Ich

ICH GUIDELINES Q, S, E, M
Presented by:
Ayesha samreen
1st year M.pharma (pharmaceutics)
KLE college of pharmacy, Bangalore1

• ICH is the “International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human
Use”.
2

• ICH is a joint initiative involving both
regulators and research-based industry
representatives of the EU, Japan and the US in
scientific and technical discussions of the
testing procedures required to assess and
ensure the safety, quality and efficacy of
medicines.
3

Objectives of ICH
• To increase international harmonization of
technical requirements to ensure that safe,
effective and high quality medicines are
developed.
• To harmonize technical requirements for
registration or marketing approval.
• To develop and register pharmaceuticals in
the most efficient and cost effective manner.
4

• To promote public health.
• To prevent unnecessary duplication of clinical
trials on humans.
• To minimize the use of animal testing
without compromising safety and
effectiveness of drug.
5

Goal of ICH
• To promote international harmonization by
bringing together representatives from the
three ICH regions (EU, Japan and USA)
• To discuss and establish common guidelines.
• To make information available on ICH, ICH
activities and ICH guidelines to any country or
company that requests the information
6

• To promote a mutual understanding of
regional initiatives in order to facilitate
harmonization processes related to ICH
guidelines regionally and globally
• To strengthen the capacity of drug regulatory
authorities and industry to utilize them.
7

Members of ICH
• ICH is comprised of representatives from six parties
that represent the regulatory bodies and research-
based industry in the European Union, Japan and the
USA.
• • In Japan, the members are the Ministry of Health,
Labour and Welfare (MHLW), and the Japan
Pharmaceutical Manufacturers Association (JPMA).
• • In Europe, the members are the European Union
(EU), and the European Federation of Pharmaceutical
Industries and Associations (EFPIA).
8

• • In the USA, the members are the Food and
Drug Administration (FDA), and the
Pharmaceutical Research and Manufacturers
of America (PhRMA).
• • Additional members include Observers from
the World Health Organization (WHO),
European Free Trade Association (EFTA), and
Canada. The Observers represent non-ICH
countries and regions.
9

ICH structure
• The ICH structure consists of the
ICH Steering Committee
ICH Coordinators
ICH Secretariat and
ICH Working Groups.
10

• ICH Steering Committee:
The Steering Committee is the body that governs
the ICH,
determines the policies and procedures for ICH,
selects topics for harmonization and
monitors the progress of harmonization
initiatives.
Each of the six ICH parties has two seats on the ICH
Steering Committee.
11

• ICH Coordinators:
• The Coordinators are fundamental to the
smooth running of the ICH and are nominated
by each of the six parties. An ICH Coordinator
acts as the main contact point with the ICH
Secretariat.
12

• ICH Secretariat:
• The Secretariat is primarily concerned with
preparations for, and documentation of,
meetings of the Steering Committee as well
as coordination of preparations for Working
Group and Discussion Group meetings.
• Information on ICH Guidelines and the
general ICH process can be obtained from the
ICH Secretariat.
13

• ICH Working Group
• Depending on the type of harmonization
activity needed, the Steering Committee will
endorse the establishment of one of three
types of working group i.e., Expert Working
Group (EWG), Implementation Working
Group (IWG) or Informal Working Group.
14

• "Quality" Topics, i.e., those relating to
chemical and pharmaceutical Quality
Assurance (Stability Testing, Impurity Testing,
etc.)
• Efficacy" Topics, i.e., those relating to clinical
studies in human subject (Dose Response
Studies, Good Clinical Practices, etc.)
15

• “ Safety” Topics, i.e., those relating to in vitro
and in vivo pre-clinical studies (Carcinogenicity
Testing, Genotoxicity Testing, etc.)
• “Multidisciplinary” Topics, i.e., cross-cutting
Topics which do not fit uniquely into one of
the above categories.
16

• Q1A - Q1F Stability
•
Q1A(R2)Stability Testing of New Drug Substances and
Products.
• Q1B Stability Testing : Photostability Testing of New Drug
Substances and Products.
• Q1C Stability Testing for New Dosage Forms.
• Q1D Bracketing and Matrixing Designs for Stability Testing
of New Drug Substances and Products.
• Q1E Evaluation of Stability Data.
• Q1F Stability Data Package for Registration Applications in
Climatic Zones III and IV.
• Q2 Analytical Validation
17

• Q3A - Q3D Impurities
• Q3A (R2) impurities in new drug substance.
• Q3B (R2) impurities in new product.
Q3C(R6) Impurities: Guideline for Residual
Solvents.
• Q3D Guideline for Elemental Impurities.
• Q3D training Implementation of Guideline for
Elemental Impurities.
18

• Q4Pharmacopoeias
• Q4 - Q4B Pharmacopoeias
Q4A Pharmacopoeial Harmonization
• Q4B Evaluation and Recommendation of
Pharmacopoeial Texts for Use in the ICH Regions
• Q4B Annex 1R1 Residue on Ignition/Sulphated
Ash
• Q4B Annex 2R1 Test for Extractable Volume of
Parenteral Preparations
19

• Q4B Annex 3R1 Test for Particulate
Contamination: Sub-Visible Particles.
• Q4B Annex 4AR1 Microbiological Examination
of Non-Sterile Products.
20

• Q4B Annex 5R1 Disintegration Test
• Q4B Annex 6 Uniformity of Dosage Units
• Q4B Annex 7R2 Dissolution Test
• Q4B Annex 8R1 Sterility Test
• Q4B Annex 9R1 Tablet Friability
21

• Q4B Annex 10R1 Polyacrylamide Gel
Electrophoresis
• Q4B Annex 11 Capillary Electrophoresis
• Q4B Annex 12 Analytical Sieving
• Q4B Annex 13 Bulk Density and Tapped
Density of Powders
• Q4B Annex 14 Bacterial Endotoxins Test
22

• Q5A - Q5E Quality of Biotechnological Products
Q5A(R1) Viral Safety Evaluation of Biotechnology
Products Derived from Cell Lines of Human or
Animal Origin.
• Q5B Analysis of the Expression Construct in Cells
Used for Production of r-DNA Derived Protein
Products.
• Q5C Stability Testing of
Biotechnological/Biological Products.
23

