This document discusses ICH guidelines related to impurities in new drug substances and products. It defines key terms like impurity, identified impurity, and potential impurity. It categorizes impurities as organic, inorganic, or residual solvents. The guidelines provide thresholds for identification, qualification, and reporting of impurities. They also classify residual solvents and elemental impurities based on their toxicity, providing permissible daily exposure limits. The guidelines aim to establish qualification of impurities at levels present in early clinical trials and provide a risk-based approach to control impurities.

1. Niha Sultana
Drug Regulatory Affairs
Evolet Healthcare
IMPURITIES Q3A-Q3D

2. • Impurity: Any component of the new drug substance that is not the chemical entity defined as the
impurity.
• Identified Impurity: An impurity for which a structural characterization has been achieved.
• Identification Threshold: A limit above (>) which an impurity should be identified.
• Impurity Profile: A description of the identified and unidentified impurities present in a new drug
substance.
• Potential Impurity: An impurity that theoretically can arise during manufacture or storage. It may or
may not actually appear in the new drug substance.
• Qualification: The process of acquiring and evaluating data that establishes the biological safety of
an individual impurity or a given impurity profile at the level(s) specified.
TERMINOLOGIES

3. • Qualification Threshold: A limit above (>) which an impurity should be qualified.
• Reporting Threshold: A limit above (>) which an impurity should be reported.
• Specified Impurity: An impurity that is individually listed and limited with a specific acceptance
criterion in the new drug substance specification. A specified impurity can be either identified or
unidentified.
• Unidentified Impurity: An impurity for which a structural characterisation has not been achieved
and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).
• Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not
individually listed with its own specific acceptance criterion, in the new drug substance
specification.
• Degradation Product: An impurity resulting from a chemical change in the drug substance
brought about during manufacture and/or storage of the new drug product by the effect of, for
example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate
container closure system.

4. CLASSIFICATION OF IMPURITIES
Organic
impurities
Inorganic
impurities
Residual
solvents
• Starting materials
• By-products
• Intermediates
• Degradation products
• Reagents, ligands and catalysts
Solvents are inorganic or
organic liquids used as
vehicles for the
preparation of solutions or
suspensions in the synthesis
of a new drug substance.
• Reagents, ligands and
catalysts
• Heavy metals or other
residual metals
• Inorganic salts
• Other materials (e.g.,
filter aids, charcoal)

5. Preamble
• Content and qualification of impurities in new drug substances produced by chemical syntheses.
• Not registered previously.
• Not applicable on new drug substances used during the clinical research stage of development.
• 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.
IMPURITIES IN NEW DRUG SUBSTANCES
Q3A(R2)

6. IMPURITIES IN NEW DRUG PRODUCTS
Q3B(R2)
• content and qualification of impurities in new drug products produced from chemically synthesised
new drug substances.
• Not registered previously.
• This guideline is complementary to the ICH Q3A(R) guideline “Impurities in New Drug
Substances”, which should be consulted for basic principles.
• 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.
• Impurities arising from excipients, leached or extracted from the container are not covered.
• does not apply to new drug products used during the clinical research stages of development.

11. IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS
Q3C(R7)
• The objective of this guideline is to recommend acceptable amounts for residual solvents in
pharmaceuticals for the safety of the patient.
• recommends use of less toxic solvents.
• Residual solvents- organic volatile chemicals that are used or produced in the manufacture of
drug substances or excipients, or in the preparation of drug products.
• does not address solvents deliberately used as excipients nor does it address solvates.

12. Classification of Residual Solvents
CLASS I SOLVENTS:
Solvents to be avoided
• Human carcinogens
CLASS III SOLVENTS:
Solvents with low toxic
potential
• low toxic potential to man
CLASS II SOLVENTS:
Solvents to be limited
• Non-genotoxic animal
carcinogens

13. Class I Solvents: Solvents to be avoided
• should not be employed in the manufacture of drug substances, excipients, and drug product.
• If unavoidable then limited should be restricted as shown
solvent Concentration limit (ppm) Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic an env. Hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Env. hazard

14. Class II: Solvents to Be Limited
• Limited because of inherent toxicity
• PDEs are given to the nearest 0.1 mg/day, and concentrations are given to the nearest 10 ppm
Solvent PDE (mg/day) Conc. Limit (ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cumene1 0.7 70
cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
Dichloromethane 6.0 600

15. Class III Solvents: solvents with Low Toxic Potential
• regarded as less toxic and of lower risk to human health.
• considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000
ppm or 0.5% under Option 1) would be acceptable without justification.
Acetic acid 2-Butanol
Heptane 3-Methyl-1-butanol
Acetone Butyl acetate
Isobutyl acetate Methylethyl ketone
Anisole tert-Butylmethyl ether
Isopropyl acetate 2-Methyl-1-propanol
1-Butanol 2Dimethyl sulfoxide
Methyl acetate Pentane

16. Solvents for which No Adequate Toxicological Data was Found
• no adequate toxicological data on which to base a PDE was found.
1,1-Diethoxypropane Methylisopropyl ketone
1,1-Dimethoxymethane Methyltetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid

17. GUIDELINE FOR ELEMENTAL IMPURITIES
Q3D(R1)
CH Q3D listed out 24 elements that need to be evaluated by drug product manufacturers, including
mercury, lead, cadmium and arsenic.
Source of elemental impurities could be from:
• residual catalysts added in synthesis
• may be present as impurities
• arising from processing equipment
• leaching from container/closure systems
• present in components of the drug product.

18. The guideline divided into following three parts:
1. The evaluation of the toxicity data for potential elemental impurities: Safety Assessment
2. The establishment of PDEs for each element of toxicological concern
3. Application of a risk-based approach to control elemental impurities in drug products.
This guideline presents a process to assess and control elemental impurities in the drug product
using the principles of risk management as described in ICH Q9.
The guideline applies to
• new finished drug products
• new drug products containing existing drug substances
• The drug products containing purified proteins and polypeptides and their derivatives,

19. Different classes based on their toxicity (PDE)
Class 3Class 2Class 1
• Highly toxic
• Special
consideration
is required
• Eg; As,
Cd,Hg and
Pb
• Relatively low
toxicity by oral
route of
administration
• Eg: Ba, Cr, Cu,
Li, Mo, Sb, and
Sn.
• Toxic to a
greater or
lesser extent
based on route
of
administration
Class 2A elements
have relatively high
probability of
occurrence
Eg: Co, Ni and V
Class 2B elements
have a reduced
probability of
occurrence
Eg: Ag, Au, Ir, Os, Pd,
Pt, Rh, Ru, Se and Tl

20. During the risk assessment, the potential contributions from each of these sources should be considered to
determine the overall contribution of elemental impurities to the drug product.”