ICH Guidline

Q1 Stability
o Q1A(R2) Stability Testing of New Drug Substances and Products Q1A

Finalised Guideline:
February 2003

Q1A(R2)

Description :

This Guideline has been revised a second time and has reached Step 4 of the ICH
process in February 2003.

This Guideline provides recommendations on stability testing protocols including

temperature, humidity and trial duration for climatic Zone I and II. Furthermore, the
revised document 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.
o Q1B Stability Testing : Photostability Testing of New Drug Substances and
Products

Finalised Guideline:
November 1996

Q1B

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in November
1996. This forms an annex to the main stability Guideline, and gives guidance on
the basic testing protocol required to evaluate the light sensitivity and stability of
new drugs and products.
o Q1C Stability Testing for New Dosage Forms

Finalised Guideline:
November 1996

Q1C

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in November
1996. It extends the main stability Guideline for new formulations of already
approved medicines and defines the circumstances under which reduced stability
data can be accepted.
o Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products

Finalised Guideline:
February 2002

Q1D

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in February
2002. This document describes general principles for reduced stability testing and
provides examples of bracketing and matrixing designs.
o Q1E Evaluation of Stability Data

Finalised Guideline:
February 2003

Q1E

Presentation on Q1E

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in February
2003. This document extends the main Guideline by explaining possible situations
where extrapolation of retest periods/shelf-lives beyond the real-time data may be
appropriate. Furthermore, it provides examples of statistical approaches to stability
data analysis.
o Q1F Stability Data Package for Registration Applications in Climatic Zones III and
IV

Guideline Withdrawal:
June 2006

Q1F Explanatory note

WHO Stability Guideline

Description :

The ICH Steering Committee endorsed the withdrawal of the Q1F Guideline at its
meeting in Yokohama, June 2006 and decided to leave definition of storage
conditions in Climatic Zones III and IV to the respective regions and WHO.
Q2 Analytical validation
o Q2(R1) Validation of Analytical Procedures: Text and Methodology Q2A, Q2B

Finalised Guidelines:
October 1994/November 1996

Q2(R1)

Description :

The tripartite harmonised ICH Guideline on Text (previously coded Q2A) was
finalised under Step 4 in October 1994. 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.

The tripartite harmonised ICH Guideline on Methodology (previously coded Q2B)

was finalised under Step 4 in November 1996. It extends the Guideline Q2A to
include the actual 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.
Q3 Impurities
o Q3A(R2) Impurities in New Drug Substances

Finalised Guideline:
October 2006

Q3A(R2)

Description :

First Recommended for Adoption at Step 4 of the ICH Process on 30 March 1995,
the Guideline was revised under Step 2 of the ICH Process on 7 October 1999 and
finalised under Step 4 on 7 February 2002 (Q3A(R1)).

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 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.

The Attachment 2 of this guideline has been revised under Step 4 without further
public consultation on 25 October 2006 (Q3A(R2)).
o Q3B(R2) Impurities in New Drug Products
 Finalised Guideline:
June 2006

Q3B(R2)

Concept Paper

Description :

This Guideline has been first revised and finalised under Step 4 in February 2003. 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
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.

The Attachment 2 of this Guideline has been revised under Step 4 without further
public consultation on 2 June 2006 (Q3B(R2)).
o Q3C(R6) Impurities: Guideline for Residual Solvents Q3C, Q3C(M)

Finalised Guideline:
November 2016

Q3C(R6)

Q3C Concept Paper (March 1994)

Q3C(R6) Step 4 - Presentation

Description :

The core tripartite harmonised ICH Guideline was finalised under Step 4 in July
1997. This recommends the use of less toxic solvents in the manufacture of drug
substances and dosage forms, and sets pharmaceutical limits for residual solvents
(organic volatile impurities) in drug products.

Maintenance Process

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 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).

Both revisions (PDE for THF and PDE for NMP) reached Step 4 of the process in
September 2002. A corrigendum to calculation formula for NMP was subsequently
approved on 28 October 2002. As per the new coding rule, they were incorporated
into the core Guideline in November 2005.

