Implementing the Principle of the 3 Rs Through the Indian Pharmacopoeia

Abstract

Quality and safety tests are required for regulatory approval of drugs and pharmaceuticals in the country to guarantee minimum safety standards, and most of these tests include animal usage. In the case of biological medicines, these safety and quality tests have to be performed on a batch-to-batch basis and require a large number of animals. Russell and Burch's 1959 principle of the 3 Rs- replacement, reduction, and refinement-is now being increasingly adopted worldwide, and various national and international pharmacopoeias have taken initiatives to safeguard animals. This article details the Indian Pharmacopoeia Commission's initiative to implement the 3 Rs through the Indian Pharmacopoeia. Explored are the deletion of animal tests, such as the abnormal toxicity test at final lot for biologicals; the replacement of in vivo methods by in vitro methods; the reduction in the number of animals used where deletion of the animal test is not possible; and the refinement of tests to cause minimal suffering to the animals. In Indian Pharmacopoeia 2014, pyrogen testing using rabbits has been replaced by the bacterial endotoxin test in the majority of biological monographs-keeping in view international trends and, especially for vaccine monographs, validated in vitro tests such as the bacterial endotoxin test as an alternative to the pyrogen test where justified and authorized. Steps are taken for introducing a single-dilution assay for the potency testing of diphtheria and tetanus vaccine (adsorbed) with the aim of minimizing number of animals used. The justified and authorized use of animals in drug manufacturing, analytic laboratories, and research will not only help in the expedited development/production of drugs but also be useful in protecting and promoting animal health.

Ensuring the quality of medicines in India: An update on the development, modernization, and harmonization of drug standards in the Indian Pharmacopoeia

“…IPC has also embraced the principles of the 3Rs (Reduction, Refinement, Replacement) in the IP 2022 edition by eliminating animal tests such as the Abnormal Toxicity Test (ATT) at final lot for biologicals by replacing the in-vivo bioassays with in-vitro assay methods, minimizing the number of animals used where elimination of the animal test is not possible, and/or refining the tests that results minimal suffering to the animals ( Rastogi et al, 2015 ). The pyrogen test specified in the IP limits the risk of a febrile reaction following the parenteral administration of drugs.…”

“…Similarly, the ATT is conducted to detect the presence of any extraneous toxic contaminants in sterile pharmaceutical preparations. Based on the WHO recommendations, the ATT requirement can be relaxed if manufacturers establish batch consistency and characterize each batch with a sufficient set of test methods approved by the National Regulatory Authority ( Rastogi et al, 2015 ). Taking this into consideration, the ATT test has been removed in thirty-three monographs of human vaccines thereby reducing the use of laboratory animals during batch-release testing.…”