Introduction to ICH

The Quality Guidelines

– An Overview

KEDAR S.RAJE

1
INDEX
 WHAT IS ICH ?
 HISTORY
 INITIATION
 INTRODUCTION
 TOPICS
 QUALITY GUDILINES

2
 ICH
 INTERNATIONAL
CONFERENCE
ON HARMONISATION (ICH) OF
TECHNICAL REQUIREMENTS
FOR REGISTRATION OF
PHARMACEUTICALS FOR
HUMAN USE.

3
WHAT?
 An agreement between
the European Union (EU),
Japan and the United States
(US)
• Joint initiative between
government regulators and
industry manufacturers.
4
WHY?
 to harmonize regulatory
requirements for the
testing, application and
approval process of
pharmaceutical
medications.

5
 Historical Overview
firstattempt by the
European Commission
(EC) member nations
during the 1980’s
EC began bilateral
discussions with both
Japan and the United
States
6
 Historical Overview
 Specific plans began to
materialize at the World
Health Organization’s
(WHO) Conference on Drug
Regulatory Authorities in
Paris in 1989
 ICH was created in April
1990 at a meeting
in Brussels
7
NEED FOR HARMONISATION
 RAPID INCREASE IN LAWS,
REGULATIONS ANG GUIDELINES FOR
TESTING SAFETY, QUALITY AND
EFFICACY OF NEW PRODUCTS
 DIFFERENT TECHNICAL
REQUIREMENTS BY REGULATORY
AGENCIES , ALTHOUGH
FUNDAMENTAL GUIDING PRINCIPLES
SAME
 INDUSTRY BECOMING GLOBAL
 DUPLICATION OF TIME CONSUMING
AND EXPENSIVE TESTING
8
 PROGRESS TOWARDS
INTERNATIONAL HARMONISATION

GOALS :
 DECREASE COUNTRY-TO-
COUNTRY DIFFERENCES IN
GUIDELINES
 DECREASE DIFFERENCES
BETWEEN REGULATORY
AUTHORITIES
9
 PROGRESS TOWARDS
INTERNATIONAL HARMONISATION

 TARGET:
 STREAMLINE DRUG
DEVELOPMENT AND
REGULATORY PROCESS
 INCREASE EFFICIENCY AND
ENFORCEMENT OF GMP, GLP
AND GCP GUIDELIENS
10
ICH FOUNDER MEMBERS
 EUROPEAN UNION :
 EUROPEAN COMMISSION (EU)
 EFPIA (EUROPEAN FEDERATION OF PHARMACEUTICAL;
INDUSTRIES, ASSOCIATIONS)
 JAPAN :
 MINISTERY OF HEALTH AND WELFARE
 JPMA ( JAPAN PHARMACEUTICAL
MANUFACTURERS ASSOCIATION). Now
known as MHLW (Ministry of Health,
Labor and Welfare).
 USA :
 FDA
 PhRMA(PHARMACEUTICAL RESEARCH
AND MANUFACTURERS OF AMERICA
11
 Initiation of ICH
 Formation of steering committee
 Agreement on terms of
references
 Expert working groups
 Eleven topics
 Four categories
12
Eleven possible topics to address
divided into four main categories
 SAFETY

 QUALITY

 EFFICACY

 MULTIDISCIPLINARY
13
 ICH Steering Committee
 Determines the policies and procedures for
ICH
 Selects topics for harmonization

 Monitors the progress of harmonization

initiatives
 Has two members for each of the six co-
sponsors, the IFPMA (International Federation
of Pharmaceutical Manufacturers &Association)
and Observers
14
 Expert Working Groups

 TheSteering Committee assigns an

EWG to each of the technical topics
selected

 Thegroups are comprised of industry

specialists on the topics discussed
from each of the six members

 Do not have a fixed membership

15
ICH QUALITY GUIDELINES
 Q 1 – Stability Testing
 Q 2 – Analytical Validation
 Q 3 – Impurities
 Q 4 – Pharmacopoeias
 Q 5 – Biotechnological Products
 Q 6 – Specifications
 Q 7 – Good Manufacturing Practices
 Q 8 – Pharmaceutical Development
 Q 9 – Quality Risk Management
 Q 10 – Pharmaceutical Quality System

16
ICH Q 1 – Stability Testing
 A set of originally five guidelines (Q1A to Q1F)
 defining
 - General aspects of stability testing (storage
 conditions, batch size and number, length of
 time...)
 - Photostability
 - Application to new dosage forms
 - Possibilities for reduced test designs
 (bracketing and matrixing)

17
ICH Q 1 – Stability Testing
 Statistical evaluation of stability data
and possibilities for extrapolation.
 - Storage conditions for stability testing in
different climatic zones.
 Shelf life assignment to APIs and
Formulations.

