The document provides information on the International Conference on Harmonization (ICH), including: - ICH aims to harmonize technical requirements for pharmaceutical registration across regions to ensure safety and efficacy. - It involves regulators and industry from the EU, Japan, and USA. - The goals are to establish common guidelines and make information available globally. - ICH guidelines cover quality, safety, efficacy, and multidisciplinary topics for drug development and review. - The document then focuses on specific ICH guidelines related to quality, including stability testing, analytical method validation, and impurities.

1. BASHANT KUMAR SAH
Mpharm 1st pharmaceutics
Nargund college of pharmacy

2. What does ICH stands for?
 The complete name of ICH is the "International Conference on
Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use".
 ICH is a joint initiative involving both regulators and research-based
industry representatives of the European Union, Japan and the USA in
scientific and technical discussions of the testing procedures required to
assess and ensure the safety, quality and efficacy of medicines.

3. What is the goal of ICH?
o The goal of ICH is to promote international harmonization by bringing
together representatives from the three ICH regions (EU, Japan and
USA) to discuss and establish common guidelines.
o Another goal of ICH is to make information available on ICH, ICH
activities and ICH guidelines to any country or company that requests
the information, and to promote a mutual understanding of regional
initiatives in order to facilitate harmonization processes related to ICH
guidelines regionally and globally, and to strengthen the capacity of
drug regulatory authorities and industry to utilize them.
o The ICH Global Cooperation Group (GCG) was formed in 1999 and is
charged with this task.

4. ICH Guidelines
Q (QUALITY) (Q1-Q11) S (SAFETY) (S1-S10,M3) E (EFFICACY) (E1-E16,
Except E13)
M (Multidisciplinary)
(M1-M8)
i.e., those relating
to chemical and
pharmaceutical
Quality
Assurance
(Stability Testing,
Impurity Testing,
etc.)
i.e., those relating
to in vitro and in
vivo pre-clinical
studies
(Carcinogenicity
Testing,
Genotoxicity
Testing, etc.)
i.e., those relating
to clinical studies
in human subject
(Dose Response
Studies, Good
Clinical Practices,
etc.)
, i.e., crosscutting
Topics
which do not fit
uniquely into one
of the above
categories
(MedDRA,
ESTRI, M3, CTD,
M5)

5. Quality
 Q1-Stability
 Q2-Analytical Validation
 Q3-Impurities
 Q4-Pharmacopoeias
 Q5-Quality of Biotechnological Products
 Q6-Specifications
 Q7-Good Manufacturing Practice
 Q8-Pharmaceutical Development
 Q9-Quality Risk Management
 Q10-Pharmaceutical Quality System

6. Q1(STABILITY)
 Q1A-STABILITY TESTING OF NEW DRUG SUBSTANCES AND
PRODUCTS, The purpose of stability testing is to provide evidence on
how the quality of a drug substance or drug product varies with time
under the influence of a variety of environmental factors such as
temperature, humidity, and light, and to establish a re-test period for
the drug substance or a shelf life for the drug product and
recommended storage conditions. GENERAL CASE

8. Q1B--PHOTOSTABILITY TESTING OF NEW DRUG
SUBSTANCES AND PRODUCTS
 A systematic approach to photostability testing is recommended
covering, as appropriate, studies such as:
 i) Tests on the drug substance;
 ii) Tests on the exposed drug product outside of the immediate pack
 iii) Tests on the drug product in the immediate pack and if necessary
 iv) Tests on the drug product in the marketing pack

9. procedure
samples should be exposed to light
providing an overall illumination
of not less than 1.2 million lux
hours and an integrated near
ultraviolet energy of not less than
200 watt hours/square meter to
allow direct comparisons to be
made between the drug substance
and drug product
 And after exposure to light the
absorbance of sample is taken in
UV visible spectrophotometry
to know the actual content of
drug after degradation by light
and after that decision is made,
either the product is
photosensitive or not.

10. Q1C- Stability Testing for New Drugs and Products
NEW DOSAGE FORMS
o A new dosage form is defined as a drug product which is a different pharmaceutical product
type, but contains the same active substance as included in the existing drug product approved
by the pertinent regulatory authority.
 Such pharmaceutical product types include products of different administration route (e.g., oral
to parenteral), new specific functionality/delivery systems (e.g., immediate release tablet to
modified release tablet) and different dosage forms of the same administration route (e.g.,
capsule to tablet, solution to suspension).
 Stability protocols for new dosage forms should follow the guidance in the parent stability
guideline in principle. However, a reduced stability database at submission time (e.g., 6 months
accelerated and 6 months long term data from ongoing studies) may be acceptable in certain
justified cases.

