Forced degradation studies are a critical element of pharmaceutical development. They play an essential role in protecting patient safety and validating the stability of a drug molecule. But why are forced degradation studies necessary, and what do they involve?
This introduction to forced degradation and pharmaceutical stress testing explains:
- What are forced degradation studies?
- What types of experiments are included in forced degradation
- How to effectively manage forced degradation study data
What Are Forced Degradation Studies?
A forced degradation study investigates the stability of a chemical or pharmaceutical product under stressful conditions (forced degradation research is also known as stress testing). “Stress” in this case means any physical or environmental conditions that a product will encounter that could cause a chemical change. Key learning outcomes of forced degradation testing include:
- Establishing likely degradation pathways and products
- Evaluating the stability of the molecule
- Validating the analytical methods used to assess chemical stability
- Gaining insight into drug packaging and storage
Forced degradation studies can be performed for any chemical, but it is essential in pharmaceutical development. Active pharmaceutical ingredients (APIs) are carefully designed and dosed to deliver a specific pharmaceutical effect. Chemical changes can compromise the drug’s efficacy or cause harmful side effects.
Typical Forced Degradation Experiments
First, it is necessary to specify the states of matter that need to be studied. A solution interacts with chemical stress differently than a pure powder or tablet. Each substance will then undergo a series of tests.
Some of the most common include:
Thermal: patients will often leave medications at elevated temperatures by accident. Maybe a package of tablets left in a car on a hot day, or the family pill cabinet is close to a stove or radiator. Companies need to ensure their drugs are safe when exposed to these conditions. Scientists test for thermal stability by leaving the medication at an elevated temperature for 1-5 days.
Photolytic: many chemical substances are light-sensitive, meaning that they degrade when exposed to a light source. Pills or tablets may be hit by low-intensity visible and UV light for weeks or months before they are taken, which can cause photolytic degradation. This is one reason many pill bottles are opaque or amber in color—reducing the amount of light that hits the pills, therefore keeping degradation to a minimum.
Acid/Base Hydrolysis: acidic or basic conditions can be stressful for drug molecules. Medications given as a liquid suspension may experience shifts in pH over time, so researchers need to ensure that the API is stable under these conditions. Conditions range between 0.1 M HCl and 0.1 M NaOH.
Tests are done based on the dosage form of the medication, for example, tablets require different tests than an injected medication or a topical cream.
How is Forced Degradation Data Used?
Now that the drugs have been stress tested, what happens next? Forced degradation research is done to protect patient health. Regulatory agencies such as the FDA in the United States and the EMA in Europe need to be satisfied that the medication is safe and effective during everyday use.
Degradation of the API is a critical indicator. Drug molecules that break down will not help patients, which means the drug will be less effective. Losing 20% or more API is considered abnormal. This is typically tracked using chromatography.
Another critical piece of information is which degradant molecules form. These degradant molecules may be biologically active, leading to unwanted side effects in the patient. Recently, Ranitidine was recalled because of a carcinogen formed by degradation.
Forced degradation studies are also essential in drug formulation. Medications are not made from a single chemical; they usually include a range of other substances known as “excipients.” These are generally not pharmaceutically active but help the drug molecule do its job. Excipients can protect drug molecules from changes in pH, moisture, or other stressful conditions. Forced degradation studies inform the formulation process.
Data acquired in forced degradation studies also influences packaging decisions, storage instructions, and shelf-life recommendations.
Managing Forced Degradation Study Data
In addition to the challenge of performing forced degradation studies, researchers must manage forced degradation data. These studies generate an incredible amount of data—a lot of tests are needed, and each sample is tested multiple times. Data must be organized in a format where researchers can make sense of the data and share it with regulators.
Forced degradation data also comes from a range of analytical instruments. Stressful conditions can cause a wide range of chemical changes, meaning that drug molecules and excipients can be changed in unpredictable ways. A combination of chromatography, mass spectrometry, NMR, and UV data is used to characterize the chemical degradants. This leads to multiple, incompatible data types, making data management even more challenging. Spreadsheet applications, such as Excel®, are often used to consolidate experimental data. Unfortunately, this often leads to versioning issues and dead analytical data.
So, how do you manage forced degradation data effectively? Luminata® is a CMC decision support tool that allows researchers to view all their analytical and process data in one interface. Consolidating information enables scientists to quickly review their experimental results without tracking down files spread across multiple computer systems. See how Luminata simplifies pharmaceutical stress testing.
Luminata also allows users to construct forced degradation project maps. This tool connects chemical and analytical to segments of the forced degradation study. Task completion is also tracked, allowing users to see the project’s progress. See this application note to learn more about Luminata’s forced degradation dynamic project maps.
While pharmaceutical stress testing is challenging, it is necessary for protecting patient health and meeting regulatory requirements. Thorough stress testing paired with strategic data management is the best way to maintain quality pharmaceuticals.