How do we assure the quality of biological medicines?

Biological medicines are a rapidly growing area of interest to many pharmaceutical companies, large and small. Under a broad definition they include not only modern high-tech products, such as monoclonal antibodies, enzymes and cytokines, but also older well-established products, such as vaccines and blood products. Despite a long history of standardisation and control of biological medicines, and an elaborate system of licensing and regulation, problems still occur because of their complexity. This review includes historical and regulatory background and three examples of problems seen with biotherapeutics: streptokinase, heparin and TGN1412.

International collaborative study to establish the 3rd International Standard for Streptokinase.

An international collaborative study was organized to calibrate a replacement for the current (2nd) International Standard (IS) for Streptokinase, stocks of which are almost exhausted. Two candidate preparations were assayed against the 2nd IS in a study involving 16 laboratories in 12 countries: preparation 88/824 (coded B), and preparation 00/464 (C and D, coded duplicates). Laboratories could use two methods provided, either a fibrin clot lysis assay or a solution chromogenic method, or an in-house method. Laboratories were encouraged to perform more than one method if possible. With the exception of one laboratory which gave outlying results for preparation 00/464, there was good agreement within and between laboratories and no significant differences between potencies using the different methods employed. This study demonstrates that a solution chromogenic assay is an acceptable format for potency determination of the streptokinase preparations in this study and fibrin is not necessary. It has now been agreed that a solution chromogenic plasminogen activation assay replace the current euglobulin reference method for streptokinase activity determination in the European Pharmacopoeia. Study participants, SSC of the International Society on Thrombosis and Haemostasis and the Expert Committee on Biological Standardization (ECBS) at the World Health Organization approved preparation 00/464 (C,D in the study) as the 3rd IS for Streptokinase with a potency of 1030 IU per ampoule.

TERIMA-2: national extension of thrombolytic treatment with recombinant streptokinase in acute myocardial infarct in Cuba.

AIM: The extension of recombinant streptokinase (rSK) use in Cuba and to evaluate its effect on in-hospital mortality of patients with acute myocardial infarct (AMI). METHODS: A phase IV clinical study was performed in 52 hospitals from the 14 Cuban provinces. Patients (any age) with ST segment elevation or bundle branch block were included if they came less than 12 h after the onset of AMI symptoms, without contraindications for thrombolytic therapy. They received 1.5 x 10(6) IU of rSK (Heberkinasa, Heberbiotec, Havana) intravenously, during one hour. Endpoints were death due to cardiac (pump failure, wall rupture, arrhythmia) or any cause and cardiovascular events at hospital release. RESULTS: The study included 2,923 patients, 22-98 years-old, 74.4% men, which represented 37.2% of the total AMI patients attended at the participating hospitals from November 1992 to May 1995. Aspirin was given to 92.5% and betablockers to 65.3%. AMI was confirmed in 93.5% of the patients. The mean symptoms--rSK infusion time interval was 5.25 h (22.3% of the patients treated within the first 3 h). 302 patients died, 80.1% of them due to cardiac causes, 12 attributed to rSK treatment, and 16 to non-cardiac causes. This 10.4% mortality represents a 4% absolute and a 28.3% relative reduction (179 lives saved per year) as compared to a survey made before rSK treatment was introduced. In a logistic regression analysis, mortality was favored by age, symptoms--infusion time. Killip class, and not having taken aspirin or betablockers. Feminine gender was close to the limit of significance. The more frequent adverse events were arrhythmias and hypotension during infusion. Major bleeding occurred in 27 patients (9 strokes). CONCLUSION: Local recombinant-DNA biotechnology can influence on a major health problem with favorable cost/ and risk/benefit balances, not possible in a developing country with an imported drug. The further extension of this treatment in the country is feasible and recommended, monitored through an appropriate pharmacosurveillance program.

[Streptokinase: correlation between different methods of biological evaluation]. / Estreptoquinasa: correlación entre diferentes métodos de valoración biológica.

A study was carried out to establish an appropriate method for streptokinase (SK) potency determination (biological assay) in order to fulfil the main function of the Instituto Nacional de Medicamentos respecting products marketed in Argentina. The potency of different commercial samples of SK was determined against the International Standard, and three internationally accepted methods were used for this purpose: fibrin plate, clot lysis and chromogenic method. The analysis of results suggests that the fibrin plate method is the least precise and reproducible. The clot lysis and chromogenic methods demonstrated great precision and reproducibility, giving a correlation coefficient of 0.99. It is concluded that both of these methods are best suited to determine potency of SK commercial products.

A collaborative study to establish the second international standard for streptokinase.

An International Standard for Streptokinase--Streptodornase (62/7) has been used to calibrate high purity clinical batches of SK since 1965. An international collaborative study, involving six laboratories, was undertaken to replace this standard with a high purity standard for SK. Two candidate preparations (88/826 and 88/824) were compared by a clot lysis assay with the current standard (62/7). Potencies of 671 i.u. and 461 i.u. were established for preparations A (88/826) and B (88/824), respectively. Either preparation appeared suitable to serve as a standard for SK. However, each ampoule of preparation A (88/826) contains a more appropriate amount of SK activity for potency testing, and is therefore preferred. Accelerated degradation tests indicate that preparation A (88/826) is very stable. The high purity streptokinase preparation, coded 88/826, has been established by the World Health Organisation as the 2nd International Standard for Streptokinase, with an assigned potency of 700 i.u. per ampoule.