Root Cause Analysis of Nitrosated Drug Substances
Nitrosamines
The presence of N-nitrosamines in the food industry has been studied since the 1970’s. As a public safety initiative, acceptable intake limits were set on these cancer-causing nitrosamines. In 2018, the Food and Drug Administration (FDA) discovered n-nitrosomine compounds in chronic pharmaceutical medication. This led regulators to research and create acceptable intake limits on more drugs (see table 2). N-nitrosomine compounds occur when nitrite reacts with a primary, secondary or tertiary amine. Vici Health Sciences can provide the following services:
Strong Chemistry Expertise
The initial emphasis should be to identify whether or not the product contains n-nitrosated compounds. Chemical structure of the active compound(s) must be reviewed to identify any primary, secondary or tertiary amines.
Custom Synthesis or Sourcing Reference Standards
If an active ingredient contains amine groups, Vici can synthesize reference standards of each potential nitrosated compound. Reference standards can be created by spiking the compound with sodium nitrite in solution to force a reaction. Subsequent purification, and chemical identity testing should be performed.
Nitrosated Compound Testing
Test the active ingredient and finished drug product for n-nitrosated compounds. Testing is conducted throughout the shelf life of the product for best results. Generally LC/MS methods should be employed. If n-nitrosated compounds are above the acceptable intake limits, or are expected to increase above limits throughout the shelf life of the product, remediation is required.
Nitrite Contamination Testing
In the event that n-nitrosated compounds are identified, a root cause analysis should be performed to identify where the contamination of nitrite occurs in the process. Each individual component should be tested for nitrite or nitrate. Depending on the source of nitrite or nitrate contamination, different remediation methods can be employed.
Case Studies
Case Study 1: The nitrosated compound is discovered in the drug substance and continues to grow during the drug product shelf life. In this scenario, each manufacturing process step of the drug substance should be reviewed and tested for nitrite and nitrate to narrow down which process step the contamination occurs. Upon narrowing down the process step, each component can be tested to determine which contains nitrite and nitrate. Switching vendors can be suitable for remediation.
Case Study 2: The nitrosated compound is discovered in the drug substance and continues to grow during the drug product shelf life, however the drug substance process can not be altered. In these scenarios, the usage of antioxidants in the drug product may reduce the growth of the nitrosated compound throughout the shelf life.
Case Study 3: If there is no nitrosated compound in the drug substance, but the nitrosated compound is discovered in the drug product, the contamination is likely from an excipient. Each excipient should be tested. Alternative vendors should be tested and excipients should be switched for the best suitable vendor