WC500002674

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February 2009 CPMP/ICH/283/95 ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Step 5 Transmission to CPMP November 1996 Transmission to interested parties November 1996 Comments requested before May 1997 Final approval by CPMP September 1997 Date for coming into operation March 1998 Part II and Part III (Tetrahydrofuran and N-Methylpyrrolidone) Transmission to CPMP July 2000 Release for consultation July 2000 Deadline for comments September 2000 Approval by CPMP September 2002 Corrigendum to calculation formula for NMP November 2002 Date for coming into operation March 2003 Update of table 2, table 3 and appendix 1 to reflect the revision of the PDEs for N-Methylpyrrolidone and Tetrahydrofuran Q3C(R4) February 2009 ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page ii/22 Impurities: Guideline for Residual Solvents Table of contents Part I........................................................................................................... 3 1. Introduction ............................................................................................ 3 2. Scope of the Guideline............................................................................. 3 3. General principles.................................................................................... 4 3.1 Classification of Residual Solvents by Risk Assessment...............................................4 3.2 Methods for Establishing Exposure Limits .................................................................4 3.3 Options for Describing Limits of Class 2 Solvents.......................................................5 3.4 Analytical Procedures.............................................................................................6 3.5 Reporting levels of residual solvents ........................................................................6 4. Limits of Residual Solvents...................................................................... 7 4.1 Solvents to be avoided...........................................................................................7 4.2 Solvents to be limited ............................................................................................7 4.3 Solvents with Low Toxic Potential ............................................................................8 4.4 Solvents for which No Adequate Toxicological Data was found ....................................9 Glossary .................................................................................................... 10 Appendix 1. List of solvents included in the Guideline............................... 11 Appendix 2. Additional background .......................................................... 15 A2.1 Environmental Regulation of Organic Volatile Solvents ..........................................15 A2.2 Residual Solvents in Pharmaceuticals ...................................................................15 Appendix 3. Methods for Establishing Exposure Limits............................. 16 PART II: .................................................................................................... 19 Impurities : Residual Solvents (Maintenance) PDE for Tetrahydrofuran.... 19 PART III: ................................................................................................... 21 Impurities : Residual Solvents (Maintenance) PDE for N- Methylpyrrolidone (NMP) .......................................................................... 21 ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page 3/22 Part I 1. Introduction The objective of this guideline is 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. Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process. This guideline does not address solvents deliberately used as excipients nor does it address solvates. However, the content of solvents in such products should be evaluated and justified. 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. Drug products should contain no higher levels of residual solvents than can be supported by safety data. Some solvents that are known to cause unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3, Table 3) should be used where practical. The complete list of solvents included in this guideline is given in Appendix 1. The lists are not exhaustive and other solvents can be used and later added to the lists. Recommended limits of Class 1 and 2 solvents or classification of solvents may change as new safety data becomes available. Supporting safety data in a marketing application for a new drug product containing a new solvent may be based on concepts in this guideline or the concept of qualification of impurities as expressed in the guideline for drug substance (Q3A, Impurities in New Drug Substances) or drug product (Q3B, Impurities in New Drug Products), or all three guidelines. 2. Scope of the Guideline Residual solvents in drug substances, excipients, and in drug products are within the scope of this guideline. Therefore, testing should be performed for residual solvents when production or purification processes are known to result in the presence of such solvents. It is only necessary to test for solvents that are used or produced in the manufacture or purification of drug substances, excipients, or drug product. Although manufacturers may choose to test the drug product, a cumulative method may be used to calculate the residual solvent levels in the drug product from the levels in the ingredients used to produce the drug product. If the calculation results in a level equal to or below that recommended in this guideline, no testing of the drug product for residual solvents need be considered. If, however, the calculated level is above the recommended level, the drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent level to within the acceptable amount. Drug product should also be tested if a solvent is used during its manufacture. ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page 4/22 This guideline does not apply to potential new drug substances, excipients, or drug products used during the clinical research stages of development, nor does it apply to existing marketed drug products. The guideline applies to all dosage forms and routes of administration. 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. See Appendix 2 for additional background information related to residual solvents. 