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Forced Degradation Studies or Stress Testing Studies:: What Are The Objectives ?
Forced Degradation Studies or Stress Testing Studies:: What Are The Objectives ?
METHOD DEVELOPMENT.
What we Stress?.
DRUG SUBSTANCE
DRUG PRODUCT.
PLACEBO.
Discrimination between
Synthetic process impurities, excipients,
degradation products derived from excipients alone and
drug related degradation products including the drug excipient
combinations.
Forced degradation studies or
Stress testing studies.
Key Point to be kept in mind :
Thermolytic Degradation,
Hydrolytic degradation,
Oxidative degradation,
Photolytic degradation.
Forced degradation studies
THERMOLYTIC DEGRADATION :
THERMOLYTIC DEGRADATION :
THERMOLYTIC DEGRADATION :
HYDROLYTIC DEGRADATION :
HYDROLYTIC DEGRADATION :
HYDROLYTIC DEGRADATION :
HYDROLYTIC DEGRADATION :
However,
For example,
HYDROLYTIC DEGRADATION :
HYDROLYTIC DEGRADATION :
Typical conditions :
Reflux using water/ 0.1M HCl/ 0.1M NaOH for stress testing
with or without co-solvent at a temperature of about 70°C.
After the stress, dilute in diluent to get the test concentration, so that
peak shapes are good.
Forced degradation studies
HYDROLYTIC DEGRADATION :
HUMIDITY STRESS :
OXIDATIVE DEGRADATION :
one of the most common mechanisms of drug degradation.
But for some compounds, degradation may occur at higher temperature due to
free radical reaction initiation.
Typical stress conditions :
PHOTOLYTIC DEGRADATION :
Degradation that results from exposure to UV or visible light.
Stress testing of placebo with other actives excluding the one at a time,
shall be performed, in order to know the non-interference from each
other.
Evaluate the peak purity for the analyte peaks for which
peak heights are less than 1000 m AU.
Try to establish the structure of the Major degradants by doing a mass study.
EVALUATION OF FORCED DEGRADATION :
If any Major degradant is having a different absorption maxima,
Preferrably it should be identified & estimated at that wavelength.
The process of adding together the assay value and levels of degradation
products to see how closely these add up to 100% of the initial value.
Estimate the assay of the final force degradation samples and assess the mass
balance. Mass balance is to be achieved at least up to 95% level.
If the mass balance is less than the required criteria investigation to be done
and justified.
EVALUATION OF FORCED DEGRADATION :
Reasons for not achieving the mass balance :
(1). Degradation products are not eluted from the HPLC column
(2). Degradation products are not detected by the detector used.
(3). Degradation products lost from the Sample matrix, due to
insolubility, volatility or adsorption losses.
(4). Parent compound lost from the sample matrix, due to insolubility,
volatility or adsorption losses.
(5). Degradation products are co-eluted with the parent compound.
(6). Degradation products are not integrated due to poor
chromatography.
(7). Inaccurate quantification due to differences in response factors.
EVALUATION OF FORCED DEGRADATION :
Reasons for not achieving the mass balance :
(1). Degradation products are not eluted from the HPLC column
(2). Degradation products are not detected by the detector used.
(3). Degradation products lost from the Sample matrix, due to
insolubility, volatility or adsorption losses.
(4). Parent compound lost from the sample matrix, due to insolubility,
volatility or adsorption losses.
(5). Degradation products are co-eluted with the parent compound.
(6). Degradation products are not integrated due to poor
chromatography.
(7). Inaccurate quantification due to differences in response factors.
EVALUATION OF FORCED DEGRADATION :
Finalization of Detector wavelengths:
After finalization of the separation of all impurities and degradants,
take the overlaid spectra of all impurities for each of the stress
conditions, along with the spectra of the analyte.
For Example,
If method is common ,
THANKS