Drug development analyte stability

Recent developments in drug discovery and drug development spurred the need for novel analytical techniques and methods. In the last decade, the biopharmaceutical industry set the pace for this demand. The nature of the industry required that novel techniques should be simple, easily applicable, and of high resolution and sensitivity. It was also required that the techniques give information about the composition, structure, purity, and stability of drug candidates. Biopharmaceuticals represent a wide variety of chemically different compounds, including small organic molecules, nucleic acids and their derivatives, and peptides and proteins. 

If the pKa of a drug substance is known in the early stages of the drug development process, the analytical assay method development, solubility and stability estimation as a function of pH, can be accomplished with a minimum number of experiments, and it can guide formulation development for IV formulations. 

Stress testing is an important part of the drug development process as it provides knowledge about the degradation chemistry of drug compounds. This knowledge is used primarily to develop stability-indicating analytical methods but is also useful for other purposes such as formulation develop-... 

Performance of stability stress studies with the drug substance early in drug development is encouraged, as these studies provide information crucial to the selection of stability indicating analytical procedures for real time studies. 

The API Assay, the Assay of Impurities and Product Stability. The central independent analytical research and quality control unit is responsible for the analytical release of both the API and the formulated drug product for the drug development programs. The central independent QC unit provides all the analytical data needed to build the analytical specification for the IND. It is recognized by those involved that the IND is a relatively raw document compared with the later NDA, which is built on data from a more developed process situation, using more refined analytical techniques. 

An analytical method is a laboratory procedure that measures an attribute of a raw material, drug substance, or a drug product. Analytical method validation is the process of demonstrating that an analytical method is reliable and adequate for its intended purpose. Any method that is utilized to determine results during drug substance and formulation development will have to be validated. Reliable data for release of clinical supplies, stability, and setting shelf life can only be generated with appropriate validated methods. 

As analytical procedures are used throughout drug development and the manufacturing and release of drug substances and drug products, the reliability of their results is essential. Important decisions such as the establishment of the shelf-life from stability studies, the need for additional toxicological trials if new impurities appear or if known impurities exceed the qualified levels, and the reworking of batches and batch release or rejection are based on analytical results. Therefore, an appropriate validation to demonstrate the performance and suitability of the analytical procedures is much more than a formal requirement. 

The primary analytical mission at this stage is to ensure that adequate documentation for quality, consistency, and stability of the clinical materials is available to bridge the drug development as safely as possible from animals to humans. 

This section, as previously discussed, frequently poses problems leading to delays in NDA approval. Particular attention should be paid to the development of adequate data from studies conducted with commercial formulations packaged in container/closure system(s) to be marketed. It is critical that adequately validated analytical methods be used as early as possible in the investigational phases of drug development—no later than the initiation of phase 3 studies. Common defects in stability studies submitted to the FDA reflect the lack of acceptable long-term or short-term accelerated stability data to support the approval of an expiration date for the product. Another common problem occurs when studies are conducted using only one container size, yet the sponsor is... 

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