Chemical stability is one of the most important issues that impacts the quality and safety of pharmaceuticals. The FDA and ICH require stability testing data to understand how the quality of an API or a drug product changes with time under the influence of environmental factors such as heat, light, and humidity.Knowledge of these stability characteristics defines storage conditions and shelf life, the selection of proper formulations and protective packaging, and is required for regulatory documentation.
Forced degradation studies typically involve the exposure of representative sample of a drug substance or drug product to the relevent stress condition of light,heat,humidity,acid/base hydrolysis and oxidation.Forced degradation plays an important role in the drug devolepment process.It furthers understanding of the chemistry of the drug substance and drug product and facilitates the devolepment of stability indicating analytical methodology.
Forced degradation, or stress testing, is carried out under even harsher conditions than those used for accelerated stability testing. Generally performed early in the drug development process, laboratories cause the potential drug to degrade under a variety of conditions – acid and base hydrolysis, photostability, peroxide oxidation, and temperature – to understand resulting byproducts and pathways that are necessary to develop stability indicating methods.
Testing of stress samples are required to demonstrate the following abilities.
1. To evaluate the stability of drug substance and drug products in solution.
2.To determine structural transformations of drug substance and drug product.
3.To detectlow concentration of potential degradation products.
4.To detect unrelated impurities in the pressence of the desired product or product related degradents.
5.To seperate the product related degradants from those derived from excipients and intact placebo.
6.To elucidate possible degradation pathways.
7.To identify degradation products that may be spontaneously generated during storage and use.
Forced degradation studies are designed to generate product related varients and devolep analytical methods to determine the degradation products formed during accelerated and long term studies.The degradation products observed in such studies are "potential" degradation products that may or may not be formed under relevant storage conditions, but these products reveal the degradation pathways available to the drug and facilitate the development of stability-indicating analytical methods.Any significant degradation product should be evaluated for potential hazard and the need for characterization and quantitation.
Forced degradation studies are designed to generate product related varients and devolep analytical methods to determine the degradation products formed during accelerated and long term studies.The degradation products observed in such studies are "potential" degradation products that may or may not be formed under relevant storage conditions, but these products reveal the degradation pathways available to the drug and facilitate the development of stability-indicating analytical methods.Any significant degradation product should be evaluated for potential hazard and the need for characterization and quantitation.
Forced degradation or stress studies of drug substances are usually conducted in solution and the solid state at temperatures exceeding accelerated stability conditions (>40°C) The degradation pathways investigated include hydrolysis, oxidation, thermolysis, photolysis, and polymerization. Hydrolysis is investigated in solution over a broad pH range and in the solid state by exposure of the drug to high relative humidity. Oxidation in solution can be investigated through control of exposure to molecular oxygen or by addition of oxidizing agents such as peroxides. The effects of thermolysis are usually assessed in the solid state by applying heat. Photolysis is investigated in solution or the solid state by irradiating samples with light with wavelengths in the 300-800 nm range; photooxidation can be investigated with light under an oxygen atmosphere. Drug substance polymerization can be investigated by measuring the rate of degradation as a function of different initial drug substance concentrations in solution and LC/MS analysis of degradation products.
Extend of degradation
A degradation level of 10-15% is considerd adequate for validation of a chromatographic purity assay.
Regulatory and Scientific Guidance by Phase
Although forced degradation studies are a regulatory requirement and scientific necessity during development, they are not considered part of the formal stability program. The guidance gives recommendations for conducting studies at the various phases of development.
Phases 1 and 2
For Phase 1 and 2 INDs, the guidance recommends that degradation studies on the drug substance be conducted for the purpose of SIM development, but there is no explicit requirement to report the findings of these studies in the IND.However, this investigator has had questions from the FDA at the IND stage on degradation chemistry related issues. From a scientific point of view, it is advisable to perform degradation studies on the drug substance in solution and the solid state after candidate selection or as early as feasible. Degradation product identities can be investigated by LC/MS, LC/DAD, or LC/NMR. Peak purity of the API can be determined by one of these hyphenated techniques or through use of orthogonal chromatographic methods. Some attempt to determine mass balance should be made. Isolation and characterization of degradation products is rarely needed this early with the exception for degradation products that are suspected to be very potent. If the molecule is chiral and predominately one stereoisomer, the stereochemical stability of the API should be examined in the degraded samples. Solid-state work should wait until the salt form has been finalized unless a less optimal form will be used in a regulated study. Stressed solid samples should be tested for content, impurities, and physical form. Though rare, there are degradation pathways that occur only in the solid state and then only in some polymorphs.
The guidance recommends only that drug products be stressed photolytically at phase 2.Scientifically, solid dosage forms should be stressed with heat, heat and high humidity, and with light. Liquid dosage forms should be stressed with heat, light, and possibly at different pH if the product contains water and is unbuffered. Stressed drug products should be examined for reactions between the API and excipients using hyphenated techniques. Clear differentiation between drug and non-drug related peaks should be made. Stressing placebo and product concurrently followed by comparison of the respective profiles can facilitate this determination. Degradation studies at this stage can readily afford insight for development of more stable formulations.
