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 z
This Session will address the implementation of ICH Residual Solvents requirements by USP and PhEur from perspective of CRO: ¾ Solvent Classification ¾ Interaction between Laboratory and API Manufacturer ¾ Selection of Methodologies
Screening methodologies Method Validation Routine vs. Qualification testing ¾ Past Chromatographic Challenges ¾ Case Studies
Introduction • Residual solvents have had official limits in the United States as set in USP 30 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 will be changed to Residual Solvents.
Introduction z 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. z 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 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 z z
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 z z
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 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 , 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
¾
Two early eluting extraneous peaks were detected on sample chromatogram.
¾
Upon laboratory investigation it was determined that these two peaks were reproducible and are process Solvents from API.
¾
In API Technical Package there was no information about those two Unknown peaks.
¾
Further investigation is pending .
z
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
¾
One Late eluting extraneous peak was detected on sample chromatogram.
¾
Laboratory Investigation suggested that Unknown peak is present in every sample preparation of API (Same Lot).
¾
In API Technical Package there was no information about this Unknown peak.
¾
Further investigation is pending
Past Challenges 2 USP OVI Method IV for Class II Solvents Chromatogram 2
Methylene Chloride
Trichloromethene
Unkown Peak Chloroform
Sample 1,4-Dioxane Standard
Past Challenges III USP OVI Method I for Class II Solvents
¾
One early eluting extraneous peak was detected on sample chromatogram.
¾
Laboratory Investigation suggested that Unknown peak is present in every sample preparation of API (Same Lot).
¾
In API Technical Package there was no information about this Unknown peak.
¾
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 Methylene Chloride Trichloroethylene Chloroform
Standard
Unknown Peak Sample Chloroform
Chloroform
Past Challenges z
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 z
Class 1 and Class 2 residual Solvents –
Chromatographic Conditions: Column: 0.32mm x 30 m fused-silica column coated with 1.8 μm layer of G43 or 0.53 mm x 30m wide-bore column coated with 3.0 μm 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) z
Class 1 and Class 2 Residual Solvents
z
Chromatographic Conditions: GC-FID Column: 0.32mm x 30 m fused-silica column coated with 0.25 μm layer of G16 or 0.53 mm x 30m wide-bore column coated with 0.25 μm 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 z
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, 3μm Temperature program: 40°C for 20 min -----50°C/min to 240°C Injection Port Temp.: 140°C Head Space Parameter: 80°C for 30, 45 and 60 min Injection Volume: 1 ml
Case Study I : Class I Solvents Incubation Time z
Graph 1
1,2-DCA 60min TCE
45min 30min
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 z z
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 μm (USP G43)
Case Study III : DMSO Selection for Non-Aqueous Soluble API z
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
