Elimination of abnormal toxicity test for sera and certain vaccines in the European Pharmacopoeia

Schwanig, Michael; Nagel, Margit; Duchow, Karin; Krämer, Beate

doi:10.1016/s0264-410x(97)00074-1

Cited by 30 publications

(12 citation statements)

References 1 publication

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“…However, a batch already released for EU and/or the United States would have to be tested for abnormal toxicity in other countries, for example, the Russian Federation and China, to be released for the local market. To the best of our knowledge, no batch which met the EMA‐ or FDA‐approved specifications delivered a positive ATT result in both of these countries (apart from false positive test results, as aforementioned) …”

Section: Release Specifications Are Set According To International Rementioning

confidence: 86%

“…Publications by the German Paul Ehrlich Institute provide evidence that the test does not serve its purpose and does not add any further information to that already obtained from QC release testing under good manufacturing practice (GMP) . A retrospective analysis of several thousand test results conducted for vaccines revealed that there were no true positive results and no batch rejection was obtained by the authority . In conclusion, there is no evidence that the ATT is useful as a predictor or control for harmful batches.…”

Section: Historical Data Analysesmentioning

confidence: 99%

“…As a consequence, and in accordance with the European Convention on the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes, the test has been deleted from approximately 80 monographs for biotechnological products, blood products, antibiotics, and vaccines based on the review of historical data . In addition, further replacement alternatives for abnormal toxicity testing for batch release of existing vaccines have been currently evaluated and strongly recommended …”

Section: Increasing International Convergencementioning

confidence: 99%

See 2 more Smart Citations

Historical Data Analyses and Scientific Knowledge Suggest Complete Removal of the Abnormal Toxicity Test as a Quality Control Test

Garbe

Ausborn

Beggs

et al. 2014

Journal of Pharmaceutical Sciences

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In the early 1900s, the abnormal toxicity test (ATT) was developed as an auxiliary means to ensure safe and consistent antiserum production. Today, the ATT is utilized as a quality control (QC) release test according to pharmacopoeial or other regulatory requirements. The study design has not been changed since around 1940. The evidence of abnormal toxicity testing as a prediction for harmful batches is highly questionable and lacks a scientific rationale. Numerous reviews of historical ATT results have revealed that no reliable conclusions can be drawn from this QC measure. Modern pharmaceutical manufacturers have thorough control of the manufacturing process and comply with good manufacturing practice rules. Contaminants are appropriately controlled by complying with the validated manufacturing processes and strict QC batch release confirming batch-to-batch consistency. Recognizing that product safety, efficacy, and stability can be ensured with strict QC measures, nowadays most regulatory authorities do not require the ATT for most product classes. In line with the replacement, reduction, and refinement (3Rs) initiative, the test requirement has been deleted from approximately 80 monographs of the European Pharmacopoeia and for the majority of product classes in the United States. For these reasons, it is recommended that the ATT should be consistently omitted world-wide and be removed from pharmacopoeias and other regulatory requirements.

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Section: Release Specifications Are Set According To International Rementioning

confidence: 86%

Section: Historical Data Analysesmentioning

confidence: 99%

Section: Increasing International Convergencementioning

confidence: 99%

See 1 more Smart Citation

Historical Data Analyses and Scientific Knowledge Suggest Complete Removal of the Abnormal Toxicity Test as a Quality Control Test

Garbe

Ausborn

Beggs

et al. 2014

Journal of Pharmaceutical Sciences

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“…The scientific relevance of general safety tests has been questioned since more than 30 years and Halder highlighted the following points: lack of specificity, reproducibility, reliability, and suitability for the intended purpose. She further provided an overview on the progress achieved in various countries and regions; for example, the ATT was removed from European Pharmacopoeia monographs for batch release testing of human vaccines already in 1997 [ 7 ], but only recently also for the production step. The US-FDA revoked the GST in 2015, whereas the WHO ECBS announced in 2018 the discontinuation of the Innocuity Test in all future WHO recommendations, guidelines and manuals for biological products published in the Technical Report Series.…”

Section: Animal Use and 3rsmentioning

confidence: 99%

Animal testing for vaccines. Implementing replacement, reduction and refinement: challenges and priorities

Akkermans

Chapsal²,

Coccia

et al. 2020

Biologicals

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Transition to in vitro alternative methods to in vivo in vaccine release testing and characterization, the implementation of the consistency approach, and a drive towards international harmonization of regulatory requirements are most pressing needs in the field of vaccines. It is critical for global vaccine community to work together to secure effective progress towards animal welfare and to ensure that vaccines of ever higher quality can reach the populations in need in the shortest possible timeframe. Advancements in the field, case studies, and experiences from Low and Middle Income Countries (LMIC) were the topics discussed by an international gathering of experts during a recent conference titled “ Animal Testing for Vaccines – Implementing Replacement, Reduction and Refinement: Challenges and Priorities ”. This conference was organized by the International Alliance for Biological Standardization (IABS), and held in Bangkok, Thailand on December 3 and 4 2019. Participants comprised stakeholders from many parts of the world, including vaccine developers, manufacturers and regulators from Asia, Europe, North America, Australia and New Zealand. In interactive workshops and vibrant panel discussions, the attendees worked together to identify the remaining barriers to validation, acceptance and implementation of alternative methods, and how harmonization could be promoted, especially for LMICs.

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“…In particular, there were concerns on its lack of specificity, poor reproducibility and its scientific relevance was questioned in global meetings and publications. In recent decades the implementation of Good Manufacturing Practices (GMP), the use of validated manufacturing processes as well as appropriate and more stringent quality control measures in production of pharmaceutical and biological products have rendered its use as questionable [ 2 , 3 ]. In 2016 the 17th International Conference of Drug Regulatory Authorities (ICDRA) held in South Africa, with participance of most of national regulatory authorities in the world, made recommendations to WHO to consider removal of the innocuity test as a requirement for lot release from WHO vaccine guidelines but encourage maintenance of some capacity to perform this test, if needed [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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

Lei

Knežević

et al. 2020

Biologicals

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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 .

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Elimination of abnormal toxicity test for sera and certain vaccines in the European Pharmacopoeia

Cited by 30 publications

References 1 publication

Historical Data Analyses and Scientific Knowledge Suggest Complete Removal of the Abnormal Toxicity Test as a Quality Control Test

Historical Data Analyses and Scientific Knowledge Suggest Complete Removal of the Abnormal Toxicity Test as a Quality Control Test

Animal testing for vaccines. Implementing replacement, reduction and refinement: challenges and priorities

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

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