Proactive method development

During early phase development there is limited knowledge about the chemistry of the new chemical entity (NCE) with respect to synthetic impurities and degradation pathways and kinetics. It is, therefore, desirable to develop an array of methods that show applicability to a broad range of potential impurities, degradation products, and excipients. The methods are intended to provide the information necessary to guide the improvement of a synthesis route or a new drug formulation. 

As the approach detailed above can result in the generation of numerous samples to be screened, it is frequently possible to combine some solutions into a set of selectivity solutions for some method development activities. However, there is also merit in analyzing the individual solutions separately to obtain information on degradation pathways and DS impurities that can facilitate the understanding of drug chemistry. 

Additional modes of HPTC include normal phase, where the stationary phase is relatively polar and the mobile phase is relatively nonpolar. Silica, diol, cyano, or amino bonded phases are typically used as the stationary phase and hexane (weak solvent) in combination with ethyl acetate, propanol, or butanol (strong solvent) as the mobile phase. The retention and separation of solutes are achieved through adsorp-tion/desorption. Normal phase systems usually show better selectivity for positional isomers and can provide orthogonal selectivity compared with classical RPLC. Hydrophilic interaction chromatography (HILIC), first reported by Alpert in 1990, is potentially another viable approach for developing separations that are orthogonal to RPLC. In the HILIC mode, an aqueous-organic mobile phase is used with a polar stationary phase to provide normal phase retention behavior. Typical stationary phases include silica, diol, or amino phases. Diluted acid or a buffer usually is needed in the mobile phase to control the pH and ensure the reproducibility of retention times. The use of HILIC is currently limited to the separation of very polar small molecules. Examples of applications 

In summary, the use of RPLC is ideal for pharmaceutical analyses because of the broad range of commercially available stationary phases because the most common RPLC mobile phases (buffers with acetonitrile or methanol) have low UV cut-off wavelengths, which facilitate high sensitivity detection for quantitation of low-level impurities and because selectivity can readily be controlled via mobile phase optimization. Additionally, the samples generated for selectivity screening (as detailed above) are typically aqueous based. In subsequent phases of pharmaceutical development, aqueous-based sample solvents are ideal for sample preparation and are, under limited constraints, compatible with MS detection required to identify impurities and degradation products. 

TABLE 2 Equal Elution Strength of Mobile Phases for RPLC 

---

To apply a screening approach to proactive method development, analyses of selectivity samples under a variety of mobile phase conditions are conducted on different HPLC columns. HPLC columns should be as orthogonaT as possible and variations in solvent composition should be designed to maximize the probability of selectivity differences. Alternate separation techniques, such as ion exchange chromatography (IC), supercritical fluid chromatography (SFC), or capillary electrophoresis (CE) may also be used to obtain orthogonality. 

During proactive method development, special attention should be drawn to four key areas, as shown in Figure 8, prior to issuing the candidate method ... 

The supportive method developed during proactive method development is used ... 

This indicates that error management comprises two strategies proactive methods are applied to prevent errors occurring, and reactive strategies are used to learn lessons from incidents that have occurred and to apply these lessons to the development of preventive measures. Both proactive and reactive methods rely on an understanding of the courses of human error based on the theories and perspectives presented in this book. The tools and tech-... 

The following considerations, when applied during method development, are likely to produce more robust, reliable, and transferable methods (a) the concerns of the customer (user) are considered in advance, (b) key process input variables are identified, (c) criticaTto-quality factors are determined, (d) several method verification tests are installed, (e) proactive evaluation of method performance during development is performed, (f) continuous customer involvement and focus are institutionalized, and (g) method capability assessment (suitability to be applied for release testing against specification limits) is established. 

Although these measures and criteria were necessary during sample analysis, it is recommended to take proactive action steps to ensure appropriate IS behavior during method development. In general, inconsistent internal standard response is typically caused by either nonideal extraction conditions such as poor extraction... 

After isolation and identification of the impurity, the structure was found to be different from the originally proposed structure. This example demonstrates the need to obtain the scientific evidence rather than rely on suggestions and proposals. Fortunately, in this case study the time line allowed ample time for method development, and this is not always the case. It is impossible to predict the complications that may arise in the isolation or characterization. Proactive involvement prior to crisis mode is desired. 

With increasing popularity and attention to proactive methods, structured methodologies are being developed to systematically explore, analyze, and implement energy conservation and waste minimization or cleaner production programs in industries. In many industries, such techniques are now being used as one of the management tools to monitor and control process efficiency and environmental liabilities. 

As emphasized in Section ILA, a proactive approach to HPLC method development should involve purposeful degradation at the early stages of development with the key degradation samples used in the method development process. See Figure 6 for an overview of the role of purposeful... 

FIGURE 6 Flow chart for the proactive role of purposeful degradation as an integral part of the method development process. 

JSA Job safety analysis is a detailed review of the safety steps related to a particular work task. The steps are recorded on a standard form that can then be used to train individuals in the best practical safe way to perform their work tasks. This is a proactive method that can help to develop a world-class safety culture. 

The focus of this chapter has been on proactive application of these analytical methods such as safety audits, development of procedures, training needs analysis, and equipment design. However, many of these methods can also be used in a retrospective mode, and this issue deserves further attention in its own right. Chapter 6 describes analytical methods for accident investigations and data collection. 

Case study 3 illustrates the use of proactive techniques to analyze operator tasks, predict errors and develop methods to prevent an error occurring. Methods for the development of operating instructions and checklists are shown using the same chemical plant as in case study 2. 

The nine strategies form a powerful set of tools to devise, construct, and refine pharmaceutical analysis methods. The proactive use of a single strategy, or the combination of several, produces unique information and inspires new perspectives on analysis. In this way, analysis methods create new mechanisms for information gathering, rather than passively waiting for a sample to be generated. And in this way LC/MS analysis capabilities partnered with samplegenerating disciplines to create new accelerated development opportunities. 

Cocrystals are becoming increasingly important as a means of controlling the properties of pharmaceutical solids by designing multiple component molecular networks that introduce the desired functionality. Because cocrystal design is based on supramolecular synthesis, it provides a powerful approach for the proactive discovery of novel pharmaceutical solid phases. Application of the fundamental concepts presented here on cocrystallization processes is essential for the pharmaceutical scientist to anticipate the formation of cocrystals during pharmaceutical processes and storage, as well as to develop reliable methods for cocrystal discovery and production. 

---