Wollo University
College of Medicine and Health
Science
Assignment presentation on Dossier and Dossier assessment process
By: Siasy Belachew ( ID -0359/-13)
Submitted to: Yimer Seid ([Link], MSc and Assnt Professor in Pharmaceutical analysis)
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Outline
Introduction
General principle
Organization of CTD
Reference
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Objective
At the end of this lesson we will be able to:
Define about Dossier
Discuss on dossier structure
And dossier evaluation
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Introduction
There is a series of guidance's that provide
recommendations for applicants preparing the CTD
for the Registration of Pharmaceuticals for Human
Use (CTD) for submission to the U.S. (FDA).
M4 –organization guidance presents the agreed upon
common format for the preparation of a well-
structured CTD for applications that will be
submitted to regulatory authorities.
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Introduction…
A common format for the technical documentation
will significantly reduce:
• The time and
• Resources needed to compile applications for registration
of human pharmaceuticals and will ease the preparation of
electronic submissions.
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Introduction…
Regulatory reviews and communication with the
applicant will be facilitated by a standard document
of common elements.
In addition, exchange of regulatory information
between regulatory authorities will be simplified.
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Introduction…
• The guidance provided and criteria specified, apply to
the preparation of complete dossiers and summary
dossiers, whether submitted in support of
applications:
• For approval of active substances
• For the registration of a plant protection product
• For the establishment of a maximum residue limit (MRL)
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Introduction…
A complete dossier consists of all the test and study
reports to be submitted, together with the summaries
of the tests and studies submitted and relevant
supporting documentation
while a summary dossier consists of that same set of
documentation, without the test and study reports.
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Introduction…
The objective is to achieve standardization, to the
extent that is practicable and feasible, of the format
and presentation of documentation submitted, with a
view to:
• Ensuring the quality and consistency of the documentation
submitted
• Facilitating efficiency and economy in the use of resources
for the preparation of that documentation;
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Introduction…
• Facilitating applicants in checking the completeness and
quality of the documentation prior to submission
• Facilitating the use of electronic media for the submission,
archiving and retrieval of the documentation submitted
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Introduction…
Facilitating efficiency and economy in the use of
resources for evaluation; and
Facilitating the development of burden sharing
arrangements by regulatory authorities, thereby
further increasing efficiency and economy in the
use of evaluative resources.
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General principles
CTD, the display of information should be
unambiguous and transparent;
• In order to facilitate the review of the basic data and to
help a reviewer become quickly oriented to the application
contents.
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Organization of the common technical
document
The CTD is organized into five modules.
Module 1 is region specific.
Modules 2, 3, 4, and 5 are intended to be common for
all regions.
Conformance with this guidance should ensure that
Modules 2 through 5 are provided in a format
acceptable to the regulatory authorities.
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Module 1.
Administrative Information and Prescribing
Information.
This module should contain documents specific to each
region;
• For example, application forms or the proposed label for use in
the region.
The content and format of this module can be specified by
the relevant regulatory authorities.
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Module 2
Common Technical Document Summaries
DOS is a summary that follows the scope and the
outline of the body of data provided in Module 3,
Module 4 and Module 5.
The DOS should not include information, data, or
justification that was not already included in other
parts of the dossier(3,4,5).
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Module 2…
The DOS should include a discussion of key issues
that integrates information from sections in the
Safety, Efficacy, and Quality Module and supporting
information from other modules.
Module 2 should begin with a general introduction to
the pharmaceutical, including its pharmacologic class,
mode of action, and proposed clinical use.
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Module 2…
DOS-PD template should always be completed and
accompanied by the product dossier for registration
with the Authority.
All sections and fields in the DOS-PD template, as
indicated in Appendix 5, that would be applicable
should be completed.
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Module 2…
The use of tables to summarize the information is
encouraged, where possible.
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Module 3. Quality
[Link] of Contents of Module 3
o A Table of Contents for the filed application should be
provided.
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Cont…
[Link] of Data
[Link] Substance 1 (Name, Manufacturer)
[Link] Information (Name, Manufacturer)
[Link] (name, manufacturer)
3.2.S.1.2 Structure (name, manufacturer)
3.2.S.1.3 General properties (name, manufacturer)
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3.2.S.1.1 Nomenclature (name, manufacturer)
Information on the nomenclature of the drug substance
should be provided. For example:
• Recommended International Non-proprietary Name (INN;
• Compendial name, if relevant
• Chemical name(s)
• Company or laboratory code
• Other non-proprietary name ( nation name …)
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3.2.S.1.2 Structure (name, manufacturer)
The structural formula
For bio-tech drug substance, the schematic amino
acid sequence indicating glycosylation sites or
Other post-translational modifications and relative
molecular mass should be provided, as appropriate.