In February 2009, Table 2, Table 3 and Appendix 1 of the Core Guideline were
updated to reflect the revision of the PDEs for N-Methylpyrrolidone and
Tetrahydrofuran (Q3C(R4)).

The most recent maintenance of the Guideline, resulting in the current Q3C(R6)
version, was to revise the PDE for Methyl isobutyl ketone (MIBK), and to add
Triethylamine (TEA) as a new solvent. Based on new data, MIBK was moved from
Class 3 (solvents with low toxic potential) to Class 2 (solvents to be limited). The
new solvent Triethylamine was included in Class 3 (solvents with low toxic
potential).
o Q3D Guideline for Elemental Impurities

Final Guideline:
December 2014

Q3D

Concept Paper

Business Plan

Audio presentation

Description :

The Q3D Guideline has reached Step 4 of the ICH process in December 2014.

This guidance aims to provide a global policy for limiting metal impurities
qualitatively and quantitatively in drug products and ingredients. The existing ICH
Q3A Guideline classifies impurities as organic, inorganic, and residual solvents. The
Q3A and Q3B Guidelines effectively address the requirements for organic
impurities. An additional Guideline Q3C was developed to provide clarification of the
requirements for residual solvents. 

 
 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
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.

Maintenance Process

A Maintenance Procedure applies to revision of the Q3D Guideline for Elemental

Impurities. These changes includes the incorporation of Permitted Daily Exposure
(PDE) for new elemental impurities(EI)/routes of administration and revising the
PDE for EI already listed in Q3D as new toxicological data for EI becomes
available.

Products administered on skin and its appendages (e.g., hair, nails) remain the
largest area where PDEs for EIs have not been established. In September 2016,
the ICH Management Committee approved the revision of the ICH Q3D Concept
Paper to include PDEs for the cutaneous and transdermal Route of Administration
to continue the process of harmonisation, where necessary. This leads to the
establishment of an Expert Working Group (EWG) to develop PDEs levels for all 24
EI included in the Q3D Guideline for products administered by the cutaneous and
transdermal routes of administration.
o Q3D training Implementation of Guideline for Elemental Impurities

Concept Paper

Business Plan

Work Plan

Q3D Training package: Modules 0-9

Description :

This Implementation Working Group (IWG) was endorsed by the ICH Steering
Committee in October 2014. Throughout the development of the Q3D Guideline,
external audiences, constituents and interested parties have clearly communicated
the complexity of the implementation approaches for this guideline. While the Q11
Guideline provides the framework, it cannot provide the detailed examples covering
the breadth of potential case studies for products within scope of the guideline.
Consequently, the ICH SC considered that the development of a comprehensive
training programme and supporting documentation sponsored by ICH was
necessary to ensure the proper interpretation and effective utilisation by industry
and regulators alike to enable a harmonised and smooth implementation of Q3D on
a global basis.
Q4 Pharmacopoeias
o Q4 Pharmacopoeias

Description :

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 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).
Q5 Quality of Biotechnological products
o Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines
of Human or Animal Origin Q5A

Finalised Guideline:
September 1999

Q5A(R1)

Description :

The tripartite harmonised ICH Guideline was finalised  under Step 4 in March 1997.
This is concerned with testing and evaluation of the viral safety of biotechnology
products derived from characterised cell lines 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.

