Need of Harmonize.
Origin of ICH.
Evolution of ICH.
Objectives of ICH.
Process of ICH Harmonization.
ICH is a “International Council for Harmonization
of Technical Requirements for Pharmaceuticals for
ICH is unique in bringing together the regulatory
authorities and pharmaceutical industry to discuss
scientific and technical aspects of pharmaceuticals.
ICH is a joint initiatives involving both regulators and
research-based industry representatives of EU, Japan
and US in scientific and technical discussions of
testing procedures required to assess and ensure the
Safety, Quality and Efficacy of medicines.
4. ORIGIN OF ICH:
Harmonization of regulatory requirements was pioneered by the
EU, Europe, in the 1980s, as the EU, Europe moved towards the
development of a single market for pharmaceuticals.
The success achieved in Europe demonstrated that
harmonization was feasible.
At the same time there were discussions between Europe, Japan
and the US on possibilities for harmonization.
The birth of ICH took place at a meeting in April 1990.
Topics selected for harmonization would be divided into Safety,
Quality and Efficacy to reflect the three criteria which are the
basis for approving and authorizing new medicinal products.
5. WHY NEED OF HARMONIZE?
The realization that it was important to have an independent
evaluation of medicinal products before they are allowed on the
market was reached at different times in different regions.
However in many cases the realization was driven by tragedies,
such as that with thalidomide in Europe in the 1960s.
For most countries, whether or not they had initiated product
registration controls earlier, the 1960s and 1970s saw a rapid
increase in laws, regulations and guidelines for reporting and
evaluating the data on safety, quality and efficacy of new
The industry, at the time, was becoming more international and
seeking new global markets; however the divergence in technical
requirements from country to country was such that industry
found it necessary to duplicate many time-consuming and
expensive test procedures, in order to market new products,
The urgent need to rationalize and harmonies
regulation was impelled by concerns over rising costs
of health care, escalation of the cost of R&D and the
need to meet the public expectation that there should
be a minimum of delay in making safe and efficacious
new treatments available to patients in need.
7. EVOLUTION OF ICH
Since ICH's inception in 1990, the ICH process has
1. FIRST DECADE:
• ICH's first decade saw significant progress in the
development of ICH Guidelines on Safety, Quality and
• Work was also undertaken on a number of important
multidisciplinary topics, which included MedDRA
(Medical Dictionary for Regulatory Activities) and the
CTD (Common Technical Document).
2. SECOND DECADE:
• Implementation of ICH Guidelines in ICH's own regions
and maintaining already existing ICH Guidelines as
science and technology continued to evolve.
3. THIRD DECADE:
• Extending the benefits of harmonisation beyond the
founding ICH regions.
• Training as well as active participation of other regions in
guideline development is seen as key effort is seen.
Aim of focusing global pharmaceutical regulatory
harmonisation work in one venue that allows
pharmaceutical regulatory authorities and notably
concerned industry organisations to be more actively
involved in ICH’s harmonisation work.
9. OBJECTIVE OF ICH
Promotion of public health through international
harmonisation that contributes to:
Prevention of unnecessary duplication of clinical trials
and post market clinical evaluations.
Development and manufacturing of new medicines.
Registration and supervision of new medicines.
Reduction of unnecessary animal testing without
compromising safety and effectiveness
To strengthen the capacity of drug regulatory
Authorities and industry to utilize them.
10. ICH MEMBERS
ICH comprises of six representative;
Founding Regulatory Members:
– JAPAN: The members are Ministry of Health, Labour and
Welfare(MHLW), and Japan Pharmaceutical Manufacturers
– EUROPE: The members are European Union(EU) and the
European Federation of Pharmaceutical Industries and
– USA: The members are Food and Drug Administration(FDA)
and the Pharmaceutical Research and Manufacturers of
Founding Industry Members :
− European Federation of Pharmaceutical Industries and
− Japan Pharmaceutical Manufacturers
− Pharmaceutical Research and Manufacturers of
12. Process of ICH Harmonization
• Building Scientific Consensus
• Agreeing on Draft Text
• Consulting Regional Regulatory Agencies
• Adopting Harmonized Guidelines
• Implementing Guidelines in ICH Region
13. ICH GUIDELINES:
The ICH Guidelines are broadly categorized into
14. 1. QUALITY GUDELINES:
Harmonisation achievements in the Quality area include pivotal
milestones such as the conduct of stability studies, defining
relevant thresholds for impurities testing and a more flexible
approach to pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.
