Residual Solvents

ICH Q3C Impurities: Residual Solvents

Contract Laboratories Perspectives
Assad J. Kazeminy, Ph.D.
President and CEO of Irvine Analytical Laboratories, Inc.

Residual Solvents
This Session will address the implementation of ICH Residual
Solvents requirements by USP and PhEur from perspective of CRO:
Solvent Classification
Interaction between Laboratory and API Manufacturer
Selection of Methodologies

Screening methodologies
Method Validation
Routine vs. Qualification testing
Past Chromatographic Challenges
Case Studies

Introduction
Residual solvents have had official limits in the United States as

set in USP 30 <467> and by the FDA in 1997 and have been
monitored by most pharmaceutical manufacturers extensively for
more than two decades in both bulk and finished products.

Residual process solvents in pharmaceutical samples are monitored

using gas chromatography (GC) with either flame ionization
detection (FID) or mass spectrometry. Based on good
manufacturing practices, measuring residual solvents is mandatory
for the release testing of all active pharmaceutical ingredients and
is routinely performed on samples of process intermediates.
On Jan 1, 2007 title of Chapter <467> will be changed to Residual
Solvents.

Introduction
Sample introduction techniques include both static and dynamic

headspace analysis, solid-phase microextraction, and direct injection of

solution containing bulk drug substance or drug product into the gas
chromatograph.
In conclusion, gas chromatograph-based procedures will continue to

dominate residual solvent testing because of its specificity for

identification of the solvent, but the use of alternative sample introduction
techniques into a gas chromatograph will continue to expand in the near
future.

Classification of Residual Solvents by Risk

Assessment
Solvents were evaluated for their possible risk to human health and placed into
one of three classes as follows:
Class 1 solvents: Solvents to be avoidedKnown human carcinogens, strongly suspected human carcinogens, and
environmental hazards.
Class 2 solvents: Solvents to be limitedNongenotoxic animal carcinogens or possible causative agents of other
irreversible toxicity such as neurotoxicity or teratogenicity. Solvents
suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potentialSolvents with low toxic potential to man; no health-based exposure limit is
needed. Class 3 solvents have PDE's of 50 milligrams (mg) or more per day

Interaction between CRO and Sponsor

In order to launch and complete studies successfully the following steps
are recommended:

Project Initiation
Provide CRO with DMF information and/or Physico/Chemical properties
of the API
Provide limits for each known residual solvent to CRO if Testing Drug
Product (Based on TDI)
Agree on choice of technology to be utilized in support of testing (GCFID or GC/MS)
Is prescreening required?
API Qualification or routine Testing?
Method Validation Scope

Interaction between CRO and Sponsor

Method Transfer
CRO required to review validation report
Feasibility
Write protocol
Generally, selectivity, LOD/LOQ and Repeatability
CRO will provide Final report for review and approval
Routine Analysis
Always start with USP <467> procedure A
Upon completion of studies CRO will provide C of A and Raw data
if deemed necessary.

Interaction between CRO and Sponsor

Screening Method
It is recommended to perform chromatographic profile for API which
residual solvent are not known and/or their respective limits are not
known.
Generally GC/MS equipped with Head Space analyzer is
recommended
Due to its greater sensitivity
Greater selectivity
In addition to chromatographic profile, following studies need to be
evaluated:
LOD/LOQ
Repeatability

Interaction between CRO and Sponsor

Follow USP Procedure A
If peak response of any peak in Test solution is to either peak in
Class I and or Class II proceed to procedure B for ID
Follow USP Procedure C for accurate quantitation of known
residual solvents

Interaction between CRO and Sponsor

Method Validation
Upon completion of screening method, the method needs to be Validated as
follow:

Selectivity
Linearity from LOQ to 120% of specified limit for each solvent
LOD/LOQ for standards and Spiked sample
Repeatability
Intermediate Precision
Accuracy: 80 to 120% of each solvent
Robustness

GC
Head Space

Interaction between CRO and Sponsor

Qualification of API
Qualify each API by evaluating 3 consecutive lots of API

If

multiple vendors of API are available, perform repeatability in triplicate

preparation for each vendor

This work is performed only once

Upon

completion of API qualification, test future lots by analyzing samples in

triplicate preparation

Interaction between CRO and Sponsor

Routine API Testing
Perform Routing Testing as follow:

