Impurity testing

A preservative is a substance that extends the shelf-life of drug products by preventing oxidation or inhibiting microbial growth.14 Preservatives must be monitored in the products since they are considered to be active components. Generic HPLC assays are typically developed for preservatives such as buty-lated hydroxytoluene (BHT), an antioxidant for solid dosage forms, and antimicrobials such as parabens, sodium benzoate, or sorbic acid in liquid formulations. For these additive components, typical assay specifications are 85-115% of label claim. 

Gradient (or isocratic) HPLC with UV detection Dissolve drug substance at -0.1-5 mg/mL Grind — extract — dilute — filter of 5 dosage units for products 

Drug substances must resolve all impurities and APIs Drug products must resolve all degradants and APIs Limit of quantitation (LOQ) 0.03-0.1% 

Area normalization against the API External standardization using well-qualified impurity reference standards 

Typically 0.05-1.0% according to ICH guidelines and dependent upon maximum daily dose 

---

The ACS committee has a general rule if two producers meet a given specification, the specification is normally so defined. Usually the methods are checked by several laboratories using samples from various sources. Because of the many different matrices in which impurities are deterrnined, even the simplest impurity tests need to be checked for accuracy in the laboratory. 

The most common types of analyses are the identification test, the quantitative determination of active ingredients or major component, and the determination of impurities. The identification test provides data on the identity of the compound or compounds present in a sample. A negative result signifies that the concentration of the compound(s) in sample is below the DL of the analyte(s). The quantitative method for the major component provides data of the exact quantity of the major component (or active ingredients) in the sample, and a reported concentration of the major component must be higher than the QL. In a Determination of impurities test, one obtains data regarding the impurity profile of a sample, and can be divided into a limit test or quantitative reporting of impurities (see Table 1, which has been modified from Refs. [1] and [8]). 

Type of analytical procedure Assay Impurity testing Quantitative Limit tests Performance characteristics Identification ... 

Sample preparation (SP) is generally not given adequate attention in discussions of pharmaceutical analysis even though its proper execution is of paramount importance in achieving fast and accurate quantification (see Chapter 5). Non-robust SP procedures, poor techniques, or incomplete extraction are the major causes of out-of-trend and out-of-specification results. The common SP techniques have been reviewed with a strong focus on tablets or capsules, as they are the primary products of the pharmaceutical industry. Detailed descriptions of SP methods for assays and impurity testing are provided with selected case studies of single- and multi-component products. 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

Finally, we will discuss the determination of the limit of quantitation or LOQ. Establishing an LOQ is required for many pharmaceutical applications such as impurity testing and cleaning validation. Limit of quantitation is the lowest concentration (%, ppm) that can be determined with acceptable precision (RSD of —5%). It is generally accepted that a signal/noise ratio at the LOQ should be at least There are... 

FIGURE 14 Waters Millennium screen showing contour map, chromatogram at 278nm and spectra of an active ingredient and a degradant of an impurity test seunple. 

D. Impurity Testing of a Controlled-release Tablet with Two APIs... 

This chapter provides the novice and the experienced analyst with an overview of sample preparation techniques focusing on solid dosage forms. It describes the best practices in the dilute and shoot approach, and the tricks of the trade in grinding, mixing, sonication, dilution and filtration of drug products. Selected case studies of sample preparations for assays and impurity testing are used to illustrate the strategies, trade-offs... 

This chapter reviews the myriad SP techniques used in pharmaceutical analysis and focuses discussion on those commonly used for pharmaceutical products, such as grinding, mixing, sonication, dilution and filtration. The best practices and technical judgments used in developing SP procedures are illustrated with several case studies of assays and impurity testing. 

ICH Guidelines for Impurity Testing Q3B(R) Impurities in New Products, 2003, http //www.ich.org/pdfICH/Q3BRStep4.pdf. 

From a practical point of view, and related to method development for impurity testing, it can be recommended that a method be developed in such a way that the impurity elutes before the main component. It will be easier to obtain a baseline separation and one that reduces quantification problems that might occur when the impurity elutes in the tail of the main peak. Moreover, the peak obtained for the main compound might be rather broad and tailing in chiral chromatography (as will be shown further in this chapter) which favors even more the development of methods with the impurity eluting first. 

During the course of chemical development, impurity profiles in drug substances may change due to changes in synthetic route and changes in the size of the batch. ICH guidelines for Impurities in New Drug Substances (ICH Q3A), require that impurity test results for... 

---