Methods development, prior considerations

The outcome of planning should include the generation of a method definition requirement document (MDRD) in which all stake holders agree, prior to method development, on the critical attributes of the method. Considerations such as what impurities/degradation products should be monitored, requisite reporting thresholds, the need for an MS-compatible method, if identical methods for DP and DS are required, etc., should be clearly decided and agreed upon by all stakeholders. 

An underlying assumption in these discussions is that SFE is a viable alternative for sample preparation procedures for a significant number of samples - even though equipment more sophisticated than traditional laboratory glassware is necessary. For example, SFE systems can be operated at temperatures up to 150 C and pressures to 600 bar using a variety of fluids. The unique characteristics of supercritical fluids which make them so attractive as solvents have been discussed fully on many occasions elsewhere (15-17) a similar discussion is outside the scope of this paper. However, in the next section we will briefly 1. explore the use of supercritical fluids from the perspective of potentially enhanced robustness and 2. outline considerations which are typically considered prior to analytical methods development and which should be employed for SFE as for any other technique. 

Figure 2. Initial considerations prior to methods development.

Most descaling and passivation processes for steels were developed prior to the widespread use of electrochemical techniques. As a result, a variety of visual and chemical tests are widely used for determining the surface cleanliness. Chemical tests have also been established to verify the presence of a robust oxide film on austenitic and ferritic stainlesses (8). These methods are very simple to conduct in a manufacturing environment, but they are qualitative in nature and rely strongly on the judgment of the inspector. Outside of the laboratory, electrochemical methods have not been widely used to evaluate cleanliness of carbon and alloy steels after pickling. Nevertheless, they are well suited for this purpose and have been examined in considerable detail in laboratory studies. 

Prior to developing an HPLC method, its intended use must be carefully considered. For example, if the analysis is required to obtain an approximate value for the amount of candidate drug, such as for a solubility experiment, a crude method may be acceptable. Alternatively, if the HPLC method is to separate and determine related substances, i.e., synthesis intermediates and degradation products, from the compound of interest, a more robust method will have to be developed. Other considerations will include the amount of compound to be determined, from what type of matrix (e.g., formulation, reaction mixture, drug substance) and the number of and how quickly analyses are to be performed. 

The stability of the reference substance in a stock solution made from a particular solvent and stored nnder a given set of conditions should be established prior to use (Section 10.2.7). Method development studies can commence prior to establishing known stability but the analyst must be aware that the analyte could be degrading in solution (or during all phases of sample processing) and take that into consideration especially when unusual or unexpected results are obtained during development. In no instance should solutions without established analyte stabihty be used for sample analysis. Also, additional stability data should be generated for any other solutions that are prepared in a different solvent and/or stored under... 

The purpose of this book is to introduce students of chemical engineering to several mathematical methods that are often essential to successfully solve real process engineering problems. The book emphasizes analytical methods even though most realistic models will be solved using numerical methods. However, prior to an extensive and expensive numerical analysis of a model, it is very useful to develop some understanding of the gross tendencies of the model. This type of understanding usually comes from the derivation of analytical solutions of a modified version of the problem under consideration. 

Before embarking on a method development experimental work, it is advisable to have a clear understanding of the purpose of the method, any prior knowledge of the analyte(s) of interest, and any identified requirements of the end user laboratory. Examples of such considerations include the following ... 

---