Removal of the innocuity test from The International Pharmacopoeia and WHO recommendations for vaccines and biological products

Abstract

The innocuity test was indicated as a quality control test to release pharmaceutical and biological products to the market. The test was intended to detect possible extraneous toxic contaminants derived from the manufacturing processes of the product. The test was included in WHO Recommendations and Guidelines for vaccines, biotherapeutics and blood products and in some monographs on antibiotics in The International Pharmacopoeia . Over the past years, the requirements in WHO Recommendations/Guidelines for conducting the test evolved such that it could be waived for routine release of product once consistency of production was established to the satisfaction of the NRA, or that the need for this test should be discussed and agreed with the NRA. However, some users of WHO written standards for biologicals (i.e., Recommendations, Guidelines) and WHO specifications for pharmaceuticals (i.e ., The International Pharmacopoeia ) requested that the innocuity test be deleted from WHO written standards based on its lack of specificity and scientific relevance. In response to that request, we studied the history of this test and its use by the member states of WHO, and the recommendations in WHO written standards. The outcomes of the study were reviewed by the relevant WHO Expert Committee on Biological Standardization and Expert Committee on Specifications for Pharmaceutical Products who then decided to discontinue this test in WHO Recommendations for vaccines and biologicals and to omit the test from The International Pharmacopoeia .

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of vaccines and biological therapeutics manufacturers

“…The Abnormal Toxicity Test (ATT) (also referred to as the General Safety Test (GST) or test for innocuity) has been widely acknowledged as being scientifically questionable, non-reproducible and non-specific [ 2 , 3 ]. The WHO Expert Committee on Biological Standardization (ECBS) followed the United States of America Food and Drug Administration (FDA), the European Pharmacopeia (Ph Eur) and others in removing this test from their requirements in 2018 [ 4 ].…”

Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps. A workshop Report

“…While a measure of success has been seen as a result of the 2019 dedicated efforts (deletion of ATT from most of the specific monographs for human vaccines from the Indian Pharmacopoeia [ 3 ]; partial deletion of ATT from NCL requirements in South Korea; additional waivers implemented in Japan), a host of other successful examples of deletions and exemptions (e.g. Europe, USA, Canada, Brazil, Argentina) [ 1 , 2 ], and the World Health Organization (WHO) recommendations [ 4 , 5 ]); a significant number of regulatory authorities (RAs) still have not changed their perspective on this test. Cooperation, information exchange and dialogue are still very much needed to assist regulators and manufacturers in evaluating and embracing change.…”

“…Dr. Dianliang Lei, from WHO, explained that since 2000, WHO has changed its stance towards ATT when proper GMPs are implemented and consistency of production ensured. After a thorough review of literature, the ECBS recommended to remove ATT from WHO's technical documentation, and to disregard it in those cases in which it is required [ 4 , 5 ]. Dr. Lei also pointed out that ATT is still a requirement for many RAs, and that multilateral discussions with regulators and manufacturers ought to be carried out to ensure the harmonization and convergence of regulations in different parts of the world.…”

Advances in COVID-19 mRNA vaccine development

“…Furthermore, for scientific and ethical standards, the international pharmacopeia and WHO urged the reduction of animal trials, and instead employing appropriate in vitro alternative approaches for evaluating mRNA safety and efficacy. 474 At present, with the expansion of COVID-19 mRNA vaccine production and the incorporation of new production lines, changes in the production process have become inevitable. It is necessary to perform inter-batch quality comparisons based on relevant regulations and standards, including procedures and data requirements preconized in WHO guidelines.…”