18
Conventional Stability Chamber Walk in Stability Chamber

Stability Chamber
19
ICH Q 1 A (R2) – Scope
 For new API and related medicinal
products
 - To provide evidence on how the quality
of an API/finished product changes with
time under the influence of Environmental
factors such as temperature, humidity and
light and to
 establish a re-test period/shelf-life for the
API/finished product
20
ICH Q 1 A (R2) – In a
Nutshell...
 Stress testing required for API
 - Long-term and accelerated testing required for API and
product, where necessary intermediate testing
 - Minimum of three representative batches
 - Testing over a minimum of 12 months at LT and 6 months
at
 accelerated conditions (with defined testing frequency)
 - Storage conditions for the “general case”, aqueous products
in semi-permeable containers, products to be stored in a
refrigerator and a freezer
 - Stability commitment

Batches should be as proposed for Stability

studies w.r.t:
Type of Formulation
Container/closure system &
Manufacturing process simulating production process 21
Stress studies:
Approach
 Investigate impurities/degradants appearing at greater than (or
approaching) the identification threshold, (the limit on
individual unknowns) under long-term and accelerated
conditions.
 Mass balance assessment if required to be based on the
decrease in assay value and the increase in the amount of
degradation products.
 Process related impurities to be monitored at release only with
no need to monitor during long-term stability. However, if
they increase during storage, or new impurities develop, they
should be considered as “degradants” or “degradation
products”, and analytical methods must be developed to
monitor them.

22
Stressed study sample (API)

23
ICH Q 1 B – In a Nutshell...
 Describes requirements on photo stability testing and defines light
exposure to be applied
 - To be tested on API – if not photosensitive, no further testing
required
 - If photosensitive, to be continued on exposed finished product
and product in primary package, product in marketing package,
where relevant
 - Where necessary, impact of light during manufacturing process to
be evaluated
 - Confirmatory testing required, where applicable
Photo stability testing light source: -
Any light source that is designed to produce an output similar to the
D65/ID65 emission standard such as an artificial daylight fluorescent
lamp combining visible and ultraviolet (UV) outputs, xenon, or metal
halide lamp.

24
Photo stability light source

25
ICH Q 1 C – In a Nutshell...
 Additional guidance to ICH Q1 A(R2) on
new dosage forms (“line extensions”) for
new substances.
 Reduced requirements as regards time to
be covered at LT storage conditions at
time of dossier submissions

26
ICH Q 1 D – In a Nutshell...
 Describes possibilities to apply reduced test
designs, i.e. bracketing and matrixing
 - Defines situations where reduced testing
can be applied without additional
justification, with justification or where it is
not applicable
 - Bracketing: testing of extremes only
 - Matrixing: testing of a different samples of
factor combinations at different time points
during the study
 - Provides example designs

27
Q1D - Bracketing and Matrixing
◦ Bracketing: testing samples on the extremes of
certain design factors (e.g., strengths, container sizes
and/or fills)
◦ Matrixing: testing a selected subset of the total
number of possible samples for all factor combinations
at a specified time point, while testing another subset of
samples at a subsequent time point
 Matrixing:
◦ applicable:
 strengths with identical or closely related
formulations
 container sizes or fills of the same C/C system
 different batches made with the same
equipment and process

28
Q1D - Bracketing and Matrixing
 Matrixing:
◦ applicable:
 strengths with identical or closely related
formulations
 container sizes or fills of the same C/C system
 different batches made with the same
equipment and process
◦ not applicable:
 different storage conditions
 different test attributes

29
Q1D - Bracketing and Matrixing
 Bracketing - Strengths:
◦ Applicable: strengths of identical or closely related formulations
◦ Applicable with additional justification (e.g., supporting data):
strengths where the relative amounts of the drug substance and
excipients vary within the product line
◦ Not applicable: different excipients among strengths
 Bracketing – Container Size, Fill:
◦ Applicable: same container closure system where either the
container size or fill varies while the other remains constant
◦ Applicable with additional justification (e.g., supporting data):
same container closure system but both the container size and
fill vary
◦ Not applicable: different container closure systems

30
Example of Bracketing Design
(Bracketing on strength and container size)

Strength 50 mg 75 mg 100 mg

Batch 1 2 3 1 2 3 1 2 3

Container 50 ml T T T T T T
size

100 ml

150 ml T T T T T T

31
Example of Matrixing Design
(Two strengths, matrixing on time point)
Time Points (month) 0 3 6 9 12 18 24 36

S Batch 1 T T T T T T
T
R S1 Batch 2 T T T T T T T
E
N Batch 3 T T T (T) T T T
G
T
Batch 1 T T T T (T) T T T
H
S2
Batch 2 T T T T T