• Q5D Derivation and Characterization of Cell
Substrates Used for Production of
• Q5E Comparability of
Biotechnological/Biological Products Subject
to Changes in their Manufacturing Process
24

• Q6A- Q6B Specifications
Q6ASpecifications : Test Procedures and
Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances
Q6BSpecifications : Test Procedures and
Acceptance Criteria for
Biotechnological/Biological Products
25

• Q7 Good Manufacturing Practice
• Q8 Pharmaceutical Development
• Q9 Quality Risk Management
• Q10 Pharmaceutical Quality System
• Q11 Development and Manufacture of Drug
Substances
• Q12 Lifecycle Management
26

Q1A(R2)Stability Testing of New Drug
Substances and Products.
• The purpose of stability testing is to provide
evidence on how the quality of a drug
substance or drug product varies with time
under the influence of a variety of
environmental factors such as temperature,
humidity, and light, and to establish a retest
period for the drug substance or a shelf life for
the drug product and recommended storage
conditions.
27

• The mean kinetic temperature in any part of
the world can be derived from climatic data,
and the world can be divided into four climatic
zones, I-IV.
• This guideline addresses climatic zones I and II
28

• Four climatic zones can be distinguished for
the purpose of worldwide stability testing, as
follows:
1. Zone I: temperate.
2. Zone II: subtropical, with possible high
humidity.
3. Zone III: hot/dry.
4. Zone IV: hot/humid.
29

Q1B Stability Testing : Photostability Testing of
New Drug Substances and Products.
• The intrinsic photostability characteristics of
new drug substances and products should be
evaluated to demonstrate that, as
appropriate, light exposure does not result in
unacceptable change.
30

• A systematic approach to photostability testing is
recommended covering, as appropriate, studies
such as:
• i) Tests on the drug substance;
• ii) Tests on the exposed drug product outside of
the immediate pack;
• iii) Tests on the drug product in the immediate
pack;
• iv) Tests on the drug product in the marketing
pack.
31

DRUG SUBSTANCE
• For drug substances, photostability testing
should consist of two parts:
1. forced degradation testing and
2. confirmatory testing.
32

• Forced degradation testing studies are those
undertaken to degrade the sample
deliberately.
• Confirmatory studies are those undertaken to
establish photostability characteristics under
standardized conditions.
33

Q1C Stability Testing for New Dosage
Forms
• The ICH harmonized Tripartite Guideline on
Stability Testing of New Drug Substances and
Products was issued on October 27, 1993.
34

• A new dosage form is defined as a drug
product which is a different pharmaceutical
product type, but contains the same active
substance as included in the existing drug
product approved by the pertinent regulatory
authority.
35

Q1D Bracketing and Matrixing Designs for Stability
Testing of New Drug Substances and Products.
• A full study design is one in which samples for
every combination of all design factors are
tested at all time points.
• A reduced design is one in which samples for
every factor combination are not all tested at
all time points.
• A reduced design can be a suitable alternative
to a full design when multiple design factors
are involved.
36

• bracketing is the design of a stability schedule
such that only samples on the extremes of
certain design factors (e.g., strength, container
size and/or fill) are tested at all time points as
in a full design.
37

• Matrixing
matrixing is the design of a stability schedule
such that a selected subset of the total
number of possible samples for all factor
combinations would be tested at a specified
time point
38

Q1E Evaluation of Stability Data.
• This guideline addresses the evaluation of
stability data that should be submitted in
registration applications for new molecular
entities and associated drug products.
39

• The guideline provides recommendations on
establishing retest periods and shelf lives for
drug substances and drug products intended
for storage at or below “room temperature”*.
• It covers stability studies using single- or
multi-factor designs and full or reduced
designs
40

Q1F Stability Data Package for Registration
Applications in Climatic Zones III and IV.
• ICH Q1 F Stability Data Package for
Registration Applications in Climatic Zones III
and IV defined storage conditions for stability
testing in countries located in Climatic Zones
III (hot and dry) and IV (hot and humid), i.e.
countries not located in the ICH regions and
not covered by ICH Q1 A (R2) Stability Testing
for New Drug Substances and Drug Products.
41

Q2 Analytical Validation
• The discussion of the validation of analytical
procedures is directed to the four most common types
of analytical procedures:
1. - Identification tests;
2. - Quantitative tests for impurities' content;
3. - Limit tests for the control of impurities;
4. - Quantitative tests of the active moiety in samples of
drug substance or drug product or other selected
component(s) in the drug product.
42

• Identification tests are intended to ensure the
identity of an analyte in a sample.
• This is normally achieved by comparison of a
property of the sample (e.g., spectrum,
chromatographic behavior, chemical reactivity,
etc) to that of a reference standard;
43

• Testing for impurities can be either a
quantitative test or a limit test for the
impurity in a sample.
• Assay procedures are intended to measure the
analyte present in a given sample.
44

Q3A - Q3D Impurities
• Q3A (R2) impurities in new drug substance.
• Impurities in new drug substances are
addressed from two perspectives:
• Chemistry Aspects include classification and
identification of impurities, report generation,
listing of impurities in specifications, and a
brief discussion of analytical procedures; and
45

• Safety Aspects include specific guidance for
qualifying those impurities that were not
present, or were present at substantially lower
levels, in batches of a new drug substance
used in safety and clinical studies
46

• CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following
categories:
1. Organic impurities (process- and drug-
related)
2. Inorganic impurities
3. Residual solvents
47

1. Organic impurities can arise during the
manufacturing process and/or storage of the
new drug substance.
• They can be identified or unidentified, volatile or
non-volatile, and include:
 Starting materials
 By-products
 Intermediates
 Degradation products
 Reagents, ligands and catalysts
48

2. Inorganic impurities can result from the
manufacturing process.
They are normally known and identified and
include:
 Reagents, ligands and catalysts
 Heavy metals or other residual metals
 Inorganic salts
 Other materials (e.g., filter aids, charcoal)
49

3. Solvents are inorganic or organic liquids used
as vehicles for the preparation of solutions or
suspensions in the synthesis of a new drug
substance.
50

