Strategy for Method Development

Steps in a common strategy for HPLC method development are summarized below  

Initial method development — scouting runs and getting the first 

Steps 1-4 are discussed here in Sections 8.2-8.5, while method validation is discussed in Chapter 9, Section 9.3. 

4 HPLC Method Development Trends in Pharmaceutical Analysis 

Some of the best practices and emergent trends in pharmaceutical method development are highlighted here and discussed further as case studies  

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As described earlier, Jordi Associates provides columns for both neutral and charged polymers. Table 13.1 lists the charge types of each phase. This will allow for planning a coherent strategy for method development. 

Matthijs, N., Perrin, C., Maftouh, M., Massart, D.L., Vander Heyden, Y. Definition and system implementation of strategies for method development of chiral separations in normal- or reversed-phase liquid chromatography using polysaccharide-based stationary phases. 7. Chromatogr. A 2004, 1041, 119-133. 

A review of capillary electrophoresis applications in pharmaceutical analysis was published in 1993, and the goal of this chapter is to provide an update on the various disciplines within the technique and includes selected applications. Recent developments in the areas of capillary technology, instrumentation, and detection will be reviewed here. Useful strategies for method development involving several classes of pharmaceuticals and biotechnology products will be addressed. The formats within capillary electrophoresis have evolved to such an extent that this chapter is not comprehensive in scope. Therefore, the reader will be directed to other reviews on the various aspects of capillary electrophoresis. Of particular interest to many separation scientists may be a special issue of an Applied Biosystems Newsletter, which addresses the future role of CE, method development in CE, and selected applications in the area of drug analysis and protein separations [7]. 

In the following case study for this pharmaceutical compound M, the method development scenario and rationale for each iteration in the method development process is highlighted. Also, a method development flow chart for gradient separations is included which can be used as a general strategy for method development (Figure 8-37). References are made in this case study to the flow chart in Figure 8-37. 

Optimisation of preparative scale chromatography has been well studied in the past [8-10]. It has been shown that the optimum conditions for an isolation vary considerably with the sample being purified or even with the particular component of a mixture required to be isolated. It was considered unlikely that we would achieve optimum conditions for any significant number of compounds and consequently our strategy for method development took a much more pragmatic approach. 

There appear to be two practical approaches utilised for method development by most separation scientists. The first approach is to rely on past experience of the confound or previous separations of a compound with a similar sttucture and then supplement this information with some information from the literature. This can usually lead to the development of some initial starting conditions. The alternative approach is usually to not consider the sample information and proceed directly to some generic starting conditions. Both of these approaches have been characterised by Snyder etal. [1] as theoretical for the former and empirical for the latter. Although both approaches have been shown to work, the optimum strategy for method development is quite often a combination of both approaches. 

The overall strategy for methods development is illustrated in the flowchart shown in Fig. 1. The individual steps are listed below, and recommended conditions are provided with a brief explanation and an illustrative example that highlights several key points. 

Hattendorf, B. and Gunther, D. (2003) Strategies for method development for an inductively coupled plasma mass spectrometer with bandpass reaction... 

The control strategy for methods developed using QbD principles is similar to that employed for methods that are validated in a traditional... 

Method qualification is based on ICH method validation guidelines. Method type (purity or identity) will dictate the level of qualification testing necessary. Several strategies for method qualification and validation exist and are based on needs, resources available, and the project timeframe. One approach is to perform minimal development and qualification, which may be necessary for projects with shorter timelines, but it may place more burden and risk on future validation activities for robustness testing, and can result in failure. As discussed in Chapter 4, an alternate approach would invest more time and resources into method development, followed by extensive qualification and robusmess testing to determine if further development is... 

Dittmann, B., Nitz, S. (2000) Strategies for the development of reliable QA/QC methods when working with mass spectrometry-based chemosensory systems. Sens. Actuators B 69 253-257. 

One method of producing a biocompatible surface is to prevent adsorption of proteins. If proteins adsorb or otherwise become attached to a polymer surface, the attachment can interfere with the normal cell functions. The interaction of a polymer surface and blood is equally problematic. A component in blood known as the Hageman factor detects hydrophobic surfaces. The signaling involves attachment of the factor to the surface and by the process of attachment, the factor becomes activated. This is the first step in the inflammation response that can lead to rejection. Thus, the development of a hydrophilic surface with minimal protein adsorption may become a strategy for the development of compatible medical devices. 

Srinivas, N. R. Evaluation of experimental strategies for the development of chiral chromatographic methods based on diastereomer formation. Biomed. Chromatogr., 2004,18, 207-233. 

To have an assay to validate, a robust assay must be developed. Chapter 3 discusses, in a systematic and pragmatic way, the approaches to the development of LBAs. This discussion focuses on the practical aspects of LBA development for use in the GLP-compliant environment. A structured strategy for the development of a validatable LBA that would withstand the rigor of prestudy and in-study method validation... 

In paying credit to the fact that the SMB is the most promising chromatographic technique for the production of enantiomerically pure chiral drugs, this technique is discussed below in a rather comprehensive way. Together with the principles, some strategies of method development are also addressed. 

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