1. ICH GUIDELINES
UNIT I – CHAPT 3
Ms. TENY SARA THOMAS
MOUNT ZION COLLEGE OF PHARMACEUTICAL
SCIENCES AND RESEARCH, ADOOR, KERALA
ASSISTANT PROFESSOR
B.PHARM SIXTH SEMESTER
PHARMACEUTICAL QUALITY ASSURANCE

2. CONTENTS
Introduction
Purpose of ICH
Participants of ICH
Process of Harmonisation
Brief Overview of Q, S, E, M
A Detailed Study on Q-Series Guidelines
ICH Stability Testing Guidelines

3. INTRODUCTION
ICH – International Council for
Harmonisation
Harmonisation – is the act of making
something consistent or compatible.
The complete name of ICH is the
International Conference on Harmonisation
of Technical Requirements for Registration
of Pharmaceuticals for Human Use.

4. PURPOSE of ICH Guidelines
•ICH is a joint initiative established in 1990 involving
both regulatory agencies and research - based industry
representatives of the European Union, Japan, and the
United States in scientific and technical discussions of
the testing procedures required to assess and ensure the
safety, quality and efficacy of medicines, and also
improve the efficiency of process for developing and
registering new medicinal products.
•More economical use of human, animal and material
resources.
•Eliminate unnecessary delay in the global development
and availability of new medicines.

5. •Maintaining safeguards on quality, safety, efficacy, and
regulatory obligations to protect public health.
•Develop policy for the ICH Medical Dictionary for
Regulatory Activities Terminology (MedRA) which
facilitates the sharing of regulatory information
internationally for medicinal products used by humans.
•To encourage implementation and integration of
common standards through communication of
information and coordination of training on harmonised
guidelines and their use.
•To monitor and update technical requirements leading
to a greater acceptance of research and data.

6. PARTICIPANTS OF ICH
The six parties to ICH represent the regulatory bodies
and research based industry in the three regions - Europe,
Japan, and USA, where the vast majority of new medicines
are currently developed.
The six ICH participants are as follows:-
1. European Commission – European Union
2. European Federation of Pharmaceutical Industries and
Associations
3. Ministry of Health, Labour, and Welfare, Japan
4. Japan Pharmaceutical Manufacturers Association
5. US Food and Drug Administration
6. Pharmaceutical Research and Manufacturers of America

7. ORGANISATION OF ICH
STEERING COMMITTEE
Global Cooperation
Group
MeDRA Management
Board
CoordinatorsSecretariat
ICH Working Groups

8. •ICH Steering Committee – is the body that
governs the ICH, determines the policies and
procedures for ICH, selects topics for harmonisation
and monitors the progress of harmonisation
initiatives. Each of the six parties has two seats on
the ICH steering committee.
•ICH Secretariat – is primarily concerned with
preparations for, and documentation of, meetings of
the Steering Committee as well as coordination of
preparations for Working Groups and discussion
group meetings. Information on ICH Guidelines and
the ICH process can be obtained from the ICH
Secretariat.

9. •ICH 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.
•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 – Expert working
group (EWG), Implementation working group
(IWG), or Informal working group (InWG).

10. •Expert Working Group – develops a harmonized
guideline that meets the objectives in the concept
paper and the business plan
•Implementation Working Group – develops
questions and answers to facilitate implementation
of existing guidelines.
•Informal Working Group – developing or
finalising a concept paper, as well as developing a
business plan.

11. ICH operates through the ICH Steering
Committee with administrative support from the ICH
Secretariat and ICH Coordinators.
The ICH 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 harmonisation by
the ICH Steering Committee are elected from
Safety, Quality, Efficacy, and Multidisciplinary
matters of a pharmaceutical drug product.

12. PROCESS of HARMONIZATION
Each harmonisation activity is initiated by a
Concept Paper which is a short summary of the
proposal. Depending on the category of harmonisation
activity a Business Plan may also be required. The
Business plan outlines the costs and benefits of
harmonising the topic proposed by the Concept Paper
The process of harmonization is a step-wise
procedure consisting of the following 5 steps. The
procedure is followed for the harmonization of all ICH
topics.

13. Step 1 – Consensus Building
The EWG works to prepare a consensus (general
agreement) draft of the technical document via e-mail,
web conferences etc,. If approved by the ICH
Management Committee, the EWG will organise
meetings to discuss on the draft. This draft is signed by
the EWG, upon reaching into an agreement and the
forwarded to the Steering Committee.

