Keywords
quality control
SPCIA
APTT
sanitary surveillance
How to Cite
Abstract
The aim of this study was to compare the methods of SPCIA and APTT to evaluate the effectiveness of the implementation of APTT as a method for assessing the safety and efficacy of unfractionated heparins in pharmaceuticals. Five lots of non-fractionated heparins (a sulfated polysaccharide used as anticoagulant) from porcine or bovine origin, and from different producers were comparatively evaluated. They were tested based on the 5th International Standard for Heparin, and they were collected by the Brazilian sanitary authorities for evaluating their purity and anticoagulant potency at the National Institute for Quality Control in Health (INCQS). Two methodologies were employed: sheep plasma coagulation inhibition assay (SPCIA) and activated partial thromboplastin time technique (APTT). An excellent correlation between the both methodologies was found, and it showed that technique is easier, faster and objective due to the use of a coagulometer for measuring the clot-forming time, instead of SPCIA assay which uses the subjective visual determination of the coagulation degree. The implementation and execution of APTT technique and the concomitant use of SPCIA assay will improve the technique sensitivity for assessing the non-fractionated heparins safety and efficacy.References
1. Silva KR, Costa R, Rached RA, Martinelli Filho M, Caldas JGMP, Carnevale FC, et al. Warfarin prevents venous obstruction after cardiac devices implantation in high-risk patients: partial analysis. Rev Bras Cir Cardiovasc. 2008;23(4):542-9.
2. Gracher AHP. Avaliação do potencial anticoagulante e antitrombótico de polissacarídeos nativos e quimicamente sulfatados de basidomicetos [tese de doutorado]. Curitiba (PR): Universidade Federal do Paraná, 2010.
3. Carvalho LCD.Inibidores seletivos da trombina, novo tratamento nticoagulante em doentes com fibrilação auricular. Aplicação do conceito dos três Rs nos ensaios de Controle da Qualidade de imunobiológicos para Raiva [tese de doutorado]. Porto. Universidade do Porto, 2011.
4. Harvey RA,Champe PC. Farmacologia Ilustrada. 2. ed. Porto Alegre (RS): Artmed; 1998.
5. Mauro MFZ, Wang R, Cristóvão SAB, Salman AA, Oliveira JB, Mangione JA.Novos inibidores da trombina: qual o estado atual das pesquisas? Rev Bras Cir Cardiovasc. 2004;12(3):130-7.
6. Junqueira DRG, Viana GT, Peixoto ERM, Barros FCR, Carvalho MG. Farmacovigilância da heparina no Brasil. Rev Assoc Med Bras. 2011;57(3):328-32.
7. WorldHealth Organization. A WHO Manual STEPS de acidentes vascular cerebrais: enfoque passo a passo para a vigilância de acidentes vascular cerebrais – 2005. [acesso 2012 Jul 29]. Disponível em: [http://www.paho. org/portuguese/ad/dpc/nc/steps-stroke.pdf ].
8. Guerrini M, Beccati D, Shriver Z, Naggi A, Viswanathan K, Bisio A, et al. Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events. Nat Biotech. 2008;26:669-75.
9. Nothenberg M. Heparina adulterada, mais um “negócio da china”. Química e Derivados [on-line], São Paulo, n. 471, 2008. [acesso 2012 fev 17]. Disponível em [http://www.quimicaederivados.com. br/revista/qd471/biofarma/biofarma.html].
10. Sociedade Brasileira de Cirurgia Cardiovascular – SBCCV. Boletim Científico Especial – Heparina 1 [on-line]. [acesso 2012 jul 31]. Disponível em: [http://www.sbccv.org. br/medica/ boletim_ esp08_01_heparina.asp].
11. Wo r l dHealth Organization. A WHO Newsletter of National Drug Regulatory Authorities (DRAs) and WHO have issued international alerts, warning letters to health professionals and information about recalls regarding contaminated heparin sodium injections – 2008. [acesso 2012 jul 30]. Disponível em: [http://www.who.int/medicines/publications/newsletter/PN 2008_2.pdf ].
12.Wu C.China records 155% increase in heparin sodium exports for Q1 [on-line]. [acesso 2012 jan 09]. Disponível em: [http://www.asia-manufacturing.com/news-328-heparin-sodium-pharmaceuticalexports-shenzhenhepalinkbiotech-news2.html].
