- The limit for total Ordinary impurities (those species in drug substances and/or drug products that have no significant, undesirable biological activity in the amounts present) is 2.0%, unless otherwise specified in the individual monograph.
- Unless otherwise specified in an individual monograph, estimation of the amount and number of ordinary impurities is made by relative methods rather than by strict comparison to individual Reference Standards. Typical evaluation methods used for ordinary impurities are thin-layer chromatographic (TLC) techniques.
- Any single impurity is calculated by ICH guideline Q3B (R2).
- An impurity resulting from a chemical change in the drug substance brought about during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system is called degradation product.
Types of Pharmaceutical Impurities
- Organic impurities (process- and drug-related),
- Inorganic impurities & Residual solvents.
- Specified impurities generally selected from monograph or API manufacturer but calculated as per ICH guideline.
- ICH regulation distinguishes three levels in the evaluation of impurities, the reporting threshold, the identification threshold and the qualification threshold. These thresholds are values from which the impurities must be reported, identified and qualified respectively.
- Reporting threshold applicable for analytical method development to report the unknown peak. But FDA suggests all peak should be reported.
- Identification threshold applicable for unknown impurity calculation. Unknown impurity calculated by retention peak.
- Qualification threshold applicable for known impurities calculation.
- Known impurities can be – Specified or Unspecified. Specified can also be identified or non-identified.
Impurity Calculation Formula
Impurity limit = TDI/MDD × 100 (%)
Thresholds for Degradation Products in New Drug Products:
|
Maxim
Daily Dose |
Threshold |
|
Reporting
Thresholds |
|
|
≤
1 g |
0.1% |
|
>
1 g |
0.05% |
|
Identification
Thresholds |
|
|
<
1 mg |
1.0%
or 5µg TDI, whichever is lower |
|
1
mg – 10 mg |
0.5%
or 20µg TDI, whichever is lower |
|
>
10 mg – 2 g |
0.2%
or 2mg TDI, whichever is lower |
|
>
2 g |
0.10% |
|
Qualification
Thresholds |
|
|
<
10 mg |
1.0%
or 50µg TDI, whichever is lower |
|
10
mg – 100 mg |
0.5%
or 200µg TDI, whichever is lower |
|
>
100 mg – 2 g |
0.2%
or 3mg TDI, whichever is lower |
|
>
2 g |
0.15% |
For example,
1. If a drug product maximum daily dose is 500 mcg, as per ICH Q3B -
- Reporting Threshold: 0.1%
- Identification Threshold: 5 mcg/500 mcg × 100 = 1.0%
- Qualification Threshold: 5 mcg/500 mcg × 100 = 1.0%
2. If a drug product maximum daily dose is 5 mg (5000 mcg), as per ICH Q3B -
- Reporting Threshold: 0.1%
- Identification Threshold: 20 mcg/5000 mcg × 100 = 0.4%
- Qualification Threshold: 1.0%
𝐑𝐎𝐔𝐍𝐃𝐈𝐍𝐆 𝐑𝐔𝐋𝐄 𝐅𝐎𝐑 𝐈𝐌𝐏𝐔𝐑𝐈𝐓𝐈𝐄𝐒 𝐀𝐒 𝐏𝐄𝐑 𝐈𝐂𝐇 𝐐3𝐀 & 𝐐3𝐁:
𝐑𝐚𝐰 𝐌𝐚𝐭𝐞𝐫𝐢𝐚𝐥: Below 1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%).
𝐅𝐢𝐧𝐢𝐬𝐡𝐞𝐝 𝐏𝐫𝐨𝐝𝐮𝐜𝐭: Below 1.0%, the results should be reported to the number of decimal places (e.g., 0.06%) in the applicable reporting threshold; at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%).