14. Step 2 – Confirmation of Consensus on the Technical
Document & Adoption of Draft Guideline by
Regulatory Members
The Steering Committee checks the technical
document and agrees based on the report of the EWG.
On the basis of the technical document, the ICH
Regulatory Members will take the actions that are
necessary to prepare a draft guideline. After
preparation, the regulatory members will declare the
draft guideline approved.

15. Step 3 – Regulatory Consultation
Step 3 occurs in three distinct stages:-
•Regional regulatory consultation :- The regulatory
authorities and industry associations in other regions can
may also comment on the draft guideline to the ICH
Secretariat.
•Discussion of the regional committee comments :- The
EWG works to address the comments received and
prepares the Experts Draft Guideline.
•Finalisation of the Experts Draft Guideline :- Expert
Draft Guideline is signed by the ICH Regulatory
Members an then forwarded to the Steering Committee to
request adoption of the ICH Process.

16. Step 4 – Adoption of an ICH Harmonised Guideline
The Steering Committee agrees to the Expert
Draft Guideline if there is sufficient agreement on the
guideline, and then declared as the ICH Harmonised
Guideline.
Step 5 – Implementation of the ICH Harmonised
Guideline
The Harmonised Guideline moves immediately to
the final step of the process that is the regulatory
implementation. The step is carried out according to the
national or regional procedures in the ICH regions.

17. BRIEF OVERVIEW OF QSEM GUIDELINES
The ICH Guidelines are divided into the
following four categories:-
1. Quality Guidelines (Q series)
2. Safety Guidelines (S series)
3. Efficacy Guidelines (E series)
4. Multidisciplinary Guidelines (M series)

18. QUALITY GUIDELINES ( Q SERIES)
Quality guidelines are those topics relating to
chemical and pharmaceutical quality assurance.
Harmonisation achievements in the Quality area include
milestones such as the conduct of the stability studies,
defining thresholds for impurities testing, and a more flexible
approach to pharmaceutical quality based on GMP risk
management.
SAFETY GUIDELINES ( S SERIES)
Safety guidelines are those topics relating to the
comprehensive set of safety guidelines to uncover the
potential risks in the in vitro and in vivo pre-clinical studies
(like carcinogenicity, genotoxicity etc). A recent
breakthrough was the assessing of QT interval prolongation
liability – the important cause of drug withdrawal.

19. EFFICACY GUIDELINES ( E SERIES)
Efficacy guidelines are the harmonisation work
carried out by ICH, concerned with the design, conduct,
safety and reporting of clinical trials ( dose response studies,
good clinical studies etc). It also covers novel types of
medicines derived from biotechnological processes and the
use of pharmacogenetics to produce better targeted
medicines.
MULTIDISCIPLINARY GUIDELINES ( M SERIES)
Multidisciplinary guidelines are those cross cutting
topics which do not fit uniquely into one of the Quality,
Safety, and Efficacy categories. Those include, the ICH
medical terminology, common technical document and
development of electronic standards for the transfer of
regulatory information.

20. A DETAILED STUDY ON THE Q-SERIES
GUIDELINES
Quality Guidelines are mainly divided into 10
subdivisions :-
Q1 – Stability
Q2 – Analytical Validation
Q3 – Impurities
Q4 – Pharmacopoeias
Q5 – Quality of Biotechnological Products
Q6 – Specifications
Q7 – Good Manufacturing Practices
Q8 – Pharmaceutical Development
Q9 – Quality Risk Management
Q10 – Pharmaceutical Quality Systems

21. Q1 – Stability
Q1 guidelines are subdivided into 6 :– Q1A – Q1F
Q1A – Stability testing of new drug substance and
products :- provides evidence on how the quality of
drug substance or product varies with time under the
influence of environmental factors.
Q1B – Photo stability testing of new drug substance or
product :- evaluates the light sensitivity and stability of
the drug substance or product.
Q1C – Stability testing of new dosage forms :- provides
evidence of stability of new formulations of approved
medicines.

22. Q1D –Bracketing and Matrixing designs for stability
testing of new drug substances or products :-
Bracketing – is the design of a stability schedule such
that samples are tested at all times on the extreme of
factors. The design assumes that the stability of any
intermediate level is represented by the stability of the
extremes tested.
Matrixing – is the design of a stability schedule such
that a selected subset of the total number of samples
are tested at a specific time point for all the factor
combinations.

23. Q1E – Evaluation of Stability Data:- The guideline
addresses the evaluation of stability data that should be
submitted in registration applications for new molecular
entities. Establishes shelf lives for drug substances or
products intended for storage at or below room
temperature
Q1F - Stability data package for registration
applications in climatic zones III and IV :- Describes
harmonised global stability testing requirements in
order to facilitate access to medicines by reducing the
number of different storage conditions.

