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AGDD 2025 | D2S04 - Nitrosamines: Known Issues and Practical Advice

U.S. Food and Drug Administration (FDA)
U.S. Food and Drug Administration (FDA)•Jun 11, 2026

Why It Matters

The framework offers a practical pathway for generic manufacturers to control nitrosamine risks in BCS 4 drugs without extensive in‑vivo studies, speeding approvals and protecting public health.

Key Takeaways

  • •Nitrosamine impurities affect 160 immediate‑release oral generics, many BCS 4.
  • •FDA permits alternative bioequivalence (ABE) studies for BCS 1‑3, not BCS 4.
  • •Proposed four‑tier risk framework subcategorizes BCS 4 drugs by solubility or permeability limits.
  • •Antioxidant addition under 10 mg per dose maintains bioequivalence in BCS 4 reformulations.
  • •Rigorous dissolution testing and PBPK modeling can waive in‑vivo BE for BCS 4.

Summary

The final session of the Advancing Generic Drug Development Workshop tackled nitrosamine impurities in immediate‑release oral generics, focusing on the unique challenges posed by BCS 4 drug substances. Presenters highlighted that out of roughly 160 nitrosamine‑impacted products, a substantial share falls into BCS classes 1‑3, while 32 are BCS 4, which exhibit low solubility and permeability, complicating traditional bioequivalence (BE) assessments.

FDA guidance now allows alternative bioequivalence (ABE) approaches for BCS 1‑3 products, using comparative dissolution and multi‑pH testing, but BCS 4 drugs still require more rigorous evaluation. To address this gap, the speakers proposed a four‑tier risk‑based framework that sub‑categorizes BCS 4 drugs as solubility‑limited, permeability‑limited, or dual‑limited, each with specific risk factors and recommended testing strategies such as PBPK modeling and targeted dissolution studies.

A case study of a high‑dose BCS 4 antibiotic illustrated the framework in practice. By adding an antioxidant below the 10 mg per dose threshold, the reformulated product achieved comparable dissolution profiles and pharmacokinetic metrics (AUC and Cmax) under both fasting and fed conditions, confirming bioequivalence without additional in‑vivo studies. The presenters emphasized that antioxidants at controlled levels do not alter permeability, aligning with FDA research on BCS 3 model drugs.

The implications are clear: generic developers can leverage the proposed risk‑based approach to streamline nitrosamine mitigation while preserving therapeutic performance, potentially reducing costly clinical studies. Wider adoption could accelerate market entry of safe, compliant generics and set a precedent for handling other impurity challenges across BCS categories.

Original Description

This session addressed known issues and provided practical advice for managing nitrosamine impurities in pharmaceutical products. The presentations covered nitrosamine impacted drug products containing BCS IV drug substances and addressed potential pitfalls in nitrosamine risk assessment and control. Pharmacology/toxicology considerations for the safety evaluation of nitrosamine impurities were discussed to support comprehensive contamination prevention and management strategies.
Timestamps
02:40 – Nitrosamine-Impacted Drug Products Containing BCS IV Drug Substances
23:44 – Addressing Potential Pitfalls in Nitrosamine Risk Assessment and Control
50:02 – Pharm/Tox Considerations for Safety Evaluation of Nitrosamine Impurities
Session Leads:
Christopher Morgan, PhD
Pharmacologist
Division of Pharmacology/Toxicology Review (DPTR)
Office of Safety & Clinical Evaluation (OSCE)
Office of Generic Drugs (OGD)
CDER | FDA
Reynolds (Rey) Cantave
PharmD Senior Regulatory Health Project Manager
Enterprise Project Management Staff
Office of Quality Assurance (OQA)
Office of Pharmaceutical Quality (OPQ)
Center for Drug Evaluation and Research (CDER) | FDA
Speakers:
Gang Zhao, PhD
Research Fellow
Division of Therapeutic Products-II (DTPII)
Office of Research & Standards (ORS)
OGD | CDER | FDA
Matthew Vera, PhD
Supervisory Chemist
Division of Product Quality Assessment II (DPQAII)
Office of Product Quality Assessment I (OPQAI)
OPQ | CDER | FDA
Xin Fu, PhD, DABT
Pharmacologist
DPTR | OSCE | OGD | CDER | FDA
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