For a mixture of API(s) or API(s) with inactive pharmaceutical ingredients (IPI), the
blending of the ingredients is considered as the first step in the manufacture of the
final product, and therefore does not fall under the definition of an API even though it
may take place in a different facility. The resultant mixture, or partially completed
final product (e.g., coated or uncoated granules) is regarded as a finished
pharmaceutical product (FPP) intermediate.
The only exceptions can be made where the API cannot exist on its own, for
example, due to insufficient stability without a stabilizing agent.
The mixing of the API with an IPI or another API therefore forms part of the
manufacturing procedure for the final product, which is addressed in section 3.2.P.3
of module 3, while the API(s) used in such mixtures should be included in section
3.2.S of module 3, according to the requirements of sections 3.2.S.1 to 3.2.S.7 and
3.2.R.6 of module 3. The formulation, API, and IPI specifications and control
procedures, packaging materials, stability, and pharmaceutical development of the
FPP intermediate are addressed in sections 3.2.P.3, 3.2.S.2, 3.2.P.4, 3.2.P.7,
3.2.P.8, and 3.2.P.2, respectively, in accordance with the requirements of the
relevant sections.
In case of blood fractions, a Plasma Master File should be included in the dossier, if
applicable.
A separate 3.2.S should be submitted for:
 Each API (in the case of a fixed-dose combination product);

 Each API manufacturer applied for;
4
http://dgda.gov/bd.
11
 Those sections that are relevant to the FPP manufacturer in terms of testing
of the API (e.g., section 3.2.S.4).
3.2.S.1 General Information (Name, Manufacturer)
3.2.S.1.1 Nomenclature (Name, Manufacturer)
The brand name, generic name, or international nonproprietary name (INN), or

chemical description of the API(s), should be provided.
3.2.S.1.2 Structure (Name, Manufacturer)
The structural formula (indicating stereochemistry, where appropriate), systematic

name, the empirical formula, and the relative molecular mass should be provided.
3.2.S.1.3 General Properties (Name, Manufacturer)
The physical and chemical properties of the API, including, for example, solubility,
particle size, and hygroscopicity, should be indicated.
The solubility of each API should be specified in terms of a unit part of the substance
per number of parts of the solvent, or in unit mass of substance in a given volume of
solvent, at a specific temperature. The solvents should include water and the
solvent(s) relevant to the product formulation.
If the API has a low solubility in water in accordance with the Biopharmaceutical
Classification System (BCS) definition, the solubility should be quantified (mg/ml).
Evidence of the occurrence of isomers, chirality, and polymorphism, where

applicable, should be indicated. The absence of isomers, chirality, and/or
polymorphism should be confirmed.
For a multisource product, the API must be identical in structure and stereochemistry
to the API used as the reference product (pharmacopoeia structure).
3.2.S.2 Manufacture (Name, Manufacturer)
3.2.S.2.1 Manufacturer(s) (Name, Manufacturer)
The name, business, and physical address of each manufacturer of the API being
applied (including any intermediate manufacturer) should be provided.
No API from any manufacturer, other than the approved manufacturer(s), may be
used.
12
Module 3.2 Body of Data
3.2.S.2.2 Description of Manufacturing Process and Process Controls (Name,

Manufacturer)
A short description of the synthesis and a flow chart that includes: the structures and
stereochemistry of starting materials and intermediates; reagents, catalysts,
solvents, isolation, and purification; and any other relevant aspects. Note that
specifications and control procedures for substances used in this process are not
generally required. (The specific processes carried out by any intermediate
manufacturer should be identified.)
Other relevant aspects, for example, preparation of sterile material (full description of
aseptic or sterilization process, including conditions), should be included or if there is
no further sterilization of the FPP.
See 3.2.R. below for alternative to this section.
3.2.S.2.3 Control of Materials (Name, Manufacturer)
1. Full details of tests and specifications for pharmaceutical ingredients used in

the production of the primary production lot should be provided; refer to the
applicable guideline of the WHO Technical Report Series: biological products:
general recommendations.5
2. In the case of biological medicines produced using the cell bank or seed lot
system, the history (origin and sources) and preparation of the seed lot and/or
cell lines should be described with specific reference to the tests that are
carried out on such a seed lot or cell bank to establish and maintain the
integrity. Refer to the European Medicines Agency (EMA)6 and or the
applicable guideline of the WHO Technical Report Series: biological products:
general recommendations.
3. Particulars of the composition of all culture media used in the preparation and
testing of a biological medicine should be given. All raw materials of animal or
human origin must be specified as well as suppliers (indicating the country of
origin) and the certificate of analysis (CoA).
4. Particulars should be given of the other biological source material from which
a biological medicine (e.g., blood fractions) is extracted, including the origin of
the culture or blood.
5
6
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000082.jsp&mid=
WC0b01ac0580027547.
13
3.2.S.2.4 Controls of Critical Steps and Intermediates (Name, Manufacturer)
Submit information relevant for the FPP manufacturer (e.g., sterile material).
Critical Steps: Tests and acceptance criteria (with justification, including experimental
data) performed at critical steps identified in section 3.2.S.2.2 above on 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. For details, refer to ICH Guidelines: Q6A and Q6B.
Additionally for Biotech: Stability data supporting storage conditions should be

provided. For details, refer to ICH Guideline Q5C.
3.2.S.2.5 Process Validation and/or Evaluation (Name, Manufacturer)
Provide full validation data on the aseptic processing and sterilization process, where
there is no further sterilization of the FPP.
3.2.S.2.6 Manufacturing Process Development (Name, Manufacturer)
For NCEs, refer to ICH M4Q.3
3.2.S.3 Characterization (Name, Manufacturer)
3.2.S.3.1 Elucidation of Structure and other Characteristics (Name,

