Impact of illegal trade on the quality of epoetin alfa in Thailand

Fotiou, Fotis; Aravind, S.R.; Wang, Pingping; Nerapusee, Osot

doi:10.1016/j.clinthera.2009.02.014

Cited by 37 publications

(28 citation statements)

References 6 publications

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“…Therefore, further investigation may be warranted of the role of unfolding and formation of irreversible dimers/aggregates as a root cause in the development of neutralising antibodies with epoetins. This suggestion is further supported by a recent report implicating aggregation as the root cause of PRCA cases following inappropriate transport and storage of Eprex ® (12). …”

Section: Discussionsupporting

confidence: 57%

“…The results of the investigations could explain the root cause of the occurrence of two cases of neutralizing antibodies in an investigational clinical trial, and adds tungsten-induced unfolding to the list of previously described root causes for PRCA, among which are leachates from the primary packaging acting as adjuvants and heat-induced aggregation (4,5,12). Our finding may also be more broadly applicable to this and other classes of therapeutic proteins and may contribute to a better understanding of immunogenicity of biopharmaceuticals.…”

Section: Discussionmentioning

confidence: 93%

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Tungsten-Induced Denaturation and Aggregation of Epoetin Alfa During Primary Packaging as a Cause of Immunogenicity

et al. 2011

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PurposeFollowing two cases of neutralizing antibodies to epoetin alfa in an investigational clinical study, a small number of individual syringes of two drug product batches were found to contain unusually high levels of aggregation at the end of the clinical trial.MethodsWe undertook an extensive analytical approach to determine the root-cause of the increased aggregation in the affected batches.ResultsSoluble tungsten was found in the syringes, most likely derived from the pins used to manufacture the syringes. Spiking of epoetin alfa with sodium polytungstate or an extract of tungsten pins used to manufacture the syringes induced the formation of aggregates, both dimers that appeared to be covalently linked by disulphide bonds as well as higher-order aggregates. Sodium polytungstate had also a strong denaturing effect on the protein.ConclusionsWe propose tungsten-mediated unfolding and aggregation of epoetin alfa in pre-filled syringes as a potential root cause for increased immunogenicity. This finding may be more broadly applicable to this and other classes of therapeutic proteins.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 93%

Tungsten-Induced Denaturation and Aggregation of Epoetin Alfa During Primary Packaging as a Cause of Immunogenicity

et al. 2011

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“…14 . Counterfeiting has recently, for example, been reported for epoetins 15,16 . For these reasons, we suggest that any copy version of a therapeutic protein, which has not been developed and assessed in line with the scientific principles of a strictly comparative development program against a reference product, should not be termed biosimilar.…”

Section: Second-generation (Next-generation) Biological/biologicmentioning

confidence: 99%

Biosimilars—why terminology matters

Weise

Bielsky²,

Smet³

et al. 2011

Nat Biotechnol

189

154

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“…A classic example of the risk associated with breaking the storage cold chain is the spike of pure red‐cell aplasia cases among the patients treated with recombinant erythropoietin . In one study conducted in Thailand following such a spike, it was found that, in retail pharmacy, 25% of erythropoietin products, presented as solution in prefilled syringes has aggregation level above manufacturer's specification; in smuggled products, this number is 58% …”

Section: Introductionmentioning

confidence: 99%