3. General principles 3.1 Classification of Residual Solvents by Risk Assessment The term "tolerable daily intake" (TDI) is used by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals and "acceptable daily intake" (ADI) is used by the World Health Organization (WHO) and other national and international health authorities and institutes. The new term "permitted daily exposure" (PDE) is defined in the present guideline as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADI's of the same substance. Residual solvents assessed in this guideline are listed in Appendix 1 by common names and structures. They 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 Non-genotoxic 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 PDEs of 50 mg or more per day. 3.2 Methods for Establishing Exposure Limits The method used to establish permitted daily exposures for residual solvents is presented in Appendix 3. Summaries of the toxicity data that were used to establish limits are published in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997. ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page 5/22 3.3 Options for Describing Limits of Class 2 Solvents Two options are available when setting limits for Class 2 solvents. Option 1: The concentration limits in ppm stated in Table 2 can be used. They were calculated using equation (1) below by assuming a product mass of 10 g administered daily. Concentration (ppm) 1000 x PDE dose = (1) Here, PDE is given in terms of mg/day and dose is given in g/day. These limits are considered acceptable for all substances, excipients, or products. Therefore this option may be applied if the daily dose is not known or fixed. If all excipients and drug substances in a formulation meet the limits given in Option 1, then these components may be used in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day should be considered under Option 2. Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day as stated in Table 2 can be used with the known maximum daily dose and equation (1) above to determine the concentration of residual solvent allowed in drug product. Such limits are considered acceptable provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limits should reflect contemporary manufacturing standards. Option 2 may be 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. Consider an example of the use of Option 1 and Option 2 applied to acetonitrile in a drug product. 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. Component Amount in formulation Acetonitrile content Daily exposure Drug substance 0.3 g 800 ppm 0.24 mg Excipient 1 0.9 g 400 ppm 0.36 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 728 ppm 3.64 mg Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg per day and thus conforms to the recommendations in this guideline. ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page 6/22 Consider another example using acetonitrile as residual solvent. 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 is given in the following table. Component Amount in formulation Acetonitrile content Daily exposure Drug substance 0.3 g 800 ppm 0.24 mg Excipient 1 0.9 g 2000 ppm 1.80 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 1016 ppm 5.08 mg In this example, the product meets neither the Option 1 nor the Option 2 limit according to this summation. 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 utilised with residual solvent at a higher level. 3.4 Analytical Procedures Residual solvents are typically determined using chromatographic techniques such as gas chromatography. Any harmonised procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a non-specific method such as loss on drying may be used. Validation of methods for residual solvents should conform to ICH guidelines Text on Validation of Analytical Procedures and Extension of the ICH Text on Validation of Analytical Procedures. 3.5 Reporting levels of residual solvents Manufacturers of pharmaceutical products need certain information about the content of residual solvents in excipients or drug substances in order to meet the criteria of this guideline. The following statements are given as acceptable examples of the information that could be provided from a supplier of excipients or drug substances to a pharmaceutical manufacturer. The supplier might choose one of the following as appropriate: • 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. (Here the supplier would name the Class 2 solvents represented by X, Y, ...) • 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%. If Class 1 solvents are likely to be present, they should be identified and quantified. "Likely to be present" refers to the solvent used in the final manufacturing step and to solvents that are used in earlier manufacturing steps and not removed consistently by a validated process. ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page 7/22 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. 4. Limits of Residual Solvents 4.1 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 1, unless otherwise justified. 1,1,1-Trichloroethane is included in Table 1 because it is an environmental hazard. The stated limit of 1500 ppm is based on a review of the safety data. TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided). Solvent Concentration 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 4.2 Solvents to be limited Solvents in Table 2 should be limited in pharmaceutical products because of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, and concentrations are given to the nearest 10 ppm. The stated values do not reflect the necessary analytical precision of determination. Precision should be determined as part of the validation of the method. TABLE 2. Class 2 solvents in pharmaceutical products. Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cyclohexane 38.8 3880 1,2-Dichloroethene 18.7 1870 Dichloromethane 6.0 600 1,2-Dimethoxyethane 1.0 100 N,N-Dimethylacetamide 10.9 1090 N,N-Dimethylformamide 8.8 880 1,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents Page 8/22 Ethyleneglycol 6.2 620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-Methoxyethanol 0.5 50 Methylbutyl ketone 0.5 50 Methylcyclohexane 11.8 1180 N-Methylpyrrolidone1 5.3 530 Nitromethane 0.5 50 Pyridine 2.0 200 Sulfolane 1.6 160 Tetrahydrofuran2 7.2 720 Tetralin 1.0 100 Toluene 8.9 890 1,1,2-Trichloroethene 0.8 80 Xylene* 21.7 2170 *usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene 4.3 Solvents with Low Toxic Potential Solvents in Class 3 (shown in Table 3) may be regarded as less toxic and of lower risk to human health. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for many of the solvents in Class 3. 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 good manufacturing practice. Table 3. Class 3 solvents which should be limited by GMP or other quality-based requirements. Acetic acid Heptane Acetone Isobutyl acetate Anisole Isopropyl acetate 1-Butanol Methyl acetate 2-Butanol 3-Methyl-1-butanol Butyl acetate Methylethyl ketone tert-Butylmethyl ether Methylisobutyl ketone Cumene 2-Methyl-1-prop