This document summarizes ICH Q3C, a guideline for residual solvents in pharmaceuticals. It classifies residual solvents into three classes based on risk: Class 1 solvents are to be avoided due to toxicity; Class 2 solvents are to be limited; Class 3 solvents have low toxic potential. It provides concentration limits for different solvent classes and describes two options for describing limits of Class 2 solvents. The guideline aims to recommend acceptable amounts of residual solvents in drugs for patient safety.
This document summarizes ICH Q3C, a guideline for residual solvents in pharmaceuticals. It classifies residual solvents into three classes based on risk: Class 1 solvents are to be avoided due to toxicity; Class 2 solvents are to be limited; Class 3 solvents have low toxic potential. It provides concentration limits for different solvent classes and describes two options for describing limits of Class 2 solvents. The guideline aims to recommend acceptable amounts of residual solvents in drugs for patient safety.
This document summarizes ICH Q3C, a guideline for residual solvents in pharmaceuticals. It classifies residual solvents into three classes based on risk: Class 1 solvents are to be avoided due to toxicity; Class 2 solvents are to be limited; Class 3 solvents have low toxic potential. It provides concentration limits for different solvent classes and describes two options for describing limits of Class 2 solvents. The guideline aims to recommend acceptable amounts of residual solvents in drugs for patient safety.
This document summarizes ICH Q3C, a guideline for residual solvents in pharmaceuticals. It classifies residual solvents into three classes based on risk: Class 1 solvents are to be avoided due to toxicity; Class 2 solvents are to be limited; Class 3 solvents have low toxic potential. It provides concentration limits for different solvent classes and describes two options for describing limits of Class 2 solvents. The guideline aims to recommend acceptable amounts of residual solvents in drugs for patient safety.
• Options for Describing Limits of Class 2 Solvents
• Analytical Procedures
• Reporting Levels of residual solvents
• Residual Solvents in Pharmaceuticals
• Glossary
www.julphar.net Introduction Residual 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.
www.julphar.net Scope of the Guideline 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 intentionally used 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
www.julphar.net Classification
Residual Solvents are classified according to
their Risk Assessments to human health to 3 main classes:
Class 1 solvents Class 2 solvents Class 3 solvents
Solvents to be Solvents to be Solvents with low avoided limited toxic potential
www.julphar.net Classification of Residual Solvents by
Known human carcinogens, strongly
Class 1 solvents suspected human carcinogens, and Solvents to be avoided Risk Assessment
environmental hazards
Class 2 solvents Non-genotoxic animal carcinogens or possible
causative agents of other irreversible toxicity Solvents to be limited such as neurotoxicity or teratogenicity.
Class 3 solvents Solvents with low toxic potential to man; no Solvents with low health-based exposure limit is needed. toxic potential
www.julphar.net Limits of Residual Solvents
www.julphar.net Class 1 Solvents Solvents 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. Concentration limit Solvent Concern (ppm) 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
www.julphar.net 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. Concentration limit Solvent PDE (mg/day) (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
www.julphar.net 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.
www.julphar.net Class 3 Solvents (Continue) Examples of Class 3 solvents which should be limited by GMP or other quality based requirements. Acetone Methylisobutyl ketone Ethyl ether
www.julphar.net 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 base a PDE was found.
•Manufacturers should supply justification for residual levels of these solvents
www.julphar.net 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.
www.julphar.net 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.
www.julphar.net 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.
www.julphar.net 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.
www.julphar.net 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.
www.julphar.net 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%.
www.julphar.net 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
www.julphar.net Residual Solvents in Pharmaceuticals Exposure 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
www.julphar.net 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 Food EPA: 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
www.julphar.net Glossary Term Meaning Term Meaning
INTERNATIONAL CONFERENCE ICH LOEL Lowest-Observed Effect Level ON HARMONISATION
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
Integrated Risk Information
IRIS ADI Acceptable Daily Intake System International Program on United States Food and Drug IPCS USFDA Chemical Safety Administration United States Environmental USEPA EWG Expert Working Group Protection Agency
