2. INTRODUCTION
The International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
(ICH) is a unique project that brings together the regulatory
authorities of Europe, Japan and the United States and experts from
the pharmaceutical industry in the three regions to discuss scientific
and technical aspects of product registration.
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3. AIM
The International Conference on Harmonisation of Technical
Requirements for the Registration of Pharmaceuticals for Human
Use (ICH) was established in 1990 as a joint regulatory/industry
project to improve, through harmonisation, the efficiency of the
process for developing and registering new medicinal products in
Europe, Japan and the United States, in order to make these products
available to patients with a minimum of delay.
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4. CONTI……
The six parties to ICH represent the regulatory bodies and research-
based industry in the three regions, Europe, Japan and the USA,
where the vast majority of new medicines are currently developed.
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5. ICH PARTIES
European Commission - European Union (EU).
European Federation of Pharmaceutical Industries and Associations
(EFPIA).
Ministry of Health, Labour and Welfare, Japan (MHLW).
Japan Pharmaceutical Manufacturers Association (JPMA).
US Food and Drug Administration (FDA).
Pharmaceutical Research and Manufacturers of America (PhRMA).
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6. OBECTIVES
More economical use of human, animal, and material resources.
Elimination of unnecessary delay in the global development &
availability of new medicines.
Maintaining safeguards on Quality, safety, efficacy and regulatory
obligations to protect public health.
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7. TOPIC OF ICH
Four Broad Categories - QSEM
Quality (Q): those relating to chemical and pharmaceutical Quality
Assurance (Stability Testing, Impurity Testing, etc.)
Safety (S): those relating to in vitro and in vivo pre-clinical studies
(Carcinogenicity Testing, Genotoxicity Testing, etc.)
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8. CONTI…..
Efficacy (E): those relating to clinical studies in human subject
(Dose Response Studies, Good Clinical Practices, etc.)
Multidisciplinary (M): cross-cutting Topics which do not fit
uniquely into one of the above categories (MedDRA, ESTRI, M3,
CTD, M5)
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10. OVERVIEW OF ICH
Q1A(R2): STABILITY TESTING OF NEW DRUGS AND
PRODUCTS
Q1B: PHOTOSTABILITY TESTING
Q1C : STABILITY TESTING OF NEW DOSAGE FORMS
Q1D: BRACKETING AND MATRIXING DESIGNS FOR
STABILITY TESTING OF DRUG SUBSTANCES AND DRUG
PRODUCTS.
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11. CONTI….
Q1E: EVALUATION OF STABILITY DATA
Q1F: STABILITY DATA PACKAGE FOR REGISTRATION IN
CLIMATIC ZONES III AND IV
Q2A: DEFINTIONS AND TERMINOLOGY: ANALYTICAL
VALIDATION
Q2B: METHODOLOGY
Q3A(R2) : IMPURITIES IN NEW DRUG SUBSTANCES
Q3B(R2) : IMPURITIES IN NEW DRUG PRODUCT
Q3C(R3) : IMPURITIES GUIDELINES FOR RESIDUAL SOLVENTS
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13. CONTI…
Q6A: SPECIFICATIONS, TEST PROCEDURES AND ACCEPTANCE
CRITERIA FOR NEW DRUG SUBSTANCES AND PRODUCTS
Q6B : SPECIFICATION TEST PROCEDURE AND ACCEPTANCE
CRITRIA FOR BIOTECHNOLOGICAL/ BIOLOGICAL PRODUCTS
Q7A: GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTS
Q8: PHARMACEUTICAL DEVELOPMENT
Q9: QUALITY RISK MANAGEMENT
Q10: PHARMACEUTICAL QUALITY SYSTEM
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14. 2. SAFETY
S1A: GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES OF
PHARMACEUTICALS
S1B: TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS
S1C(R2): DOSE SELECTION FOR CARCINOGENICITY STUDIES OF
PHARMACEUTICALS
S2(R1): GUIDANCE ON GENOTOXICITY TESTING AND DATA
INTERPRETATION FOR PHARMACEUTICALS INTENDED FOR HUMAN
USE
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15. CONTI…
S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT
OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES
S3B: PHARMACOKINETICS:GUIDANCE FOR REPEATED DOSE TISSUE
DISTRIBUTION STUDIES
S4: DURATION OF CHRONIC TOXICITY TESTING IN ANIMALS
(RODENT AND NON RODENT TOXICITY TESTING)
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16. S5(R2): DETECTION OF TOXICITY TO REPRODUCTION FOR MEDICINAL
PRODUCTS & TOXICITY TO MALE FERTILITY
S6(R1): ADDENDUM TO ICH S6: PRECLINICAL SAFETY EVALUATION
OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS
S6: PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY-
DERIVED PHARMACEUTICALS
