Regulatory agencies expect companies to control these impurities and set appropriate limits to ensure patient safety.
One common question is:
How do we decide the specification (acceptance limit) for a nitrosamine in a drug product?
The answer is simple:
There is no single limit that applies to every product.
The specification depends on the drug product and must be established using a scientific, risk-based approach.
A typical approach includes:
Identify where nitrosamines could come from, such as the API, excipients, manufacturing process, packaging, or storage conditions.
Perform a risk assessment to determine whether nitrosamines can form or be introduced during manufacturing or storage.
Find the regulatory Acceptable Intake (AI) for the identified nitrosamine.
Calculate the product-specific specification using the Maximum Daily Dose (MDD).
Specification (ppm) = Acceptable Intake (ng/day) ÷ Maximum Daily Dose (mg/day)
Example:
If the AI for NDMA is 96 ng/day and the Maximum Daily Dose is 1000 mg/day:
96 ÷ 1000 = 0.096 ppm
So, the proposed specification for NDMA would be NMT (Not More Than) 0.096 ppm.
However, the calculation alone is not enough.
The proposed specification should also be supported by:
- A proper nitrosamine risk assessment
- A validated analytical method that can accurately detect nitrosamines below the proposed limit
- Development, validation, commercial, and stability batch data showing that the manufacturing process consistently meets the specification
- A strong manufacturing control strategy to prevent or minimize nitrosamine formation
A nitrosamine specification should be scientifically justified, achievable during routine manufacturing, supported by analytical data, and compliant with current regulatory requirements.
Read also: How do you control multiple nitrosamine contaminants in a product?
Resource Person: Vijay Agrawal