Batch 3 T T T T T

T: Sample tested; (T): Sample tested if full shelf life data will not
be available before approval.
32
Importance of Analytical Methods in
Development Stability Studies
 Without analytical methods it is not
possible to know what has happened
during stability
◦ Assay
◦ Impurities/Degradation Products
◦ Dissolution
◦ Chiral Purity
◦ Preservative Content

33
Methods Must be Stability-
Indicating
 Analytical methods must effectively separate and
permit quantification of degradants (including use of
purity tests)
 Any significant changes in drug substance or drug
product quality over time must be detectable
◦ Increase in degradants
◦ Change in dissolution behavior
◦ Change in stereochemistry
 cis to trans or vice-versa
 optical isomers interconverting

34
Method Validation
 Types of Analytical Procedures to be
Validated
◦ Identification tests;
◦ Quantitative tests for impurities' content;
◦ Limit tests for the control of impurities;
◦ Quantitative tests of the active moiety in samples
of drug substance or drug product or other
selected component(s) in the drug product.
 Drug product assay
 This will also include quantifying dissolution results

35
API Stability: Specifications
Specifications: test attributes susceptible to change.
 Testing should cover physical, chemical, biological and
microbiological attributes e.g. appearance, assay,
degradation plus others susceptible to change.
 For impurities, a specification for individual and total
impurities must be set. Numerical data for individual
(known and unknown) and total impurities to be
reported instead of conforms or complies.
 NB: The upper and lower acceptance criteria limits for
innovator products are based on the potency and/or
impurity levels of the clinical lots and safety and
efficacy considerations. There is no justification,
normally, for generic source to request for less stringent
specifications.
36
Other parameters to be monitored
 Commonly where the API is of low solubility and
micronized, and the FPP is low dose - PSD is critical
 Due to the potential for settling of material on storage,
stability results for PSD should be provided to address
this issue.
 Moisture is particularly important for solid orals in
blisters and strips.
 Efficacy of additives and assay of preservatives
 Container/closure interactions, when applicable

37
Minimum Data Requirements at time
of submission – API and FPP

*Where long-term conditions are 30ºC±2ºC/65%±5%RH or

30ºC±2ºC/75%±5%RH, there is no intermediate condition.

38
“Significant Change”
“Significant Change” is an important or remarkable
change in any physical or chemical condition of the
pharmaceutical product. These changes may occur in
the product during the stability study of the drug
product.
If long-term studies are conducted at 25°C ± 2°C/60% RH
± 5% RH and “significant change” occurs at any time
during 6 months’ testing at the accelerated storage
condition, additional testing at the intermediate storage
condition should be conducted and evaluated against
significant change criteria. The initial application
should include a minimum of 6 months’ data from a 12-
month study at the intermediate storage condition.

39
Significant Change”
For API - defined as failure to meet its specification
For an FPP, significant change under accelerated and intermediate testing
conditions is any of:
 1. A 5% change in assay from its initial value; or failure to meet the
acceptance criteria for potency when using biological or immunological
procedures;
 2. Any degradation product’s exceeding its acceptance criterion;
 3. Failure to meet the acceptance criteria for appearance, physical
attributes, and functionality test (e.g., color, phase separation,
resuspendibility, caking, hardness, dose delivery per actuation); however,
some changes in physical attributes (e.g., softening of suppositories, melting
of creams) may be expected under accelerated conditions; and, as
appropriate for the dosage form:
 4. Failure to meet the acceptance criterion for pH; or
 5. Failure to meet the acceptance criteria for dissolution for 12 dosage
units.

40
 Tablet degradation at stability test
Initial Tablet conditions

Significant
Change
41
Stability Commitment
 This is required when data did not cover the proposed re-
test/shelf life (Primary Stability Study Commitment) and/or
the primary stability batches studied did not consist of three
production scale batches (Commitment Stability Studies)
 The applicant must commit to conducting long-term stability
trials on the next production scale batches that are
manufactured. The number of batches required depends on
the number of production scale batches provided in the
primary studies (to make at least 3 production batches)

For all post-approval commitments:

 A signed and dated commitment is required.
 An authorised, dated and detailed protocol should be
provided, including storage conditions, testing frequency,
specifications, test methods…

42
ICH Q 2 – Analytical Validation
 A guideline defining the validation
parameters needed for a variety of
Analytical methods and describing
characteristics to be considered for the
validation of analytical procedures
included in a marketing authorisation
dossier

