Q3C GUIDELINE FOR RESIDUAL SOLVENTS

Q3C
GUIDELINE FOR RESIDUAL
SOLVENTS

Contents
• Introduction
• Scope of the Guideline
• Classification
• Limits of Residual Solvents
• Options for Describing Limits of Class 2 Solvents
• Analytical Procedures
• Reporting Levels of residual solvents
• Residual Solvents in Pharmaceuticals
• Glossary

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 manufacturing
techniques.
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.

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
toxicologically acceptable for some residual solvents.
The guideline applies to all dosage forms and routes of administration.
This guidelines does not address all possible solvents, only those
identified in drugs at that time, neither address solvents intentionally
used as excipients nor solvates.
The maximum acceptable intake per day of residual solvent in
pharmaceutical products is defined as “permitted daily exposure” (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” is used
Scope of the Guideline

Classification
Residual Solvents are classified according to
their Risk Assessments to human health to
3 main classes:
Class 1 solvents
Solvents to be
avoided
Class 2 solvents
Solvents to be
limited
Class 3 solvents
Solvents with low
toxic potential

ClassificationofResidualSolventsby
RiskAssessment
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 carcinogens or possible
causative agents of other irreversible toxicity
such as neurotoxicity or teratogenicity.
Class 3 solvents
Solvents with low toxic
potential
Solvents with low toxic potential to man; no
health-based exposure limit is needed.

Class 1 Solvents
Solvents to Be Avoided
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 as
shown inTable unless otherwise justified.
Solvent
Concentration
limit
(ppm)
Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and environmental hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Environmental hazard

Class 2 Solvents
Solvents to be limited
Solvents in class 2 should be limited in pharmaceutical products because
of their inherent toxicity.
Examples of class 2 solvent in the below table.
Solvent PDE (mg/day)
Concentration limit
(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

Class 3 Solvents (Solvents with low toxic potential)
•Solvents in Class 3 may be regarded as lower risk to human health.
However, there are no long-term toxicity or carcinogenicity studies for
many of the solvents in Class 3.
•These solvents are considered of no human health hazard
•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 of 50 mg per
day or less (corresponding to 5000 ppm or 0.5% under Option 1) would
be acceptable without justification.
• Higher amounts may also be acceptable provided they are realistic in
relation to manufacturing capability and GMP.

Class 3 Solvents (Continue)
Acetone Methylisobutyl ketone Ethyl ether
Acetic acid Heptane Dimethyl sulfoxide Ethyl formate
Anisole Ethanol Formic acid
Methyl acetate Ethyl acetate 3-Methyl-1-butanol
Butyl acetate tert-Butylmethyl ether Isobutyl acetate
1-Butanol Methylethyl ketone 1-Pentanol
2-Methyl-1-propanol Heptane Isopropyl acetate
2-Butanol Pentane 1-Propanol
Examples of Class 3 solvents which should be limited by GMP or
other quality based requirements.

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 base a PDE
was found.
•Manufacturers should supply justification for residual levels of
these solvents in pharmaceutical products.
•Examples :
1,1-Diethoxypropane Methylisopropyl ketone
1,1-Dimethoxymethane Methyltetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid
Solvents for which No AdequateToxicological Data was Found

Options for Describing Limits of Class 2 Solvents
These options are used to describe the limit of Class 2 solvents.
Testing should be performed for residual solvents when production or
purification processes are known to result in the presence of such
solvents.
Option 1:
By assuming a product mass of 10 g administered daily.
Concentration (ppm) = 1000 x PDE / Dose
Here, PDE is given in terms of mg/day and dose is given in g/day.
No further calculation is necessary provided that the daily dose does
not exceed 10 g.
Option 2:
Products that are administered in doses greater than 10 g per day.
Applied by adding the amounts of a residual solvent present in each of
the components of the drug product. The sum of the amounts of
solvent per day should be less than that given by the PDE.

Example for Option 2
The permitted daily exposure to acetonitrile is 4.1 mg 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 given in the following table.
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 recommendations in this guideline.

