Forced Degradation


Forced degradation or alternatively referred to as stress testing is undertaken to demonstrate specificity when developing stability indicating methods, especially when little is known about potential degradation products. The studies can also provide information about the degradation pathways and degradation products that could form during storage. These studies may also help facilitate development in areas such as formulation development, manufacturing, and packaging, in which knowledge of chemical behaviour can be used to improve a drug product. 

Reasons for carrying out forced degradation studies include: 

- Development and validation of stability-indicating methodology 

- Determination of degradation pathways of drug substances and drug products 

- Discernment of degradation products in formulations that are related to drug substances versus those that are related to non–drug substances (e.g., excipients)

- Structure elucidation of degradation products

- Determination of the intrinsic stability of a drug substance molecule.

Some defining characteristics of stress testing studies are:

- Typically carried out on one batch of material 

- Not part of the formal stability program 

Typical stress conditions are: 

Stress Condition

Example 

Acid/Base 

0.01 to 0.1N 

Oxidative 

0.3%H2O2 

Light 

1200 Lux h 

Temperature 

10°C to 70°C 

Temperature/ 

Humidity 

10°C to 70°C & 

60% to 90% RH 

The experimental protocol for degradation studies of new drug substances and drug products ideally will result in samples that either have been degraded ~10% or have been exposed to an amount of energy that slightly exceeds that supplied under accelerated storage conditions recommended by the ICH guidelines on stability testing (eg 40°C/75%RH for 6 months). 

Forced degradation studies should be conducted whenever a stability-indicating method is required. Studies may need to be repeated as methods, processes, or formulations change. The goal is to generate a degradation profile that mimics what would be observed in formal stability studies under ICH conditions.  

Suggested equipment and exposure levels for photostability stress testing, as illustrated below, are described in ICH guidelines. 

To confirm the effectiveness of the analytical methods used to examine for degradation products it is essential to perform   mass balance calculations. This is the process of adding the assay value and levels of degradation products to see how closely these add to 100% of the initial value. Taking into account the uncertainties of measurement a variation between 97 to 104% can be considered acceptable.  

In cases in which substantial mass loss is observed, efforts to account for the missing mass should be made such as consideration of response factors or the formation of highly retained or volatile degradation products.  

Butterworth Laboratories Ltd has experience of developing and validating analytical methods for Quality Control purposes using a wide range of techniques.

The Projects Department at Butterworth would be happy to discuss any requirements you may have with regards to Forced Degradation/Stress Testing for Drug Substances or Drug Products.

 

For more information please contact  David Bell, Head of Projects

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