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Core of the CTD-Module 3
-MOHANA THAKKAR
M. PHARM (PHARMACEUTICS)
DATE:23 SEPTEMBER 2022
Objective
To provide insight about expectations of
GCC and Health Canada on Quality (CMC)
portion in submission/application by
Sponsor.
Module 3-Quality
• The Quality section of the Common Technical Document provides a harmonized
structure and format for presenting CMC (Chemistry, Manufacturing and
Controls) information in a registration dossier.
Module 3 content
Module Content
3.1 Module 3 table of contents
3.2 Body of data
3.3 Literature references
3.2 BODY OF
DATA
3.2.S Drug Substance:
The drug substance information can be submitted in one of
the following options:
1. Certificate of suitability (CEP); or
2. Drug master file (DMF); or
3. Complete information on the “3.2.S drug substance”
sections.
GCC: Unless justified, the number of Active Pharmaceutical
Ingredients (API) suppliers must not exceed two sources for
each API.
3.2.S.1 General
Information
3.2.S.1.1 Nomenclature:
Information on the nomenclature of the drug substance(s) should
be provided. E.g.: Recommended International Nonproprietary
Name (INN).
3.2.S.1.2 Structure:
The structural formula, including relative and absolute
stereochemistry, the molecular formula, and the relative molecular
mass should be provided.
3.2.S.1.3 General Properties:
Physicochemical and other relevant properties of the drug substance
should be listed.
E.g.: Appearance, Polymorphic form, Solubility profile, Partition
coefficients, melting or boiling points.
3.2.S.2
Manufacture
3.2.S.2.1 Manufacturer(s):
The name, address, and responsibility of each manufacturer.
3.2.S.2.2 Description of Process and Process Controls:
Detailed information on the starting material(s) including the
name of the manufacturer(s)/supplier(s), route of synthesis
and specifications which should be justified by supporting
data.
3.2.S.2.3 Control of Materials:
For each starting material, the name, manufacturing site,
and the address of each manufacturer should be indicated.
3.2.S.2
Manufacture
3.2.S.2.4 Control of Critical Steps and Intermediates:
Tests & Acceptance criteria performed at critical steps.
3.2.S.2.5 Process Validation and/or Evaluation:
Process validation studies for aseptic processing and
sterilization.
For non-sterile drug substances, process validation and/or
evaluation studies need not be provided in a regulatory
submission.
3.2.S.2.6 Manufacturing Process Development:
Significant changes made to the manufacturing process
and/or manufacturing site of the drug substance.
3.2.S.3
Characterization
3.2.S.3.1 Elucidation of Structure and Other Characteristics:
Confirmation of structure based on synthetic route and spectral
analyses.
For pharmacopeial drug substance(s):
GCC: copies of the IR spectrum of the drug substance run
concomitantly with a reference standard.
CANADA: copies of the Infrared (IR) and Ultraviolet (UV) spectra of
the drug substance for each source.
3.2.S.3.2 Impurities:
Drug-Related Impurities (e.g., API starting materials, by-products,
intermediates, chiral impurities, degradation products).
Process-related impurities (e.g., residual solvents, reagents,
catalysts).
3.2.S.4 Control
of Drug
Substance
3.2.S.4.1 Specifications:
Both-DS & DP manufacturer.
Tests, acceptance criteria and reference to analytical methods.
Health Canada:
The assay should include the chemical formula so that it is clear
as to how the dose is declared (i.e., free acid/base vs. salt)
Injectable products: Bacterial endotoxins test with an
appropriate limit should be included.
3.2.S.4.2 Analytical Procedure:
The analytical procedures used for testing the drug substance.
Not necessary to provide copies of the compendial analytical
procedures.
Health Canada: HPLC/UPLC-Method of choice for determining
drug-related impurities.
GCC: HPLC/GC-Method of choice for determining drug-related
impurities.
3.2.S.4.3 Validation of Analytical Procedures:
Analytical validation information including experimental data for the
analytical procedures.
For in-house methods, full validation are required.
Verification of compendial methods is necessary. Why ?
Compendial methods are typically validated based on an API originating
from a specific manufacturer. Different sources of the same API can contain
impurities and/or degradation products that were not considered during
the development of the monograph.
If Compendial method used to control API-related impurity, not specified in
monograph?
Full validation of the method is expected with respect to those impurities.
If compendial standard is claimed and an in-house method is used as an
alternative method (e.g., for assay or specified impurities)?
Equivalence of the in-house and compendial methods should be
demonstrated.
3.2.S.4.4 Batch Analyses
Description of batches and results of batch analyses.
The discussion of results should focus on observations noted for
the various tests, rather than reporting as “All tests meet
specifications”.
3.2.S.4.5 Justification of Specification
Discussion on the inclusion of certain tests, evolution of tests,
analytical procedures and acceptance criteria, etc.
3.2.S.5 Reference Standards or Materials
The source of reference standards or reference
materials (e.g., House, USP, BP, Ph. Eur.).
Certificate of analysis for reference standards or
reference materials .
Characterization and evaluation of non-compendial
reference standards (e.g., method of manufacture,
elucidation of structure, certificate of analysis,
calibration against an official standard).
3.2.S.6 Container/Closure Systems
Identification of materials of construction of each
primary packaging component and their specifications.
