Residual solvents USP <467> ICH Q3C Classification of Residual Solvents by Risk Assessment Options for Determining Levels of Class 2 Residual Solvents Methods For Establishing Exposure Limits Analytical Procedures

1. RESIDUAL SOLVENTS
USP <467>
Presented by:
Aditya Sharma
M.S. (Pharm)
Pharmaceutical Analysis
NIPER Guwahati
1

2. CONTENTS
Introduction
Classification of Residual Solvents by Risk Assessment
Options for Determining Levels of Class 2 Residual Solvents
Methods For Establishing Exposure Limits
Analytical Procedures
Conclusion
References
2

3. 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.
3
Figure 1: Outline of Organic Volatile Impurities
Organic
Volatile
Impurities
Proposed in PF
14(2)(1988)
Solvents found
in a final
dosage form
No
Therapeutic
Benefit
Acceptance
criteria
based on
relative
toxicity
Limits to 7
solvents
Applied
only to Drug
Substances
and some
excipients
Residual
Solvents,
USP <467>
(Official on
July 1, 2007)
ICH
Q3C(November
06, 1996)

4. 4
Classification of
Residual Solvents
by Risk Assessment
Class 1 Residual
Solvents
(Solvents to be Avoided)
Known human
carcinogens.
Strongly suspected
human carcinogens.
Environmental hazards.
Class 2 Residual
Solvents
(Solvents to be Limited)
Non-genotoxic animal
carcinogens or possible
causative agents of other
irreversible toxicity, such as
neurotoxicity or
teratogenicity
Class 3 Residual
Solvents
(Solvents with Low Toxic
Potential)
Low toxic potential to humans;
Class 3 residual solvents may have
PDEs of up to 50 mg or more per
day.
e.g. acetone, acetic acid, heptane,
pentane, ethanol, etc.
Figure 2: Classification of Residual Solvents by Risk Assessment
Examples of Class 1 Residual
Solvents are benzene, 1,1-
Dichloromethane, etc. having
conc.n limit(ppm) of 2 and 8
respectively.
Examples of Class 2 Residual
Solvents are acetonitrile,
chloroform, toluene,
pyridine, tetrahydrofuran ,
etc. having PDE(mg/day)
value of 4.1, 3.6, 8.9, 2.0, 7.2
respectively.

5. Options for Determining Levels of Class 2 Residual Solvents
5
Option 1—Concentration Limit Option 2—Summation of Components Content
• The values for Class 2 solvents were calculated
using the equation below by assuming a product
weight of 10 g administered daily.
 Concentration (ppm) = (1000 µg/mg × PDE)/dose
• Option 2 must be used to demonstrate
compliance with this chapter where the
maximum daily dose of the official product
exceeds 10 g/day or where at least one
component in the formulation exceeds the
Option 1 limits.

6. Component Amount in
Formulation
(g)
Acetonitrile
Content
(ppm)
Daily
Exposure
(mg)
Drug substance 0.3 800 0.24
Excipient 1 0.9 400 0.36
Excipient 2 3.8 800 3.04
Official product 5.0 728 3.64
Table 1: Example of Meeting the Requirement for Acetonitrile as per Option 2
Consider the example of the application of Option 1 and Option 2 limits to acetonitrile concentration in an
official product. The PDE for acetonitrile is 4.1 mg/day, thus the Option 1 limit is 410 ppm.
Excipient 1 meets the Option 1 limit, but the official substance, Excipient 2, and Official product do not meet the
Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg/day and thus conforms to the
recommendations in this chapter.
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7. Methods For Establishing Exposure Limits
Animal Toxicity Study For Determining PDE for Tetrahydrofuran:
Groups of 50 male and 50 female rats were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by
inhalation, 6 hours per day, 5 days per week, for 105 weeks. THF exposure in the most sensitive species, the
male rat at 200 ppm was used for the PDE calculation.
PDE = 71.65 x 50 = 7.165 mg/day = 7.2 mg/day
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5 x10 x1x10 x1
PDE = NOEL x Weight Adjustment
F1 x F2 x F3 x F4 x F5
F1 = 5 for extrapolation from rats to humans
F2 = 10 to account for differences between individual humans
F3 = 1 for studies that last at least one half lifetime (1 year for rodents)
F4 = 10 for a teratogenic effect without maternal toxicity
F5 = 1 because the no effect level was determined
NOEL: Abbreviation for no-observed-effect level.
PDE: Abbreviation for permitted daily exposure.

8. ANALYTICAL PROCEDURES
• Residual solvents are typically determined using chromatographic techniques such as gas chromatography.
• If only Class 3 solvents are present, a nonspecific method such as loss on drying (LOD) may be used.
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Figure 3: Decision tree for the control of Class 3 residual solvents. Modified from Ref. USP General Chapter <467> Residual Solvents,
USP41-NF36 2S, Official March 01, 2019.
Are
Class 1
or 2
solvents
in test
article
﹖
LOD ≤ 0.5% LOD ≥ 0.5%
Quantitate
Class 1, 2
and 3
residual
solvents
Quantitate
Class 1 and
2 residual
solvents
Quantitate
Class 3
residual
solvents
Meets Class
3
requirements
NO YES
NO
NO YES
YES

9. • GC is the technique of choice for the identification and quantification of residual solvents.
• The two most common approaches are direct injection (dissolved sample is injected directly into the GC
injection port) and headspace analysis.
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GAS CHROMATOGRAPHY
Figure 4: Diagrammatic Representation of Gas Chromatography
*GC-Gas Chromatography

