Low pH, caprylate incubation as a second viral inactivation step in the manufacture of albumin: Parametric and validation studies

Anna Johnston, Eric Uren, David Johnstone, John Wu

研究成果: 雜誌貢獻文章

37 引文 (Scopus)

摘要

Caprylate has long been used as a stabiliser for albumin solutions, as well as a precipitation agent for immunoglobulins, ceruloplasmin and more recently in removing contaminants during albumin purification. Its virucidal properties have been explored and it has been proposed that the non-ionised form of the caprylate acid disrupts the integrity of the lipid bilayer and membrane associated proteins of enveloped viruses. The studies reported here further explore the use of this fatty acid to inactivate lipid-enveloped viruses in albumin manufactured for therapeutic use. Caprylate concentrations considered above solubility limits were adopted. Acidic pH was used to maximise the percentage of non-ionised caprylate and elevated temperatures were used to enhance inactivation rates. Parameters were manipulated to determine the relationship between pH, temperature and caprylate: protein ratio. These studies demonstrated that elevated temperature and low pH were critical in achieving significant reduction in virus infectivity and that the rate and extent of inactivation was sensitive to changes in caprylate:protein ratio and to changes in pH. Final inactivation conditions of 10% w/v protein, 16 mM caprylate, pH 4.5 and 30°C were chosen to minimise protein dimerisation and to achieve greater than 4 log10inactivation of the most resistant virus tested, bovine viral diarrhoea virus. Validation studies using both model and relevant blood borne viruses demonstrated this to be a robust and effective viral inactivation step and is complementary to the commonly used pasteurisation viral inactivation step, thus providing an additional margin of safety to this valuable therapeutic blood product.
原文英語
頁(從 - 到)213-221
頁數9
期刊Biologicals
31
發行號3
DOIs
出版狀態已發佈 - 一月 1 2003
對外發佈Yes

指紋

Caprylates
Virus Inactivation
Validation Studies
Viruses
Albumins
Proteins
Blood
Temperature
Pasteurization
Protein Multimerization
Lipid bilayers
Dimerization
Bovine Viral Diarrhea Viruses
Ceruloplasmin
Fatty acids
Lipid Bilayers
Lipids
Therapeutic Uses
Purification
Solubility

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Immunology and Microbiology(all)
  • Pharmacology

引用此文

Low pH, caprylate incubation as a second viral inactivation step in the manufacture of albumin : Parametric and validation studies. / Johnston, Anna; Uren, Eric; Johnstone, David; Wu, John.

於: Biologicals, 卷 31, 編號 3, 01.01.2003, p. 213-221.

研究成果: 雜誌貢獻文章

@article{c854f12709424fc3bc5c39298f452d02,
title = "Low pH, caprylate incubation as a second viral inactivation step in the manufacture of albumin: Parametric and validation studies",
abstract = "Caprylate has long been used as a stabiliser for albumin solutions, as well as a precipitation agent for immunoglobulins, ceruloplasmin and more recently in removing contaminants during albumin purification. Its virucidal properties have been explored and it has been proposed that the non-ionised form of the caprylate acid disrupts the integrity of the lipid bilayer and membrane associated proteins of enveloped viruses. The studies reported here further explore the use of this fatty acid to inactivate lipid-enveloped viruses in albumin manufactured for therapeutic use. Caprylate concentrations considered above solubility limits were adopted. Acidic pH was used to maximise the percentage of non-ionised caprylate and elevated temperatures were used to enhance inactivation rates. Parameters were manipulated to determine the relationship between pH, temperature and caprylate: protein ratio. These studies demonstrated that elevated temperature and low pH were critical in achieving significant reduction in virus infectivity and that the rate and extent of inactivation was sensitive to changes in caprylate:protein ratio and to changes in pH. Final inactivation conditions of 10{\%} w/v protein, 16 mM caprylate, pH 4.5 and 30°C were chosen to minimise protein dimerisation and to achieve greater than 4 log10inactivation of the most resistant virus tested, bovine viral diarrhoea virus. Validation studies using both model and relevant blood borne viruses demonstrated this to be a robust and effective viral inactivation step and is complementary to the commonly used pasteurisation viral inactivation step, thus providing an additional margin of safety to this valuable therapeutic blood product.",
keywords = "Albumin, Caprylate, Stability, Viral inactivation",
author = "Anna Johnston and Eric Uren and David Johnstone and John Wu",
year = "2003",
month = "1",
day = "1",
doi = "10.1016/S1045-1056(03)00062-9",
language = "English",
volume = "31",
pages = "213--221",
journal = "Biologicals",
issn = "1045-1056",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Low pH, caprylate incubation as a second viral inactivation step in the manufacture of albumin