Q2: Analytical Validation
Q5A-Q5E: Quality of Biotechnology Products
Q7: Good Manufacturing Practice
Q8: Pharmaceutical Development
Q9: Quality Risk Management
Q10: Pharmaceutical Quality System
Q11: Development and Manufacturing of Drug Substances
Q12: Lifecycle Management
Q13: Continuous Manufacturing of Drug Substances
Q14: Analytical Procedure Development
16. 2. SAFETY GUIDELINES:
ICH has produced a comprehensive set of safety
Guidelines to uncover potential risks like
carcinogenicity, genotoxicity and reprotoxicity.
S1A-S1C: Carcinogenic Studies
S2: Genotoxicity Studies
S3A-S3B: Toxicokinetics and Pharmacokinetics
S4: Toxicity Testing
S5: Reproductive Toxicology
S6: Biotechnological Products
S7A-S7B: Pharmacological Studies
S8: Immunotoxicology Studies
S9: Nonclinical Evaluation for Anticancer
S10: Photosafety Evaluation
S11: Nonclinical Pediatric Safety
S12: Nonclinical Distribution Consideration for
Gene Therapy Products
18. 3. EFFICACY GUIDELINES:
Efficacy heading is concerned with the design, conduct, safety
and reporting of clinical trials. It also covers novel types of
medicines derived from biotechnological processes and the use
of pharmacogenetics/ pharmacogenomics techniques to produce
better targeted medicines.
E1: Clinical Safety for Drugs used in Long-term Treatment
E3: Clinical Study Reports
E4: Dose Response Studies
E5: Ethnic factors
E6: Good Clinical Practice
E7: Clinical Trials In Geriatric Population
E8: General Consideration For Clinical Trials
E9: Statistical Principles For Clinical Trials
E10: Choice Of Control Group In Clinical Trials
E11-E11A: Clinical Trials In Pediatric Person
E12: Clinical Evaluation By Therapeutic Category
E14: Clinical Evaluation Of QT
E15: Definitions In Pharmacogenetics/ Pharmacogenomics
E16: Qualifications In Genomic Markers
E17: Multi-regional Clinical Trials
E18: Genomic Sampling
E19: Safety Data Collections
E20: Adaptive Clinical Trials
20. 4. MULTIDISCIPLINARY GUIDESLINES:
It includes the ICH medical terminology (MedDRA), the
Common Technical Document (CTD) and the development of
Electronic Standards for the Transfer of Regulatory Information
M1: MedDRA Terminology
M2: Electronic Standard
M3: Nonclinical Safety Studies
M4: Common Technical Document(CTD)
M5: Data Elements And Standards For Drug Dictionaries
M6: Gene Therapy
M7: Mutagenic Impurities
M8: Electronic Common Technical Document(eCTD)
M9: Biopharmaceutical Classification System Based Biowavers
M10: Bioanalytical Method Validation
22. QUALITY GUIDELINES:
The quality guidelines conduct of stability studies, defining
relevant thresholds for impurities testing and a more flexible
approach to pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.
Q1A(R2): Stability Testing of New Drug Substances and
The purpose of stability testing is to provide evidence on how
the quality of drug product or drug substance varies with time
under the influence of variety of environmental factors such as
temperature, humidity, light and to establish a re-test period for
drug substance or shelf life for drug product.
23. Q1B: Photostability Testing of New Drug
Substances and Products:
Gives guidance on the basic testing protocol required
to evaluate the light sensitivity and stability of new
drugs and products.
Q1C: Stability Testing for New Dosage Forms:
Gives guidance for new formulations of already
approved medicines and defines the circumstances
under which reduced stability data can be accepted.
24. Q1D: Bracketing and Matrixing Designs for
Stability Testing of New Drug Substances and
Q1E: Evaluation of Stability Data:
This guidelines address the evaluation of stability data
the should be submitted in registration applications for
new molecular entities and associated drug products.
Provides recommendations on establishing shelf-lives
for drug substances and drug products intended for
storage at or below “room temperature”.
25. Q1F: Stability Data Package for Registration
Applications in Climatic Zones III AND IV:
Describes harmonized global stability testing
requirement in order to facilitate access to medicines
by reducing number of different storage conditions.
WHO conducted a survey amongst this members states
to find consensus on 30°C/65% RH as long-term
storage condition for hot-dry and hot-humid regions.
