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ICH GUIDELINES

PRSENTED BY: ANSHUL SHARMAM.PHARM (ANALYSIS)

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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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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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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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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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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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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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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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ICH

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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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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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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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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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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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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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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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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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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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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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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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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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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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. 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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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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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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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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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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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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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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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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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

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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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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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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.

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ATTACHMENT 1 Thresholds

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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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Example 1: 0.5 g Maximum Daily Dose

Reporting threshold = 0.05%

Identification threshold = 0.10%

Qualification threshold = 0.15%

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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 exceeded.

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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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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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