residual solvent analysis as impurities, there control methods types of residual solvents

2. PRESENTED BY-
SANTHOSH KUMAR T S
M.PHARM (PH ANALYSIS)
1ST YEAR
A PRESENTATION ON
IMPURITIES IN RESIDUAL SOLVENTS
KARNATAKA COLLEGE OF PHARMACY
BANGALORE
FACILITATED TO-
Dr. C. SREEDHAR SIR
HEAD OF THE DEPARTMENT
(PH. ANALYSIS)

3. CONTENTS
• Introduction
• General principles
• Scope of theGuideline
• Classification
• Analytical Procedures
• Limits of Residual Solvents
• Reporting Levels of residual solvents

4. Introduction
Residual solvents in Pharmaceuticals are defined in ICH Q3Cas
organic volatile chemicals that are used or produced in the
manufacture of drug substances, excipients or in the preparation of
drug products. They are not completely removed by practical
manufacturing techniques.
PURPOSE
Residual solvents are used in manufacture either to enhance the
yield or determine characteristics of the substancessuchascrystal
form, purity and solubility.There is no therapeutic benefit from
residual solvents.
Since there isno therapeutic benefit from residual solvents,
all residual solvents should be removed completely to the extent
possible to meet product specifications, good manufacturing
practices, or other quality-based requirements.

5. • Torecommend acceptable amounts for residual solvents in
pharmaceuticalsfor the safety of the patient.
• The guideline recommends useof less toxic solvents and describes
levels considered to be toxicologically acceptablefor someresidual
solvents.
• Theguideline appliesto all dosageforms and routes of administration.
• This guidelines does not address all possible solvents, only those
identified in drugsat that time, neither address solvents intentionally
used asexcipients norsolvates.
• The maximum acceptable intake per day of residual solvent in
pharmaceuticalproducts is defined as“permitted daily exposure” (PDE)
• Previously, another terms were usedlike “Tolerable daily intake” (TDI)&
“Acceptable daily intake” (ADI) by different organization & authorities,
but now usually this new term “PDE” is used
Scopeof theGuideline

7. Classification
ResidualSolvents are classifiedaccordingto their Risk
Assessmentsto human health to 3mainclasses:
Class1solvents
Solvents to be
avoided
Class2solvents
Solvents to be
limited
Class3solvents
Solvents withlow
toxic potential

8. Classification of Residual Solventsby
RiskAssessment
Class1 solvents
Solvents tobe
avoided
Known human carcinogens, strongly
suspected human carcinogens,and
environmental hazards
Class2 solvents
Solvents tobe
limited
Non-genotoxic animal carcinogens or
possible causative agents of other
irreversible toxicity such asneurotoxicity
orteratogenicity.
Class3 solvents
Solvents with low
toxic potential
Solvents with low toxic potential to man;
no health-based exposure limitis
needed.
Class 4 solvents : no adequate toxicological data is available for these group of solvents

10. Analytical Procedures
• Residual solvents are typically determined using
chromatographic techniques such asgaschromatography.
• Any harmonizedprocedures for determining levels of residual
solvents asdescribed in the pharmacopoeiasshouldbe used.
• Manufacturers would be free to select the most appropriate one.
• validatedanalytical procedurefor aparticular application.
• If onlyClass3solventsare present, anonspecificmethod such asloss
on drying may be used.

11. • Gaschromatograph equippedwith
• HeadspaceSampler
• Flame Ionization Detector (FID)
• Mass-selective Detector (MSD) (optionally) for identification &
confirmation

13. aG43Column
a G16 column also looks similar in appearance

17. HeadspaceVial

18. • If we look at the
anatomy of a headspace
vial wecan begin to see
the relationshipof the
vial components and
how we can control
these parameters to
create analytical
methods.
• Volatile components
partition from the
sample phase and
equilibrate in the vial
headspace.
ACI Limited

19. Principle for analysis of residual solvents
• Residual solvent analysis by static HS/GC can be enhanced by careful
consideration of two basic concepts—partition coefficient (K) and phase
ratio (β).
• Partition coefficients and phase ratios work together to determine the
final concentration of volatile compounds in the headspace of sample
vials.
• The partition coefficient (K) is defined as the equilibrium distribution of
an analyte between the sample and gas phases. Compounds that have
low K values will tend to partition more readily into the gas phase, and
have relatively high responses and low limits of detection.
• The phase ratio (β) is defined as the volume of the headspace over the
volume of the sample in the vial. Lower values for β (i.e., larger sample
sizes) will yield higher responses for compounds with inherently low K
values.

