Fae
`
`Guidance for Industry
`
`Q3C — Tables and List
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`February 2012
`ICH
`
`Revision 2
`
`g
`
`EKHIBH
`
`1
`1
`
`AKBM 1095 g
`AKBM 1095
`
`

`
`
`
`Guidance for Industry
`
`Q3C — Tables and List
`
`Addffiona! copies are a1:aL-’ab{e_fi'om.'
`
`Ofiice of Communicarions
`Dimrision ofDmg Information, W05}, Room 2210
`Cemerfor Drug Evahraiion and Re.s'earch
`Food and Drug /idmim'srrar:'on
`10903 New Hanrpshi:-e Ave.
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`Phone." 30.“ 796-3400,‘ Fax: 30I—84 7-8 7} 4
`drug:'rf0@fda. hhs: gov
`!:.=‘!p.'.:’.3’wu'w. [a'(I_.,g'0vr1')3':rg.sfG1JfdanCeCo.=J3gzIitI:1CeReguIaI0I‘Fluff;J'3Jatr:IIom‘Gu:'a'aflc‘eS/default.hnn
`
`and/or
`
`Office of Commurawatfon, Outreach and
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`Cemerfor Bfoiogics Evaluamm and Research
`Food and Drug Adminfsrrarion
`140.’ Rockville Pike, Rockvifle, MD 20852-1448
`h:rp:.f.fivwwfda. gov/B:'oJ'ogic.s-BioodVaccines.-’(}uida;:ce C.'omp;'ia:1ceReguiaIorvb{formorIfa:VGuidam-ex/defoulr.him
`(Te!) 800-835-4 709 or 30} -82 7-} 800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`February 2012
`ICH
`
`Revision 2
`
`2
`
`

`
`
`
`Crintains Nonbrhdirig Rec0mmem!a{r'r)ns'
`
`Guidance for Industry]
`
`Q3C — Tables and List
`
`It
`This guidance represents the Food and Drug Administration's (FDA’s) current thinking on this topic.
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`You can use an alternative approach if that approach satisfies the requirements of the applicable statutes
`and regulations.
`lfyou want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance.
`lfyou cannot identify the appropriate FDA stall] call the appropriate
`
`number listed on the title page ofthis guidance.
`
`I.
`
`INTRODUCTION
`
`This is the companion document for the International Conference on Harmonisation of Technical
`Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance for industry
`Q3C Impur.r'Ii'e.s*.' Residual Solvents (1997), which makes recommendations as to what amounts of
`residual solvents are considered safe in pharmaceuticals.
`
`This document may be updated if proposals for change are submitted to the International
`Conference on Harmonisation (ICH) Steering Committee. Proposals for change and the ICI-I
`Steering Committee final decision on any proposed changes will be announced through a notice
`in the Federal Register prior to the updating ofthis document. The guidance was revised in
`November 2003 to reflect updated recommendations for N-Methylpyrrolidone and
`Tetrahydrofuran and in February 2012 to reflect an updated recommendation for cumene.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word shoufd in Agency guidances means that something is suggested or
`recommended, but not required.
`
`I This document was developed within the Expert Working Group (Quality) of the International
`Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
`and has been subject to consultation by the regulatory parties, in accordance with the lCl-1 process. This document
`was endorsed by the ICH Steering Committee at Step 4 of the ICH process in July 1997. At Step 4 of the process,
`the final drait is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United
`States. This guidance was published in the Federal Register on December 24, 1997 (62 FR 67377), and is
`applicable to drug and biological products.
`
`3
`
`