11.  Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products
 Q1E: Evaluation of Stability Data This guideline addresses the evaluation of
stability data that should be submitted in registration
applications for new molecular entities and associated drug products. The
guideline provides recommendations on establishing shelf lives for drug
substances and drug products intended for storage at or below “room
temperature”
 Q1F: Stability Data Package for Registration Applications in Climatic Zones III
and IV Describes harmonized global stability testing requirements in order to
facilitate access to medicines by reducing the number of different storage
conditions. WHO conducted a survey amongst their member states to find
consensus on 30°C/65% RH as the long term storage conditions for hot-dry and
hot-humid regions.17

12. Q2(R1): VALIDATION OF ANALYTICAL PROCEDURES;
TEXT AND METHODOLOGY
Types of Analytical Procedures to be Validated
 - Identification tests
 - Quantitative tests for impurities' content
 - Limit tests for the control of impurities
 - Quantitative tests of the active moiety in samples of drug substance or drug product or other
selected component(s) in the drug product.
Typical validation characteristics are;
o Accuracy
o Precision
o Repeatability
o Intermediate Precision
o Specificity Detection Limit
o Quantitation Limit
o Linearity
o Range
Furthermore revalidation may be necessary
in the following circumstances: -
-changes in the synthesis of the drug
substance
- changes in the composition of the
finished product
- changes in the analytical procedure.
The degree of revalidation required
depends on the nature of the changes.
Certain other changes may require
validation as well.

13. Q3A-IMPURITIES IN NEW DRUG SUBSTANCES
 This document is intended to provide guidance for registration applications
on the content and qualification of impurities in new drug substances
produced by chemical synthesis and not previously registered in a region or
member state.
 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.
Impurities can be classified into the following categories:
 Organic impurities (process- and drug-related)
 Inorganic impurities
 Residual solvents

14. Q3B-IMPURITIES IN NEW DRUG PRODUCTS
 This document provides guidance for registration applications on the
content and qualification of impurities in new drug products produced
from chemically synthesised new drug substances not previously
registered in a region or member state.
 This guideline addresses only those impurities in new drug products
classified as degradation products of the drug substance or reaction
products of the drug substance with an excipient and/or immediate
container closure system

15. Maximum Daily Dose1 Threshold2,3
 1 g 0.1%
> 1 g 0.05%
Maximum Daily Dose1 Threshold2, 3
< 1 mg 1.0% or 5 µg TDI, whichever is lower
1 mg - 10 mg 0.5% or 20 µg TDI, whichever is lower
>10 mg - 2 g 0.2% or 2 mg TDI, whichever is lower
> 2 g 0.10%
Maximum Daily Dose1 Threshold2,3
< 10 mg 1.0% or 50 µg TDI, whichever is lower
10 mg - 100 mg 0.5% or 200 µg TDI, whichever is lower
>100 mg - 2 g 0.2% or 3 mg TDI, whichever is lower
> 2 g 0.15%
Notes on Attachment 1
1 The amount of drug
substance administered per
day
2 Thresholds for degradation
products are expressed either
as a percentage of the drug
substance or as total daily
intake (TDI) of the degradation
product. Lower thresholds can
be appropriate if the
degradation product is
unusually toxic.
3 Higher thresholds should
be scientifically justified.
Attachment 1: Thresholds for Degradation Products in New
Drug Products
Reporting Thresholds
Identification Thresholds
Qualification Thresholds

16. 0.00
0.20
0.40
0.60
0.80
1.00
0 500 1000 1500 2000 2500
PercentageofDrugSubstance
Maximum Daily Dose Expressed in mg of Drug Substance
Reporting
Identification
Qualification
0.00
0.20
0.40
0.60
0.80
1.00
0 5 10 15 20
PercentageofDrugSubstance
Maximum Daily Dose Expressed in mg of Drug Substance
Expanded Scale:
Reporting
Identification
Qualification
Illustration of Thresholds for Reporting,
Identification, and Qualification of
Degradation Products in New Drug Products
as a Function of
Maximum Daily Dose1
1 Note : Actual threshold values should be taken from the preceding
table in this attachment.