10. Final Gaseous Phase
Concentration
Gaseous Phase
“Headspace”
VS
VG
VV
Initial Sample
Phase
Concentration
Co
CG
Δ Temp.
Δ Time
Sample Phase
Solvent Molecule Volatile Analyte Molecule
Sample Preparation/Introduction Techniques
• Sample preparation is a function of how the sample is intended to be introduced into the instrument and what
solvents are being measured.
Techniques are:
1. Headspace
2. Direct injection
3. Solvent micro-extraction
4. Purge and Trap
5. Dispersive liquid-liquid micro-extraction
6. Solid phase micro-extraction (SPME)
7. Single drop micro extraction (SDME)
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Figure 5: Headspace Gas Chromatography

11. GC parameter Procedure A Procedure B Procedure C
Sample
Preparation
Water-soluble
articles
Water-insoluble
articles
About 250 mg of the tested material dissolved in a 25 mL volumetric flask with water and
then 5.0 mL of this solution transferred to head space vial filled with 1.0 mL of water.
About 500 mg of the tested material dissolved in a 10 mL volumetric flask with N,N
dimethylformamide and then 1.0 mL of this solution transferred to head space vial filled with
5.0 mL of water.
Column 6% cyanopropyl-phenyl-
94%-dimethyl polysiloxane
(USP G43)
Polyethylene glycol
(USP G16))
6% cyanopropyl-phenyl-
94%-dimethyl polysiloxane
(USP G43)
Dimensions A. 30m × 0.32 mm
B. 30m × 0.53 mm
Film thickness A. 1.8 μm
B. 3.0 μm
0.25 μm A. 1.8 μm
B. 3.0 μm
Temperature program 40°C for 20 min
Ramp at 10°C
Hold at 240°C for 20 min
50°C for 20 min
Ramp at 6°C
Hold at 165°C for 20 min
40°C for 20 min
Ramp at 10°C
Hold at 240°C for 20 min
Detector Flame ionization
Carrier gas linear velocity ~35 cm/s (for helium)
Injector 140°C (Headspace)
Split ratio 1:5 (can be adjusted)
Headspace parameters 1 2 3
Equilibration temperature 80°C 105°C 80°C
Equilibration time 60 min 45 min 45min
Transfer line temperature 85°C 110°C 105°C
Pressurization time ≥60s ≥60s ≥60s
Injection volume 1ml 1ml 1ml
Table
2:
Pharmacopoeial
procedures
A,
B
and
C
chromatographic
and
headspace
conditions.
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12. Preparation of test
and standard
solution
Procedure A
Peaks
corresponding
to residual
solvent have
areas less
than
standards
﹖
Passes the test no
further action
Procedure B
Peaks
corresponding
to residual
solvent have
areas less
than
standards
﹖
Passes the test no
further action
Procedure C
Calculate amount
of residual
solvents found
Is the
article
under test
is an official
product
﹖
Do the results
meet option 1
concentration
limits
﹖
Do the
results meet
option 2
levels for
PDE
﹖
Label to indicate
residual solvent
and amount found
Fails the Test
Passes the test no
further action
NO
NO
NO
NO
YES
YES
YES
YES
NO
Decision
Tree
12
Figure 6: Diagram relating to the identification of residual solvents and the
application of limit tests.

13. Conclusion
• Residual solvents from the processes in the manufacturing of pharmaceuticals are hazardous and cause
serious problems and must be removed.
• Certain methods like thermogravimetric analysis, loss on drying are simple but lack specificity to identify the
volatile analyte, spectroscopic and spectrometric methods lacked sensitivity.
• Gas chromatographic techniques are ideal for residual solvent analysis. They are selective for
characterization of residual solvents and also sensitive to accurately determine these solvents in trace
amounts, when present in pharmaceutical substances.
• Recognizing the need to control the presence of these solvents, which are likely to cause undesirable toxic
effects. United States Pharmacopoeia (USP-NF XXIV) has identified their potential hazardous effects and
provides methods for their detection in pharmaceuticals.
• The methods includes direct injection method, head space analysis, solid phase micro extraction (SPME)
method and the new technique known as single drop micro extraction (SDME).
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14. References
• USP General Chapter <467> Residual Solvents, USP41- NF36 2S, Official March 01, 2019
• ICH Guideline. Impurities: Guideline for Residual Solvents Q3C(R6), October 20, 2016.
• EMA Annexes to: CPMP/ICH/283/95 Impurities: Guideline for Residual Solvents & CVMP/VICH/502/99
Guideline on Impurities: Residual Solvents, February 20, 2013.
• Puranik S, Pai P, Rao G. Organic volatile impurities in pharmaceuticals. Indian Journal of Pharmaceutical
Sciences. 2007;69(3):352-358.
• Grodowska K, Parczewski A. Analytical Methods for Residual Solvents Determination in Pharmaceutical
Products. Acta Poloniae Pharmaceutica. 2010; 67(1):135-141.
• Witschi C, Doelker E. Residual solvents in pharmaceutical products: acceptable limits, influences on
physicochemical properties, analytical methods and documented values. European Journal of Pharmaceutics
and Biopharmaceutics. 2010;43(3):215-242.
• D'Autry W, Zheng C, Wolfs K et al. Mixed aqueous solutions as dilution media in the determination of
residual solvents by static headspace gas chromatography. Journal of Separation Science. 2011;34(11):1299-
1308.
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