Compatibility
Certificate of Compliance
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions:
Type of studies
Protocols
Results of the studies
Information: storage conditions, batch number, batch
size, batch type, batch manufacturing date, container
closure system and testing intervals (completed and
proposed), results and conclusion.
Health Canada: If route of synthesis is changed, then
results for at least 2 pilot scale batches with minimum of
3 months of long-term and accelerated testing should be
provided at the time of filing.
General case for stability studies of the drug substance
Study Storage condition Minimum time period covered
by data at submission
GCC Health Canada
Long-term 30℃ ± 2℃/ 65% RH±
5% RH
OR
30 °C ± 2 °C/75% RH ±
5% RH
25°C ± 2°C / 60% RH ±
5% RH
GCC : 12 months
Health Canada: 12 months
(6 months for existing
drug substances)
Accelerated 40℃ ± 2℃/ 75% RH±
5% RH
40°C ± 2°C / 75% RH ±
5% RH
Intermediate - 30°C ± 2°C / 65% RH ±
5% RH
6 months (if applicable as per
ICH)
3.2.S.7.2 Post-
approval Stability
Protocol and
Commitment
At least one batch per year of
API manufactured at each
commercial site (unless none is
produced that year) should be
added to the continuing
stability monitoring program.
GCC: If stability data on
Primary batches is submitted, a
commitment to place the first
two/three production batches
on long-term stability studies
through the proposed retest
period should be provided.
GCC Guidelines Health Canada
a. Number of batch(s) and
different batch sizes
b. Relevant physical, chemical,
microbiological and biological
test methods;
c. Acceptance criteria;
d. Reference to test methods;
e. Description of the container
closure system(s);
f. Testing frequency;
g. Description of the conditions
of storage
a. Number of batches and
batch sizes;
b. Tests and acceptance
criteria;
c. Container closure
system(s);
d. Testing frequency; and
e. Storage conditions (and
tolerances) of samples.
Minimum requirements:
3.2.S.7.3
Stability Data
GCC Guidelines Health Canada
• Results to be provided in tabular
format. Separate table for each
batch.
• Results to be provided in
tabular, graphical, or
narrative.
• Actual numerical results should
be provided. Vague statements -
“within limits” or “conforms”
shall not be mentioned.
• If significant change observed
between three and six months’
testing at accelerated storage
condition, re-test period to be
proposed based on long-term
storage condition.
• If significant change
observed between three
and six months’ testing at
accelerated storage
condition, intermediate
condition testing
recommended.
3.2.P Drug Product:
3.2.P.1 Description and Composition of the Drug Product:
Description of the dosage form;
Detailed composition with overages, if any on a per unit basis and function of each component.
Quality standard and grades (e.g., “Microcrystalline Cellulose NF (PH 102)”)
Reconstitution diluent
Health Canada: Intra and extra-granular excipients should be listed separately in tabular
form.
Container and closure used for the dosage form.
3.2.P.2 Pharmaceutical Development
Essentials:
1. Components of the Drug Product
2. Drug Product: Formulation development, Overages, Physicochemical, Biological Properties.
3. Manufacturing Process Development
4. Container Closure System
5. Microbiological Attributes
6. Compatibility
Quality by Design Approach:
Defining QTPP (Quality Target Product Profile): Targeting Product Profile of desired Quality.
CQAs (Critical Quality Attributes), CMAs (Critical Material Attributes), CPPs (Critical Process
Parameters)
3.2.P.3
Manufacture
3.2.P.3.1 Manufacturer(s): name, address, and
responsibility of each manufacturer, including contractors,
and each proposed production site involved in
manufacturing and testing.
GCC: Manufacturing Authorization, Marketing Authorization
and GMP certificate.
3.2.P.3.2 Batch Formula:
All proposed individual batch sizes.
All components of the dosage form (may or may not appear
in Final Drug product, e.g., Solvents)
GCC: Official letter indicating the expected production size
range and confirmation that the range will not be changed
before getting Prior approval.
Flow diagram of the manufacturing process with Critical
Process Parameters.
A narrative description of the manufacturing process,
including packaging.
Sterile Products: validated sterilization parameters (e.g.,
load size, autoclave program, gamma radiation dose,
processing aids) and equipment (e.g., compounding vessels,
sterilizing filters, filling syringes).
GCC: the class of the areas (e.g., A, B, …etc) should be
stated for each activity (e.g., compounding).
3.2.P.3.3 Description of
Manufacturing Process
and Process Controls:
3.2.P.3.4
Controls of
Critical Steps
and
Intermediates
Critical Steps: Tests and acceptance criteria should be provided.
Intermediates: Information on the quality and control of intermediates
isolated during the process.
Examples: Potential In-process controls:
(i) granulations:moisture, blend uniformity, bulk and tapped densities.
(ii) solid oral products: average weight, weight variation, hardness, thickness,
friability.
(iii) semi-solids: viscosity, homogeneity, pH, evaluation of phase separation.
(iv) transdermal patches: assay of drug-adhesive mixture.
(v) metered dose inhalers: fill weight/volume, leak testing.
(vi) dry powder inhalers: assay of drug-excipient blend, moisture.
(vii) liquids: pH, specific gravity, bioburden.
(viii) parenteral: bioburden prior to sterilization (Health Canada),
100% visual inspection (appearance, clarity), pH, fill volume/weight, filter
integrity, particulate matter, container closure integrity test.