17. 'Raw' Result
(%)
Reported Result
(%)
(Reporting Threshold =
0.1%)
Total Daily Intake (TDI)
of the Degradation
Product
(rounded result in μg)
Action
Identification Threshold
0.2%
exceeded?
Qualification Threshold
200 μg TDI
exceeded?
0.04 Not reported 20 None None
0.2143 0.2 100 None None
0.349 0.31 150 Yes None1
0.550 0.61 300 Yes Yes1
Example 1: 50 mg Maximum Daily Dose
Reporting threshold: 0.1%
Identification threshold: 0.2%
Qualification threshold: 200 μg

18. Q3C-IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS
 The objective of this guideline is to recommend acceptable amounts for residual solvents in
pharmaceuticals for the safety of the patient.
 The guideline recommends use of less toxic solvents and describes levels considered to be
toxicologically acceptable for some residual solvents.
Classification of Residual Solvents by Risk Assessment
 Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspected human carcinogens, and
environmental hazards.for ex.
 Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible causative agents of other irreversible
toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant
but reversible toxicities.
 Class 3 solvents: Solvents with low toxic potential
Solvents with low toxic potential to man; no health-based exposure limit is needed.
Class 3 solvents have PDEs of 50 mg or more per day.

19. Solvent Concentration
limit (ppm)
Concern
Benzene 2 Carcinogen
Carbon
tetrachloride
4 Toxic and
environmental hazard
1,2-
Dichloroethane
5 Toxic
1,1-
Dichloroethene
8 Toxic
1,1,1-
Trichloroethane
1500 Environmental hazard
TABLE 1. Class 1 solvents in pharmaceutical products (solvents that
should be avoided).

20. Solvent PDE (mg/day) Concentration limit (ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cumene 0.7 70
Cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
Dichloromethane 6.0 600
1,2-Dimethoxyethane 1.0 100
N,N-Dimethylacetamide 10.9 1090
N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380
2-Ethoxyethanol 1.6 160
Ethyleneglycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3000
2-Methoxyethanol 0.5 50
Methylbutyl ketone 0.5 50
Methylcyclohexane 11.8 1180
N-Methylpyrrolidone 5.3 530
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
TABLE 2. Class 2 solvents in pharmaceutical products.
PDE-permitted daily exposure
PPM-parts per million (1mg/litre)

21. TABLE 3. Class 3 solvents which should be limited by GMP or other quality-
based requirements.
Acetic acid Heptane
Acetone Isobutyl acetate
Anisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl acetate Methylethyl ketone
tert-Butylmethyl ether Methylisobutyl ketone
Dimethyl sulfoxide 2-Methyl-1-propanol
Ethanol Pentane
Ethyl acetate 1-Pentanol
Ethyl ether 1-Propanol
Ethyl formate 2-Propanol
Formic acid Propyl acetate

22. Q3D-GUIDELINE FOR ELEMENTAL IMPURITIES
 Elemental impurities in drug products may arise from several sources; they
may be residual catalysts that were added intentionally in synthesis or may be
present as impurities (e.g., through interactions with processing equipment or
container/closure systems or by being present in components of the drug
product).
 Because elemental impurities do not provide any therapeutic benefit to the
patient, their levels in the drug product should be controlled within acceptable
limits
There are three parts of this guideline:
 The evaluation of the toxicity data for potential elemental impurities;
 The establishment of a Permitted Daily Exposure (PDE) for each element of
toxicological concern
 Application of a risk-based approach to control elemental impurities in drug
products
for ex. Cd,Pb,As,Hg,V,Pd,etc
)/(
)/(
)/(
daygproductdrugofamountdaily
daygPDE
ggionConcentrat

 

23. Q4B-EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS
ON
RESIDUE ON IGNITION/SULPHATED ASH GENERAL CHAPTER
It is further divided into following 14 annex
 • Q4B Annex 1: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Residue on
Ignition/Sulphated Ash
 • Annex 2:Test for Extractable Volume of Parenteral Preparations
 • Annex 3: Test for Particulate Contamination: Sub-Visible Particles
 • Annex 4A: Microbiological Examination of Non-Sterile Products: Microbial
 Enumeration Tests
 • Annex 4B: Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-organisms
 • Annex 4C: Microbiological Examination of Non-Sterile Products: Acceptance Criteria for Pharmaceutical Preparations and
Substances for Pharmaceutical Use
 • Annex 5:Disintegration Test
 • Annex 6: Uniformity of Dosage Units
 • Annex 7: Dissolution Test
 • Annex 8: Sterility Test
 • Annex 9: Tablet Friability
 • Annex 10: Polyacrylamide Gel Electrophoresis
 • Annex 11: Capillary Electrophoresis
 • Annex 12: Analytical Sieving
 • Annex 13: Bulk Density and Tapped Density of Powders
 • Annex14 :Bacterial Endotoxins Test

24. Q5A-Q5E---Quality of biotechnological products:
Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell
Lines of Human or Animal Origin
 This document is concerned with testing and evaluation of the viral safety of biotechnology
products derived from cell lines of human or animal origin (i.e. mammalian, avian, insect)
 The objective 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.
 Three principal, complementary approaches have evolved to control the potential viral
contamination of Biotechnology products
a) selecting and testing cell lines and other raw materials, including media components, for the
absence of undesirable viruses which may be infectious and/or pathogenic for humans
b) Testing the capacity of the processes to clear infectious viruses.
c) testing the product at appropriate steps for absence of contminating infectious viruses.

