ICH Guidelines

INTRODUCTION
 The International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
(ICH) is a unique project that brings together the regulatory
authorities of Europe, Japan and the United States and experts
from the pharmaceutical industry in the three regions to discuss
scientific and technical aspects of product registration.

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 AIM
 The International Conference on Harmonisation of Technical
Requirements for the Registration of Pharmaceuticals for Human
Use (ICH) was established in 1990 as a joint regulatory/industry
project to improve, through harmonisation, the efficiency of the
process for developing and registering new medicinal products in
Europe, Japan and the United States, in order to make these products
available to patients with a minimum of delay.
 The six parties to ICH represent the regulatory bodies and research-
based industry in the three regions, Europe, Japan
and the USA, where the vast majority of new medicines are
currently developed.
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 ICH is the “International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use”.

 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.

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 ICH (April 1990)

• International Conference on Harmonisation (ICH) was created in

april 1990
• The European Medicines Agency publishes scientific guidelines
that are harmonised between Europe, Japan and the United
States of America
• ICH guidelines are provided for: Quality, Safety and Efficacy of
medicines.
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.

 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.

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ICH located

The ICH Secretariat is based in Geneva. The

biennial meetings and conferences of the ICH
Steering Committee rotate between the EU, Japan,
and the USA.

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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
 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.

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 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).

• 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. 6
 MISSION
Harmonisation for Better Health

To make recommendations towards achieving

greater harmonisation in the interpretation and
application of technical guidelines and requirements
for pharmaceutical product registration and the
maintenance of such registrations
 PURPOSE

 To Harmonize of technical requirements for registration or

marketing approval
 To Ensure quality, safety, efficacy of medicines
 To prevent unnecessary duplication of clinical trials on
humans
 To Minimize the use of animal testing without compromising
safety and effectiveness
 To promote public health
 history
HISTORY
Need to harmonize, Because of the following reasons:
1. Industry becoming global
2. Duplicate test procedures
 time consuming
 expensive
3. Increase R &D costs
4. Meeting public demand
• Initiation of ICH
• 1980s Formulate European community
• 1989s WHO conference on DRA, Paris
• 1990s birth of ICH (created by all three Japan, USA & Europe)
• Topic of harmonization divided into : safety, quality and
efficacy
 ICH structure
region Regulatory body
Japan MHLW ( ministry of health, labour and
welfare)

Europe EU (European unions)

US FDA
ꢀICH structure
The ICH structure consists of the ICH Steering Committee,
ICH Coordinators, ICH Secretariat and ICH Working
Groups.

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.

ꢀ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.
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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.

ꢀ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.

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ICH OPERATION
ICH operates through the ICH Steering Committee with
administrative support from the ICH Secretariat and ICH
Coordinators.

The Steering Committee meets at least twice a year . During these

meetings, new topics will be considered for adoption, reports are
received on the progress of existing topics, and maintenance and
implementation of the guidelines are discussed.

The topics identified for harmonization by the Steering Committee

are selected from Safety, Quality, Efficacy, and Multidisciplinary
matters.

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ꢀSteps in the ICH process

Step-1: Drafts are prepared and circulated through

many revisions until a "final harmonised draft" is
completed

Step-2: This draft is signed by the EWG as the agreed-

upon draft and forwarded to the Steering Committee
for signing which signifies acceptance for
consultation by each of the six co-sponsors

Step-3: The three regulatory sponsors initiate their

normal consultation process to receive comments.
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 Step-4 is reached when the Steering Committee
agrees that there is sufficient scientific consensus on
the technical issues. This endorsement is based on
the signatures from the three regulatory parties to
ICH affirming that the Guideline is recommended
for adoption by the regulatory bodies of the three
regions.

 Step-5: The process is complete when the guidelines

are incorporated into national or regional internal
procedures(implementation in the 3 ICH regions.)

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 Process of Harmonisation

ICH harmonisation activities fall into 4 categories;

1.Formal ICH Procedure
2.Q&A Procedure
3.Revision Procedure
4.Maintenance Procedure
BRIEF OVERVIEW OF QSEM WITH SPECIAL EMPHASIS ON Q-
SERIES GUIDELINES
•Carcinogenicity (carcinogen any
substance that produce cancer)
•Genotoxicity (genetic toxicity)
The ICH topics are divided into four categories
•Reprotoxicity toxicity related to
•Q – QUALITY GUIDELINES
reproduction
•S – SAFETY GUIDELINES
•E - EFFICACY GUIDELINES
•M - MULTIDISCIPLINARY GUIDELINES

•ICH medical terminology (MedDRA)

•Common Technical Document (CTD)
•The development of Electronic
Standards for the Transfer of Regulatory
Information (ESTRI).
 "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.)
 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.