20. Principle for analysis of residual solvents
Striving for the lowest values for both K and β when preparing samples
will result in higher concentrations of volatile analytes in the gas phase
and, therefore, better sensitivity

21. INTERPRETATION OF RESULTS

23. Class1Solvents
Solvents to Be Avoided
Solvents in Class1should not be employed in the manufacture of
drug substances,excipients,and drug products because of their
unacceptable toxicity or their deleterious environmental effect.
However, if their use is unavoidable in order to produce adrug
product with a significant therapeutic advance, then their levels
should be restricted as shown inTableunlessotherwise justified.
Solvent
Concentration
limit (ppm)
Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and environmentalhazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Environmental hazard

24. Class2Solvents
Solvents to belimited
Solventsin class2 should be limited in pharmaceutical products
because of their inherent toxicity.
Examples of class2 solvent in the below table.
Solvent PDE (mg/day)
Concentrationlimit
(ppm)
Acetonitrile 4.1 410
Chloroform 0.6 60
Cyclohexane 38.8 3880
Formamide 2.2 220
Methanol 30 3000
N-Methylpyrrolidone 5.3 530
Tetrahydrofuran 7.2 720
Xylene 21.7 2170
Toluene 8.9 890

25. Class3 Solvents (Solvents with low toxicpotential)
• Solvents in Class3may be regarded aslower risk to human health.
However, there have no long-term toxicity or carcinogenicitystudies for
many of the solvents inClass3.
• Thesesolvents areconsideredof no human health hazard
• Availabledata indicate that they are lesstoxic in acuteor short-term
studies and negative in genotoxicity studies.
• It is considered that amounts of these residual solvents of 50mg per day
or less(correspondingto 5000ppm) would be acceptable without
justification.
• Higher amountsmay alsobeacceptableprovided (iff) they are realistic in
relation to manufacturing capability andGMP.

26. (Cont.)
Acetone Methylisobutyl ketone Ethyl ether
Acetic acidHeptane Dimethyl sulfoxide Ethyl formate
Anisole Ethanol Formic acid
Methyl acetate Ethyl acetate 3-Methyl-1-butanol
Butyl acetate tert-Butylmethyl ether Isobutyl acetate
1-Butanol Methylethyl ketone 1-Pentanol
2-Methyl-1-propanol Heptane Isopropylacetate
2-Butanol Pentane 1-Propanol
Examplesof Class3solventswhich should be limited byGMPor
other qualitybased requirements.

27. •Examples :
1,1-Diethoxypropane
1,1-Dimethoxymethane
2,2-Dimethoxypropane
Isooctane
Isopropyl ether
Methylisopropyl ketone
Methyltetrahydrofuran
Petroleum ether
Trichloroacetic acid
Trifluoroacetic acid
Solvents for which No Adequate
Toxicological Data was Found
• The following solvents may also be of interest to manufacturers of
excipients, drug substances,or drug products.
• However, no adequate toxicological data on which to baseaPDE
wasfound.
• Manufacturers should supply justification for residuallevels of
these solvents inpharmaceutical products.

28. Reporting levels of residual solvents

29. Options for Describing Limits of Class 2
Solvents
These options are used to describe the limit of Class 2 solvents. Testing
should be performed for residual solvents when production or purification
processes are known to result in the presence of such solvents.
Option 1:
By assuming a product mass of 10 g administered daily.
Concentration (ppm) = 1000 x PDE / Dose
Here, PDE is given in terms of mg/day and dose is given in g/day. No further
calculation is necessary provided that the daily dose does not exceed 10 g.
Option 2:
Products that are administered in doses greater than 10 g per day. Applied
by adding the amounts of a residual solvent present in each of the
components of the drug product. The sum of the amounts of solvent per
day should be less than that given by the PDE.

