After APIs, Carcinogens NDMA and NDEA Now Impacting Formulations

Feb. 15, 2019

The CDE organized the drafting of the Warning on the Risk of Nitrosamine Compound Formation in the API Processes on the basis of literature research and reaction mechanism analysis, to provide technical reference for the risk of nitrosamine compound formation in the API research and production.

Jan. 10, 2020

The CDE released on its website the Technical Guidelines for the Research of Nitrosamine Impurities in Chemical Drugs (Draft for Comment) to fill in gaps in China’s regulation and technical requirements for the research of nitrosamine impurities in chemical drugs.

• Risk of introducing nitrosamine impurities by the processes

• As far as is known, NDMA and NDEA impurities may form through the nitrosation mechanism, i.e., under certain conditions, amines, especially secondary amines, will react with sodium nitrite (NaNO2) or other nitrosation reagents to form nitrosamine impurities.

• The use of materials that can introduce secondary amines and nitrites (including starting materials, solvents, reagents, catalysts, and intermediates, etc.) in the same process step will lead to a high risk of introducing nitrosamine impurities; and the separate use of materials that can introduce secondary amines and nitrites in different process steps may also form nitrosamine impurities.

• Besides the secondary amine structures in materials themselves, possible sources of secondary amines include primary amines, tertiary amines and quaternary ammonium that may introduce secondary amine impurities; amide solvents (such as N,N-dimethylformamide, N-methylpyrrolidone) that may form secondary amines under appropriate conditions (such as acidity, and high temperature).

• Possible sources of nitrosation reagents include nitrites, alkyl nitrites, nitrous acid, substances prepared from nitrites (such as sodium azide), and oxidized amines, etc.

• Nitrosamine impurities may also form during the manufacture or storage of formulations when there are certain conditions.

• Risk of introducing nitrosamine impurities by contamination

• The use of materials (starting materials, intermediates, solvents, reagents, and catalysts, etc.) contaminated by nitrosamine impurities during the API manufacturing may bring the risk of nitrosamine impurities.

• The use of recycled materials will also lead to the risk of introducing nitrosamine impurities. Examples of recycled materials observed to be contaminated with nitrosamines include orthoxylene, tributyltin chloride (used as a source of tributyltin azide), and N,Ndimethylformamide (DMF).

• Cross-contaminations are caused due to insufficient cleaning of the production line that produces different varieties.

• Risk caused by the degradation

• Some drugs will degrade to form nitrosamine impurities, for example, ranitidine will form nitrosamine impurities under high temperature.

• Based on avoidance

• "Based on avoidance" refers to avoiding the formation of nitrosamine impurities as far as possible at the pharmaceutical R&D stage from aspects of API process route selection, material selection and quality control, and process condition optimization, etc. according to the causes of nitrosamine impurity formation and strictly implementing various operation specifications during the production. Pharmaceutical producers shall fully communicate with material manufacturers (APIs shall include starting materials, solvents, reagents, catalysts, and intermediates, etc., and formulations shall include APIs, excipients, and packaging materials, etc.), to systematically assess the material production and recycling processes. The risk assessment methods can be the FMEA or FMECA mentioned in ICH Q9 Quality Risk Management or other scientific and reasonable methods. If risks of nitrosamine impurity formulation are identified in the assessment, the necessity of using nitrites and the related reagents and solvents that may form nitrosamine impurities shall be first analyzed, and the selection of the production process that may form nitrosamine impurities shall be avoided as far as possible.

• Supplemented by control

• "Supplemented by control" strategy refers to that when a pharmaceutical product is assessed to have the risk of nitrosamine impurity residues which cannot be avoided by the related process, the process step shall be adjusted to the early stage as far as possible, and subsequent multi-step operations shall be used to reduce such risk. The nitrosamine structure that may form shall be analyzed according to the process route, the process shall be optimized, and a detailed course control strategy shall be made, to guarantee the effective removal of such impurities during the production. In the case of nitrosamine impurities as a result of degradation, the conditions for the degradation shall be analyzed, and the risk of degradation impurity formation shall be reduced by optimizing the production process, prescription, and storage conditions, etc. Appropriate analytical methods shall be established for varieties identified to have the risk of nitrosamine impurity residues, to make sure that the nitrosamine impurities in the finished products are lower than the limit requirements.

• Limit control

• The Threshold of Toxicological Concern (TTC) of 1.5μg/day mentioned in ICH M7(R1) is insufficient for the risk control.

• For nitrosamine impurities whose TD50 (50% tumor incidence) can be found in the databases of the authoritative organizations, their TD50 is generally sourced from the databases of the authoritative organizations such as CPDB.

• For nitrosamine impurities whose TD50 cannot be found in the databases of the authoritative organizations, the following methods can be selected to separately obtain the control limits of the nitrosamine impurities, and the minimums thereof are recommended:

1. The data released or risk assessment methods established by the international authoritative organizations such as WHO and International Programme on Chemical Safety (IPCS) can be used for reference.

2. For those whose structures are similar to the nitrosamine impurities that have TD50 values, such TD50 values can be used as a guide for the impurity limit calculation.

• Risk control throughout the lifecycle

1. For the products applied for marketing, the applicants shall assess the risk of nitrosamine impurities during the R&D, sufficiently research the varieties identified to have the risk of nitrosamine impurity residues, submit in the corresponding chapter of the application data the research data and detection results of nitrosamine impurities and pay attention to that the batch or lot of samples used for the research must be representative and have scientific basis.

2. For marketed pharmaceutical products, pharmaceutical product approval holders/manufacturers shall also actively assess the risk of nitrosamine impurities. If such risk exists, they can carry out research with reference to the requirements of these Guidelines and other related guidelines and take corresponding measures according to the research results, to avoid or minimize the exposure of nitrosamine impurities to patients.