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 Quality Guidelines "Quality" Topics, i.e., those
relating to chemical and pharmaceutical Quality
Assurance (Stability Testing, Impurity Testing,
etc.)

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 QGUIDELINES
Q – QUALITY – QUALITY GUIDELINES
Q1 S Stability
Q2 A Analytical validation
Q3 I Impurities
Q4 P Pharmacopoeias
Q5 B Quality of Biotechnology Products
Q6 S Specifications
Q7 API Good Manufacturing Guide for Active Pharmaceutical Ingredients

Q8 PD Pharmaceutical Development

Q9 QRM Quality Risk Management

Q 10 PQS Pharmaceutical Quality System

Q 11 DMDS Development and Manufacture of Drug Substances (Chemical

Entities Biotechnological/Biological Entities)

Q 12 LCM Life Cycle Management

 Q – QUALITY GUIDELINES
Q 1 A – Q 1 F Stability
• Q1A – Stability Testing of New Drug Substances and
Products
• Q1 B – Stability Testing : Photo Stability 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 Application in
Climatic Zones III and IV
Q2 (R1) – Validation of Analytical Procedures: Text and
Methodology
 Q3A- Q3D Impurities
• Q3A - Impurities in New Drug Substances
• Q3B – Impurities in New Drug Products
• Q3C– Impurities : Guideline for Residual Solvents
• Q3D – Impurities : Guideline for Elemental Impurities
• Q4 – Pharmacopoeias
• Q4A – Pharmacopoeial Harmonisation
• Q4B – Evaluation and Recommendation of Pharmacopoeial Tex t for
use in the ICH Regions

• Q4B Annex 2(R1) – Test for Extractable Volume of Parenteral

Preparation General Chapter
• Q4B – Annex 3(R1) – Test for Particulate Contamination : Sub-
Visibal Particales General Chapter
 • Q4B – Annex 4A(R1) – Microbiological Examination of Non-
Sterile Products : Microbial Enumeration Tests General
Chapter
• Q4B – Annex 4B(R1) – Microbiological Examination of Non-
Sterile Products : Test for Specified Micro-Organism General
Chapter
• Q4B – Annex 4C(R1) – Microbiological Examination of Non-
Sterile Products : Acceptance Criteria for Pharmaceutical
Preparations and Substances for Pharmaceutical use General
Chapter
• Q4B – Annex 5(R1) – Disintegration Test General Chapter
• Q4B Annex 6 (R1) – Uniformity of Dosage Units General
Chapter
• Q4B Annex 7(R2) – Dissolution Test General Chapter
• Q4B Annex 8(R1) – Stability Test General Chapter
• Q4B Annex 9(R1) – Tablet Friability General Chapter
• Q4B Annex 10(R1) – Polyacrylamide Gel Electrophoresis
General Chapter
• Q4B Annex 11 – Capillary Electrophoresis General Chapter
• Q4B Annex 12 – Analytical Sieving General Chapter
• Q4B Annex 13 – Bulk Density and Tapped Density of
Powders General Chapter
• Q4B Annex 14 – Bacterial Endotoxin Test General Chapter
 Q5A-Q5E Quality of Biotechnology Products

• Q5A (R1) – Viral Safety Evaluation of Biotechnology Products

Derived from Cell Lines of Human or Animal Origin
• Q5B – Quality of Biotechnology Products :
• Q5C – Quality of Biotechnology Products :Quality of
Biotechnological
• Q5D – Derivation and Characterisation of Cell Substrates
used for Production of Biotechnological/Biological Products
• Q5E – Comparability of Biotechnological/Biological Products
Subject to Changes in their Manufacturing Process
• Q6A-Q6B Specifications
• Q6A – Specifications : Test Procedure and Acceptance
Criteria for New Drug Substances and New Drug Products:
Chemical Substances
• Q6B – Specifications : Test Procedure and Acceptance
Criteria for Biotechnological/Biological
• Q7 – Good Manufacturing Guide for Active
Pharmaceutical Ingredients
• Q8(R2) – Pharmaceutical Development
• Q9 – Quality Risk Management
• Q10 – Pharmaceutical Quality System
• Q11 – Development and Manufacture of Drug Substances
(Chemical Entities Biotechnological/Biological Entities)
• Q12 – Life Cycle Management
 S – SAFETY GUIDELINES
S – SAFETY GUIDELINES
• S1A - S1C Carcinogenicity Studies

