Purposeful degradation

There are many examples, as cited above, which have demonstrated that the EC oxidation products for a given compound often coincide with metabolites observed in biological assays (Volk et al., 1988, 1989 Getek et al., 1989 Deng and Van Berkel, 1999 Jurva et al., 2000 van Leeuwen et al., 2005). These and other EC oxidation products may also be observed in purposeful degradation or stability studies. One must recognize, however, that enzyme-catalyzed, chemical and EC oxidations are often very complex and involve different phenomena. 

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. 

Determine feasibility for related compounds Analyze all related compounds available (process impurities, degradation products, etc.) and perform purposeful degradation on the API. Determine interferences. 

Prepare placebo sample and determine if interfering placebo peaks are present. Purposefully degrade placebo and determine if interfering degradant peaks are present. 

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. 

A. Sample Screening Recommendations for Purposeful Degradation Samples... 

Degradants (Purposeful Degradation) Key challenge samples Isolated degradants Isolated Fractions Small scale synthesis Phase Equilibrium Supernatants Raw materials Isolated Intermediates... 

Purposeful degradation experiments determine major degradation pathways and flags marker compounds for those pathways. 

Meets criteria for KPSS, not seen in real stability (6 months 40°C/75% RH or 2 years 30°C/60% RH) Stability samples act as a reality check for purposeful degradation and they can be used to determine if a... 

Seen in drug substance stability samples at >0.05%, but not in purposeful degradation... 

Potential Key Predictive Samples (KPSS) (Purposeful degradation samples, mother liquors, FGs, etc.)... 

For a given API, there can be numerous ways to mix and match the available samples to construct the method development sample set. During early stages of development, only a few isolated intermediates and purposeful degradation samples may be available, making sample set selection relatively easy. Later in development, more isolated samples of the major degradants... 

The preparation of cocktail samples should be documented in a notebook, and that notebook ID should be used to name the sample for injection, along with a convenient naming convention. For example, NB-12345-001 PD UV/PD thermal could be used to define a mixture of two purposeful degradation samples into a cocktail sample. 

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

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

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. 

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