Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The Valsartan Case and its Consequences for the Global Supply of Pharmaceutical Active Ingredients

Dr. Karim Sempf (Abschlußjahr: 2019)

Summary
Language: English
The problem began in 2012 with a change of the valsartan synthesis by ZHP. This change was notified to the EDQM and the FDA. Both regulators reviewed the change and accepted it without any changes to the analytical methods monitoring possible impurities. Moreover, both assessments didn´t see the possibility of the formation of nitrosamines, namely NDMA and NDEA.
Unfortunately, ZHP was one of the few valsartan manufacturers in the world, so the problem became soon worldwide. All over the world, valsartan batches had to be recalled.
What was missed during the assessment was the fact that the newly introduced solvent DMF was containing or would be degraded into dimethylamine under harsh conditions. This dimethylamine reacts with nitrous acid to give rise to NDMA, a well-known carcinogenic substance belonging to the called "cohort of concern".
Assessing the toxicology of NDMA is not possible with the usually used TTC ("threshold of toxicological concern") concept. The toxicological assessment has to be derived from the animal data. The calculated limits give a conservative estimate of contamination levels associated with a probability of one additional cancer occurring in 100.000 persons. With the levels of NDMA and NDEA determined in valsartan tablets by newly introduced analytical methods, the risk caused by these levels can be calculated. For patients exposed for 6 years to NDMA-contaminated valsartan, the theoretical excess risk of cancer during lifetime is calculated to be 21.5 in 100,000. This is approximately 0.02%. Compared to the normal probability in Europe to develop cancer (e.g. in Germany reportedly 50.3% in men and 43.5% in women; in Italy 62% in men and 59% in women), that´s considered as very low.
A Danish epidemiological study confirmed these findings. The study compared the number of cancers occurring in a group of patients taking NDMA-contaminated valsartan products to the number of cancers occurring in a group of patients taking non-contaminated valsartan products. The study showed no increase of cancer with the fact of taking NDMA-contaminated valsartan products.
The NDMA contamination of valsartan raises the question of the control of mutagenic impurities. The assessment procedures of the EDQM and the U.S. FDA in case of a change of the drug substance synthesis seem to be insufficient when it comes to genotoxic impurities.
Several corrective and preventive actions would have to be taken in order to improve the process. Using state-of-the art analytical technologies (mainly MS-techniques) to compare the impurities profile of the drug substance before and after a synthesis change, is surely one of these CAPAs. It should also be made mandatory to include an organic chemist in the assessment teams.
Pages: 34, Annexes: 5, Pages: 20