Module 3 - Strategic case studies in practice

2.2.2.5. The historical aminophenazone case

2.2.2.5.1. Confirmed root-causes in the aminophenazone case

In 1977, the German BGA (Bundesgesundheitsamt, former German Federal Health authority, predecessor of BfArM, PEI) released a recommendation to withdraw aminophenazone (i.e. amidopyrine) preparations from the market [Eisenbrand et al. (1979); BGA Press release Nr. 16/77 (1977)]. This market withdrawal was linked to the fact that even aminophenazone API batches were found to be contaminated significantly with NDMA (NDMA levels up to 340 µg/kg = 340 ng/g = 340 ppb). The final decision was made to supersede a previous recommendation [Eisenbrand et al. (1979); BGA Press release Nr 13/75, (1975)] to re-formulate aminophenazone preparations by adding ascorbic acid as anti-oxidant to prevent nitrosation and NDMA formation. Such NDMA formation from aminopyrine was previously discovered in-vitro and in-vivo by Lijinsky et al. (1973) and associated with liver tumours in rats. As consequence, the aminophenazone monograph was deleted from pharmacopoeias including Ph. Eur. It is noted that a revision is currently under consideration for aminophenazone in Pharmacopea Italica, and an NDMA specification limit for API has been introduced in any remaining medicinal products containing aminophenazone in Italy. According to Mirvish et al. (1974), the formation of NDMA in aminophenazone API has been related to the reaction with nitrous acid anhydride (N 2 O 3 ) and subsequent formation of the corresponding 4- hydroxypyrazol-3-one derivative. According to Lijinsky et al. (1973), NDMA is formed by direct reaction of aminophenazone API with nitrous acid (HNO 2 ) and subsequent formation of the corresponding 4- hydroxypyrazol-3-one derivative. At that time, aminophenazone API was manufactured by two similar processes, both utilizing sodium nitrite for a nitrosation procedure, followed by subsequent reduction and methylation reactions [Kleemann, Engel (1978)]. Aminophenazone has a non-aromatic pyrazolone ring, substituted with a dimethylamine group at the 4-position. Hydrolytic degradation leads to the generation of the corresponding 4-hydroxypyrazol-3- one derivative and the release of DMA [Reisch et al. (1969); Reisch et al. (1967)]. In case of sodium nitrite carry-over from the previous manufacturing step, formation of NDMA has to be expected. Eisenbrand et al. (1979) stated that NDMA formation was caused by carry-over of sodium nitrite into the final step of aminophenazone synthesis, leading to the conclusion that NDMA was formed as an API degradation product via hydrolysis and subsequent nitrosation as shown below.

HO

N

HO

N O

N O

H 2 O

NaNO 2

N O

N

N

N

N

N

O

H

N

NDMA

DMA

Aminophenazone 4-Hydroxy-1,5-dimethyl-2-phenyl -1,2-dihydro-3 H -pyrazol-3-one

Scheme 2.2.2.5.1-4 NDMA formation in aminophenazone API via hydrolytic degradation and subsequent nitrosation [Eisenbrand et al. (1979); Reisch et al. (1969); Reisch et al. (1967)] In summary, NDMA was generated in aminophenazone API by a critical compound combination of a labile dimethylamino substance with sodium nitrite carried over as the NOx source. Although the origin of NDMA is the same as observed for valsartan, i.e. the combination of sodium nitrite and DMA, the cases differ in the origin of DMA (solvent degradant vs. API degradant). With regard to the

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