25. 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.
 This leads to conflicting standards for the same product, increased expenses
and opportunities for error as well as a potential cause for interruption of
product supply.
 Q6A: Specifications : Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products : Chemical Substances
The main objective of this guideline is to establish a single set of global
specifications for new drug substances and new drug products.
This guideline addresses specifications, i.e., those tests, procedures, and
acceptance criteria which play a major role in assuring the quality of the new
drug substance and new drug product during shelf life.

26. Q7: Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients
The main objective of this guideline is that to maintain the quality of the
active pharmaceutical ingredients
 Personnel:
 Buildings and Facilities:
 process equipment:
 Documentation and Records

27. Q8(R2): Pharmaceutical Development
 This guideline is intended to provide guidance on the contents of
Pharmaceutical
Development of drug products
 The aim of pharmaceutical development is to design a quality product
and its manufacturing process to consistently deliver the intended
performance of the product.
 The Pharmaceutical Development section also describe the type of
dosage form and the formulation that are suitable for the intended use.
 Q8 gives information about Drug Substance, Excipients, Container
Closure System.

28. Q9: Quality Risk Management
 The purpose of this document is to offer a systematic approach to
quality risk management.
 This guideline provides principles and tools for 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.

29. Q10: Pharmaceutical Quality System
 This document establishes a new ICH tripartite guideline describing a
model for an effective quality management system for the
pharmaceutical industry, referred to as the Pharmaceutical Quality
System.
 comprehensive model for an effective pharmaceutical quality system is
based on International Standards Organization (ISO) quality concepts,
includes applicable Good Manufacturing Practice (GMP) regulations

30. Safety
 S1-Carcinogenicity Studies
 S2-Genotoxicity Studies
 S3-Toxicokinetics and Pharmacokinetics
 S4-Toxicity Testing
 S5-Reproductive Toxicology
 S6-Biotechnological Products
 S7-Pharmacology Studies
 S8-Immunotoxicology Studies
 S9-Nonclinical evaluation for anticancer pharmaceuticals
 S10-Photosafety Evaluation

31. S1-Carcinogenicity Studies
S1A: Guideline on the Need for Carcinogenicity
Studies of Pharmaceuticals
 Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals
 Carcinogenicity studies should be performed for any pharmaceutical
whose expected clinical use is continuous for at least 6 months.
 This document provides a consistent definition of the circumstances
under which it is necessary to undertake carcinogenicity studies on
new drugs. These recommendations take into account the known risk
factors as well as the intended indications and duration of exposure.
 The objectives of carcinogenicity studies are to identify a tumorigenic
potential in animals and to assess the relevant risk in humans.

32. S1B: Testing for Carcinogenicity of Pharmaceuticals
 This document provides guidance on the need to carry out
carcinogenicity studies in both mice and rats, and guidance is also
given on alternative testing procedures which may be applied without
jeopardizing safety.
S1C(R2): Dose Selection for Carcinogenicity Studies of
Pharmaceuticals
This document addresses the criteria for the selection of the high dose to
be used in carcinogenicity studies on new therapeutic agents to
harmonize current practices and improve the design of studies.

33. S2– Genotoxicity
 S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for
Pharmaceuticals Intended for Human Use
This guidance is a combination of ICH S2A and S2B guidelines
S2A: Guidance on Specific Aspects of Regulatory
Genotoxicity Tests for Pharmaceuticals
This document provided specific guidance and recommendations for in vitro
and in vivo tests and on the evaluation of test results. It includes terms related to
genotoxicity tests to improve consistency in applications.

34. S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for
Pharmaceuticals :
o This document addresses two fundamental areas of genotoxicity testing: the
identification of a standard set of assays to be conducted for registration, and
the extent of confirmatory experimentation in any particular
genotoxicity assay in the standard battery
o The purpose of this guideline is to optimize the standard genetic toxicology
battery for prediction of potential human risks, and for interpretation of
results, with the ultimate goal of improving risk characterization for carcinogenic
effects that have their basis in changes in the genetic material.