30. Example for Option 2
The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, the
Option 1 limit is 410 ppm. The maximum administered daily mass of a
drug product is 5.0 g, and the drug product contains two excipients. The
composition of the drug product and the calculated maximum content
of residual acetonitrile are given in the following table.
Excipient 1 meets the Option 1 limit, but the drug substance, excipient
2, and drug product do not meet the Option 1 limit. however, the
product meets the Option 2 limit of 4.1 mg per day and thus conforms
to the recommendations in this guideline.

31. Reporting levels of residual solvents
• Manufacturers ofpharmaceuticalproductsneedcertaininformationabout
thecontentofresidualsolventsinexcipientsordrugsubstances.
• Thefollowingstatements aregivenintheICHGuidelineasacceptable
examples of the information that could beprovided from asupplier of
excipientsordrugsubstancesto apharmaceuticalmanufacturer.
• OnlyClass3solventsarelikely to bepresent. Lossondryingislessthan
0.5%.
• OnlyClass2solventsX,Y,...arelikely to bepresent.All arebelowthe
Option 1limit.
• OnlyClass2solventsX,Y,...andClass3solventsarelikely to be
present. Residual Class2solvents are below the Option 1limit and
residual Class3 solvents are below0.5%.

32. Reporting levels of residual solvents
• IfClass1solvents arelikely to bepresent, they shouldbeidentified
and quantified.
• If solvents ofClass2orClass3arepresent at greater than theirOption 1limits
or 0.5%,respectively, theyshould be identified and quantified.
• Manufacturer could provide a summary of efforts made to reduce the
solvent level to meet the guideline value and provide a risk-benefit
analysis to support allowing the product to be utilized with residual
solvent at ahigherlevel.
• Higherlevels of residual solvents may beacceptablein certain casessuchas
short term (30daysor less) or topical application. Justification for these
levels should be made on acaseby casebasis.

33. Residual Solvents inPharmaceuticals
Exposurelimitsinthisguidelineareestablishedbyreferring to
methodologies andtoxicity data describedin EHCandIRIS
monographs.
However,somespecificassumptionsaboutresidualsolventsto beused inthe
synthesisandformulationof pharmaceuticalproductsshouldbe takeninto
accountinestablishingexposurelimits:
• Patients usepharmaceuticalsto treat their diseasesorfor prophylaxisto
preventinfectionordisease.
• Residualsolventsareunavoidable componentsin pharmaceutical
productionandwill oftenbeapartof drugproducts.
• Residualsolventsshouldnot exceedrecommended levelsexceptin
exceptional circumstances.

34. • Data from toxicological studiesthat are usedto determine
acceptable levels for residual solvents should havebeengenerated
usingappropriate protocolssuchasthosedescribed.
Example:- FDARedBookandEPA.
FDARedBook:ToxicologicalPrinciples for theSafetyAssessmentof
Direct FoodAdditives and ColorAdditivesUsedin Food
EPA:USEnvironmental ProtectionAgency

35. References:
• www.google.com
• www.pdfdrive.net
• www.Slideshares.in
Impurities:Guideline for ResidualSolventsQ3C(R5)
EMA: CVMP/VICH/502/99 Guideline on impurities: residual solvents ,
Annex I: specifications for class 1and class 2 residual solvents in active
substances

37. Glossary
Term Meaning Term Meaning
ICH
INTERNATIONALCONFERENCE
ON HARMONISATION
LOEL
Lowest-Observed Effect
Level
WHO World HealthOrganization NOEL No-Observed EffectLevel
GMP Good ManufacturingPractice PDE Permitted DailyExposure
EHC Environmental HealthCriteria TDI Tolerable Daily Intake
IRIS
Integrated RiskInformation
System
ADI Acceptable DailyIntake
IPCS
International Programon
Chemical Safety
USFDA
United States Food and Drug
Administration
USEPA
United StatesEnvironmental
Protection Agency
EWG ExpertWorkingGroup