WHO issues guidance on nitrosamine controls in drug manufacturing
The World Health Organization (WHO) released draft guidance for comment this month on good manufacturing practices (GMP) for the prevention and control of contamination of nitrosamines, which are a probable human carcinogen.The new GMP guideline applies to all manufacturers of excipients, active pharmaceutical ingredients (APIs), and finished pharmaceutical products. Among other things, the document covers definitions of nitrosamines, impurities currently causing concern, and performance of root cause analyses and risk assessments.
WHO advised companies to identify biological, chemical, and physical risks or harms that should be controlled in every stage of production.
“In order to control the presence of nitrosamines in pharmaceutical products, manufacturers should be familiar with the root causes of nitrosamine impurities in their products,” the guideline noted.
A thorough risk management plan should be established and implemented.
“The risk assessment should be comprehensive and include but not be limited to the premises, equipment, materials, route of synthesis, production process, interaction between chemicals, excipients, solvents, APIs, packaging components as well as the intended use of the product and route of administration,” according to the guidance.
WHO is accepting comments on the guidance by email and through an online platform, with a deadline for submission of feedback by June 9.
Global safety concerns, worldwide recalls
Nitrosamines and their precursors are found in typically small quantities in food products and other consumer products like processed meats, alcoholic beverages, and cosmetics, WHO noted. Presence below recommended intake limits in pharmaceutical products does not present a health risk, but people exposed to impurities over the limit over time could suffer.
“Several epidemiological reports have described the influence of nitrosamines on the risk of developing esophageal cancers, colon cancers, hepatocellular cancers, and other devastating forms of cancers,” wrote Bannimath Gurupadayya, PhD, et al in a recent review in the Journal of Pharmaceutical Analysis.
The discovery of impurities in APIs and approved products has spurred the “abrupt recall” of drugs, including sartans and metformin, and contamination is a leading cause of pharmaceutical withdrawals.
“The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects,” Gurupadayya et al wrote.
The US Food and Drug Administration (FDA) released final guidance on managing nitrosamines risks last year. (RELATED: FDA sets acceptable intake limits for nitrosamines in drugs, Regulatory Focus 7 August 2023)
Thorough risk assessment
The WHO guidance notes that risk in pharmaceutical products depends on three factors: daily dose, length of time on medication, and level of nitrosamine impurity in the finished product. According to WHO, the following impurities are currently causing concern, but companies need to be alert to new threats:
- N-nitrosodimethylamine (NDMA)
- N-nitrosodiethylamine (NDEA)
- N-nitrosodiisopropylamine (NDIPA)
- N-nitroso-N-methyl-4 aminobutanoic acid (NMBA)
- 1-methyl-4-nitrosopiperazine (MNP)
- N-nitrosoethylisopropylamine (NEIPA)
- N-nitrosodibutylamine (NDBA)
The WHO document offers a long list of questions companies should ask themselves during risk assessments, including the following:
- Is there a possibility of formation of nitrosamine impurities? If so, what are the controls to reduce/eliminate the formation?
- How easy is it to detect these nitrosamine impurities?
- What could be the possible source of the formation of nitrosamine impurities?
- What is the nature of risk, probability of occurrence and severity/consequences?
- Has an appropriate supplier qualification been done to ensure there is no risk of contamination of material at the supplier?
- Are the raw and starting materials, and excipients of appropriate purity and quality?
Unfortunately, contaminants can be difficult to remove and detect with conventional tests. The guidance includes an overview of analytical procedures.
Balancing risks and benefits
At the end of the document, WHO offers recommendations on best practices for manufacturers of excipients, active pharmaceutical ingredients, and full package production.
Companies need to act quickly on nitrosamine risk assessment, “as early as during product development,” as well as thereafter, WHO advised. And they should be aware that average nitrosamine and potential nitrosamine precursors vary from batch to batch of excipients, due to differences in source materials and processing methods.
The national medicines regulatory authority (NMRA) reviews issues, assessing benefits and risks of products with levels of nitrosamine that exceed limits to determine if a recall is needed.
“When considering the withdrawal, the NMRA should balance the impact on the patient if the product will no longer be available,” WHO says. “This should involve determining the availability of alternative products or treatments on their own market and the clinical impact of stopping or switching to a different treatment.”
WHO plans to have a revised working document incorporating feedback ready for its Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) in August or September.
