Pharmaceutical Forced Degradation (Stress Testing) Endpoints: A Scientific Rationale and Industry Perspective

Zelesky, Todd; Baertschi, Steven W.; Foti, Chris; Allain, Leonardo R.; Hostyn, Steven; Franca, Juçara Ribeiro; Li, Yi; Marden, Stacey; Mohan, Shikhar; Ultramari, Mariah; Huang, Zongyun; Adams, Neal; Campbell, John M.; Jansen, Patrick J.; Kotoni, Dorina; Laue, Christian

doi:10.1016/j.xphs.2023.09.003

Cited by 14 publications

(5 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, acidic and basic conditions often induce a more rapid degradation than oxidation processes. The ICH guidelines stipulate that a minimum of 20 % of the drug should partially degrade to warrant further validation [20] . Therefore, the specific degradation days noted in our study are determined based on reaching this threshold of degradation for each respective conditions.…”

Section: Resultsmentioning

confidence: 99%

“…The ICH guidelines stipulate that a minimum of 20 % of the drug should partially degrade to warrant further validation. [20] Therefore, the specific degradation days noted in our study are determined based on reaching this threshold of degradation for each respective conditions. Accordingly, adequately degraded products were detected using HPLC-PDA, and the percentage degradation was recorded at 256 nm.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Forced Degradation Products of Olmesartan Medoxomil and their In Vitro Genotoxicity Assessment by Comet Assay using HEK Cells

Wankhade,

Nikhil,

Jain

et al. 2024

ChemistrySelect

View full text Add to dashboard Cite

This study designed to characterize major forced degradation products of Olmesartan Medoxomil (OM) and to perform genotoxicity profiling using acid, base, and hydrogen peroxide‐induced stress degradation studies. The isolation of degradation products was conducted on flash chromatography using FlashPure ECOFLEX C18 4 g column with gradient elution and diode array detection‐based fraction collection, and characterized by mass spectrometry. Three impurities (impurity‐1, 2, and 3) were identified with respective m/z values of 447.213, 461.229, and 463.208. The genotoxic potential of impurities was assessed by in silico prediction, and in vitro comet assay using HEK cells. The extent of DNA damage was analyzed using Comet Assay IV imaging software. For impurity‐1, head and tail lengths and their respective total intensities were significantly (p<0.001) larger than those of dimethyl sulfoxide (solvent) control and comparable to positive control. Other parameters such as mean grey level and total area of comet were statistically significant as compared with the solvent and positive controls. Overall, impurity‐1 was a possible genotoxic impurity and a known major degradation product in OM tablet dosage form. In silico prediction also revealed impurity‐1 as toxicity class 3, whilst impurities 2 and 3 were of toxicity class 4.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Forced Degradation Products of Olmesartan Medoxomil and their In Vitro Genotoxicity Assessment by Comet Assay using HEK Cells

Wankhade,

Nikhil,

Jain

et al. 2024

ChemistrySelect

View full text Add to dashboard Cite

show abstract

“…21 FD is a method used to induce the degradation of TVB under settings exhibiting greater severity than the accelerated conditions and undergoes decomposition to produce degradation components that serve as an indicator of the drug molecule stability and the chemical behavior of the drug, which further support the pharmaceutical product development and their packaging. 22–24 As per the ICH guideline, the FD study aims to disclose potential degradation products to assist in evaluating the stability and reveal degradation pathways. It also validates the stability-indicating methods used.…”

Section: Methods Validationmentioning

confidence: 99%

Development and validation of the RP-HPLC method for quantification of tavaborole

Prajapati,

Jain,

Bajpai

2024

Anal. Methods

View full text Add to dashboard Cite

show abstract

“…Determining the set of stress conditions and experimental execution specifics needed to induce the potential degradation pathways most relevant to pharmaceutical storage, distribution, and use requires consideration of several factors, not least, the physicochemical properties of the DS under study. Making the design of these studies and interpretation of the results a complex activity. , Stress testing is often first initiated in Discovery (i.e., preclinical) and is typically repeated at least once during the clinical phase of development, in addition to excipient compatibility, and long-term DS and DP stability studies. , …”

Section: Introductionmentioning

confidence: 99%

“…Making the design of these studies and interpretation of the results a complex activity. 6,7 Stress testing is often first initiated in Discovery (i.e., preclinical) and is typically repeated at least once during the clinical phase of development, in addition to excipient compatibility, and long-term DS and DP stability studies. 8,9 Due to the complexity of organic reaction chemistry and the diverse chemical environments pharmaceuticals experience, identifying the degradation mechanism(s), root causes, and control strategies is challenging.…”

Section: ■ Introductionmentioning

confidence: 99%

In Silico Prediction of Pharmaceutical Degradation Pathways: A Benchmarking Study Using the Software Program Zeneth

Hemingway,

Baertschi,

Benstead

et al. 2024

Org. Process Res. Dev.

Self Cite

View full text Add to dashboard Cite

Zeneth, a software application for the prediction of chemical degradation of small organic molecules, incorporates a knowledge base of rules to predict degradation pathways. In addition, the knowledge base contains property predictors that modulate the predicted likelihood of a given degradation product. In this study, a C−H bond dissociation energy (C−H BDE) predictor, which has been integrated into the software, was utilized. To determine this software's predictive capabilities [using its knowledge base (2020.1.0 KB)], experimentally derived degradation profiles for 25 drug substances were compared to Zeneth predictions. These degradation profiles were derived from forced degradation studies, including accelerated and long-term stability studies, aligned with International Council for Harmonisation (ICH) guidelines. In addition, two case studies highlighting how prediction data can be utilized to confirm experimental data or assist with the identification of unknown degradation products have been presented. The specificity of prediction results was evaluated; transformation types that often predict degradation products not observed experimentally were identified, and an assessment of the causes is presented. The sensitivity for the study group was also evaluated using a historic knowledge base (2012.2.0 KB), enabling an assessment of how the predictive capabilities have improved over this period; the comparison demonstrated a 40% increase in sensitivity. This study has demonstrated that the ongoing expansion and optimization of this in silico tools knowledge base continues to result in improvements in its predictive capability and its ability to impart insight into the drug degradation knowledge space to aid pharmaceutical development.

show abstract

Pharmaceutical Forced Degradation (Stress Testing) Endpoints: A Scientific Rationale and Industry Perspective

Cited by 14 publications

References 28 publications

Forced Degradation Products of Olmesartan Medoxomil and their In Vitro Genotoxicity Assessment by Comet Assay using HEK Cells

Forced Degradation Products of Olmesartan Medoxomil and their In Vitro Genotoxicity Assessment by Comet Assay using HEK Cells

Development and validation of the RP-HPLC method for quantification of tavaborole

In Silico Prediction of Pharmaceutical Degradation Pathways: A Benchmarking Study Using the Software Program Zeneth

Contact Info

Product

Resources

About