title: Historical data analyses and scientific knowledge suggest complete removal of the abnormal toxicity test as a quality control test.
abstract: 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.
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Global Technical Operations, Basel, Switzerland. Electronic address: joerg.garbe@roche.com.
authors.forename: Joerg H O
authors.initials: JHO
authors.lastname: Garbe
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Global Technical Operations, Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ausborn
authors.affiliation: AbbVie Ltd., Maidenhead, England.
authors.forename: Claire
authors.initials: C
authors.lastname: Beggs
authors.affiliation: F. Hoffmann-La Roche Ltd., Roche Pharma and Early Development, Roche Innovation Center, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Bopst
authors.affiliation: MSD Europe Inc., Brussels, Belgium.
authors.forename: Angelika
authors.initials: A
authors.lastname: Joos
authors.affiliation: GlaxoSmithKline, Moscow, Russian Federation.
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Kitashova
authors.affiliation: Genzyme, Moscow, Russian Federation.
authors.forename: Olga
authors.initials: O
authors.lastname: Kovbasenco
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Global Technical Operations, Basel, Switzerland.
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Schiller
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Schwinger
authors.affiliation: Bristol-Myers Squibb, Moscow, Russian Federation.
authors.forename: Natalia
authors.initials: N
authors.lastname: Semenova
authors.affiliation: MSD Pharmaceuticals, Moscow, Russian Federation.
authors.forename: Lilia
authors.initials: L
authors.lastname: Smirnova
authors.affiliation: Eisai Ltd., Hatfield, England.
authors.forename: Fraser
authors.initials: F
authors.lastname: Stodart
authors.affiliation: Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: Thomas
authors.initials: T
authors.lastname: Visalli
authors.affiliation: MSD Europe Inc., Brussels, Belgium.
authors.forename: Lisette
authors.initials: L
authors.lastname: Vromans
mesh_terms: D023401:Animal Use Alternatives; D000818:Animals; D003257:Consumer Product Safety; D004340:Drug Contamination; D004355:Drug Stability; D005189:False Positive Reactions; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D010602:Pharmacopoeias as Topic / Q000266:history / Q000592:standards; D011786:Quality Control; D015203:Reproducibility of Results; D018570:Risk Assessment; D013678:Technology, Pharmaceutical / Q000266:history / Q000379:methods* / Q000592:standards; D018675:Toxicity Tests / Q000266:history / Q000592:standards; D014612:Vaccines / Q000266:history / Q000592:standards / Q000633:toxicity*
chemical_list: D014612:Vaccines
keywords: abnormal toxicity test; analysis; biotechnology; general safety; innocuity test; pharmacopoeia; quality control; regulatory science; toxicity; vaccines