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Latest achievements of the Ph.Eur. Commission for 3Rs

Since 1986, the European Pharmacopoeia (Ph. Eur.) Commission and its experts have worked continuously to ensure that the 3R principles of Replacement, Reduction and Refinement of animal testing are applied when revising or drafting the texts published in the Ph. Eur. The major milestones that have marked these past years are described below.

During its 142nd Session (April 2012) and several years into an extensive and ambitious programme of works launched as part of harmonisation with VICH Guidelines 41 and 44, the Ph. Eur. Commission adopted some 80 veterinary vaccine monographs in addition to the general monograph on Vaccines for veterinary use and two general chapters (5.2.6 and 5.2.9), revised for greater consistency with European regulations. The work programme also included monographs on vaccines for other species that were outside the scope of the VICH Guidelines, targeting harmonisation of the tests for increased virulence performed during vaccine development as a means of substantially reducing the number of animals used for testing.

During the same session, the Ph. Eur. Commission also voted to delete the target animal batch safety test (TABST) waiver, an option available for established vaccines since 2004, from all Ph. Eur. veterinary vaccines. This became effective on 1st April 2013.

In June 2012, following adoption of the general chapter Residual pertussis toxin and irreversibility of pertussis toxoid (2.6.33), 9 revised monographs on human vaccines to reference this new general chapter were also adopted. The protocol described in the chapter, which is based on the outcome of a study from the Biological Standardisation Programme (BSP), facilitated standardisation of the method and therefore reduces the unnecessary use of animals.

The Ph. Eur.'s commitment to the 3Rs continued with the inclusion of provisions for additional systems to monitor the consistency of production, firstly in the General Notices (146th Ph. Eur. Commission Session), and then in the general monograph Vaccines for veterinary use (0062) and in three individual veterinary vaccine monographs, Canine leptospirosis vaccine (inactivated) (0447), Bovine leptospirosis vaccine (inactivated) (1939) and Infectious bovine rhinotracheitis vaccine (inactivated) (2674) (153rd Session). This was done in conjunction with implementation of the revised Directive 2010/63/EU on the protection of animals used for scientific purposes, and both recognised manufacturers’ efforts to develop new test methods and encouraged them to develop in vitro alternatives. It was also a reflection of the growing control over vaccine production in general.

At its 153rd Session in November 2015, the Ph. Eur. Commission also adopted the revised general monograph Vaccines for veterinary use together with around 40 veterinary vaccine monographs in order to allow manufacturers to switch from an animal test for vaccine identification to an in vitro test, when appropriate. Not only was the reference to the antibody induction test for identification of all inactivated vaccines deleted from these monographs, but inactivation testing of all inactivated veterinary vaccines was revised to allow manufacturers to omit the second inactivation test.

In November 2015, the Ph. Eur. Commission's attention turned to the current requirements for extraneous agent testing. The aim was to rationalise these requirements without in any way compromising safety. To this end, a reference to the new general chapter 5.2.13, which lays down the requirements for healthy chicken flocks used for the production of inactivated vaccines for veterinary use, was introduced into 8 veterinary vaccine monographs. This rendered the test for specified extraneous agents previously performed on each final product obsolete. As part of the same initiative, the revised texts on Tests for extraneous agents in viral vaccines for human use (2.6.16) and Cell substrates for the production of vaccines for human use (5.2.3) were adopted at the 156th Session of the Ph. Eur. Commission. The changes include deletion of the tests on adult mice and guinea pigs and restricting the use of the test on suckling mice and control eggs to cases in which the tests provide risk mitigation.

Extensively overhauled with input from industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories, the revised version of the general chapter Monocyte-activation test (2.6.30) was adopted by the Commission at its 155th Session. Revision of this chapter (first published in the Ph. Eur. in 2010) was intended to promote use of the test by stakeholders particularly as a replacement for the pyrogens test which is conducted on laboratory animals.

Again encouraging the transition from in vivo to in vitro methods, the Ph. Eur. groups of experts on vaccines have developed a new general chapter entitled Substitution of in vivo method(s) by in vitro method(s) for the quality control of vaccines (5.2.14). The text was adopted at the 156th Session and provides guidelines on validation of substitute methods where a direct head-to-head comparison with an existing in vivo method is not possible

In November 2017 at its 159th Session, the Ph. Eur. Commission adopted 49 monographs, 36 of which were on vaccines for human use, which had been revised to remove the reference to the test for abnormal toxicity. General chapter Abnormal toxicity (2.6.9) will therefore no longer be cited in any monograph and will also be deleted. As a result, the test for abnormal toxicity will be completely suppressed from the Ph. Eur. as of Supplement 9.6 (implementation date 1 January 2019).

As a result of the Ph. Eur. Commission’s efforts, no Ph. Eur. monographs on medicinal products derived from human blood and plasma describe any tests requiring the use of animals. As far as human and veterinary vaccines are concerned, an in vitro method has in many cases been introduced as an alternative to or replacement for in vivo testing. One example is the introduction of a validated ELISA method for determination of antigen content in Assay of hepatitis A vaccine (2.7.14) as an alternative to the serology assay in mice, a change that was adopted at the 149th Ph. Eur. Commission Session in June 2014. Various strategies are also used to promote reduction and refinement with regard to in vivo assays, for example serology assays or single dilution assays for diphtheria, tetanus, acellular pertussis and rabies (veterinary/human) vaccines.

These decisions are fully in line with the EDQM’s mission to promote and protect human and animal health, and with its commitment to the 3R principles.

To conclude, the Ph. Eur. Commission welcomes any data supporting the replacement of the remaining in vivo methods and proposals for replacement methods, both of which can be sent to the Commission Secretariat via the Helpdesk.

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