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3.2.S.1.3 General properties (name, manufacturer)
A list should be provided of physicochemical and
Other relevant properties of the drug substance,
including biological activity for Biotech.
This information can be used in developing the
specifications, in formulating FPPs, and in testing for
release and stability purposes.
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Cont…
The physical and chemical properties of the API
should be discussed
• including the physical description, solubility in common
solvents
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3.2. S.2 Manufacture (Name, Manufacturer)
3.2. S.2.1 Manufacturer(s) (name, manufacturer)
• The name and address
• and responsibility of each manufacturer, including
contractors,
• and each proposed production site or facility involved in
manufacturing and testing should be provided.
• The list of manufacturers/companies should specify the
actual addresses of production
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Cont…
• A valid manufacturing authorization should be provided for
the production of APIs.
• If available, a certificate of GMP compliance should be
provided in the PD in Module 1.
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3.2.S.2.2 Description of manufacturing process
and process controls (name, manufacturer)
The description of the drug substance manufacturing
process represents the applicant’s commitment for the
manufacture of the drug substance.
Information should be provided to adequately
describe the manufacturing process and process
controls.
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Cont…
For a synthetic drug substance, a flow diagram of the
synthetic process(es) should be provided that includes
• Molecular formulae, weights
• Yield ranges,
• Chemical structures of starting materials,
• Intermediates,
• Reagents and API reflecting stereochemistry,
• And identifies operating conditions and solvents.
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Cont…
A sequential procedural narrative of the
manufacturing process should be submitted.
Alternate processes should be explained and
described with the same level of detail as the primary
process.
Reprocessing steps should be identified and justified.
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3.2. S.2.3 Control of materials (name, manufacturer)
Materials used in the manufacture of the drug
substance.
Information on the quality and control of these
materials should be provided.
The carry-over of impurities of the starting materials
for synthesis into the final API should be considered
and discussed.
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3.2. S.2.4 Controls of critical steps and intermediates
(name, manufacturer)
Critical Steps: Tests and acceptance criteria (with
justification including experimental data)
Intermediates: Information on the quality and control of
intermediates isolated during the process should be
provided.
Specifications for isolated intermediates should be
provided.
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Cont…
Additionally for Biotech: Stability data supporting
storage conditions should be provided. (Reference:
ICH Guideline Q5C)
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3.2. S.2.5 Process validation and/or evaluation
(name, manufacturer)
It is expected that the manufacturing processes for all
APIs are properly controlled.
• If the API is prepared as sterile, a complete description
should be provided for aseptic processing and/or
sterilization methods.
Control for storage and transportation should also be
provided .
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Cont…
For drug substances, sufficient information should be
provided on validation and evaluation studies to
demonstrate that the manufacturing process is
suitable for its intended purpose
The plan for conducting the study should be
described and the results, analysis and conclusions
from the executed study should be provided.
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3.2.S.2.6 Manufacturing process development
(name, manufacturer)
The significance of the change should be assessed by
evaluating its potential to impact the quality of the drug
substance
For manufacturing changes that are considered
significant, data from comparative analytical testing on
relevant drug substance batches should be provided to
determine the impact on quality of the drug substance.
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3.2.S.3 Characterization (Name, Manufacturer)
3.2.S.3.1 Elucidation of structure and other
characteristics (name, manufacturer)
• Elucidation of structure
• Isomerism/stereochemistry
• Polymorphism
• Particle size distribution
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3.2.S.3.2 Impurities (name, manufacturer)
Information on impurities should be provided.
[Reference: ICH Guidelines Q3A, Q3C, Q5C, Q6A,
and Q6B]
• Identification threshold
• Qualification of impurities
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3.2.S.4 Control of Drug Substance (name,
manufacturer
Specification (name, manufacturer)
Analytical procedures (name, manufacturer)
Validation of analytical procedures (name,
manufacturer)
Batch analyses (name, manufacturer)
Justification of specification (name, manufacturer)
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3.2.S.5 Reference Standards or Materials
(Name, Manufacturer)
Reference standards or materials used in the testing of
the API should be provided
o (e.g., those used for the identification, purity, assay tests).
These could be classified as primary or secondary
reference standards.
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3.2.S.6 Container Closure System (Name,
Manufacturer)
A description of the container closure system(s)
should be provided, including the identity of
materials of construction of each primary packaging
component, and their specifications.
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3.2.S.7 Stability (Name, Manufacturer)
3.2.S.7.1Stability summary and conclusions (name,
manufacturer)
• Stress testing
• Accelerated and long-term testing
• Proposed storage statement and re-test period
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3.2. S.7.2 Post-approval stability protocol and
stability commitment (name, manufacturer)
• Primary stability study commitment
• Commitment stability studies
• Ongoing stability studies
Stability data (name, manufacturer)
• The actual stability results used to support the proposed re-
test period should be included in the dossier.