Manufacturer)
Provide structure (including stereochemistry) elucidation for NCEs.
Proof of correctness of structure for a well-known API (e.g., infrared [IR]

spectrometric comparison against an official standard, such as US or BP
pharmacopoeia) may be acceptable. In the case of enantiomers, an additional test is
required to confirm its identity.
If the API is not described in a monograph of any of the official pharmacopoeias, no

official standard is available, in which case sufficient evidence (nuclear magnetic
resonance, IR, mass spectrometry, elemental analysis, etc., with interpretation)
should be provided in support of the structure and stereochemistry.
3.2.S.3.2 Impurities (Name, Manufacturer)
Provide a description of impurities, indicating the possible source of impurities and a

clear distinction between actual and possible impurities.
Provide a description of possible degradation products.
14
3.2.S.4 Control of Active Pharmaceutical Ingredient (Name, Manufacturer)
3.2.S.4.1 Specifications (Name, Manufacturer)
Include the API manufacturer’s and FPP manufacturer’s (if different) specifications of
the API in tabulated format, not narrative. Indicate clearly if these specifications are
the same.
Additional specifications (e.g., isomers, chirality, polymorphs, as well as impurities,

particle size distribution, residual solvents, where relevant) should be submitted for
all APIs.
Specifications and the control procedures for the particle size of APIs that have a low
solubility in water in accordance with the BCS definition and for those which the
DGDA may request should be submitted, and the solubility quantified, unless
justified. Particle size should be given in International Systems of Units (SI).
Exemption from this requirement may be granted if the API is administered as a clear
solution.
3.2.S.4.2 Analytical Procedures (Name, Manufacturer)
Include detailed methods used for quality testing (identification, assay, determination
of related substances, residual solvents, etc.), including chromatograms for the API
manufacturer and FPP manufacturer (if different). When pharmacopoeia methods
are used, these should be current and may be referred to.
3.2.S.4.3 Validation of Analytical Procedures (Name, Manufacturer)
Include validation reports, where relevant. In-house methods require full validation.
Pharmacopoeia methods require system suitability and linearity, where applicable.
3.2.S.4.4 Batch Analyses (Name, Manufacturer)
For NCEs, extensive batch analysis is required; also for batches used in clinical
studies.
Submit valid CoAs from the API manufacturer relating to at least two batches for
NCEs and generics.
3.2.S.4.5 Justification for Specifications (Name, Manufacturer)
Full justification is required for in-house standards claimed. For details refer to ICH
Q6A.3
15
No justification is required for pharmacopoeia standards claimed unless there are

additional tests.
3.2.S.5 Reference Standards or Materials (Name, Manufacturer)
For NCEs and well-known non-compendial APIs, at least the following information on
the primary reference standard should be provided:
 Purification method, if applicable

 Establishment of purity (potency)
 CoA, with a potency statement
If a pharmacopoeia monograph is claimed, the pharmacopoeia standard should be

used.
Secondary standards should always be established against the

pharmacopoeia/primary standard. Refer to WHO Technical Report Series 943,
Annex 3 (2009)7 for more details.
3.2.S.6 Container Closure System (Name, Manufacturer)
A description of the container closure system(s) should be provided, including the

identity of construction materials for each primary packaging component, and their
specifications. The specifications should include a description and identification (and
critical dimensions, with drawings, where appropriate). Non-compendial methods
(with validation) should be included, where appropriate.
For non-functional secondary packaging components (e.g., those that do not provide
additional protection) only a brief description should be provided. For functional
secondary packaging components, additional information should be provided.
The suitability should be discussed with respect to, for example, choice of materials,
protection from moisture and light, compatibility of the construction materials with the
API, including absorption to container and leaching, and/or safety of materials of
construction.
3.2.S.7 Stability (Name, Manufacturer)
3.2.S.7.1 Stability Summary and Conclusions (Name, Manufacturer)
The storage requirements for the API, as specified by the manufacturer of the API
and/or prescribed in the pharmacopoeia or acceptable standard reference, should be
specified, and a description of the API container closure system should be included.
7
http://apps.who.int/prequal/info_general/documents/TRS953/TRS_953-Annex3.pdf.
16
If a specific storage temperature is not specified in any acceptable reference, an

instruction to protect from excessive heat, freezing, moisture, and light should be
included, unless justified.
The proposed retest period should be indicated.
3.2.S.7.2 Post-Approval Stability Protocol and Stability Commitment (Name,

Manufacturer)
The post-approval stability protocol and stability commitment should be provided. For
more details, please refer to the ICH guidelines Q1A and Q5C.
3.2.S.7.3 Stability Data (Name, Manufacturer)
1. Include results of stability studies performed on the API obtained by the route
of synthesis described in section 3.2.S.2.2 when stored in the proposed
container closure system.
2. Provide the conditions under which degradation products are formed (stress
testing).
3. A validated stability-indicating assay method, described in full, should be used

in these studies, unless the method for related substances is specific and
quantitative, such as using High Performance Liquid Chromatography (HPLC)
technique.
4. Supporting chromatograms, where relevant, should be included in the

methods or validation section.
5. Stability data on NCE APIs should be generated according to the stability

guideline (refer to ICH Q1B); for well-known chemical entities supporting
literature may be submitted.
6. For biological medicines, stability of the primary production lot and all
intermediates (if not used immediately) should be provided.
3.2.P Pharmaceutical Product (Name, Dosage Form)
3.2.P.1 Description and Composition of the Pharmaceutical Product

(Name, Dosage Form)
1. The formulation should show the INN or approved names, generic, and/or
chemical names of all APIs, and polymorph (if relevant), and approved names
of IPIs, including those that do not remain in the final product after
17
manufacturing, for example, granulating agents and gases used for flushing.
IPIs not present in the final product should be indicated.
The ingredients for in-situ preparations, pre-mixes, FPP intermediates, cores,

coating, etc. should be listed/grouped together and identified accordingly.
2. The name and the quantity of the API and the name and quantity provided
under “Composition” in the package insert and patient information leaflet (PIL)
should correspond. The name and quantity of the API per dosage unit should
also correspond to the final product specifications.
Justification should be provided for deviations.
The theoretical quantity of the base of the API should be indicated if a

compound, for example, a hydrate, solvate, or salt, is used.
If the moisture content or other characteristic of an API is relevant to the

quantity of the IPIs used in the formulation, this should be mentioned in a
footnote.
3. A product may contain more than one API provided that:
a) each API makes a contribution to the claimed indications;

