Nitrosamine Risk Assessments in Oligonucleotides

The European Medicines Agency, the U.S. Food and Drug Administration, and other regulatory agencies expect that all pharmaceutical products be assessed for the potential presence of N-nitrosoamine (nitrosamine) impurities. This white paper addresses general considerations for nitrosamine risk assessments of oligonucleotide products. The authors propose a general risk assessment platform which should facilitate safe, consistent development of new treatments and alignment with regulatory expectations.

Introduction

The presence of N-nitrosoamines (nitrosamines) in pharmaceutical products gained the attention of health authorities with the discovery of N-nitrosodimethylamine (NDMA) in valsartan in 2018. Over the subsequent months, NDMA and other related nitrosamines were discovered in further sartan medications and then in additional product classes and drugs such as ranitidine. In response to this growing public health crisis, health authorities issued guidance requiring marketing authorization holders (MAHs) to perform nitrosamine risk assessments for all synthetic drug products on the market and, if warranted, carry out confirmatory testing and make changes to the product manufacture or control strategy. The requirement was later expanded to include biological products/medicines and marketing applications for new products. In addition, some health authorities have included productsin clinical development in the scope of nitrosamine assessments. It is essential for industry to develop robust risk assessment processes and control strategies to ensure that medicines administered to patients are safe.

The potential risk to pharmaceutical products to contain nitrosamines is briefly discussed in ICH Guideline M7 (R1) on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. The guidance identifies nitrosamines as part of the cohort of concern, compounds which can display extremely high carcinogenic potency and therefore require more stringent control (typically to ng/day levels). Principles for assessing the potential risk of nitrosamine contamination have been prescribed by various health authorities. Pharmaceutical companies and their suppliers have collaborated to develop a common implementation strategy, which has been converted by the European Federation of Pharmaceutical Industries and Associations (EFPIA) working group into the Workflows for Quality Risk Management of Nitrosamine Risks in Medicines. Under the auspices of EFPIA, a general position for the risk assessment of biological products has also been developed.

Building on this precedent, this Perspective describes general considerations and principles that can be used to perform nitrosamine risk assessments for oligonucleotide products. This Perspective considers synthetic production methods for oligonucleotides. Nucleotide products such as mRNA vaccines that are prepared using biological methods are considered to be within the scope of the EFPIA position paper on biological products. Nucleotide products manufactured using biological methods are not considered here, although some of the discussion, for example on purification methods, may be relevant to risk assessments for such products. Chemically synthesized therapeutic oligonucleotides include antisense

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