Gas Chromatography -2 OVI
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Transcript of Gas Chromatography -2 OVI
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Residual solvents
New USP General Chapter
Session II
Mr. Shantanu Chobhe
DGM-Analytical Services
Unichem Laboratories Ltd., Mumbai
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Introduction
..residual solvents in pharmaceuticals aredefined as organic volatile chemicals that areused or produced in the manufacture of drugsubstances or excipients, or in the preparation ofdrug products.
ICH, USP, EP
[Note: residual solvents refers to the amount notremoved during the purification of the product]
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Introduction
Residual solvents are one of the three maintypes of impurities in pharmaceutical articles,the other two being organic and inorganicimpurities.
Therefore, Various Pharmacopeiasfrequentlyinclude a test for residual solvents, together withprocedures for the test and acceptance criteria.
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Introduction
The implementation of modern standards tocontrol these types of impurities has occupiedregulatory agencies, pharmaceuticalmanufacturers, and pharmacopeias for many
years.
Substantial progress in the overall effort camewith development of the ICH Q3C Guideline in
1997 (Impurities: Guideline for Residual Solvents)and subsequent adoption of this Guideline as aFDA guidance.
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History
Chapter of USP was Organic VolatileImpurities(OVI)
Individual monographs specify which method tofollow.
OVIs controlled: Chloroform (60 ppm), Dioxane (380ppm), 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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HistoryICH Q3C and EP
ICH Q3C Published in July 1997
Revised in 2002
EP adopts the ICH Q3C guideline in 1999.
General Chapter 5.4. An introductory paragraphand reproduces the ICH Guideline
Chapter 2.4.24 Identification and control of residualsolvents (Test methods for Class 1, 2 and 3Residual Solvents)
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History
USP incorporates ICH Q3Cclassificationand evaluation system and EPprocedures.
USP was not consistent with ICH Q3CImpurity guideline (1997)
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Revision of USP GeneralChapter
First proposal to amend General Chapter 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 ICHguideline.
The title changed from
Organic volatile Impuritiesto
Residual Solvents.All drug substances, excipients, and products are
subject to relevant control of residual solvents,
even when no test is specified in the individualmonograph.
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.
The solvents are limited according to the
principles defined and the requirements specified
in Residual solvents, using the general
methods presented therein or use of othersuitable methods.
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Revised :Main Points
1. Testing is to be performed only for solventslikely to be present
used or produced in the final manufacturingstep
used in previous steps and not removed bya validated procedure.
2. The limits for acceptable concentrations listedin the Chapter are for drug products,not forits components.
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Contd.. Revised :Main Points
4. The concentration in the drug product may be
calculated from the contributions ofcomponents
determined experimentally; mandatory if
solvents are used in its manufacture cumulative calculation exceeds limits
5. Manufacturers of drug products may rely ondata provided by the suppliers of components
6. Provides unambiguous identification andquantification methods
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Contd.. Revised :Main Points
7. Includes options to allow use of materials thatexceed the limits established.
8. The procedures described in this general
chapter are to be applied wherever possible.Otherwise, manufacturers may select the mostappropriate validated analytical procedure fora particular application.
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Risk Based classification of Solvents
Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspectedhuman carcinogens, and environmental hazards.
Class 2 solvents: Solvents to be limitedNon-genotoxic animal carcinogen or possiblecausative agents of others irreversible toxicitysuch as neurotoxicity or teratogenicity.
Class 3 solvents: Solvents with low toxic
potentialSolvents with low toxic potential to humanbeings.
f
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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 fromPDE 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 is10 g or less, or when the daily dose is not known orfixed.
Class 3:PDE is 50 mg/day (unless otherwise stated inthe individual monograph.), corresponding to aconcentration 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): Shouldnot be used in the manufacturing of drugsubstances, excipients or drug productsbecause of unacceptable toxicities or
deleterious environmental effects of theresidual solvents.
However if their use is unavoidable, theirlevels should be restricted as shown in
Table 1.
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Table 1. Class 1 Residual Solvents
Solvent Limit
(ppm)
Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic andenvironmental Hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Environmental Hazard
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Limits of Residual Solvents: Class 2
Class 2: 27 solvents
Class 2 Residual Solvents: should be limited indrug substances, excipients, and drugproducts because of their inherent toxicities.
Their levels should be restricted as shown in
Table 2. Concentration limits (ppm) varybetween 50 (methylbutylketone) and 3880(cyclohexane).
