presentationOsterberg

8/6/2019 presentationOsterberg

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Impurities: Residual SolventsImpurities: Residual Solvents

ICH: Q3CICH: Q3C

Robert E. Osterberg, R.Ph., Ph.D., FellowRobert E. Osterberg, R.Ph., Ph.D., Fellow

--ATSATS

Aclairo Pharmaceutical Development GroupAclairo Pharmaceutical Development Group

Vienna, VirginiaVienna, Virginia

USP 1/2007USP 1/2007


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ICH and Residual SolventsICH and Residual Solvents

11-- Purpose and History of the ICH:Purpose and History of the ICH:

a) Beginninga) Beginning

b) Organisationb) Organisation

c) Expert Working Groups (EWGs)c) Expert Working Groups (EWGs)

22-- Q3C Guidance DocumentQ3C Guidance Document

a) Organisation, data used,a) Organisation, data used,assumptions madeassumptions made

b) Classes of solvents and examplesb) Classes of solvents and examples

c) Maintenancec) Maintenance


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What is the ICH?What is the ICH?

IInternationalnternational CConference ononference onHHarmonisation of Technicalarmonisation of Technical

Requirements for RegistrationRequirements for Registrationof Pharmaceuticals for Humanof Pharmaceuticals for Human

UseUse


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Purpose of the ICHPurpose of the ICH

PurposePurpose --to make recommendations onto make recommendations onways:ways:

--to achieve greater harmonisation in theto achieve greater harmonisation in the

interpretation, application of technicalinterpretation, application of technicalguidelines and presentation of documentationguidelines and presentation of documentation

--to reduce or obviate the need to duplicateto reduce or obviate the need to duplicate

testing in R&D of new medicinestesting in R&D of new medicines--to make better economical use of human,to make better economical use of human,

animal and material resourcesanimal and material resources

--to eliminate delay in drug developmentto eliminate delay in drug development--to maintain safeguards on quality, safety andto maintain safeguards on quality, safety andefficacy and regulatory obligations to protectefficacy and regulatory obligations to protectpublic health.public health.


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ICH TopicsICH Topics

Five main subject areas:Five main subject areas:

11-- QQualityuality22-- SafetySafety

33-- EfficacyEfficacy44-- MultidisciplinaryMultidisciplinary

55-- Regulatory CommunicationsRegulatory Communications


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Q3C Impurities: Residual SolventsQ3C Impurities: Residual SolventsGuidanceGuidance objectiveobjective--to recommendto recommend

acceptable amounts for residual solventsacceptable amounts for residual solventsin pharmaceuticals for the safety of thein pharmaceuticals for the safety of thepatientpatient

Residual Solvents =Residual Solvents = organicorganic volatilevolatilechemicals used or produced in thechemicals used or produced in the

making of drug substances or excipientsmaking of drug substances or excipientsor in the preparation of drug products.or in the preparation of drug products.


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Q3C continuedQ3C continued

The guidance:The guidance:

--recommends use of less toxic solventsrecommends use of less toxic solvents

--gives toxicologically acceptable levels ofgives toxicologically acceptable levels ofsomesome solventssolvents

--does not address all possible solvents,does not address all possible solvents,only those identified in drugsonly those identified in drugs at thatat that

timetime--does not address solvents deliberatelydoes not address solvents deliberately

used as excipients nor solvates.used as excipients nor solvates.


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--There is no therapeutic benefit from residualThere is no therapeutic benefit from residualsolvents so,solvents so,

--Drug products should contain no higher levelsDrug products should contain no higher levelsthan can be supported by safety data.than can be supported by safety data. **

--Use of Class 1 solvents (most toxic) should beUse of Class 1 solvents (most toxic) should be

avoided unlessavoided unless stronglystronglyjustified.justified.

--Class 2 solvents should be limited to protectClass 2 solvents should be limited to protect

patients from potential toxicities.patients from potential toxicities.--Class 3 solvents (least toxic) should be usedClass 3 solvents (least toxic) should be used

where practical.where practical.

** and be patient acceptableand be patient acceptable


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The guidance:The guidance:

--doesdoes notnot apply to potential new drugapply to potential new drug

substances, new excipients or drug productssubstances, new excipients or drug productsused during clinical stages of drugused during clinical stages of drugdevelopment, nor to existing marketed drugdevelopment, nor to existing marketed drug

products.products.--applies toapplies to allall dosage forms and routes ofdosage forms and routes of

administration.administration.

--butbut higherhigher levels may be acceptable in certainlevels may be acceptable in certaincases such as shortcases such as short--term use (


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Class 1 solventsClass 1 solvents:: Substances to be avoidedSubstances to be avoided

i.e., known human carcinogens, stronglyi.e., known human carcinogens, strongly

suspected human (genotoxic)suspected human (genotoxic)carcinogens andcarcinogens and environmental hazards.environmental hazards.