26. Q2-ANALYTICAL VALIDATION:
Q2(R1): Validation of Analytical Procedures:
Text and Methodology
The objective of validation of an analytical procedure
is to demonstrate that it is suitable for its intended
Gives validation parameter needed for variety of
It also discusses the characteristics that must be
considered during validation of analytical procedures.
Types of analytical procedures to be validated;
Quantitative tests for impurities' content;
Limit tests for the control of impurities;
Quantitative tests of the active moiety in Samples of drug
substance or drug product or other selected component(s) in the
Typical validation characteristics which should be considered
are listed below:
Detection Limit Range
Quantization Limit Repeatability
Linearity Intermediate Precision
28. Q3A-Q3D- IMPURITIES:
Q3A(R2): Impurities in New Drug Substances:
Provide guidance for registration applications on the
content and qualification of impurities in new drug
substances produced by chemical syntheses and not
previously registered in a region or member state.
This guidelines addresses the chemistry & safety aspects
Chemistry aspects include classification and identification
of impurities, report generation, listing of impurities in
specifications, and a brief discussion of analytical
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
Impurities can be classified into the following categories:
Organic impurities (process- and drug-related)
Q3B (R2) Impurities In New Drug Product:
Provides guidance for registration applications on the
content and qualification of impurities in new drug products
produced from chemically synthesized new drug
substances not previously registered in a region or
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. This guideline
also does not apply to new drug products used during the
clinical research stages of development.
30. Q3C(R5); GUIDELINE FOR RESIDUAL
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.
Benzene(class I): 2ppm
Chloroform(class II): 60ppm
Methyl acetate(class III): 5000ppm
31. Q4: PHARMACOPOEIS:
Q4A: Pharmacopoeial Harmonization:
Pharmacopoeial authorities working together through
Pharmacopoeial Discussion Group(PDC) for
harmonization of Pharmacopoeias.
Q4B: Evaluation & Recommendation of
Pharmacopoeial Text for use of ICH Regions:
This document describes a process for the evaluation and
recommendation by the Q4B Expert Working Group
(EWG) of selected Pharmacopoeial texts to facilitate their
recognition by regulatory authorities for use as
interchangeable in the ICH regions.
The guidelines also include annex from annex1 – annex14
32. Q5A-Q5E-QUALITY OF BIOTECHNOLOGICAL
Q5A(R1): Viral Safety Evaluation f biotechnology
products derived from cell lines of human or animal
This document is concerned with testing and evaluation
of the viral safety of biotechnology products derived from
characterized cell lines of human or animal origin (i.e.,
mammalian, avian, insect) and outlines data that should
be submitted in the marketing application/registration
The objective is to provide a general frame work for virus
testing experiments for evaluation of virus clearance and
the design of viral tests and clearance evaluation studies.
Three principal, complementary approaches have
evolved to control the potential viral
contamination of biotechnology products:
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;
Assessing the capacity of the production
processes to clear infectious viruses;
Testing the product at appropriate steps of
production for absence of contaminating
34. Q5B Quality Of Biotechnological 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.
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 recombinant DNA derived proteins.
This document is not intended to cover the whole
quality aspect of rDNA derived medicinal products.
Analysis of the expression construct at the nucleic
acid level should be considered as part of the overall
evaluation of quality,
35. Q5C Quality of biotechnological products
Stability testing of biotechnological/biological
The guidance stated in this applies to well-characterized
proteins and polypeptides, their derivatives and products of
which they are components, and which are isolated from
tissues, body fluids, cell cultures, or produced using rDNA
Thus, the document covers the generation and submission
of stability data for products such as cytokines
(interferon's, interleukins, colony-stimulating factors and
tumor necrosis factors), erythropoietin’s, plasminogen
activators, blood plasma factors, growth hormones and
growth factors, insulin, monoclonal antibodies, and
vaccines consisting of well-characterized proteins or
The document does not cover antibiotics, allergenic
extracts, heparins, vitamins, whole blood, or cellular blood
36. Q5D Derivation And Characterization Of Cell
This guideline covers cell substrates having a cell
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.
Q5E Comparability Of Biotechnological/Biological
Products Subject To Changes In Their
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
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.
