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Q1A(R2): Stability Testing of New Drug Substances and
Products (Second Revision)
This
guideline has been revised a second time in order to accommodate
for the consequences of Q1F and has reached Step 4 of the ICH
process on 6 February 2003.
This
guideline provides recommendations on stability testing
protocols including temperature, humidity and trial duration.
Furthermore, the revised document takes into account the
requirements for stability testing in Climatic Zones III and IV
in order to minimize the different storage conditions for
submission of a global dossier. |
Q1A(R2) |
Implementation (Step 5) :
EU : Adopted by CPMP, March 2003, issued as CPMP/ICH/2736/99
MHLW : Adopted June 3, 2003, PFSB/ELD Notification No.
0603001
FDA : Published in the Federal Register, Vol, 68, No.
225, Friday, November 21, 2003; pages 65717-18 |
Status :
Step 5
February 2003 |
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Q1B: Photostability Testing of New Drug
Substances and Products
The
tripartite harmonised ICH guideline was finalised (Step 4) in
November 1996. This forms an annex to the main stability
guideline, and give guidance on the basic testing protocol
required to evaluate the light sensitivity and stability of new
drugs and products. |
Q1B |
Implementation (Step 5) :
EU: Adopted by CPMP,
December 96, issued as CPMP/ICH/279/95
MHLW: Adopted May 97, PAB/PCD Notification No.422
FDA: Published in the Federal Register, Vol. 62, No. 95,
May 16, 1997, pages 27115-27122. |
Status :
Step 5
November 1996 |
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Q1C: Stability Testing for New Dosage Forms
The
tripartite harmonised ICH guideline was finalised (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. |
Q1C |
Implementation (Step 5) :
EU: Adopted by CPMP,
December 96, issued as CPMP/ICH/280/95
MHLW: Adopted May 97, PAB/PCD Notification No.425
FDA: Published in the Federal Register, Vol. 62, No. 90,
May 9, 1997, pages 25634-25635 |
Status :
Step 5
November 1996 |
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Q1D,
Q1E, Q1F
The ICH
Steering Committee agreed that the main stability guideline
should be complemented by the following topics : Matrixing and
Bracketing (Q1D), Statistical Analysis and Interpretation of
Data (Q1E), Data Package for Registration in Climatic Zones III
and IV (Q1F) |
|
Q1D: Bracketing and Matrixing Designs for
Stability Testing of Drug Substances and Drug Products
The
tripartite harmonised ICH guideline was finalised (Step 4) in
February 2002. This document describes general principles for
reduced stability testing and provides examples of bracketing
and matrixing designs. |
Q1D |
Implementation (Step 5) :
EU: Adopted by CPMP, Februar 2002, CPMP/ICH/4104/00
MHLW: Adopted on July 31, 2002 as PFSB/ELD Notification
No. 0731004
FDA: Published in the Federal Register, Vol 68, No. 11;
January 16, 2003; pages 2339-2340 |
Status :
Step 5
February 2002 |
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Q1E: Evaluation of Stability Data
The
tripartite harmonised ICH guideline was finalised (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. |
Q1E |
Implementation (Step 5) :
EU: Adopted by CPMP, March 2003, issued as CPMP/ICH/420/02
MHLW: Adopted June 3, 2003, PFSB/ELD Notification No.
