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Abstract
Background: Reports from the World Health Organization have suggested that counterfeit medicines
pose a serious problem in developing countries. An investigation of anti-erythropoietin
antibody—mediated pure red cell aplasia in Thailand found evidence of drug smuggling,
which may have serious safety implications.
Objective: This study assessed the authenticity and quality of epoetin alfa samples in Thailand.
Methods: Samples of epoetin alfa—prefilled syringes were collected from the pharmacies at
2 major hospitals (62 samples), 8 retail pharmacies (41 samples), and Thai authorities
(30 samples confiscated from smugglers at 2 airports, and 6 samples from a condominium
used by smugglers). These samples were tested against the European Union Pharmacopeia
specifications for aggregate content in epoetins of <2%. The integrity of epoetin
alfa distribution channels, coldchain processes (maintenance at 2°C–8°C), primary
and secondary packaging components (eg, batch number, expiration date, appearance,
letter size), and company's confidential features (eg, nature of the ink, type and
quality of the paper, other covered features) were also investigated. The main outcome
measures were protein aggregate content, determined by sodium dodecyl sulfate polyacrylamide
gel electrophoresis and Western blotting; and isoform distribution, assessed by isoelectric
focusing and Western blotting.
Results: Epoetin alfa samples obtained from the company's cold-chain and authorized distribution
channels met all quality standards, as did all epoetin alfa samples obtained from
the hospital pharmacies. However, evidence showed that some samples were being smuggled
or sold illegally through certain unauthorized retail pharmacies. The epoetin alfa
samples obtained from both airports and the condominium were stored improperly at
room temperature. Aggregate levels exceeded the specification of <2% in 11 samples
from 2 of the retail pharmacies (range, 1.2%–3.1%), 15 samples from the Dongmuang
Airport (range, 2.2%–17.0%), and all 6 samples from the condominium (range, 10.5%–19.8%).
All samples from the 2 hospitals, 8 retail pharmacies, and Suvarnabhumi Airport had
the authentic 6 isoform bands. Samples from Dongmuang Airport and the condominium
appeared to have the 6 characteristic bands, but positive confirmation was difficult
because of band smearing caused by a high level of aggregates. All features of primary
and secondary packaging were found to be authentic.
Conclusions: This investigation found evidence that some epoetin alfa samples were smuggled into
Thailand without proper cold chain, contained high levels of protein aggregates, and
were sold illegally through certain retail pharmacies. The Thai authorities have intervened
to stop such unauthorized products from reaching patients. Strenuous efforts must
be made to prevent illegal cross-border smuggling of biopharmaceuticals without proper
cold chain because of the serious safety implications for patients in developing countries.
Key words:
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References
- Review of PRCA in Thailand (2004–2007): An update on the investigation into the recent anti-EPO antibody-mediated PRCA cases in Thailand. Johnson & Johnson Pharmaceutical Research and Development, Bangkok, Thailand2008
- Bioequivalence and the immunogenicity of biopharmaceuticals.Nat Rev Drug Discov. 2002; 1: 457-462
- Counterfeit medicines.(Fact sheet no. 275. Revised 14 November 2006 [WHO Web site]) (Accessed June 25, 2008)
- Counterfeit medicines. Bitter pills.BMJ. 2007; 335: 1120-1121
- (Electronic Medicines Compendium, Eprex 2000, 4000, 10000 IU/ml pre-filled syringes. 6.4 Special precautions for storage) (Accessed November 10, 2008)
- Erythropoietin concentrated solutions.Pharmeuropa. January 2002; 14.1 (Accessed February 2, 2009): 94-99
- Technical investigations into the cause of the increased incidence of antibody-mediated pure red cell aplasia associated with Eprex®.European Journal of Hospital Pharmacy Practice. 2004; 5 (Accessed February 2, 2009): 86-91
- Effects of protein aggregates: An immunologic perspective.AAPS J. 2006; 8: E501-E507
- Interferon immunogenicity: technical evaluation of interferon-alpha 2a.J Interferon Cytokine Res. 1997; 17: S15-S21
- A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group.Blood. 1993; 81: 2180-2186
- Biosimilar epoetins: How similar are they?.Euro Hosp Pharm. 2004; 3 (Accessed January 20, 2009): 243-247
- Evaluation of the activity and characterization of recombinant human erythropoietin in pharmaceuticals [in Portuguese].Arq Bras Endocrinol Metab. 2003; 47 (Accessed June 25, 2008): 183-189
- Gaps in the quality and potential safety of biosimilar epoetins in the developing world: An international survey, Presented at the XLIV ERA-EDTA CongressJune 21—24, 2007 (Barcelona, Spain. Abstract SaP350)
- Pure red cell aplasia due to follow-on epoetin.Kidney Int. 2008; 74: 1617-1622
- (FDA) Consumer magazine: Curbing counterfeit drugs [FDA Web site].(September–October 2006) (Accessed June 25, 2008)
- WHO reports counterfeit drugs are a global calamity.Nephrol News Issues. 2007; 21: 22
Article info
Publication history
Accepted:
January 9,
2009
Identification
Copyright
© 2009 Excerpta Medica Inc. All rights reserved. Published by Elsevier Inc.