Q3B (R2) impurities in new product.
• This guideline addresses only those impurities
in new drug products classified as degradation
products of the drug substance or reaction
products of the drug substance with an
excipient and/or immediate container closure
system (collectively referred to as
“degradation products”).
51

Q3C(R6) Impurities: Guideline for Residual
Solvents.
• Residual solvents in pharmaceuticals are
defined here as organic volatile chemicals that
are used or produced in the manufacture of
drug substances or excipients, or in the
preparation of drug products.
52

• all residual solvents should be removed to the
extent possible to meet product
specifications, good manufacturing practices,
or other quality-based requirements.
53

• Class 1 solvents:
Solvents to be avoided Known human
carcinogens, strongly suspected human
carcinogens, and environmental hazards.
Solvents to be limited Non-genotoxic animal
carcinogens or possible causative agents of other
irreversible toxicity such as neurotoxicity or
teratogenicity. Solvents suspected of other
significant but reversible toxicities.
54

Solvents with low toxic potential Solvents with
low toxic potential to man; no health-based
exposure limit is needed. Class 3 solvents have
PDEs of 50 mg or more per day
55

Q3D Guideline for Elemental
Impurities.
• The elements included in this guideline have
been placed into three classes based on their
toxicity and likelihood of occurrence in the
drug product.
56

• The elemental impurity classes are The elements, As,
Cd, Hg, and Pb, are human toxicants that have limited
or no use in the manufacture of pharmaceuticals.
• Their presence in drug products typically comes from
commonly used materials (e.g., mined excipients).:
• Class 2: Elements in this class are generally considered
as route-dependent human toxicants.
• Class 2 elements are further divided in sub-classes 2A
and 2B based on their relative likelihood of occurrence
in the drug product.
57

• Class 2A elements have relatively high probability
of occurrence in the drug product and thus
require risk assessment across all potential
sources of elemental impurities and routes of
administration (as indicated).
• The class 2A elements are: Co, Ni and V.
• Class 2B elements have a reduced probability of
occurrence in the drug product related to their
low abundance and low potential to be co-
isolated with other materials.
58

• The elemental impurities in class 2B include:
Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl.
• Class 3:
The elements in this class have relatively low
toxicities by the oral route of administration
(high PDEs, generally > 500 µg/day) but may
require consideration in the risk assessment
for inhalation and parenteral routes.
59

• The elements in this class include: Ba, Cr, Cu,
Li, Mo, Sb, and Sn
60

Q4 - Q4B Pharmacopoeias
• Q4Pharmacopoeias
• The three organizations (USP, JP & EP)
conduct their harmonization efforts through a
tripartite pharmacopeial harmonization
program known as the Pharmacopoeial
Discussion Group (PDG)
61

Q4B Annex 1R1 Residue on
Ignition/Sulphated Ash
• [ an appropriate sample weight is chosen,
typically 1-2 g, to result in a level of residue
sufficient to be accurately measurable by
weight (typically 1 mg). If not specified in the
monograph, the appropriate sample weight
should be justified, and the sample weight
and the acceptance criteria should be
specified in the application dossier.]
62

• When sponsors or manufacturers change their
existing methods to the implemented
pharmacopoeial texts that are referenced, any
change notification, variation, and/or prior
approval procedures should be handled in
accordance with established regional
regulatory mechanisms pertaining to
compendial changes.
63

Q4B Annex 2R1 Test for Extractable Volume of
Parenteral Preparations
• FDA consideration:
the pharmacopoeial texts can be considered
as interchangeable. However, FDA might
request that a company demonstrate that the
chosen method is acceptable and suitable for
a specific material or product, irrespective of
the origin of the method.
64

• EU consideration:
Regulatory authorities can accept the
reference in a marketing authorization
application, renewal or variation application
citing the use of the corresponding text from
another pharmacopoeia.
65

Q4B Annex 3R1 Test for Particulate
Contamination: Sub-Visible Particles.
• For nominal 100-mL parenteral products, the
FDA considers testing criteria from all three
pharmacopoeias as interchangeable.
66

Q4B Annex 5R1 Disintegration Test
• Disintegration, can be used as interchangeable
in the ICH regions subject to the conditions
detailed below.
• For tablets and capsules larger than 18 millimeters
(mm) long for which a different apparatus is used, the
disintegration Test is not considered to be
interchangeable in the ICH regions.
67

• The Disintegration Test is not considered to be
interchangeable in the ICH regions for dosage forms
referred to in the regional compendia as delayed-
release, gastro-resistant, or enteric-coated.
• Product-specific parameters such as media and the use
of discs should be specified in the application dossier.
68

Q4B Annex 6 Uniformity of Dosage
Units
• Uniformity of Dosage Units, can be used as
interchangeable in the ICH regions subject to
the following conditions:
• Unless the 25 milligrams (mg)/25% threshold limit is
met, the use of the Mass/Weight Variation test as an
alternative test for Content Uniformity is not
considered interchangeable in all ICH regions.
69

• If a correction factor is called for when different
procedures are used for assay of the preparation and
for the Content Uniformity Test, the correction factor
should be specified and justified in the application
dossier.
70

Q4B Annex 7R2 Dissolution Test
• The declaration of interchangeability applies to the
Basket Apparatus (Apparatus 1), the Paddle Apparatus
(Apparatus 2), and the Flow-Through Cell.
• The Dissolution Test is not considered to be
interchangeable in the ICH regions when enzymes are
used in the media.
71

• The Dissolution Test is not considered to be interchangeable
in the ICH regions for use of large vessels (greater than 1
liter).
• Product-specific parameters such as media, stirring rate,
sampling time, and the use and type of sinkers should be
specified and justified in the application dossier.
72

Q4B Annex 8R1 Sterility Test
• Sterility Tests, can be used as interchangeable
in the ICH regions subject to the conditions
detailed below. Testing conditions for medical
devices, such as sutures, are outside the scope
of the ICH recommendation.
• Diluting and rinsing fluids should not have antibacterial
or antifungal properties if they are to be considered
suitable for dissolving, diluting, or rinsing an article
under test for sterility.
73

• When testing liquid parenteral preparations with a nominal
volume of 100 milliliters in batches of more than 500
containers, the test is considered interchangeable if the
minimum number of containers selected is either 20 or is 2
percent of the total number of containers, whichever is lower.
74