0603004
FDA: Published in the Federal Register / Vol. 69, N° 110,
Tuesday June 8, 2004, pages 32010-32011 |
Status :
Step 5
February 2003 |
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Q1F: Stability Data Package for
Registration Applications in Climatic Zones III and IV
The ICH Steering Committee endorsed the withdrawal of
the Q1F guideline at its meeting in Yokohama, June 2006
Click
here to open the Explanatory Note
|
Q1F Explanatory Note |
Guideline
withdrawn on June 8, 2006
EU:
Withdrawal notification and Explanatory Note, issued as
CPMP/ICH/421/02, June 2006
MHLW: Withdrawal adopted 3rd July 2006, PFSB/ELD
Notification n° 0703001
FDA: Withdrawn from CDER's guidance page on
7/6/2006 and will be listed in the next FDA annual
guidance agenda published in the Federal Register. |
Status: Withdrawal
June 2006 |
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Q2(R1): Validation of Analytical
Procedures: Text and Methodology
The core
tripartite harmonised ICH text (previously coded Q2A) was
finalised (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
addendum tripartite harmonised ICH text (previously coded Q2B)
was finalised (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
addendum has been incorporated into the core guideline in
November 2005. |
Q2(R1) |
Implementation of the core guideline (Step 5) :
EU: Adopted by CPMP,
November 94, issued as CPMP/ICH/381/95
MHLW: Adopted July 95, PAB/PCD Notification No.755
FDA: Published in the Federal Register, Vol. 60, March 1,
1995, pages 11260 |
Status :
Step 5
October 1994 (core) |
|
(Addendum incorporated in
the core guideline ) |
Implementation status of the Addendum (Step 5) :
EU: Adopted by CPMP,
December 96, issued as CPMP/ICH281/95
MHLW: Adopted October 97, PMSB/ELD Notification No.338
FDA: Published in the Federal Register, Vol. 62, No. 96,
May 19, 1997, pages 27463-27467 |
Status :
Step 5
November 1996 |
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Q3A(R2): Impurities in New Drug Substances (Revised
Guideline)
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 Recommended for
Adoption under Step 4 on 7 February 2002 by the ICH
Steering Committee.
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 Step4 without further public
consultation on 25 October 2006. |
Q3A(R2) |
Implementation (Step 5) :
EU: Adopted by
CPMP, February 2002, CPMP/ICH/2737/99 (Revision of
CPMP/ICH/142/95) Revised Attachment 2 adopted by
CPMP October 2006.
MHLW: Adopted on 16 December 2002,
Notification ELD n° 1216001 Revision of
Attachment 2 to be notified
FDA: Published in the Federal Register, Vol,
68, No. 68, Tuesday February 11, 2003; p. 6924-6925
Revision of Attachment 2 to be notified |
Status : Step 5
October 2006 |
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Q3B(R2): Impurities in New Drug
Products (Revised Guideline)
This guideline has been
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 Step4 without further public
consultation on 2 June 2006. |
Q3B(R2) |
Implementation (Step 5) :
EU: Adopted by
CPMP, March 2003, issued as CPMP/ICH/2738/99;
Revised Attachment 2 Adopted by CPMP, June 2006,
CPMP/ICH/2738/99
MHLW: Adopted on 24 June 2003, PFSB/ELD
Notification n° 0624001; Revised Attachment 2
Adopted 3rd July 2006, PFSB/ELD Notification N°
0703004.
FDA: Published in the Federal Register, Vol,
68, No. 220, Friday November 14, 2003; p.
64628-64629
with the Revised Attachment 2. |
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Q3C(R3): Impurities: Guideline for
Residual Solvents
The
tripartite harmonised ICH guideline was finalised (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.
Impurities: Guideline for Residual Solvents (Maintenance)
A
Maintenance process has been done to revise PDEs, as new
toxicological data for solvents becomes available.
The two
documents have reached Step 4 of the process in September 2002.
Limit
values for two residual solvents in drug products were revised
on basis of the newly recognized toxicity data; lower PDE
(permissible daily exposure) for N-Methylpyrrolidone
being kept in Class 2 (limited by health-basis) and for
Tetrahydrofuran being placed into Class 2 from Class 3 (no
health-based).
