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Pharmaceutical Technology QUALITY AND REGULATORY SOURCEBOOK EBOOK MARCH 2022 7 The most commonly used guidelines for method validation come from the ICH and the United States Pharmacopeia (USP). The ICH guideline is quality guidance ICH Q2(R1), and the USP guidance is found in the USP general chapter 1225 (4, 5). Based on the type of method, each of these guidance documents defines what aspects of the method are required to be validated. For validation, the attributes include accuracy, precision, repeatability, linearity and range, specificity, limit of detection, and limit of quantitation based on the type of method and intended purpose. Although not explicitly defined in the require- ments, an area of emphasis by most regulatory authorities is method robustness. ICH guidance Q2(R1) has the following definition: "the robust- ness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliber- ate variations in method parameters and provides an indication of its reliability during normal usage" (3). Robustness evaluations are performed during method validation; however, method robustness can be established during method development. While the ICH validation requirements were writ- ten for drug products and are generally appropriate for biologics methods, the elements may not be directly applicable to the device attributes of a combination product. For tests related to device attributes, gage re- peatability and reproducibility (GR&R) studies can be performed to validate methods and establish the suit- ability of the measurement system for analysis of the product attribute. GR&R studies separate the sources of variation in measurement between the method/ operator, equipment, and the component being mea- sured. For a pre-filled syringe, a test—such as inside diameter or injection force (i.e., the force required to move the plunger down the barrel of a syringe)— would be validated by GR&R. The inside diameter is measured using a caliper, and the injection force is measured using a mechanical testing instrument. The method attributes for validation in each case are essentially the same (accuracy, bias, linearity, sta- bility, precision, repeatability, reproducibility). The only element missing from GR&R is specificity. In the cases mentioned previously, the instruments (gages) are designed to measure one attribute only. The cali- pers measure diameter (distance), and the mechanical testing instrument provides results in units of force. Specificity is not required per se, as these specialized instruments are inherently specific. In addition to the USP and ICH guidance, there are many good references for method validation. These include the Eurachem Guide publication, The Fit- ness for Purpose of Analytical Methods: A Laboratory Guide to Method Validation and Related Topics and the Australian Pesticides and Veterinary Medicines Authorities' Guidelines for the Validation of Analyti- cal Methods for Active Constituent, Agricultural and Veterinary Chemical Products (6,7). These guidelines present the topic of method validation from a slightly different perspective than the ICH or USP and give insight into validation characteristics and how valida- tion studies should be performed. Good methods call for good validation During the review of analytical tests for combination products, it is possible to observe good methods that have been poorly validated. In one instance, a company developing a drug-coated product developed a dissolu- tion method that was discriminating for both formu- lation and process parameters. The development work was solid, and it was clear the method worked. How- ever, on validation, they did not appropriately validate the method range. The product was manufactured in multiple sizes (lengths and diameters), resulting in a