b) the effect of combining the APIs in one product does not decrease the
safety, efficacy, or quality (including stability) of the product significantly;
c) the product provides rational concurrent therapy for a significant proportion
of the target population (e.g., tuberculostatic combinations).
4. Each pharmaceutical ingredient should be listed with its quantity per dosage
unit. This would include the vehicle(s), solvent(s), or base(s) (excluding
quantities of coating solvents). In the absence of an approved name (INN) or
chemical name, a chemical description or characterization of the substance
should be given. If so required and relevant, the proprietary name of the IPI
may be included in addition to the approved name.
The approved name for each ingredient should be standardized throughout

the application.
Where applicable, special characteristics of the IPI, for example, lyophilised,

micronised, solubilised, emulsified, or form (e.g., anhydrous, monohydrate)
and/or source (e.g., the botanical source of starch) should be indicated.
18
The grade of IPIs, also when a pharmacopoeia monograph covers more than
one grade (e.g., viscosity of methyl cellulose), and the type of water (e.g.,
purified, water for injection), where relevant, should be indicated.
The use of IPIs that are not described in official pharmacopoeia is strongly
discouraged and should be justified. This includes flavorant, fragrance,
colorant, and ink.
5. The purpose of each IPI should be briefly described. If the IPI is used for
multiple purposes in the formulation, each purpose should be mentioned.
The name of each API and IPI should correspond and the quantities correlate
with those reflected in the batch formulation submitted in section 3.2.P.3.2 of
module 3, and the batch manufacturing record submitted or made available
for inspection.
6. Some IPIs are single chemical entities, while others are combinations. Some
are chemically transformed (e.g., modified starch). For excipients that are
mixtures of chemically related or unrelated components, for example, polyol
esters (mixture of mono, di, and tri esters), direct compression excipients,
solutions, or film coating formulations, or excipients that are chemically
modified, the nature and quantity of each such excipient should be specified.
The qualitative composition of inks should be specified.
The composition of these mixtures/combinations could be attached to the

formulation information or included separately on the next page.
7. Any overages for the API should be given separately. The label claim quantity
should be provided and the excess quantity indicated as the actual quantity or
as a percentage. For example, 500 mg + 5 mg (= 1 %) overage.* (*Use the
asterisk to indicate the justification for the overage.)
The reason for the overage should be indicated/justified, for example, with
reference to batch results, in section 3.2.P.2.2.2 of module 3.
8. If a potency adjustment for the API has to be made, a statement to the effect
that the actual quantity of the API will depend on the potency and the IPI(s)
that will be used to adjust the bulk quantity should be made. The manner in
which the adjustment will be made should also be specified.
If the moisture content or other characteristic of an IPI is relevant to the

quantity of the IPI used in the formulation, this should be mentioned in a
footnote.
19
9. Permitted flavoring and coloring agents (that comply with directives of the
European Union [EU] or the register of the US Food and Drug Administration
[USFDA]), in many instances because of their complexity, may be described
in terms of their main constituents only, provided that a conclusive
identification is given in the relevant section.
The Color Index Numbers or the colorant reference number, in accordance

with the EU or USFDA directive on colorants, should be included in the
formulation.
The use of dyes, printing ink, coating materials, flavorants, and organic
solvents is subject to the same safety and quality requirements that apply to
medicinal substances.
10. The content of alcohol, if included in medicines for oral administration, should
comply with the requirements of the Alcohol Content of Medicines guideline
(EMA or USFDA guidelines).
11. If a vehicle is added up to the required volume or mass of the product, the
actual or estimated quantity of that vehicle may be indicated. Expressions
such as “add up to” and “q.s.” are acceptable. Solutions added to adjust the
pH should be described in terms of composition and strength (e.g., normality,
molarity), but it is not necessary to state the actual quantity added as none or
only minute quantities may be required.
12. In the case of capsules, the fill mass as well as the capsule size, composition,
and mass should be indicated.
13. The theoretical mass should be indicated for uncoated tablets. In the case of
coated dosage forms, the theoretical mass of the core, coating material, as
well as the total mass of the dosage form/unit should be indicated and the IPIs
used for each should be grouped separately.
14. For biological medicines, the details of any solution supplied by the
manufacturer for the reconstitution before use of a dried biological medicine
that is offered for sale in a dried form should be supplied.
15. Toxicity levels per dosage unit should be indicated for all solvents and for
other ingredients when required by the DGDA. Levels should be indicated as
per the most recent edition of The Complete Drug Reference by United States
Pharmacopoeia or other related document.
20
3.2.P.2 Pharmaceutical Development (Name, Dosage Form)
A pharmaceutical development report (generally of not more than 25 pages on A4

paper) should be submitted with each application. It should include at least an overall
conclusion and the following information:
3.2.P.2.1 Components of the Pharmaceutical Product (Name, Dosage Form)
3.2.P.2.1.1 Active Pharmaceutical Substance(s) (Name, Dosage Form)
 Comment on the synthesis of the API(s);

 Discussion of all the physicochemical properties, for example, solubility (in
terms of BCS classification), water content, particle size distribution, crystal
properties, polymorphs, chirality, isomers, and stability of the API that can
influence the performance of the final product.
 The compatibility of the API with excipients listed in section 3.2.P.1 should be
discussed.
 Provide studies (literature) on the proposed excipients. If the excipients are
the same as those of the reference product, this information is not required.
 In the case of fixed-dose combination (FDC) products, extensive studies on
API-API compatibility under various conditions (aqueous medium and solid
state) should be provided. For well-established combinations, literature
information may suffice, if available. In general, the pharmaceutical
development and quality aspects of FDC products should be in accordance
with the WHO Technical Report Series No. 929, “Guidelines for Registration
of Fixed-dose Combination Medicinal Products” (2005)8 or the most recent
revision.
3.2.P.2.1.2 Inactive Pharmaceutical Ingredients or Excipients (Name, Dosage

Form)
 Submit an explanation of the function of the excipients.