Both
revisions (PDE for THF and PDE for NMP) have been incorporated
into the core Guideline in November 2005. |
Q3C(R3) |
Implementation (Step 5) :
EU: Adopted by CPMP,
September 97, issued as CPMP/ICH/283/95
MHLW: Adopted March 1998, PMSB/ELD Notification No.307
FDA: Published in the Federal Register, Vol. 62, No. 247,
December 24, 1997, page 67377
Q3C Tables and List [Word]
or [PDF]
(Posted 11/12/2003); published in FR, Vol.68, No. 219, Thursday,
November 13, 2003; pages 64352-64353 |
Status :
Step 5
July 1997 |
PDE for
Tetrahydrofuran
(THF)
(Incorporated into the core guideline) |
Implementation for THF (Step 5) :
EU: Adopted by CPMP,
September 2002, issued as CPMP/ICH/1940/00
MHLW: Adopted 25 December 2002, Notification ELD N°
1225006
FDA: The revised PDE is reflected in the Q3C Tables
and List [Word]
or [PDF]
(Posted 11/12/2003); published in FR, Vol.68, No. 219, Thursday,
November 13, 2003; pages 64352-64353 |
Status :
Step 5
September 2002 |
PDE for
N-Methylpyrrolidone
(NMP)
Correction
(Incorporated into the core guideline)
|
Implementation for NMP (Step 5) :
EU: Adopted by CPMP,
September 2002, issued as CPMP/ICH/1940/00
MHLW: Adopted 25 December 2002, Notification ELD N°
1225006
FDA: The revised PDE is reflected in the Q3C Tables
and List [Word]
or [PDF]
(Posted 11/12/2003); published in FR, Vol.68, No. 219, Thursday,
November 13, 2003; pages 64352-64353 |
Status :
Step 5
September 2002 |
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Q4: Pharmacopoeias
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 about 10 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). |
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Q4A: Pharmacopoeial Harmonisation
The
Pharmacopoeial authorities, working together through the
Pharmacopoeial Discussion Group (PDG), have been closely
involved with the work of ICH since the outset and 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. |
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Q4B: Regulatory Acceptance of Analytical
Procedures and/or Acceptance Criteria
(RAAPAC)
At the request
of the ICH Steering Committee, an Expert
Working Group was formalised in November
2003 to address the "Regulatory Acceptance
of Pharmacopoeial Interchangeability". The
EWG has prepared a Work Plan (endorsed by
the Steering Committee) as a foundation for
its activities. It is anticipated that full
implementation of the Q4B EWG Work Plan will
result in a level of clarity, in one place,
to:
-
Facilitate the
regulatory acceptance of PDG-harmonised
text.
-
Clearly
indicate (electronically) the regulatory
interchangeability status of harmonised
text for each of the regulatory regions,
as well as to indicate the effective
date to begin use on applicable
regulatory documents.
-
Ensure that
from a regulatory perspective that the
interchangeability is based on sound
science.
-
Facilitate
regulatory and industry access to the
"benchmarked" harmonised text, ensuring
that all are aware of exactly what text
has been reviewed and given a status for
interchangeability. This is deemed as
essential for the regulatory acceptance
of interchangeability.
-
Working with
the Pharmacopoeial Discussion Group,
expedite the implementation for the
interchangeability.
This Guideline addresses RAAPAC for the
three ICH regions, especially for APAC
provided by PDG. It also provides
flexibility so that the Q4B EWG can
evaluate, and regulatory authorities can
choose to accept, non-PDG text.
Given the nature of this topic, no
Concept Paper was developed for Q4B.
|
Q4B |
Consultation (Step
3) :
EU:
Transmitted to CHMP, June 2006, issued as
EMEA/CHMP/ICH/222007/2006, deadline for
comments by September 2006
MHLW: Released for consultation 31st
July 2006, PFSB/ELD, deadline for comments
29th September 2006.
FDA: Published in the Federal
Register on August 8, 2006, Vol. 71 Nr. 152,
pages 45059-45060. Deadline for comments by
October 10, 2006. |
Status : Step 3
June 2006 |
|
Q4B Annex I:
Residue on Ignition/Sulphated Ash General
Chapter
Analytical Procedures and/or Acceptance
Criteria
(APAC)
The ICH Q4B Guideline describes a process to
facilitate the three ICH-region Regulatory
Acceptance of Analytical Procedures and/or
Acceptance Criteria (RAAPAC).