Health Canada: Maximum recommended limits for in-process weight
variation.
3.2.P.3.5
Process
Validation
and/or
Evaluation
Description, documentation, and results of the validation and/or
evaluation studies.
Health Canada: Process Validation Protocol or Validation Report
GCC: Process Validation Protocol and “A letter of commitment” to conduct
prospective validation on three consecutive production scale batches and to
report immediately any out of specification (OOS) results to the authority.
Sterile Products:
Health Canada: Validation should be completed prior to submission and
Validation Report to be provided with summary of process validation studies.
GCC: “A letter of commitment” to conduct prospective validation on three
consecutive production scale batches including the sterilization process and to
report immediately any out of specification (OOS) results to the authority.
3.2.P.4 Control
of Excipients
3.2.P.4.1 Specifications:
Health Canada: Specifications for only non-compendial monograph.
GCC: Specifications to be provided also if standard claimed is compendial
monograph.
3.2.P.4.2 Analytical Procedures:
Non-compendial analytical procedures used to generate testing results.
3.2.P.4.3 Validation of Analytical Procedures:
Analytical validation information, including experimental data, for the non-
compendial analytical procedures used for testing the excipients.
3.2.P.4.4 Justification of Specifications:
Discussions on tests supplementary to compendial monograph.
Certificate of Analysis from Vendor and Supplier (FP manufacturer).
3.2.P.4.5 Excipients of Human or Animal Origin:
List of excipients of human or animal origin.
TSE/BSE certificate.
3.2.P.4.6 Novel Excipients:
Excipients used for the first time in a drug product or by a new
route of administration.
Details of manufacture, characterization, and controls, with
supporting safety data (nonclinical and/or clinical) should be
provided according to the drug substance format.
(Details to be included in 3.2.A.3).
3.2.P.5 Control
of Drug Product
3.2.P.5.1 Specifications:
 Release and Shelf-Life Specifications.
Acceptance criteria for Release Specifications should be more stringent.
Why?
To ensure that shelf-life acceptance criteria are met throughout the labelled
shelf life of the drug product.
Health Canada: Drug product specifications in accordance with C.02.018
and C.02.019 of the Food and Drug Regulations from the site responsible for
release (e.g., drug product manufacturer, importer or distributor).
The assay should include the chemical formula.
Dissolution method parameters (e.g., dissolution apparatus, rotation speed,
dissolution medium and volume) should be listed as a footnote to the table
or directly in the description of the test.
Minimum Specifications:
GCC: Appearance, identification, assay, purity, pharmaceutical tests (e.g.,
dissolution), physical tests (e.g. loss on drying, hardness, friability, particle
size, apparent density), uniformity of dosage units, identification of coloring
materials, identification and assay of antimicrobial or chemical preservatives
(e.g., antioxidants) and microbial limit tests.
3.2.P.5 Control
of Drug Product
Specific tests and criteria that are not addressed by ICH’s
Q6A guideline.
Health Canada:
Recommended tests to be included in Specifications:
Dosage Form Specific Tests Recommended*
Modified-release products Drug –Release method discriminatory with
respect to formulation.
Inhalation and Nasal
Products
Consistency of delivered dose, particle size
distribution, moisture content, leak rate, microbial
limits, preservative assay, sterility, and weight loss.
Suppositories Uniformity of dosage units, melting point.
Transdermals Peel or shear force, mean weight per unit area, in
vitro drug release, monitoring for crystal growth.
Aqueous Solutions pH, uniformity of dosage units, antimicrobial
preservative content, antioxidant preservative
content, osmolality/osmolarity, particulate matter
(for sterile products)
Sterile solutions - sterility, bacterial endotoxins
3.2.P.5.2 Analytical Procedures
Non-compendial analytical procedures.
GCC: HPLC & GC are method of choice for Impurities determination and Assay.
System suitability tests (SSTs) are an integral part of the method. Why?
 To ensure the satisfactory performance of the chosen chromatographic system.
HPLC and GC purity methods should include SSTs for resolution and repeatability.
3.2.P.5.3 Validation of Analytical Procedures:
Analytical validation information, including experimental data.
Validation reports for non-compendial analytical procedures.
Verification for compendial methods: Specificity, Accuracy and Repeatability.
GCC: If compendial method is used to control related substances, not specified in monograph, full method validation for
related substances to be submitted.
3.2.P.5.4 Batch
Analyses
Description of batches and
batch analysis results.
Deviations and Out of
Specification (OOS) test results
should be investigated and
summarized.
Number of batches and batch sizes
Health Canada GCC
1. Minimum three batches-minimum pilot scale. 1. Minimum two pilot
scale batches.
Pilot scale batch requirement: -
• Solid oral dosage forms-Minimum 1/10th of full
production scale or 1,00,000 tablets or
capsules, whichever larger.
-
• Liquid dosage forms & Powder for
reconstitution into solution: Minimum 1/10th of
full production scale or 20 litres, whichever is
the larger. If proposed commercial batch size is
<20 Litres, maximum proposed commercial
batch size.
-
3.2.P.5.5 Characterization of Impurities
Potential degradation products and finished product process-related
impurities.
3.2.P.5.6 Justification of Specifications
 Discussions on omission or inclusion of certain tests, evolution of tests,
analytical procedures and acceptance criteria, differences from the
compendial standard(s).
