UPDATE ICH GUIDELINE
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Stability Testing of New Drug Substances
1 Q1A(R2)
and Products
Stability Testing: Photostability Testing of
2 Q1B
New Drug Subtances and Products
3 Stability Testing for New Dosage Forms
Bracketing and Matrixing Designs for
4 Stability Testing of New Drug Subtances
and Products
5 Evaluation of Stability Data
Stability Data Package for Registration
6 Q1F
Applications in Climatic Zones III and IV
Validation of Analytical Procedures: Text
7 Q2(R1)
and Methodology
8 Impurities in New Drug Subtances
9 Impurities in New Drug Products
Impurities: Guideline for Residual
10
Solvents
11 Guideline for Elemental Impurities
Implementation of Guideline for
12
Elemental Impurities
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This Guideline provides recommendations on stability testing
protocols including temperature, humidity and trial duration for
climatic Zone I and II. Furthermore, the revised document
Februari 2003 takes into account the requirements for stability testing in
Climatic Zones III and IV in order to minimise the different
storage conditions for submission of a global dossier.
This forms an annex to the main stability Guideline, and gives
November 1996 guidance on the basic testing protocol required to evaluate the
light sensitivity and stability of new drugs and products.
It extends the main stability Guideline for new formulations of
Q1C November 1996 already approved medicines and defines the circumstances
under which reduced stability data can be accepted.
This document describes general principles for reduced
Q1D Februari 2002 stability testing and provides examples of bracketing and
matrixing designs.
This document extends the main Guideline by explaining
possible situations where extrapolation of retest periods/shelf-
Q1E Februari 2003 lives beyond the real-time data may be appropriate.
Furthermore, it provides examples of statistical approaches to
stability data analysis.
The ICH Steering Committee endorsed the withdrawal of the
Q1F Guideline at its meeting in Yokohama, June 2006 and
Juni 2006 decided to leave definition of storage conditions in Climatic
Zones III and IV to the respective regions and WHO.
This identifies the validation parameters needed for a variety of
analytical methods. It also discusses the characteristics that
must be considered during the validation of the analytical
procedures which are included as part of registration
applications. It extends the Guideline Q2A to include the actual
November 1996 experimental data required, along with the statistical
interpretation, for the validation of analytical procedures.
The Guideline on Methodology has been incorporated into the
Guideline on Text in November 2005 and then renamed
Q2(R1), without any changes in the contents of the two
Guidelines.
The Guideline addresses the chemistry and safety aspects of
impurities, including the listing of impurities in specifications
and defines the thresholds for reporting, identification and
Q3A(R2) Oktober 2006 qualification. The revision of the guideline has allowed
clarifying some inconsistencies, to revise the decision tree, to
harmonize with Q3B and to address some editorial issues.
It complements the Guideline on impurities in new drug
substances and provides advice in regard to impurities in
products containing new, chemically synthesized drug
substances. The Guideline specifically deals with those
impurities which might arise as degradation products of the
drug substance or arising from interactions between drug
substance and excipients or components of primary packaging
Q3B(R2) Juni 2006 materials. The Guideline sets out a rationale for the reporting,
identification and qualification of such impurities based on a
scientific appraisal of likely and actual impurities observed, and
of the safety implications, following the principles elaborated in
the parent Guideline. Threshold values for reporting and
control of impurities are proposed, based on the maximum
daily dose of the drug substance administered in the product.
A Maintenance process has been done to revise Permitted
Daily Exposure (PDE), as new toxicological data for solvents
become available. Limit values for three residual solvents in
Q3C(R6) November 2016 drug products were revised on basis of the newly recognised
toxicity data; lower PDE for N-Methylpyrrolidone being kept in
Class 2 (limited by health-basis) and for Tetrahydrofuran and
Cumene being placed into Class 2 from Class 3 (no health-
based).
ICH Q3D Elemental Impurities is a quality guideline for the
control of elemental impurities in new drug products (medicinal
products), and it establishes Permitted Daily Exposures (PDEs)
for 24 Elemental Impurities (EIs) for drug products
Q3D Desember 2014 administered by the oral, parenteral and inhalation routes of
administration. In addition, guidance is provided in Q3D on
how to develop an acceptable level for EIs for drug products
administered by other routes of administration.
Q3D Training Oktober 2014
 UPDATE ICH GUIDELINE
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Q6A activity provided the framework on how to set
specifications for drug substances to address how regulators
and manufacturers might avoid setting or agreeing to
conflicting standards for the same product, as part of the
registration in different regions. The resulting ICH Q6A
Guideline provides harmonised guidance in this area. With the
passage of the Chemical Substances (Q6A) ICH Guideline, the
13 Pharmacopoeias Q4 harmonisation of several compendial test chapters has been
considered as critical by the ICH Steering Committee. These
chapters are at various stages of harmonisation among the
three pharmacopeial organisations (USP, JP & EP). The three
organisations conduct their harmonisation efforts through a
tripartite pharmacopeial harmonisation program known as the
Pharmacopoeial Discussion Group (PDG).

