Professional Documents
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Introduction
..residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.
ICH, USP, EP [Note: residual solvents refers to the amount not removed during the purification of the product]
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Introduction
Residual solvents are one of the three main types of impurities in pharmaceutical articles, the other two being organic and inorganic impurities.
Therefore, Various Pharmacopeias frequently include a test for residual solvents, together with procedures for the test and acceptance criteria.
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Introduction
The implementation of modern standards to control these types of impurities has occupied regulatory agencies, pharmaceutical manufacturers, and pharmacopeias for many years. Substantial progress in the overall effort came with development of the ICH Q3C Guideline in 1997 (Impurities: Guideline for Residual Solvents) and subsequent adoption of this Guideline as a FDA guidance.
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History
Chapter <467> of USP was Organic Volatile Impurities(OVI) Individual monographs specify which <467> method to follow. OVIs controlled: Chloroform (60 ppm), Dioxane (380 ppm), Methylene Chloride (600 ppm) and Trichloroethylene (80 ppm)
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ICH Q3C
General Chapter 5.4. An introductory paragraph and reproduces the ICH Guideline Chapter 2.4.24 Identification and control of residual solvents (Test methods for Class 1, 2 and 3 Residual Solvents)
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History
USP incorporates ICH Q3C classification and evaluation system and EP procedures. USP was not consistent with ICH Q3C Impurity guideline (1997)
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proposal to amend General Chapter <467> and General Notices published in PF 29(4), 2003.
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Changes Done
The
requirements have been aligned with the ICH guideline. The title changed from Organic volatile Impurities to Residual Solvents. All drug substances, excipients, and products are subject to relevant control of residual solvents, even when no test is specified in the individual monograph. If solvents are used during production, they are of suitable quality.
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Contd
.. Changes Done
The
toxicity and residual level of each solvent are taken into consideration. solvents are limited according to the principles defined and the requirements specified in Residual solvents <467>, using the general methods presented therein or use of other suitable methods.
The
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Testing is to be performed only for solvents likely to be present used or produced in the final manufacturing step used in previous steps and not removed by a validated procedure. The limits for acceptable concentrations listed in the Chapter are for drug products, not for its components.
2.
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Contd..
4.
5.
6.
The concentration in the drug product may be calculated from the contributions of components determined experimentally; mandatory if solvents are used in its manufacture cumulative calculation exceeds limits Manufacturers of drug products may rely on data provided by the suppliers of components Provides unambiguous identification and quantification methods
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Contd..
7.
Includes options to allow use of materials that exceed the limits established. The procedures described in this general chapter are to be applied wherever possible. Otherwise, manufacturers may select the most appropriate validated analytical procedure for a particular application.
8.
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Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Non-genotoxic animal carcinogen or possible causative agents of others irreversible toxicity such as neurotoxicity or teratogenicity.
Class 1: concentration limits, in ppm, are provided in a Table. They should not be exceeded unless otherwise stated in the individual monograph.
Class 2: concentration limits are to be calculated from PDE with the formula: Concentration (ppm) = 1000 PDE/dose, where PDE is in mg/day and dose is in g/day. A table is provided, to be used when the daily dose is 10 g or less, or when the daily dose is not known or fixed.
Class 3: PDE is 50 mg/day (unless otherwise stated in the individual monograph.), corresponding to a concentration of 0.5% for daily doses of 10 g or less.
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Class 1 Residual Solvents (Table 1): Should not be used in the manufacturing of drug substances, excipients or drug products because of unacceptable toxicities or deleterious environmental effects of the residual solvents. However if their use is unavoidable, their levels should be restricted as shown in Table 1.
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5 8 1500
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Class 2: 27 solvents Class 2 Residual Solvents: should be limited in drug substances, excipients, and drug products because of their inherent toxicities. Their levels should be restricted as shown in Table 2. Concentration limits (ppm) vary between 50 (methylbutylketone) and 3880 (cyclohexane). When Class 2 residual solvents are used (or produced) in the manufacturing or purification process, they should be identified and quantified
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N-Methylpyrrolidone
Nitromethane Pyridine Sulfolane Tetrahydrofuran Tetralin Toluene Trichloroethylene Xylenes
N,NN,N-
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Option 1: All the components of the drug product (drug substances and excipients) meet the concentration limits (ppm) listed in Table 2, and the daily dose does not exceed 10 g: drug product passes. Option 2: At least one of the components of the drug product exceeds the concentration limits (ppm), or the daily dose exceeds 10 g: the daily exposure to a solvent (calculated as the sum of the components contributions) should be less than the PDE (mg).
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PDE acetonitrile = 4.1 mg/day, thus Option 1 limit is 410 ppm (from Table 2). 5.0 g drug product/day. Composed of two excipients
Component Amount in Formulation (g) 0.3 0.9 3.8 5.0 Acetonitrile Content-Limit (ppm) 800 (exceeds) 400 (pass) 800 (exceeds) 728 (exceeds)* Daily Exposure (mg) 0.24 0.36 3.04 3.64 (PASS)*
Excipients 1 meets Option 1 limit of 410 ppm. Drug substance, excipients 2, and drug product do not meet Option 1 limit of 410 ppm. Drug product however, does meet Option 2 limit of 4.1 mg/day.
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PDE acetonitrile = 4.1 mg/day, thus Option 1 limit is 410 ppm (from Table 2). 5.0 g drug product/day. Composed of two excipients
Component Amount in Formulation (g) Acetonitrile ContentLimit (ppm) Daily Exposure (mg)
Drug Substance
Excipient 1 Excipient 2 Drug Product Calculated data*
0.3
0.9 3.8 5.0
800 (exceeds)
2000 (exceeds) 800 (exceeds) 1016 (exceeds)*
0.24
1.80 3.04 5.08 (FAIL)*
Drug product does not meet Option 1 limit (410 ppm) or Option 2 limit (4.1 mg/day). Manufacturer could test to see if manufacturing reduced the level of acetonitrile in the drug product below 410 ppm; if so it passes.
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Class 3: 27 solvents Less toxic and of lower risk to human health Unless otherwise stated in the individual monograph, PDE is NMT 50 mg/day, corresponding to a concentration limit of 5000 ppm for daily doses not greater than 10 g of product. Use Loss on Drying in NMT 0.5%. If the monograph allows for a concentration resulting in more than 50 mg/day, Class 3 solvents must be identified and quantified.
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tert-Butylmethyl ether
Cumene Dimethyl sulfoxide Ethanol Ethyl acetate Ethyl ether Ethyl formate Formic acid
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No adequate toxicological data on which to base a PDE was found. Residual levels of these solvents in drug products shall be justified. Table 4.Other Residual Solvents
1,1-Diethoxypropane 1,1-Dimethoxypropane 2,2-Dimethoxypropane Isooctane Isopropyl ether Methyl isopropyl ketone Methytetrahydrofuran Petroleum ether Trichloroacetic acid Trifluroacetic acid
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ICH: Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure . . . EP: . . . The methodology in the general analytical method (2.2.24) is to be applied wherever possible. Otherwise an appropriate validated method is to be employed.
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USP:
. . . The procedures described in . . . This general chapter are to be applied whenever possible. Otherwise manufacturers may select the most appropriate validated analytical procedure for a particular application . . .
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A-Identification and Limit Test Procedure B-Confirmatory Test Procedure C-Quantitative Test
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Whether
Class 3 solvents are" likely to be present" and identity of all Class 3 solvents present at greater than 0.5%
All
The
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Thank You !
Any Questions ?
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