3.2.P.6 Reference Standards or Materials
 Source of Reference Standards/Materials (USP, BP, etc.)
 COA of Reference Standards
 Characterization and evaluation of non-official (e.g., non- compendial)
reference standards.
3.2.P.7 Container/Closure System
COA, Specifications and Method of Analysis (Non-compendial) for all
primary packaging components.
A brief description for secondary packaging components.
Health Canada: Specifications, from both-Vendor and Drug Product
manufacturer.
Certificates of compliance (Vendor/Drug Product manufacturer)
3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusions
Summary of types of studies conducted, protocols used and the results of the studies.
GCC: “Stability Testing of Active Pharmaceutical Ingredients (APIs) and Finished
Pharmaceutical Products (FPPs)” guideline of GCC should be followed.
Health Canada: ICH Q1A, Q1B, Q1C, Q1D, Q1E
Summary of Types of studies conducted, Protocols used and the results.
Photostability testing should be conducted on at least one primary batch of the drug product.
In-use stability studies. (One of the batches towards end of its shelf life).
For a drug product posing a higher risk (e.g., sterile drug product), transportation study is
required.
General case for stability studies of the drug product
Study Storage condition Minimum time period covered by data
at submission
GCC Region Canada
Long-term 30℃ ± 2℃/ 65% RH±
5% RH
OR
30 °C ± 2 °C/75% RH ±
5% RH
25°C ± 2°C / 60% RH ±
5% RH
GCC region: 12 months
Health Canada: 12 months
(6 months for existing drug substances)
Accelerated 40℃ ± 2℃/ 75% RH±
5% RH
40°C ± 2°C / 75% RH ±
5% RH
6 months
Intermediate - 30°C ± 2°C / 65% RH ±
5% RH
6 months (if applicable as per ICH)
3.2.P.8.2 Post-
approval Stability
Protocol and
Commitment
At least one batch per year of API
manufactured at each commercial
site (unless none is produced that
year) should be added to the
continuing stability monitoring
program.
If stability data on Primary
batches is submitted, a
commitment to place the first two
(GCC)/three (HC) production
batches on long-term stability
studies through the proposed
retest period should be provided.
GCC Guidelines Health Canada
a. Number of batch(s) and
different batch sizes
b. Relevant physical, chemical,
microbiological and biological
test methods;
c. Acceptance criteria;
d. Reference to test methods;
e. Description of the container
closure system(s);
f. Testing frequency;
g. Description of the conditions
of storage
a. Number of batches and
batch sizes;
b. Tests and acceptance
criteria;
c. Container closure
system(s);
d. Testing frequency; and
e. Storage conditions (and
tolerances) of samples.
Minimum requirements:
3.2.P.8.3
Stability Data
GCC Guidelines Health Canada
• Results to be provided in tabular
format. Separate table for each batch.
• Results to be provided in
tabular, graphical, or narrative.
• Actual numerical results should be
provided. Vague statements -“within
limits” or “conforms” shall not be
mentioned.
• Actual numerical results should
be provided. Vague statements
-“within limits” or “conforms”
shall not be mentioned.
• If significant change observed between
three and six months’ testing at
accelerated storage condition, re-test
period to be proposed based at long-
term storage condition.
• If significant change observed
between three and six months’
testing at accelerated storage
condition, intermediate
condition testing
recommended.
• - • Impurities observed above the
reporting threshold should be
reported and identified by
name if known, or by retention
time or applicable code if
unknown.
3.2. A Appendices
3.2.A.1 Facilities
and Equipment
3.2.A.2
Adventitious
Agents Safety
Evaluation
3.2.A.3 Excipients
3.2.R Regional
Information
3.2. R UAE CANADA
3.2.R.1 Alcohol Content
Declaration
PRODUCTION
DOCUMENTATION
R.1.1 Executed
Production Documents
R.1.2 Master
Production Documents
(MPDs)
3.2.R.2 Porcine/Pork-
content/origin
Medical devices
3.2.R.3 The diluents and
colouring agents
in the product
formula
Acceptable
compendial
monographs
3.3 Literature
References
KEY LITERATURE REFERENCED SHOULD BE
PROVIDED, IF APPLICABLE.
Different
Scenarios-UAE
How to submit the information in Quality module if a drug
product contains more than one drug substance?
one complete “3.2.S” section should be provided for one
drug substance, followed by other complete “3.2.S” sections
for each drug substance.
 For a drug product with multiple strengths:
one complete “3.2.P” section should be provided with the
information for the different strengths provided within the
subsections. One complete copy of the dossier should be
provided for each strength.
For a drug substance from multiple manufacturers:
one complete “3.2.S” section should be provided for the
drug substance from one manufacturer, followed by other
complete “3.2.S” sections for each drug substance
manufacturer.
Different
Scenarios-UAE
For a drug product with multiple container closure
systems (e.g. bottles and unit dose blisters):
one complete “3.2.P” section should be provided with the
information for the different presentations provided within
the subsections.
For multiple drug products (e.g. tablets and a parenteral
product):
A separate dossier is required for each drug product.
For a drug product supplied with reconstitution diluent(s):
the information on the diluent should be provided in a
separate part “3.2.P” if the diluent is co-packaged with the
drug product.
 if the diluent is not co-packaged with the drug product, the
compatibility of the diluent with the drug product should be
discussed in 3.2.P.2.6.
