Residual solvents in pharmaceutical products

1. ICH GUIDELINE : Q3C GUIDELINE
FOR RESIDUAL SOLVENTS
By
A.Nagakrishna Rao

2. Contents:
 Introduction
 Scope of theGuideline
 Classification
 Limits of Residual Solvents
 Options for Describing Limits of Class 2 Solvents
 Analytical Procedures
 Reporting Levels ofresidual solvents
 Residual Solvents in Pharmaceuticals

3. Introduction
• 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
manufacturingtechniques.
• 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 to the extent possible to
meet product specifications, good manufacturing practices, or
other quality-based requirements.

4. ScopeoftheGuideline
• 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 toxicologicallyacceptable for someresidualsolvents.
• Theguideline applies to all dosageforms androutes ofadministration.
• This guidelines does not address all possible solvents, only those
identified in drugs at that time, neither address solvents intentionally
usedas excipients nor solvates.
• The maximum acceptable intake per day of residual solvent in
pharmaceutical products isdefined as“permitteddailyexposure”(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”isused

5. Classification
ResidualSolventsareclassifiedaccordingto theirRisk
Assessmentstohumanhealthto 3mainclasses
Class 1
Solvents to be
avoided
Class 2
solvents to be
limited
Class 3
Solvents with low
toxic potential

6. Limits of ResidualSolvents

7. Classification of Residual solvents by
Risk assessment
Class 1 solvents to be avoided
Known human carcinogens, Strongly suspected
human carcinogens ,Environmental hazards
Class 2 solvents to be limited
Nongenotoxic animal or possible causative
agents of other irreversible toxicity, such as
neurotoxicity or teratogenicity
Class 3 solvents with low toxic potential
Solvents with low toxic potential to human: no
health-based exposure limit isneeded.

8. Class1Solvents
SolventstoBeAvoided
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 asshown in Tableunlessotherwise justified.
Solvent
Concentrationlimit
(ppm)
Concern
Benzene 2 Carcinogen
Carbontetrachloride 4 Toxicandenvironmental hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Environmentalhazard

9. Class2Solvents
Solventstobelimited
Solvents in class 2 should be limited in pharmaceutical products
because of their inherent toxicity. Examples of class 2 solvent in the
belowtable
Solvent PDE(mg/day)
Concentrationlimit
(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

10. Class 3Solvents
(Solvents with low toxicpotential)
• Solvents in Class3 may be regarded as less toxic lower risk to human
health. However, there are no long-term toxicity or carcinogenicity
studiesfor manyof the solvents in Class3.
• Thesesolvents are considered of no human healthhazard
• Available data indicate that they arelesstoxic in acute or short-term
studies and negative in genotoxicitystudies.
• It isconsidered that amountsof these residualsolvents of 50mgper
dayor less(corresponding to 5000ppm or0.5%underOption 1)would
be acceptable without justification.
• Higher amountsmayalsobe acceptable provided they are realistic in
relation to manufacturing capability andGMP

11. • Examplesof Class3solvents which should be limited by GMPor
otherquality basedrequirements
Class 3Solvents(Continue)
Acetone Methylisobutyl ketone Ethylether
Aceticacid, Heptane Dimethyl sulfoxide Ethylformate
Anisole Ethanol Formicacid
Methyl acetate Ethylacetate 3-Methyl-1-butanol
Butylacetate tert-Butylmethyl ether Isobutylacetate
1-Butanol Methylethyl ketone 1-Pentanol
2-Methyl-1-propanol Heptane Isopropylacetate
2-Butanol Pentane 1-Propanol

12. • 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 baseaPDEwasfound.
• Manufacturers should supply justification for residual levels of
thesesolvents in pharmaceuticalproducts
Solvents forwhichNoAdequateToxicologicalData was Found
•Examples:
1,1-Diethoxypropane
1,1-Dimethoxymethane
2,2-Dimethoxypropane
Isooctane
Isopropylether
Methylisopropylketone
Methyltetrahydrofuran
Petroleumether
Trichloroaceticacid
Trifluoroaceticacid

13. Options for Describing Limits of Class 2 Solvents
Twooptionsareavailablewhensetting limits for Class2solvents.
Testingshould be performed for residual solvents when production or
purification processesare knownto result in the presenceof suchsolvents.
Option1:
Byassumingaproduct massof 10gadministered daily.
Concentration(ppm)=1000xPDE/Dose
Here,PDEisgivenin terms of mg/day anddoseisgivening/day.
Nofurther calculation isnecessaryprovided that the daily dosedoesnot
exceed10g.
Option2:
Productsthat are administered in dosesgreater than 10gperday.
Appliedbyaddingthe amounts of aresidualsolvent present in eachof the
components of the drug product. Thesum of theamounts of solventper
dayshouldbelessthanthatgivenbythePDE.