(Please note that a typographic error has been corrected on 23 September 1999 on
Table A-1. the Genome of the Reovirus 3 is RNA (and not DNA as previously
printed). The correction was integrated in the Guideline that was then renamed
Q5A(R1)).
Q6 Specifications
o Q6A Specifications : Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances
 Finalised Guideline:
October 1999

Q6A

Decision Trees

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in October
1999. This addresses the process of selecting tests and methods and setting
specifications for the testing of drug substances and dosage forms. Account has
been taken of the considerable guidance and background information which are
present in existing regional documents.
o Q6B Specifications : Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products

Finalised Guideline:
March 1999

Q6B

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in March 1999.
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 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 Good manufacturing practice
o Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7A

Finalised Guideline:
November 2000

Q7

Concept Paper

Description :

Early in the ICH Process it was agreed that there was adequate international
 agreement on the technical aspects of Good Manufacturing Practices (GMP) for
Pharmaceutical Products and that further harmonisation action through ICH was not
needed. Recently, however, attention has focused on the need to formalise GMP
requirements for the components of pharmaceutical products - both active and
inactive. In February 1998, the ICH Steering Committee agreed that GMP for Active
Pharmaceutical Ingredients (APIs) should be adopted as an ICH Topic.

When this topic was adopted, the Steering Committee took steps to ensure that due
account was taken of the work already in progress by PIC/S, FDA and other parties.
In view of the unusually wide implications of this Topic, a much extended EWG has
been established which includes, in addition to the six ICH parties and the
Observers, experts representing IGPA (generics industry), WSMI (self medication
industry) and PIC/S. With respect to the latter representatives from China, India and
Australia have been invited to participate.
o Q7 Q&As Questions and Answers: Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients

Finalised Q&As: June 2015

Q7 Questions and Answers

Concept Paper

Work Plan

Description :

The Guideline reached Step 4 of the ICH process on June 2015.

Experience gained with the implementation of the ICH Q7 Guideline since its
finalisation in 2000 shows that uncertainties related to the interpretation of some
sections exist. Technical issues with regard to GMP of APIs – also in context with
new ICH Guidelines - are addressed in this Question and Answer document in
order to harmonise expectations during inspections, to remove ambiguities and
uncertainties and also to harmonise the inspections of both small molecules and
biotech APIs.
Q8 Pharmaceutical Development
o Q8(R2) Pharmaceutical Development

Finalised Guideline:
August 2009

Q8(R2)

Concept Paper
 ICH Q8/Q9/Q10 Training Material

Description :

The core tripartite harmonised ICH Guideline was finalised under Step 4 in
November 2005. 
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 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.

The annex to the tripartite harmonised ICH text was finalised under Step 4 in
November 2008 and incorporated into the core Guideline, which was then renamed
Q8(R1).

The annex provides further clarification of key concepts outlined in the core
Guideline. In addition, this annex describes the principles of quality by design
(QbD). The annex is not intended to establish new standards: however, it shows
how concepts and tools (e.g., design space) outlined in the parent Q8 document
could be put into practice by the applicant for all dosage forms. Where a company
chooses to apply quality by design and quality risk management (Q9: Quality Risk
Management), linked to an appropriate pharmaceutical quality system, then
opportunities arise to enhance science- and risk-based regulatory approaches (see
Q10: Pharmaceutical Quality System).

The Q8(R1) Guideline was revised in Summer 2009 to reflect minor corrections to
Example 2 on page 23 (Q8(R2)).
o Q8/9/10 Q&AsR4 Q8/Q9/Q10 - Implementation

Finalised Q&As:
November 2010

Q8/9/10 Questions and Answers (R4)

Q8/9/10 Points to Consider (R2)

Concept Paper

ICH Q8/Q9/Q10 Training Material

Description :

Since reaching Step 4 and publication within the ICH regions, experiences by all
 parties with the implementation of the ICH Q8(R2), Q9 and Q10 Guidelines have
resulted in the need for 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.

The document with the first and second set of Q&As was finalised under Step 4 in
April and June 2009, respectively.

In October 2009, a third set of Q&As was developed and approved by the Steering
Committee for integration in the Q&A document (Q8/Q9/Q10 Q&As (R3)).

In November 2010, a fourth set of Q&As was developed and approved by the
Steering Committee for integration in the Q&A document (Q8/Q9/Q10 Q&As (R4)).