References:
Registration of a Conventional Pharmaceutical Product E-CTD Requirements-UAE.
GCC Guidelines for Stability Testing of API & FPP
The GCC Data Requirements for Human Drugs Submission.
GUIDANCE DOCUMENT:Quality (Chemistry and Manufacturing) Guidance: New Drug
Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)-Health Products
and Food Branch-Canada.
WHO good manufacturing practices for sterile pharmaceutical products-Annex 6
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Module-3-Quality_Mohana Thakkar_23 Sep 2022 (1).pdf

  • 1. Core of the CTD-Module 3 -MOHANA THAKKAR M. PHARM (PHARMACEUTICS) DATE:23 SEPTEMBER 2022
  • 2. Objective To provide insight about expectations of GCC and Health Canada on Quality (CMC) portion in submission/application by Sponsor.
  • 3. Module 3-Quality • The Quality section of the Common Technical Document provides a harmonized structure and format for presenting CMC (Chemistry, Manufacturing and Controls) information in a registration dossier. Module 3 content Module Content 3.1 Module 3 table of contents 3.2 Body of data 3.3 Literature references
  • 4. 3.2 BODY OF DATA 3.2.S Drug Substance: The drug substance information can be submitted in one of the following options: 1. Certificate of suitability (CEP); or 2. Drug master file (DMF); or 3. Complete information on the “3.2.S drug substance” sections. GCC: Unless justified, the number of Active Pharmaceutical Ingredients (API) suppliers must not exceed two sources for each API.
  • 5. 3.2.S.1 General Information 3.2.S.1.1 Nomenclature: Information on the nomenclature of the drug substance(s) should be provided. E.g.: Recommended International Nonproprietary Name (INN). 3.2.S.1.2 Structure: The structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided. 3.2.S.1.3 General Properties: Physicochemical and other relevant properties of the drug substance should be listed. E.g.: Appearance, Polymorphic form, Solubility profile, Partition coefficients, melting or boiling points.
  • 6. 3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s): The name, address, and responsibility of each manufacturer. 3.2.S.2.2 Description of Process and Process Controls: Detailed information on the starting material(s) including the name of the manufacturer(s)/supplier(s), route of synthesis and specifications which should be justified by supporting data. 3.2.S.2.3 Control of Materials: For each starting material, the name, manufacturing site, and the address of each manufacturer should be indicated.
  • 7. 3.2.S.2 Manufacture 3.2.S.2.4 Control of Critical Steps and Intermediates: Tests & Acceptance criteria performed at critical steps. 3.2.S.2.5 Process Validation and/or Evaluation: Process validation studies for aseptic processing and sterilization. For non-sterile drug substances, process validation and/or evaluation studies need not be provided in a regulatory submission. 3.2.S.2.6 Manufacturing Process Development: Significant changes made to the manufacturing process and/or manufacturing site of the drug substance.
  • 8. 3.2.S.3 Characterization 3.2.S.3.1 Elucidation of Structure and Other Characteristics: Confirmation of structure based on synthetic route and spectral analyses. For pharmacopeial drug substance(s): GCC: copies of the IR spectrum of the drug substance run concomitantly with a reference standard. CANADA: copies of the Infrared (IR) and Ultraviolet (UV) spectra of the drug substance for each source. 3.2.S.3.2 Impurities: Drug-Related Impurities (e.g., API starting materials, by-products, intermediates, chiral impurities, degradation products). Process-related impurities (e.g., residual solvents, reagents, catalysts).
  • 9. 3.2.S.4 Control of Drug Substance 3.2.S.4.1 Specifications: Both-DS & DP manufacturer. Tests, acceptance criteria and reference to analytical methods. Health Canada: The assay should include the chemical formula so that it is clear as to how the dose is declared (i.e., free acid/base vs. salt) Injectable products: Bacterial endotoxins test with an appropriate limit should be included. 3.2.S.4.2 Analytical Procedure: The analytical procedures used for testing the drug substance. Not necessary to provide copies of the compendial analytical procedures. Health Canada: HPLC/UPLC-Method of choice for determining drug-related impurities. GCC: HPLC/GC-Method of choice for determining drug-related impurities.
  • 10. 3.2.S.4.3 Validation of Analytical Procedures: Analytical validation information including experimental data for the analytical procedures. For in-house methods, full validation are required. Verification of compendial methods is necessary. Why ? Compendial methods are typically validated based on an API originating from a specific manufacturer. Different sources of the same API can contain impurities and/or degradation products that were not considered during the development of the monograph. If Compendial method used to control API-related impurity, not specified in monograph? Full validation of the method is expected with respect to those impurities. If compendial standard is claimed and an in-house method is used as an alternative method (e.g., for assay or specified impurities)? Equivalence of the in-house and compendial methods should be demonstrated.
  • 11. 3.2.S.4.4 Batch Analyses Description of batches and results of batch analyses. The discussion of results should focus on observations noted for the various tests, rather than reporting as “All tests meet specifications”. 3.2.S.4.5 Justification of Specification Discussion on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, etc.
