ICH- Q3 Impurity

a brief description of ich guidline Q3. Impurity

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.

7. 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.

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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. Elemental impurities NO Therapeutic benefit Controlled

14. The guideline divided into following three parts: The evaluation of the toxicity data for potential elemental impurities: Safety Assessment The establishment of PDEs for each element of toxicological concern 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,

15. Different classes based on their toxicity (PDE ) Class 3 Class 2 Class 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 

16. 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.” 

17. Thank You