GOOD CLINICAL PRACTICE - ICH, GCP

ICH GUIDELINES
requirements for
ICH: International Conference on Harmonization of technical
registration of pharmaceuticals for human use.

purpose of ICH is to reduce (or) obviate the need to duplicate the testing carried
The
during the research and development of new medicines by recommending ways
out
greater harnmonization in the interpretation and application of technical
to achieve
registration.
guidelines and requirements for product

ICH-STRUCTURE

has been jointly undertaken by both regulators and

ICH is an initiative that
pharmaceutical industry.
developing new drugs have been the focus of ICH.
Technical requirements for
confined to Western Europe, US and Japan,
mainly
Hence the scope of ICH is
developed.
where bulk of new drugs are
steering committee, which is supported by
ICH is administered by ICH
ICH Secretariat.
by International Federation of pharmaceutical
supported
ICH Secretariat is
manufacturers Association (|FPMA).

ICH PARTICIPANTS

FOUNDER MEMBERS:
representing the regulatory bodies and the
comprises of six founder members
ICH
based industry in EU, Japan and the US.
research

Steering committee

PhRMA
FDA
EU European Union
EFPIA : European Federation of pharmaceutical industries and associations.
MHLW : Ministry of Health, Labor and Welfare (Japan).
JPMA :Japan pharmaceutical manufacturers Association.
FDA :US Food and Drug Administration.
PhRMA :Pharmaceutical Research and Manufacturers of America.

ICHCOORDINATORS:
Each of six groups has a designed coordination, who acts as the main point of
contact with the ICH Secretariat.
Each party has an established contact network of experts within their own region
to ensure that they reflect the views and policies of co-sponsor, they represent in
various discussions.

OBSERVERS:

In addition to expert groups, ICH has observers to act as a link with non-1CH
countries and regions.
Ex: WH0, EFTA (European free trade area)

ICH SECRETARIAT:
" It is supported by IFPMAand operates from its offices in Geneva.
It is mainly concerned with:
1) Preparations for and documentation of meetings of the steering committee.
2) Coordination of preparations for meeting of the expert working groups & six
party drafting groups.

IFPMA (INTERNATIONAL FREEDOM OF PHARMACEUTICAL

MANUFACTURERS ASSOCIATION):
It represents the research based pharmaceutical industry and other manufacturers
of prescription medicines in 56 countries worldwide.
IFPMA runs the 1CH Secretariat.
ICH STEERING COMMITTEE:
" It governs ICH.
Determines policies and procedures for ICH.
Selects topic for harmonization.
MonitorS progress of harmonization initiatives.

ICH WORKING GROUP:

Expert working group.

Implementation working group.
Informal working group.

IGH GUIDELINES:
ICH includes four categories of guidelines:
a) Quality guidelines
b) Efficacy guidelines
c) Safety guidelines
d) Multi-disciplinary guidelines

1. QUALITY GUIDELINES:
This refers to chemical and pharmaceutical quality assurance.
Ex: Stability testing
Impurity testing
Quality guidelines consist of several sub-guidelines as follows:

a) Q1 (Q1A -Q1F) 8) Q7
b) Q2 h) Q8
c) Q3(Q3A - Q3D) i) Q9
d) Q4 (Q4A -Q4B) i) Q10
e) Q5 (Q5A - Q5E) k) Q11
Q6 (Q6A- Q6B) 1) Q12
a) Q1 GUIDELINES:
It deals with stability.
It includes QlA - QIF

Q1A Stability testing of new drug substances and products.

Q1B Photo-stability testing of new drug substances and products.
Q1C Stability testing of new dosage forms.
Q1D Bracketing and matrixing designs for stability testing of new drug substances and products.
Q1E Evaluation of stability.
Q1F Stability data package for registration applications in cinematic zones Il &IV.

The purpose of stability testing is to provide evidence on how the quality of a

drug substance (or) drug product varies with the time under the influence of a
variety of environmental factors such as temperature, humidity and light.
To establish a retest period for the drug substance (or) a shelf life for the drug
product.
Photo-stability testing is required toevaluate the light sensitivity and stability of
new drugs and products.
Stability testing for new dosage fornms is required to provide new formulations of
already approved medicines.
Evaluation of stability data provides recommendations on products intended for
storing at (or) below room temperature.

b) Q2 GUIDELINES:
It deals with analytical validation.
Validation of analytical procedures - Text & methodology.
This validation is to show that it is suitable for its intended purpose.
Provides validation parameters needed for analytical methods.
Analytical procedures that need to be validated are:
1) Identification tests.
2) Quantitative tests for impurities content.
3) Limit tests for control of impurities.
 c) Q3 GUIDELINES:
It deals with impurities.
It includes Q3A - Q3D.

Q3A Impurities in new drug substances.

Q3B Impurities in new drug products.
Q3C Guidelines for residual solvents.