13. Carlos MML, Freitas PDFS. Estudo da cascata de coagulação sanguínea e seus valores de referência. Acta Vet Bras. 2007;1(2):49-55.
14. Farmacopeia Brasileira. 4ª ed. Parte II, fasc. 5. São Paulo (SP): Atheneu, 2003.
15.Vaccari SF, Liberato BJ, Masiero SMK, Fronza M, Dalmora SL. Avaliação comparativa da atividade biológica de heparinas não-fracionadas em produtos farmacêuticos. Rev Bras Hemat Hemot. 2003;25(2):103-10.
16.UnitedStatesPharmacopeia.Heparin Information. [acesso 2012 ago 08]. Disponível em: [http://www.usp.org/hottopics/heparin.html].
17.WorldHealth Organization. A WHO guide to good manufacturing pratice (GMP) requirements, Part 2: Validation. Chp. 15 Validation of analytical assays [Press]. Genebra; 1997. p. 65-9.
18. Avaliação da Potência da Heparina Sódica – Método de Determinação do Grau de Inibição da Coagulação. In: MANUAL da Qualidade. Rio de Janeiro (RJ): INCQS/FIOCRUZ. Seção 10 (65.3320.005).
19.Melo EI, Pereira MS, Cunha RS, Sá MPL, Mourão PAS.Controle da qualidade das preparações de heparina disponíveis no Brasil: implicações na cirurgia cardiovascular. Rev Bras Cir Cardiovasc. 2008;23(2):169-74.
20.European Pharmacopoeia.Council of Europe [online] – EDQM. CombiStats v. 4.0. [acesso 2011 jul 10]. Disponível em[http://www.combistat.eu/].
21. Siegel S, Castellan Júnior NJ. Estatística não-paramétrica para ciências do comportamento. 2ª ed. Porto Alegre (RS): Artmed; 2006.
22. Dalmora SL, Junior LB, Vaccari SF, Fronza M, Oliveira PR, Rolim CMB.Validation of the anti-factor IIa assay and potency assessment of enoxaparin in pharmaceutical formulations. Farmaco. 2005;60(3):225–9.
23. Moura WC, Gallina NM F, Fuches RM M, Romijn PC, Leite JPG. Validation of a virus neutralization potency test in BHK-21 cells for rabies immunoglobulins in a two-center study. J Virol Meth. 2008;154:7-13.
24. Dalmora SL, Souto RB, Silva LM, Lana AD, Schutkoski R, Vaccari SF. Biological potency evaluation and physicochemical characterization of unfractionated heparins. Rev Bras Hematol Hemoter. 2009;31(5):326-32.
25. Moura WC. Aplicação do conceito dos Três Rs nos ensaios de Controle da Qualidade de imunobiológicos para Raiva [tese de mestrado]. Rio de Janeiro (RJ): Instituto Nacional de Controle de Qualidade em Saúde/Fundação Oswaldo Cruz, 2009.
26. Santos C. Estatística descritiva – Manual de Auto-Aprendizagem. Lisboa: Sílaba; 2007.
27. Cavalheiro Filho C, Chamone DAF, Rached RA, Maffei FH. Heparinas: momento atual. Rev Assoc Med Bras. 2008;54(6). [acesso 2012 jun 15] Disponível em: [http://www.scielo.br/scielo.php ?script= sci_arttext&pid=S0104-423020080006000 01&lng=en&nrm=iso ].
28.Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S. Contaminated heparin associated with adverse clinical events and activation of the contact system. New Engl J Med. 2008;358:2457-67.
29.Dryjski M, Dryjski H. Heparin induced thrombocytopenia. Va s c Endovasc Surg. 1996;11(3):260-9.
30. Gomes WJ, Braile DM. A busca de soluções para o problema das heparinas no mercado nacional. Rev Bras Cir Cardiovasc. 2009;17(2):167-8.
31. Robinson JA, Lewis BE. Plasmapheresis in the management of heparin-induced thrombocytopenia. Semin Hematol. 1999;36(1):29-32.
32. Francis JL, Palmer III GJ, Moroose R, Drexler A. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thoracic Surg. 2003;75:17.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2012 Instituto Adolfo Lutz Journal