Residual solvents as impurities

residual solvent analysis as impurities, there control methods
types of residual solvents

1. PRESENTED BY- SANTHOSH KUMAR T S M.PHARM (PH ANALYSIS) 1 ST YEAR A PRESENTATION ON IMPURITIES IN RESIDUAL SOLVENTS KARNATAKA COLLEGE OF PHARMACY BANGALORE FACILITATED TO- Dr. C. SREEDHAR SIR HEAD OF THE DEPARTMENT (PH. ANALYSIS)

2. CONTENTS Introduction General principles Scope of the Guideline Classification Analytical Procedures Limits of Residual Solvents Reporting Levels of residual solvents

3. Int r oduction Residual solvents in Pharmaceuticals are defined in ICH Q3C as organic volatile chemicals that are used or produced in the manufacture of drug substances , excipients or in the preparation of drug products. They are not completely removed by practical manufacturing techniques. PURPOSE Residual solvents are used in manufacture either to enhance the yield or determine characteristics of the substances such as crystal form, purity and solubility. There is no therapeutic benefit from residual solvents. Since there is no therapeutic benefit from residual solvents , all residual solvents should be removed completely to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements.

4. 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. The guideline applies to all dosage forms and routes of administration. This guidelines does not address all possible solvents, only those identified in drugs at that time, neither address solvents intentionally used as excipients nor solvates. The maximum acceptable intake per day of residual solvent in pharmaceutical products is defined as “permitted daily exposure” (PDE) Previously, another terms were used like “ Tolerable daily intake ” (TDI) & “ Acceptable daily intake ” (ADI) by different organization & authorities, but now usually this new term “PDE” is used Scope of the Guideline

5. Classification of Residual solvents

6. Classification

7. Classification of Residual Solvents by Risk Assessment Class 1 solvents Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards Class 2 solvents Solvents to be limited Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Class 3 solvents Solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 4 solvents : no adequate toxicological data is available for these group of solvents

8. Analytical Procedures

9. Analytical Procedures R esidual solvents are typically determined using chromatographic techniques such as gas chromatography . A ny harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used. M anufacturers would be free to select the most appropriate one . validated analytical procedure for a particular application . I f only Class 3 solvents are present, a nonspecific method such as loss on drying may be used.

10. Gas chromatograph equipped with Headspace Sampler Flame Ionization Detector ( FID) Mass-selective Detector (MSD) (optionally ) for identification & confirmation

11. a G43 Column a G16 column also looks similar in appearance

12. Headspace Vial

13. If we look at the anatomy of a headspace vial we can begin to see the relationship of the vial components and how we can control these parameters to create analytical methods. Volatile components partition from the sample phase and equilibrate in the vial headspace. ACI Limited

14. Principle for analysis of residual solvents • Residual solvent analysis by static HS/GC can be enhanced by careful consideration of two basic concepts—partition coefficient (K) and phase ratio (β ). • Partition coefficients and phase ratios work together to determine the final concentration of volatile compounds in the headspace of sample vials. • The partition coefficient (K) is defined as the equilibrium distribution of an analyte between the sample and gas phases. Compounds that have low K values will tend to partition more readily into the gas phase, and have relatively high responses and low limits of detection. • The phase ratio (β) is defined as the volume of the headspace over the volume of the sample in the vial. Lower values for β (i.e., larger sample sizes) will yield higher responses for compounds with inherently low K values.

15. Principle for analysis of residual solvents Striving for the lowest values for both K and β when preparing samples will result in higher concentrations of volatile analytes in the gas phase and, therefore, better sensitivity

16. INTERPRETATION OF RESULTS

17. Limits of Residual Solvents

18. Class 1 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 unless otherwise justified. Solvent C oncentr a tion 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

19. Class 2 Solvents Solvents to be limited Solvents in class 2 should be limited in pharmaceutical products because of their inherent toxicity. Examples of class 2 solvent in the below table. Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1 410 Chloroform 0.6 60 Cyclohexane 38.8 3880 Formamide 2.2 220 Methanol 30 3000 N-Methylpyrrolidone 5.3 530 Tetrahydrofuran 7.2 720 Xylene 21.7 2170 Toluene 8.9 890

20. Class 3 Solvents (Solvents with low toxic potential ) S olvents in Class 3 may be regarded as lower risk to human health . However, there have no long-term toxicity or carcinogenicity studies for many of the solvents in Class 3. T hese solvents are considered of no human health hazard A vailable data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. I t is considered that amounts of these residual solvents of 50 mg per day or less ( corresponding to 5000 ppm ) would be acceptable without justification. H igher amounts may also be acceptable provided ( iff ) they are realistic in relation to manufacturing capability and GMP.

