Origin of Organic Impurities
Impurities are a crucial quality attribute of drug products because they can impact the safety and efficacy of the product. The specification for organic impurities in drug products must include the degradation products expected to occur during commercial manufacturing and under recommended storage conditions. Typically, organic impurities that need to be controlled in drug products are degradation products arising from the decomposition of the active pharmaceutical ingredient (API) or from interactions between the API and excipients and/or primary packaging. These impurities can be identified or unidentified. Impurities that are not degradation products (i.e., process-related impurities from the API) are usually not controlled in drug products because they are typically controlled in the API, and these impurities are not expected to increase over time. If there is evidence that impurities from the API may increase over time (i.e., they are also degradation products of the drug product), they must be controlled in both the API and the drug product.
Establishing Specification for Organic Impurities
A threshold-based approach from the ICH Q3B (R2) guideline can be used to control organic impurities in drug products generated during manufacturing or storage. Due to the dose-related toxicity, the thresholds are based on the amount of API administered per day. The amount of API administered per day is based on maximum recommended labeled dosage by the manufacturer. Lower thresholds may be appropriate if a degradation product exhibits unusual toxicity or produces undesired pharmacological effects.
Three thresholds need to be considered when establishing specification:
- Reporting Threshold: The limit above which a degradation product needs to be reported. The quantitation limit for the analytical method should not be greater than the reporting threshold and can be considered as the disregard limit of the analytical method.
- Identification Threshold: The limit above which a degradation product needs to be structurally identified. By regulation, unspecified degradation products must not be exceeded the identification threshold.
- Qualification Threshold: The limit above which a degradation product needs to be safety qualified.
The guidance to set the organic impurity limits based on the total daily intake (TDI) is specified in the table below:
If the qualification thresholds are exceeded the value given in the table and sufficient data are not available to qualify the proposed acceptance criterion of a degradation product, additional studies may be appropriate as per the guidance below:
In summary, the organic impurity specification for drug products must include the following degradation products, where applicable:
- Specified identified degradation products.
- Specified unidentified degradation products.
- Unspecified degradation products.
- Total degradation products (unless otherwise indicated, the total degradation products are the sum of all specified and unspecified degradation products above the reporting threshold).
References:
