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Impurities ICH Q3 Guidelines Au Vivek Jain
- 1. As Per PCIRegulations /B. Parm. VI Sem./Pharmaceutical Quality Assurance UNIT-1 ICH Q 3 GUIDELINE • Presented By: VIVEK JAIN • M.Pharm. (Pharmaceutical Analysis) • Associate Professor • ADINA Institute Of Pharmaceutical Sciences, Sagar (M.P.) • EMAIL:[email protected]
- 2. ICH Q 3GUIDELINE IMPURITIES DRUG PRODUCT & DRUG SUBSTANCE
- 3. Objective of theguideline • The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product. The control of impurities is currently a critical issue to the pharmaceutical industry • Objective: To makes recommendation to applicant on reporting, identifying & qualifying information on impurities in new drug substance
- 4. What is Impurity •ICH defines impurities as substances in the API that are not the API itself. • OR Any component of drug substance that is not the chemical entity • Or for drug product that is not the drug substance or an excipient • ICH Status: Q3A- Q3D Impurities • Q3A (R2) Impurities in New Drug Substances • Q3B (R2) – Impurities in New Drug Products • Q3C (R5) – Impurities : Guideline for Residual Solvents • Q3D – Impurities : Guideline for Elemental Impurities
- 5. Definitions • Impurity: Anycomponent of the new drug product that is not the drug substance or an excipient in the drug product. • Impurity Profile: A description of the identified and unidentified impurities present in a drug product. • Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified.
- 6. • 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. • Degradation Profile: A description of the degradation products observed in the drug substance or drug product.
- 7. • Identified DegradationProduct: A degradation product for which a structural characterisation has been achieved. • Unidentified Degradation Product: A degradation product for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).
- 8. • Qualification Threshold:A limit above (>) which a degradation product should be qualified. • Reporting Threshold: A limit above (>) which a degradation product should be reported. • Identification Threshold: A limit above (>) which a degradation product should be identified.
- 9. Types of impurity •Organic • Inorganic • Residual solvents
- 10. Organic • Organic impuritiesmainly arise during the synthesis, purification(manufacturing process )and or storage of the drug substance • Organic imps can be classified like... Starting materials Intermediate Degradation products Reagents, ligand and catalysts
- 11. Inorganic Inorganic impurities derivefrom the manufacturing process and excipients. Generally, excipients contain high levels of heavy metals such as arsenic, bismuth, cadmium, chromium, copper, iron, lead, mercury, nickel and sodium. Sometimes they might present in the product during processing or they leached from packing material Heavy metals Inorganic salts Other materails like filter aids, charcoal
- 12. Residual solvents (ICHQ3 C guideline) • Residual solvents are potentially undesirable substances. They either modify the properties of certain compounds or may be hazardous to human health. The residual solvents also affect physicochemical properties of the bulk drug substances such as crystallinity of bulk drug, which in turn may affect the dissolution properties, odor and color changes in finished products • Residual solvents are those solvents which are used as vehicles for the preparation of solution / suspensions in the synthesis of a new drug substance
- 13. objective of thisguideline • The 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 • Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. • Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data.
- 14. As per theICH guidelines, the solvents used in the manufacturing of drug substances classified in to four types • Class 1 solvents: Solvents to be avoided • Class 2 solvents: Solvents to be limited • Class 3 solvents: Solvents with low toxic potential • Class 4 solvents: Solvents for which No Adequate Toxicological Data was Found
- 15. As per theICH guidelines, the solvents used in the manufacturing of drug substances classified in to four types • a) Class I solvents: Solvents to Be Avoided Solvents in Class 1 should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity or their deleterious environmental effect. However, if their use is unavoidable in order to produce a drug product with a significant therapeutic advance, then their levels should be restricted as shown in Table 1.
- 16. Residual solvent Concentrationlimit (ppm) Benzene 2 ( Carcinogenic) Carbon tetrachloride 4 (Toxic) 1,1 Dichloro ethene 8 (Toxic) 1,2 Dichloro ethene 5 (Toxic) 1,1,1 trichloro ethane 1500 (Environmental hazard)
- 17. • b) ClassII solvents: Solvents to Be Limited Class II solvents usage should be limited in pharmaceutical products because of their inherent toxicity. • Table 2 lists class II solvents with their daily permissible exposure.
- 18. Solvent PDE (mg/day)Concentration limit (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cumene 1 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 Methylisobutylketone2 45 4500 N- Methylpyrrolidone3 5.3 530
- 19. • c) ClassIII Solvents: Solvents with Low Toxic Potential These are less toxic and possess lower risk to human health than class I or class II • Long-term toxicity or carcinogenicity not reported, which is evident from the available data for the solvents under this category. The use of class III solvents in pharmaceuticals does not have any serious health hazard. Some of the solvents are; Acetic acid, anisole, butanol, 2butanol, isopropyl acetate, methylacetate, butylacetate, ter-butyl methyl ether, pentene, cumene, Dimethyl sulfoxide, ethanol, ethylacetate, formicacid, heptane, isobutyl ketone, tetrahydrofuran, 1-pentanol, 2propanol, methyl isobutyl ketone, propylacetate, 3methyl- 1-butanol, methyl ethylketone.
- 20. • d) ClassIV Solvents: Class IV solvents, adequate toxicological data is not available. The manufacturers should justify the residual levels for these solvents in pharmaceutical products. The solvents under class IV are 1, 1-diethoxy propane, 1-1-dimethoxy propane, 2-2 • 2dimethoxy propane, methyl isopropyl ketone, isooctane, isopropyl ether, methyl tetrahydrofuran, petroleum ether, trichloro acetic acid.
- 21. Thresholds for DegradationProducts in New Drug Products • Reporting Thresholds Maximum Daily Dose Thresholds ≤ 1 g 0.1% > 1 g 0.05%
- 22. Identification Thresholds • Maximum DailyDose Thresholds < 1 mg 1.0% or 5 µg TDI, whichever is lower 1 mg - 10mg 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%
- 23. Qualification Thresholds Maximum DailyDose Thresholds < 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%