WHO releases new guidelines for preventing nitrosamine contamination
The World Health Organisation (WHO) has released draft guidelines to combat the presence of potentially carcinogenic nitrosamine impurities in medicines. In 2018, the discovery of high levels of nitrosamines in a number of leading drugs briefly threatened to disrupt global supplies of the world’s most vital medicines, but a global scientific effort spearheaded by regulators like the US Food and Drug Administration and the European Medicines Agency has largely eased the pressure. WHO’s new nitrosamine guidelines therefore offer welcome additional guidance to manufacturers – including advice on Good Manufacturing Practices, risk assessment, root cause analysis, and analytical procedures.
The World Health Organisation (WHO) has released new recommendations for limiting the presence of potentially carcinogenic nitrosamine impurities in medicines.
Its draft guidelines on preventing small-molecule and nitrosamine drug-substance-related impurities (NDSRIs) add to global efforts aimed at combating the threat to many of the world’s essential medicines.
The new guidance – which could be approved by WHO’s expert committee on pharmaceutical preparations (ECSPP) in September – builds on the previous work of regulators such as The US Food and Drug Administration (FDA) and The European Medicines Agency (EMA).
What do the WHO nitrosamine guidelines say?
Applicable “to all manufacturers of excipients, active pharmaceutical ingredients (APIs) and finished pharmaceutical products”, the guidelines outline a number of steps that producers should take to ensure the safety of their products.
Three key principles are that manufacturers should:
be familiar with the root causes of nitrosamine impurities in their products
establish and implement a comprehensive risk management plan
comply with current Good Manufacturing Practices (GMPs) for excipients, APIs and finished pharmaceutical products (FPPs)
Assessing contamination sources
In addition, WHO says that manufacturers should perform assessments of whether their products are at risk of containing nitrosamine impurities, and to ensure that impurity levels do not exceed the acceptable limits.
It adds that the risk assessment should be comprehensive, and include at least the following potential contamination sources:
premises and equipment
materials, including excipients, solvents, and APIs
synthesis routes and production processes
interaction between chemicals
packaging components
the intended use of the product and route of administration
Analysing the root causes of contamination
The new advice also recommends carrying out a root cause analysis to determine both possible and probable causes of nitrosamine contamination, which should include:
Have solvents (fresh and recovered) been considered for possible contamination?
What is the quality and purity of the solvent used in any step of the processing?
Is any nitrosating agent used?
Is any secondary or tertiary amine present in the manufacturing process, e.g. raw materials, intermediate, reagent, solvent?
Is any amide, amine or ammonium salt present in the substance(s) e.g. raw materials, intermediate, reagent, solvent?
Are nitrites (NO2-), nitrous acid, nitrates (NO3-), nitric acid, or azides (N3-) or their sources present in any excipients (e.g., microcrystalline cellulose), processing aids (e.g., water, nitrogen)?
Are peroxides present in any of the excipients or processing aids?
Are nitrites (NO2-), nitrous acid, nitrates (NO3-), nitric acid, or azides (N3-) or their sources present in chemically synthesised APIs?
Recommended testing procedures
High levels of potentially carcinogenic N-Nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in blood pressure, heartburn and anti-diabetic drugs first began to pose a significant threat to global drug supplies in 2018.
And the situation later took a turn for the worse with the discovery of NDSRIs - a new class of nitrosamine impurities intrinsically linked to the APIs of many drug products.
“All of a sudden [for maybe] 20%, 30%, even 40% of all existing drugs across major classes... there (was) a major risk of having to take these drugs off the market,” recalled Andrew Teasdale, the senior principal scientist in impurity management at Astra Zeneca.
“We seemed to be heading towards a catastrophic loss of critical medicines.”
Progress made in combating nitrosamines in drugs
However, considerable progress has been made since 2018 on understanding and limiting the threat of both small molecule nitrosamine impurities and NDSRIs in drug products.
Regulators on both sides of the Atlantic demanded that manufacturers carry out a comprehensive review of all human medicines for the possible presence of small molecule nitrosamines, and submit changes to manufacturing processes where they were detected above permitted levels.
According to the EMA, the global response rate to regulators’ demands for risk evaluations of active substances and finished drugs stood at over 96% in September 2023 - with just 2.5% of products assessed containing greater than permitted levels of nitrosamines.
Another significant advance was the adoption of the FDA’s Carcinogenic Potency Categorisation Approach (CPCA)– a predictive solution to recommending AI limits for NDSRIs for which no direct mutagenicity data exists.
Under the CFCA, the mutagenic and carcinogenic potential of an NDSRI can be generated based on its structural features and – once such structural studies have been carried out – drugs can be placed in one of five potency categories.
The fact that most drugs fall into the least restricted Category 5 under CFCA means that nitrosamine-related pressures on the supply of most drugs have greatly eased.
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