On October 24, 2022, Aurobindo Pharma USA, Inc. voluntarily recalled two lots of Quinapril and Hydrochlorothiazide Tablets (USP 20mg / 12.5mg) from the U.S. market due to presence the of nitrosamine, N-Nitroso-Quinapril, which was present in concentrations above the proposed interim limit (FDA, 2022). Aurobindo Pharma began shipping the subject batches (QE2021005-A and E2021010-A) to customers across the United States starting in May of 2021. According to FDA, Aurobindo Pharma had not received any reports of adverse events related to this recall as of October 25, 2022.

Starting in 2018, the U.S. Food and Drug Administration released a series of warnings and issued recalls for several pharmaceuticals contaminated with the nitrosamine, N-nitrosodimethylamine (NDMA). FDA reported that “[i]mproved technology enable[d] the detection of even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA” (FDA, 2020).

NDMA is classified as “probably carcinogenic to humans” by the International Agency for Research on Cancer (IARC) (IARC, 2021). In addition, NDMA is classified by the EPA as a “probable human carcinogen” (EPA IRIS, 2002), based on sufficient evidence of carcinogenicity in animals. However, these regulatory designations were based on studies in animals, and the animal studies that evaluated the carcinogenicity of NDMA do not lend themselves to reliable extrapolation for trying to predict any cancer risk in humans. For example, humans do not metabolize NDMA in a similar manner to rodents.

To guide the pharmaceutical industries, various regulatory agencies conducted risk assessments for nitrosamines using the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7(R1) guidelines. These guidelines are intended to assess and control for mutagenic impurities in pharmaceuticals to limit potential carcinogenic risk. It was suggested that 96 ng/day of NDMA would approximate a 1 in 100,000 theoretical increased cancer risk for a lifetime exposure in humans.

Since 2018, various pharmaceutical companies have issued recalls of their products due to nitrosamine contamination, including Valsartan, Zantac, Metformin, and Chantix. However, the more recent recalls have involved novel nitrosamines, many of which have no current toxicity data, and are larger in structure than NDMA. It is likely that, based on nitrosamine mode of action, larger or bulkier nitrosamine compounds may be even less carcinogenically potent than smaller nitrosamines such as NDMA.

Our firm understands that personal injury litigation surrounding nitrosamine impurities in pharmaceuticals has been increasing in the past few years. We recommend that those who have detected nitrosamine impurities in their products conduct a thorough health risk assessment so they can fully characterize the possible health risks to users, as well as the strength of their defense if they are drawn into the courtroom.

Our scientists at Paustenbach and Associates have nearly 40 years of experience in conducting pharmaceutical safety assessments and in evaluating the potential health risks of impurities in consumer products. We recently submitted comments to the ATSDR regarding their toxicological profile for NDMA, and presented a poster titled Current Thoughts on Risk Assessment Methodologies used to Assess the Carcinogenic Risk of N-Nitrosodimethylamine (NDMA) at the Society of Toxicology (SOT) 2022 annual meeting. We were also experts in litigation where our opinion letter was partially instrumental in informing a judge on the scientific and risk assessment aspects of NDMA contamination in a pharmaceutical product; where a summary judgement was issued.

Please contact Sarah Brown at sbrown@paustenbachandassociates.com for more information regarding our capabilities.

References

EPA IRIS (2002). “N-Nitrosodimethylamine; CASRN 62-75-9.” U.S. Environmental Protection Agency.

FDA (2022). “Aurobindo Pharma USA, Inc. Initiates Voluntary Nationwide Recall of Two (2) Lots of Quinapril and Hydrochlorothiazide Tablets USP 20mg/12.5mg, Due to the Detection of N-Nitroso Quinapril Impurity.” Accessed 11/7/22 at https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/aurobindo-pharma-usa-inc-initiates-voluntary-nationwide-recall-two-2-lots-quinapril-and.

FDA (2020). “FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products, U.S. Food & Drug Administration.” U. S. F. a. D. Administration.

IARC (1978). “Some N-Nitroso Compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.” International Agency for Research on Cancer. Lyon (FR).

ICH M7 (2017). “The Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.” U. S. F. a. D. Administration.