Q3D Implementation of guidelines for elemental impurities.

These guidelines address the chemistry and the safety aspects of impurities.
> Listing of impurities
> Threshold limit
> Identification and qualification

d) 04 GUIDELINES:
" It deals with pharmacopoeias.
" It includes:

Q4A Pharmacopoeial harmonization.

Q4B Evaluation and recommendation of Pharmacopoeial texts for use in ICH regions.

These provide Pharmacopoeial texts to facilitate their recognition by regulatory

authorities for use.

e) Q5 GUIDELINES:
It deals with quality of biotechnological products.
" It includes Q5A -Q5E.

Viral safety evaluation of biotechnology products derived from cell lines of human (or)
Q5A
animal origin.
Analysis of the expression construct in cells used for the production of r-DNA derived
Q5B
protein Products.

Q5C Stability testing of biotechnological (or) biological products.

Derivation and characterization of cells substrates used for production of bio
Q5D
technological (or) biological products.
 Compatibility of biotechnological (or) biological products subject to change in their
Q5E
manufacturing process.

It provides broad guidance on appropriate standards for cell substrates.

To provide general framework for virus testing clearance and design of viral tests
& clearance evaluation studies.

) Q6 GUIDELINES:
It deals with specifications for new drug substances and products.
" It includes Q6A - Q6B.

Test procedures and acceptance criteria for new drugs answers and new drug
Q6A
products, chemical substances.
Q6B Tested procedures and acceptance criteria for technological (or)
biological products.
These guidelines are to establish a single set of global
specifications for new drug
substance and drug products.
The specifications play a major role in
assuring the quality of new drug substance
and a new drug product during shelf life.

g) Q7 GUIDELINES:

It deals with GMP

(Good manufacturing practice)
guidelines for active
pharmaceutical ingredients.
OBJECTIVE:
" Tomaintain the
quality of active
h) Q8 GUIDELINES:
pharmaceutical ingredient (API).
It deals with
pharmaceutical development.
To provide guidance on
the contents of pharmaceutical
products. development of drug
Q8 give
information about drug substance,
etc. excipients, container closure system
i) 09 GUIDELINES:
It deals
 Principles of quality risk management include: evaluation of the risk to qualify to
quality should be based on scientific knowledge and the links to patient
protection.

i) Q10 GUIDELINES:
It deals with pharmaceutical quality system.
It also includes applicable GMP regulations.

k) Q11 GUIDELINES:
It deals with development and manufacture of drug substance both chemical
entities and biotechnological (or) biological entities.

) Q12 GUIDELINES:
It deals with technical and regulatory considerations for pharmaceutical product
life-cycle management.
This guideline provides a globally agreed framework to facilitate the management
of such post approval CMC changes in a predictable and efficient manner across
the product life-cycle.

2. SAFETY GUIDELINES:

It mainly deals with in-vivo and in-vitro preclinical studies.

Safety guidance consists of several sub guidelines as follows:

a) S1 GUIDELINES:

It is based on carcinogenicity studies.

It includes SlA - S1C

S1 Rodent carcinogenicity studies for human pharmaceuticals.

S1A Carcinogenicity studies of pharmaceuticals.
S1B Testing for carcinogenicity of pharmaceuticals.
S1C Dose selection for carcinogenicity studies of pharmaceuticals.

These are to identify tumorigenic potential animals and to assess the relevant risk
in humans.
b) S2 GUIDELINES:

It is based on Genotoxicity studies.

It provides guidance on specificaspects of regulatory Genotoxicity tests for
pharmaceuticals.
To improve consistency in applications.

c) S3 GUIDELINES:

It is based on pharmacokinetic and toxicokinetic studies.

It includes S3A - S3B note for guidance on toxicokinetics.

S3A Assessment of systemic exposure in toxicity studies.

S3AQ & AS Assessment of systemic exposure focus on micro sampling.
S3B Guidance for repeated dose tissue distribution studies.

Objective: To describe systemic exposure achieved in animals and its relationship to

dose level & the time course of the toxicity study.

d) S4 GUIDELINES:

It deals with duration of chronic toxicity testing in animals (Rhodent and non
rodent toxicity testing).

Objective: To set out considerations that are apply to chronic toxicity testing in
rodents and non rodents as a part of safety evaluation of a medical product.
Rodents six months duration
Non rodents nine month duration

e) S5 GUIDELINES:

It deals with reproductive toxicology.

It defines the periods of treatment to be used in animals to better reflect the
human exposure to medical products &allow more specific identification of
stages at risk.
It gives recommendation on the strategy of reproductive toxicity testing on
chemicals and medical products. It also addresses male fertility investigation.
) S6 GUIDELINES:
" It deals with preclinical safety evaluation of biotechnological pharmaceuticals.
It addresses the use of animal models of disease, determination of when
genotoxicity assays and carcinogenicity studies to be performed.

g) S7 GUIDELINES:

The assessment of the effect of pharmaceuticals on ventricular repolarization and

pro-arrhythemic risk is the subject of active investigation.
It deals with pharmacology studies.
" It includes S7A - S7B.