Q6A Specifications: Test Procedures And
Acceptance Criteria, For New Drug Substances
And New Drug Products:
This guideline is intended to assist to the extent
possible, in the establishment of a single set of global
specifications for new drug substances and new drug
products. It provides guidance on the setting and
justification of acceptance criteria and the selection of
test procedures for new drug substances of synthetic
chemical origin, and new drug products produced
Guidance is provided with regard to acceptance
criteria which should be established for all new
drug substances and new drug products, i.e.
universal acceptance criteria, and those that are
considered specific to individual drug substances
and/or dosage forms.
This guideline addresses only the marketing
approval of new drug products (including
combination products) and, where applicable,
new drug substances;
39. Q6B Specifications: Test Procedures And
Acceptance Criteria For
Document apply to proteins and polypeptides, their
derivatives, and products of which they are
components (e.g., conjugates). These proteins and
polypeptides are produced from recombinant or non-
recombinant cell-culture expression systems and can
be highly purified and characterized using an
appropriate set of analytical procedures.
Document may also apply to other product types
such as proteins and polypeptides isolated from
tissues and body fluids. To determine applicability,
manufacturers should consult with the appropriate
This document is not applicable to the regulation of
preclinical and/or clinical research material.
40. Q7 Good Manufacturing Practice Guide
For Active Pharmaceutical Ingredient:
This document 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. It is also intended to help ensure
that APIs meet the requirements for quality and
purity that they purport or are represented to
It include all operations of receipt of materials,
production, packaging, repackaging, labeling,
relabeling, quality control, release, storage and
distribution of APIs and the related controls.
41. Q8 (R2) Pharmaceutical Development:
This guideline is intended to provide guidance on
the contents of section pharmaceutical
development for drug products.
The aim of pharmaceutical development is to
design quality product and its manufacturing
process to consistently deliver the intended
performance of product.
Pharmaceutical development section also
describe type of dosage form and formulation
suitable for intended use.
42. Q9 Quality Risk Management:
This guideline provides principles and examples of tools
for quality risk management that can be applied to
different aspects of pharmaceutical quality.
These aspects include development, manufacturing,
distribution, and the inspection and submission/review
processes throughout the lifecycle of drug substances,
drug (medicinal) products, biological and biotechnological
products (including the use of raw materials, solvents,
excipients, packaging and labeling materials in drug
(medicinal) products, biological and biotechnological
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
The level of effort, formality and documentation of the
quality risk management process should be
commensurate with the level of risk.
Q10 Pharmaceutical Quality System:
This guideline applies to the systems supporting the
development and manufacture of pharmaceutical drug
substances (i.e., API) and drug products, including
biotechnology and biological products, throughout the
For the purposes of this guideline, the product lifecycle
includes the following technical activities for new and
1. Pharmaceutical development 2. Technology transfer
44. Q11 Development And Manufacture Of Drug
Substances (Chemical Entities &
It addresses aspects of development and
manufacture that pertain to drug substance, including
the presence of steps designed to reduce impurities.
In addition, ICH Q11 provides further clarification on
the principles and concepts described in ICH
Guidelines on Pharmaceutical Development (Q8),
Quality Risk Management (Q9) and Pharmaceutical
Quality System (Q10) as they pertain to the
development and manufacture of drug substance.
45. Q12 Technical And Regulatory Considerations
For Pharmaceutical Product Lifecycle
This guideline provides a framework to facilitate
the management of post-approval
CMC(Chemistry, Manufacturing and Controls)
changes in a more predictable and efficient
It is also intended to demonstrate how increased
product and process knowledge can contribute to
a reduction in the number of regulatory
Effective implementation of the tools and enablers
described in this guideline should enhance
industry’s ability to manage many CMC changes
effectively under the firm’s Pharmaceutical
Quality System (PQS) with less need for
46. Q13 Continuous Manufacturing Of Drug
Substances And Drug Products:
The new ICH guideline will establish harmonized scientific
and technical requirements needed to fulfill regulatory
expectations for the implementation and assessment of
CM to improve access to medicines. An ICH guideline
would facilitate international harmonization and could
reduce barriers to the adoption of CM technology.
Q14 Analytical Procedure Development:
The new guideline is proposed to harmonize the
scientific approaches of Analytical Procedure
Development, and to provide the principles relating to
the description of Analytical Procedure Development
process. This new guideline is intended to improve
regulatory communication between industry and
regulators and facilitate more efficient, sound
scientific and risk-based approval as well as post-
approval change management of analytical
Harmonization achievements in the quality area
include pivotal milestones such as the conduct of
stability studies, defining relevant thresholds for
impurities testing and a more flexible approach to
pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.