ICH GUIDELINES

REPRESENTED BYKOMAL R. D.
M.PHARM.SEM-II

Guided By:
Dr. J.B.Dave
Dr. R. Badmanaban

DEPARTMENT OF QUALITY ASSURANCE

SHRI SARVAJANIK PHARMACY COLLEGE
MEHSANA, GUJARAT

What does ICH stand for ?

The complete name of ICH is the
International Conference
on Harmonization of Technical
Requirements for Registration of
Pharmaceuticals for Human use.

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Introduction :
ICH established in 1990 as a joint
initiative involving both regulators
and research-based industry
representatives of the European
Union ,Japan and the USA in
scientific and technical discussion of
the testing procedures required to
assess and ensure the safety,
quality and efficacy of medicines.
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What is the purpose of ICH ?

The objective of ICH is to
increase international
harmonization of technical
requirements to ensure that
safe , effective and high
quality medicines are
developed and registered in
the most efficient and costeffective manner.
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What is the goal of ICH ?

The goal of ICH is to promote
international harmonization by
bringing together representatives
from the three regions ( EU ,
Japan and USA ) to discuss and
establish common guidelines.

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NEED FOR HARMONISATION

Rapid increase in laws, regulations and
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.
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Who are the members ?

JAPAN

- Ministry of Health , Labour and

Welfare ( MHLW )
- Japan Pharmaceutical
Manufacturers
Associations ( JPMA )
Europe
- European Union ( EU ).
- European federation of
Pharmaceutical Industries
and Associations ( EFPIA ).

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USA

- Food and Drug Administration

( FDA).
- 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.

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How is ICH structured ?

The ICH structure consists of following groups.

1 - ICH steering committee.

2 - ICH coordinators.
3 - ICH secretariat.
4 - ICH working group.
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ICH Steering Committee

It governs the ICH , determines the

policies and procedures for ICH , selects

topics for
harmonization and monitors the
progress
Each of of
the six parties has two seats on
initiatives .
theharmonization
ICH steering committee.
Each of the observers nominates nonvoting participants to attend the ICH steering
committee meetings.
IFPMA (The International Federation
of Pharmaceutical Manufacturers &
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Associations)

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ICH Coordinators
The coordinators are fundamental
to the smooth running of the ICH and
are nominated by each of the six
parties .

An ICH coordinators acts as the

main contact point with the ICH
secretariat and to ensure that ICH
document are distributed to
appropriate person within the area of
their responsibility.

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ICH Secretariat

It operates from IFPMA and provide

support to the ICH Steering Committee.

It is primarily concerned with

preparations for, and documentation of,
meetings of the steering committee as well
as the coordination of working group and
discussion group meeting.
It provides administrative support for the
GCG(Global cooperation group) and
MedDRA.
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Expert Working Groups

The Steering Committee assigns an EWG
to each of the technical topics selected.
The groups are comprised of industry
specialists on the topics discussed from each
of the six members.
Do not have a fixed membership.

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What are the steps in the ICH process?

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The ICH Topics are divided into

four major categories:
Quality (Q)

Safety (S)
Efficacy (E)

Multidisciplinary topics (M)

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QUALITY

Q1 : STABILITY
Q2 : ANALYTICAL VALIDATION
Q3 : IMPURITIES
Q4 : PHARMACOPOEIAS
Q5 : BIOTECHNOLOGICAL QUALITY
Q6 : SPECIFIACATIONS
Q7 : GMP
Q8 : PHARMACEUTICAL DEVELOPMENT
Q9 : QUALITY RISK MANAGEMANT
Q10: PHARMACEUTICAL QUALITY
SYSTEM
Q11:
DEVELOPMENT AND
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MANUFACTURE OF DRUG

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Q1 Stability Testing

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Q1A(R2) Stability Testing of New Drug

Substances and Products
The guideline addresses the information to be
submitted in registration applications for new
molecular entities and associated drug products.
This guideline does not currently seek to cover
the information to be submitted for abbreviated
or abridged applications, variations, clinical trial
applications, etc.
Specific details of the sampling and testing for
particular dosage forms in their proposed
container closures are not covered in this
guideline.
Further guidance on new dosage forms
and on biotechnological/biological products
can be found in ICH guidelines Q1C and Q5C,
respectively.

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Q1B Photo stability Testing of New Drug

Substances and Products
The guideline primarily addresses the generation of
photo stability information for submission in
Registration Applications for new molecular entities and
associated drug products.
The guideline does not cover the photo stability
of drugs after administration (i.e. under conditions
of use) .
A systematic approach to photo stability 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;
and if necessary ;
iii) Tests on the drug product in the immediate pack;
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and if necessary ;
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Q1C Stability Testing for New

Dosage Forms
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.
Stability Protocols For New Dosage Forms
Should Follow The Guidance In The Parent
Stability Guideline In Principle.

