The thresholds and procedures for setting impurity limits are defined primarily by ICH Q3A (R2) and ICH Q3B (R2) guidelines.
1. Thresholds of Impurities
a. Reporting Threshold
The level at which an impurity must be reported in the Certificate of Analysis (CoA) or regulatory submission. It ensures transparency in impurity monitoring.
Example: For a drug substance with a maximum daily dose of 1 g, the reporting threshold is 0.05%.
b. Identification Threshold
The level at which an impurity must be chemically characterized to determine its structure and origin. This helps in understanding the potential sources of impurities (e.g., degradation, synthesis by-products).
Example: For a drug substance with a daily dose ≤ 2 g, the threshold is 0.1%.
c. Qualification Threshold
The level above which the safety of an impurity must be assessed through toxicological studies. This ensures that the impurity does not pose significant risks to patients.
Example: For a drug substance with a daily dose ≤ 2 g, the threshold is 0.15%.
2. Fixing Limits Based on Thresholds
The limits of impurities are set using a combination of scientific, safety, and regulatory criteria. Below are the key steps:
Step 1: Determine the Maximum Daily Dose (MDD)
- Calculate the highest dose of the drug likely to be consumed daily.
- Use this value to determine thresholds as defined in the ICH guidelines.
Example:
- For a drug with an MDD of 500 mg:
- Reporting threshold: 0.05% (500 mg × 0.05% = 0.25 mg/day).
- Identification threshold: 0.1% (500 mg × 0.1% = 0.5 mg/day).
- Qualification threshold: 0.15% (500 mg × 0.15% = 0.75 mg/day).
Step 2: Analytical Method Validation
Develop and validate robust analytical methods (e.g., HPLC, GC, LC-MS) with appropriate sensitivity to detect and quantify impurities at the threshold levels.
Ensure the methods meet the following criteria:
- LOD (Limit of Detection): Below the reporting threshold.
- LOQ (Limit of Quantification): Below or equal to the reporting threshold.
Step 3: Identify the Source of Impurities
Raw Materials and Synthesis: Identify starting materials and intermediates contributing to impurities.
- Degradation: Conduct stability studies to detect degradation products.
- Excipients: Evaluate excipient-related impurities in the formulation.
Step 4: Toxicological Qualification
If an impurity exceeds the qualification threshold:
- Conduct genotoxicity studies to rule out DNA damage.
- Perform toxicological evaluations, such as NOAEL (No Observed Adverse Effect Level) studies.
- Use a Threshold of Toxicological Concern (TTC) approach for impurities with unknown toxicity.
Read also:
- Pharmaceutical Impurities Calculator
- Maximum Daily Dose Database
- Difference Between Related Substances and Impurities
