Drug Substance and Drug Product Workflows for Quality Risk Management for the Presence of Nitrosamines in Medicines

Abstract

The ICH M7 guidance “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” requires that drug substances and drug products be assessed for potential mutagens including N-nitroso compounds. N–Nitrosamines are a class of N-nitroso compounds within the cohort of concern as defined in ICH M7 because they can display carcinogenic potency with acceptable intakes in the range of ng/day rather than μg/day. Therefore, control to levels below the ICH M7 threshold of toxicological concern may be required. Following the detection of certain simple N-nitrosamines in marketed medicines between 2018 and 2019, health authorities requested that marketing authorization holders assess all their products (both chemical entities and biologics) for the presence of N-nitrosamines. It became important to establish scientifically robust and reliable approaches for the assessment of small molecule drug substances and products for the potential presence or formation of N-nitrosamines. Included are workflows and associated guidance to enable the reader to risk assess drug substances and drug products that contain chemical entities for the potential presence or formation of N-nitrosamines. These workflows and guidance are the culmination of five years of cross industry collaborations. They are based on known and emerging risk factors for the presence and formation of N-nitrosamines. In combination with regulatory guidance, these are considered as a “best practice” within the Pharmaceutical Industry for conducting drug substance and drug product assessments.

Introduction

As part of delivering medicines to patients, marketing authorization holders (MAH)/Applicants are expected to work with the manufacturers of their drug substances and drug products to assess for the potential presence or formation of mutagens. This includes implementing appropriate control strategies in alignment with the ICH M7 guideline, (1) when such impurities are identified, (1) to ensure that levels within drug products (DPs) are maintained below their acceptable daily intake or threshold of toxicological concern (TTC). ICH M7 highlights that some structural groups are identified to be of such high potency that intakes even below the TTC would theoretically be associated with a significant carcinogenic risk. This group of high potency mutagenic carcinogens referred to as the “cohort of concern,” comprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds.

In 2018 the FDA announced voluntary recalls of several medicines containing valsartan following detection of N-nitrosodimethylamine (NDMA). (2) Following the identification of other simple N-nitrosamines within Sartans and other medicines during the 2018–2019 period, (3) a referral according to Article 5(3) of Regulation (EC) No 726/2004 was triggered by the European Medicines Agency (EMA) Executive Director (ED) requesting the Committee for Medicinal Products for Human Use (CHMP) to conduct a scientific evaluation for the presence of nitrosamines in human medicines containing chemically synthesized drug substances (DSs). This referral led to a call for review to MAHs on 19 September 2019 requesting the review of human medicines containing chemically synthesized DSs for the possible presence of N-nitrosamines (N-nitrosamine and nitrosamine are synonymous and are used interchangeably throughout), to analytically test all products at risk and to introduce changes to the marketing authorizations (MAs) within 3 years. Other Health Authorities issued comparable calls for review─some with different timelines.
It was initially considered that the most likely root cause for the presence of N-nitrosamines within pharmaceutical DPs would be from the DS route of manufacture particularly given the widespread use of amine-containing reagents and solvents. Established root causes subsequently expanded to include potential formation of N-nitrosamines in the DP due to the prevalence of nitrite in common excipients. (4)

Figure 1. Nitrosamine “triangle”. — **Figure 1** Nitrosamine “triangle”.

To provide clarity and a common scientifically robust approach to nitrosamine risk assessments, the quality group of the European Federation of Pharmaceutical Industries and Agencies (EFPIA) worked together to define a risk assessment workflow and accompanying guidance notes for the assessment of DS and DP manufacture for the potential presence of N-nitrosamines. The group was formed from cross-industry representatives who shared their knowledge of the scientific literature, learnings and emerging risk factors. The first workflow was published online in 2020 and has been updated to align with evolving regulatory guidance and emerging knowledge of hazards and risk factors which can impact the DS and DP. The third and latest version of this workflow is described and expanded on herein.

The predominant source of nitrosamines originates from the concomitant presence of a vulnerable amine, a nitrosating agent and conditions conducive toward nitrosation wherein a vulnerable amine is defined as an amine which upon nitrosation leads to the formation of a stable nitrosamine. This generates a ‘nitrosamine triangle’ (Figure 1), the basis of any nitrosamine risk assessment, whereby removal of one aspect can lead to a no risk outcome. An additional element of the risk assessment considers potential nitrosamines introduced into the manufacturing process via input materials. At a high level, the overall workflow follows the ICH Q9 framework for risk assessment and risk management. This framework comprises of four stages (Figure 2).

Figure 2. Risk Assessment framework. — **Figure 2**. Risk Assessment framework.

All stages can lead to a “no risk” outcome or to progression to the next stage. The first stage, hazard identification, is to identify any theoretical hazard of nitrosamine presence or formation. Only identified hazards progress to the second stage, risk analysis, which aligns with ICH M7 principles and consists of confirming that the theoretical hazard identified is indeed possible and quantifying this risk against an acceptable limit. If the risk is deemed to require further assessment, stage 3, risk evaluation, which consists of analytical testing, is then performed. The outcome of the risk evaluation could lead to a “no risk” outcome or to risk control activities, which constitute the fourth stage.

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Olivier Dirat, Michael W. Urquhart, Heather Akehurst, Michael J. Burns, Krista L. Dobo, James Harvey, Nadine Kuhl, Joerg Schlingemann, Paula Tomlin, and Christian Wetter, Drug Substance and Drug Product Workflows for Quality Risk Management for the Presence of Nitrosamines in Medicines, Organic Process Research & Development Article ASAP, DOI: 10.1021/acs.oprd.5c00097