  • 12. 3.2.S.5 Reference Standards or Materials The source of reference standards or reference materials (e.g., House, USP, BP, Ph. Eur.). Certificate of analysis for reference standards or reference materials . Characterization and evaluation of non-compendial reference standards (e.g., method of manufacture, elucidation of structure, certificate of analysis, calibration against an official standard). 3.2.S.6 Container/Closure Systems Identification of materials of construction of each primary packaging component and their specifications. Compatibility Certificate of Compliance
  • 13. 3.2.S.7 Stability 3.2.S.7.1 Stability Summary and Conclusions: Type of studies Protocols Results of the studies Information: storage conditions, batch number, batch size, batch type, batch manufacturing date, container closure system and testing intervals (completed and proposed), results and conclusion. Health Canada: If route of synthesis is changed, then results for at least 2 pilot scale batches with minimum of 3 months of long-term and accelerated testing should be provided at the time of filing.
  • 14. General case for stability studies of the drug substance Study Storage condition Minimum time period covered by data at submission GCC Health Canada Long-term 30℃ ± 2℃/ 65% RH± 5% RH OR 30 °C ± 2 °C/75% RH ± 5% RH 25°C ± 2°C / 60% RH ± 5% RH GCC : 12 months Health Canada: 12 months (6 months for existing drug substances) Accelerated 40℃ ± 2℃/ 75% RH± 5% RH 40°C ± 2°C / 75% RH ± 5% RH Intermediate - 30°C ± 2°C / 65% RH ± 5% RH 6 months (if applicable as per ICH)
  • 15. 3.2.S.7.2 Post- approval Stability Protocol and Commitment At least one batch per year of API manufactured at each commercial site (unless none is produced that year) should be added to the continuing stability monitoring program. GCC: If stability data on Primary batches is submitted, a commitment to place the first two/three production batches on long-term stability studies through the proposed retest period should be provided. GCC Guidelines Health Canada a. Number of batch(s) and different batch sizes b. Relevant physical, chemical, microbiological and biological test methods; c. Acceptance criteria; d. Reference to test methods; e. Description of the container closure system(s); f. Testing frequency; g. Description of the conditions of storage a. Number of batches and batch sizes; b. Tests and acceptance criteria; c. Container closure system(s); d. Testing frequency; and e. Storage conditions (and tolerances) of samples. Minimum requirements:
  • 16. 3.2.S.7.3 Stability Data GCC Guidelines Health Canada • Results to be provided in tabular format. Separate table for each batch. • Results to be provided in tabular, graphical, or narrative. • Actual numerical results should be provided. Vague statements - “within limits” or “conforms” shall not be mentioned. • If significant change observed between three and six months’ testing at accelerated storage condition, re-test period to be proposed based on long-term storage condition. • If significant change observed between three and six months’ testing at accelerated storage condition, intermediate condition testing recommended.
  • 17. 3.2.P Drug Product: 3.2.P.1 Description and Composition of the Drug Product: Description of the dosage form; Detailed composition with overages, if any on a per unit basis and function of each component. Quality standard and grades (e.g., “Microcrystalline Cellulose NF (PH 102)”) Reconstitution diluent Health Canada: Intra and extra-granular excipients should be listed separately in tabular form. Container and closure used for the dosage form.
  • 18. 3.2.P.2 Pharmaceutical Development Essentials: 1. Components of the Drug Product 2. Drug Product: Formulation development, Overages, Physicochemical, Biological Properties. 3. Manufacturing Process Development 4. Container Closure System 5. Microbiological Attributes 6. Compatibility Quality by Design Approach: Defining QTPP (Quality Target Product Profile): Targeting Product Profile of desired Quality. CQAs (Critical Quality Attributes), CMAs (Critical Material Attributes), CPPs (Critical Process Parameters)
  • 19. 3.2.P.3 Manufacture 3.2.P.3.1 Manufacturer(s): name, address, and responsibility of each manufacturer, including contractors, and each proposed production site involved in manufacturing and testing. GCC: Manufacturing Authorization, Marketing Authorization and GMP certificate. 3.2.P.3.2 Batch Formula: All proposed individual batch sizes. All components of the dosage form (may or may not appear in Final Drug product, e.g., Solvents) GCC: Official letter indicating the expected production size range and confirmation that the range will not be changed before getting Prior approval.
  • 20. Flow diagram of the manufacturing process with Critical Process Parameters. A narrative description of the manufacturing process, including packaging. Sterile Products: validated sterilization parameters (e.g., load size, autoclave program, gamma radiation dose, processing aids) and equipment (e.g., compounding vessels, sterilizing filters, filling syringes). GCC: the class of the areas (e.g., A, B, …etc) should be stated for each activity (e.g., compounding). 3.2.P.3.3 Description of Manufacturing Process and Process Controls:
  • 21. 3.2.P.3.4 Controls of Critical Steps and Intermediates Critical Steps: Tests and acceptance criteria should be provided. Intermediates: Information on the quality and control of intermediates isolated during the process. Examples: Potential In-process controls: (i) granulations:moisture, blend uniformity, bulk and tapped densities. (ii) solid oral products: average weight, weight variation, hardness, thickness, friability. (iii) semi-solids: viscosity, homogeneity, pH, evaluation of phase separation. (iv) transdermal patches: assay of drug-adhesive mixture. (v) metered dose inhalers: fill weight/volume, leak testing. (vi) dry powder inhalers: assay of drug-excipient blend, moisture. (vii) liquids: pH, specific gravity, bioburden. (viii) parenteral: bioburden prior to sterilization (Health Canada), 100% visual inspection (appearance, clarity), pH, fill volume/weight, filter integrity, particulate matter, container closure integrity test. Health Canada: Maximum recommended limits for in-process weight variation.