Chromatographic non-interference
LOD/LOQ
System Suitability
Bracketing Standards
Sample (n=3)
Blank
Bracketing Standard

Selection of Methodologies

To determine Residual Solvents, many quality-control labs in

pharmaceutical manufacturing employ GC-FID for the determination
of residual solvents that are included in either USP <467> or ICH
guidelines.
Because some of the solvents co-elute, these labs must use at least two
different separation phases. Co-elution is not a problem with mass
spectrometric detection, as most co-eluting analytes have unique ions.
The mass spectrometer also provides a means to identify unknown or
unexpected contaminants.
With the 5975 inert Mass Selective Detector (MSD), a single analysis
provides both selected ion monitoring (SIM) for sensitive quantitation
and full-scan spectra for identification of unknowns.

Selection of Methodologies

According to published list in ICH Q3C , there are 61

solvents.

This list would be a challenge for separation on any single

GC phase , as critical coelution will be inevitable.

In ICH guideline, residual solvents are grouped based on

their toxicity, both class I and class 2 need to be analyzed
by sensitive and specific methodologies. However, class
3 could be assayed by non-specific techniques, such as
weight loss on drying <731>, due to their low toxicity.

Selection of Methodologies

Due to the advance in head space technology-mainly dynamic

sampling techniques, and dual column capability faster analysis, better
sensitivity and specificity is possible (MACH system allows up to 4
columns).

Restek group has reported separation of 23 residual solvents in 8 min

by utilizing dual column separation on MACH system. MACH is an
Agilent GC 6890 equipped with Gerstel Modular Accelerated Column
Heater (MACH)

Figure 1. Agilent GC/MS equipped with Head Space Analyzer

Agilent Technologies, 6890N Network GC system,
MS: Agilent Technologies, 5975 inert XL Mass Selective Detector
Data aAnalysis: Software: G1701DA ChemStation,

Figure 2.

CTC Autosampler System for Headspace and Liquid Injection.

Past Challenges 1
USP OVI Method IV for Class II Solvents

Two early eluting extraneous peaks were detected on sample chromatogram.

Upon laboratory investigation it was determined that these two peaks were
reproducible and are process Solvents from API.

In API Technical Package there was no information about those two Unknown
peaks.

Further investigation is pending .

Past Challenges 1
USP OVI Method IV for Class II Solvents
Chromatogram 1

Unknown Peaks
Methylene Chloride

Trichloromethene
Sample

Chloroform
1,4-Dioxane
Standard

Past Challenges 2
USP OVI Method IV for Class II Solvents

One Late eluting extraneous peak was detected on sample chromatogram.

Laboratory Investigation suggested that Unknown peak is present in every

sample preparation of API (Same Lot).

In API Technical Package there was no information about this Unknown

peak.

Further investigation is pending

Past Challenges 2
USP OVI Method IV for Class II Solvents
Chromatogram 2

Methylene Chloride

Trichloromethene

Chloroform

Unkown Peak

Sample
Standard

1,4-Dioxane

Past Challenges III

USP OVI Method I for Class II Solvents

One early eluting extraneous peak was detected on sample chromatogram.

Laboratory Investigation suggested that Unknown peak is present in every

sample preparation of API (Same Lot).

In API Technical Package there was no information about this Unknown

peak.

No attempt was made for Identification of Unknown peak.

Past Challenges 3

USP OVI Method IV for Class II Solvents

Chromatogram 3

Methylene Chloride
1,4-Dioxane

Unknown Peak

Methylene Chloride
Trichloroethylene
Chloroform

Standard
Sample

Chloroform

Chloroform

Past Challenges
Lesson Learned

Perform API Screening by Utilizing GC/MS

Ask for DMF

Qualify your API

Published Methodologies in USP

Procedure A (Profiling) for Water-Soluble Article
Class 1 and Class 2 residual Solvents

