The document discusses guidelines from the International Conference on Harmonisation (ICH) regarding impurities in new drug substances. It defines impurities and how they are classified, and provides guidance on identifying, qualifying, and establishing acceptance criteria for impurities. Impurities include organic impurities from the manufacturing process, inorganic impurities, and residual solvents. The guidelines aim to provide a systematic approach to evaluating and controlling impurities to ensure the safety and quality of pharmaceutical products.

1. ICH GUIDELINES
PRSENTED BY: ANSHUL SHARMA
M.PHARM (ANALYSIS)
1

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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9. ICH
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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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12. CONTI….
 Q4: PHARMACOPOEIA
 Q4A: PHARMACOPOEIAL HARMONIZATION
 Q5A: VIRAL SAFETY EVALUATION
 Q5B: GENETIC STABILITY
 Q5C: STABILITY OF BIOTECHNOLOGY PRODUCTS
 Q5D: CELL SUBSTRATES
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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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22. 22

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

36. ATTACHMENT 1
 Thresholds
36

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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42. 42