Q4B Annex 9R1 Tablet Friability
• For interchangeability, the loss of mass for a
single determination should be not more than
1.0 percent, unless otherwise specified in the
dossier.
• When three determinations are conducted,
then the mean loss of mass for the three
determinations should be not more than 1.0
percent, unless otherwise specified in the
dossier.
75

Q5A - Q5E Quality of
Biotechnological Products
76

Q5A(R1) Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin.
• This document is concerned with testing and
evaluation of the viral safety of biotechnology
products derived from cell lines of human or
animal origin (i.e., mammalian, avian, insect)
77

• The objective is to provide a general
framework for virus testing experiments for
the evaluation of virus clearance and the
design of viral tests and clearance evaluation
studies.
78

• Three principal, complementary approaches have evolved to
control the potential viral contamination of biotechnology products:
•
• a) selecting and testing cell lines and other raw materials, including
media components, for the absence of undesirable viruses which
may be infectious and/or pathogenic for humans;
• b) Testing the capacity of the processes to clear infectious viruses;
• c) testing the product at appropriate steps for absence of
contaminating infectious viruses.
79

Q5B: Quality of Biotechnological Products : Analysis of the Expression
Construct in Cells Used for Production of r-DNA Derived Protein
Products
• This document presents guidance regarding
the characterization of the expression
construct for the production of recombinant
DNA protein products in eukaryotic and
prokaryotic cells.
• expression construct should be analysed using
nucleic acid techniques.
80

• The expression construct is defined as the
expression vector containing the coding
sequence of the recombinant protein.
81

Q5C Stability Testing of
• the applicant should develop the proper
supporting stability data for a
biotechnological/biological product and consider
many external conditions which can affect the
product’s potency, purity and quality.
• Primary data to support a requested storage
period for either drug substance or drug product
should be based on long-term, real-time, real-
condition stability studies.
82

Q5D: Derivation and Characterization of Cell Substrates
Used for Production of Biotechnological/Biological Products
• The objective of this guideline is to provide broad
guidance on appropriate standards for cell substrates.
• This guideline covers cell substrates having a cell
banking system.
• In this document, “cell substrate” refers to microbial
cells or cell lines derived from human or animal
sources that possess the full potential for generation of
the desired biotechnological/biological products for
human in vivo or ex vivo use.
83

Q5E: Comparability of Biotechnological/ Biological
Products Subject to Changes in Their Manufacturing
Process
• The objective of this document is to provide
principles for assessing the comparability of
biotechnological/ biological products before
and after changes are made in the
manufacturing process for the drug substance
or drug product.
84

• Therefore, this guideline is intended to assist
in the collection of relevant technical
information which serves as evidence that the
manufacturing process changes will not have
an adverse impact on the quality, safety and
efficacy of the drug product.
85

Q6 : Specifications for New Drug
Substances and Products
• Bulk drug substance and final product
specifications are key parts of the core
documentation for world-wide product license
applications.
• This leads to conflicting standards for the
same product, increased expenses and
opportunities for error as well as a potential
cause for interruption of product supply
86

Q6A: Specifications : Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug
Products : Chemical Substances
• The main objective of this guideline is to
establish a single set of global specifications
for new drug substances and new drug
products.
• A specification is defined as a list of tests,
references to analytical procedures, and
appropriate acceptance criteria, which are
numerical limits, ranges
87

• This guideline addresses specifications, i.e.,
those tests, procedures, and acceptance
criteria which play a major role in assuring the
quality of the new drug substance and new
drug product during shelf life.
88

• Universal Tests:
• The following tests are considered generally
applicable to all new drug substances and
drug products.
 Description
 Identification
 Assay
 Impurities
89

• Specific Tests for drug substances :
 Physicochemical properties
 Particle size
 Polymorphic forms
 Tests for chiral new drug substances
 Water content
 Inorganic impurities
 Microbial limits
90

• Specific Tests for drug products(oral dosage form):
 Particle size distribution:
 Dissolution
 Disintegration
 Hardness/friability
 Uniformity of dosage units:
 Microbial limits
 Antioxidant preservative content:
 Alcohol content:
 Rheological properties:
 Redispersibility
91

• Specific Tests for drug products (Parenteral Drug Products):
 Uniformity of dosage units
 Particle size distribution
 pH (Osmolarity)
 Sterility
 Endotoxins/Pyrogens
 Particulate matter
 Water content
 Antimicrobial preservative
 Antioxidant preservative content
 Functionality testing of delivery system
92

Q6B: Specifications : Test Procedures and Acceptance
Criteria for Biotechnological/Biological Products
• This document provides guidance on justifying
and setting specifications for proteins and
polypeptides which are derived from
recombinant or non-recombinant cell cultures.
• • A valid biological assay to measure the
biological activity should be provided by the
manufacturer.
93

• Examples of procedures used to measure
biological activity include:
• Animal-based biological assays, which measure
an organism's biological response to the product;
• Cell culture-based biological assays, which
measure biochemical or physiological response at
the cellular level;
• Biochemical assays, which measure biological
activities such as enzymatic reaction rates or
biological responses induced by immunological
interactions.
94

Q7: Good Manufacturing Practice Guide for
Active Pharmaceutical Ingredients
• The main objective of this guideline is that to
maintain the quality of the active
pharmaceutical ingredients
 Personnel
 Buildings and Facilities
 Process equipment
 Documentation and Records
95

Q8(R2): Pharmaceutical Development
• This guideline is intended to provide guidance
on the contents of Pharmaceutical
Development of drug products
• The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
•
96

• The Pharmaceutical Development section also
describe the type of dosage form and the
formulation that are suitable for the intended
use.
• Q8 gives information about Drug Substance,
Excipients, Container Closure System.
97

Q9: Quality Risk Management
• The purpose of this document is to offer a systematic
approach to quality risk management.
• This guideline provides principles and tools for quality
risk management that can be applied to all aspects of
pharmaceutical quality including development,
manufacturing, distribution; and the inspection and
submission/review processes throughout the lifecycle of
drug substances and drug (medicinal) products, biological
and biotechnological products, including the use of raw
materials, solvents, excipients, packaging and labeling
materials.
98