• S2 Genotoxicity Studies
• S3A - S3B Toxicokinetics and Pharmacokinetics
• S4 Toxicity Testing
• S5 Reproductive Toxicology
• S6 Biotechnological Products.
• S7A - S7B Pharmacology Studies
• S8 Immunotoxicology Studies
• S9 Nonclinical evaluation for anticancer
pharmaceuticals
• S10 Photo safety evaluation
• S11 Nonclinical paediatric safety
 E - EFFICACY GUIDELINES
• E1 Clinical Safety For Drugs Used In Long-Term Treatment.
• E2A - E2F Pharmacovigilance.
• E3 Clinical Study Reports.
• E4 Dose-Response Studies.
• E5 Ethnic Factors. Code.
• E6 Good Clinical Practice.
• E7 Clinical Trials In Geriatric Population.
• E8 General Considerations For Clinical Trials
• E9 Statistical Principles For Clinical Trials
• E10 Choice Of Control Group In Clinical Trials
• E11 Clinical Trials In Paediatric Population
• E12 Clinical Evaluation By Therapeutic Category
• E14 Clinical Evaluation Of QT
• E15 Definitions Of Pharmacogenetics
• E16 Qualification Of Genomic Biomarkers
• E17 Multiregional Clinical Trials
• E18 Genomic Sampling
• E19 Safety Data Collection
 M - MULTIDISCIPLINARY GUIDELINES
• M1 MedDRA Terminology
• M2 Electronic Standards
• M3 Nonclinical Safety Studies
• M4 Common Technical Document
• M5 Data Elements and Standards for
Drug Dictionaries
• M6 Gene Therapy
• M7 Genotoxic Impurities
• M8 Electronic Common Technical
Document (eCTD)
• M9 Biopharmaceutics Classification
System-based Biowaivers
• M10 Bioanalytical Method Validation
 Stability guideline

• General:
• Definition: Stability of pharmaceutical product may be
defined as the ability of pharmaceutical dosage form to
maintain the physical, chemical, microbiological and
therapeutics properties during the time of storage and
usage by the patient
• 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 re-test period for the drug substance or a shelf life
for the drug product and recommended storage conditions.
 Stability protocol For Drug Substance
• General
• Stress testing
• Selection of batches
• Container and closure system
• Specifications
• Testing frequency
• Storage conditions
• Stability Commitment
• Evaluation
• Statements/Labeling
 Stress Testing
• It is also known as force degradation study
• Stress testing of the drug substance can help identify
the likely degradation products, which can in turn
help establish the degradation pathways and the
intrinsic/natural stability of the molecule.
• Stress testing is likely to be carried out on a single
batch of the drug substance.
• It should include the effect of temperatures,
humidity (e.g., 75% RH or greater) where appropriate
oxidation, and photolysis on the drug substance.
 Selection of Batches
• At least three primary batches of the drug substance
should be representative to quality of the material
used for production scale.
• Container Closure System
• The stability studies should be conducted on the drug
substance packaged in a container closure system that
is the same as the packaging proposed for storage and
distribution.
• Specification
• Specification, which is a list of tests, reference to
analytical procedures, and proposed acceptance
criteria, is addressed in ICH Q6A and Q6B.
 Testing Frequency
frequency of testing should be sufficient to establish the
stability profile of the drug substance.
• For long-term studies, (For drug substances with a
proposed re-test period) at least 12 months, the
frequency of testing at the long term storage condition
should normally be every 3 months over the first year,
every 6 months over the second year, and annually
thereafter through the proposed re-test period.
• At the accelerated storage condition, a minimum of
three time points, including the initial and final time
points (e.g., 0, 3, and 6 months), from a 6-month study is
recommended.
• For intermediate studies: Min. 4 time points (0, 6, 9, 12
months) for a 12 months study
 StorageStorage
Conditions General
Conditions case
General case
Study Storage conditions Minimum

time period

Long term* 25°C ± 2°C

12
60% RH ± 5% RH
months

Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months

**

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months

 . Drug substances intended for storage in a
refrigerator

Long term 5°C ± 3°C 12 months

Accelerated 25°C±2°C 6 months

 Drug substances intended for storage in a
freezer

Long term - 20°C ± 5°C 12 months

Stability Commitment

• In case where data submitted for registration do not cover

the proposed shelf life it is necessary to give commitment
to continue the stability studies post approval in order to
firmly establish the shelf life.

• Where the submission includes long term stability data

from three production batches covering the proposed shelf
life, a post approval commitment is considered
unnecessary.
 Evaluation
• The purpose of the stability study is to establish re-test
period for DS and shelf life for drug product for future
batched based on evaluation of results obtained from
chemical, physical, biological, microbiological tests

• A systematic approach should be adopted in the

presentation and evaluation of the stability information,
which should include, as appropriate, results from the
physical, chemical, biological, and microbiological tests,
including particular attributes of the dosage form (for
example, dissolution rate for solid oral dosage forms).
 Statements/Labeling
• A storage statement should be established for the labeling
in accordance with relevant national/regional
requirements.
• The statement should be based on the stability evaluation
of the drug product.
• There should be a direct link between the label storage
statement and the demonstrated stability of the drug
product.
• An expiration date should be displayed on the container
label.