  • 22. 3.2.P.3.5 Process Validation and/or Evaluation Description, documentation, and results of the validation and/or evaluation studies. Health Canada: Process Validation Protocol or Validation Report GCC: Process Validation Protocol and “A letter of commitment” to conduct prospective validation on three consecutive production scale batches and to report immediately any out of specification (OOS) results to the authority. Sterile Products: Health Canada: Validation should be completed prior to submission and Validation Report to be provided with summary of process validation studies. GCC: “A letter of commitment” to conduct prospective validation on three consecutive production scale batches including the sterilization process and to report immediately any out of specification (OOS) results to the authority.
  • 23. 3.2.P.4 Control of Excipients 3.2.P.4.1 Specifications: Health Canada: Specifications for only non-compendial monograph. GCC: Specifications to be provided also if standard claimed is compendial monograph. 3.2.P.4.2 Analytical Procedures: Non-compendial analytical procedures used to generate testing results. 3.2.P.4.3 Validation of Analytical Procedures: Analytical validation information, including experimental data, for the non- compendial analytical procedures used for testing the excipients. 3.2.P.4.4 Justification of Specifications: Discussions on tests supplementary to compendial monograph. Certificate of Analysis from Vendor and Supplier (FP manufacturer).
  • 24. 3.2.P.4.5 Excipients of Human or Animal Origin: List of excipients of human or animal origin. TSE/BSE certificate. 3.2.P.4.6 Novel Excipients: Excipients used for the first time in a drug product or by a new route of administration. Details of manufacture, characterization, and controls, with supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format. (Details to be included in 3.2.A.3).
  • 25. 3.2.P.5 Control of Drug Product 3.2.P.5.1 Specifications:  Release and Shelf-Life Specifications. Acceptance criteria for Release Specifications should be more stringent. Why? To ensure that shelf-life acceptance criteria are met throughout the labelled shelf life of the drug product. Health Canada: Drug product specifications in accordance with C.02.018 and C.02.019 of the Food and Drug Regulations from the site responsible for release (e.g., drug product manufacturer, importer or distributor). The assay should include the chemical formula. Dissolution method parameters (e.g., dissolution apparatus, rotation speed, dissolution medium and volume) should be listed as a footnote to the table or directly in the description of the test. Minimum Specifications: GCC: Appearance, identification, assay, purity, pharmaceutical tests (e.g., dissolution), physical tests (e.g. loss on drying, hardness, friability, particle size, apparent density), uniformity of dosage units, identification of coloring materials, identification and assay of antimicrobial or chemical preservatives (e.g., antioxidants) and microbial limit tests.
  • 26. 3.2.P.5 Control of Drug Product Specific tests and criteria that are not addressed by ICH’s Q6A guideline. Health Canada: Recommended tests to be included in Specifications: Dosage Form Specific Tests Recommended* Modified-release products Drug –Release method discriminatory with respect to formulation. Inhalation and Nasal Products Consistency of delivered dose, particle size distribution, moisture content, leak rate, microbial limits, preservative assay, sterility, and weight loss. Suppositories Uniformity of dosage units, melting point. Transdermals Peel or shear force, mean weight per unit area, in vitro drug release, monitoring for crystal growth. Aqueous Solutions pH, uniformity of dosage units, antimicrobial preservative content, antioxidant preservative content, osmolality/osmolarity, particulate matter (for sterile products) Sterile solutions - sterility, bacterial endotoxins
  • 27. 3.2.P.5.2 Analytical Procedures Non-compendial analytical procedures. GCC: HPLC & GC are method of choice for Impurities determination and Assay. System suitability tests (SSTs) are an integral part of the method. Why?  To ensure the satisfactory performance of the chosen chromatographic system. HPLC and GC purity methods should include SSTs for resolution and repeatability. 3.2.P.5.3 Validation of Analytical Procedures: Analytical validation information, including experimental data. Validation reports for non-compendial analytical procedures. Verification for compendial methods: Specificity, Accuracy and Repeatability. GCC: If compendial method is used to control related substances, not specified in monograph, full method validation for related substances to be submitted.
  • 28. 3.2.P.5.4 Batch Analyses Description of batches and batch analysis results. Deviations and Out of Specification (OOS) test results should be investigated and summarized. Number of batches and batch sizes Health Canada GCC 1. Minimum three batches-minimum pilot scale. 1. Minimum two pilot scale batches. Pilot scale batch requirement: - • Solid oral dosage forms-Minimum 1/10th of full production scale or 1,00,000 tablets or capsules, whichever larger. - • Liquid dosage forms & Powder for reconstitution into solution: Minimum 1/10th of full production scale or 20 litres, whichever is the larger. If proposed commercial batch size is <20 Litres, maximum proposed commercial batch size. -
  • 29. 3.2.P.5.5 Characterization of Impurities Potential degradation products and finished product process-related impurities. 3.2.P.5.6 Justification of Specifications  Discussions on omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, differences from the compendial standard(s). 3.2.P.6 Reference Standards or Materials  Source of Reference Standards/Materials (USP, BP, etc.)  COA of Reference Standards  Characterization and evaluation of non-official (e.g., non- compendial) reference standards. 3.2.P.7 Container/Closure System COA, Specifications and Method of Analysis (Non-compendial) for all primary packaging components. A brief description for secondary packaging components. Health Canada: Specifications, from both-Vendor and Drug Product manufacturer. Certificates of compliance (Vendor/Drug Product manufacturer)
  • 30. 3.2.P.8 Stability 3.2.P.8.1 Stability Summary and Conclusions Summary of types of studies conducted, protocols used and the results of the studies. GCC: “Stability Testing of Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs)” guideline of GCC should be followed. Health Canada: ICH Q1A, Q1B, Q1C, Q1D, Q1E Summary of Types of studies conducted, Protocols used and the results. Photostability testing should be conducted on at least one primary batch of the drug product. In-use stability studies. (One of the batches towards end of its shelf life). For a drug product posing a higher risk (e.g., sterile drug product), transportation study is required.
