USP 467- Regulation for Residual Solvents in Pharmaceuticals

Residual solvents in pharmaceuticals are defined 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 residual solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of a drug substance or an excipient may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical element in the synthetic process. But in most cases, they are not completely removed during the production process, so they could be toxic and carcinogenic after being taken by humans. In recent years, they have increasingly attracted attention from all quarters. In accordance with the United States Pharmacopeia (USP) 467 document regulations on residual solvents, all raw materials, excipients, and preparations must comply with the relevant regulations for residual solvents, even if not specified in the text. This requirement is consistent with the guiding principles of the ICH.

Solvent Classification

According to USP 467, drug products should contain no higher levels of residual solvents that can be supported by safety data. Generally residual solvents are divided into three categories to assess the risks they may pose to human health as shown in table 1.

Table 1 Residual solvents classification and assessment¹

Limits of Residual Solvents

Class 1 residual solvents should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicities or deleterious environmental effects. However, if their use is unavoidable in order to produce a medicinal product with a significant therapeutic advance, then their levels should be restricted as shown in table 2, unless otherwise stated in the individual monograph.

Table 2 The limits of class 1 residual solvents¹ (Solvents that should be avoided)

In the USP 467, the value of PDEs was used to limit. PDE (Permitted Daily Exposure) refers to the daily average maximum dose that an organic solvent is allowed to ingest without causing toxicity. Class 2 residual solvents should be limited in drug substances, excipients, and drug products because of the inherent toxicities of the residual solvents. If Class 2 residual solvents are present at greater limits than table 2, they should be re-identified and quantified.

Table 3 The limits of class 2 residual solvents¹

Class 3 residual solvents may be regarded as less toxic and of lower risk to human health than Class 1 and Class 2 residual solvents. 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 residual solvents in Class 3. Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.

Table 4 The class 3 residual solvents¹
(Limited by GMP or other quality-based requirements in drug substances, excipients, and drug products)

Identification of Residual Solvents

Because the USP deals with drug products, as well as active ingredients and excipients, it may be acceptable that in some cases, some of the components of the formulation will not dissolve completely. A flow diagram for the application of the residual solvent limit tests is shown in figure 1. The following procedures are useful to identify and quantify residual solvents when the information regarding which solvents are likely to be present in the material is not available. When the information about the presence of specific residual solvents is available, only Procedure C is needed to quantify the amount of residual solvents present.

Figure 1. Diagram relating to the identification of residual solvents and the application of limit tests¹

References

• United States Pharmacopeia <467> Residual Solvents, 2012.

• ZHANGJun-wei.(2004) ‘Review for determination method of organical residual solvent in drug.’ Phamacopeia research, 3:10.

• ClaudiaWitschi, EricDoelker,(1997) ‘Residual solvents in pharmaceutical products: acceptable limits, influences on physicochemical properties, analytical methods and documented values’, Drug R&D, 215-242.

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