An impurity caused by a chemical change in the drug ingredient during manufacturing and/or storage of the drug product due to, for example, light, temperature, pH, water, or reactivity with an excipient and/or the immediate container-closure system.
Drug product degradation cannot be predicted using stability tests of the drug ingredient in solid or solution. Nonactive pharmaceutical components (excipients) can interact with the medicinal substance or catalyze breakdown events. Impurities in the excipients can also cause degradation of the final product that was not previously noticed in the drug ingredient.
When a formulation is exposed to light, other chemicals, such as excipients or contaminants, absorb it and become excited, transferring energy to the drug molecule, resulting in photoreaction. Purposeful degradation tests are conducted to determine the drug substance's physical and chemical compatibility with excipients. These drug product investigations are based on the chemical makeup of the formulation. Heat, light, and humidity are common ingredients in therapeutic product compositions. (Although this ICH guideline provides a starting point, there is no detailed strategy for carrying out method-critical pharmacological investigations.)
The drug product stress conditions should result in approximately 10-20% degradation of the active drug substance or represent a reasonable maximum condition achievable for a given formulation. The specific conditions (intensity and length of time) used will depend on the chemical characteristics of the drug product. For all drug product studies, it is critical to run the proper controls: the drug substance, drug product, and placebo. For the most complete understanding of the degradation pathway, all three samples should be taken at each kinetic point and analyzed by the pharmaceutical drug candidate HPLC screening method. In the chromatographic screening of degradation samples, it is extremely useful to use the same methods for drug substance and drug product to allow easier understanding of chromatographic differences.
The first step in impurity and degradation profiling is to separate both major and minor components by chromatography. For the latter, LC is most preferred, while GC is most suited for volatile components. All impurities and degradation products above ∼ 0.1% are required to be identified, which can be done easily by spiking standard(s) into the sample. For those peaks that remain unidentified, one simple way is isolation, followed by structure elucidation through routine spectral tools. But several times, difficulties may be encountered in enriching specific minutiae, especially those unstable by nature. In these situations, the only way is to carry out structure elucidation of components of interest through the use of hyphenated techniques. Apart from extensively used LC-MS tools, the LC-NMR technique plays a significant role in confirming structures of unidentified impurities and degradation products.
Degradation impurities, also known as degradation-related impurities (DRIs), are substances that arise while a pharmaceutical product undergoes chemical changes over time. Several environmental factors can cause these alterations, including:
• Temperature fluctuations
•Light exposure
• Moisture and oxygen
• pH Change