Residual solvents guidelines

Where toxic gases or solvents have been used in the manufacturing process, validation data on their removal and relevant release and shelf life specifications and acceptance limits should be included in the dossier (taking into account the ICH guidelines on residual solvents and the CPMP guideline on ethylene oxide usage). These can be discussed in the development pharmaceutics section or elsewhere. 

Guideline on Impurities Residual Solvents Availability Notice... 

The Aspen NRTL-SAC solvent database was identified from the list of solvents presented in the pharmaceutical based International Committee on Harmonization s guidelines for residual solvents in API [28], Hexane, Acetonitrile and Water were selected as the basis for the X, Y and Z segments respectively, the binary interaction parameters for the segments together with molecular descriptors in terms of X,Y and Z segments were then regressed from experimental vapour-liquid and liquid-liquid equilibrium data from the Dechema database. The list of solvent parameters that were used in the case study are given in Table 13. 

ICH Steering Committee, 1997, ICH Harmonised Tripartite guideline, Impurities Guideline for Residual Solvents, Q3C. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 

International Conference on Harmonization (ICH) (1997), Guideline on residual solvents, ICH, Geneva. 

The long-term stability of an oral liquid formulation can also be affected by a number of unexpected reasons. Contamination by solvents used during the tank cleaning or even in the manufacture of excipients or API can be a source of instability of an oral solution. Uncontrolled levels of Class I, II, or III solvents could lead to the rejection of a batch or an excipient vendor. Class III solvents have a permitted daily exposure of 50 mg or less per day. (See the International Conferences on Harmonization, Impurities Guidelines for Residual Solvents. Q3C, Federal Register 1997 62(247) 67377 and also http //www.fda.gov/cvm/Guidance/guidelOO.PDF). 

S. Kojima, Guidelines for Residual Solvents, Fourth International Conference on Harmonization (ICH4),Belgium, Bruxelles, 1997. 

Q3C(M) Impurities guideline for residual solvents (maintenance, in consultation)... 

List taken from International Conference on Harmonization (ICH), harmonized tripartite (Europe, Japan, United States) guideline entitled Impurities Guideline for Residual Solvents. The above solvents are categorized as Class 3 solvents, with low toxic potential to man. Class 3 solvents have permitted daily exposures (PDEs) of 50 mg or more per day. 

Guideline for Residual Solvents,. International Conference on Harmonization, 1999. 

Impurities Guideline for Residual Solvents ICH Harmonized Tripartite Guideline (Q3C), 1997. 

The ICH guideline on impurities is also integrated into the technical guide, and the guideline on residual solvents has been integrated into a general chapter of the European Pharmacopeia. 

The contents of standards and test methods in the application form should follow the guidelines on standards and test methods for new drugs (Notification No. 586 of the PAB, 1994). Regcirding impurities, it should refer the guidelines on impurities for new drug substance cmd new drug products (Notification No. 877 and 539 of the PAB, 1995 and 1997). The guidelines on residual solvents should cilso refer to residual solvents (Notification No. 307 of the PAB in 1998). 

A number of solvents that are used for the synthesis of the API or formulation of the drug product can be present in the drug product. The content of these solvents, which are commonly called organic volatile impurities (OVI), is generally determined by the OVI methods specified in the compendia. Their content is controlled by the guidelines offered by various bodies (see Chapter 2). Residual solvents can affect the stability of drug product (see Sections IV. D and E). 

Early-stage small-scale synthesis methods will often create a different profile of impurities or degradants than drug supplies produced by scaled-up processes. Every batch of drug used in nonclinical studies must have a certificate of analysis that clearly specifies the purity levels and the quantities of impurities (which may include residual solvents, unreacted starting materials or degradants). The impurities must be reviewed in terms of the potential contribution that they can make to toxic effects that may be manifested in the nonclinical studies. There are ICH guidelines that pertain to impurities and to the extent to which additional toxicity studies need to be performed... 

Basic chemical data, identification, purity and test methods should follow the Guidelines Setting Specifications and Test Methods of New Drugs , notified in May 2001. Several others dealing with analytical validation, impurities or residual solvents were established on the basis of ICH agreements. When available, standards published in the JP or other quality standards (cf. section on Quality standards ) represent the references for specifications and test methods. 

Residual solvents, which are organic or inorganic liquids used during the manufacturing process (in fact, a separate guideline has been issued on residual solvents, and details are provided in Section III.D.3.C)... 

This guideline was drafted as a joint working group exercise between experts from both the analytical chemistry and the toxicology fields. Residual solvents in pharmaceuticals are defined as the organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients or in the preparation of drug products. 

The guideline applies mainly to drug substances and excipients, because if the levels of residual solvents in those materials are controlled, then the levels in drug products made from them are defined. The exception is when a solvent is used in the manufacturing process for a drug product, for example, the solvent-based film coating of tablets. In this case, a specification for the solvent must be set for the drug product. 

Impurities Guideline for residual solvents. ICH Guideline Q3C. Details as in reference 1. 

ICH (1997a). ICH GuideUne Q3C Impurities Guidelines for residual solvents. ICH Harmonized Tripartite Guideline Q3C, http //www.ich.org. 

---