35. S3A –S3B--- Toxicokinetics and Pharmacokinetics:
S3A: Note for Guidance on Toxicokinetics: The Assessment of Systemic
Exposure in Toxicity Studies
 ICH guidelines do not require toxicokinetic studies to be conducted,
except in pregnant, lactating animals, before initiating reproductive
studies.
 In this context, toxicokinetics is defined as the generation of
pharmacokinetic data, either as an integral component in the conduct of
non-clinical toxicity studies or in specially designed supportive studies, in
order to assess systemic exposure.
 This document gives guidance on developing test strategies in
toxicokinetics and the need to integrate these pharmacokinetics into
toxicity testing, in order to aid in the interpretation of the toxicology
findings and and their relevance to clinical safety issues

36. S3B: Pharmacokinetics: Guidance for Repeated
Dose Tissue Distribution Studies
 Tissue distribution studies are essential in providing information on
distribution and accumulation of the compound and/or metabolites,
especially in relation to potential sites of action; this information may
be useful for designing toxicology and pharmacology studies and for
interpreting the results of these experiments.
 This document gives guidance, when the repeated dose tissue
distribution studies should be considered (i.e., when appropriate data
cannot be derived from other sources). It also gives recommendations
on the conduct of such studies

37. S4: Duration of Chronic Toxicity Testing in Animals (Rodent and Non-
Rodent Toxicity Testing)
 The objective of this guidance is to set out the considerations that apply
to chronic toxicity testing in rodents and non rodents as part of the
safety evaluation of a medicinal product
 Rodents(a study of 6 months duration)
 Non-rodents(a study of nine months duration).

38. S5: Detection of Toxicity to Reproduction for Medicinal Products &
Toxicity to Male Fertility
 This document provides guidance on tests for reproductive toxicity.
 It defines the periods of treatment to be used in animals to better
reflect human exposure to medical products and allow more specific
identification of stages at risk.
 It should encourage the full assessment on the safety of chemicals on
the development of the offspring.

39. S6: Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals
This document covers the pre-clinical safety testing requirements for
biotechnological products. It addresses the use of animal models of
disease, determination of when genotoxicity assays and carcinogenicity
studies should be performed, and the impact of antibody formation on
duration of toxicology studies.
The primary goals of preclinical safety evaluation are:
1) to identify an initial safe dose and subsequent dose in humans;
2) to identify potential target organs for toxicity and for the study of
whether such toxicity is reversible;
3) to identify safety parameters for clinical monitoring

40. S7A: Safety Pharmacology Studies for Human
Pharmaceuticals
 This guideline was developed to protect clinical trial participants and
patients receiving marketed products from potential adverse effects of
pharmaceuticals
 This document addresses the definition, objectives and scope of safety
pharmacology studies.
 It also addresses which studies are needed before initiation of Phase 1
clinical studies as well as information needed for marketing.

41. S7B : The Nonclinical Evaluation of the Potential for Delayed
Ventricular Repolarization (QT Interval Prolongation) By Human
Pharmaceuticals
 This guideline describes a non-clinical testing strategy for assessing the
potential of a test substance to delay ventricular repolarization.
 This guideline includes information concerning nonclinical assays and
integrated risk assessments.

42. S8 : Immunotoxicity Studies for Human
Pharmaceuticals
 This guideline addresses the recommendations on nonclinical testing
for immunosuppressant.
 The guideline might also apply to drugs in which clinical signs of
immunosuppressant are observed during clinical trials and following
approval to market.
 The term immunotoxicity in this guideline will primarily refer to
immunosuppressant, i.e. a state of increased susceptibility to infections
or the development of tumors.

43. S9: Nonclinical Evaluation for Anticancer
Pharmaceuticals
 This guideline provides information for pharmaceuticals that are only
intended to treat cancer in patients with late stage or advanced
regardless of the route of administration, including both small molecule
and biotechnologyderived pharmaceuticals.
 It describes the type and timing of nonclinical studies in relation to the
development of anticancer pharmaceuticals and references other
guidance as appropriate.
 This guideline aims to facilitate and accelerate the development of
anticancer pharmaceuticals and to protect patients from unnecessary
adverse effects, while avoiding unnecessary use of animals and other
resources

44. REFERENCES
 ICH guidlines of quality and safety
 http://www.ich.org/products/guidelines/quality/article/quality-
guidelines.html
 http://www.ich.org/products/guidelines/safety/article/safety-
guidelines.html

45. THANK YOU