 For multisource products, state whether excipients are the same as in the
reference product.
 Non-compendial excipients should be avoided in generic products.
Safety/toxicity profile of the excipients should be submitted if it is non-
compendial.
 All the excipients used during the development should be clearly listed in
tabulated form (see the sample table below).
8
http://apps.who.int/medicinedocs/en/d/Js19979en/.
21
List of Excipients Used
Inactive Ingredient Name(s) Dosage Dosage Pharmacopoeia Maximum Potency

Strength Unit Reference Allowed
3.2.P.2.2 Final Pharmaceutical Product (Name, Dosage Form)
3.2.P.2.2.1 Formulation Development (Name, Dosage Form)
 Data or literature (including the qualitative composition of the innovator

product) on any interactions likely to occur, or that may occur, under given
circumstances between the API and excipients should be provided.
 For multisource products, include a tabulated comparison of the qualitative
composition, appearance, physical parameters, impurity profiles, and other
relevant parameters of the test and reference/innovator products.
 Discussion of the relevant physicochemical parameters (e.g., dissolution and
choice of medium, effect of pH) should be provided. The dissolution conditions
and acceptance criteria should be derived from the multipoint comparative
data generated for the batch used in the bioequivalence/biowaiver studies.
 Provide information on tablet “scoring,”, if applicable
o Functional scoring:
 Provide data from a study on the uniformity of dosage units of the tablet
halves in terms of United States Pharmacopoeia (USP) or European
Pharmacopoeia (Ph Eur)/British Pharmacopoeia (BP)
recommendations. The data generated should support and be in line
with the dosage and directions outlined in the PI/PIL.
o Non-functional scoring:
 This should be explained / justified. It should be indicated as non-

functional in the PI/PIL.
 Pre-formulation testing;
 Clinical trial formulations;
 Discussion or explanation of novel formulations and novel IPI composition,
function, and safety;
22
 Any differences in the formulation during the development should be indicated

clearly in tabulated form;
 Stability (may refer to section 3.2.P.8);
 Discussion of the stability of the final product formulation, the parameters and
specifications used during stability, and to confirm quality for lot release;
 Conclusion on stability and shelf-life allocation.
3.2.P.2.2.2 Overages (Name, Dosage Form)
Provide the following information:
 A justification/explanation for overages.

 Overages for the sole purpose of extending the shelf-life of the FPP are
generally not acceptable, unless justified.
3.2.P.2.2.3 Physicochemical and Biological Properties (Name, Dosage Form)
 Parameters relevant to the performance of the final product, such as pH, ionic
strength, dissolution, redispersion, reconstitution, particle size distribution,
aggregation, polymorphism, rheological properties, biological activity or
potency, and/or immunological activity, should be addressed.
 Show that no precipitation will occur with poorly soluble APIs formulated at a
non-physiological pH or formulated with co-solvents.
3.2.P.2.3 Manufacturing Process Development (Name, Dosage Form)
The selection and optimization of the manufacturing process described in 3.2.P.3.3,

the critical aspects, in particular, should be explained. Where relevant, the method of
sterilization should be explained and justified, and compatibility with production
equipment (e.g., filter media).
Differences between the manufacturing process(es) used to produce pivotal clinical

batches and the process described in 3.2.P.3.3 that can influence the performance of
the product should be discussed.
3.2.P.2.4 Container Closure System (Name, Dosage Form)
The suitability of the container closure system described in 3.2.P.7 used for storage,
transportation (shipping), and use of the final product should be discussed. This
discussion should consider, for example: choice of materials; protection from
moisture and light; compatibility of the construction materials with the dosage form
(including sorption to container and leaching, injections with rubber closures); safety
of construction materials; and performance, such as reproducibility of the dose
23
delivery from the device when presented as part of the FPP product (e.g.,
inhalers/aerosols).
3.2.P.2.5 Microbiological Attributes (Name, Dosage Form)
Where appropriate, the microbiological attributes of the dosage form should be

discussed, including, for example: the rationale for not performing microbial limit
testing for non-sterile products, and the selection and effectiveness of preservative
systems in products containing antimicrobial preservatives. This should be
determined on at least one stability batch (aging).
For sterile products, the integrity of the container closure system to prevent microbial
contamination should be addressed, as well as in-use stability testing, whether there
is a preservative or not, including eye drops. Also see 3.2.P.8.
3.2.P.2.6 Compatibility (Name, Dosage Form)
The compatibility of the FPP with:
 Reconstitution diluent(s);
 IV solutions: provide data or reference to primary references;
 Dosage devices (e.g., precipitation of API in solution; sorption on injection
administration sets; adsorption by in-line filters) should be addressed to
provide appropriate and supportive information for the labeling.
3.2.P.3 Manufacture (Name, Dosage Form)
3.2.P.3.1 Manufacturer(s) (Name, Dosage Form)
If more than one pharmaceutical manufacturing facility/site is involved in any of the

manufacturing or packaging processes, the complete name and physical address of
each site should be given, the various stages of manufacturing and packaging at
each site clearly identified, and the declaration of similarity included in section 1.7.5.
of module 1. If all the stages of manufacturing and packaging are performed at one
site, a statement confirming this will suffice.
An inspection flow diagram, also of FPP intermediates, clearly indicating the sites
and processes, including clear distinction between primary and secondary packers,
should be included. (section 1.7.10 of module 1).
3.2.P.3.2 Batch Formula (Name, Dosage Form)
The batch manufacturing formulation, also for FPP intermediates, and the batch
size(s) (number of dosage units) should be included. If more than one batch size is
indicated, the batch formulation for each of the batch sizes should be given.
24
3.2.P.3.3 Description of Manufacturing Process and Process Controls (Name,

Dosage Form)
The following should be submitted:
 A comprehensive flow diagram, detailing the various stages of manufacturing.
 A comprehensive description of the manufacturing procedures, detailing the

various stages of manufacturing, derived from the master manufacturing
documents.
The type and size of manufacturing equipment (including sieve sizes in metric
units), duration of treatment, temperature, light and humidity conditions,
machine settings (e.g., rotation speed or rpm), and other relevant details
should be indicated.
For sterile manufacturing, the grades of clean areas should also be indicated.
 A brief description of the packaging procedure:
A brief description of the packaging procedure reflecting the stages,

temperature, humidity, and other conditions applicable for the packaging of
specific dosage forms (e.g., effervescent tablets and granules) should be
included.
For sterile manufacturing, the grades of clean areas should also be indicated.
The frequency of all in-process control tests (analytical, microbiological,

physical, packaging, and labeling) should be shown in the flow diagram or
specified in the description.
 Either a copy of the Master Batch Manufacturing and Packaging Document or

