In implementing this ICH guidance, Health Canada endorses the principles and practices described therein. This document should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances. Please note that the ICH website is only available in English. It is recognized that the scope and subject matter of current Health Canada guidances may not be entirely consistent with those of the ICH guidances that are being introduced as part of our commitment to international harmonization and the ICH Process.
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Reproduction is authorised provided the source is acknowledged. Scope of the Guideline General principles Limits of Residual Solvents List of solvents included in the Guideline Additional background Methods for Establishing Exposure Limits 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.
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. 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. 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. Summaries of the toxicity data that were used to establish limits are published in Pharmeuropa, Vol. 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.
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. 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. The maximum administered daily mass of a drug product is 5. The composition of the drug product and the calculated maximum content of residual acetonitrile are given in the following table.
Component Amount in.
ICH Topic Q3C (R4) Impurities: Guideline for Residual
Documents to be published This document recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. It recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Read together with the annexes on specifications for class 1 and class 2 residual solvents in active substances and residues of solvents used in the manufacture of finished products. In , ICH was notified by an external party of a discrepancy between Summary Table 2 of the guideline and the monograph for EG listed in Appendix 5. The PDE indicated in the monograph was 3. This issue was presented to the Q3C EWG for discussion and given the lack of any additional information or awareness of a supporting rationale for the value listed in Summary Table 2, the EWG considered the discrepancy to be a transcription error in the Summary Table 2. Keywords: Organic solvent, impurity, limits, class, reporting levels, permitted daily exposure PDE , toxicological Current effective version.
ICH Q3C (R6) Residual solvents