• PRINCIPLES OF QUALITY RISK MANAGEMENT
• Two primary principles of quality risk
management are:
 The evaluation of the risk to quality should be
based on scientific knowledge and ultimately
link to the protection of the patient; and
The level of effort and documentation of the
quality risk management process should be
commensurate with the level of risk.
99

Q10: Pharmaceutical Quality System
• This document establishes a new ICH tripartite
guideline describing a model for an effective
quality management system for the
pharmaceutical industry, referred to as the
Pharmaceutical Quality System.
• comprehensive model for an effective
pharmaceutical quality system is based on
International Standards Organization (ISO) quality
concepts, includes applicable Good
Manufacturing Practice (GMP) regulations
100

Q11: Development and Manufacture
of Drug Substances
• This guideline describes approaches to
developing and understanding the
manufacturing process of the drug substance,
and also provides guidance on what
information should be provided in Module 3
of the Common Technical Document (CTD)
101

• For the purpose of this guideline, the terms “traditional” and
“enhanced” are used to differentiate two possible approaches.
• In a traditional approach, set points and operating ranges for
process parameters are defined and the drug substance control
strategy is typically based on demonstration of process
reproducibility and testing to meet established acceptance criteria.
• In an enhanced approach, risk management and scientific
knowledge are used more extensively to identify and understand
process parameters and unit operations that impact critical quality
attributes (CQAs) and develop appropriate control strategies
applicable over the lifecycle of the drug substance which may
include the establishment of design space(s).
102

• S1A - S1C Carcinogenicity Studies
 S1Rodent Carcinogenicity Studies for Human
Pharmaceuticals
 S1ANeed for Carcinogenicity Studies of Pharmaceuticals
 S1BTesting for Carcinogenicity of Pharmaceuticals
 S1C(R2)Dose Selection for Carcinogenicity Studies of
Pharmaceuticals
• S2 Genotoxicity Studies
S2(R1)Guidance on Genotoxicity Testing and Data
Interpretation for Pharmaceuticals Intended for Human Use
104

• S3A - S3B Toxicokinetics and
Pharmacokinetics

S3A Note for Guidance on Toxicokinetics: The
Assessment of Systemic Exposure in Toxicity
Studies
S3B Pharmacokinetics: Guidance for Repeated
Dose Tissue Distribution Studies
105

• S4 Toxicity Testing
• S5 Reproductive Toxicology

S5(R2)Detection of Toxicity to Reproduction for Medicinal
Products & Toxicity to Male Fertility
 S5(R3)Revision of S5 Guideline on Detection of Toxicity to
Reproduction for Human Pharmaceuticals
• S6 Biotechnological Products
S6(R1)Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals
106

• S7A - S7B Pharmacology Studies

S7A Safety Pharmacology Studies for Human
Pharmaceuticals
S7B The Non-Clinical Evaluation of the
Potential for Delayed Ventricular
Repolarization (QT Interval Prolongation) by
Human Pharmaceuticals
107

• S8 Immunotoxicology Studies
• S9 Nonclinical Evaluation for Anticancer
Pharmaceuticals
• S10 Photosafety Evaluation
• S11 Nonclinical Safety Testing
108

S1Rodent Carcinogenicity Studies for
Human Pharmaceuticals
• Carcinogenicity studies should be performed
for any pharmaceutical whose expected
clinical use is continuous for at least 6 months.
• This document provides a consistent
definition of the circumstances under which it
is necessary to undertake carcinogenicity
studies on new drugs.
109

• These recommendations take into account the
known risk factors as well as the intended
indications and duration of exposure.
• The objectives of carcinogenicity studies are
to identify a tumorigenic potential in animals
and to assess the relevant risk in humans.
110

S1A Need for Carcinogenicity Studies
of Pharmaceuticals
• This document provides guidance on the need
to carry out carcinogenicity studies in both
mice and rats, and guidance is also given on
alternative testing procedures which may be
applied without jeopardizing safety.
111

S1C(R2): Dose Selection for Carcinogenicity
Studies of Pharmaceuticals
• This document addresses the criteria for the
selection of the high dose to be used in
carcinogenicity studies on new therapeutic
agents to harmonize current practices and
improve the design of studies.
112

S2(R1): Guidance on Genotoxicity Testing and Data
Interpretation for Pharmaceuticals Intended for Human
Use
• This guidance is a combination of ICH S2A and
S2B guidelines:
• S2A: Guidance on Specific Aspects of Regulatory
Genotoxicity Tests for Pharmaceuticals;
• This document provided specific guidance and
recommendations for in vitro and in vivo tests
and on the evaluation of test results. It includes
terms related to genotoxicity tests to improve
consist
114

• S2B: Genotoxicity: A Standard Battery for
Genotoxicity Testing for Pharmaceuticals :
• This document addresses two fundamental
areas of genotoxicity testing:
A) the identification of a standard set of assays
to be conducted for registration, and the extent
of confirmatory experimentation in any
particular genotoxicity assay in the standard
battery.
115

B) Registration of pharmaceuticals requires a
comprehensive assessment of their genotoxic
potential. It is clear that no single test is capable
of detecting all relevant genotoxic agents.
Therefore, the usual approach should be to
carry out a battery of in vitro and in vivo tests
for genotoxicity
116

• The purpose of this guideline is to optimize
the standard genetic toxicology battery for
prediction of potential human risks, and for
interpretation of results, with the ultimate
goal of improving risk characterization for
carcinogenic effects that have their basis in
changes in the genetic material.
117

S3A –S3B--- Toxicokinetics and
Pharmacokinetics:
118

S3A: Note for Guidance on Toxicokinetics: The
Assessment of Systemic Exposure in Toxicity
Studies
• ICH guidelines do not require toxicokinetic
studies to be conducted, except in pregnant,
lactating animals, before initiating reproductive
studies.
• In this context, toxicokinetics is defined as the
generation of pharmacokinetic data, either as an
integral component in the conduct of non-clinical
toxicity studies or in specially designed
supportive studies, in order to assess systemic
exposure.
119

• This document gives guidance on developing
test strategies in toxicokinetics and the need
to integrate these pharmacokinetics into
toxicity testing, in order to aid in the
interpretation of the toxicology findings and
and their relevance to clinical safety issues
120