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3.2. P Drug Product (or Finished Pharmaceutical
Product (FPP)) (Name, Dosage Form)
3.2.P.1 Description and Composition of the FPP
(Name, Dosage Form)
• Description of the dosage form
• Composition of the dosage form
• Description of accompanying reconstitution diluent(s)
• Type of container and closure
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3.2.P.2 Pharmaceutical Development (Name,
Dosage Form)
Pharmaceutical development information should
include:
• Definition of the quality target product profile
• Identification of the potential critical quality attributes of
the FPP
• Discussion of the potential CQAs of the API(s), excipients,
and container closure
• Discussion of the selection criteria for the manufacturing
process and the control strategy
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3.2.P.2.1 Components of the FPP (name,
dosage form)
Active pharmaceutical ingredient (name, dosage form)
Excipients (name, dosage form)
3.2.P.2.2 Finished pharmaceutical product (name,
dosage form)
Formulation development (name, dosage form)
In vitro dissolution or drug release
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Cont…
Overages (name, dosage form)
Physicochemical and biological properties (name,
dosage form)
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3.2.P.2.3 Manufacturing process development
(name, dosage form)
The scientific rationale for the choice of the
manufacturing, filling, and packaging processes that
can influence FPP quality and performance should be
explained.
The scientific rationale for the selection,
optimization, and scale-up of the manufacturing
process described
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3.2.P.2.4 Container closure system (name,
dosage form)
The suitability of the container closure system used
for the storage, transportation and use of the FPP
should be discussed.
Choice of materials, protection from moisture and
light, compatibility of the materials of construction
with the dosage form
And safety of materials of construction, and
performance should be discussed.
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3.2.P.2.5 Microbiological attributes (name,
dosage form)
Appropriate, the microbiological attributes of the
dosage form should be discussed.
The rationale for not performing microbial limits
testing for non-sterile products and the selection and
effectiveness of preservative systems.
The effectiveness of the agent should be justified and
verified by appropriate studies
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3.2.P.2.6 Compatibility (name, dosage form)
The compatibility of the FPP with reconstitution
diluent(s) or dosage devices should be addressed to
provide appropriate and supportive information for
the labeling.
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3.2.P.3 Manufacture (name, dosage form)
Manufacturer(s) (name, dosage form)
Batch formula (name, dosage form)
Description of manufacturing process and process
controls (name, dosage form)
Controls of critical steps and intermediates (name,
dosage form)
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Module 4: non-clinical study reports
It deals with the toxicity testing intended to justify the
stability and safety of the product.
The module is included for completeness to indicate
the appropriate format and placement of the
nonclinical data(ICH M4S (R2).
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Module 5: clinical study reports
5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies
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5.3 Clinical Study Reports
Reports of Biopharmaceutics Studies
Bioavailability (BA) study reports
Comparative BA and BE study reports
In vitro–in vivo correlation study reports
Reports of bioanalytical and analytical methods for
human studies
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5.3.2 Reports of Studies Pertinent to
Pharmacokinetics Using Human Biomaterials
Plasma protein binding study reports
Reports of hepatic metabolism and drug interaction
studies
Reports of studies using other human biomaterials
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5.3.3 Reports of Human Pharmacokinetic
(PK) Studies
Healthy subject PK and initial tolerability study
reports
Patient PK and initial tolerability study reports
Intrinsic factor PK study reports
Extrinsic factor PK study reports
Population PK study reports
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5.3.4 Reports of Human Pharmacodynamics'
(PhD) Studies
Healthy subject PD and PK/PD study reports
Patient PD and PK/PD study reports
Reports of Efficacy and Safety Studies
Study reports of controlled clinical studies pertinent to the
claimed indication
Study reports of uncontrolled clinical studies
Reports of Post-Marketing Experience
Case Report Forms and Individual Patient Listings
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Evaluation process
WAHO and NMRAs will assign application numbers
serially to applications received and evaluate them on
(FIFO) basis.
At country level evaluation will be done by in
country evaluators using this guideline and Standard
Operating Procedures for evaluation of dossiers.
Decisions on registration shall be based on the dossier
evaluation report, QC report and inspection report on
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compliance to cGMP.
Reference
1. Guideline IH. Organization of the Common
Technical Document for the Registration of
Pharmaceuticals for Human Use M4. Geneva: ICH.
2004.
2. Medicines registration harmonization in Africa
3. registration of pharmaceutical products for human
use in the economic community of west African
states
4. International conference on harmonization of
technical requirements for registration of
pharmaceuticals for human use
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