T2 - Parametric and validation studies

AU - Johnston, Anna

AU - Uren, Eric

AU - Johnstone, David

AU - Wu, John

PY - 2003/1/1

Y1 - 2003/1/1

N2 - Caprylate has long been used as a stabiliser for albumin solutions, as well as a precipitation agent for immunoglobulins, ceruloplasmin and more recently in removing contaminants during albumin purification. Its virucidal properties have been explored and it has been proposed that the non-ionised form of the caprylate acid disrupts the integrity of the lipid bilayer and membrane associated proteins of enveloped viruses. The studies reported here further explore the use of this fatty acid to inactivate lipid-enveloped viruses in albumin manufactured for therapeutic use. Caprylate concentrations considered above solubility limits were adopted. Acidic pH was used to maximise the percentage of non-ionised caprylate and elevated temperatures were used to enhance inactivation rates. Parameters were manipulated to determine the relationship between pH, temperature and caprylate: protein ratio. These studies demonstrated that elevated temperature and low pH were critical in achieving significant reduction in virus infectivity and that the rate and extent of inactivation was sensitive to changes in caprylate:protein ratio and to changes in pH. Final inactivation conditions of 10% w/v protein, 16 mM caprylate, pH 4.5 and 30°C were chosen to minimise protein dimerisation and to achieve greater than 4 log10inactivation of the most resistant virus tested, bovine viral diarrhoea virus. Validation studies using both model and relevant blood borne viruses demonstrated this to be a robust and effective viral inactivation step and is complementary to the commonly used pasteurisation viral inactivation step, thus providing an additional margin of safety to this valuable therapeutic blood product.

AB - Caprylate has long been used as a stabiliser for albumin solutions, as well as a precipitation agent for immunoglobulins, ceruloplasmin and more recently in removing contaminants during albumin purification. Its virucidal properties have been explored and it has been proposed that the non-ionised form of the caprylate acid disrupts the integrity of the lipid bilayer and membrane associated proteins of enveloped viruses. The studies reported here further explore the use of this fatty acid to inactivate lipid-enveloped viruses in albumin manufactured for therapeutic use. Caprylate concentrations considered above solubility limits were adopted. Acidic pH was used to maximise the percentage of non-ionised caprylate and elevated temperatures were used to enhance inactivation rates. Parameters were manipulated to determine the relationship between pH, temperature and caprylate: protein ratio. These studies demonstrated that elevated temperature and low pH were critical in achieving significant reduction in virus infectivity and that the rate and extent of inactivation was sensitive to changes in caprylate:protein ratio and to changes in pH. Final inactivation conditions of 10% w/v protein, 16 mM caprylate, pH 4.5 and 30°C were chosen to minimise protein dimerisation and to achieve greater than 4 log10inactivation of the most resistant virus tested, bovine viral diarrhoea virus. Validation studies using both model and relevant blood borne viruses demonstrated this to be a robust and effective viral inactivation step and is complementary to the commonly used pasteurisation viral inactivation step, thus providing an additional margin of safety to this valuable therapeutic blood product.

KW - Albumin

KW - Caprylate

KW - Stability

KW - Viral inactivation

UR - http://www.scopus.com/inward/record.url?scp=0041519036&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041519036&partnerID=8YFLogxK

U2 - 10.1016/S1045-1056(03)00062-9

DO - 10.1016/S1045-1056(03)00062-9

M3 - Article

C2 - 12935811

AN - SCOPUS:0041519036

VL - 31

SP - 213

EP - 221

JO - Biologicals

JF - Biologicals

SN - 1045-1056

IS - 3

ER -