43
ICH Q 2 – ... In a Nutshell
 Defines criteria for the validation of the
four most common types of analytical
procedures:
 - identification tests
 - quantitative tests for impurities
 - limit tests for the control of impurities
 - quantitative tests for the active moiety
in API or finished product or other
selected components in the product

44
ICH Q 2 – ... In a Nutshell
 Defines typical analytical validation
 characteristics, to which tests to apply them
 and examples on the “how to”
 - Accuracy
 - Precision
 - Repeatability
 - Intermediate Precision
 - Specificity
 - Detection Limit
 - Quantitation Limit
 - Range

45
HPLC QUARTENARY GRADIENT GAS CHROMATOGRAPH WITH
SYSTEM HEAD SPACE ANALYZER

Commonly used Lab

Instruments
46
ICH Q 3 – Impurities
 A set of three guidelines addressing the
chemistry and safety aspects of impurities,
including the listing of impurities in
specifications. Defines the thresholds for
reporting, identification and qualification of
impurities in API and finished product.
Specific guideline on residual solvents.
 IMPURITY: - Any thing in the API or FPP which is
not of desired entity. Needs to be
limited/Controlled during the manufacturing
process.

47
ICH Q 3 A(R) – in a Nutshell
 Classifies impurities
 - organic impurities
 • Starting materials
 • By-products
 • Intermediates
 • Degradation products
 • Reagents, ligands, catalysts
 - Inorganic impurities
 • Reagents, ligands, catalysts
 • Heavy metals or other residual metals
 • Inorganic salts
 • Other impurities, e.g. filter aids, charcoal…
 - Residual solvents

48
ICH Q 3 A(R) – in a Nutshell
 Defines rationale for the reporting and control of
impurities as well as requirements for listing
impurities in specifications:
􀂙 Organic Impurities
 - Each specified identified impurity
 - Each specified unidentified impurity
 - Any unspecified impurity with acceptance
criterion of NMT the identification threshold
􀂙 Residual solvents
􀂙 Inorganic impurities

49
SAMPLE: - IBUPROFEN at RT 32.59
min. Rest are the impurities

IMPURITIES DETECTED BY
HPLC
50
Solvent std & sample Solvent injected with name as std

Residual solvents by GC
51
ICH Q 3 A(R) – in a Nutshell
 Definitions
 Identified impurity:
…. impurity for which a structural
characterisation has been achieved
 Qualification:
….is the process of acquiring and evaluating
data that establishes the biological safety of
an individual impurity or a given impurity
profile at the level(s) specified.

52
ICH Q 3 A(R) – in a Nutshell
 Definitions
Specified impurity:
… impurity that is individually listed and limited with a specific
acceptance criterion in the specification. Can be either
identified or unidentified.
Unidentified impurity:
… impurity for which a structural characterisation has not
been achieved and that is solely defined by qualitative
analytical properties, e.g. chromatographic retention time
Unspecified impurity:
… impurity that is limited by a general acceptance criterion,
but not individually listed with its own specific acceptance
criterion in the specification

53
Thresholds for Impurities in API
Maximum Reporting Identification Qualification
Daily Dose Threshold Threshold Threshold
≤ 2 g/day 0.05 % 0.10 % or 1.0 mg/day 0.15 % or 1.0mg/day
(whichever is lower) (whichever is lower)

> 2 g/day 0.03 % 0.05 % 0.05 %

♦ number of decimal digits: two below 1.0 %, one above 1.0 %

♦ application of conventional rounding rules
♦ total impurities > reporting threshold

54
ICH Q 3 C – in a Nutshell
 Recommends acceptable amounts for
residual solvents in pharmaceuticals for
the safety of patients, recommends use of
less toxic solvents and describes levels
considered to be toxicologically
acceptable for some solvents. Non-
exhaustive list of solvents included in the
guideline as annexed.

55
Classification of Residual Solvents
Class I  Known human carcinogens,
strongly suspected human
carcinogens, and environmental
⇒ solvents to be hazards
avoided
 Non- genotoxic animal carcinogens
 Class II or possible causative agents of
other irreversible toxicity. Solvents
suspected of other significant but
⇒ solvents to be reversible toxicities.
limited
Solvents with low toxic potential to
 Class III

man; no health-based exposure
limit is needed
⇒ solvents with low
toxic potential

56
Classification of Residual Solvents
Class I  Benzene, carbon tetrachloride,
1,2-dichloroethane, 1,1-
⇒ solvents to be dichloroethene, 1,1,1-
trichloroethane.
avoided
 Acetonitrile, chloroform,
cyclohexane, dioxane,
Class II methanol, methylbutylketone,
tetrahydrofuran, toluene, ...
⇒ solvents to be limited

Class III  Acetone, butanol, butyl

acetate, DMSO, ethanol, ethyl
⇒ solvents with low acetate, ethyl ether, heptane,
isopropanol, methyl ethyl
toxic potential ketone, ...