Records for a batch or the Batch Records should be available for inspection,
or be available on request.
3.2.P.3.4 Controls of Critical Steps and Intermediates (Name, Dosage Form)
The frequency of all in-process control tests (analytical, microbiological, physical,

packaging, and labeling) should be shown in the flow diagram or specified in the
description.
3.2.P.3.5 Process Validation and/or Evaluation (Name, Dosage Form)
A process validation protocol (VP) or validation report (VR) should be submitted.
25
The validation of the maximum holding time of the final product before packaging,
and the holding time of FPP intermediates before further processing should also be
addressed. The conditions during storage and/or shipping should be covered.
If different sterilization methods are used, validation of each method should be

addressed in the VP or VR that is provided. This would include a description of the
sterilization processes, aseptic manipulation, in-process controls, and grades of
clean areas. Validation should include the validation of the maximum holding time
before packing into the final container, and the holding time of FPP intermediates
before further processing.
New Applications for Registration:
A VP or a VR should be included in 3.2.P.3.5. If the VP is submitted, the VR should

be submitted only if and when requested by the DGDA.
Applications for Change in Applicant/Manufacturer/Packer/Laboratory
A VP or VR should be submitted with each application for a change in manufacturer

or laboratory, or a change in the applicant where it also involves a change in the
manufacturer.
If the validation has already been done, it should be indicated as such in the
application, and the VP and VR have to be submitted.
3.2.P.4 Control of Inactive Pharmaceutical Ingredients (Name, Dosage

Form)
The approved name of each ingredient should concur with that reflected in the
formulation in section 3.2.P.1.
3.2.P.4.1 Specifications (Name, Dosage Form)
Compendial and Non-Compendial
1. Specifications (titles and the limits) of all the IPIs and also the IPIs of FPP
intermediates, should be listed. Adherence to current pharmacopoeia
requirements (BP, USP, and Ph Eur), where applicable, is recommended, in
which case it is not necessary to list specifications. Any deviation from such
specifications should be fully substantiated (e.g., non-inclusion of a specific
impurity specification due to a different route of synthesis).
26
Use of any other pharmacopoeia should be justified and acceptable to the

DGDA. In the latter case, copies of the relevant monographs should be
included.
More than one pharmacopoeia may be used for the IPIs provided that each
individual reference is used fully, and not partially or selectively. For example:
 the USP may be used for starch and the BP for lactose;
 an individual IPI may be referenced fully in two or more recognized
pharmacopoeia simultaneously;
 an in-house specification consisting of all parameters and that includes the
most stringent criteria of acceptance of two or more recognized
pharmacopoeia.
For non-pharmacopoeia entities, the specifications should be at the

pharmacopoeia level, i.e., based on current pharmacopoeia requirements for
similar pharmacopoeia entities. (See ICH Q6A.Error! Bookmark not
efined.)
2. Functionality specifications that confirm the IPI characteristics should be

indicated.
3. Colorants and flavorants should comply with either one of the following:
 At least a specification and control procedure regarding the chemical

identification, a statement that the flavorants comply with the general
requirements, and that the colorants comply with the purity criteria. At least
a specification and control procedure regarding chemical identification and
a statement that it complies with the directives of the EU or the register of
the USFDA.
4. Microbial limits and control procedures for all organic ingredients of natural
origin should be included (e.g., maize starch is an organic IPI of natural origin
[test], but selenium dioxide is an inorganic IPI of natural origin [no test]).
5. Empty capsule specifications should include the description, moisture content,

disintegration time, and microbial limits.
6. The absence of diethylene glycol should be specified for propylene glycol and
glycerine if the dosage form is for oral or parenteral administration.
7. Specifications and control procedures should be included for intermediate

preparations used as ingredients in the formulation as well as for each of the
27
ingredients contained in the intermediate preparation. If stock preparations of

the intermediate preparation are used, specification and control procedures to
ensure the stability and confirm the identity should be included.
8. For biological medicines:
a) Specifications for the primary production lot used in the manufacture of

the final filling lot of a biological medicine and specifications for all
ingredients for the diluent should be listed.
b) Tests for a biological source material should include tests to confirm
the identification, safety, and potency of the primary production or bulk
lot used in the manufacture of the final filling lot.
c) Parameters and criteria of acceptance to confirm the identification,
safety, and potency of the product should be provided.
3.2.P.4.2 Analytical Procedures (Name, Dosage Form)
Control procedures for all IPIs should be fully described. These should include
physicochemical tests, purity tests, solubility and assay, and any other relevant tests.
When pharmacopoeia methods are used, they should be current and may be
referred to.
3.2.P.4.3 Validation of analytical procedures (Name, Dosage Form)
Analytical validation information, including experimental data, for the analytical

procedures used for testing the excipients should be provided, where appropriate.
(Refer to ICH Guidelines Q2R1, Q6B.9)
3.2.P.4.4 Justification for Specifications (Name, Dosage Form)
Justification for the proposed excipient specification should be provided, where

appropriate. (Refer ICH Guidelines Q3C and Q6B.9)
3.2.P.4.5 Excipients of Human or Animal Origin (Name, Dosage Form)
Refer to section 3.2.A.3 and ICH M4Q.Error! Bookmark not defined.
3.2.P.4.6 Novel Excipients (Name, Dosage Form)
For excipients(s) used for the first time in a FPP or by a new route of administration,
full details of manufacture, characterization, and controls, with cross-references to
supporting safety data (non-clinical and/or clinical) should be provided according to
the API format. (Details may be found in section 3.2.A.3.)
9
28
3.2.P.5 Control of Pharmaceutical Product (Name, Dosage Form)
3.2.P.5.1 Specification(s) (Name, Dosage Form)
1. Specifications (titles and limits) should be listed for in-process controls, FPP
intermediate controls, final product controls (batch release), stability controls,
and the reconstituted or diluted final product (if applicable). (If the in-process
controls are submitted in section 3.2.P.3.3 of module 3, a cross reference will
suffice.) In-process controls should be clearly identified as such, including
those performed on bulk (e.g., liquids and semi-solids prior to packaging).
If a product is included in a recognized pharmacopoeia, any deviation from the
relevant monograph should be justified.
2. The description of the final product and the description given under
“Identification” in the package insert should correspond. The description
should be such that visual identification of counterfeit medicines is facilitated,
where possible.
3. If any specification is not appropriate for a particular product, an explanation

