The Center for Complex Generics

FDA and the Center for Research on Complex Generics (CRCG) hosted a public workshop on June 15, 2023: Mitigation Strategies for Nitrosamine Drug Substance Related Impurities: Quality and Bioequivalence Considerations for Generic Products

• Download the agenda
• Download the speaker bios

Workshop Date and Time: 

June 15, 2023; 8:30 a.m. – 5:30 p.m.

About the Event:

The presence of N-nitrosamines in drug products can be a potential health concern. Some N-nitrosamines may increase the risk of cancer if people are exposed to them above acceptable intake limits and over long periods of time. Since the recent findings of N-nitrosamines in some types of drug products and considering their potential harmful effects to human health, regulatory agencies and drug manufacturers have been working continuously to understand the root causes of N-nitrosamine formation, assess the risks of N-nitrosamines, for human health, and take appropriate actions to reduce or prevent the presence of N-nitrosamines in active pharmaceutical ingredients (APIs) and drug products. N-nitrosamine drug substance related impurities (NDSRIs) are a class of N-nitrosamine sharing structural similarity to the API (having API or API sub-fragment in the chemical structures) that are receiving considerable attention among regulatory authorities.

The purpose of this workshop is to discuss the risks of forming NDSRIs in certain drug products, strategies to mitigate these risks, and considerations in assessing the safety risks of NDSRIs. The workshop will also discuss approaches to prevent or mitigate the formation of such impurities, for example, by adding a suitable antioxidant and/or pH modifier to drug products. Finally, the workshop will discuss the potential impacts of such reformulation on the bioequivalence of generic products, and strategies to efficiently address these issues.

Workshop Topics:

• Reviewing the risk factors from APIs, excipients and/or manufacturing processes in the formation of NDSRIs and strategies to mitigate these risks
• Reviewing considerations in assessing the safety risks of NDSRIs
• Discussing the potential impacts of reformulation on the bioequivalence of generic products and strategies to efficiently address these issues

FDA and the Center for Research on Complex Generics (which is a collaboration between the University of Maryland School of Pharmacy and the University of Michigan College of Pharmacy) are dedicated to advancing programs that stimulate scientific dialogue, disseminate current insights about complex generics, and generate new knowledge in support of FDA’s mission to promote and protect the public health by increasing access to safe and effective generic medicines.

Audience:

This workshop is primarily for the generic drug industry and other involved collaborators, including consultants and contract research organizations that support generic drug applications.

Workshop Recordings: 

• Session 1-Part 1-Welcome, Intro, Talks
• Session 1-Part 2-Talks, Panel
• Session 2-Talks, Panel
  
• Session 3-Talks, Panel, Closing Remarks

Workshop Outline:

Welcome
James Polli, PhD, Co‐Director, CRCG
Anna Schwendeman, PhD, Co-Director, CRCG

Opening Remarks
Robert Lionberger, PhD, Director, ORS, OGD, CDER, FDA 

Nitrosamine Drug Substance Related Impurities (NDSRIs) - Workshop Overview
Andre Raw, PhD, Associate Director for Science and Communication, OLDP, OPQ, CDER, FDA 

Session 1: Risk of Forming NDSRIs and Strategies to Mitigate These Risks
This session will discuss the risk factors coming from both APIs and excipients in the formation of NDSRIs, and analytical methods used to quantify N-nitrosamines in pharmaceuticals. The speakers and panelists will also discuss the strategies to control impurities during the synthesis of APIs and excipients, and other strategies to prevent the formation of NDSRIs in a drug product during its shelf-life.

Introduction to Session and Speakers
Andre Raw, PhD, Associate Director for Science and Communication, OLDP, OPQ, CDER, FDA

Distilling a Complex Problem into Quantitative Tools and Approaches to Address N-nitrosamine Formation Risk in Drug Products
Justin Moser, BS, Principal Scientist, Pharmaceutical Sciences, Merck & Co., Inc.