The pharmacopoeial authorities, working together through the

14 Pharmacopoeias Harmonisation
Evaluation and Recommendation of
15 Pharmacopoeial Texts for Use in the ICH
Regions
Residue on Ignition/Sulphated Ash
16
General Chapter
Test for Extractable Volume of Parenteral
17
Preparations General Chapter
Test for Particulate Contamination: Sub-
18
Visible Particles General Chapter.
Microbiological Examination of Non-
19 Sterile Products: Microbial Enumeration
Tests General Chapter
Microbiological Examination of Non-
20 Sterile Products: Tests for Specified
Micro-organisms General Chapter
Microbiological Examination of Non-
Sterile Products: Acceptance Criteria for
21 Pharmaceutical Preparations and
Substances for Pharmaceutical Use
General Chapter
22 Disintegration Test General Chapter
Uniformity Dosage Units General
23
Chapter.
24 Dissolution Test General Chapter
25 Sterility Test General Chapter
26 Tablet Friability General Chapter
Polyacrylamide Gel Electrophoresis
27
General Chapter
Capillary Electrophoresis General
28
Chapter
29 Analytical Sieving General Chapter
Bulk Density and Tapped Density of
30
Powders General Chapter
Bacterial Endotoxins Test General
31
Chapter
32 FAQ
Viral Safety Evaluation of Biotechnology
33 Products Derived from Cell Lines of
Human or Animal Origin
Pharmacopoeial Discussion Group (PDG), have been closely
involved with the work of ICH since the outset and
Q4A harmonisation between the major pharmacopoeias, which
started before ICH, has proceeded in parallel. The ICH
Steering Committee receives regular reports on the status of
pharmacopoeial harmonisation at its meetings
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
Q4B November 2007 regions and since 2010 in Canada. Following favourable
evaluations, ICH will issue topic-specific annexes with
information about these texts and their implementation.
Implementation of the Q4B annexes is intended to avoid
redundant testing by industry.
Q4B Annex This annex is the result of the Q4B process for Residue on
September 2010
1R1 Ignition/Sulphated Ash General Chapter.
Q4B Annex This annex is the result of the Q4B process for the Test for
September 2010
2R1 Extractable Volume of Parenteral Preparations General
Chapter.
This annex is the result of the Q4B process for Test for
Q4B Annex Particulate Contamination: Sub-Visible Particles General
September 2010
3R1 Chapter.
This annex is the result of the Q4B process for Microbiological
Q4B Annex Examination of Non-Sterile Products: Microbial Enumeration
September 2010
4AR1 Tests General Chapter.
This annex is the result of the Q4B process for Microbiological
Q4B Annex Examination of Non-Sterile Products: Tests for Specified Micro-
September 2010
4BR1 organisms General Chapter.
This annex is the result of the Q4B process for Microbiological
Examination of Non-Sterile Products: Acceptance Criteria for
Q4B Annex Pharmaceutical Preparations and Substances for
September 2010
4CR1 Pharmaceutical Use General Chapter.
Q4B Annex This annex is the result of the Q4B process for Disintegration
September 2010
5R1 Test General Chapter.
This annex is the result of the Q4B process for Uniformity
Q4B Annex 6 November 2013
Dosage Units General Chapter.
Q4B Annex This annex is the result of the Q4B process for Dissolution Test
November 2010
7R2 General Chapter.
Q4B Annex This annex is the result of the Q4B process for Sterility Test
September 2010
8R1 General Chapter
Q4B Annex This annex is the result of the Q4B process for Tablet Friability
September 2010
9R1 General Chapter.
Q4B Annex This annex is the result of the Q4B process for Polyacrylamide
September 2010
10R1 Gel Electrophoresis General Chapter.
This annex is the result of the Q4B process for Capillary
Electrophoresis General Chapter. It contains the
Q4B Annex 11 Juni 2010
Interchangeability Statement from Health Canada.
This annex is the result of the Q4B process for Analytical
Q4B Annex 12 Juni 2010 Sieving General Chapter. It contains the Interchangeability
Statement from Health Canada.
This annex is the result of the Q4B process for Bulk Density
and Tapped Density of Powders General Chapter. It contains
Q4B Annex 13 Juni 2012
the Interchangeability Statement from Health Canada.
This annex is the result of the Q4B process for Bacterial
Endotoxins Test General Chapter. It contains the
Q4B Annex 14 Oktober 2012
Interchangeability Statement from Health Canada.
The Q4B Expert Working Group (EWG) developed a set of
Frequently Asked Questions (FAQs) to help users of the Q4B
Q4B FAQs Guideline and Annexes to understand the use and implication
of these documents.
This is concerned with testing and evaluation of the viral safety
of biotechnology products derived from characterised cell lines
Q5A(R1) September 1999 of human or animal origin. The purpose is to provide a general
framework for virus testing experiments for the evaluation of
virus clearance and the design of viral tests and clearance
evaluation studies.