S7A Safety pharmacology studies for human pharmaceuticals.

Non clinical evaluation of the potential for delayed ventricular
S7B
repolarization (QT prolongation) by human pharmaceuticals.

This guidance describes a non clinical testing strategy for assessing the potential
of a test substance to delay ventricular repolarization.

h) S8 GUIDELINES:

It deals with immunological studies.

Itprovides recommendations on non-clinical testing for immuno-suppressants.
i) s9 GUIDELINES:
" It deals with non-clinical evaluation for anti cancer pharmaceuticals.

) S10 GUIDELINES:
It deals with photo-safety evaluation of pharmaceuticals.

k) S11 GUIDELINES:

It deals with non-clinical safety testing in support of development of pediatric

medicines.
3) EFFICACY GUIDELINES:

" It deals with clinical study in human subjects.

Ex: Dose response studies, good clinical practice, etc
" It concerned with the design, conduct, safety and reporting of clinical trials. .
" It includes El - E20.

1) E1 Clinical safety for drugs used in long term treatment.

2) E2
Pharmacovigilance (Development of safety update report).
3) E3 Structure and content of clinical study reports.
4) E4 Dose response information to support drug registration i.e., Dose-response studies.
5) Ethentic factors (in the acceptability of foreign clinical data).
6) E6 Good clinical practice.
7) E7 Clinical trials in geriatric population.
8) E8 General considerations for clinical trials.

9) E9 Statistical principles for clinical trials.

10) E10 Choice of control group and related issues in clinical trials.
11) E11 Clinical trials in paediatric population.
12) E12 Principles for clinical evaluation by therapeutic category.
13) E14 Clinicalevaluation of QT.
14) E15 Definitions in pharmaco-genetics,/ pharmaco-genomics, (Genomic biomarkers etc.)
15) E16 Qualification of genomic biomarkers.
16) E17 (General principle on planning or designing) Multi-regional clinical trials.
17) E18 Genomic sampling (Methodologies for future use).
18) E19 Safety data collection
19) E20 Adaptive clinical trials
 4) MULTI-DISCIPLINARY GUIDELINES:

It includes M1 - M8.

MEDRA terminology.
1) M1
(MEDRA -Medical Dictionary for Regulatory Activities.)
2) M2 Electronic standards for transfer of regulatory information
3) M3 Non-clinical safety studies
4 M4 Common technical document(CTD)
5) M5 Data elements &standards for drug dictionaries
6) M6 virus and gene therapy vector shading and transmission.
7) M7 Genotoxic impurities.
8) M8 Electronic CTD

GCP GUIDELINES

Good clinical practice (GCP) is an international quality standard that is provided

by ICH.
GCP is defined as a standard for: Design, conduct, performance monitoring,
auditing,recording, analysis and reporting of clinical trials that provide assurance
that the drug and other reported results are credible and accurate, and that the
rights integrity and confidentiality of the trial subjects are protected.

PRINCIPLES OF GCP:

It includes 2.1 to 2.13

Clinical trials should be conducted in accordance with ethical principles (as per
2.1
declaration of Helsinki)
1)
Clinical trials should be conducted in harmony with GCP and other applicable
regulatory requirements.
Before a trial is initiated, focus on the risk versus benefit ratio.
2) 2.2 Foreseeable risks and subject inconveniences should be weighed against
anticipated benefits for the trial subject and society.
Trial should be initiated and conducted only if anticipated benefits outweigh risk.
Consideration of trial subjects that should prevail over interests of science and
society are:
3) 2.3
Rights
Safety
Well-being
4) 2.4 Clinical and non clinical information of a drug product should be adequate to
conduct the proposed clinical trial.
5) 2.5 Clinical trials should be scientifically sound & described in aclear, detail protocol.
6) 2.6 Clinical Trials should be conducted in compliance with a protocol that has been
approved by IRB/IEC.
7) 2.7 Aqualified physician is responsible for medical care of trial subjects and medical
decisions made on behalf of trial subjects.
2.8 Each individual involved in conducting a trial should be qualified by education,
8)
training and experience in order to perform his or her respective tasks.
9) 2.9 Freely given informed consent should be obtained from every trial subject prior to
clinical trial participation.
10) 2.10 Allclinical trials information should be recorded, handled and stored safely, which
can help in accurate reporting, interpretation and verification.
11) 2,11 Confidentiality of records, (Ex: subjects identification) should be protected in
accordance to applicable regulatory requirements.
Investigational products should be manufactured, handled, stored in accordance
12) 2.12
with applicable GMP guidelines.
They should be used in accordance with approved protocol.
13) 2.13 Systems with procedures that assure quality of every aspect of the trial should be
implemented.