57
ICH Q3 C – in a Nutshell
 Defines options for the definition of acceptance
criteria for class 2 solvents
Option 1
⇒ tabulated limits,
calculated on the basis of a TDI of 10 g of the
product
Option 2
⇒ not all individual components of a product have
to comply with the tabulated limits – the total
content of the solvent has to be below the
permitted daily intake (PDE)

58
 ICH Q3 C – in a Nutshell
 Example for option 2
Concentration = 1000 x PDE
Dose
• *PDE: 4.1 mg/day, limit: 410 ppm

Component Amount in Content Daily Intake

Formulation Acetonitrile *

API 0.3 g 800 ppm 0.24 mg

Excipient1 0.9 g 400 ppm 0.36 mg
Excipient2 3.8 g 800 ppm 3.04 mg

Drug 5.0 g 728 ppm 3.64 mg

Product

59
ICH Q 4 – Pharmacopoeias
 Harmonisation of 10 general methods
referred to in the ICH specification
guideline ICH Q 6A is undertaken by the
Pharmacopoeial Discussion Group (PDG).
ICH Q4 B evaluates selected
pharmacopoeial texts to facilitate their
recognition by regulatory authorities as
interchangeable in the ICH region. Adopts
specific annexes for the different texts.

60
ICH Q 5 – Biotechnological
Products
 A set of five guidelines defining
requirements on various specifics for
biotechnological products:
 - viral safety
 - Analysis of the expression construct in
cells used for production of r-DNA
derived protein products
 - Stability testing

61
ICH Q 5 – Biotechnological
Products
 Derivation and characterisation of cell
substrates
 - Comparability of
biotechnological/biological products
subject to changes in the manufacturing
process.

62
ICH Q 6 – Specifications
 Two guidelines addressing the selection of
tests and methods and setting specifications
for quality control of API and finished
products (chemicals and biotechnologically
derived proteins and polypeptides).
 Intended to assist in the establishment of a
single set of global specifications for API and
finished product. Provides guidance on the
setting and justification of acceptance
criteria and the selection of test procedures.

63
ICH Q 6A – ... In a Nutshell
 Specification:
…. A list of tests, references to analytical
procedures and appropriate acceptance
criteria, which are numerical limits, ranges or
other criteria for the tests described.
 Establishes the set of criteria to be met in
order to be considered “acceptable for
intended use”.
 … “Conformance to specification” means
that the API/product will meet the
acceptance criteria WHEN tested

64
ICH Q 6A – ... In a Nutshell
Specifications (cont.):
…. Are proposed/justified by applicant and approved by
regulatory authorities as conditions of approval
…. Are one part of a total control strategy for the
API/product. Other parts or this strategy include
thorough product characterisation during
development and adherence to GMP (!!)
… are chosen to confirm the quality… rather than to
establish full characterisation, should focus on those
characteristics useful in ensuring the safety and
efficacy of the product.

65
ICH Q 6A – ... In a Nutshell
 Defines universal tests/criteria for
 - API
 - Finished product

 Defines additional specific

tests/criteria for
 - API
 - Finished product
 􀂙Solid oral dosage forms
 􀂙Oral liquids
 􀂙Parenteral drug products
66
Universal Tests/Criteria - API
 Description
 Identification
⇒ specific for the substance (e.g.: IR, HPLC/UV (DAD),
HPLC/MS, GC/MS)
 Assay
⇒ specific / stability indicating procedure often possible
to use method that is also used for quantification of
impurities (e.g. HPLC)
 Impurities (organic, inorganic, residual
solvents)
⇒ specific /stability-indicating procedure
⇒ Decision tree # 1 on extrapolation of meaningful
limits

67
Universal Tests/Criteria – Drug
Product
Description
Identification
⇒ specific (IR, HPLC/UV (DAD), HPLC/MS, GC/MS)
Assay
⇒ specific / stability-indicating procedure (e.g. HPLC, which is
also used for impurities quantification, where applicable,
results of content uniformity test can be used)
Impurities (organic, inorganic, residual solvents)
⇒ specific /stability-indicating procedure: degradation products
and impurities arising during the manufacturing process
⇒ Decision tree #2 on extrapolation of meaningful limits