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17. S7A: SAFETY PHARMACOLOGY STUDIES FOR HUMAN
PHARMACEUTICALS
S7B: THE NON-CLINICAL EVALUATION OF THE POTENTIAL FOR
DELAYED VENTRICULAR REPOLARIZATION (QT INTERVAL
PROLONGATION) BY HUMAN PHARMACEUTICALS
S8: IMMUNOTOXICITY STUDIES FOR HUMAN PHARMACEUTICALS
S9: NONCLINICAL EVALUATION FOR ANTICANCER
PHARMACEUTICALS
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18. 3) EFFICACY:
E1: THE EXTENT OF POPULATION EXPOSURE TO ASSESS CLINICAL SAFETY
E2A: CLINICAL SAFETY DATA MANAGEMENT
E2B(R2): MAINTENANCE OF THE ICH GUIDELINE ON CLINICAL SAFETY
DATA MANAGEMENT
E2B(R3): REVISION OF THE ICH GUIDELINE ON CLINICAL SAFETY DATA
MANAGEMENT
DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY
REPORTS
E2C(R1): CLINICAL SAFETY DATA MANAGEMENT: PERIODIC SAFETY
UPDATE REPORTS FOR MARKETED DRUGS
E2D: POST-APPROVAL SAFETY DATA MANAGEMENT: DEFINITIONS AND
STANDARDS FOR EXPEDITED REPORTING
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19. E2E: PHARMACOVIGILANCE PLANNING
E2F: DEVELOPMENT SAFETY UPDATE REPORT
E3: STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS
E4: DOSE-RESPONSE INFORMATION TO SUPPORT DRUG
REGISTRATION
E5(R1): ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN
CLINICAL DATA
E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE
E7: STUDIES IN SUPPORT OF SPECIAL POPULATIONS:GERIATRICS
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20. E8: GENERAL CONSIDERATIONS FOR CLINICAL TRIALS
E9: STATISTICAL PRINCIPLES FOR CLINICAL TRIALS
E10: CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL
TRIALS
E11: CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE
PEDIATRIC POPULATION
E12: PRINCIPLES FOR CLINICAL EVALUATION OF NEW
ANTIHYPERTENSIVE DRUGS
E14: THE CLINICAL EVALUATION OF QT/QTC INTERVAL PROLONGATION
AND PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC
DRUGS
E15: DEFINITIONS FOR GENOMIC BIOMARKERS, PHARMACOGENOMICS,
PHARMACOGENETICS, GENOMIC DATA AND SAMPLE CODING
CATEGORIES
E16: GENOMIC BIOMARKERS RELATED TO DRUG RESPONSE:
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21. MULTIDISCIPLINARY GUIDELINES
M1- MedDRA : Medical Terminology
M2- ESTRI: Electronic Standards for the Transfer of Regulatory
Information
M3- (R2): Nonclinical Safety Studies for the Conduct of Human
Clinical Trials and Marketing Authorization for Pharmaceuticals
M4- CTD: The Common Technical Document
M5 : Data Elements and Standards for Drug Dictionaries
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23. IMPURITIES IN NEW DRUG
SUBSTANCES Q3A(R2)
1. PREAMBLE: This document is intended to provide guidance for
registration applications on the content and qualification of
impurities in new drug substances produced by chemical syntheses
and not previously registered in a region or member state.
It is not intended to apply to new drug substances used during the
clinical research stage of development.
The following types of drug substances are not covered in this
guideline: biological/biotechnological, peptide, oligonucleotide,
radiopharmaceutical, fermentation product and semi-synthetic
products derived therefrom, herbal products, and crude products of
animal or plant origin.
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24. . Impurities in new drug substances are addressed from two
perspectives: Chemistry Aspects include classification and
identification of impurities, report generation, listing of impurities in
specifications, and a brief discussion of analytical procedures; and
Safety Aspects include specific guidance for qualifying those
impurities that were not present, or were present at substantially lower
levels, in batches of a new drug substance used in safety and clinical
studies.
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25. 2. CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:
Organic impurities (process- and drug-related)
Inorganic impurities
Residual solvents
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26. Organic impurities can arise during the manufacturing process
and/or storage of the new drug substance. They can be identified or
unidentified, volatile or non-volatile, and include:
Starting materials
By-products
Intermediates
Degradation products
Reagents, ligands and catalysts
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27. Inorganic impurities can result from the manufacturing process.
They are normally known and identified and include:
• Reagents, ligands and catalysts
Heavy metals or other residual metals
Inorganic salts
Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles for the
preparation of solutions or suspensions in the synthesis of a new
drug substance.