What if the product meets neither the Option 1 nor
the Option 2 limit ?
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 a
higher level.

Specifications for class 1 and class 2 residual
solvents in active substances
A) Class 1 solvents used as starting materials
They should be routinely controlled, either in a suitable intermediate
or in the final active substance.
B) Class 1 solvents present as an impurity
It should be NMT 30 % of the specified limit, in a suitable
intermediate or in the final active substance. Supporting data should
be presented on 6 consecutive pilot scale batches or 3 consecutive
industrial scale batches.
C) Class 2 solvents used in the last step of the synthesis
It should be routinely controlled in the final active substance.
D) Class 2 solvents used prior to the last step of the
synthesis
It should be NMT 10 % of the acceptable concentration limit (e.g.,
acetonitrile 41 ppm). Supporting data should be presented on 6
consecutive pilot scale batches or 3 consecutive industrial scale
batches.

Analytical Procedures
•Residual solvents are typically determined using
chromatographic techniques such as gas chromatography.
•Any harmonized procedures for determining levels of residual
solvents as described in the pharmacopoeias should be used.
•Manufacturers would be free to select the most appropriate
validated analytical procedure for a particular application.
•If onlyClass 3 solvents are present, a nonspecific method such
as loss on drying may be used.

• Gas chromatograph equipped with
• Headspace Sampler
• Flame Ionization Detector (FID)
• Mass-selective Detector (MSD)
(optionally)for identification &
confirmation

• If we look at the
anatomy of a
headspace vial we can
begin to see the
relationship of the vial
components and how
we can control these
parameters to create
analytical methods.
• Volatile components
partition from the
sample phase and
equilibrate in the vial
headspace.
ACI Limited

Principle for analysis of residual solvents
(continued…)
• Residual solvent analysis by static HS/GC can be enhanced by careful
consideration of two basic concepts—partition coefficient (K) and
phase ratio (β).
• Partition coefficients and phase ratios work together to determine
the final concentration of volatile compounds in the headspace of
sample vials.
• The partition coefficient (K) is defined as the equilibrium distribution
of an analyte between the sample and gas phases. Compounds that
have low K values will tend to partition more readily into the gas
phase, and have relatively high responses and low limits of detection.
• The phase ratio (β) is defined as the volume of the headspace over the
volume of the sample in the vial. Lower values for β (i.e., larger
sample sizes) will yield higher responses for compounds with
inherently low K values.

Principle for analysis of residual solvents
(continued…)
• Striving for the lowest
values for both K and β
when preparing samples
will result in higher
concentrations of volatile
analytes in the gas phase
and, therefore, better
sensitivity
ACI Limited

Overview of Method for Residual
SolventTesting
• USP <467> is divided into two separate sections based upon sample
solubility: water-soluble and water-insoluble articles.The
methodology for both types of articles is similar, but the diluent used
in both standard and sample preparations differs based upon the
solubility of the test article.
• The test method consists of three procedures (A, B, and C), that are
designed to identify, confirm, and then quantify residual solvents in
drug substances and products .
• The revised USP <467> method consists of a static headspace
extraction coupled with a gas chromatographic separation and flame
ionization detection.

Procedure A - Identification
• Procedure A is the first step in the identification process and is performed on a
G43 column to determine if any residual solvents are present in the sample at
detectable levels.
• First, Class 1 standard and system suitability solutions and Class 2 Mix A
standard solutions are assayed under the method-specified operating
conditions to establish system suitability.
• All peaks in the Class 1 system suitability solution must have a signal-to-noise
ratio not less than 3, the Class 1 standard solution must have a 1,1,1-
trichloroethane response greater than 5, and the resolution of acetonitrile and
dichloromethane must be not less than 1 in the Class 2 Mixture A solution.
• When system suitability has been achieved, the test solutions are assayed
along with the Class 1 and Class 2 Mixtures A and B standard solutions. If a
peak is determined in the sample that matches a retention time and has a
greater response than that of a corresponding reference material, then
Procedure B is performed for verification of the analyte.