`
`Comains Nonbinding Reconrmentiaffons
`
`II.
`
`LIST OF SOLVENTS INCLUDED IN THE Q3C GUIDANCE
`
`Solvent
`
`Acetic acid
`
`Acetone
`
`Aceton itrile
`
`Anisole
`
`Other Names
`
`Ethanoic acid
`
`2-Propanonc
`Propan-2-one
`
`Methoxybenzene
`
`Benzene
`
`Bcnzol
`
`1 -Butanol
`
`2-Butane]
`
`n-Butyl alcohol
`Butan-l—ol
`
`sec-Butyl alcohol
`Butan-2-ol
`
`Structure
`
`CH 3COOH
`
`CH3COCH3
`
`CH3(CH2)3OH
`
`CH3CH2Ci-I(0H)CH3
`
`Butyl acetate
`
`Acetic acid butyl
`
`ester
`
`CH3COO{CH;)3CH3
`
`rerr-Butylmethyl ether
`
`2-Methoxy-2-methyl-propane
`
`(CI-l3)3COCH3
`
`Carbon tetrachloride
`
`Tetrachloromethane
`
`Chlorobcnzene
`
`Chloroform
`
`Cumene
`
`Trichlorornethane
`
`Isopropyibenzene
`(1-Mcthyhethylbenzene
`
`CCL.
`
`©-cl
`
`CI-{C13
`
`CGH5-CH{CH3)2
`
`Cyclohexane
`
`Hexamethylenc
`
`C)
`
`1,2«Dichloroethane
`
`1,1-Dichloroethcne
`
`1 ,2-Dichloroethene
`
`sym-Dichloroetliane
`Ethylene dichloride
`Ethylene chloride
`
`1,1 -Dichloroethylene
`Vinylidene chloride
`
`1,2-D ichloro ethylene
`Acetylene dichloride
`
`Cl-l2ClCH2Cl
`
`I-I2@CCl2
`
`Cll--IC=CHCl
`
`4
`
`Class
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 1
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 1
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 1
`
`Class 1
`
`Class 2
`
`

`
`
`
`D ichlorom ethane
`
`l ,2—Dimcthoxyethane
`
`N,N-
`Dimethylacetamide
`
`N,N- Dimethy lformamide
`
`Dimethyl sulfoxide
`
`] ,4-Dioxane
`
`Ethanol
`
`2~Ethoxyethanol
`
`Contains Noiibinrling Rec'0mmenr!tm7(;:-is
`
`Methylene chloride
`
`Cl'lgCl:
`
`Ethyleneglyeol dimcthyl ether
`Monoglyme
`Dimethyl Ccllosolve
`
`H3COCH3Cl*lgOCl-lg
`
`DMA
`
`DMF
`
`Methylsulfinylmethane
`Methyl sulfoxide
`DMSO
`
`p-Dioxane
`[l,4]Dioxane
`
`Ethyl alcohol
`
`Cellosolve
`
`CH3CON(CH_~,);
`
`HCON(Cl-l3);
`
`(Cl-l_~.}3SO
`
`r—\
`00L7
`
`Cl-l3CHgOll
`
`CH3CHgOCH2CHgOH
`
`Ethyl acetate
`
`Acetic acid ethyl ester
`
`CH3COOCH3CH3
`
`Ethyleneglycol
`
`Ethyl ether
`
`1,2-Dihydroxyethane
`1,2-Ethaned iol
`
`Diethyl ether
`Ethoxyethane
`1,1’-Oxybisethane
`
`HOCH3C.H2OH
`
`C.H3CH2OCH2CH3
`
`Ethyl fonnate
`
`Formic acid ethyl ester
`
`HCO OCl'l;,;Cl'l3
`
`Formamide
`
`Formic acid
`
`I-leptane
`
`l-Iexane
`
`Methanainide
`
`n-l-Ieptane
`
`n-Hexane
`
`HCOT‘-lHg
`
`HCOOH
`
`CH3(CH2)5CH3
`
`Cl"I3(Cl‘l2]4Cl‘l3
`
`lsobutyl acetate
`
`Acetic acid isobutyl ester
`
`CH3COOCH;CH(Cl-I3);
`
`Isopropyl acetate
`
`Acetic acid isopropyl ester
`
`Cl'l3COOCl-l{Cl-l3);
`
`Methanol
`
`Methyl alcohol
`
`CI-l3OH
`
`2-Mcthcxyethanol
`
`Methyl Cellosolvc
`
`CH3OCl'l2Cl“lgOH
`
`Methyl acetate
`
`Acetic acid methyl ester
`
`Cl-l3COOCH3
`
`3-Methy|- l -butanol
`
`lsoamyl alcohol
`lsopentyl alcohol
`3-Methylbutam l -0]
`
`(CI‘I3)gCl-lCl-I2Cl-l;»Ol-I
`
`Class 2
`
`Class 2
`
`Class 2
`
`C|ass2
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 3
`
`5
`
`