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Q1D Bracketing And Matrixing Designs For Stability

Testing Of New Drug Substances And Products
This document provides guidance on bracketing
and matrixing study designs. Specific principles
are defined in this guideline for situations in which
bracketing or matrixing can be applied.

Bracketing

:-

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.
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Example of a Bracketing Design

Strength

50 mg

Batch

Container

15 ml

size

100ml

500ml

75 mg

Key: T = Sample tested

100 mg

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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. At a
subsequent time point, another subset of
samples for all factor combinations would be
tested.

When a secondary packaging system

contributes to the stability of the drug product,
matrixing can be performed across the
packaging systems.
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Examples of Matrixing Designs

Time point (months)

Strength S1

Batch 1

Batch 2

Batch 3

Batch 1

Batch 2

Batch 3

S2

12

T
T

T
T

18

24

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T
T

T
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Q1E Evaluation of Stability Data

This guideline is intended to provide
recommendations on how to use stability data
generated in accordance with the principles detailed
in the ICH guideline Q1A(R) Stability Testing of New
Drug Substances and Products (hereafter referred to
as the parent guideline) to propose a retest period or
shelf life in a registration application.
This guideline describes when and how
extrapolation can be considered when proposing a
retest period for a drug substance or a shelf life for a
drug product that extends beyond the period
covered by available data from the stability study
under the long-term storage condition (hereafter
referred to as long-term data).
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Q2 : ANALYTICAL VALIDATION
This document presents a discussion of the
characteristics for consideration during the
validation of the analytical procedures
This text presentation serves as a collection of
terms, and their definitions, and is not intended to
provide direction on how to accomplish validation.
Validation Characteristics
1. Accuracy

4. Detection Limit

5. Quantitation Limit
Precision
Repeatability
6. Linearity
Intermediate Precision
7. Range
3. Specificity
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2.

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Q3 : IMPURITIES

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Q3A Impurities In New Drug Substances

This document is intended to provide guidance for
registration applications on the content and
qualification of impurities in new drug substances
produced by chemical synthesis .
It is not intended to apply to new drug substances
used during the clinical research stage of
development.
Excluded from this document are: (1) extraneous
contaminants that should not occur in new drug
substances and are more appropriately addressed
as Good Manufacturing Practice (GMP) issues, (2)
polymorphic forms, and (3) enantiomeric
impurities.
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Q3B Impurities In New Drug Products

o 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 in this
guideline).
o Impurities arising from excipients present in the
new drug product or extracted or leached from
the container closure system are not covered by
this guideline.

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Q3C Guideline For Residual Solvents

The objective of this guideline is to recommend
acceptable amounts for residual solvents in
pharmaceuticals for the safety of the patient. The
guideline recommends use of less toxic solvents and
describes levels considered to be toxicologically
acceptable for some 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.

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Class 1 solvents: Solvents to be avoided

Known human carcinogens, strongly suspected
human carcinogens, and environmental hazards.
e.g. Benzene ,carbon tetrachloride etc.
Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible
causative agents of other irreversible toxicity such
as neurotoxicity or teratogenicity. e.g. Acetonitrile ,
chlorobenzene etc.
Class 3 solvents: Solvents with low toxic potential
Solvents with low toxic potential to man; no healthbased exposure limit is needed. e.g. Acetic acid ,
acetone etc.
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Q3D Guideline For Metal Impurities

It is proposed that a new harmonised tripartite
guideline be developed to provide a global policy for
limiting metal impurities qualitatively and
quantitatively in drug products and ingredients
This guideline would focus on the establishment of
appropriate limits for specific metals, without
necessarily providing details on the analytical
procedures to be used.

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Q4 : PHARMACOPOEIAS

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Q5 : BIOTECHNOLOGICAL QUALITY

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Q5A Viral Safety Evaluation Of Biotechnology Products

Derived From Cell Lines Of Human Or Animal Origin
The purpose of this document is to provide a general
framework for virus testing, experiments for the
assessment of viral clearance and a recommended
approach for the design of viral tests and viral
clearance studies.

Q5B Analysis Of The Expression Construct In Cells Used

For Production Of R-DNA Derived Protein Products
This document presents guidance regarding the
characterisation of the expression construct for the
production of recombinant DNA protein products in
eukaryotic and prokaryotic cells. This document is
intended to describe the types of information that
are considered valuable in assessing the structure
of the expression construct used to produce
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recombinant DNA derived proteins.

