Q3C

GUIDELINE FOR RESIDUAL SOLVENTS

Contents• Introduction

• Scope of the Guideline

• Classification

• Limits of Residual Solvents

• Options for Describing Limits of Class 2 Solvents

• Analytical Procedures

• Reporting Levels of residual solvents

• Residual Solvents in Pharmaceuticals

• Glossary

IntroductionResidual solvents in Pharmaceuticals are defined in ICH Q3C as 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.

Residual solvents are used in manufacture either to enhance the yield or determine characteristics of the substances such as crystal form, purity and solubility. There is no therapeutic benefit from residual solvents.

Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements.

To recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.

The guideline applies to all dosage forms and routes of administration.

This guidelines does not address all possible solvents, only those identified in drugs at that time, neither address solvents intentionallyused as excipients nor solvates.

The maximum acceptable intake per day of residual solvent in pharmaceutical products is defined as “permitted daily exposure” (PDE)

Previously, another terms were used like “Tolerable daily intake” (TDI) & “Acceptable daily intake” (ADI) by different organization & authorities, but now usually this new term “PDE” is used

Scope of the Guideline

Classification

Residual Solvents are classified according to their Risk Assessments to human health to

3 main classes:

Class 1 solventsSolvents to be

avoided

Class 2 solvents Solvents to be

limited

Class 3 solvents Solvents with low

toxic potential

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Class 1 solvents

Solvents to be avoided

Known human carcinogens, strongly suspected human carcinogens, and

environmental hazards

Class 2 solvents

Solvents to be limited

Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity

such as neurotoxicity or teratogenicity.

Class 3 solvents

Solvents with low toxic potential

Solvents with low toxic potential to man; no health-based exposure limit is needed.

Limits of Residual Solvents

Class 1 SolventsSolvents to Be Avoided

Solvents in Class 1 should 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 a drug product with a significant therapeutic advance, then their levels should be restricted as shown in Table unless otherwise justified.

SolventConcentration

limit(ppm)

Concern

Benzene 2 Carcinogen

Carbon tetrachloride 4 Toxic and environmental hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1500 Environmental hazard

Class 2 Solvents

Solvents to be limited

Solvents in class 2 should be limited in pharmaceutical products because of their inherent toxicity.

Examples of class 2 solvent in the below table.

Solvent PDE (mg/day)Concentration limit

(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

Class 3 Solvents (Solvents with low toxic potential)

•Solvents in Class 3 may be regarded as lower risk to human health.

However, there are no long-term toxicity or carcinogenicity studies for

many of the solvents in Class 3.

•These solvents are considered of no human health hazard

•Available data indicate that they are less toxic in acute or short-term

studies and negative in genotoxicity studies.

• It is considered that amounts of these residual solvents of 50 mg per

day or less (corresponding to 5000 ppm or 0.5% under Option 1) would

be acceptable without justification.

• Higher amounts may also be acceptable provided they are realistic in

relation to manufacturing capability and GMP.

Class 3 Solvents (Continue)

Acetone Methylisobutyl ketone Ethyl ether

Acetic acid Heptane 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 Isopropyl acetate

2-Butanol Pentane 1-Propanol

Examples of Class 3 solvents which should be limited by GMP or other quality based requirements.

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 base a PDE was found.

•Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.

• Examples :

1,1-Diethoxypropane Methylisopropyl ketone

1,1-Dimethoxymethane Methyltetrahydrofuran

2,2-Dimethoxypropane Petroleum ether

Isooctane Trichloroacetic acid

Isopropyl ether Trifluoroacetic acid

Solvents for which No Adequate Toxicological Data was Found

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.

Example for Option 2

The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, theOption 1 limit is 410 ppm. The maximum administered daily mass of adrug product is 5.0 g, and the drug product contains two excipients. Thecomposition of the drug product and the calculated maximum content ofresidual 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.

What if the product meets neither the Option 1 nor the Option 2 limit ?

The manufacturer could test the drug product to determine if the

formulation process reduced the level of acetonitrile. If the level

of acetonitrile was not reduced during formulation to the allowed

limit, then the manufacturer of the drug product should take

other steps to reduce the amount of acetonitrile in the drug

product. If all of these steps fail to reduce the level of residual

solvent, in exceptional cases the 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 a

higher level.

Specifications for class 1 and class 2 residual solvents in active substances

A) Class 1 solvents used as starting materials

They should be routinely controlled, either in a suitable intermediate or in the final active substance.

B) Class 1 solvents present as an impurity

It should be NMT 30 % of the specified limit, in a suitable intermediate or in the final active substance. Supporting data should be presented on 6 consecutive pilot scale batches or 3 consecutive industrial scale batches.

C) Class 2 solvents used in the last step of the synthesis

It should be routinely controlled in the final active substance.

D) Class 2 solvents used prior to the last step of the synthesis

It should be NMT 10 % of the acceptable concentration limit (e.g., acetonitrile 41 ppm). Supporting data should be presented on 6 consecutive pilot scale batches or 3 consecutive industrial scale batches.

Analytical Procedures

•Residual solvents are typically determined using

chromatographic techniques such as gas chromatography.

•Any harmonized procedures for determining levels of residual

solvents as described in the pharmacopoeias should be used.

•Manufacturers would be free to select the most appropriate

validated analytical procedure for a particular application.

• If only Class 3 solvents are present, a nonspecific method such

as loss on drying may be used.

• Gas chromatograph equipped with

• Headspace Sampler

• Flame Ionization Detector (FID)

• Mass-selective Detector (MSD) (optionally)for identification & confirmation

a G43 Column

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Headspace Vial

• If we look at the anatomy of a headspace vial we can begin to see the relationship of 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.

