Module-3-Quality_Mohana Thakkar_23 Sep 2022 (1).pdf

This presentation gives detailed information about the Quality portion of CTD as per GCC & Health Canada guidelines

1. Core of the CTD- Module 3
-MOHANA THAKKAR
M. PHARM (PHARMACEUTICS)
DATE:23 SEPTEMBER 2022

2. Objective
Toprovideinsightaboutexpectationsof
GCCandHealthCanadaonQuality(CMC)
portioninsubmission/applicationby
Sponsor.

3. Module 3-Quality
•TheQualitysectionoftheCommonTechnicalDocumentprovidesaharmonized
structureandformatforpresentingCMC(Chemistry,Manufacturingand
Controls)informationinaregistrationdossier.
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.1.1Nomenclature:
Informationonthenomenclatureofthedrugsubstance(s)should
beprovided.E.g.:RecommendedInternationalNonproprietary
Name(INN).
3.2.S.1.2Structure:
Thestructuralformula,includingrelativeandabsolute
stereochemistry,themolecularformula,andtherelativemolecular
massshouldbeprovided.
3.2.S.1.3GeneralProperties:
Physicochemicalandotherrelevantpropertiesofthedrugsubstance
shouldbelisted.
E.g.:Appearance,Polymorphicform,Solubilityprofile,Partition
coefficients,meltingorboilingpoints.

6. 3.2.S.2
Manufacture
3.2.S.2.1Manufacturer(s):
Thename,address,andresponsibilityofeachmanufacturer.
3.2.S.2.2DescriptionofProcessandProcessControls:
Detailedinformationonthestartingmaterial(s)includingthe
nameofthemanufacturer(s)/supplier(s),routeofsynthesis
andspecificationswhichshouldbejustifiedbysupporting
data.
3.2.S.2.3ControlofMaterials:
Foreachstartingmaterial,thename,manufacturingsite,
andtheaddressofeachmanufacturershouldbeindicated.

7. 3.2.S.2
Manufacture
3.2.S.2.4ControlofCriticalStepsandIntermediates:
Tests&Acceptancecriteriaperformedatcriticalsteps.
3.2.S.2.5ProcessValidationand/orEvaluation:
Processvalidationstudiesforasepticprocessingand
sterilization.
Fornon-steriledrugsubstances,processvalidationand/or
evaluationstudiesneednotbeprovidedinaregulatory
submission.
3.2.S.2.6ManufacturingProcessDevelopment:
Significantchangesmadetothemanufacturingprocess
and/ormanufacturingsiteofthedrugsubstance.

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&DPmanufacturer.
Tests,acceptancecriteriaandreferencetoanalyticalmethods.
HealthCanada:
Theassayshouldincludethechemicalformulasothatitisclear
astohowthedoseisdeclared(i.e.,freeacid/basevs.salt)
Injectableproducts:Bacterialendotoxinstestwithan
appropriatelimitshouldbeincluded.
3.2.S.4.2 AnalyticalProcedure:
Theanalyticalproceduresusedfortestingthedrugsubstance.
Notnecessarytoprovidecopiesofthecompendialanalytical
procedures.
HealthCanada:HPLC/UPLC- Methodofchoicefordetermining
drug-relatedimpurities.
GCC:HPLC/GC- Methodofchoicefordeterminingdrug-related
impurities.

10. 3.2.S.4.3 Validation of Analytical Procedures:
Analyticalvalidationinformationincludingexperimentaldataforthe
analyticalprocedures.
Forin-housemethods,fullvalidationarerequired.
Verificationofcompendialmethodsisnecessary.Why?
CompendialmethodsaretypicallyvalidatedbasedonanAPIoriginating
fromaspecificmanufacturer.DifferentsourcesofthesameAPIcancontain
impuritiesand/ordegradationproductsthatwerenotconsideredduring
thedevelopmentofthemonograph.
IfCompendialmethodusedtocontrolAPI-relatedimpurity,notspecifiedin
monograph?
Fullvalidationofthemethodisexpectedwithrespecttothoseimpurities.
Ifcompendialstandardisclaimedandanin-housemethodisusedasan
alternativemethod(e.g.,forassayorspecifiedimpurities)?
Equivalenceofthein-houseandcompendialmethodsshouldbe
demonstrated.

11. 3.2.S.4.4BatchAnalyses
Descriptionofbatchesandresultsofbatchanalyses.
Thediscussionofresultsshouldfocusonobservationsnotedfor
thevarioustests,ratherthanreportingas“Alltestsmeet
specifications”.
3.2.S.4.5JustificationofSpecification
Discussionontheinclusionofcertaintests,evolutionoftests,
analyticalproceduresandacceptancecriteria,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.7.1StabilitySummaryandConclusions:
Typeofstudies
Protocols
Resultsofthestudies
Information:storageconditions,batchnumber,batch
size,batchtype,batchmanufacturingdate,container
closuresystemandtestingintervals(completedand
proposed),resultsandconclusion.
HealthCanada: Ifrouteofsynthesisischanged,then
resultsforatleast2pilotscalebatcheswithminimumof
3monthsoflong-termandacceleratedtestingshouldbe
providedatthetimeoffiling.

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)
Accelerated40℃±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
Atleastonebatchperyearof
APImanufacturedateach
commercialsite(unlessnoneis
producedthatyear)shouldbe
addedtothecontinuing
stabilitymonitoringprogram.
GCC:Ifstabilitydataon
Primarybatchesissubmitted,a
commitmenttoplacethefirst
two/threeproductionbatches
onlong-termstabilitystudies
throughtheproposedretest
periodshouldbeprovided.
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 productsDrug –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 1/10
th
of full
production scale or 1,00,000 tablets or
capsules, whichever larger.
-
•Liquid dosage forms & Powder for
reconstitution into solution: Minimum 1/10
th
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: ICHQ1A,Q1B,Q1C,Q1D,Q1E
SummaryofTypesofstudiesconducted,Protocolsusedandtheresults.
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)
Accelerated40℃±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.1Alcohol Content
Declaration PRODUCTION
DOCUMENTATION
R.1.1 Executed
Production Documents
R.1.2 Master
Production Documents
(MPDs)
3.2.R.2Porcine/Pork-
content/origin
Medical devices
3.2.R.3The 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