Early phase methods validation

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. 

The validation report should contain reference to the analytical methods (specific code number used as identifier within the pharmaceutical organization) and the corresponding drug substance or product name. Note that for early-phase method validation reports the results maybe filled in a predefined table and compared against the acceptance criteria. However, for late-phase validation, more explicit reports are generated explaining each and every experiment, with detailed steps of sample and standard preparation. 

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... 

Early phase methods usually adopt a simple way to establish method sensitivity by preparing a 0.05% solution of the API relative to the standard solution, which is injected multiple times during validation to obtain an RSD value (<15%, N=6). Later, this solution is injected every time the method is used to assure that adequate sensitivity is observed at the time of use. 

An additional key validation criterion for early phase methods is an evaluation of solution stability to establish that the API and related substances do not degrade in the solvent system used for sample preparation. This allows for limits to be set for solution lifetime. 

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. 

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. 

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. 

TABLE 4 Assay Method Validation in Early Phase for Drug Substance and Drug Product... 

Specification limit. Note that the reporting level can never be lower than the limit of quantitation (LOQ) of the method. However, during early-phase validation for drug products, if authentic degradation products are not available, then low amounts of API are added (LOQ to 120% specification limit of largest impurity) to the placebo and the recovery experiment is performed. 

A transition phase could be envisaged by researches, regulators, and stakeholders in which a set of minimal validation requirements for screeifing/early warning methods are proposed and agreed on, whereas customary full requirements continue to be enforced for official methods for statutory analyses. 

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. 

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