Purposeful degradation samples

Sample Screening Recommendations for Purposeful Degradation Samples 

Material balance assessments are critical in confirming that degradants have not been missed and can identify drug/degradant co-elutions. A low bias in the material balance can be due to a number of factors. When performing solution degradation studies, low recovery can be due to poor solubility of 

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

For compounds with one or more stereocenters, it is prudent to screen the key samples (10-20% degradation timepoint) with the current chiral purity method to determine if the degradation pathway is stereospecific. From the achiral method development perspective, stereospecific degradation pathways will not affect the outcome of the method development process, but this information can affect the impurity control strategy for the compound. 

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

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. 

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

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

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... 

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... 

As emphasized in Section ILA, a proactive approach to HPLC method development should involve purposeful degradation at the early stages of development with the key degradation samples used in the method development process. See Figure 6 for an overview of the role of purposeful... 

CP-944,629 is a substituted l,2,4-triazolo[4,3-a]pyridine. This compound was designed as a selective inhibitor of the stress-activated kinase p38a, and was nominated as potential disease-modifying drug for rheumatoid arthritis (RA). Purposeful degradation experiments performed on this compound was analyzed by RP-HPLC with UV detection. Analysis of the solid-state photostability samples indicated a lack of mass balance with an assay value of 25% impurities totaling 18% by total area percent. Closer inspection of the sample revealed imdissolved material in the bottom of the volumetric flask. This case study focuses on the identification of the degradation product that resulted in the undissolved material and source of the lack of mass balance. 

DEGRAD STABILjcIs Section 1.8.4 The analysis of stability reports often suffers from the fact that the data for each batch of product is scrutinized in isolation, which then results in a see-no-evil attitude if the numerical values are within specifications. The analyst is in a good position to first compare all results gained under one calibration (usually a day s worth of work) irrespective of the products/projects affected, and then also check the performance of the calibration samples against experience, see control charts, Section 1.8.4. In this way, any analytical bias of the day will stand out. For this purpose a change in format from a Time-on-Stability to a Calendar Time depiction is of help. 

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