• The primary objective of toxicokinetics is: to
describe the systemic exposure achieved in
animals and its relationship to dose level and
the time course of the toxicity study.
121

S3B: Pharmacokinetics: Guidance for
Repeated Dose Tissue Distribution Studies
• Tissue distribution studies are essential in
providing information on distribution and
accumulation of the compound and/or
metabolites, especially in relation to potential
sites of action; this information may be useful
for designing toxicology and pharmacology
studies and for interpreting the results of
these experiments.
122

• This document gives guidance, when the
repeated dose tissue distribution studies
should be considered (i.e., when appropriate
data cannot be derived from other sources). It
also gives recommendations on the conduct
of such studies
123

S4: Duration of Chronic Toxicity Testing in Animals
(Rodent and Non-Rodent Toxicity Testing)
• The objective of this guidance is to set out the
considerations that apply to chronic toxicity
testing in rodents and non rodents as part of
the safety evaluation of a medicinal product
 Rodents(a study of 6 months duration)
 Non-rodents(a study of nine months
duration).
124

S5: Detection of Toxicity to Reproduction for
Medicinal Products & Toxicity to Male Fertility
• This document provides guidance on tests for
reproductive toxicity.
• It defines the periods of treatment to be used
in animals to better reflect human exposure to
medical products and allow more specific
identification of stages at risk.
125

• It should encourage the full assessment on the
safety of chemicals on the development of the
offspring.
126

S6: Preclinical Safety Evaluation of
Biotechnology-Derived Pharmaceuticals
• This document covers the pre-clinical safety
testing requirements for biotechnological
products. It addresses the use of animal
models of disease, determination of when
genotoxicity assays and carcinogenicity studies
should be performed, and the impact of
antibody formation on duration of toxicology
studies.
127

• The primary goals of preclinical safety
evaluation are:
1) to identify an initial safe dose and subsequent
dose in humans;
2) to identify potential target organs for toxicity
and for the study of whether such toxicity is
reversible;
3) to identify safety parameters for clinical
monitoring.
128

S7A: Safety Pharmacology Studies for Human
Pharmaceuticals
• This guideline was developed to protect clinical
trial participants and patients receiving marketed
products from potential adverse effects of
pharmaceuticals
• This document addresses the definition,
objectives and scope of safety pharmacology
studies.
• It also addresses which studies are needed
before initiation of Phase 1 clinical studies as well
as information needed for marketing.
129

S7B : The Nonclinical Evaluation of the Potential for
Delayed Ventricular Repolarization (QT Interval
Prolongation) By Human Pharmaceuticals
• This guideline describes a non-clinical testing
strategy for assessing the potential of a test
substance to delay ventricular repolarization.
• This guideline includes information
concerning nonclinical assays and integrated
risk assessments.
130

S8 : Immunotoxicity Studies for Human
Pharmaceuticals
• This guideline addresses the
recommendations on nonclinical testing for
immunosuppressant.
• The guideline might also apply to drugs in
which clinical signs of immunosuppressant are
observed during clinical trials and following
approval to market.
131

• The term immunotoxicity in this guideline will
primarily refer to immunosuppressant, i.e. a
state of increased susceptibility to infections
or the development of tumors.
132

S9: Nonclinical Evaluation for
Anticancer Pharmaceuticals
• This guideline provides information for
pharmaceuticals that are only intended to
treat cancer in patients with late stage or
advanced disease regardless of the route of
administration, including both small molecule
and biotechnologyderived pharmaceuticals.
133

• It describes the type and timing of nonclinical
studies in relation to the development of
anticancer pharmaceuticals and references
other guidance as appropriate.
134

• This guideline aims to facilitate and accelerate
the development of anticancer
pharmaceuticals and to protect patients from
unnecessary adverse effects, while avoiding
unnecessary use of animals and other
resources
135

• E1 Clinical Safety for Drugs used in Long-Term
Treatment
• E2A - E2F Pharmacovigilance
E2AClinical Safety Data Management: Definitions
and Standards for Expedited Reporting
• E2B(R3)Clinical Safety Data Management: Data
Elements for Transmission of Individual Case
Safety Reports
• E2B(R3) IWGImplementation: Electronic
Transmission of Individual Case Safety Reports
137

• E2C(R2)Periodic Benefit-Risk Evaluation
• E2D Post-Approval Safety Data Management:
Definitions and Standards for Expedited
Reporting
• E2E Pharmacovigilance Planning
• E2F Development Safety Update Report
138

• E3 Clinical Study Reports
• E4 Dose-Response Studies
• E5 Ethnic Factors
• E6 Good Clinical Practice
• E7 Clinical Trials in Geriatric Population
• E8 General Considerations for Clinical Trials
139

• E9 Statistical Principles for Clinical Trials
• E10 Choice of Control Group in Clinical Trials
• E11 Clinical Trials in Pediatric Population
• E12 Clinical Evaluation by Therapeutic
Category
• E14 Clinical Evaluation of QT
140

• E15 Definitions in Pharmacogenetics /
Pharmacogenomics
• E16 Qualification of Genomic Biomarkers
• E17 Multi-Regional Clinical Trials
• E18 Genomic Sampling
• E19 Safety Data Collection
141

E1 Clinical Safety for Drugs used in
Long-Term Treatment
• This document gives recommendations on the
number of patients and duration of exposure
for the safety evaluation of drugs intended for
the long-term treatment of non-life-
threatening conditions
•
142

• This guidelines gives information on duration
of drug exposure and its relationship to both
time and magnitude of occurrence of adverse
events
143

E2A - E2F Pharmacovigilance
144

E2A: Clinical Safety Data Management
: Definitions and Standards
• This document gives standard definitions and
terminology for key aspects of clinical safety
reporting.
• It also gives guidance on mechanisms for
handling adverse drug reactions in the
investigational phase of drug development
145

E2B(R3): Clinical Safety Data Management Data
Elements for Transmission of Individual Case Safety
Reports
• The objectives of the working group is to
identify, define and standardize the data
elements for the transmission of individual
case safety reports(adverse reactions, adverse
event reports).
146