When Class 2 residual solvents are used (or
produced) in the manufacturing or purificationprocess, they should be identified andquantified
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Table 2. Class 2 Residual Solvents
SolventPDE
(mg/day)Limit (ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
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
Ethylene glycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3000
SolventPDE
(mg/day)Limit (ppm)
2-Methoxyethanol 0.5 50
Methylbutylketone 0.5 50
Methylcyclohexane 11.8 1180
Methylene chloride 6.0 600
N-Methylpyrrolidone 5.3 530
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetrahydrofuran 7.2 720
Tetralin 1.0 100Toluene 8.9 890
Trichloroethylene 0.8 80
Xylenes 21.7 2170
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Options for Determining Levels of Class 2Residual Solvents in Drug Products
Option 1:
All the components of the drug product (drug substancesand excipients) meet the concentration limits (ppm)listed in Table 2, and the daily dose does not exceed 10g: drug product passes.
Option 2:
At least one of the components of the drug productexceeds the concentration limits (ppm), or the dailydose 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 1limit is 410 ppm
(from Table 2). 5.0 g drug product/day. Composed of two excipients
Excipients 1 meets Option 1limit of 410 ppm. Drug substance, excipients 2, and drug product do not meet
Option 1limit of 410 ppm. Drug product however, does meet Option 2limit of 4.1 mg/day.
Component Amount inFormulation
(g)
AcetonitrileContent-Limit
(ppm)
Daily Exposure
(mg)
Drug Substance 0.3 800 (exceeds) 0.24
Excipient 1 0.9 400 (pass) 0.36
Excipient 2 3.8 800 (exceeds) 3.04
Drug Product
Calculated data*
5.0 728 (exceeds)* 3.64 (PASS)*
E l 2 O ti 1 d O ti 2 ith
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Example 2: Option 1 and Option 2, withacetonitrile
PDE acetonitrile = 4.1 mg/day, thus Option 1limit is 410 ppm
(from Table 2). 5.0 g drug product/day. Composed of two excipients
Drug product does not meet Option 1limit (410 ppm) or Option 2limit (4.1mg/day).
Manufacturer could test to see if manufacturing reduced the level ofacetonitrile in the drug product below 410 ppm; if so it passes.
Component Amount inFormulation
(g)
Acetonitrile Content-Limit
(ppm)
Daily Exposure
(mg)
Drug Substance 0.3 800 (exceeds) 0.24
Excipient 1 0.9 2000 (exceeds) 1.80
Excipient 2 3.8 800 (exceeds) 3.04
Drug Product
Calculated data*
5.0 1016 (exceeds)* 5.08 (FAIL)*
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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 ofproduct.
Use Loss on Drying in NMT 0.5%.
If the monograph allows for a concentration
resulting in more than 50 mg/day, Class 3solvents must be identified and quantified.
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Table 3. Class 3 Residual Solvents
Acetic acid Heptane
Acetone Isobutyl acetateAnisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl acetate Methylethylketone
tert-Butylmethyl ether Methylisobutylketone
Cumene 2-Methyl-l-propanol
Dimethyl sulfoxide Pentane
Ethanol 1-Pentanol
Ethyl acetate 1-Propanol
Ethyl ether 2-Propanol
Ethyl formate Propyl acetate
Formic acid
O h id l l
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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 shallbe justified.
Table 4.Other Residual Solvents1,1-Diethoxypropane Methyl isopropyl ketone
1,1-Dimethoxypropane Methytetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluroacetic acid
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Analytical Procedures (ICH, EP)
ICH:Any harmonized procedures for
determining levels of residual solvents asdescribed in the pharmacopoeias should beused, if feasible. Otherwise, manufacturerswould be free to select the most appropriate
validated analytical procedure . . . EP:. . . The methodology in the general
analytical method (2.2.24)is to be appliedwherever possible. Otherwise an appropriate
validated method is to be employed.
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Analytical Procedures USP
USP:. . . The procedures described in . . . Thisgeneral chapter are to be applied wheneverpossible. Otherwise manufacturers mayselect the most appropriate validatedanalytical procedure for a particularapplication . . .
Id tifi ti C t l d
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Identification, Control, andQuantification 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 exceeds0.5%.
Manufacturers statement regarding
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Manufacturers statement regardingResidual solvents
Statement/Declaration shall include-
All Class 1 solvents used or generated
All Class 2 solvents "likely to be present
Whether Class 3 solvents are" likely to be present" andidentity 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 identifiedabove
C l l i f S d d i
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Calculation of Standard concentrationSample 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 / Factori.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 ?