The result of forced degradation studies are required to be included in phase-III IND filing.
Forced degradation studies typically involve the exposure of representative sample of a drug substance or drug product to the relevent stress condition of light,heat,humidity,acid/base hydrolysis and oxidation.Forced degradation plays an important role in the drug devolepment process.It furthers understanding of the chemistry of the drug substance and drug product and facilitates the devolepment of stability indicating analytical methodology.
Forced degradation, or stress testing, is carried out under even harsher conditions than those used for accelerated stability testing. Generally performed early in the drug development process, laboratories cause the potential drug to degrade under a variety of conditions – acid and base hydrolysis, photostability, peroxide oxidation, and temperature – to understand resulting byproducts and pathways that are necessary to develop stability indicating methods.
Testing of stress samples are required to demonstrate the following abilities.
1. To evaluate the stability of drug substance and drug products in solution.
2.To determine structural transformations of drug substance and drug product.
3.To detectlow concentration of potential degradation products.
4.To detect unrelated impurities in the pressence of the desired product or product related degradents.
5.To seperate the product related degradants from those derived from excipients and intact placebo.
6.To elucidate possible degradation pathways.
7.To identify degradation products that may be spontaneously generated during storage and use.
Forced degradation studies are designed to generate product related varients and devolep analytical methods to determine the degradation products formed during accelerated and long term studies.The degradation products observed in such studies are "potential" degradation products that may or may not be formed under relevant storage conditions, but these products reveal the degradation pathways available to the drug and facilitate the development of stability-indicating analytical methods.Any significant degradation product should be evaluated for potential hazard and the need for characterization and quantitation.
Forced degradation studies are designed to generate product related varients and devolep analytical methods to determine the degradation products formed during accelerated and long term studies.The degradation products observed in such studies are "potential" degradation products that may or may not be formed under relevant storage conditions, but these products reveal the degradation pathways available to the drug and facilitate the development of stability-indicating analytical methods.Any significant degradation product should be evaluated for potential hazard and the need for characterization and quantitation.
Forced degradation or stress studies of drug substances are usually conducted in solution and the solid state at temperatures exceeding accelerated stability conditions (>40°C) The degradation pathways investigated include hydrolysis, oxidation, thermolysis, photolysis, and polymerization. Hydrolysis is investigated in solution over a broad pH range and in the solid state by exposure of the drug to high relative humidity. Oxidation in solution can be investigated through control of exposure to molecular oxygen or by addition of oxidizing agents such as peroxides. The effects of thermolysis are usually assessed in the solid state by applying heat. Photolysis is investigated in solution or the solid state by irradiating samples with light with wavelengths in the 300-800 nm range; photooxidation can be investigated with light under an oxygen atmosphere. Drug substance polymerization can be investigated by measuring the rate of degradation as a function of different initial drug substance concentrations in solution and LC/MS analysis of degradation products.
Extend of degradation
A degradation level of 10-15% is considerd adequate for validation of a chromatographic purity assay.
Regulatory and Scientific Guidance by Phase
Although forced degradation studies are a regulatory requirement and scientific necessity during development, they are not considered part of the formal stability program. The guidance gives recommendations for conducting studies at the various phases of development.
Phases 1 and 2
For Phase 1 and 2 INDs, the guidance recommends that degradation studies on the drug substance be conducted for the purpose of SIM development, but there is no explicit requirement to report the findings of these studies in the IND.However, this investigator has had questions from the FDA at the IND stage on degradation chemistry related issues. From a scientific point of view, it is advisable to perform degradation studies on the drug substance in solution and the solid state after candidate selection or as early as feasible. Degradation product identities can be investigated by LC/MS, LC/DAD, or LC/NMR. Peak purity of the API can be determined by one of these hyphenated techniques or through use of orthogonal chromatographic methods. Some attempt to determine mass balance should be made. Isolation and characterization of degradation products is rarely needed this early with the exception for degradation products that are suspected to be very potent. If the molecule is chiral and predominately one stereoisomer, the stereochemical stability of the API should be examined in the degraded samples. Solid-state work should wait until the salt form has been finalized unless a less optimal form will be used in a regulated study. Stressed solid samples should be tested for content, impurities, and physical form. Though rare, there are degradation pathways that occur only in the solid state and then only in some polymorphs.
The guidance recommends only that drug products be stressed photolytically at phase 2.Scientifically, solid dosage forms should be stressed with heat, heat and high humidity, and with light. Liquid dosage forms should be stressed with heat, light, and possibly at different pH if the product contains water and is unbuffered. Stressed drug products should be examined for reactions between the API and excipients using hyphenated techniques. Clear differentiation between drug and non-drug related peaks should be made. Stressing placebo and product concurrently followed by comparison of the respective profiles can facilitate this determination. Degradation studies at this stage can readily afford insight for development of more stable formulations.
The result of forced degradation studies are required to be included in phase-III IND filing.
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