GMP-Update - What's new in Germany and the EU? - Part 1

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Concerning the GMP regulations there hasn't been much change in the past calendar year. But some changes can be expected for the year 2020. The long awaited annexes 1 and 21 of the EU-GMP Guidelines are expected to be published finally, for example. But more about that later. This and most of the remaining content of this series of articles were part of a live webinar presented by Dr Bernd Renger on 5 December, 20191.

Nitrosamine Impurities

Nitrosamine impurities in several medicinal products; this is one of the uppermost topics in the minds of the pharmaceutical industry, authorities, pharmacies and patients alike. Are or were the concerns always justified, however? As far as supply shortages are concerned, surely. About the background:

"Nitrosamines" is an abbreviated designation for N-nitrosamines which are formed by the reaction of secondary amines, for example N-Nitrosodimethylamin (NDMA) or Dimethylnitrosamin (DMNA):

At least in the past it had an interesting widespread technical application, for instance as additive in curing of rubber. Today nitrosamines can still be found in latex and rubber (stopper but also balloons), cosmetic products, tobacco and tobacco smoke. But many foodstuffs also contain nitrosamines. The main sources are beer, smoked meat products (bacon, salami, and ham), fresh and smoked fish, spices and cheese.2

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Carcinogenity of nitrosamines was reported by scientists of the German Cancer Research Center (DKFZ), Heidelberg, already in 1967. According to a classification by WHO's International Agency for Research on Cancer nitrosamines belong to the so-called "cohort of concern", a group of highly potent mutagenic carcinogens.3 For that reason they are excluded from the concept of Threshold of Toxicological Concern (TTC) in the ICH Guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. This means that the limit for the daily intake should be below 1.5 ??g. This is the same value as for aflatoxins.


Fig. 1: NDMA

Traces of N-nitrosodimethylamine and later also N-nitrosodiethylamine were detected in the active pharmaceutical ingredient Valsartan of two Chinese manufacturers in July 2018. N-nitrosodimethylamine has presumably been formed during the manufacture of the tetrazole ring using sodium nitrite as a reagent. But this has only been the beginning. Very rapidly it became apparent that other sartans also were affected and further contaminations with Nnitroso compounds were detected. Subsequent investigations revealed additional other potential sources such as carryover of nitrosamines from precursors, reagents or solvents or the use of recycled solvents. This led to a number of recalls of medicinal products manufactured with API from the manufacturers concerned.

The European risk assessment procedure according to Article 31 Directive 2001/83/EC was completed in January 2019 and an EMA press release followed in February 20194.

Temporary limits were established on the basis of an assessment by EMA's Safety Working Party (SWP) with different limits for the different sartans. The limits ranged between 0.3 and 3.0 ppm. The list was expanded to other N-Nitrosamines in August 2019. The transition period for compliance with the limits is two years. After this time, a general limit of < 0.03 ppm will have to be complied with.

Unfortunately, the problems have spread even further. NDMA was identified in some batches of Pioglitazone from India in April 2019. In a press release dated 26 April, 2019 the EMA required again a review of the routes of synthesis.5 The FDA reported about NDMA impurities in Ranitidin in August 2019. This triggered investigations of Ranitidin products in the EU as well as several recalls.

On 13 September 2019 EMA's Executive Director asked the Committee for Medicinal Products for Human Use (CHMP) to provide guidance for avoiding the presence of nitrosamine impurities in human medicines containing chemically synthesised active substances.6 Furthermore, there was collaboration with the EDQM to include limits and monographs in pharmacopoeias. On 26 September 2019 an important step was carried out: Th e EMA published the "Information on nitrosamines for marketing authorisation holders"7 requesting that marketing authorisation holders for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines. A risk assessment to be concluded at the latest within six months is supposed to be the basis for the internal measures. Products regarded as potentially at risk also have to be tested. In parallel, the EMA issued a Q&A Paper "Information on nitrosamines for marketing authorisation holders" which has been enhanced in the meantime.

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Two statements show that the US FDA takes a much more relaxed and maybe realistic approach to the situation concerning the limits and the ubiquitous occurrence of nitrosamines:

"Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts expected to be found in common foods."
(FDA Statement alerting patients and health care professionals of NDMA found in samples of ranitidine, 13 September 2019)8

"Through our testing so far, we have found levels of NDMA in ranitidine that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats."
(FDA Statement on new testing results, including low levels of impurities in ranitidine drugs, 1 November, 2019)9

This article will be continued in the next issue of the GMP Journal.


Wolfgang Schmitt
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP.

1 A recording of the webinar can be found here:
2 See also "Nitrosamine in Lebensmitteln" (Nitrosamines in food) University of Landau:

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