ICH Q3C.docx

1、ICH Q3CICH Guideline for Residual SolventsQ3CRapporteur: Dr. Shigeo Kojima Date: 16 July 1997 Step 4 Document1. INTRODUCTION 2. SCOPE OF THE GUIDELINE 3. GENERAL PRINCIPLES 3.1 CLASSIFICATION OF RESIDUAL SOLVENTS BY RISK ASSESSMENT 3.2 METHODS FOR ESTABLISHING EXPOSURE LIMITS 3.3 OPTIONS FOR DESCRIB

2、ING LIMITS OF CLASS 2 SOLVENTS 3.4 ANALYTICAL PROCEDURES 3.5 REPORTING LEVELS OF RESIDUAL SOLVENTS 4. LIMITS OF RESIDUAL SOLVENTS 4.1 SOLVENTS TO BE AVOIDED 4.2 SOLVENTS TO BE LIMITED 4.3 SOLVENTS WITH LOW TOXIC POTENTIAL 4.4 SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL DATA WAS FOUND GLOSSARY APPEN

3、DIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE APPENDIX 2. ADDITIONAL BACKGROUND A2.1 ENVIRONMENTAL REGULATION OF ORGANIC VOLATILE SOLVENTS A2.2 RESIDUAL SOLVENTS IN PHARMACEUTICALS APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS 1. INTRODUCTIONThe objective of this guideline is to recommend

4、 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 organi

5、c 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 enha

6、nce 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

7、 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 produc

8、ts 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 justifi

9、ed 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

10、 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 appli

11、cation 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 thr

12、ee guidelines. 2. SCOPE OF THE GUIDELINEResidual 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 so

13、lvents. 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

14、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 recomm

15、ended 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. This guideline does not apply to potential new drug subs

16、tances, 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 sh

17、ort 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 PRINCIPLES3.1 CLASSIFICATION OF RESIDUAL SOLVENTS BY RISK ASSESSMENT The term tolera

18、ble 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 p

19、ermitted daily exposure (PDE) is defined in the present guideline as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADIs of the same substance. Residual solvents assessed in this guideline are listed in Appendix 1 by common names and structures.

20、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

21、 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 l

22、imit is needed. Class 3 solvents have PDEs of 50 mg or more per day. 3.2 METHODS FOR ESTABLISHING EXPOSURE LIMITSThe 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

23、 Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997.3.3 OPTIONS FOR DESCRIBING LIMITS OF CLASS 2 SOLVENTSTwo 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 assum

24、ing a product mass of 10 g administered daily. (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

25、drug substances in a formulation meet the limits given in Option1, 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 Optio

26、n 2. Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option1. 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 all

27、owed 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 manufactur

28、ing 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

29、 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. T

30、he 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 g800 ppm0.24 mgExcipient 1 0.9 g400 ppm0.36 mgExcipient 2 3.8 g800 ppm3.04 mgDrug Pro

31、duct 5.0 g728 ppm3.64 mgExcipient 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. Consider another exampl

32、e 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 g800 ppm0.24 mgExcipient 1 0.9 g2000 ppm1.80 mgExcipient 2 3.8 g800 ppm3.04 mgDrug Product 5.0 g1016 ppm