should be included. Other parameters not appropriate for stability testing
should also be included (e.g., a specification for residual organic solvents
used during the coating procedure or sterility).
The limits and acceptance criteria for each parameter (physical, chemical, and
microbial, if applicable) should be fully described. To state ''complies'' for
acceptance criteria is not acceptable.
Physical and Other Properties
4. At least the following physical and other properties additional to those listed in
the Stability Guideline, should be specified, as appropriate, for the dosage
form, unless the omission is justified:
a) Tablets, lozenges, capsules, suppositories
Theoretical mass, average mass and mass limits, uniformity of dosage

units, divisibility of scored tablet with the relevant mass uniformity of the
divided tablet.
Intactness of coating, in the case of coated tablets, if the coating has a

protective purpose. If not appropriate for a particular product (e.g., film
coat), an explanation should be included.
29
Microbial testing, as lot release requirement for capsules, is not a

requirement if microbial testing of the empty capsules is performed and
submitted in section 3.2.P.4 of module 3.
For soft gelatin capsules containing oily liquid, peroxide value /acid value/
iodine value and any other appropriate parameter, suspension content
uniformity of each should be provided.
b) Emulsions, suspensions, solutions:
Alcohol content, tonicity (eye and nasal preparations), fill volume or mass,
deliverable volume. Peroxide value/acid value/iodine value and any other
appropriate parameter for oily preparations should be included
c) Powders, granules (including those for reconstitution), metered dose

inhalation aerosols: Fill volume or mass.
d) Ointments, creams
Peroxide value/acid value/iodine value and any other appropriate

parameter for oily preparations should be included.
e) Parenterals
Evaluation of FPP intermediates for parenterals should also include

homogeneity, and FPP intermediate sterile powders should also include
evaluation of sterility and bacterial endotoxin testing.
f) FPP intermediate (defined in the WHO Guideline to Good Manufacturing

Practices as partially completed final product, pre-mixes, microspheres,
granules, coated granules, sterile powders, etc.).
FPP intermediates should also include evaluation of homogeneity and

other appropriate parameters relevant to the FPP intermediate
product/dosage form.
Assay/Content
5. The limits of acceptance for the content of each active ingredient should be
expressed as a percentage of the label claim. Limits greater than 5.0 % of the
label claim should be justified, except in the case of vitamins.
6. Uniformity of dosage units should be in accordance with the general

requirements of the current editions of the official pharmacopoeia. Note that
30
the uniformity has been harmonized in the ICH region (see ICH guideline Q4B
Annex 6).10
Also refer to the WHO Technical Report Series 929, “Guidelines for the
Registration of Fixed-dose Combination Medicinal Products” (2005) or the
most recent revision.
FPP intermediates, including parenterals, should also be evaluated for

homogeneity. (Refer paragraph 4. above.)
Dissolution and Disintegration
7. Batch release and stability specifications for all solid oral dosage forms,
including chewable tablets and suspensions, where applicable, should include
a requirement for the dissolution of the API(s) (generally single point for
immediate release, multipoint for modified release), unless otherwise
determined by the DGDA.
8. Disintegration time, where relevant, for example, for chew tablets, matrix
tablets, and soft gelatin capsules, should be determined on all batches on
which dissolution is not determined as a requirement for lot release as well as
for stability. Disintegration time may be used as a lot release requirement for
preparations containing multivitamins and minerals, unless a dissolution
requirement for a specific product is included in the USP, in which case
dissolution should be done as a lot release requirement.
Preservative Efficacy
9. The preservative efficacy of relevant dosage forms and/or presentations (e.g.,

multi-dose vials, eye drops) should be specified in section 3.2.P.5.1 and
presented in section 3.2.P.8 of module 3. However, once established for the
lowest limit of preservative content specification, it is not a routine batch test
requirement.
Endotoxins
10. For a product from a non-biological origin that has endotoxin levels, the
validation data, as required by the USP/BP/Ph Eur, should be submitted.
11. If the endotoxin levels are not determined according to the method in a
recognized pharmacopoeia, the validation data should be submitted for
evaluation.
10
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q4B/Q4B_Annex_6_Step_
4.pdf.
31
3.2.P.5.2 Analytical Procedures (Name, Dosage Form)
All control procedures, other than those from a recognized pharmacopoeia,

should be described in full, with calculations included, where relevant.
If an analysis is not technologically possible (e.g., complex extracts), an
explanation and alternative quality criteria should be submitted.
3.2.P.5.3 Validation of Analytical Procedures (Name, Dosage Form)
1. The full validation data of the assay method of the API related to batch
release should be submitted. Chromatograms confirming the separation of the
API from the degradation products, if relevant, should be included.
2. It should be demonstrated that the assay method is stability-indicating, i.e., it
should distinguish between the API(s) and the degradation product(s).
3. If the assay method used to determine the API content is not stability-
indicating, it cannot be used for assaying after importation.
4. If the assay method (chromatographic) is taken from one of the latest

recognized pharmacopoeias, other partial validation data (e.g., system
suitability and specificity) should be submitted.
5. If an assay method different from the batch release method is used for
stability testing, the validation of the assay method and a full description
thereof should be submitted.
6. Supportive chromatograms for the validation should be submitted, if relevant.
7. All other quantitative assay methods (e.g., preservatives, degradation

products, antioxidants, dissolution assay) should be validated and the
validation data included.
If not in accordance with the relevant pharmacopoeia, an explanation should

be included for the deviation. All the relevant limits should also be justified by
stability or batch data.
3.2.P.5.4 Batch Analyses (Name, Dosage Form)
1. Complete batch analysis data for at least two batches (pilot or production)
of the final product should be submitted with the application.
2. For imported products, at least the identification and assay of the API
content should be performed by an approved laboratory (Finished Product
32
Release Control [FPRC]) after importation. This is to verify that the product
has not been affected adversely during transport.
3.2.P.5.5 Characterization of Impurities (Name, Dosage Form)
Information on the characterization of impurities should be provided, if not

previously provided in section 3.2.S.3.2 (Impurities) (Refer to ICH Guidelines
Q3B, Q5C, Q6A, Q6B.9)
3.2.P.5.6 Justification for Specifications (Name, Dosage Form)
Justification for the proposed final product specifications should be provided.

