Risk Assessment and Expert Review of N-Nitrosamine Contaminants

Existing risk assessment processes¹ and expert reviews are working well for normal mutagenic impurities.² As such, the identification of N-nitrosamine impurities in valsartan drug substances and products in mid-2018, came as a big shock to industry and regulators alike.² When other members of the sartan class were also implicated; together with pioglitazone, ranitidine, metformin it became clear that this was a significant global crisis.³

The perceived wisdom^4,5 for the formation of these impurities is that excess nitrite under acidic conditions can form nitrous acid. This is then free to react with secondary amines, e.g., dimethylamine, diethylamine, which are often present as impurities in solvents and reagents,⁶ which then form the corresponding N-nitrosamine, i.e., N-nitrosodimethylamine (NDMA) or N-nitrosodiethylamine (NDEA), respectively.

It is well known that risk assessments can also be biased by known risks, e.g., hydrazoic acid formation in the valsartan synthetic route, masking the potential risks of N-nitrosamine formation. ³ The US Food and Drug Administration (FDA) highlighted in early 2019, that although they had issued a recent guidance on mutagenic impurities risk assessments during March 2018, that “neither regulators nor industry fully understood how NDMA and NDEA could form during this particular manufacturing process”.⁷ 

Ongoing poor GMP compliance in India and China is partly to blame for unease with purely risk-based approaches.^2,3 N-nitrosamine contamination was also identified as a result of unsatisfactory cleaning practices and resultant cross-contamination in large multi-purpose Indian facilities. FDA recently sent a warning letter to Maylan, India for “failure to adequately clean equipment and utensils”, linked with the valsartan-contamination issue.⁸ The recent guidance from FDA,⁴ European Medicines Agency (EMA)⁹ and others, indicates that if the risk assessment does identify a potential risk, then the product needs to be tested and control strategies implemented.  However, even in those cases where there is a comprehensive risk assessment supported by extensive analytical data there can be a reluctance amongst regulators to accept that there is not an issue. In candesartan, the tetrazole ring is introduced early in the synthesis, giving ample opportunity for the down-stream chemistry to remove these toxic impurities by various purging processes.¹⁰ However, there still appears to be an expectation that manufacturers demonstrate absence of N-nitrosamine contamination in all candesartan medicinal products.³

The initial regulatory response to “valsartan” contamination issue was measured and appropriate, i.e., acceptable input (AI) limits. However, this response rapidly escalated into avoidance, risk-based assessments/testing and control strategies at very low levels, i.e., < AI. In the US there are 20/30 ppb limits⁴ and in the EU 10% AI has been proposed, i.e., < 8.3 ppb for NDEA.⁹ However, as AIs are viewed as virtually safe doses (VSD) there appears to be no merit from a safety perspective in demanding lower limits.³ Are these ppb methodologies robust enough? There have been at least two reported instances where the methods were not fit for purpose. The application of a GC-MS method for the determination of NDMA in ranitidine resulted in significant over-estimation of NDMA.¹¹ Secondly, levels of NDMA in metformin were over-estimated – due to matrix interference from residual solvent in the active pharmaceutical ingredient. Additionally, there may not be enough worldwide capacity of these sophisticated, very sensitive methodologies, i.e., GC/LC-MS/MS (Q³).¹² 

Nitrosamines are everywhere; in the environment, food, water and there is a significant endogenous formation. ICH M7(R1)¹ indicates that, “Higher acceptable intakes may be justified when human exposure to the impurity will be much greater from other sources, e.g., food, or endogenous metabolism e.g., formaldehyde.” EMA, and other agencies, argued from a clinical perspective that the “theoretical risk of cancer was very low and was itself based on a worst-case scenario” and that discontinuation of affected medicines was a bigger risk to long term health than potential exposure to N-nitrosamines. Therefore, against this background, why are the various regulatory agencies reluctant to accept AI-based limits; as AIs are VSDs?  Consequently, are the current regulatory positions proportionate and fit for purpose?