Identification of residual solvent in sample
by comparing with reference standard
ACI Limited 27

Procedure B - Confirmation
• Once a residual solvent is identified and found to be above the percent daily
exposure limit, Procedure B is performed to confirm analyte identity.
• A G16 capillary column is used here as a confirmation column, because it
yields an alternate selectivity compared to a G43 column. The same standard
and system suitability preparations are used in Procedures A and B.
• The system suitability requirements differ here in that the Class 1 standard
solution must have a benzene response greater than 5 and the resolution of
acetonitrile and cisdichloroethene must not be less than 1 in the Class 2
Mixture A solution, a change from the original version.
• If the analyte identified in Procedure A again matches the retention time and
exceeds the peak response of the reference materials (with the same
exception to 1,1,1-trichloroethane), the analyst must quantify the analyte
using Procedure C.
28

Confirmation of residual solvent in sample by
comparing retention time and peak response
ACI Limited 29

Procedure C – Quantification
• Once a residual solvent has been identified and verified, Procedure C
is used to quantify the analyte by analyzing the sample against
compound-specific reference materials.
• Individual standards are prepared by diluting the analyte in solution
to a concentration of 1/20 of the concentration limit given under
concentration limitTable 1 or 2 of the method.
• Following the procedure and instrument conditions in either
Procedure A or B (whichever provides the most definitive results), a
quantifiable result is produced.
• For water-insoluble articles, the same procedure is followed, except
dimethylformamide or dimethylsulfoxide is used as the diluent.
30

Confirmation of residual solvent in sample by analyzing the
sample against compound-specific reference materials.
ACI Limited 31

Reporting levels of residual solvents
•Manufacturers of pharmaceutical products need certain information about
the content of residual solvents in excipients or drug substances.
•The following statements are given in the ICH Guideline as acceptable
examples of the information that could be provided from a supplier of
excipients or drug substances to a pharmaceutical manufacturer.
OnlyClass 3 solvents are likely to be present. Loss on drying is less than 0.5%.
Only Class 2 solvents X,Y, ... are likely to be present. All are below theOption
1 limit.
Only Class 2 solvents X,Y, ... and Class 3 solvents are likely to be present.
Residual Class 2 solvents are below the Option 1 limit and residual Class 3
solvents are below 0.5%.

Reporting levels of residual solvents
•If Class 1 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 and quantified.
•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 a higher 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 levels should be
made on a case by case basis.
Example for Residual Solvents Declaration

Residual Solvents in Pharmaceuticals
Exposure limits in this guideline are established by referring to
methodologies and toxicity data described in EHC and 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 exposure limits:
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 a part of drug products.
3) Residual solvents should not exceed recommended levels except in
exceptional circumstances.
EHC: Environmental Health Criteria
IRIS: Integrated Risk Information System

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 FDA Red Book and EPA*.
FDA Red Book:Toxicological Principles for the Safety Assessment of Direct Food Additives and
Color Additives Used in Food
EPA: US Environmental Protection Agency
References:
Impurities: Guideline for Residual SolventsQ3C(R5)
EMA: CVMP/VICH/502/99 Guideline on impurities: residual solvents , Annex I: specifications for
class 1 and class 2 residual solvents in active substances

Glossary
Term Meaning Term Meaning
ICH
INTERNATIONALCONFERENCE
ON HARMONISATION
LOEL
Lowest-Observed Effect
Level
WHO World Health Organization NOEL No-Observed Effect Level
GMP Good Manufacturing Practice PDE Permitted Daily Exposure
EHC Environmental Health Criteria TDI Tolerable Daily Intake
IRIS
Integrated Risk Information
System
ADI Acceptable Daily Intake
IPCS
International Program on
Chemical Safety
USFDA
United States Food and Drug
Administration
USEPA
United States Environmental
Protection Agency
EWG ExpertWorking Group

Q3C GUIDELINE FOR RESIDUAL SOLVENTS

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