68
Examples off Specific
Tests//Criteria -- API
 Physicochemical properties
⇒ pH, melting point/range, refractive index ...
 Particle size
⇒ API in solid or suspension drug products
Decision tree #3
 Polymorphic forms
⇒ crystalline forms. Solvates, hydrates, thermal
analysis (DSC, DTA), IR, microscopy, X-ray
Powder diffraction, ... For the finished product
normally dissolution as surrogate parameter
⇒ Decision tree #4(1)-4(3)

69
Examples of Specific Tests/Criteria – Solid Oral
Dosage Forms

 Dissolution
⇒ in-vitro-release of active from the product.
single point-measurement for immediate
release products multiple time point
sampling for extended release, two-stage
testing for delayed release dosage forms
⇒Decision tree # 7 (1-3)
 Disintegration
⇒ may be substituted for dissolution for
rapidly dissolving products containing active
which is highly soluble throughout the
physiological range.
70
ICH Q 7 – GMP for API
 A guideline defining GMP requirements
for the manufacture of API – based on
existing regional and international (PIC/S)
guidance, elaborated jointly with
representatives from the generic and self-
medication industry, PIC/S, Australia, India
and China.

71
ICH Q 7 - .... In a Nutshell
 Introduction
 - Quality Management
 - Personnel
 - Buildings and Facilities
 - Process Equipment
 - Documentation and Records
 - Materials Management
 - Production and In-Process Controls

72
ICH Q 7 - .... In a Nutshell
 Packaging and Identification / Labelling of
 APIs and Intermediates
 - Storage and Distribution
 - Laboratory Controls
 - Validation
 - Change Control
 - Rejection and Re-Use of Material
 Complaints and Recalls

73
ICH Q 7 - .... In a Nutshell
 Agents, Brokers, Traders, Distributors,
 Repackers and Relabellers
 - Specific Guidance for APIs
 manufactured by Cell
 Culture/Fermentation
 - APIs for Clinical Trials
 - Glossary

74
ICH M4 Q – Common
Technical Document
 defines a common format for the
marketing authorisation application in the
ICH region, BUT addresses only
format/structure, not the specific
requirements.

CTD merely indicates the location where

information has to be provided

75
Submission of the Dossier
 Structure of
the common
Technical
Document
(CTD)

76
ICH CTD TRIANGLE

77
Module 1:
 Module 1 of the CTD describes the
administrative information and prescribing
information.
 information about the regulatory
requirements for applications of prescription
medicines to be registered in various
regulatory nations. (i.e. obtain marketing
authorization).
 In the nutshell provides information about
the Environmental Assessment, declarations
and forms.
78
Module 2: Overviews and
summaries
 2.1CTD Modules 2-5
 2.2 Introduction
 2.3 Quality Overall Summary
 2.4 Nonclinical Overview
 2.5 Clinical Overview
 2.6 Nonclinical Summary
 2.7 Clinical Summary

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Module 3: Quality
General Structure/Drug Substance
 3.2 S Drug Substance
 3.2 S1 General Information
 3.2 S2 Manufacture
 3.2 S3 Characterisation
 3.2 S4 Control of Drug Substance
 3.2 S5 Reference Standards or
Materials
 3.2 S6 Container Closure System
 3.2 S7 Stability

80
General Structure/Drug
Product
 3.2 P Drug Product
 3.2 P1 Description and Composition of
the Drug Product
 3.2 P2 Pharmaceutical Development
 3.2 P3 Manufacture
 3.2 P4 Control of Excipients
 3.2 P5 Control of Drug Product
 3.2 P6 Reference Standards or
Materials
 3.2 P7 Container Closure System
 3.2 P8 Stability

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Module 3
 Module 3 in nutshell provides details
information about the following under
various sections as described above;
- Drug substance
- Drug Product
- Appendices
- Batch information

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Module 4: Safety (nonclinical study reports)

 Module 4 describes the format and

organisation of the nonclinical (pharmaco-
toxicological) data relevant to the
application.
Module 5: Efficacy (clinical study reports)
Module 5 describes the format and
organisation of the clinical data relevant to
the application.

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Module 4 & 5
 The Nonclinical Overview (Module 4)
should present an integrated and critical
assessment of the pharmacologic,
pharmacokinetic, and toxicological
evaluation of the pharmaceutical product.
 CTD-Efficacy (Module 5) describes the
structure and format of the clinical data in
an application, including summaries and
detailed study reports

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Module 4 & 5 Contents
Module 4 Content
 4.1Module 4 table of contents
 4.2Study reports
 4.3Literature references
Module 5
 5.1Module 5 table of contents
 5.2Tabular listing of all clinical studies
 5.3Clinical study reports
 5.4Literature references

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ICH Q8 Pharmaceutical Development (New
Quality Paradigm (i.e. Quality Concept)
 It is based on the concept of Quality By Design
(QBD).
 The pharmaceutical Quality by Design(QbD) is a
systematic approach to development that begins
with predefined objectives and emphasizes product
and process understanding and process control,
based on sound science and quality risk
management.
 Quality by Design (QbD) is emerging to enhance
the assurance of safe, effective drug supply to the
consumer, and also offers promise to significantly
improve manufacturing quality performance.

