Key Takeaways
- Chapters on pyrogens, histamine and depressor substances – which all involve animal tests – will no longer feature in the European Pharmacopoeia (Ph. Eur) as of its 12th edition.
- The 12th Edition of the Ph. Eur will be published in July 2025, and enter into force in January 2026.
- Measures to revise texts in the Ph. Eur omitting the rabbit pyrogen test and to adopt a new chapter on pyrogenicity were published last year, with an implementation date of 1 July 2025.
All general animal safety tests are being abolished from the European Pharmacopoeia (Ph. Eur), in a move that marks another significant milestone in the elimination of animal tests from the pharmacopoeia.
Following the European Pharmacopoeia Commission’s decision last June to remove from the Ph. Eur all references to the general chapter on pyrogens (2.6.8), which describes the rabbit pyrogen test (RPT), chapter 2.6.8 is now being removed entirely.
In addition, two other general chapters involving animal testing are also being removed from the Ph. Eur. These are the chapters on histamine (2.6.10) – which uses guinea pigs – and depressor substances (2.6.11) – which uses cats.
Furthermore, 14 monographs are being revised to delete either the reference to the histamine chapter or the requirement to eliminate or minimize substances that lower blood pressure.
Chapters 2.6.8, 2.6.10 and 2.6.11 will no longer feature in the Ph. Eur as of its 12th edition, which will be published in July 2025, and enter into force in January 2026.
Together with the suppression of the general chapter on abnormal toxicity (2.6.9) in 2017, the EPC has now abolished all general animal safety tests in the Ph. Eur, said the European Directorate for the Quality of Medicines & HealthCare (EDQM), which last month announced the EPC’s decision to remove the latest three chapters.
The directorate noted that the animal tests involved had been present in the Ph. Eur for many years to ensure the safety of parenteral medicines, before the development of the modern analytical techniques that are now available and good manufacturing practice conditions.
It said the suppression of the latest three chapters was in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes, and was another step in the EPC’s ongoing efforts to replace, reduce and refine (3R principles) the use of animals for monograph requirements.
When the EPC decided to remove the RPT from its monographs last June, its Swiss delegation said the move was “a significant step forward in terms of animal welfare,” and would “send out a strong message across the world.”
Medicine developers were told that they would be responsible for selecting a suitable in vitro test to control the pyrogenicity of their product.
Pyrogens
The removal of the general chapter on pyrogens follows the EPC’s adoption last June of 57 revised texts in the Ph. Eur from which the RPT was deleted, and a new general chapter on pyrogenicity (5.1.13).
The revised texts omitting the RPT and the newly adopted chapter on pyrogenicity were published in supplement 11.8 of the Ph. Eur, with an implementation date of 1 July 2025.
The EDQM said it would be the responsibility of medicine developers to select a suitable in vitro test (eg, the monocyte-activation test) to control the pyrogenicity of their product, based on a risk assessment as described in the new general chapter.
Pyrogens are fever-inducing contaminants that may unintentionally be present in medicines administered by injection (including vaccines, blood products, radiopharmaceuticals, antibiotics and large volume solutions for infusion). Their detection is therefore essential to ensure that medicines administered by this route are safe.
Histamine & Depressor Substances
The chapters on histamine and depressor substances describe tests that measure the effect of histamine and histamine-like substances.
The EDQM pointed to a Histamine Strategy Paper published last year that concluded that histamine and depressor substance animal tests were outdated, non-specific, not reproducible and not in line with the 3R policy.
“They were added to many monographs as safety tests before GMP and modern purification techniques were in place,” the paper said. “From the very start of elaboration of these monographs, 60 years ago, the relevance of these biological tests has been questioned and the absence of positive batches has been a trigger to delete these tests. However, the references to histamine or depressor substances have remained in texts, providing a false sense of safety to certain users.”