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

22. Examples : 1,1-Diethoxypropane 1,1-Dimethoxymethane 2,2-Dimethoxypropane Isooctane Isopropyl ether Methylisopropyl ketone Methyltetrahydrofuran Petroleum ether Trichloroacetic acid Trifluoroacetic acid Solvents for which No Adequate Toxicological Data was Found The following solvents may also be of interest to manufacturers of excipients, drug substances, or drug products. However, no adequate toxicological data on which to base a PDE was found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.

23. Reporting levels of residual solvents

24. Options for Describing Limits of Class 2 Solvents These options are used to describe the limit of Class 2 solvents. Testing should be performed for residual solvents when production or purification processes are known to result in the presence of such solvents. Option 1: By assuming a product mass of 10 g administered daily. Concentration (ppm) = 1000 x PDE / Dose Here , PDE is given in terms of mg/day and dose is given in g/day. No further calculation is necessary provided that the daily dose does not exceed 10 g. Option 2 : Products that are administered in doses greater than 10 g per day. Applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE.

25. Example for Option 2 The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, the Option 1 limit is 410 ppm. The maximum administered daily mass of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile are given in the following table. Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. however, the product meets the Option 2 limit of 4.1 mg per day and thus conforms to the recommendations in this guideline.

26. Reporting levels of residual solvents M anufacturers of pharmaceutical products need certain information about the content of residual solvents in excipients or drug substances. T he following statements are given in the ICH Guideline as acceptable examples of the information that could be provided from a supplier of excipients or drug substances to a pharmaceutical manufacturer. Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%. Only Class 2 solvents X,Y, ... are likely to be present. All are below the Option 1 limit. Only Class 2 solvents X,Y, ... and Class 3 solvents are likely to be present. Residual Class 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%.

27. Reporting levels of residual solvents I f Class 1 solvents are likely to be present, they should be identified and quantified. I f solvents of Class 2 or Class 3 are present at greater than their Option 1 limits or 0.5%, respectively, they should be identified and quantified. M anufacturer could provide a summary of efforts made to reduce the solvent level to meet the guideline value and provide a risk-benefit analysis to support allowing the product to be utilized with residual solvent at a higher level. H igher levels of residual solvents may be acceptable in certain cases such as short term (30 days or less) or topical application. Justification for these levels should be made on a case by case basis.

28. Residual Solvents in Pharmaceuticals Exposure limits in this guideline are established by referring to methodologies and toxicity data described in EHC and IRIS monographs . However, some specific assumptions about residual solvents to be used in the synthesis and formulation of pharmaceutical products should be taken into account in establishing exposure limits: Patients use pharmaceuticals to treat their diseases or for prophylaxis to prevent infection or disease . Residual solvents are unavoidable components in pharmaceutical production and will often be a part of drug products . Residual solvents should not exceed recommended levels except in exceptional circumstances .

29. Data from toxicological studies that are used to determine acceptable levels for residual solvents should have been generated using appropriate protocols such as those described . E xample :- FDA Red Book and EPA. FDA Red Book: Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food EPA: US Environmental Protection Agency

30. References : www.google.com www.pdfdrive.net www.Slideshares.in Impurities: Guideline for Residual Solvents Q3C(R5) EMA: CVMP/VICH/502/99 Guideline on impurities: residual solvents , Annex I : specifications for class 1 and class 2 residual solvents in active substances

31. T H A N K Y O U

32. Glossary Term Meaning Term Meaning ICH INTERNATIONAL CONFERENCE ON HARMONISATION LOEL Lowest-Observed Effect Level WHO World Health Organization NOEL No-Observed Effect Level GMP Good Manufacturing Practice PDE Permitted Daily Exposure EHC Environmental Health Criteria TDI Tolerable Daily Intake IRIS Integrated Risk Information System ADI Acceptable Daily Intake IPCS International Program on Chemical Safety USFDA United States Food and Drug Administration USEPA United States Environmental Protection Agency EWG Expert Working Group