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Q5C Stability Testing Of

Biotechnological/Biological Products
The purpose of this document is to give guidance to
applicants regarding the type of stability studies that
should be provided in support of marketing
applications.

Q5D Derivation And Characterisation Of Cell Substrates

Used For Production Of Biotechnological/Biological
Products
The objective of this guideline is to provide
broad guidance on appropriate standards for
the derivation of human and animal cell lines
and microbial cells to be used to prepare
biotechnological/biological products
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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. 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.
The document
does not prescribe any particular
analytical, nonclinical or clinical strategy.
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The main emphasis of the document is on 37

Q6 : SPECIFIACATIONS

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Q6A Specifications: Test Procedures And Acceptance

Criteria 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, or other criteria for the
tests described. It establishes the set of criteria to
which a drug substance or drug product should
conform to be considered acceptable for its
it doesuse.
intended
not address drug substances or drug
products during the clinical research stages of drug
development.
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 This guideline may be applicable to synthetic and

semi-synthetic antibiotics and synthetic peptides of
low molecular weight;
However, it is not sufficient to adequately
describe specifications of higher molecular
weight peptides and polypeptides, and
biotechnological/biological products.
Radiopharmaceuticals, products of
fermentation, oligonucleotides, herbal products
and crude products of animal or plant origin are
similarly not covered.
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Q7 : GMP ( GOOD MANUFACTURING PRACTICE )

This document (Guide) is intended to provide
guidance regarding good manufacturing practice
(GMP) for the manufacturing of active
pharmaceutical ingredients (APIs) under an
appropriate system for managing quality.
This Guide covers APIs that are manufactured
by chemical synthesis, extraction, cell
culture/fermentation, by recovery from natural
sources, or by any combination of these
processes.

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 This Guide excludes all vaccines, whole cells,

whole blood and plasma, blood and plasma
derivatives (plasma fractionation), and gene
therapy APIs. However, it does include APIs that
are produced using blood or plasma as raw
materials.
The Guide does not apply to medical gases,
bulk-packaged drug (medicinal) products, and
manufacturing/control aspects specific to
radiopharmaceuticals.

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Q8 : PHARMACEUTICAL DEVELOPMENT
The Pharmaceutical Development section provides
an opportunity to present the knowledge gained
through the application of scientific approaches and
quality risk management to the development of a
product and its manufacturing process.
The guideline does not apply to contents of
submissions for drug products during the clinical
research stages of drug development.

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Q9 : QUALITY RISK MANAGEMANT

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, formality and documentation

of the quality risk management process should be
commensurate with the level of risk.
quality risk management can facilitate better
and more informed decisions, can provide
regulators with greater assurance of a
companys ability to deal with
potential
risks .
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Q10: PHARMACEUTICAL QUALITY SYSTEM

ICH Q10 describes one comprehensive model
for an effective pharmaceutical quality system
that is based on International Standards
Organization (ISO) quality concepts, includes
applicable Good Manufacturing Practice (GMP)
regulations and complements ICH Q8
Pharmaceutical Development and ICH Q9
Quality Risk Management.
ICH Q10 is a
model for a pharmaceutical quality system that
can be implemented throughout the different
Implementation
ICH Q10 throughout the
stages
of a productof
lifecycle.
product lifecycle should facilitate innovation
and continual improvement and strengthen
the
link
between
pharmaceutical
development and manufacturing activities.

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Q11: Development and

Manufacture of Drug Substances
o It is a new tripartite high level Technical
Guidance harmonising the scientific and technical
principles relevant to the design, development and
manufacture of drug substances as part of a total
control strategy designed to ensure product quality
.
o The guideline will not address:
- Information relevant to the manufacturing
process development of the Drug Product (to
be covered by Q8 and Q8(R1));
- Qualification of facilities and equipment
and other activities covered by(e.g.,
GMP ICH Q7).
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guidance
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Efficacy
E1

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E2D

Dose-response Information To
Support Drug
Registration
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E5

General Considerations For Clinical Trials

Statistical Principles For Clinical Trials

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E10

The Clinical Evaluation Of Qt/Qtc Interval

Prolongation & Proarrhythmic Potential For Nonantiarrhythmic Drugs

Definitions For Genomic Biomarkers,

Pharmacogenomics, Pharmacogenetics, Genomic
Data , Sample Coding Category
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Safety (S)
S1A

Genotoxicity : A Standard Battery For

Genotoxicity Testing Of Pharmaceuticals

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S3A

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S7A

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Multidisciplinary topics
(M)

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REFERENCES
www.ich.org
Introduction of ICH
Quality
Safety
Efficacy
Multidisciplinary
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