`
`Comains Nonbindfng Reconmtemlatfons
`
`Methylbutyl ketone
`
`2-Hexanonc
`
`Hexan-2-one
`
`Methylcyclohexane
`
`Cyclohexylmethane
`
`Methylcthyl ketone
`
`Methylisobutyl ketone
`
`2-Methyl—l -propanol
`
`2—Butanone
`MEK
`B11tan—2-one
`
`4-Methylpcnlan-2-one
`4-Methyl-2-pemanone
`MIBK
`
`[sobutyl alcohol
`2-Melhylpropan-1-ol
`
`N-Methylpyrrolidone
`
`1—Methylpy1'r0lidin~2-one
`
`1 -Methyl-2-pyrrolidinone
`
`Nitromcthane
`
`Pcntane
`
`1-Pentanol
`
`l -Propanol
`
`2-Propanol
`
`Q-Pentane
`
`Amyl alcohol
`Pentan-1-ol
`
`Pentyl alcohol
`
`Propan-1-ol
`Propyl alcohol
`
`Propan-2-ol
`Isopropyl alcohol
`
`Propyl ace-tale
`
`Acetic acid propyl ester
`
`Pyridine
`
`Sulfolane
`
`Tetrahydrothiopheno 1,1-dioxide
`
`Tetrahydrofuran
`
`Tetramethylene oxide
`Oxacyclopentano
`
`Tetra] in
`
`Toluene
`
`1,2,3,4-Tetrahydro-naphthalene
`
`Methylbenzene
`
`1,1,1 -Trichloroethane
`
`Methylchloroform
`
`1,1,2-Trichlorocthene
`
`Trichloroethono
`
`Xylene‘
`
`Dimethybcmvene
`Xylol
`
`6
`
`Cl-l3(CH2)3COCl-[3
`
`C>cHa
`
`Cl-l3Cl-l;;_COCI-I3
`
`CI-I_~.COCH 3C1 l(Cl-lg )2
`
`(Cl-l3}2CHCl-I20]-I
`
`UsN 0
`CH3
`
`CH3NO2
`
`CI 3{ CHQJ3
`
`CH3(CH2J3CHgOH
`
`CH3CH3CH2OH
`
`(CH3)2CHOI-I
`
`CH3COOCl-IZCHECH3
`
`CM
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 2
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 3
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 2
`
`Class 1
`
`Class 2
`
`Class 2
`
`

`
`Contains Nrmbinrling Recrrnrnrendations
`
`'Usuaily 60% In-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl beiizelie.
`
`III.
`
`SOLVENTS GROUPEI} BY CLASS
`
`Solvents in Class 1 (Table 1) should not be employed in the manufacture of drug substances,
`excipients, and drug products because oftheir unacceptable toxicity or their deleterious
`environmental effect. However, iftheir 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,
`unless otherwisejustified. The solvent 1,1,1-Trichloroethane is included in Table 1 because it is
`an environmental hazard. The stated limit of 1,500 ppm is based on a review of the safety data.
`
`Table 1. — Class 1 Solvents in Pharmaceutical Products (Solvents That Should Be Avoided)
`
`Solvent
`
`Benzene
`
`Carbon tetrachloride
`
`1,2-Dichloroethane
`
`1,1~Dioh1oroethene
`
`Concentration Limit
`(ppm)
`
`2
`
`4
`
`S
`
`8
`
`Concern
`
`Carcinogen
`
`Toxic and environmental hazard
`
`Toxic
`
`Toxio
`
`1,1,1-Trichloroethane
`
`1,500
`
`Environmental hazard
`
`5
`
`7
`
`

