By Douglas B. Farquhar and Richard A. Lewis, Hyman, Phelps & McNamara
Failure to detect nitrosamines, failure to notify FDA when nitrosamines appear in finished drug products, failure to identify impurities in drugs that may be nitrosamines, even having a deviation in pH of an active pharmaceutical ingredient that might conceivably contribute to the formation of nitrosamines in a finished drug product. All of these deviations discussed in FDA inspectional observations and warning letters have caused serious issues for manufacturers of APIs or finished drug products.
In August, FDA issued a final guidance entitled, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs). NDSRIs are a particular focus for FDA, because they are a nitrosamine subcategory that share structural similarity to drug API.
The guidance, which provides details about nitrosamines and FDA’s experience regulating them, explicitly applies to all finished drug products, including prescriptions, over-the-counter, and unauthorized drugs, to “prescription and OTC drug products in clinical development,” and to both API and drug manufacturers. In other words, it’s a sweeping application across the industry. An earlier FDA guidance, revised in 2021:
- urged manufacturers to conduct risk assessments for nitrosamines in APIs and drug products,
- conduct confirmatory testing if risks are identified, and
- report changes in formulation or manufacturing as required in approved and pending NDAs and ANDAs.
There were tables in each guidance that appear to be consistent where they overlap, but also include different nitrosamines/NDSRIs (FDA guidances are not generally binding law, but, rather, express FDA policy).
The new final guidance, by its own terms, establishes “a recommended framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs.”
It further defines the AI as being, “a level that approximates an increased cancer risk of one additional case in 100,000 people based on a conservative assumption of daily exposure to the impurity over a lifetime (70 years).”
The guidance then goes on to categorize the types of NDRSIs, to suggest the appropriate acceptable intake limits for drugs and sets a timetable for manufacturers — or those with pending applications — to review their drug products and take appropriate action.
This second half of this guidance beginning with the “Flowchart to Predict the Carcinogenic Potency Category of an NDSRI and Identify an Associated Recommended AI Limit” takes one back to basic organic chemistry and breaks down the key structural and electronic considerations into a step-by-step guide. The substitution of the α-carbons and the electronic effects of the deactivating or activating groups yield tangible scores that one can apply to determine a potency score and therefore the recommended acceptable intake. Perhaps most importantly, the guidance concludes with examples of how manufacturers would apply this framework to nitroso compounds.
All drug manufacturers and API manufacturers would be well served to examine the guidance, and perform analysis suitable for their products, to determine whether further assessment is necessary.
A version of this article was published first on Hyman, Phelps & McNamara’s FDA Law Blog. It is republished here with permission.
About the Authors:
Douglas Farquhar is a director at Hyman, Phelps & McNamara. Since joining the firm in 1997, he has advised pharmaceutical and medical device manufacturers and wholesalers, compounding pharmacies, and individuals on a wide range of enforcement activities, including consent decrees, criminal investigations, debarment issues, arbitration proceedings, civil seizures, FDA inspection issues, and injunctions. He has a broad understanding of the investigatory process and has negotiated settlements and resolutions for both industry and government.
Richard Lewis is a senior regulatory device and biologics expert at Hyman, Phelps & McNamara. He started his career in the FDA’s Center for Devices and Radiological Health in the division of chemistry and toxicology. Later, he moved to CBER’s Office of Compliance and Biologics Quality where he worked on manufacturing reviews and pre-license inspections. While at CBER, he was the principal advisor for all device submissions in Manufacturing and Review Branch 2.