residual solvents: ich q3c impurities: residual solvents · ¾solvent classification ......

Residual SolventsResidual Solvents

ICH Q3C Impurities: Residual SolventsContract Laboratories Perspectives

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

Residual SolventsResidual Solvents

This Session will address the implementation of ICH Residual Solvents requirements by USP and PhEur from perspective of CRO:

Solvent ClassificationInteraction between Laboratory and API ManufacturerSelection of Methodologies

Screening methodologiesMethod ValidationRoutine vs. Qualification testing

Past Chromatographic ChallengesCase Studies

IntroductionIntroduction

• 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.

IntroductionIntroduction

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 foridentification 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 Classification of Residual Solvents by Risk AssessmentAssessment

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 avoided-Known human carcinogens, strongly suspected human carcinogens, and

environmental hazards. Class 2 solvents: Solvents to be limited-Nongenotoxic 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 potential-Solvents 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 SponsorInteraction 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 (GC-

FID or GC/MS)• Is prescreening required?• API Qualification or routine Testing?• Method Validation Scope


• Method TransferCRO required to review validation reportFeasibilityWrite protocolGenerally, selectivity, LOD/LOQ and RepeatabilityCRO will provide Final report for review and approval

• Routine AnalysisAlways start with USP <467> procedure AUpon completion of studies CRO will provide C of A and Raw data if deemed necessary.


• 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


• 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


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

SelectivityLinearity from LOQ to 120% of specified limit for each solventLOD/LOQ for standards and Spiked sampleRepeatabilityIntermediate PrecisionAccuracy: 80 to 120% of each solventRobustness

• GC• Head Space


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


Routine API TestingPerform Routing Testing as follow:

Chromatographic non-interferenceLOD/LOQSystem Suitability Bracketing StandardsSample (n=3)BlankBracketing Standard

Selection of MethodologiesSelection 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.


• 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 3could be assayed by non-specific techniques, such as weight loss on drying <731>, due to their low toxicity.


• 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 ColumnHeater (MACH)

Figure 1. Agilent GC/MS equipped with Head Space AnalyzerAgilent 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 1Past Challenges 1USP OVI Method IV for Class II SolventsUSP 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 .


Chromatogram 1

Methylene Chloride

1,4-Dioxane

Trichloromethene

Chloroform

Unknown Peaks

Sample

Standard


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


Chromatogram 2

Chloroform

1,4-Dioxane

Trichloromethene

Methylene Chloride

Sample

Standard

Unkown Peak

Past Challenges IIIPast Challenges IIIUSP OVI Method I for Class II SolventsUSP 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.


Chromatogram 3

Methylene Chloride

Chloroform

Trichloroethylene

Chloroform

Methylene Chloride

Chloroform

1,4-Dioxane

Unknown Peak Standard

Sample

Past ChallengesPast Challenges

Lesson Learned

Perform API Screening by Utilizing GC/MS

Ask for DMF

Qualify your API

Published Methodologies in USPPublished Methodologies in USPProcedure A (Profiling) for Procedure A (Profiling) for WaterWater--Soluble ArticleSoluble Article

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 G43Carrier: He or N2 with linear velocity of 35 cm/sec and split ratio of 1:5Column temperature: 50 °C – 6 °C /min--165 °C hold for 20 minInjection port: 140 °CDetector Temperature: FID @ 250 °C Method of Injection: Static Head Space

Note: USP Residual Solvent standards are available

Published Methodologies in USPPublished Methodologies in USPProcedure B (Peak ID)Procedure B (Peak ID)

Class 1 and Class 2 Residual Solvents

Chromatographic Conditions:GC-FIDColumn: 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 G16Carrier: He or N2 with linear velocity of 35 cm/sec and split ratio of 1:5Column temperature: 40 °C –10 °C /min--240 °C Injection port: 140 °CDetector Temperature: 250 °C Method of Injection: Static Head Space

Published Methodologies in USPPublished Methodologies in USPProcedure CProcedure 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:

BlankSystem SuitabilityStandard SolutionTest SolutionSpiked Test SolutionStandard Solution

Screening MethodScreening 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 TimeCase 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 AnalyzerColumn: Phenomenex ZB-624, 30 m x 0.53 mm, 3μmTemperature program: 40°C for 20 min -----50°C/min to 240°CInjection Port Temp.: 140°CHead Space Parameter: 80°C for 30, 45 and 60 minInjection Volume: 1 ml

Case Study I : Class I Solvents Incubation TimeCase Study I : Class I Solvents Incubation TimeGraph 1

0 500 1000 1500 2000 2500 3000 3500

Benzene

TCE

1,2-DCA

60min45min30min

Peak Area

Case Study I : Class I Solvents Incubation TimeCase 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 SolventsCase 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, Case Study II : Screening Method For Class II Solvents, ResultsResults

Methylene ChlorideTrichloromethene Toluene

Blue: Spike sampleRed: BlankGreen: Unspike Sample

Case Study III : DMSO Selection for NonCase Study III : DMSO Selection for Non--Aqueous Aqueous Soluble APISoluble API

Objective: To evaluate chromatographic profile of various DMSOScope: 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)


Results

DMSO A (Blank)

DMSO A with Sample


DMSO B (Blank)

DMSO B with Sample


DMSO C with Sample

DMSO C (Blank)

SummarySummary

Review API DMF or Technical Package Perform Screening of APIQualify API

AcknowledgementAcknowledgement

Ruggero Pocci Ruggero Pocci GC Group LeaderGC Group LeaderDavid PrideDavid Pride GC ScientistGC ScientistHamid ForouharHamid Forouhar QC managerQC managerMai Zhang,PhD Mai Zhang,PhD Sr. ScientistSr. Scientist

residual solvents: ich q3c impurities: residual solvents · ¾solvent classification ......

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