Testing should be performed for those residual solvents that are used or produced in the manufacture or purification of drug substances, excipients or drug. Where the limits to be applied comply with those given below, tests for residual solvents are not generally mentioned in specific monographs, because the. Pharm Res. Mar;20(3) Residual solvent testing: a review of gas- chromatographic and alternative techniques. B'Hymer C(1). Author information.
Testing Residual Solvents
ICH Class 1 and 2 compounds need chromatographic determination and therefore make up the residual solvent reference standards used in this analysis. Class 2 Mixture C contains higher boiling solvents not readily detectable by headspace analysis and therefore has been omitted in the second supplement of USP30 NF25 or the interim revision announcement. These solvents are to be assayed by other appropriately validated procedures.
Under the updated methodology, the diluent used in standard and sample preparations differs for the water-soluble and water-insoluble articles; water is used for water-soluble articles, whereas dimethylformamide or dimethylsulfoxide is used for water-insoluble articles.
However, the methodology for both water-soluble and water-insoluble articles is very similar. The test method for both sections consists of three procedures A, B and C that are designed to identify, confirm and then finally quantify residual solvents found to present in drug substances and products. Procedure A was performed using a Tekmar HT3 pressured loop autosampler to demonstrate implementing analyses using a transfer line.
Procedure B was performed using an Overbrook Scientific HTH to demonstrate implementing analyses using a syringe injection. Procedure A is the first step in the identification process and is performed on a G43 Rtx or column, as a means of determining if any residual solvents are present in the sample at detectable levels.
First, Class 1 standard and system suitability solutions and a Class 2 Mix A standard solutions are assayed under the given operating conditions to determine suitability of the chromatographic system.
All peaks in the Class 1 system suitability solution must have a signal-to-noise ratio not less than 3, the Class 1 standard solution must have a 1,1,1-trichloroethane response greater than 5, and in the Class 2 Mixture A solution the resolution of acetonitrile and dichloromethane must not be less than 1. When system suitability has been achieved, the test solutions are then assayed along with the Class 1 and Class 2 Mixtures A and B standard solutions.
In the event that a peak is determined in the sample that matches a retention time and has a response greater than that of a corresponding reference material, the analyst then proceeds to Procedure B for verification of the analyte. An exemption is made for 1,1,1-trichloroethane, where a response greater than times the peak response denotes an amount above the percent daily exposure limit.
The resolution between acetonitrile and dichloromethane is easily achieved using an Rtx or column and a 1mm split liner, coupled to a transfer line injection. Once a residual solvent is identified and found to be above the percent daily exposure limit, Procedure B is then performed to confirm analyte identity.
A G16 capillary column Stabilwax is used here as a confirmation column because it yields an alternate selectivity when compared to that of a G43 column. The same residual solvent mixes used in Procedure A, both standard and system suitability preparations, are again analyzed on this column. The system suitability requirements differ here in that the Class 1 standard solution must have a benzene response greater than 5 and the resolution of acetonitrile and cis-dichloroethene must not be less than 1 in the Class 2 Mixture A solution.
If the analyte identified in Procedure A again matches the retention time and exceeds the peak response of the reference materials, again with the same exception to 1,1,1-trichloroethane , the analyst must now quantify the analyte using Procedure C. Figures 4 through 6 illustrate the analysis of residual solvent mixes Class 1, Class 2A and B on a Stabilwax column. Again, the system suitability on a Stabilwax column, used in conjunction with a 2 mm liner and syringe headspace injection, is easily achieved.
Lastly, when a residual solvent is identified and verified in both Procedures A and B, the analyst then performs Procedure C to quantify the analyte. This is done by analyzing the sample against the specific, individual reference material for the analyte identified.
Following the procedure given and the instrument conditions in either Procedure A or B, depending upon which procedure provides the most definitive results, a quantifiable result is produced. Although the second supplement contains a change that allows for modifications to the split ratio, liner and column choices are still important. Both the Rtx and the Stabilwax columns can easily pass system suitability criteria, and the use of smaller bore liners see Tech Tip can increase peak efficiency.
Solvents are also very important for the creation of drugs and other pharmaceutical products. For example, solvents are often used at the beginning of the manufacturing process to create the active ingredients for ointments and other topical products.
Residual solvents are solvents that are used in the manufacturing of materials that are not completely removed after processing. Sometimes solvents are a critical part of the actual makeup of the product. For example, solvents can be used in glue and adhesive manufacturing to control the drying properties.
However, there are guidelines for the amount of residual solvents that can be left behind and still be considered safe. At unsafe levels, they can either be harmful to the environment or humans. For example, removing cleaning solvents is essential during the processing of a circuit board. It can also determine whether the proper solvent purging process was followed during product development.
For example, ethanol and other solvents are often used in the production of pharmaceutical products. Since pharmaceutical products are ingested or implanted in the body, residual solvent testing is critical to ensure that solvents are not present at health threatening levels. Solvents are also frequently used in the production of plastic packaging for various food products. If too much of the solvent is retained in the packaging, it could give off an unappetizing odor or spoil the taste of the food.
Testing can quantify the level of residual solvents and determine if they will cause odor or taste issues. During this process, the sample is injected into a gas chromatograph to volatilize the sample and separate the various components. The separated components then go into a mass selective detector to identify how much of each element is present.
Residual Solvents Testing
Residual solvents in pharmaceutical products are defined as organic volatile compounds. Residual solvents are necessary to ameliorate the. Quality Control in Pharmaceuticals: Residual Solvents Testing and Analysis. Changqin Hu and Ying Liu. National Institutes for Food and Drug. Parent Guideline: Impurities: Guideline for Residual Solvents. Q3C. Approval by .. Therefore, testing should be performed for residual solvents.