The ICH Quality IWG also prepared ‘Points to Consider’ covering topics relevant to
the implementation of Q8(R2), Q9 and Q10, which supplement the existing
Questions & Answers and workshop training materials already produced by this
group. The document with the first and second set of Points to Consider Document
was finalised in June and November 2011, respectively.  
Q9 Quality risk management
o Q9 Quality Risk Management

Finalised Guideline:
November 2005

Q9

Concept Paper

Business Plan

ICH Q9 Briefing Pack

ICH Q8/Q9/Q10 Training Material

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in November
2005.
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, 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.
o Q8/9/10 Q&AsR4 Q8/Q9/Q10 - Implementation
 Finalised Q&As:
November 2010

Q8/9/10 Questions and Answers (R4)

Q8/9/10 Points to Consider (R2)

Concept Paper

ICH Q8/Q9/Q10 Training Material

Description :

Since reaching Step 4 and publication within the ICH regions, experiences by all
parties with the implementation of the ICH Q8(R2), Q9 and Q10 Guidelines have
resulted in the need for 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.

The document with the first and second set of Q&As was finalised under Step 4 in
April and June 2009, respectively.

In October 2009, a third set of Q&As was developed and approved by the Steering
Committee for integration in the Q&A document (Q8/Q9/Q10 Q&As (R3)).

In November 2010, a fourth set of Q&As was developed and approved by the
Steering Committee for integration in the Q&A document (Q8/Q9/Q10 Q&As (R4)).

The ICH Quality IWG also prepared ‘Points to Consider’ covering topics relevant to
the implementation of Q8(R2), Q9 and Q10, which supplement the existing
Questions & Answers and workshop training materials already produced by this
group. The document with the first and second set of Points to Consider Document
was finalised in June and November 2011, respectively.  
Q10 Pharmaceutical quality system
o Q10 Pharmaceutical Quality System

Finalised Guideline:
June 2008

Q10

Concept Paper

Business Plan
 Presentation on Q10

ICH Q8/Q9/Q10 Training Material

Description :

The tripartite harmonised ICH Guideline was finalised under Step 4 in June 2008.
This Guideline applies to pharmaceutical drug substances and drug products,
including biotechnology and biological products, 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.

o Q8/9/10 Q&AsR4 Q8/Q9/Q10 - Implementation

Finalised Q&As:
November 2010

Q8/9/10 Questions and Answers (R4)

Q8/9/10 Points to Consider (R2)

Concept Paper

ICH Q8/Q9/Q10 Training Material

Description :

Since reaching Step 4 and publication within the ICH regions, experiences by all
parties with the implementation of the ICH Q8(R2), Q9 and Q10 Guidelines have
resulted in the need for 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.

The document with the first and second set of Q&As was finalised under Step 4 in
April and June 2009, respectively.

In October 2009, a third set of Q&As was developed and approved by the Steering
Committee for integration in the Q&A document (Q8/Q9/Q10 Q&As (R3)).

In November 2010, a fourth set of Q&As was developed and approved by the
Steering Committee for integration in the Q&A document (Q8/Q9/Q10 Q&As (R4)).

The ICH Quality IWG also prepared ‘Points to Consider’ covering topics relevant to
the implementation of Q8(R2), Q9 and Q10, which supplement the existing
Questions & Answers and workshop training materials already produced by this
 group. The document with the first and second set of Points to Consider Document
was finalised in June and November 2011, respectively.  
Q11 Development and manufacture of drug substance
o Q11 Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities)

Finalised Guideline:
May 2012

Q11

Concept Paper

Business Plan

Audio Presentation

Description :

The Guideline reached Step 4 of the ICH process on 1 May 2012.

This new guidance is proposed for Active Pharmaceutical Ingredients (APIs)

harmonising the scientific and technical 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.

Q12 Life cycle management

o Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management

Concept Paper

Business Plan

Work Plan

Description :

This topic was endorsed by the ICH Steering Committee in September 2014.

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 lifecycle.
Adoption of this new ICH Guideline will promote innovation and continual
improvement, and strengthen quality 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.