Last week’s round -up;
05-09 July 2021
Ph. Eur. to put an end to rabbit pyrogen test
The Ph. Eur. Commission has decided to completely replace the rabbit pyrogen test (RPT) in the Ph. Eur. with a suitable in-vitro alternative, within approximately 5 years. The test was first published in the Ph. Eur. in 1986 and consists of measuring the rise in body temperature evoked in rabbits by the intravenous injection of a sterile solution of the substance to be examined. Most pyrogens are bacterial endotoxins and can be detected using the bacterial endotoxins test (BET) (Ph. Eur. general chapters 2.6.14 Bacterial endotoxins and 2.6.32 Test for bacterial endotoxins using recombinant factor C). However, non-endotoxin pyrogens may also be present in certain cases and these are not detected by the BET. General chapter 2.6.30 Monocyte-activation test (MAT), provides an in-vitro alternative to the RPT that is capable of detecting both endotoxin and non-endotoxin pyrogens. However, the RPT is still extensively used to detect pyrogens in favour of the MAT. There are also currently 59 Ph. Eur. texts that make reference to the RPT and the Ph. Eur. aims to replace the test for pyrogens for all these texts and eventually completely eliminate the RPT.
New FDA Studies Show No Post-ingestion NDMA From Ranitidine
In April 2020, FDA pulled all ranitidine products from the market due to the risk of contamination with the potential carcinogen N-nitrosodimethylamine (NDMA). Recently the FDA has led two studies which showed that NDMA is not produced in the human body after ingestion of ranitidine. One study involved a randomized crossover clinical trial of 18 participants who ingested either 300 mg of ranitidine or placebo and then ingested either a noncured-meats diet or a cured-meats diet. The study found no statistically significant difference in urinary NDMA levels between participants ingesting ranitidine or the placebo, thus, the presence or absence of cured meats did not affect urinary NDMA levels. The second study involved the addition of 150 mg ranitidine to simulated gastric fluid followed by the variation of gastric nitrite concentrations from the upper range of physiologic levels to supraphysiologic levels. The acidity of the simulated gastric fluid was also varied and it was found that “NDMA did not form when gastric nitrite concentrations were at the upper range of physiologic or at nitrite concentrations as much as 50-fold greater than the upper range”.
Updated EMA Nitrosamines Q&A
The EMA has updated its Questions and Answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. The following Q&As have been updated: • Q&A 3. For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities? • Q&A 10. Which limits apply for nitrosamines in medicinal products?
Revised EMA Investigational Medicinal Products Dossier Guidance
The EMA has released the following revised guidelines with tracked changes for public consultation: · Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials. · Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials. The changes bring the guidances into compliance with the Clinical Trials Regulation (CTR) and relate to the classification of a change to IMP/auxiliary medicinal product quality data to either a substantial modification (Art. 2.2.13), a change relevant to the supervision of the trial (Art. 81.9) or a non-substantial modification (changes outside the scope of substantial modifications and changes irrelevant to the supervision of the trial). The draft guidance documents are open for comments until the 31st August 2021.