24. Q2 – Analytical Validation
The objective of validation of an analytical
procedure is to demonstrate that it is suitable for its
intended purpose. It gives the validation parameters
needed for a variety of analytical methods and the
characteristics that must be considered during the
validation.
Types of analytical procedures to be validated:-
•Limit tests
•Identification tests
Characteristics include – accuracy, precision,
detection limit, quantitation limit, detection limit.

25. Q3 – Impurities
Q3 guidelines are subdivided into 3 :- Q3A – Q3C
Q3A – Impurities in a New Drug Substances
Q3B – Impurities in a New Drug Products
The guideline addresses the chemistry and safety aspects of
impurities. Impurities are of 3 types:- organic , inorganic, and
residual impurities.
Chemistry aspects include classification and identification of
impurities, listing of impurities , generating reports etc.
Safety aspects include specific guidance for qualifying those
impurities that were not present or were at lower levels in
batches of drug substance or product used in safety or clinical
trials
Q3C – Impurities in Residual Solvents – prescribes the limits
of certain solvents

26. Q4 – Pharmacopoeias
Q4 describes a process for the evaluation and
recommendation given by EWG for selecting
pharmacopoeial texts to facilitate their recognition by
regulatory authorities for use in different ICH regions.
It involves mainly the tests for :-
•Microbiological examination of non – sterile products
•Test for particulate examination
•Disintegration and dissolution test
•Uniformity tests, sterility tests
•Tablet friability, bulk density, tapped density of
powders etc.,

27. Q5 – Quality of Biotechnological Products Q5A – Q5E
•Q5A is concerned with testing and evaluation of viral
safety of biotechnology products derived from cell lines of
human or animal origin. Provides a general framework for
virus testing experiments.
•Q5B is concerned with the analysis of expression
construct in cells used for production of rDNA derived
products.
•Q5C is concerned with the stability testing of
biotechnological products.
•Q5D is concerned with derivation and characterisation of
cell substrates.
•Q5E is subjected with the comparability of biologicals to
changes in their manufacturing process.

28. Q6 – Specifications
•Q6 are related to the specifications for a new drug substances
and products
•Specifications are key parts of documentation for world – wide
product license applications.
•Main objective of this guideline is to establish a set of
specifications for the drug substance or product.
•Description, identification, assay, and impurities are the
universal tests considered applicable for the drug.
•Specific tests for Drug Substance include, particle size, water
content, microbial limits, physicochemical properties etc.
•Specific tests for Drug Products include, dissolution,
disintegration, hardness, friability uniformity tests etc.
•This document also provides guidance on justifying an setting
specifications for proteins, and polypeptides from cell cultures.

29. Q7 – Good Manufacturing Practices
This document is intended to provide guidance
regarding GMP for the manufacturing of API under an
appropriate system for managing quality. It is also
intended to help ensure that APIs meet the requirements
for quality and purity.
Q7 mainly involves the following:-
•Active Pharmaceutical Ingredient
•Organisation & Personnel
•Buildings & Facilities
•Process Equipments
•Documentation & Records

30. Q8 – Pharmaceutical Development
Q8 is intended to provide guidance on the
contents of pharmaceutical development of drug
products.
The aim of Q8 is to design a quality product and
its manufacturing process to consistently deliver the
intended performance of the product.
Q8 also describes the type of dosage form and the
formulation that are suitable for the intended use.
Q8 gives information about drug substance, drug
product, excipients, and container – closure system.

31. Q9 – Quality Risk Management
Q9 offers 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 and distribution
•Inspection and submission or review processes of use
of raw materials, solvents, excipients, packaging and
labelling materials used in drug substances an drug
products.

32. Q10 – Pharmaceutical Quality System
Q10 establishes a new ICH guideline describing a
model for an effective quality management system for
the pharmaceutical industry.
Comprehensive model for an effective
pharmaceutical quality system is based on International
Standards Organisation (ISO) quality concepts which
also includes the GMP regulations.

33. ICH STABILITY TESTING GUIDELINES
Stability testing is a complex set of procedures involving
considerable cost, time consumption, and scientific expertise in
order to build in quality, safety and efficacy in a drug
formulation.
•Determines and assures the identity, potency, and purity of
ingredients
•Stability is defined as the capability of a particular formulation
in a specific container/closure system to remain within its
physical, chemical, microbiological, toxicological specifications
etc.
•The choice of test conditions in the guideline is based on an
analysis of the effects of climatic conditions in 3 regions –
Europe, Japan, & USA. The mean kinetic temp. in any part of
the world can be derived from the climatic data. The world is
divided into 4 climatic zones.

