In the latest CDER Science Spotlights, available (here), the FDA provides some insight into the development of the Carcinogenic Potency Categorization Approach (CPCA) to determine recommended acceptable intake limits of N-nitrosamine impurities in drug products. The latest revision of the Nitrosamine Impurity guidance updated in September 2024 (here) provided better integration of the overall assessment and handling of N-nitrosamine impurities that also aligned with the August 2023 publication of the Recommended Acceptable Intake Limits of Nitrosamine Drug Substance Related Impurities (NDSRIs) guidance (or RAIL guidance) (here). The FDA uses this CDER Science Spotlight to provide background on the need for determining acceptable intake limits for novel nitrosamines and how the approach recommended in the guidances was developed.
As many have become all too familiar, NDSRIs are a set of N-nitrosamine impurities that share a structural relationship with the drug substance used in many drug products. N-nitrosamines as a group of molecules are potentially carcinogenic so the presence of an N-nitrosamine impurity in a drug product poses a potential cancer risk for patients taking that drug. This risk must be assessed adequately for the drug product. Some level of acceptance or rejection must be applied to the
N-nitrosamine impurities that may form in that drug product to know if a product is safe as is, or if changes must be made to make the product safe for patients to continue to use. As NDSRIs share a structural relationship with many drug substances, there is little known about them which includes little to no safety data upon which to set acceptable intake limits. Nitrosamine impurity assessments have also led to the discovery of other novel nitrosamine impurities that have little or no safety data available. Attempts have been made to derive a structure-activity relationship approach to identify a surrogate compound with known safety data to assess a novel impurity but there are many interpretations of acceptable surrogates that also led to differing opinions on acceptable intake limits. This dilemma was addressed by the FDA and other international regulators through the creation of the Carcinogenic Potency Categorization Approach (CPCA).
The CPCA uses the chemical structure of the nitrosamine impurity to place the impurity into one of five categories with assigned acceptable intake limits. Distinctive features of a nitrosamine molecule can either enhance its metabolic activity thereby increasing its potential carcinogenic activity, or they can reduce the activity and therefore reduce its potential carcinogenic activity. These activating or deactivating structural features allow nitrosamine molecules to be separated or categorized based on these structural features. As described by the FDA, the CPCA was developed using a set of eighty-one nitrosamine impurities as the training set where activating and deactivating features of the molecules were identified, then a scoring scheme was assigned that was used to categorize them into five groups, and an acceptable intake limit was assigned to each category using the safety data on hand for the training set. An unknown impurity could then be compared to the same set of activating or deactivating features based on the structural patterns present in the impurity to place it into one of the five categories defined using the training set. The flow chart provided in the RAIL guidance was developed to make the approach easier to use. An applicant can then review each structural feature present in the N-nitrosamine impurity to place the impurity into one of the five categories, and the acceptable intake limit for that category can be used with that N-nitrosamine impurity.
The FDA notes that the approach will continue to be refined as more data becomes available, but the use of the CPCA should provide a more effective assessment of the impact of N-nitrosamine impurities on drug products and fewer disagreements on the acceptable intake limits assigned to these impurities.
If you have questions on applying the CPCA or need further assistance with nitrosamine impurity issues, please contact Lachman Consultants at LCS@LachmanConsultants.com for a consultation.