`
`Crmtuins Nanlfindirrg R ec0mmendatr'ons
`
`Solvents in Class 2 (Table 2) should be limited in pharmaceutical products because oftheir
`inherent toxicity. PDES are given to the nearest 0.1 mgfday, and concentrations are given to the
`nearest 10 ppm. The stated values do not reflect the necessary analytical precision of
`determination. Precision should be determined as part of the validation ofthe method.
`
`Table 2. -— Class 2 Solvents in Pharmaceutical Products
`
` Solvent PDE {mgiday} Concentration Limit (ppm)
`
`
`Acetonilrile
`4. l
`410
`
`Chlorobenzene
`
`Chloroform
`
`Cyclohexane
`
`Cumcnc
`
`1,2-Dichloroethene
`
`Dichloromethane
`
`1,2-Dirnethoxy eth ane
`
`N,N -Dimethylacetamide
`
`N,N~Dimethylformarnide
`
`1,4-Dioxane
`
`2-Ethoxyethanol
`
`Ethyieneglyco]
`
`Formamide
`
`Hcxane
`
`Methanol
`
`2-Meth oxyethanol
`
`Methylbutyl ketone
`
`Methylcyciohexane
`
`N-Methylpyrrolidone
`
`Nitromethane
`
`Pyridine
`
`Sulfoiane
`
`Tetrahydro furari
`
`Tetra] in
`
`Toluene
`
`1,1,2-Trichloroethene
`
`Xylene'
`
`3.6
`
`0.6
`
`38.8
`
`0.7
`
`18.7
`
`6.0
`
`1.0
`
`10 .9
`
`8.8
`
`3 .8
`
`1 .6
`
`6.2
`
`2.2
`
`2.9
`
`30.0
`
`0.5
`
`0.5
`
`1 1.8
`
`5.3
`
`0 .5
`
`2.0
`
`1.6
`
`7.2
`
`1.0
`
`8.9
`
`0 .8
`
`21.7
`
`‘Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.
`
`6
`
`8
`
`8
`
`360
`
`60
`
`3,880
`
`70
`
`1,870
`
`600
`
`100
`
`1,090
`
`880
`
`3 80
`
`1 60
`
`620
`
`220
`
`290
`
`3,000
`
`50
`
`50
`
`1,180
`
`530
`
`50
`
`200
`
`160
`
`720
`
`100
`
`890
`
`80
`
`2,170
`
`

`
`Comfmhs Nonbinding Recommendations
`
`Solvents in Class 3 (Table 3) may be regarded as less toxic and of lower risk to human health.
`Class 3 includes no solvent known as a human health hazard at levels normally accepted in
`pharmaceuticais. However, there are no long-term toxicity or carcinogenicity studies For many
`ofthe solvents in Class 3. Available data indicate that they are less toxic in acute or short-term
`studies and negative in genotoxicity studies. It is considered that amounts of these residual
`solvents of50 mg per day or less (corresponding to 5,000 ppm or 0.5 percent under Option 1)
`would be acceptable without justification. Higher amounts may also be acceptable provided they
`are realistic in relation to manufacturing capability and good manufacturing practice (GMP).
`
`Table 3. — Class 3 Solvents Which Should Be Limited by GMP or Other Quality—Based
`Requirements
`
`Acetic acid
`
`Acetone
`
`Anisole
`
`l -Butanol
`
`2-Butanol
`
`Butyi acetate
`
`rerr-Butylrnethyl ether
`
`Dimethyl sulfoxide
`
`Ethanol
`
`Ethyl acetate
`
`Ethyl ether
`
`Ethyl formate
`
`F ormic acid
`
`Heptane
`
`Isobutyl acetate
`
`Isopropyl acetate
`
`Methyl acetate
`
`3-Methy]—1—butanol
`
`Methylethyl ketone
`
`Methylisobutyl kctonc
`
`2—Methyl- I -propanol
`
`Pent-ane
`
`l—Pentar1ol
`
`l~Propanol
`
`2-Propanol
`
`Propyl acetate
`
`9
`
`

`
`Contains Nonbinding Recommendations
`
`The solvents listed in Table 4 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
`were found. Manufacturers should supplyjustifieation for residual levels ofthese solvents in
`pharmaceutical products.
`
`Table 4. — Solvents for Which No Adequate Toxicological Data Were Found
`
`1,1-Diethoxypropane
`
`1 , l—Di111ethox)/methane
`
`2,2-Dimethoxypropane
`
`lsooetane
`
`Isopropyi ether
`
`Methylisopropyl ketune
`
`Methyltetrahydmfuran
`
`Petroleum ether
`
`Trichloroacetic acid
`
`Trifluoroacetic acid
`
`8
`
`10
`
`10