Degradation studies purposeful

The ICH Guideline on Stability Testing of New Drug Substances and Products provides some guidance on stress testing or purposeful degradation  

Quantitative analytical methods that are based on the characteristic structural, chemical or biological properties of each active ingredient of a drug product and that will distinguish each active ingredient from its degradation products so that the active ingredient content can be accurately measured. 

This approach can lead to significant method rework if the degradation sample set was developed and analyzed at the validation stage and then proves the method to be nonstability indicating. One problem with this approach is that if any of the degradation products are unknown or unanticipated, method development has to be reinitiated very late in the process. In situations such as this, further method development is required after significant validation work has already been performed. 

If in later-stage studies significant ICH stability data are available, emphasis can be placed on the degradants observed with ICH stability conditions. 

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Alsante KM, Salisbury JJ, Hatajik TD, Snyder KD. Investigation of ICH photostability for purposeful degradation studies option 1 vs option 2. Pharmaceutical Photostability 01. Research Triangle Park North Carolina. 19 July 2001. 

Preventive Strategy. The firm should have an SOP for the validation of analytical methods that contains specificity requirements. If so, the firm would have shown in the specificity portion of the validation that X and Y indeed form the critical resolution pair. If this were proven in the specificity section with confirmation of the resolution of unknown impurities during a purposeful degradation study, this FDA-483 citation would have been avoided. 

Demonstration of a stability-indicating assay through purposeful degradation studies. 

Purposeful degradation studies of the drug substance include appropriate solution and solid-state stress conditions (e.g., acid/base hydrolysis, heat, humidity, oxidation, and light exposure, in accordance with ICH guidelines). Guidelines from the United States Pharmacopoeia (USP), ICH, and FDA provide a brief outline of drug substance conditions. The ICH guidelines specifically state ... 

If there are multiple salt forms or polymorphs being developed in parallel, it is helpful to perform comparative purposeful degradation studies on each form. Additionally, if there are stability issues with a particular salt form, it is advantageous to analyze the salt without drug substance as a control through the method development process as well as the free acid/base form of the com-... 

Using the conditions and kinetic time point ranges in this guidance, a purposeful degradation study will take approximately 6 weeks. This time frame and number of kinetic points taken can be reduced by a factor of 2 for early-stage work where timelines are typically much shorter. 

The following considerations should be taken into account when planning photostability experiments. One key concern is competing thermal reactions that may complicate photostability purposeful degradation studies. The samples should be irradiated under temperature-controlled conditions to minimize... 

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