• Following its submission to ISO for
development as an International Standard.
Key parts of this updated guideline will be
incorporated into the Implementation Guide
for Electronic Transmission of Individual Case
Safety Reports Message Specification which is
currently available for public awareness.
147

E2C(R1): Clinical Safety DataManagement:
Periodic Safety Update Reports for Marketed
Drugs
• This document gives guidance on the format
and content of safety updates, which need to
be provided at regular intervals to regulatory
authorities to ensure maximum efficacy and
to avoid duplication of marketed drugs .
148

E2D: Post-Approval Safety Data
Management: Definitions and Standards
• This document provides a standardized
procedure for post-approval safety data
management.
• The definitions of the terms specific to post-
approval phase are also provided.
149

• The practices of the data management were
standardized in such cases obtained from
consumers, literatures, internets which are all
specific to postapproval data management.
150

E2E: Pharmacovigilance Planning
• This guideline is intended to aid in planning
pharmacovigilance activities, especially in
preparation for the early post marketing of a
new drug (in this guideline, the term "drug"
denotes chemical entities, biotechnology-
derived products, and vaccines).
151

• The main focus of this guideline is on a Safety
Specification and Pharmacovigilance Plan that
might be submitted at the time of license
application.
152

• The guideline describes a method for
summarizing the important identified risks of
a drug, important potential risks, and
important missing information, including the
potentially at-risk populations and situations
where the product is likely to be used that
have not been studied.
153

E2F: Development Safety Update
Report
• The main focus of the DSUR is collection of
data from clinical trials of investigational
drugs including biological’s, with or without a
marketing approval.
• The DSUR should provide safety information
from all ongoing clinical trials that the sponsor
is conducting or has completed during the
review period including:
154

 clinical trials conducted using an
investigational drug whether with or without a
marketing approval, i.e., human
pharmacology, therapeutic exploratory and
therapeutic confirmatory trials (Phase I – III)
 clinical trials conducted using marketed drugs
in approved indications, i.e., therapeutic use
trials (Phase IV)
155

 other therapeutic use of an investigational
drug
 comparability trials conducted to support
changes in the manufacturing process of
medicinal products
156

E3: Structure and Content of Clinical
Study Reports
• This document describes the format and content
of a study report that will be acceptable in all
three ICH regions. It consists of a core report
suitable for all submissions and appendices.
• The clinical study report described in this
guideline is an integrated full report of an
individual study of any therapeutic, prophylactic
or diagnostic agent (referred to herein as drug or
treatment) conducted in patients.
157

• The guideline is intended to assist sponsors for
the development of a report that is complete,
free from ambiguity, well organized and easy
to review
158

• STRUCTURE AND CONTENT OF CLINICAL
STUDY REPORTS
 Title page
 Table of contents for the individual clinical
study report
 List of abbreviations and definition of terms
 Ethics (ethical conduct of the study, patient
information and consent )
159

• Investigators and study administrative structure
 Introduction
 Study objectives
• Overall study design and plan - description
 Selection of study population
 Selection of doses in the study
 Efficacy and safety variables
 Efficacy results and tabulations of individual
patient data
 Safety evaluation
160

E4: Dose-Response Information to Support
Drug Registration
• This document gives recommendations on the
design and conduct of studies to assess the
relationship between doses, blood levels and
clinical response throughout the clinical
development of a new drug.
161

• This information can help in identifying an
appropriate starting dose, to adjust dosage to
the needs of a particular patient, and a dose
beyond which unacceptable side effects are
seen.
162

E5(R1): Ethnic Factors in the
Acceptability of Foreign Clinical Data
The purpose of this guidance is to facilitate the
registration of medicines among ICH regions.
• This document addresses the intrinsic
characteristics of the drug recipient and
extrinsic characteristics associated with
environment and culture that could affect the
results of clinical studies carried out in regions
163

• Describes the concept of the "bridging study"
that a new region may request to determine
whether data from another region are
applicable to its population.
164

E6(R1): Good Clinical Practice :
Consolidated Guideline
• Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for
designing, conducting, recording and reporting
trials that involve the participation of human
subjects.
• This Good Clinical Practices document describes
the responsibilities and expectations of all
participants in the conduct of clinical trials,
including investigators, monitors, sponsors .
165

• GCPs cover aspects of monitoring, reporting
and achieving of clinical trials and
incorporating these into Essential Documents
and on the Investigator's Brochure.
166

E7-E11----CLINICAL TRIALS:
167

E7 Clinical Trials in Geriatric Population
• This document provides recommendations on
the special considerations which apply in the
design and conduct of clinical trials of
medicines that are likely to have significant
use in the elderly.
168

• E.g.: New Molecular Entities that are likely to
have significant use in the elderly, because
the disease intended to be treated is
characteristically a disease of ageing ( e.g.,
Alzheimer's disease)
169

E8: General Considerations for Clinical
Trials
• This document sets out the general scientific
principles for the conduct, performance and
control of clinical trials.
• The guideline addresses a wide range of
subjects in the design and execution of clinical
trials.
170

• The ICH document "General Considerations
for Clinical Trials" is intended to:
• (a)describe internationally accepted principles
and practices in the conduct of both individual
clinical trials and overall development strategy
for new medicinal products
171

• (b) facilitate the evaluation and acceptance of
foreign clinical trial data by promoting
common understanding of general principles
• c) present an overview of the ICH clinical
safety and efficacy documents and facilitate
the user's access to guidance
172

• (d) provide a separate glossary of terms used
in the ICH clinical safety and efficacy related
documents that pertain to clinical trials
173

E9: Statistical Principles for Clinical
Trials
• This biostatistical guideline describes essential
considerations on the design and analysis of
clinical trials, especially the "confirmatory"
(hypothesis-testing) trials that are the basis
for demonstrating effectiveness.
174

E10: Choice of Control Group and
Related Issues in Clinical Trials
• This document addresses the choice of control
groups in clinical trials.
• Control groups in clinical trials can be
classified on the basis of two critical
attributes:
(1) the type of treatment used and
(2) the method of determining who will be in
the control group
175

• The type of control treatment may be any of
the following four:
(1) placebo,
(2) no treatment,
(3) different dose or regimen of the study
treatment, or
(4) a different active treatment.
176