86
Design of Experiment
(DOE)
 Define Problem (s)
 Determine Objectives
 Brainstorm
 Design experiment
 Conduct experiment & collect data
 Analyze data
 Interpret results
 Verify predicted results

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88
89
Quality Target Profile
 From the beginning up
to the end, keep in mind
that the result of
development is a robust
product & manufacturing
process with an
acceptable control
strategy that ensures the
overall quality &
performance of the drug
product.
 Determine the Critical
Quality Attributes
(CQAs)

90
Definition of Design Space
 The multidimensional combination and
interaction of input variables (e.g., material
attributes) and process parameters that have
been demonstrated to provide assurance
of quality.

91
Q8 in nutshell…..
 Quality Product
Target
Product Design and
Profile Understanding

Process Design Control

and Strategy
Understanding

Continuous
Improvement

92
Advantages of QbD
 Better understanding of the process.
 Less batch failure.
 More efficient and effective control of
change.
 Return on investment / cost savings.
 An enhance QbD approach to
pharmaceutical development provides
opportunities for more flexible regulatory
approaches.
 Realistic risk perceptions.

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Advantages of QbD contd….
 More efficient technology transfer to
manufacturing.
 For the consumer, greater drug
consistency.
 Improved yields, lower cost, less
investigations, reduced testing, etc.
 More drug availability and less recall.
 Continuous improvement over the total
product life cycle.
 And above all; First time right: lean assets
management.
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ICH Q9: Quality Risk Management
(QRM)
 It provides principles and examples
of tools for Quality Risk
Management that can be applied to
different aspects of pharmaceutical
quality such as :
 Development

 Manufacturing

 Distribution

 Inspection
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ICH Q9: Quality Risk Management
(QRM)
3 Stages:
 Risk identification: what are the hazards?
 Risk analysis: risk associated with identified
hazards
 Risk evaluation: comparison of identified and
analyzed risk against a given risk criteria

3 fundamental questions:
 What might go wrong?
 What is the likelihood it will go wrong?:
Probability
 What are the consequences? : Severity

96
Risk Management
methodology
 Basic risk management facilitation methods
(Flow charts, check sheets etc.).
 Failure Mode Effects Analysis (FMEA).
 Failure Mode, Effects and Criticality Analysis
(FMECA).
 Fault Tree Analysis (FTA).
 Hazard Analysis and Critical Control Points
(HACCP).
 Hazard Operability Analysis (HAZOP).
 Preliminary Hazard Analysis (PHA). etc

97
Q9: Benefits of Quality Risk
Management Approach
Establishment of a systematic, well-informed and
thorough method of decision making which leads to
greater transparency and predictability
 Increased knowledge of exposure to risk

A greater assurance to regulators of a

company’s ability to deal with potential risks
 Fostering continuous improvement and quality by
design generally leading to enhanced product
quality .

 Enables right “decision making”

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ICH Q10: Pharmaceutical Quality
Systems (PQS)
 ICH Q10 aims to promote a paradigm shift from
discrete GMP compliance procedures at each
stage of the product lifecycle to a comprehensive
quality systems approach over the lifecycle of the
product. In short we can say purpose of Q10 is to
establish a modern quality system.
 The objective of Q10 is to establish a new
tripartite guideline describing the model for an
effective quality management system for the
pharmaceutical industry, referred to as the
Pharmaceutical Quality System

99
Why do we Need a ‘Modern Effective
PQS’?
 Good business practice !
 Significant changes in external business
environment
◦ Fewer new products / ‘blockbusters’
◦ Reduced margins / greater competition /
low-cost sources
◦ Focus on efficient, effective organizations
and lean processes
◦ Effectively resolve Public health issues
◦ Marketed products ARE safe and
efficacious

100
Why do we Need a ‘Modern Effective
PQS’?
 Historically innovation and improvement have been constrained
◦ Inflexible regulatory environment
◦ Focus on Compliance, not Science and Risk-Based approach = BLIND
COMPLIANCE
◦ Industry margins didn’t provide drive for change
 GMPs do not provide a ‘full modern’ Quality System
◦ Originated in 1970s – only incrementally added to
◦ ISO Quality Management thinking not embedded
◦ SOPs focused on GMP compliance
◦ Need to be complemented
 ULTIMATE VISION: - “To develop a harmonised
pharmaceutical quality system applicable across the
lifecycle of the product emphasising an integrated
approach to quality risk management and science.”
For maximum utility need to consider 8/9/10
together i.e.
Q8/9/10 Implementation Work Group