Abbreviations

References

1. ICH M7(R1). ICH guideline M7 on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. European Medicines Agency. https://www.ema.europa.eu/en/ich-m7-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential. Current Step 4 version dated March 31, 2017. Accessed May 20, 2021.

2. Snodin DJ, Elder DP. Short commentary on NDMA (N-nitrosodimethylamine) contamination of valsartan products. Regul Toxicol Pharmacol. 2019;103:325–329. doi: 10.1016/j.yrtph.2019.01.007

3. Elder DP, Johnson GE, Snodin DJ. Tolerability of risk: A commentary on the nitrosamine contamination issue. JPharmSci. 2021;110(6):2311–2328. doi: 10.1016/j.xphs.2021.02.028

4. Control of nitrosamine impurities in human drugs − guidance for industry R1. U.S. Food and Drug Administration. https://www.fda.gov/media/141720/download. Updated February 24, 2021. Accessed May 20, 2021.

5. Lessons learnt from presence of N-nitrosamine impurities in sartan medicines. European Medicines Agency. https://www.ema.europa.eu/en/documents/report/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines_en.pdf. Published June 23, 2020.  Accessed May 20, 2021.

6. Allmendinger T, Bixel D, Clarke A, Di Geronimo L. Carry over of impurities: A detailed exemplification for glycopyrrolate (NVA237). Org. Process Res. Dev. 2012;16(11):1754–1769. doi: 10.1021/op3001788

7. Gottlieb S., Woodcock J. FDA statement on the FDA’s ongoing investigation into valsartan and ARB class impurities and the agency’s steps to address the root causes of the safety issues. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-ongoing-investigation-valsartan-andarb-class-impurities-and-agencys-steps. Published January 25, 2019. Accessed June 12, 2021.

8. Update − FDA warns Mylan for cGMP violations. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-pressannouncements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan#5f16904a2cdfe. Published November 13, 2019. Accessed on June 12, 2021.

9. European Medicines Regulatory Network approach for the implementation of the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 for nitrosamine impurities in human medicines. European Medicines Agency. https://www.ema.europa.eu/en/documents/referral/european-medicines-regulatory-network-approach-implementation-chmp-opinion-pursuant-article-53/2004-nitrosamine-impurities-human-medicines_en.pdf. Published June 12, 2021. Accessed May 21, 2021.

10. Burns MJ, Teasdale A, Elliott E, Barber CG. Controlling a cohort: use of mirabilis based purge calculations to understand nitrosamine-related risk and control strategy options. Org Proc Res Dev. 2020;24(8):1531–1535. doi: 10.1021/acs.oprd.0c00264

11. Valisure citizen petition on ranitidine. Valisure. https://www.valisure.com/wp-content/uploads/Valisure-Ranitidine-FDA-Citizen-Petition-v4.12.pdf. Published September 9, 2019. Accessed June 12, 2021.

12. Yang J, Marzan TA, Ye W, Sommers CD, et al. A cautionary tale: quantitative LCHRMS analytical procedures for the analysis of N-nitrosodimethylamine in metformin. AAPS J. 2020;22(89):1–8. doi: 10.1208/s12248-020-00473-w

About the author

Dr Elder studied chemistry at Newcastle upon Tyne (BSc, MSc), before moving to Edinburgh to study for a PhD in crystallography. He is a visiting professor (King’s College, London). Dr Elder has 44 years of experience at a variety of different pharmaceutical companies (Sterling, Syntex and GSK). He is currently a CMC consultant.

Dr Elder is a member of the British Pharmacapoeia (Expert Advisory Group PCY: Pharmacy), a Fellow of the Royal Society of Chemistry (RSC), UK and the immediate past chairman of the Joint Pharmaceutical Analysis Group, UK.

He has presented regularly on drug development and drug delivery. He has over 160 publications and given 178 external presentations at scientific symposia. He has co-edited two books: the Analytical Characterisation and Separation of Oligonucleotides and their Impurities and ICH Quality Guidelines: An Implementational Guide