Impurities case study

In the characterization of low-level pharmaceutical impurities. Prudent decision-making is necessary to select the most advantageous technologies and capabilities specific for each project. Such selections are made to overcome extreme limitations in sensitivity or resolution, or both, that standard techniques would afford. The following two case studies covers show how new NMR technologies and techniques were employed to solve real pharmaceutical challenges. 

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. 

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. 

CASE STUDY 2 EXAMPLE OF A FEASIBILITY STUDY FOR IMPURITY PROFILING... 

Delmau, L.H., Bonnesen, P.V., Moyer, B.A. 2004. A solution to stripping problems caused by organophilic anion impurities in crown-ether based solvent extraction systems A case study of cesium removal from radioactive wastes. Hydrometallurgy 72 (1-2) 9-19. 

Ahuja S, Aisante KM, eds. Handbook of Isolation and Characterization of Impurities in Pharmaceuticals. Vol. 5. Separation Science and Technology Alsante KM, Hatajik TD, Lohr LL, Santafianos D, Sharp TR. Solving Impurity/Degradation Problems Case Studies. Chapter 14. San Diego, CA Academic Press 2003 361-400. 

Delmau, L. H., Bonnesen, P. V., and Moyer, B. A. A Solution to Stripping Problems Caused by Organophilic Anion Impurities in Crown-Ether Based Solvent Extraction Systems, A Case Study of Cesium Removal from Radioactive Wastes, Hydrometallurgy 72(1,2) (2004), 9-19. 

CASE STUDY 2 CHALLENGES DUE TO NONDRUG-RELATED IMPURITIES 245... 

The most widely used method of challenging the legitimacy of the process used to manufacture the generic product is to undertake an impurity profile study of the drug substance extracted from the competing product, in short to check its impurity fingerprint vs. your own product. Most companies can describe cases. One in my experience occurred when an Italian company decided to market Amikacin, at that time a patented Bristol-Myers product, in Korea. 

It is important to note that, in typical practical situations in which cost constraints play an important role, impurity-concentration measurements are available for only a few units (and, more often than not, just for a single unit). Thus, a model of the evolution of the total impurity inventory (such as those developed in the examples above, i.e., Equations (4.43) and (4.45)) is not well suited for controller design. Rather, an appropriate coordinate change of the type in Equation (4.33) should be used to obtain a model of the evolution of the measured concentration variable in the slow time scale. An example of this approach is presented in the case study following this section. 

The goal of this case study is to illustrate some generic issues raised by the conceptual design of a large-scale process involving several reaction and separation sections interconnected in a complex plant with recycles. The study emphasizes the intricate effects of handling the removal of numerous impurities generated in different reactors by a common separation system, with implications on process dynamics and plantwide control. 

Alsante and co-workers174 reported an interesting case study for the identification of impurities of pharmaceuticals using a multidisciplinary approach to the problem. The active molecule (89) was used as a model system and the characterization of the dimeric structure derived from the active pharmaceutical (90) was described. 

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