Performance Characteristics of Mass Spectrometry‐Based Analytical Procedures for Quantitation of Nitrosamines in Pharmaceuticals: Insights from an Inter‐laboratory Study
Jingyue (Jan) Yang, PhD, Senior Research Scientist, DPA, OTR, OPQ, CDER, FDA

Reducing Nitrosamines Without the Use of Scavengers: The Critical Role of Excipients–An Excipient Manufacturer’s View
Sander van Gessel, MEng, Director, Oral Solid Dose, DFE Pharma 

Control Strategies for NDSRIs Originating from Impurity Amines in APIs
Martin Ehlert, PhD, Vice President, Global API R&D, Apotex Inc.

Effectiveness of Antioxidants in Selected Model Drugs: Mitigation Strategy and Impact of Reformulation in Their Stability
Diaa Shakleya, PhD, Senior Research Scientist (Pharmacologist), DPQR, OTR, OPQ, CDER, FDA

Assessment of a Diverse Array of Nitrite Scavengers in Solution and Solid State: A Study of Inhibitory Effect on the Formation of Alkyl-Aryl and Dialkyl N-Nitrosamine Derivatives
Marko Trampuž, MPharm, PhD, Scientist, Early Development, SDC Slovenia, Lek d.d., Sandoz

Determination of Nitrite in Pharmaceutical Excipients; Air as Source for Higher Nitrite Levels
Rok Grahek, PhD, Head, Analytical Research Department, SDC Slovenia, Lek d.d., Sandoz 

Panel Discussion

• Moderator: Andre Raw, PhD, Associate Director for Science and Communication, OLDP, OPQ, CDER, FDA
• Panelists:
  Bhagwant Rege, PhD, Director, DB, ONDP, OPQ, CDER, FDA
  Diaa Shakleya, PhD, Senior Research Scientist (Pharmacologist), DPQR, OTR, OPQ, CDER, FDA
  Jingyue (Jan) Yang, PhD, Senior Research Scientist, DPA, OTR, OPQ, CDER, FDA
  Justin Moser, BS, Principal Scientist, Pharmaceutical Sciences, Merck & Co., Inc.
  Lanyan (Lucy) Fang, PhD, Deputy Director, DQMM, ORS, OGD, CDER, FDA
  Marko Trampuž, MPharm, PhD, Scientist, Early Development, SDC Slovenia, Lek d.d., Sandoz
  Martin Ehlert, PhD, Vice President, Global API R&D, Apotex Inc.
  Mrunal A. Jaywant, PhD, PGDMM, Vice President of R&D, USP India
  Rok Grahek, PhD, Head, Analytical Research Department, SDC Slovenia, Lek d.d., Sandoz
  Sander van Gessel, MScEng, Director, Oral Solid Dose, DFE Pharma
  Zdenko Časar, PhD, Head, Early Development, SDC Slovenia, Lek d.d., Sandoz

Session 2: Safety & Risk Assessment of NDSRIs for Human Health
This session will focus on considerations for assessing the safety of NDSRIs. The speakers and panelists will discuss current efforts by the FDA and drug manufacturers to assess the potential risk of NDSRIs for human health and to predict the activity and potency of NDSRIs by utilizing quantitative structure–activity relationship (QSAR) models or other relevant quantitative tools. 

Introduction to Session and Speakers
Robert T. Dorsam, PhD, Director, DPTR, OSCE, OGD, CDER, FDA

Nitrosamine Drug Impurities and Nitrosamine Drug Substance Related Impurities: Optimizing Mutagenicity Testing
Robert H. Heflich, PhD, Director, DGMT, NCTR, FDA 

Why Do Nitrosamine Potencies Vary So Widely? Mechanistic Rationales for the Effects of Structural Features on Activity
David Ponting, MA, MSci, PhD, Principal Scientist, Lhasa Limited

Using Structure-Activity Relationships to Inform Setting Acceptable Intakes for Nitrosamine Impurities
Naomi Kruhlak, PhD, Scientific Lead, DARS, OCP, OTS, CDER, FDA 

Investigations into Nitrosamine Drug Substance Related Impurities – Mechanistic and Safety Science Investigations Across Key Drug Classes
Hydrochlorothiazide – a twist in the tail
Andrew Teasdale, BSc (Hons), PhD, Senior Principal Scientist, AstraZeneca

Position Papers for Classes of NDSRIs
Raphael Nudelman, PhD, ERT, Senior Director Impurity Expert, Teva Pharmaceutical Industries Ltd.