This topic-specific annexe is the output of
the Q4B Step 2 process for residue on
ignition/sulphated ash and will be added to
the guideline after Step 4. The APAC
was submitted by PDG. |
Q4B-Annex I |
Consultation (Step
3) :
EU:
Transmitted to CHMP, June 2006, issued as
EMEA/CHMP/ICH/222063/2006, deadline for
comments by September 2006
MHLW: Released for consultation 31st
July 2006, PFSB/ELD, deadline for comments
29th September 2006.
FDA: Published in the Federal
Register on August 8, 2006, Vol. 71, Nr.
152, pages 45058-45059. Deadline for
comments by October 10, 2006. |
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Q6 : Specifications for New Drug Substances and
Products
Bulk drug substance and final product
specifications are key parts of the core documentation for
world-wide product license applications. However, there is
little international guidance on how to set such specifications
with a result that regulators and manufacturers often find
themselves setting or agreeing to conflicting standards for the
same product, as part of the registration in different regions.
This leads to increased expenses and opportunities for error as
well as a potential cause for interruption of product supply.
Work is therefore underway to provide
harmonised guidance in this area. The Topic is divided into two
parts: Chemical Substances (Q6A) and Biotechnological/Biological
Substances (Q6B).
The harmonisation of about 10
compendial test chapters have been considered as critical by the
ICH Steering Committee to attaining full utility of the ICH Q6A
guideline. 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 representatives of
the PDG were participants in the ICH Q6A EWG and continue to
collaborate with the Q6A EWG on completion of the harmonisation
for the test chapters.
The members of the PDG are also
proposing to the ICH Steering Committee mechanisms for the
continued participation in the ICH process for compendial
harmonisation topics. |
|
Q6A: Specifications : Test Procedures and
Acceptance Criteria for New Drug Substances and New Drug
Products : Chemical Substances
The
tripartite harmonised ICH guideline was finalised (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. |
Q6A
Decision Trees |
Implementation (Step 5) :
EU: Adopted by CPMP,
November 1999, issued as CPMP/ICH/367/96
MHLW: Adopted May 1, 2001, PMSB/ELD, Notification No. 568
FDA: Published in the Federal Register, December 29,
2000, Volume 65, Number 251, Notices, Page 83041-83063 |
Status :
Step 5
October 1999 |
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Q6B: Specifications : Test Procedures and
Acceptance Criteria for Biotechnological/Biological Products
The
tripartite harmonised ICH guideline was finalised (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. |
Q6B |
Implementation (Step 5) :
EU: Adopted by CPMP, March
99, issued as CPMP/ICH/365/96
MHLW: Adopted May 1, 2001, PMSB/ELD, Notification No. 571
FDA: Published in the Federal Register, August 18, 1999:
64FR Page 44928 |
Status :
Step 5
March 1999 |
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Q7 : Good Manufacturing Practices for
Pharmaceutical Ingredients
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 |
|
Q7:
Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients
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. |
Q7 |
Implementation (Step 5) :
EU: Adopted by CPMP,
November 2000, issued as CPMP/ICH/1935/00
MHLW: Adopted November 2, 2001, PMSB Notification No.
1200
FDA: Published in the Federal Register, Vol. 66, No 186,
September 25, 2001, Pages 49028 to 49029 |
Status :
Step 5
November 2000 |
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Q8: Pharmaceutical Development
The
tripartite harmonised ICH guideline was finalised (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. |
Q8 |
Implementation (Step 5) :
EU: Transmission to CHMP and to Interested Parties in
December 2004. Issued as EMEA/CHMP/167068/2004-ICH. Deadline for
comments : June 2005. Final approval by CHMP: November 2005.
Date for coming into operation: May 2006.
MHLW: To be notified.
FDA: To be notified. |
Status :
Step 5
November 2005 |
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Q9: Quality Risk Management
The
tripartite harmonised ICH guideline was finalised (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. |
Q9 |
Implementation (Step 5) :
EU: To be notified.
MHLW: To be notified.
FDA: To be notified. |
Status :
Step 5
November 2005 |
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