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Analysis of the Expression Construct in
34 Cells Used for Production of r-DNA
Derived Protein Products
Stability Testing of
35
Biotechnological/Biological Products
Derivation and Characterisation of Cell
36 Substrates Used for Production of
Biotechnological/Biological Products
Comparability of
Biotechnological/Biological Products
37
Subject to Changes in their
Manufacturing Process
Specifications: Test Procedures and
Acceptances Criteria for New Drug
38
Subtances and New Drug Products:
Chemical Subtances
Specifications: Test Procedures and
39 Acceptance Criteria for
Biotechnological/Biological Products
Good Manufacturing Practice Guide for
40
Active Pharmaceutical Ingredients
Questions and Answers: Good
Q7 Questions
41 Manufacturing Practice Guide for Active
and Answers
Pharmaceutical Ingredients
42 Pharmaceutical Development
43 Quality Risk Management
44 Pharmaceutical Quality System
45 Implementation
Development and Manufacture of Drug
46 Subtances (Chemical Entities and
Biotechnological/Biological Entities
UPDATE ICH GUIDELINE
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It advises on the types of information that are considered
Q5B November 1995 valuable in assessing the structure of the expression construct
used to produce recombinant DNA derived proteins.
This document augments the stability Guideline (Q1A above)
and deals with the particular aspects of stability test
Q5C November 1995 procedures needed to take account of the special
characteristics of products in which the active components are
typically proteins and/or polypeptides.
This document provides broad guidance on appropriate
standards for the derivation of human and animal cell lines and
Q5D Juli 1997 microbes used to prepare biotechnological/biological products
and for the preparation and characterisation of cell banks to be
used for production.
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
Q5E November 2004 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. The main emphasis of the
document is on quality aspects.
This addresses the process of selecting tests and methods and
setting specifications for the testing of drug substances and
Q6A Oktober 1999 dosage forms. Account has been taken of the considerable
guidance and background information which are present in
existing regional documents.
This document provides guidance on justifying and setting
specifications for proteins and polypeptides which are derived
from recombinant or non-recombinant cell cultures. The scope
of this part is initially limited to well-characterised
biotechnological products, although the concepts may be
Q6B Maret 1999 applicable to other biologicals as appropriate. In view of the
nature of the products, the topic of specifications include in-
process controls, bulk drug, final product and stability
specifications and give guidance for a harmonised approach to
determining appropriate specifications based on safety,
process consistency, purity, analytical methodology, product
administration and clinical data considerations.
Q7 November 2000
Juni 2015
This Guideline is intended to provide guidance on the contents
of Section 3.2.P.2 (Pharmaceutical Development) for drug
products as defined in the scope of Module 3 of the Common
Technical Document (ICH topic M4). The guideline does not
apply to contents of submissions for drug products during the
Q8(R2) Agustus 2009 clinical research stages of drug development. However the
principles in this guideline are important to consider during
these stages. This guideline might also be appropriate for other
types of products. To determine the applicability of this
guideline for a particular type of product, applicants should
consult with the appropriate regulatory authorities.
This Guideline provides principles and examples of tools of
quality risk management that can be applied to all aspects of
pharmaceutical quality including development, manufacturing,
Q9 November 2005 distribution, and the inspection and submission/review
processes throughout the lifecycle of drug substances and
drug (medicinal) products, biological and biotechnological
products, including the use of raw materials, solvents,
excipients, packaging and labeling materials.
This Guideline applies to pharmaceutical drug substances and
drug products, including biotechnology and biological products,
Q10 Juni 2008 throughout the product lifecycle. The elements of Q10 should
be applied in a manner that is appropriate and proportionate to
each of the product lifecycle stages, recognising the
differences among, and the different goals of each stage.
Experiences by all parties with the implementation of the ICH
Q8(R2), Q9 and Q10 Guidelines have resulted in the need for
Q8/9/10 November 2010 some clarification. The Questions and Answers developed by
the Quality Implementation Working Group (IWG) are intended
to facilitate the implementation of the Q8(R2), Q9 and Q10
Guidelines, by clarifying key issues.
This new guidance is proposed for Active Pharmaceutical
Ingredients (APIs) harmonising the scientific and technical
Q11 May 2012 principles relating to the description and justification of the
development and manufacturing process (CTD sections S 2.2.
- S 2.6) of Drug Substances including both chemical entities
and biotechnological/biological entities.
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These Q&As are intended to provide additional clarification and
Questions and Answers: Selection and to promote convergence on the considerations for the selection
47 Justification of Starting Materials for the Q11 Q&A November 2016 and justification of starting materials and on the information
Manufacture of Drug Subtances that should be provided in marketing authorisation applications
and/or Master Files. The focus of the Q&A document is on
chemical entity drug substances.

This new guideline is proposed to provide guidance on a

framework to facilitate the management of post-approval
Chemistry, Manufacturing and Controls (CMC) changes in a
more predictable and efficient manner across the product
Technical and Regulatory Considerations lifecycle. Adoption of this new ICH Guideline will promote
48 for Pharmaceutical Product Lifecycle innovation and continual improvement, and strengthen quality
Management assurance and reliable supply of product, including proactive
planning of supply chain adjustments. It will allow regulators
(assessors and inspectors) to better understand the firms
Pharmaceutical Quality Systems (PQSs) for management of
post-approval CMC changes. This new guideline is intended to
complement the existing ICH Q8 to Q11 Guidelines.