Chromatographic Conditions:
Column: 0.32mm x 30 m fused-silica column coated with 1.8 m layer of
G43 or 0.53 mm x 30m wide-bore column coated with 3.0 m layer of G43
Carrier: He or N2 with linear velocity of 35 cm/sec and split ratio of 1:5
Column temperature: 50 C
6 C /min--165 C hold for 20 min
Injection port: 140 C
Detector Temperature: FID @ 250 C
Method of Injection: Static Head Space

Note: USP Residual Solvent standards are available

Published Methodologies in USP

Procedure B (Peak ID)
Class 1 and Class 2 Residual Solvents
Chromatographic Conditions:
GC-FID
Column: 0.32mm x 30 m fused-silica column coated with 0.25 m layer of
G16 or 0.53 mm x 30m wide-bore column coated with 0.25 m layer of G16
Carrier: He or N2 with linear velocity of 35 cm/sec and split ratio of 1:5
Column temperature: 40 C 10 C /min--240 C
Injection port: 140 C
Detector Temperature: 250 C
Method of Injection: Static Head Space

Published Methodologies in USP

Procedure C
Class 1 and Class 2 Residual Solvents for Water-Soluble Article
Follow Procedure A or B for Quantification of each Residual Solvent
Injection Sequence is as follows:

Blank
System Suitability
Standard Solution
Test Solution
Spiked Test Solution
Standard Solution

Screening Method
It is recommended to perform chromatographic profile for API which residual
solvents are not known and/or their respective limits are not known
Generally GC/MS equipped with Head Space analyzer is recommended
Due to its greater sensitivity
Greater selectivity
In addition to chromatographic profile, following studies need to be evaluated:
LOD/LOQ
Repeatability
Follow USP Procedure A
If peak response of any peak in Test solution is to either peak in Class I
and or Class II proceed to procedure B for ID and
Follow USP Procedure C for accurate quantitation of known residual
solvents

Case Study I : Class I Solvents Incubation Time

Objective: To assess affect of incubation time on recovery of Class I
solvents in water soluble Matrix.
Methodology:
Instrument: Agilent GC-FID equipped with Headspace Analyzer
Column: Phenomenex ZB-624, 30 m x 0.53 mm, 3m
Temperature program: 40C for 20 min -----50C/min to 240C
Injection Port Temp.: 140C
Head Space Parameter: 80C for 30, 45 and 60 min
Injection Volume: 1 ml

Case Study I : Class I Solvents Incubation Time

Graph 1

1,2-DCA
60min
45min
30min

TCE

Benzene
0

500

1000

1500

2000

2500

3000

3500

Peak Area

Case Study I : Class I Solvents Incubation Time

Conclusion:
Incubation time had minimum effect on each residual solvent
recovery.

However,

it is highly recommended to consider conducting robustness

studies on critical GC and Head Space parameters.

Case Study II : Screening Method For Class II Solvents

Objective : To evaluate a Screening method for water soluble Class II solvents

Scope of the Work: Selectivity, LOD/LOQ, System Suitability and Repeatability

Case Study II : Screening Method For Class II Solvents,

Results
Blue: Spike sample
Red: Blank
Green: Unspike Sample

Trichloromethene
Methylene Chloride

Toluene

Case Study III : DMSO Selection for Non-Aqueous

Soluble API
Objective: To evaluate chromatographic profile of various DMSO
Scope: Selectivity of method for non Aqueous soluble API was assessed by
utilization of different grades of DMSO as diluent
Method: GC/FID equipped with Head Space Analyzer
Column: ZB 624, 30 m x 0.53 mm, 3 m (USP G43)

Case Study III : DMSO Selection for Non-Aqueous

Soluble API
Results

DMSO A (Blank)

DMSO A with Sample

Case Study III : DMSO Selection for Non-Aqueous

Soluble API

DMSO B (Blank)

DMSO B with Sample

Case Study III : DMSO Selection for Non-Aqueous

Soluble API

DMSO C (Blank)

DMSO C with Sample

Summary

Review API DMF or Technical Package

Perform Screening of API
Qualify API

Acknowledgement
Ruggero Pocci
David Pride
Hamid Forouhar
Mai Zhang,PhD

GC Group Leader
GC Scientist
QC manager
Sr. Scientist

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