Module 3 - Strategic case studies in practice

impurities [Wu et al. (2011)]. The exact sources of these trace impurities have not been investigated, but it is possible that they come from process water, processing steps requiring acid titration, bleaching, and potentially from oxidation in air as the excipient is being heated in a drying process. Some reports on formation of N- nitrosamines in medicinal products have been received suggesting a link to interaction of APIs with nitrites in excipients but not with nitrates. Accordingly, this possibility is considered a probable root-cause, suggesting, the need to initiate research e.g. in collaboration with academia. In September 2019, a new root-cause for contamination of medicinal products with NDMA/NDEA was identified and reported to the authorities. NDMA/NDEA appear to have been formed during printing of the lidding foils and that formation of N- nitrosamines was caused by reaction of nitrocellulose in the lidding foil with amine containing printing ink [dimethylamine (DMA) and diethylamine (DEA)] and transferred to the finished product during heat-sealing blistering process via vaporization and condensation on the finished product. Since the deflagration temperature of plasticized nitrocellulose chips e.g. lies above 180 °C, generating different nitrogen oxides upon thermally induced decomposition according to Balser et al. [Ullmann's Encyclopedia of Industrial Chemistry (2012)], liberation of nitrogen oxides from nitrocellulose and subsequent nitrosating of amines in the printing drug ink is regarded plausible.

Table 2.2.3-1 Critical Compound Combinations responsible for N -nitrosamine contamination of finished medicinal products N -Nitrosamine NOX Source Amine Source Amine nitrosated by NOX Critical Compound Combination

O

N H DMA

Nitrocellulose (on lidding foil)

Printing ink (on lidding foil)

Lidding foil/printing ink

N N

NDMA

O NN

N H

Nitrocellulose (on lidding foil )

Printing ink (on lidding foil)

Lidding foil/printing ink

DEA

NDEA

In summary, the formation of N- nitrosamines is linked in this case to a critical compound combination (CCC), consisting of the concomitant presence of secondary/tertiary amines in printing ink and nitrocellulose as nitrosating agent in the lidding foil during printing/packaging, which was considered plausible so far. This root-cause can be eliminated by replacing nitrocellulose based lidding foils by nitrocellulose-free lidding foils. Considering that nitrocellulose represents a widely used primary packaging material for finished medicinal products, this root cause should be investigated by MAHs for their medicinal products packaged in blisters.

EMA/369136/2020

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