Panel Discussion

• Moderator: Robert T. Dorsam, PhD, Director, DPTR, OSCE, OGD, CDER, FDA
• Panelists:
  Andrew Teasdale, BSc (Hons), PhD, Senior Principal Scientist, AstraZeneca
  David Ponting, MA, MSci, PhD, Principal Scientist, Lhasa Limited
  Naomi Kruhlak, PhD, Scientific Lead, DARS, OCP, OTS, CDER, FDA
  Raphael Nudelman, PhD, ERT, Senior Director Impurity Expert, Teva Pharmaceutical Industries Ltd.
  Robert H. Heflich, PhD, Director, DGMT, NCTR, FDA
  Sruthi King, PhD, Deputy Director, DPTR, OSCE, OGD, CDER, FDA

Session 3: Impact of Reformulation on the Bioequivalence of Generic Products and FDA Perspectives on Reformulated Generics
This session will focus on the potential impact of reformulations (e.g., adding a suitable antioxidant to the existing formulation) on the
bioequivalence of generic products and strategies to efficiently address these challenges. The speakers and panelists will discuss current and future research efforts to evaluate the effect of an antioxidant in the formulation on the absorption and/or the bioavailability of APIs, and to utilize modeling and simulation approaches to assess the bio-inequivalence risks in the event of a reformulation. The speakers and panelists will discuss perspectives relating to potential bioequivalence approaches for generic products that are reformulated to mitigate NDSRIs formation.

Introduction to Session and Speakers
Khondoker Alam, PhD, Senior Staff Fellow, DQMM, ORS, OGD, CDER, FDA

Use of a Novel Technology, the In Vitro Dissolution Absorption System, to Investigate the Effects of Antioxidants on the Intestinal Permeation of BCS Class III Drugs
Chris Bode, PhD, Vice President of Scientific Affairs, Pharmaron

Effects of Antioxidants in Drugs Products on Intestinal Drug Transporters
Sook Wah Yee, MPharm, PhD, Assistant Adjunct Professor, University of California, San Francisco 

Physiologically Based Pharmacokinetic (PBPK) Absorption Modeling to Evaluate the Impact of Excipients on Bioequivalence of BCS Class III Drug Products
Fang Wu, PhD, Senior Pharmacologist, DQMM, ORS, OGD, CDER, FDA

FDA Guidance - Control of Nitrosamines in Human Drugs
Dongmei Lu, PhD, Policy Lead, OPPQ, OPQ, CDER, FDA

Panel Discussion

• Moderator: Khondoker Alam, PhD, Senior Staff Fellow, DQMM, ORS, OGD, CDER, FDA
• Panelists:
  Andre Raw, PhD, Associate Director for Science and Communication, OLDP, OPQ, CDER, FDA
  Bhagwant Rege, PhD, Division Director, DB, ONDP, OPQ, CDER, FDA
  Bing Li, PhD, Associate Director for Science, OB, OGD, CDER, FDA
  Chris Bode, PhD, Vice President of Scientific Affairs, Pharmaron
  Dongmei Lu, PhD, Policy Lead, OPPQ, OPQ, CDER, FDA
  Fang Wu, PhD, Senior Pharmacologist, DQMM, ORS, OGD, CDER, FDA
  Lanyan (Lucy) Fang, PhD, Deputy Director, DQMM, ORS, OGD, CDER, FDA
  Sook Wah Yee, MPharm, PhD, Assistant Adjunct Professor, University of California, San Francisco

Closing Remarks
Lanyan (Lucy) Fang, PhD, Deputy Director, DQMM, ORS, OGD, CDER, FDA

For more information: If you have any questions about this workshop please contact info@complexgenerics.org.