Drug Development Solutions

Nitrosamine related productrecalls and risk assessments

Following the discovery in 2018 of N-nitrosodimethylamine (NDMA), a potential human carcinogen, in a number of Sartan drug formulations, the same nitrosamine has now been detected in batches of Zantac® and other related generic Ranitidine products.In September 2019, the EMA requested that manufacturers should perform a risk assessment exercise for all drug products containing chemically synthesised active pharmaceutical ingredients (APIs) in regard to the possible presence of nitrosamines. Other risk factors to be considered in this assessment include the daily exposure of the patient to the drug product and the length of treatment.

Analytical test data will be subsequently required for any drug products identified as a high risk for the potential presence of nitrosamines.

The impact of adverse test results may be severe, potentially leading to product recalls or manufacturers being required to introduce modified production processes. It is therefore vital that any analytical testing is performed using methodology that is proven to be both accurate and reliable.

Background

Nitrosamines may be formed during the drug production process due to side reactions between starting materials and related degradants and impurities, plus solvents and catalysts, but there is also the potential for cross contamination from the use of recycled solvents.

Nitrosamines are considered potential highly potent genotoxic carcinogens (such that exposures even below the theoretical threshold of concern (TTC) limit of 0.15 µg / day may be associated with an unacceptable risk of carcinogenicity). Following metabolic activation, they can directly bind with the DNA to form mutagenic adducts. In carcinogenicity studies, they have been seen to induce (sometimes at extremely low doses and / or following just a single treatment) tumours in multiple organs and tissues, regardless of the species tested.

Science for a safer world

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For further information on how LGC can assist with analytical testing, please contact us:

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Nitrosamine impurity analysis

Scientists within LGC’s Impurity and Contamination Centre of Excellence (part of our Drug Development Solutions business) have developed and validated a robust test method suitable for the detection of a full range of potential nitrosamine impurities. These include:

- N-nitrosodimethylamine (NDMA) - N-nitrosodiethylamine (NDEA) - N-nitrosodibutylamine (NDBA) - N-nitrosodiisopropylamine (NDIPA) - N-nitrosoethylisopropylamine (NEIPA) - N-nitrosomethylphenylamine (NMPA) - N-nitroso-n-methyl-4-aminobutyric acid (NMBA)

The current method, based on the latest triple quadrupole LC-MS/MS technology, as specified by the FDA, provides the specificity and sensitivity needed to both confirm the presence, and where required, provide an accurate determination of the levels of nitrosamines.

The method is capable of readily achieving the required ppb detection limits, either as a limit test or to provide a fully quantitative assay, and is suitable for the analysis of a wide range of APIs and drug product forms including:

- Tablets - Liquids - Syrups - Capsules - Creams

Quality accreditation

Our Impurity and Contamination Centre of Excellence comprises two UK laboratories, which are regularly inspected by the UK MHRA for cGMP compliance.

Nitrosamine reference standards

High quality certified reference standards are vital for the qualification and validation of analytical methods.

LGC Standards is a leading global producer and distributor of reference materials and proficiency testing schemes for pharmaceutical and other industry sectors.

LGC is, therefore, able to ensure our own reliable and efficient supply chain of nitrosamine related reference standards required for analytical testing.

Related services

Other expertise and analytical solutions offered by our Impurity and Contamination Centre of Excellence include:

• Organic impurity characterisation and structural elucidation

• Inorganic trace analysis• Extractable and leachable testing• Contamination and foreign particulate analysis

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