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How Bio-questionable are the Different Recombinant Human Erythropoietin Copy Products in Thailand?

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ABSTRACT

Purpose

The high prevalence of pure red cell aplasia in Thailand has been associated with the sharp increase in number of recombinant human erythropoietin (rhEPO) copy products, based on a classical generic regulatory pathway, which have entered the market. This study aims to assess the quality of rhEPO copy products being used in Thailand.

Methods

Twelve rhEPO copy products were purchased from pharmacies in Thailand, shipped under controlled cold chain conditions to the Netherlands and characterized using (1) high performance size-exclusion chromatography, (2) asymmetrical flow field-flow fractionation, (3) sodium dodecyl sulfate polyacrylamide gel electrophoresis in combination with (4) Western blotting and additionally tested for (5) host cell protein impurities as well as (6) endotoxin contamination.

Results

Some of the tested rhEPO copy products showed high aggregate levels and contained a substantial amount of protein fragments. Also, one of rhEPO copy products had a high endotoxin level, exceeding the FDA limit.

Conclusions

Our observations show that some of the tested copy products on the Thai market differ significantly from the originator rhEPO product, Epogen®. This comparison study supports a link between the quality attributes of copy rhEPO products and their immunogenicity.

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Abbreviations

AF4:

asymmetrical flow field-flow fractionation

CHO:

Chinese hamster ovary

EPO-BRP:

erythropoietin—biological reference product

FDA:

Food and Drug Administration

HMW:

high molecular weight

HP-SEC:

high performance size exclusion chromatography

HSA:

human serum albumin

LAL:

limulus amebocyte lysate

LMW:

low molecular weight

PRCA:

pure red cell aplasia

R-AUC:

relative-area under the curve

RHEPO:

recombinant human erythropoietin

SDS-PAGE:

sodium dodecyl sulfate polyacrylamide gel electrophoresis

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by an educational grant from HEXAL AG, Holzkirchen, Germany. The authors also thank Linda McPhee for critically reviewing the manuscript. L.A.H., V.B., W.J., S.R., K.P., A.A. and H.S. declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands

    Liem Andhyk Halim, Vera Brinks & Huub Schellekens

  2. Division of Drug Delivery Technology Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

    Wim Jiskoot & Stefan Romeijn

  3. Division of Nephrology, Faculty of Medicine, Chulalongkorn University, 1873 Pathumwan, Bangkok, Thailand, 10330

    Kearkiat Praditpornsilpa

  4. Department of Pharmacology, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayuthaya Road, Rajathevi, Bangkok, 10400, Thailand

    Anunchai Assawamakin

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  1. Liem Andhyk Halim
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  2. Vera Brinks
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Correspondence to Huub Schellekens.

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Halim, L.A., Brinks, V., Jiskoot, W. et al. How Bio-questionable are the Different Recombinant Human Erythropoietin Copy Products in Thailand?. Pharm Res 31, 1210–1218 (2014). https://doi.org/10.1007/s11095-013-1243-9

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  • DOI: https://doi.org/10.1007/s11095-013-1243-9

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