(Refer to ICH Guidelines Q3B, Q6A and Q6B.9)
3.2.P.6 Reference Standards or Materials (Name, Dosage Form)
For NCEs and well-known non-compendial APIs, at least the following

information on the primary reference standard should be provided:
 Purification method, if applicable

 Establishment of purity (potency)
 CoA, with a potency statement
If a pharmacopoeia monograph is claimed, the pharmacopoeia standard

should be used.
Secondary standards should always be established against the

pharmacopoeia/primary standard. For more details, refer to WHO Technical Report
Series 943, Annex 3 (2007).11
3.2.P.7 Container Closure System (Name, Dosage Form)
1. The immediate container specifications (titles and limits), including the nature
of the material, dimensions, and sketches, where applicable, as well as those
of patient ready packs, the closure system, wadding, and any other
component in direct contact with the product, where applicable, and a
description of the control procedures, should be supplied.
They should include:
 The moisture and gas permeability of polyvinyl chloride (PVC), if not

already supported by real time stability data of the product (not relevant
for PVC forming a base layer of aluminum blisters); and
11
http://whqlibdoc.who.int/trs/WHO_TRS_943_eng.pdf.
33
 Heat seal bond strength/intactness of the blister (integrity of the seal) –

section 3.2.P.3.3 may be referred to for further details.
2. A description of the control procedures performed by the manufacturer of the

final product should be given.
3. A brief description of the outer container, if any, should also be given. At least
the nature of the material should be mentioned (e.g., outer cardboard carton).
4. The description of the container and that reflected in the package insert under
“Presentation” and in the stability studies should correspond. To facilitate the
visual identification of counterfeit medicines (also by the public), the
description should include the type, color, and clarity of the container (e.g.,
clear plastic/silver aluminum blister).
5. If the product is packed in bulk containers, the type of material of the container
should be described.
The maximum period that the product may be stored (bulk) before final
packaging should be given in section 3.2.P.3.3 of module 3. The nature of the
container should be given in section 3.2.P.7 of module 3, with supporting data
provided in section 3.2.P.8 of module 3.
6. The type of material and the dimensions, including sketches of ampoules,

vials, aerosols, applicators, and administration sets should be given. Sketches
of containers for oral dosage forms and blister packs are not required.
7. All pack sizes should be described in the submission.
8. If equivalent or more protective immediate container packaging material than

that used in stability testing or approved (post-registration), is applied for, data
to substantiate the claim should be submitted (e.g., USP permeation test).
9. Child-protective measures should be employed with regard to the retail sale of

salicylates, paracetamol, and iron tablets or capsules. Smaller sales packs
and blister packaging are regarded as suitable child protective measures.
3.2.P.8 Stability (Name, Dosage Form)
3.2.P.8.1 Stability Summary and Conclusion (Name, Dosage Form)
A tabulated summary of the data, clearly indicating the number and types /sizes
(production, pilot, or experimental) of batches, packaging material, storage
34
conditions and storage period, and manufacturer of the API with API batch numbers,
should be included for each final product manufacturer.
3.2.P.8.2 Post-Approval Stability Protocol and Stability Commitment (Name,

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

Refer to ICH guidelines Q1A and Q5C.
3.2.P.8.3 Stability Data (Name, Dosage Form)
All applications for registration of a medicine should be submitted with stability data,
in accordance with the minimum requirements given in the Stability guideline.
3.2.A Appendices
3.2.A.1 Facilities and Equipment (Name, Manufacturer)
For Biotech:
A diagram should be provided illustrating the manufacturing flow, including

movement of raw materials, personnel, waste, and intermediates in and out of the
manufacturing areas. Information should be presented with respect to adjacent areas
or rooms that may be of concern for maintaining integrity of the product.
Information on all developmental or approved products manufactured or manipulated

in the same areas as the applicant's product should be included.
A summary description of product-contact equipment and its use (dedicated or multi-

use) should be provided. Information on preparation, cleaning, sterilization, and
storage of specified equipment and materials should be included, as appropriate.
Information should be included on procedures (e.g., cleaning and production

scheduling) and design features of the facility (e.g., area classifications) to prevent
contamination or cross-contamination of areas and equipment where operations for
the preparation of cell banks and product manufacturing are performed.
3.2.A.2 Adventitious Agents Safety Evaluation (Name, Dosage Form,

Manufacturer)
Information assessing the risk of potential contamination with adventitious agents

should be provided in this section.
35
For Non-Viral Adventitious Agents:
Detailed information should be provided on the avoidance and control of nonviral

adventitious agents (e.g., transmissible spongiform encephalopathy agents, bacteria,
mycoplasma, fungi). This information may include, for example, certification and/or
testing of raw materials and excipients and control of the production process, as
appropriate for the material, process, and agent.
Reference: ICH guidelines Q5A, Q5D, and Q6B.
For Viral Adventitious Agents:
Detailed information from viral safety evaluation studies should be provided in this
section.
Viral evaluation studies should demonstrate that the materials used in production are
considered safe, and that the approaches used to test, evaluate, and eliminate the
potential risks during manufacturing are suitable. The applicant should refer to ICH
guidelines Q5A, Q5D, and Q6B for more details.
Information essential to evaluate the virological safety of materials of animal or

