Early phase methods development, validation

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. 

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. 

If a secondary method is required during early phase development, a level 3 method is developed and validated to support phase 2b or early phase 3 clinical studies. This method should be capable of separating all components of interest identified up to this stage of pharmaceutical development. In cases where the initial primary method is still viable, the level 1-level 2 method may be maintained. As in early development, the use of an orthogonal method to evaluate DS generated via new synthetic schemes and to evaluate new formulations remains an important means of assuring that the primary method is sufficient for characterizing DS and DP. 

If a secondary method is required during level 1-level 2 development, a level 3 method is developed and validated to support phase 2b or early phase 3 clinical studies. This method should be capable of separating all components of interest identified up to this stage of pharmaceutical development. 

Analytical methods used to determine purity and potency of an experimental API that is very early in development will need a less rigorous method validation exercise than would be required for a quality control laboratory method at the manufacturing site. An early phase project may have only a limited number of lots to be tested and the testing may be performed in only one laboratory by a limited number of analysts. The ability of the laboratory to control the method and its use is relatively high, particularly if laboratory leadership is clear in its expectations for the performance of the work. 

This chapter will discuss the role of the analytical chemist in the preformulation process and highlight the methods that will need to be developed, validated and utilized to support these studies. An assortment of analytical techniques is needed to measure a number of critical quality attributes of the new molecular entity such as solubility, purity, and crystalline habit. The methods will be used to make important decisions such as the choice of salt form, or which sohd oral dosage form has the best probability of providing adequate exposure in an early phase clinical study. These analytical tools are critical to the decision that a pharmaceutical development organization uses to evaluate the first round of solid dosage form development prior to the availability of clinical data. 

Analytical Development of API and Drug Products. Early methods to support synthetic and formulation developments are often developed in the form of potency assay, impurities/related substance assay, dissolution, Karl Fischer, identity, chiral method, and content uniformity. These analytical methods are developed and validated in a fast and timely manner to support all phase II studies. 

Another professional organization headquartered in central Europe, APV (International Association for Pharmaceutical Technology, Mainz, Germany), developed the topic further in two seminars in Gelsenkirchen in late 1981 and early 1982 [6]. Speakers from industry demonstrated how validation could be applied to industrial activities and how a balance between resources allocation and results could be achieved. Oral dosage forms, topicals, and sterile products, as well as analytical methods during development, transfer, and production phases were discussed. 

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