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Session II

Residual solvents New USP General Chapter<467>


Mr. Shantanu Chobhe DGM-Analytical Services Unichem Laboratories Ltd., Mumbai

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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)

Four methods: I, IV, V, and VI


Standards: reagent grade solvents Direct injection or Headspace (Method IV) Column: G27 (Method I), G43 (Methods IV and V), various supports and coatings (Method VI) Dissolving solvent: water or the solvent specified in the monograph
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ICH Q3C

History ICH Q3C and EP

Published in July 1997 Revised in 2002

EP adopts the ICH Q3C guideline in 1999.

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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Revision of USP General Chapter<467>


First

proposal to amend General Chapter <467> and General Notices published in PF 29(4), 2003.

Changes made effective (Mandatory) from 1st July 2008.

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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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Revised <467>:Main Points


1.

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.

Revised <467>:Main Points

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..

Revised <467>:Main Points

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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Risk Based classification of Solvents

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 carcinogen or possible causative agents of others irreversible toxicity such as neurotoxicity or teratogenicity.

Class 3 solvents: Solvents with low toxic potential

Solvents with low toxic potential to human beings.


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Limits of Residual Solvents

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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Limits of Residual Solvents: Class 1

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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Table 1. Class 1 Residual Solvents


Solvent Limit (ppm) 2 4 Concern

Benzene Carbon tetrachloride

Carcinogen Toxic and environmental Hazard Toxic Toxic Environmental Hazard

1,2-Dichloroethane 1,1-Dichloroethene 1,1,1-Trichloroethane

5 8 1500

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Limits of Residual Solvents: Class 2


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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Table 2. Class 2 Residual Solvents


Solvent Acetonitrile Chlorobenzene Chloroform Cyclohexane 1,2-Dichloroethene 1,2Dimethoxyethane PDE (mg/day) 4.1 3.6 0.6 38.8 18.7 1.0 10.9 8.8 3.8 1.6 6.2 2.2 2.9 30.0 Limit (ppm) 410 360 60 3880 1870 100 1090 880 380 160 620 220 290 3000 Solvent 2-Methoxyethanol Methylbutylketone Methylcyclohexane Methylene chloride PDE (mg/day) 0.5 0.5 11.8 6.0 5.3 0.5 2.0 1.6 7.2 1.0 8.9 0.8 21.7 Limit (ppm) 50 50 1180 600 530 50 200 160 720 100 890 80 2170

N-Methylpyrrolidone
Nitromethane Pyridine Sulfolane Tetrahydrofuran Tetralin Toluene Trichloroethylene Xylenes

N,NN,N-

Dimethylacetamide Dimethylformamide 1,4-Dioxane 2-Ethoxyethanol Ethylene glycol Formamide Hexane Methanol

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Options for Determining Levels of Class 2 Residual Solvents in Drug Products


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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Example 1: Option 1 and Option 2, with acetonitrile


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)*

Drug Substance Excipient 1 Excipient 2 Drug Product Calculated data*


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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Example 2: Option 1 and Option 2, with acetonitrile


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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Limits of Residual Solvents: Class 3


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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Table 3. Class 3 Residual Solvents


Acetic acid Acetone Anisole 1-Butanol 2-Butanol Butyl acetate Heptane Isobutyl acetate Isopropyl acetate Methyl acetate 3-Methyl-1-butanol Methylethylketone Methylisobutylketone 2-Methyl-l-propanol Pentane 1-Pentanol 1-Propanol 2-Propanol Propyl acetate

tert-Butylmethyl ether
Cumene Dimethyl sulfoxide Ethanol Ethyl acetate Ethyl ether Ethyl formate Formic acid
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Other Residual solvents


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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Analytical Procedures (ICH, EP)

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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Analytical Procedures USP

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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Identification, Control, and Quantification of Residual Solvents

Class 1 and Class 2 Residual Solvents


Procedure

A-Identification and Limit Test Procedure B-Confirmatory Test Procedure C-Quantitative Test

Class 3 Residual Solvents

LOD, followed if necessary by Gas Chromatography analysis if it exceeds 0.5%.

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Manufacturers statement regarding Residual solvents


Statement/Declaration shall includeAll All

Class 1 solvents used or generated Class 2 solvents "likely to be present

Whether

Class 3 solvents are" likely to be present" and identity of all Class 3 solvents present at greater than 0.5%
All

other solvents "likely to be present, as applicable.

The

expected control limits for the solvents identified above


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Calculation of Standard concentration


Sample containing Methanol as a residual solvent Limit as per ICH: 3000 ppm Sample concentration: 500 mg of sample in 5 mL of DMF (diluent) Factor is (5ml / 0.5g) = 10 Standard concentration: Absolute concentration = ICH limit / Factor i.e. 3000 / 10 = 300 ppm

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Calculation of residual solvent


Standard preparation: 30mg of Methanol to 100mL with DMF

Calculations: Methanol content in ppm


Area in sample Wt of Std (g) 5 ---------------------- X -------------- X --------------- X 106 Area in std 100 Wt of spl (g)

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Thank You !
Any Questions ?

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