E11: Clinical Investigation of Medicinal
Products in the Pediatric Population
• This document addresses the conduct of
clinical trials of medicines in pediatric
populations.
• This document will facilitate the development
of safe and effective use of medicinal product
in pediatrics.
177

• Specific clinical study include:
(1) timing of initiation of pediatric studies
during medicinal product development
(2) types of studies (pharmacokinetic,
pharmacokinetic/ pharmacodynamic (PK/PD),
efficacy, safety)
(3) age categories
(4) ethics of pediatric clinical investigation.
178

E12-Guidelines for Clinical Evaluation by
Therapeutic Category
• The ICH Efficacy Guidelines are applicable to
all therapeutic classes of drugs, but there are
some therapeutic classes which need
individual drug evaluation guidelines among
the ICH regions.
179

E12: Principles for Clinical Evaluation of New
Antihypertensive Drugs
• This document provides general principles for
the clinical evaluation of new anti-
hypertensive drugs.
180

• It describes core principles for the evaluation
of antihypertensives that are accepted in the
three ICH regions, but some region-specific
differences remain, therefore this document
should be considered an "ICH Principle
Document" rather than an "ICH Guideline".
181

E14: The Clinical Evaluation of QT/QTc Interval
Prolongation and Pro-Arrhythmic Potential for Non-
Antiarrhythmic Drugs
• This document provides recommendations to
sponsors concerning the design, conduct,
analysis, and interpretation of clinical studies
to assess the potential of a drug to delay
cardiac repolarization.
182

• This assessment should include testing the
effects of new agents on the QT/QTc interval
as well as the collection of cardiovascular
adverse events.
183

• The investigational approach used for a
particular drug should be individualized,
depending on the pharmacodynamic,
pharmacokinetic, and safety characteristics of
the product, as well as on its proposed clinical
use.
184

E15: Definitions for Genomic Biomarkers,
Pharmacogenomics, Pharmacogenetics, Genomic Data
and Sample Coding Categories
• In order to develop harmonised approaches to
drug regulation, it is important to ensure that
consistent definitions of terminology are being
applied across all constituents of the
International Conference on Harmonisation
(ICH).
185

• An agreement on definitions will facilitate the
harmonization in the discipline of
pharmacogenomics and pharmacogenetics for
global drug development and approval
processes.
186

E16: Genomic Biomarkers Related to Drug Response:
Context, Structure and Format of Qualification
Submissions
• The guideline describes recommendations
regarding context, structure, and format of
regulatory submissions for qualification of
genomic biomarkers(E15).
187

• clinical and non-clinical genomic biomarkers
related to drug response including
pharmacokinetics, pharmacodynamics,efficacy
and safety aspects.
188

Multidisciplinary Guidelines
189

• M1 MedDRA Terminology
• M2 Electronic Standards
• M3 Nonclinical Safety Studies
• M4 Common Technical Document
• M5 Data Elements and Standards for Drug
Dictionaries
190

• M6 Gene Therapy
• M7 Genotoxic Impurities
• M8 Electronic Common Technical Document
(eCTD)
• M9 Biopharmaceutics Classification System-
based Biowaivers
• M10 Bioanalytical Method Validation
191

M1 Medical Terminology
• New Medical Dictionary for Regulatory
Activities Terminology (MedDRA) was
developed by the working group of ICH and is
owned by the International Federation of
Pharmaceutical Manufacturers and
Associations (IFPMA) acting as trustee for the
ICH steering committee.
192

• It provides an international medical dictionary
applicable to all phases of product
development.
• Its goal is to provide a comprehensive and
specific terminology to help standardize,
facilitate and simplify regulatory processes.
193

M2 Electronic Standards for Transmission
of Regulatory Information (ESTRI)
• Facilitate international electronic
communication by evaluating and
recommending the specifications
• The first Specification developed by the M2
EWG was the Individual Case Safety Report
(ICSR), created as the electronic message for
the ICH E2B(R2)
194

• The second Specification developed by the M2
EWG was the Electronic Common Technical
Document (eCTD) created as the electronic
message for the Common Technical Document
developed by the ICH M4.
195

• ICH M2 has initiated the development of the
Next Major Version of the eCTD (eCTD NMV)
to improve robustness, flexibility and long
term stability of the message.
196

M3(R2): Guidance on Non-Clinical Safety Studies for the
Conduct of Human Clinical Trials and Marketing Authorization
for Pharmaceuticals
• The present guidance represents the
consensus that exists regarding the type and
duration of nonclinical safety studies and their
timing to support the conduct of human
clinical trials and marketing authorization for
pharmaceuticals.
197

• The nonclinical safety assessment for
marketing approval of a pharmaceutical
usually includes pharmacology studies,
general toxicity studies, toxicokinetic and
nonclinical pharmacokinetic studies,
reproduction toxicity studies, genotoxicity
studies and, for drugs that have special cause
for concern or are intended for a long duration
of use
198

• The goals of the nonclinical safety evaluation
generally include a characterisation of toxic
effects with respect to target organs, dose
dependence, relationship to exposure, and,
when appropriate,potential reversibility.
199

• This information is used to estimate an initial
safe starting dose and dose range for the
human trials and to identify parameters for
clinical monitoring for potential adverse
effects.
200

M4:The Common Technical Document
• The Common Technical Document provides a
harmonized structure and format for new
product applications. The Common Technical
Document was agreed upon in November
2000 in San Diego, USA.
201

• This Common Technical Document is divided
into four separate sections.
• The four sections address the
application organisation (M4 organise),
the Quality section (M4Q),
the Safety section (M4S) and
 the Efficacy section (M4E) of the harmonised
application
202

• An electronic version of the Common
Technical Document (eCTD) developed by the
eCTD Implementation Working Group. The
Electronic Common Technical Document
(eCTD) allows for the electronic submission of
the Common Technical Document (CTD) by an
applicant to regulator
203

M5: Data Elements and Standards for
Drug Dictionaries
• This document provides guidance on the
harmonized standards related to core sets of
medicinal product information and medicinal
product terminology.
• Facilitate the exchange and practical use of
medicinal product data by regulators and
pharmaceutical industry.
204

• References
• www.ich.org
205

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