Overview of Degradation Products

As per ICH guidelines of Q3A and Q3B complete identification required of degradation products in the drug substance or the drug product

Degradation Products in the Drug Substance

Drug substance degradation products are defined as the impurities that are observed above the ICH Q3A reporting threshold during the storage of the drug substance in the proposed long-term storage conditions in primary and secondary packaging.

A degradation product exceeding the ICH Q3A identification threshold requires full identification as per below Table 1.

Daily Dose of Drug Substance (mg/day)/Degradation Product Level	Identification
Less than 2000 ˂ 0.05 %	Not Required
0.05 % to 0.10 % with no increase	Not Required
0.05 % to 0.10 % with increase	Required
> 0.10 % or 1 mg/day	Required
More than 2000 ˂ 0.03 %	Not Required
0.03 % to 0.05 % with no increase	Not Required
0.03 % to 0.05 % with increase	Required
> 0.05 %	Required

Note: *Whichever is lower.

Table 1: Identification thresholds for degradation products/impurities in the drug substance

The increase observed in the degradation products level likely may exceed the official (ICH Q3A) identification thresholds. As per ICH Q3A, degradation products were observed between the identification and reporting threshold and showed an increasing trend. In this case, a full identification study is required. Following are some examples that can be considered for trending:

1. If any unknown impurity shows an increasing trend in the submission batch. It is expected that in the next batches the same unknown impurity would be exceeded the identification threshold.
2. If the initial submission batch shows an unknown impurity close to the identification threshold then there are definite chances of exceeding it above the identification threshold in

(b) In (initial) GMP batches, if the levels for an impurity are already near the identification threshold, the possibility of an excursion above the identification threshold is a normal variation in batch-to-batch levels.

Degradation Products in the Drug Product:

Degradation products in the drug product are formed due to degradation of the drug substance or its by-products, excipient interaction, with primary packing material. The degradation products that are observed above the ICH Q3B reporting threshold during the stability study of the drug product in the projected long-term storage conditions. Degradation products may be formed during the manufacturing of the drug product or due to interaction with primary packaging material. The structure of the degradation products observed in the drug product will be identified when they are above the ICH Q3B qualification threshold, which varies depending on the dose. Following is Table 2 for the identification threshold of degradation products/impurities in the drug product.

Daily Dose of Drug Substance (mg/day)/Degradation Product Level	Identification
˂ 1 ˂ 1.0 % or ˂ 5 µg TDI*	Not Required
> 1.0 % or > 5 µg TDI*	Complete Identification Required
1 to 10 ˂ 0.5 % or ˂ 20 µg TDI*	Not Required
> 0.5 % or > 5 µg TDI*	Complete Identification Required
> 10 to 2000 ˂ 0.2 % or ˂ 200 µg TDI*	Not Required
> 0.2 % or > 200 µg TDI*	Complete Identification Required
> 2000	Not Required
˂ 0.1 % > 0.1 %	Complete Identification Required

    Note: *Whichever is lower, TDI: Total daily intake of the degradation product

Table 2: Identification threshold of degradation products/impurities in the drug product.

References:

1. International Conference on Harmonisation (ICH). Harmonized Tripartite Guideline: Impurities in New Drug Products Q3B,
2. International Conferences on Harmonization, Draft Revised Guidance on Impurities in New Drug Substances. Q3A,
3. International Conferences on Harmonization, Impurities–Guidelines for Residual Solvents. Q3C,
4. Methods for Stability Testing of Pharmaceuticals, Series Editor, Y. James Kang, Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky, USA,
5. Ahuja S. Impurities Evaluation of Pharmaceuticals. New York: Marcel Dekker; 1998,
6. ICH. Harmonized Tripartite Guideline: Stability Testing of New Drug Substances and Products Q1A,
7. ICH. Harmonized Tripartite Guideline: Photostability Testing of New Drug Substances and Products ICH Q1B,
8. ICH. Harmonized Tripartite Guideline: Stability Testing for New Dosage Forms ICH Q1C, ICH. Harmonized Tripartite Guideline: Evaluation of Stability Data ICH

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