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Principle for analysis of residual solvents (continued…)

• 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.

Principle for analysis of residual solvents (continued…)

• 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

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Overview of Method for Residual Solvent Testing

• USP <467> is divided into two separate sections based upon sample solubility: water-soluble and water-insoluble articles. The methodology for both types of articles is similar, but the diluent used in both standard and sample preparations differs based upon the solubility of the test article.

• The test method consists of three procedures (A, B, and C), that are designed to identify, confirm, and then quantify residual solvents in drug substances and products .

• The revised USP <467> method consists of a static headspace extraction coupled with a gas chromatographic separation and flame ionization detection.

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Procedure A - Identification• Procedure A is the first step in the identification process and is performed on a

G43 column to determine if any residual solvents are present in the sample atdetectable levels.

• First, Class 1 standard and system suitability solutions and Class 2 Mix Astandard solutions are assayed under the method-specified operatingconditions to establish system suitability.

• All peaks in the Class 1 system suitability solution must have a signal-to-noiseratio not less than 3, the Class 1 standard solution must have a 1,1,1-trichloroethane response greater than 5, and the resolution of acetonitrile anddichloromethane must be not less than 1 in the Class 2 Mixture A solution.

• When system suitability has been achieved, the test solutions are assayedalong with the Class 1 and Class 2 Mixtures A and B standard solutions. If apeak is determined in the sample that matches a retention time and has agreater response than that of a corresponding reference material, thenProcedure B is performed for verification of the analyte.

Identification of residual solvent in sample by comparing with reference standard

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Procedure B - Confirmation

• Once a residual solvent is identified and found to be above the percent dailyexposure limit, Procedure B is performed to confirm analyte identity.

• A G16 capillary column is used here as a confirmation column, because ityields an alternate selectivity compared to a G43 column. The same standardand system suitability preparations are used in Procedures A and B.

• The system suitability requirements differ here in that the Class 1 standardsolution must have a benzene response greater than 5 and the resolution ofacetonitrile and cisdichloroethene must not be less than 1 in the Class 2Mixture A solution, a change from the original version.

• If the analyte identified in Procedure A again matches the retention time andexceeds the peak response of the reference materials (with the sameexception to 1,1,1-trichloroethane), the analyst must quantify the analyteusing Procedure C.

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Confirmation of residual solvent in sample by comparing retention time and peak response

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Procedure C – Quantification

• Once a residual solvent has been identified and verified, Procedure Cis used to quantify the analyte by analyzing the sample againstcompound-specific reference materials.

• Individual standards are prepared by diluting the analyte in solutionto a concentration of 1/20 of the concentration limit given underconcentration limit Table 1 or 2 of the method.

• Following the procedure and instrument conditions in eitherProcedure A or B (whichever provides the most definitive results), aquantifiable result is produced.

• For water-insoluble articles, the same procedure is followed, exceptdimethylformamide or dimethylsulfoxide is used as the diluent.

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Confirmation of residual solvent in sample by analyzing the

sample against compound-specific reference materials.

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Reporting levels of residual solvents

•Manufacturers of pharmaceutical products need certain information about

the content of residual solvents in excipients or drug substances.

• The following statements are given in the ICH Guideline as acceptable

examples of the information that could be provided from a supplier of

excipients or drug substances to a pharmaceutical manufacturer.

Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%.

Only Class 2 solvents X, Y, ... are likely to be present. All are below the Option

1 limit.

Only Class 2 solvents X, Y, ... and Class 3 solvents are likely to be present.

Residual Class 2 solvents are below the Option 1 limit and residual Class 3

solvents are below 0.5%.

Reporting levels of residual solvents

• If Class 1 solvents are likely to be present, they should be identified and

quantified.

• If solvents of Class 2 or Class 3 are present at greater than their Option 1 limits or

0.5%, respectively, they should 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 a higher level.

•Higher levels of residual solvents may be acceptable in certain cases such as short

term (30 days or less) or topical application. Justification for these levels should be

made on a case by case basis.

Example for Residual Solvents Declaration

Residual Solvents in PharmaceuticalsExposure limits in this guideline are established by referring to methodologies and toxicity data described in EHC and IRIS* monographs.

However, some specific assumptions about residual solvents to be used in the synthesis and formulation of pharmaceutical products should be taken into account in establishing exposure limits:

1) Patients (not the general population) use pharmaceuticals to treat their diseases or for prophylaxis to prevent infection or disease.

2) Residual solvents are unavoidable components in pharmaceutical production and will often be a part of drug products.

3) Residual solvents should not exceed recommended levels except in exceptional circumstances.

EHC: Environmental Health Criteria

IRIS: Integrated Risk Information System

4) Data from toxicological studies that are used to determine acceptable levels for residual solvents should have been generated using appropriate protocols such as those described for example by FDA Red Book and EPA*.

FDA Red Book: Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in FoodEPA: US Environmental Protection Agency

References:Impurities: Guideline for Residual Solvents Q3C(R5)EMA: CVMP/VICH/502/99 Guideline on impurities: residual solvents , Annex I: specifications for class 1 and class 2 residual solvents in active substances

Glossary

Term Meaning Term Meaning

ICHINTERNATIONAL CONFERENCE ON HARMONISATION

LOELLowest-Observed Effect Level

WHO World Health Organization NOEL No-Observed Effect Level

GMP Good Manufacturing Practice PDE Permitted Daily Exposure

EHC Environmental Health Criteria TDI Tolerable Daily Intake

IRISIntegrated Risk Information System

ADI Acceptable Daily Intake

IPCSInternational Program on Chemical Safety

USFDAUnited States Food and Drug Administration

USEPAUnited States EnvironmentalProtection Agency

EWG Expert Working Group