US FDA issues guidance on DNA-mutating pharma impurities
Drugmakers will be expected to show their assessments of mutation risks of their drug candidates throughout clinical trials and in marketing applications. The guidelines will not be applied retrospectively to products already on the market. The rules on acceptable risk levels vary according to a patient’s length of treatment.
Impurities: what’s the acceptable risk?
Impurities are present at some level in all pharmaceuticals, due to chemical synthesis and degradation.
While guidance exists for most types of impurities, until now manufacturers had little advice about DNA-reactive impurities. These substances have the potential to cause damage to patients’ DNA even at low levels, which can lead to mutations and to cancer.
This type of mutagenic carcinogen is usually detected with a bacterial reverse mutation assay.
The non-binding recommendations produced by the US FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) define “acceptable risk” levels for cancer from drugs over a lifetime of exposure. “Approximately one additional cancer per million” is the potential maximum in early drug development, growing to “approximately 1 in 100,000” for later R&D and marketed products.
“These risk levels represent a small theoretical increase in risk when compared to human overall lifetime incidence of developing any type of cancer, which is greater than 1 in 3,” says the advice.
Hazard control
To perform hazard assessment, manufacturers should analyse actual and potential impurities by combing already available data on substances and classify them as Class 1, 2, or 5 (below). If literature is not available, they should assess Structure-Activity Relationships to predict bacterial mutagenicity, and place the compound in Class 3, 4, or 5.
Class | Definition | Hazard control action |
1 | Known mutagenic carcinogens | Control at or below compound-specific acceptable limit |
2 | Known mutagens with unknown carcinogenic potential (bacterial mutagenicity positive, no rodent carcinogenicity data) | Control at or below acceptable limits (appropriate Threshold of Toxicological Concern (TTC)) |
3 | Alerting structure, unrelated to the structure of the drug substance; no mutagenicity data | Control at or below acceptable limits (appropriate TTC) or conduct bacterial mutagenicity assay If non-mutagenic = Class 5 If mutagenic = Class 2 |
4 | Alerting structure, same alert in drug substance or compounds related to the drug substance (e.g. process intermediates) which have been tested and are nonmutagenic | Treat as non-mutagenic impurity |
5 | No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicity | No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicity |
The classification of impurities affects the allowed treatment time of patients.
“Acceptable intakes of mutagenic impurities are recommended for limited treatment periods during clinical development of up to 1 month, 1 to 12 months and more than 1 year up to completion of Phase 3 clinical trials.”
Duration of treatment | < 1 month | >1 - 12 months | >1 - 10 years | >10 years to lifetime |
Daily intake [µg/day] | 120 | 20 | 10 | 1.5 |
The FDA says it may justify higher maximum intakes when exposure to the chemical is likely to be much higher from other sources, such as food.When more than one impurity is identified in a substance, the combined acceptable intake is slightly increased for long-term treatment: patients may receive up to 60μg per day for therapies lasting one to twelve months, 30μg per day for courses up to ten years, and 5μg each day for lifetime prescriptions.
The guidance does not affect biologics, including peptides and radiopharmaceuticals. It can apply to new excipients as well as active pharmaceutical ingredients.
The document was finalised last year by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which has recommended the FDA, EMA and Japanese regulator PMDA adopt it.