34. CLIMATIC
ZONE
DEFINITION
STORAGE
CONDITIONS
I
Temperature
climate
21℃ , 45% RH
II
Subtropical, and
Mediterranenan
climate
25℃ , 60% RH
III Hot, dry, climate 30℃ , 35% RH
IV
Hot, humid
climate
30℃ , 70% RH
CLIMATIC ZONES

35. STRESS TESTING - refers to the testing of a drug
substance to determine whether the performance is
satisfactory under any extreme and unfavourable
conditions.
•Identifies the stability affecting factors such as
temperature, humidity, and light and to select packing
materials which protects the formulation against such
effects.
•Identify potential degradants of API and assess if they
can be formed during the manufacture or storage.
•To select the manufacturing process for a particular
drug substance.
STABILITY TESTING OF DRUG SUBSTANCE

36. Temperature
A thin layer of the drug substance is wetted with
water and is kept at 80℃ for 4 weeks in a petri-dish with
sampling once a week.
Humidity
A thin layer of the drug substance is wetted with
water and kept at 40 ℃ and 100% RH for 4 weeks in a petri
dish with sampling once in 2 weeks.
Oxidation
Oxygen is bubbled slowly through a oxygen saturated
aqueous solution/suspension of the API for 24 hours with
sampling every 8hrs.
Assay of the sample is conducted and the changes
are noted.

37. Testing Frequency
•General – every 3 months first year, every 6 months
second year, then annually through proposed test
period
•Accelerated storage conditions – a min of 3 time
points (0,3,6 months), including the initial and final
time points from a 6 month study, is recommended.
•Intermediate storage conditions – a min of 4 time
points (0,6,9,12 months) , including the initial and
final time points from a 12 month study, is
recommended.

38. Storage Conditions
General
•Long term studies (12 months) - 25℃ & 60% RH or 30℃ &
65% RH
•Intermediate studies (6 months) - 30℃ & 65% RH
•Accelerated studies (6 months) - 40℃ & 75% RH
Drug substance stored in a Refrigerator
•Long term - 5℃ ± 3℃
•Accelerated - 25℃ & 60% RH
•If significant change between 3 & 6months testing, a
discussion should be provided to address the effect of the
factors.
Drug substance stored in a Freezer
•Long term – (-20)℃ ± 3℃

39. Evaluation :- The data may show some little
degradation, that it is apparent from looking at the
data that the requested re-test period is granted.
A storage statement should be established for
the labelling in accordance with the national or
regional requirements. Where applicable, specific
instructions should be provided.

40. PHOTOSTABILITY TESTING - refers to the testing
of a drug product to determine whether the appropriate
light exposure does not result into unacceptable changes
in the dosage form.
•Photo stability deals with the effect of light on stability
of pharmaceutical products.
•Data should be provided on at least 3 primary batches
of the drug product.
•Stability testing should be conducted on the dosage
form packed in the container – closure system
proposed for marketing.
STABILITY TESTING OF DRUG PRODUCTS

41. Testing Frequency
•General – every 3 months first year, every 6 months
second year, then annually through proposed test
period
•Accelerated storage conditions – a min of 3 time
points (0,3,6 months), including the initial and final
time points from a 6 month study, is recommended.
•Intermediate storage conditions – a min of 4 time
points (0,6,9,12 months) , including the initial and
final time points from a 12 month study, is
recommended.

42. Light Sources
Light sources described below may be used for
photostability testing :-
1. Any light source that is used to produce an output
similar to D65/ID65 emission. D65 – outdoor
daylight. ID65 – indoor direct daylight.
2. Cool white flourescent and near ultra violet lamp.
UV lamp should have maximum energy emission
between 350-370nm.
Samples should be exposed to light side to
side to ensure specific light exposure is obtained.

43. Storage Conditions
General
•Long term studies (12 months) - 25℃ & 60% RH or 30℃ & 65% RH
•Intermediate studies (6 months) - 30℃ & 65% RH
•Accelerated studies (6 months) - 40℃ & 75% RH
Drug products packed in impermeable containers
•Stability studies for such products can be conducted under any controlled or
ambient humidity condition.
Drug products packed in semi-permeable containers
•Should be evaluated for potential water loss in addition to physical,
chemical, biological and mirobiological stability.
•They should withstand low RH environments.
Drug products stored in a Refrigerator
•Long term - 5℃ ± 3℃
•Accelerated - 25℃ & 60% RH
Drug products stored in a Freezer
•Long term – (-20)℃ ± 3℃