Document Detail

Evaluation of the immuno-stimulatory potential of stopper extractables and leachables by using dendritic cells as readout.
MedLine Citation:
PMID:  19226629     Owner:  NLM     Status:  MEDLINE    
Recombinant protein pharmaceuticals may bear some risks and undesirable side effects, such as the appearance of immunogenic reactions. The increased incidence of antibody-mediated pure red cell aplasia (PRCA) outside the United States after administration of a human serum albumin (HSA)-free EPREX (recombinant human erythropoietin alpha) formulation was explained with the generation of rubber stopper related leachables, possibly acting as immunogenic adjuvants. In our study, we have investigated the potential of extractable and leachable preparations of three different pharmaceutical relevant stoppers to generate a "danger signal" in a dendritic cell assay. Furthermore, the investigated extractable and leachable preparations were characterized by NMR and a micelle-based polysorbate quantification method. In summary, we could demonstrate that stopper extractables, either generated by extraction or by leaching conditions, were not acting as danger signals for dendritic cells. Instead we identified degradation products of polysorbate 80, oleic acid and follow-up products, occur only under very accelerated conditions (100 degrees C for 4 days) as a potential stimulator for these immune cells. As this degradation did not occur at real-time, the authors however do not consider their finding to be linked to any direct safety implications of polysorbate-containing formulations in clinical practice.
Robert Mueller; Anette Karle; Anne Vogt; Harald Kropshofer; Alfred Ross; Karsten Maeder; Hanns-Christian Mahler
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  98     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-08-31     Completed Date:  2010-01-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3548-61     Citation Subset:  IM    
F. Hoffmann-La Roche Ltd, Formulation R&D Biologics, Pharmaceutical and Analytical R&D, Basel, Switzerland.
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MeSH Terms
Adjuvants, Immunologic / chemistry*,  pharmacology*
Antigens, CD86 / analysis
Chemistry, Pharmaceutical
Chromatography, High Pressure Liquid
Dendritic Cells / drug effects*
Drug Contamination*
Drug Packaging*
Epoetin Alfa / analysis
Excipients / analysis
Magnetic Resonance Spectroscopy
Mass Spectrometry
Monocytes / drug effects
Oleic Acid / analysis
Polysorbates / analysis
Rubber / chemistry
Spectrophotometry, Ultraviolet
Up-Regulation / drug effects
Reg. No./Substance:
0/Adjuvants, Immunologic; 0/Antigens, CD86; 0/Excipients; 0/Micelles; 0/Polysorbates; 112-80-1/Oleic Acid; 113427-24-0/Epoetin Alfa; 9006-04-6/Rubber

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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