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28. Since these are generally of known toxicity, the selection of
appropriate controls is easily accomplished (see ICH Guideline
Q3C on Residual Solvents). Excluded from this document are:
(1) extraneous contaminants that should not occur in new drug
substances and are more appropriately addressed as Good
Manufacturing Practice (GMP) issues,
(2) polymorphic forms, and
(3) enantiomeric impurities
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29. RATIONALE FOR THE REPORTING
AND CONTROL OF IMPURITIES
Organic Impurities : the actual and potential impurities most likely to arise
during the synthesis, purification, and storage of the new drug substance.
the chemical reactions involved in the synthesis, impurities associated with raw
materials that could contribute to the impurity profile of the new drug substance,
and possible degradation products.
This discussion can be limited to those impurities that might reasonably be
expected based on knowledge of the chemical reactions and conditions involved.
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30. the structure of actual impurities present in the new drug substance
at a level greater than (>) the identification threshold given in
Attachment 1 (e.g., calculated using the response factor of the drug
substance) should be described.
Note that any impurity at a level greater than (>) the identification
threshold in any batch manufactured by the proposed commercial
process should be identified. In addition, any degradation product
observed in stability studies at recommended storage conditions at
a level greater than (>) the identification threshold should be
identified.
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31. When identification of an impurity is not feasible, a summary of
the laboratory studies demonstrating the unsuccessful effort should
be included in the application. Where attempts have been made to
identify impurities present at levels of not more than (≤) the
identification thresholds, it is useful also to report the results of
these studies.
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32. INORGANIC IMPURITIES
Inorganic impurities are normally detected and quantified using
Pharmacopoeial or other appropriate procedures. Carry-over of
catalysts to the new drug substance should be evaluated during
development. The need for inclusion or exclusion of inorganic
impurities in the new drug substance specification should be
discussed.
Acceptance criteria should be based on pharmacopoeial standards or
known safety data 32
33. SOLVENTS
The control of residues of the solvents used in the manufacturing
process for the new drug substance should be discussed and
presented according to the ICH Q3C Guideline for Residual
Solvents.
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34. Chemical Development Studies: Studies conducted to scale-up, optimise,
and validate the manufacturing process for a new drug substance.
Enantiomeric Impurity: A compound with the same molecular formula
as the drug substance that differs in the spatial arrangement of atoms within
the molecule and is a non-superimposable mirror image.
Extraneous Contaminant: An impurity arising from any source
extraneous to the manufacturing process.
Herbal Products: Medicinal products containing, exclusively, plant
material and/or vegetable drug preparations as active ingredients. In some
traditions, materials of inorganic or animal origin can also be present.
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35. Identified Impurity: An impurity for which a structural
characterisation has been achieved.
Identification Threshold: A limit above (>) which an impurity
should be identified.
Impurity: Any component of the new drug substance that is not the
chemical entity defined as the new drug substance.
Impurity Profile: A description of the identified and unidentified
impurities present in a new drug substance. 35
37. ATTACHMENT 2 Illustration of Reporting Impurity Results
for Identification and Qualification in an Application
The attachment is only illustrative and is not intended to serve as
template how results on impurities should be presented in an
application file.
Normally raw data are not presented.
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38. 38
Example 1: 0.5 g Maximum Daily Dose
Reporting threshold = 0.05%
Identification threshold = 0.10%
Qualification threshold = 0.15%
39. NOTES
1) After identification, if the response factor is determined to differ
significantly from the original assumptions, it may be appropriate
to re-measure the actual amount of the impurity present and re-
evaluate against the qualification threshold (see Attachment 1).
2) To verify if a threshold is exceeded, a reported result has to be
evaluated against the thresholds as follows: when the threshold is
described in %, the reported result rounded to the same decimal
place as the threshold should be compared directly to the
threshold. When the threshold is described in TDI, the reported
result should be converted to TDI, rounded to the same decimal
place as the threshold and compared to the threshold. For example
the amount of impurity at 0.12% level corresponds to a TDI of
0.96 mg (absolute amount) which is then rounded up to 1.0 mg; so
the qualification threshold expressed in TDI (1.0 mg) is not
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40. Notes on Attachment 3
a) If considered desirable, a minimum screen (e.g., genotoxic
potential), should be conducted. A study to detect point mutations
and one to detect chromosomal aberrations, both in vitro, are
considered an appropriate minimum screen.
b) If general toxicity studies are desirable, one or more studies
should be designed to allow comparison of unqualified to qualified
material. The study duration should be based on available relevant
information and performed in the species most likely to maximise
the potential to detect the toxicity of an impurity. On a case-by-case
basis, single-dose studies can be appropriate, especially for
singledose drugs. In general, a minimum duration of 14 days and a
maximum duration of 90 days would be considered appropriate.
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41. c) Lower thresholds can be appropriate if the impurity is
unusually toxic.
d) For example, do known safety data for this impurity or its
structural class preclude human exposure at the
concentration present?
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