Analytical Methodology for CMC
Robust test methods are a foundation for chemistry, manufacturing, and controls (CMC) dossiers. Test methods to describe and monitor a drug product’s identity, potency, purity, and stability must be developed, optimized, and validated before the product is used in clinical (and pivotal preclinical) studies and for release to distribution. For a majority of pharmaceutical drug products, liquid chromatography (LC) is the technique of choice to measure identity and purity attributes. This white paper outlines some best practices for expedient and successful LC test method development and validation. Most of these principles apply to methods other than LC, as well.
Define the Objective
Often there are competing goals for the requirements for measuring identity, potency, and purity, thus separate test methods may need to be established. For instance, identity and potency methods may call for rapid tests suited to routine monitoring while purity methods may require exquisite sensitivity and selectivity. Therefore, one should determine at the outset acceptable metrics for accuracy, precision, limits of detection, and specificity. If a method is to be used for stability testing, it must be shown to be stability indicating and selective. Limitations on instrumentation also should be defined. If a method will need to be transferred, it is preferable to establish acceptable hardware, software, and mode of detection. For example, many want methods that avoid mass selective detection, preferring common photometric means of detection.
Explore the Design Space
Reverse phase HPLC (or UPLC) is frequently the obvious choice for small organic molecule test methods. In some cases, though, other approaches need to be considered from the outset to arrive at an optimal method. The increasing number of therapeutic agents that are proteins or other biologically derived constituents demands consideration of other techniques such as ion exchange and size exclusion chromatography.
Broad consideration of fundamental options at the outset: LC mode, column selection, sample preparation, mobile phase and gradient, mode of detection, and instrument parameters, all yield benefit to deriving a robust method. Promising approaches may then be honed to identify specific suitable conditions.
Hands at the Bench
With a plan established the experimentalist may then conduct development activities in a concerted fashion. It is advantageous to have experienced scientists involved at the exploratory phase of method development. Early experiments and keen observations throughout the process guide the steps of honing in on suitable sample preparation, mobile phase considerations, and instrument parameters. Observations made at the bench in the middle of work generally reward with relevant insights faster than retrospective review of data. In a complimentary manner, good documentation practices pave the way to faster positive outcomes. One must document all reagents and apparatus, material handling considerations, and procedures.
Assuming successful completion of the creative phase, establishing conditions and parameters that fulfill the needed objectives, basic performance properties must be measured. Accuracy, precision, and linearity are minimum requirements to show suitable performance. To show the selectivity of a method to discern degradation products and other impurities formalized forced degradation studies must be carried out. Subjection of samples to stressed conditions – heat, light, acid, base, and oxidation – until degradation products can be detected is followed by adjustment of method conditions to show noninterference between the active peak and impurities. Response factors and relative response factors of known and identified degradants must be established. The better performance properties are measured during the development stage by Robustness studies, the more confident one can be that the finalized method can be validated suitably.
Formalized guidelines for validation of procedures active pharmaceutical products are described by the ICH, as well as the FDA and USP. ICH Guidance Q2R1 describes principles for validation of specificity, linearity, range, accuracy, precision, detection and quantitation limits, robustness, and system suitability. Details for these parameters may vary among techniques and circumstances. However, the general requirements stand among most analytical procedures in which it is critical to have confidence.
Circumstances in which there are no Compendial or other officially documented tests for a given substance or product necessitate new method development. The development scientist must carefully scope and execute the project to assure success. Attention to details early in the development process leads to assurance of a straightforward validation process and to reliable methods suited for the purposes for which they are intended.
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