14. Example for Option2
The permitted daily exposure to acetonitrile is 4.1mg 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 givenin the followingtable.
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 recommendationsin thisguideline.

15. WhatiftheproductmeetsneithertheOption1
northeOption 2limit?
The manufacturer could test the drug product to determine if the
formulation process reduced the level of acetonitrile. If the level of
acetonitrile was not reduced during formulation to the allowed
limit, then the manufacturer of the drug product should take other
steps to reduce the amount of acetonitrile in the drug product. If all
of these steps fail to reduce the level of residual solvent, in
exceptional cases the manufacturer 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 ahigherlevel.

16. Specificationsforclass1and class2
residual solventsinactivesubstances
A) Class1solventsusedas startingmaterials
Theyshould be routinely controlled, either in asuitable intermediate
orin the final activesubstance.
B) Class1solventspresentas animpurity
It should beNMT30%of the specifiedlimit, in asuitableintermediate
or in the final active substance.Supportingdata should be presented
on 6 consecutive pilot scalebatchesor 3consecutive industrial scale
batches.
C) Class2solventsusedinthelaststepofthesynthesis
It should beroutinely controlled in the final active substance.
D) Class2solventsusedpriortothelaststepofthesynthesis
It should be NMT10%of the acceptable concentration limit (e.g.,
acetonitrile 41ppm). Supportingdata should be presented on 6
consecutive pilot scalebatchesor 3consecutive industrial scalebatches.

17. • Residual solvents are typically determined using chromatographic
techniques suchasgaschromatography.
• Any harmonized procedures for determining levels of residual
solventsas described in the pharmacopoeiasshould beused.
•Manufacturers would be free to select the most appropriate
validatedanalytical procedurefor aparticularapplication.
• If only Class3 solvents are present, a nonspecific method such as
losson drying maybeused.
Analytical Procedures

18. •Manufacturers of pharmaceutical products need certain information
about the content of residualsolvents in excipientsor drugsubstances.
•Thefollowing statements are given in the ICHGuideline asacceptable
examples of the information that could be provided from a supplier
of excipientsor drug substancesto apharmaceuticalmanufacturer.
OnlyClass3solvents arelikely to bepresent. Losson drying islessthan0.5%.
OnlyClass2solvents X,Y,... arelikely to bepresent. All arebelow the Option1 limit.
OnlyClass2solvents X,Y,... andClass3solvents arelikely to bepresent. Residual Class2
solvents arebelow the Option 1limit andresidual Class3solvents arebelow 0.5%.
Reporting levelsofresidual solvents

19. Reporting levelsofresidual solvents
•If Class1 solvents are likely to be present, they should be identified
and quantified.
•If solvents of Class 2 or Class 3 are present at greater than their Option 1
limits or 0.5%,respectively,they should be identified andquantified.
•Manufacturer 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 ahigher level.
•Higher levels of residual solvents may be acceptable in certain cases such as
short term (30 days or less) or topical application. Justification for these
levelsshould be madeon acaseby casebasis.

20. ResidualSolventsinPharmaceuticals
Exposure limits in this guideline are established by referring to methodologies and
toxicity data described in EHCand 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 exposurelimits:
1) Patients (not the general population) use pharmaceuticals to treat their
diseases or for prophylaxis to prevent infection or disease.
2) Residual solvents are unavoidable components in pharmaceutical
production and will often be apart of drug products.
3) Residual solvents should not exceed recommended levels except in exceptional
circumstances.
4) 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 for example by FDARedBook andEPA*.
Environmental Health Criteria (EHC)
Integrated Risk Information System (IRIS)