Examples:Examples: concentration limitconcentration limitbenzene 2 ppmbenzene 2 ppm

carbon tetrachloride 4 ppmcarbon tetrachloride 4 ppm

1,21,2--dichloroethane 5 ppmdichloroethane 5 ppm

1,11,1--dichloroethene 8 ppmdichloroethene 8 ppm

1,1,11,1,1--trichloroethane 1,500 ppmtrichloroethane 1,500 ppm

Q3C i dQ3C ti d


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Class 2 solventsClass 2 solvents

: Substances to be limited, i.e., non: Substances to be limited, i.e., non

--

genotoxic carcinogens, teratogens,genotoxic carcinogens, teratogens,genotoxicants, solvents that can cause severegenotoxicants, solvents that can cause severe

butbut reversiblereversible CNS, liver, kidney, etc. toxicities.CNS, liver, kidney, etc. toxicities.ExamplesExamples:: concentration limitconcentration limit

cyclohexane 3880 ppmcyclohexane 3880 ppm

dichloromethane 600 ppmdichloromethane 600 ppm

NMP 530 ppmNMP 530 ppm ((4,840 ppm4,840 ppm))

pyridine 200 ppmpyridine 200 ppmtoluene 890 ppmtoluene 890 ppm

xylene 2170 ppmxylene 2170 ppmtetrahydrofuran 720 ppmtetrahydrofuran 720 ppm ((12,10012,100 ppm)ppm)


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Class 3 solvents: Substances with lowClass 3 solvents: Substances with lowtoxic potential. Amounts should nottoxic potential. Amounts should not

exceed 50 mg/day or 5,000 ppm or 0.5%exceed 50 mg/day or 5,000 ppm or 0.5%ExamplesExamples::

acetone ethanol DMSO heptaneacetone ethanol DMSO heptaneisopropyl acetate methylethyl ketoneisopropyl acetate methylethyl ketone

butyl acetate ethyl acetate 1butyl acetate ethyl acetate 1--pentanolpentanolethyl ether tetrahydrofuranethyl ether tetrahydrofuran**


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Class 4 solvents: Substances for which noClass 4 solvents: Substances for which noadequate toxicological data were found.adequate toxicological data were found.

(a PDE can not be determined)(a PDE can not be determined)

ExamplesExamples::

isopropyl ether 1.1isopropyl ether 1.1--dimethoxymethanedimethoxymethane

methylisopropyl ketone isooctanemethylisopropyl ketone isooctane

petroleum ether trichloroacetic acidpetroleum ether trichloroacetic acid


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PDE Calculation for Class 2 SolventsPDE Calculation for Class 2 Solvents

NOEL x Human Body WeightNOEL x Human Body Weight

PDE =PDE = ------------------------------------------------------------------------------------

F1 x F2 x F3 x F4 x F5F1 x F2 x F3 x F4 x F5

F1 = extrapolation between speciesF1 = extrapolation between species

F2 = variability among individualsF2 = variability among individuals

F3 = study durationF3 = study duration

F4 = severity of toxicityF4 = severity of toxicity

F5 = used if NOEL not establishedF5 = used if NOEL not established


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Exposure LimitsExposure Limits

Limits for Class 2 solvents:Limits for Class 2 solvents:Option 1:Option 1:

Concentration (ppm) =1000xPDE/doseConcentration (ppm) =1000xPDE/dose--dose = 10g/d ofdose = 10g/d of solventsolvent

Option 2: add the amounts of a residualOption 2: add the amounts of a residual

solvent present in each of thesolvent present in each of thecomponents of the drug product. Thecomponents of the drug product. Thesum should be < PDE.sum should be < PDE.


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Q3C Maintenance EWGQ3C Maintenance EWG

Instituted in 1999 and a regulatory rapporteurInstituted in 1999 and a regulatory rapporteurwas selected.was selected.

PDE could be modified if reliable and morePDE could be modified if reliable and more

relevant toxicity data was obtained.relevant toxicity data was obtained.

In June 2000, 2 reports were received by theIn June 2000, 2 reports were received by the

EWG, NMP and THF.EWG, NMP and THF.ActionsActions::

NMPNMP-- PDE from 48.4 to 207 to 5.3 mg/dPDE from 48.4 to 207 to 5.3 mg/d

THFTHF-- PDE from 121 to 7.2 mg/dPDE from 121 to 7.2 mg/d

EGEG-- PDE of 6.2 mg/d forPDE of 6.2 mg/d for longlong term use;term use;

40 mg/d for40 mg/d for shortshort term useterm use


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