human origin (e.g., biological fluids, tissue, organ, cell lines) should be provided.
(See related information in sections 3.2.S.2.3, and 3.2.P.4.5.) For cell lines,
information on the selection, testing, and safety assessment for potential viral
contamination of the cells and viral qualification of cell banks should also be
provided. (See related information in section 3.2.S.2.3.)
The selection of virological tests that are conducted during manufacturing (e.g., cell
substrate, unprocessed bulk, or postviral clearance testing), should be justified. The
type of test, sensitivity, and specificity of the test, if applicable, and frequency of
testing should be included. Test results to confirm, at an appropriate stage of
manufacture, that the product is free from viral contamination should be provided.
(See related information in sections 3.2.S.2.4 and 3.2.P.3.4.) In accordance with ICH
guidelines Q5A and Q6B, results for viral testing of unprocessed bulk should be
included.
In accordance with ICH guideline Q5A, the rationale and action plan for
assessing viral clearance and the results and evaluation of the viral clearance
studies should be provided. Data may include those that demonstrate the validity
of the scaled-down model compared to the commercial scale process, the
adequacy of viral inactivation or removal procedures for manufacturing
equipment and materials, and manufacturing steps that are capable of removing
or inactivating viruses. (See related information in sections 3.2.S.2.5 and
3.2.P.3.5.) For details, refer to the ICH guidelines Q5A, Q5D, and Q6B.
36
3.2.A.3 Novel Excipients
For excipients(s) used for the first time in a FPP or by new route of administration,
full details of manufacture, characterization and controls, with cross-references to
supporting safety data (non-clinical and/or clinical) should be provided according to
the API format.
3.2.R Regional Information
Any additional medicinal substance and/or medicine product information specific to

each region, e.g., in Asia, should be provided in section R of the application.
Applicants should consult the appropriate regional guidance and/or regulatory
authorities for additional guidance.
37
MODULE 3.3 LITERATURE REFERENCES
Key literature referenced should be provided, if applicable.
38
REFERENCES
1. Department of Health, Republic of South Africa, Medicines Control Council.

Pharmaceutical and Analytical CTD/eCTD.
http://www.mccza.com/genericDocuments/2.25_PA_CTD_Aug14_v4.pdf.
Published June 2010. Revised August 2014. Accessed February 2014.
2. International Conference on Harmonisation. Quality Guidelines.
3. USFDA. International Conference on Harmonisation – Quality.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/ucm065005.htm. Accessed February 2014.
4. European Medicines Agency. ICH: Topic M 4
Common Technical Document for the Registration of Pharmaceuticals for Human
Use – Organisation CTD.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20
09/09/WC500002721.pdf. Effective February 2004. Accessed February 2014.
5. WHO Technical Report Series 937. WHO Expert Committee on Specifications for
Pharmaceutical Preparations. http://whqlibdoc.who.int/trs/who_trs_937_eng.pdf.
Published 2006. Accessed February 2014.
6. WHO Technical Report Series 929. WHO Expert Committee on Specifications
for Pharmaceutical Preparations.
http://apps.who.int/prequal/info_general/documents/trs929/who_trs_929.pdf.
7. Technical Report Series: biological products: general recommendations.
http://www.who.int/biologicals/publications/trs/areas/biological_products/en/.
39

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DIRECTORATE GENERAL

MINISTRY OF HEALTH & FAMILY WELFARE

GUIDELINE FOR THE SUBMISSION

Version 1 released for pilot implementation and comments

The Directorate General of Drug Administration (DGDA) of Bangladesh is changing

The DGDA is also planning to implement PharmaDex to track registration

The Systems for Improved Access to Pharmaceuticals and Services (SIAPS)

To adopt the CTD and implement PharmaDex, a series of workshops were

Major Gen Md. Jahangir Hossain Mollik

API active pharmaceutical ingredient

MODULE 2.1 TABLE OF CONTENTS

Module 2.2 Background of the Quality Overall Summary ........................................... 2

Although, the CTD is organized by modules, the guidance providing

 Guidance on the quality section of the CTD (module 2, Quality Overall

Submission of Bangladesh CTD: General Guidelines and Module 1. For information

Module 1 - Administrative Information and Prescribing Information

Relevant administrative documentation and the proposed label for use in

Module 2 - Summary of the Dossier

Module 4 - Nonclinical Study Reports

Module 4 of the dossier contains the nonclinical (pharmacotoxicological) data

Module 5 - Clinical Study Reports

In cases concerning well-known active pharmaceutical ingredients, the DGDA may

Schematic of the Organization of the ICH CTD

2.3.S Active Pharmaceutical Ingredient (API) [Name, Manufacturer]

2.3.S.1 General Information [Name, Manufacturer]

Information from section 3.2.S.1 of module 3 should be included here.

2.3.S.2 Manufacture [Name, Manufacturer]

Information from section 3.2.S.2 of module 3 should be included here.

 Information on the manufacturer.

2.3.S.3 Characterization [Name, Manufacturer]

For New Chemical Entities (NCE):

A summary of the interpretation of evidence of structure and isomerism, as described

A description of the desired product and product-related substances and a summary

For NCE and Biotech:

A tabulated summary of the data provided in section 3.2.S.3.2 of module 3, with

2.3.S.4 Control of Active Pharmaceutical Ingredient [Name, Manufacturer]

Specifications from section 3.2.S.4.1 of module 3 should be imported directly to this

2.3.S.5 Reference Standards or Materials [Name, Manufacturer]

Information from section 3.2.S.5 of module 3 (tabulated presentation, where

2.3.S.6 Container Closure System [Name, Manufacturer]

2.3.S.7 Stability [Name, Manufacturer]

This section should include a summary of the studies undertaken (conditions,

The post-approval stability protocol, as described in section 3.2.S.7.2 of module 3,

2.3.P Pharmaceutical Product [Name, Dosage Form]

2.3.P.1 Description and Composition of the Pharmaceutical Product

Information from section 3.2.P.1 of module 3 should be provided.

2.3.P.2 Pharmaceutical Development [Name, Dosage Form]

2.3.P.3 Manufacture [Name, Dosage Form]

Information from section 3.2.P.3 of module 3 should be included here.

 Information on the manufacturer.

 A flow diagram, as provided in section 3.2.P.3.3 of module 3, should be

2.3.P.4 Control of Inactive Pharmaceutical Ingredients (Excipients)

A brief summary of the quality of excipients, as described in section 3.2.P.4 of

2.3.P.5 Control of Pharmaceutical Product [Name, Dosage Form]

Specifications from section 3.2.P.5.1 of module 3 should be imported directly to this

A tabulated summary of the batch analyses provided under section 3.2.P.5.4 of

2.3.P.6 Reference Standards or Materials [Name, Dosage Form]

Information from section 3.2.P.6 of module 3 (tabulated presentation, where

2.3.P.7 Container Closure System [Name, Dosage Form]