Early phase method development

Early-phase method development typically begins with the receipt of drug substance from laboratory-scale synthesis and purification. Along with the API, the following information should be requested (or generated) ... 

Results of the study indicate that it is possible to simultaneously detect the active drug substance and most related substances at 0.1% (w/w). Furthermore, the method provides different selectivity than reversed-phase HPLC. As a broader conclusion, this indicates orthogonality to reversed-phase HPLC and suggests the viability of SFC in support of early-phase method development. 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

During the early stages of drug discovery, a suitable candidate must be selected from a limited number of structurally related compounds that may have a similar pharmacological profile. At that point, information from in vitro systems would provide important and particularly useful selection criteria. However, results from in vitro models are often not yet available at the early phases of development, or they exist only for a limited number of compounds. Accordingly, there is an urgent need for in silico methods that would allow prediction of the pharmacological properties in humans from the experimental model systems. 

For early phase methods emphasis is placed on specificity and these methods generally require less extensive validation than those in final development. The following method parameters should be included in... 

CE methods are developed and utilized in pharmaceutical QC for early to late phases of drug development. Chapter 4 covers the approaches for late-phase development for small molecules that can be used in early-phase development, as well as for large-molecular-weight compounds. Late-phase method development in pharmaceutical QC is performed for required stability studies and for release of the drug product or drug substance validation batches, and is intended to be transferred to the operational QC laboratories for release testing of the production batches. Preferably, late-phase methods should be fast, robust, reliable, and transferable. Therefore it is crucial to devote adequate time, thought, and resources to the development of such methods. 

An example of the minimum requirement for potency assay of the drug substance and drug product is tabulated in Table 4. Note that the postponement of intermediate precision is aligned with previous discussion that the use of early phase analytical method resides mainly in one laboratory and is used only by a very limited number of analysts. Each individual company s phased method validation procedures and processes will vary, but the overall philosophy is the same. The extent of and expectations from early phase method validation are lower than the requirements in the later stages of development. The validation exercise becomes larger and more detailed and collects a larger body of data to ensure that the method is robust and appropriate for use at the commercial site. 

CRITICAL ASSESSMENT OF THE METHOD In case of drugs which are administered i.m., the pre-clinical i.m. toxicological is an important assay in the early phases of development. Often sings of i.m. local intolerance can be avoided or local tolerance can be improved by changes of the vehicle. 

It is unrealistic to envision that a single method can be developed for the determination of the API and related substances in both drug substance and drug product and, at the same time, be optimized to support all phases of pharmaceutical development. Instead, the development of a test method should be conducted in the context of a critical examination of what the method will be used to measure and the method validated to demonstrate that these criteria have been met. For early-phase methods, regulatory guidelines are unspecific, whereas, for late-phase methods, regulatory expectations provide a comprehensive set of performance goals that a method should achieve. 

Accordingly, the method development guidelines provided here for early-phase methods are flexible and are intended as guidance only. For late-phase methods, there is considerably less flexibility in approach. A comprehensive discussion of method validation is presented in Chapter 12. Validation issues will be addressed here only in the context of developing methods that satisfy the requisite validation requirements. 

Unlike early-phase methods, the criteria for late-phase release and stability studies are well defined by regulatory guidelines (see Chapter 12). Although it has been emphasized earlier that discussion of validation issues will not be a primary focus of this chapter, method development must be performed in the context of meeting regulatory expectations. Minimal discussion of regulatory considerations will, therefore, be interjected, where applicable, to the discussion of method development. 

All phases of analytical development are ideally supported by chemical separation techniques such as HPLC, TLC, GC, SFC, and CE. HPLC continues to be the primary method of analysis throughout the pharmaceutical development process. Although HPLC is limited in its ability to separate more than 15-20 components in a single analysis, and variations in columns and instrumentation manufacturer to manufacturer complicate transfer of methods, HPLC can readily be implemented to meet ICH requirements for method performance. For early-phase methods, HPLC can be coupled dynamically to mass and nuclear magnetic resonance spectrometers to facilitate the identification of unknown impurities. In later phases, HPLC can be implemented in a fully automated format as a high-throughput method for release and stability testing. 

The enthusiasm for the pharmaceutical potential of the monocyclic P-lactams was matched by renewed interest in the chemistry of these compounds both in industry and academe. This review will focus on recent developments in the chemistry of monocyclic P-lactam antibiotics, emphasizing new or improved methods for construction of the azetidinone ring as opposed to a discussion of the functional group manipulation of preformed P-lactams and the structure-activity relationships of the ultimate products. Emphasis will be placed on key advances in the preparation of true monocyclic antibiotics and intermediates for their synthesis and not on the voluminous chemistry dealing with the preparation of azetidinone intermediates for the synthesis of bicyclic compounds such as penems. The latter topic is covered elsewhere in this volume. The review is intended to cover the period from 1983 through early 1989 with an emphasis on more recent developments. Attention is drawn to previous reviews [4-14] which deal with the early phases of development of the monocyclic p-lactam antibiotics as well as those aspects of their chemistry not discussed in this work. 

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