101
Q10-SCOPE
 Applies to systems supporting the
development and manufacture of
pharmaceutical drug substances (API) and
drug products, including biotechnology and
biological products, throughout the product
lifecycle
 Both newly developed and existing products
fall within the scope
 Apply in a manner appropriate and
proportionate to the stage of lifecycle
 The enablers provide the means for science
and risk based decisions related to product
quality through the lifecycle

102
Q10-SCOPE
 Knowledge Management
◦ Manage knowledge from development through
commercialisation to discontinuation
i.e.PRODUCT LIFE CYCLE
A new product progresses through a sequence of stages from
introduction to growth, maturity, and decline. This sequence is
known as the product life cycle and is associated with changes in
the marketing situation, thus impacting the marketing strategy and
the marketing mix.

103
Implementation of Q10 should facilitate

 Innovation and continual improvement

throughout the product lifecycle; and
 Strengthen the link between
pharmaceutical development and
manufacturing organisations

104
Management Responsibilities
 One of the most Essential component
 Not just about compliance
◦ Visible leadership to establish and maintain a company
wide culture and commitment to quality and
improvement
◦ Monitor performance of the PQS and act
◦ Provide resources.
 Quality cannot be owned by the Q Unit
◦ Management is accountable
◦ But independent assessments / audits are key

105
Management Responsibilities

106
Management Responsibilities…
 Should define Clear roles, responsibilities and
governance processes are essential
◦ Quality Policy - standards and direction of
organisation
◦ Quality Planning - convert into objectives / plans
◦ Resources - allocations and competence
◦ Communication - Q items to appropriate audiences
◦ Management Reviews
 Product and Process performance
 PQS performance

107
 ICH Q10 Pharmaceutical Quality System
Pharmaceutical Technology Commercial
Discontinuation
Development Transfer Manufacturing

Investigational products
 GMP
Management Responsibilities

Process Performance & Product Quality Monitoring

PQS Corrective Action / Preventive Action (CAPA)
elements Change Management
Management Review

Knowledge Management
Enablers
Quality Risk Management

a person or thing that makes

something possible. 108
Another diagram - The EU regulatory point of view on
integration of different ICH quality concepts

Regulatory

Pharmac
Quality
eutical Quality Risk
Develop System Analysis
ment
Q10 Q9
Q8

Exisisting
GMP
Q7

109
In the nutshell…Q10( PQS) Must
be Adaptable …
 To meet the needs of the organizational structure
◦ Site, Region, Division, Corporate
◦ Inclusive of Outsourcing Activities
 To meet the needs of the goals of the lifecycle
◦ Development
◦ Tech Transfer
◦ Commercial Manufacturing
◦ Discontinuance
 The effectiveness of a PQS should be demonstrated at a
commercial site

110
ICH Guidelines in pipeline
Q11
 ICH guideline Q11 on development and manufacture of drug
substances (chemical entities and biotechnological/biological entities) .
 Linking Material Attributes and Process Parameters to Drug Substance
CQAs - Chemical Entity .
 Control Strategy-Risk Management
 Design Space
 Lifecycle Management
 In short, ICH Q11 is an admixture of ICH Q8+ICH Q9+ICH Q10
quality guidelines applied to the process development and life cycle
management of Active Pharmaceutical Ingredients (API).
 ICH Q12 guideline is under draft stage & is relevant to Life Cycle
Management

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ICH Guidelines in pipeline
Q12
ICH Q12 guideline is under draft stage & is relevant to Life Cycle
Management
This new guideline is proposed to provide guidance on a framework to
facilitate the management of post-approval Chemistry, Manufacturing and
Controls (CMC) changes in a more predictable and efficient manner
across the product lifecycle.
Adoption of this new ICH Guideline will promote innovation and
continual improvement, and strengthen quality assurance and reliable
supply of product, including proactive planning of supply chain adjustments.
It will allow regulators (assessors and inspectors) to better understand
the firms Pharmaceutical Quality Systems (PQSs) for management of post-
approval CMC changes.
This new guideline is basically intended to complement the existing ICH
Q8 to Q11 Guidelines, and includes a core Guideline as well as
Annexeures.

112
An ICH
Guideline is
FDA Guidance

113
THAT’S ALL
THANK YOU

114