  • 31. General case for stability studies of the drug product Study Storage condition Minimum time period covered by data at submission GCC Region Canada Long-term 30℃ ± 2℃/ 65% RH± 5% RH OR 30 °C ± 2 °C/75% RH ± 5% RH 25°C ± 2°C / 60% RH ± 5% RH GCC region: 12 months Health Canada: 12 months (6 months for existing drug substances) Accelerated 40℃ ± 2℃/ 75% RH± 5% RH 40°C ± 2°C / 75% RH ± 5% RH 6 months Intermediate - 30°C ± 2°C / 65% RH ± 5% RH 6 months (if applicable as per ICH)
  • 32. 3.2.P.8.2 Post- approval Stability Protocol and Commitment At least one batch per year of API manufactured at each commercial site (unless none is produced that year) should be added to the continuing stability monitoring program. If stability data on Primary batches is submitted, a commitment to place the first two (GCC)/three (HC) production batches on long-term stability studies through the proposed retest period should be provided. GCC Guidelines Health Canada a. Number of batch(s) and different batch sizes b. Relevant physical, chemical, microbiological and biological test methods; c. Acceptance criteria; d. Reference to test methods; e. Description of the container closure system(s); f. Testing frequency; g. Description of the conditions of storage a. Number of batches and batch sizes; b. Tests and acceptance criteria; c. Container closure system(s); d. Testing frequency; and e. Storage conditions (and tolerances) of samples. Minimum requirements:
  • 33. 3.2.P.8.3 Stability Data GCC Guidelines Health Canada • Results to be provided in tabular format. Separate table for each batch. • Results to be provided in tabular, graphical, or narrative. • Actual numerical results should be provided. Vague statements -“within limits” or “conforms” shall not be mentioned. • Actual numerical results should be provided. Vague statements -“within limits” or “conforms” shall not be mentioned. • If significant change observed between three and six months’ testing at accelerated storage condition, re-test period to be proposed based at long- term storage condition. • If significant change observed between three and six months’ testing at accelerated storage condition, intermediate condition testing recommended. • - • Impurities observed above the reporting threshold should be reported and identified by name if known, or by retention time or applicable code if unknown.
  • 34. 3.2. A Appendices 3.2.A.1 Facilities and Equipment 3.2.A.2 Adventitious Agents Safety Evaluation 3.2.A.3 Excipients
  • 35. 3.2.R Regional Information 3.2. R UAE CANADA 3.2.R.1 Alcohol Content Declaration PRODUCTION DOCUMENTATION R.1.1 Executed Production Documents R.1.2 Master Production Documents (MPDs) 3.2.R.2 Porcine/Pork- content/origin Medical devices 3.2.R.3 The diluents and colouring agents in the product formula Acceptable compendial monographs
  • 36. 3.3 Literature References KEY LITERATURE REFERENCED SHOULD BE PROVIDED, IF APPLICABLE.
  • 37. Different Scenarios-UAE How to submit the information in Quality module if a drug product contains more than one drug substance? one complete “3.2.S” section should be provided for one drug substance, followed by other complete “3.2.S” sections for each drug substance.  For a drug product with multiple strengths: one complete “3.2.P” section should be provided with the information for the different strengths provided within the subsections. One complete copy of the dossier should be provided for each strength. For a drug substance from multiple manufacturers: one complete “3.2.S” section should be provided for the drug substance from one manufacturer, followed by other complete “3.2.S” sections for each drug substance manufacturer.
  • 38. Different Scenarios-UAE For a drug product with multiple container closure systems (e.g. bottles and unit dose blisters): one complete “3.2.P” section should be provided with the information for the different presentations provided within the subsections. For multiple drug products (e.g. tablets and a parenteral product): A separate dossier is required for each drug product. For a drug product supplied with reconstitution diluent(s): the information on the diluent should be provided in a separate part “3.2.P” if the diluent is co-packaged with the drug product.  if the diluent is not co-packaged with the drug product, the compatibility of the diluent with the drug product should be discussed in 3.2.P.2.6.
  • 39. References: Registration of a Conventional Pharmaceutical Product E-CTD Requirements-UAE. GCC Guidelines for Stability Testing of API & FPP The GCC Data Requirements for Human Drugs Submission. GUIDANCE DOCUMENT:Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)-Health Products and Food Branch-Canada. WHO good manufacturing practices for sterile pharmaceutical products-Annex 6