Examination of the biological safety of a drug derived from mammalian organs.

In order to assess the safety of a biological drug, a variety of factors have to be examined and then brought into an overall context considering the specific aspects of each individual product. Quoting Trasylol, the aprotinin (CAS 9087-70-1) drug extracted from bovine lungs as an example for such an approach, the complete procedure is discussed. The rationale of a safety concept, its implementation including safety related validation studies, and the combinatorial evaluation of results from these validations with underlying specificities for manufacture allow for an overall safety assessment. Validation of the removal/inactivation capacity of the manufacturing process for bovine spongiform encephalopathy (BSE) and various viruses showed high reduction potentials. These results constitute the cornerstone for the conclusion that Trasylol is safe with regard to BSE and viruses.

Reduction of the infectivity of scrapie agent as a model for BSE in the manufacturing process of Trasylol.

The Trasylol manufacturing process was investigated with respect to its capacity for the inactivation/removal of infectivity causing bovine spongiform encephalopathy (BSE). Four process steps were selected for this investigation and scaled down to laboratory scale. Authentic samples of bovine lungs used in the Trasylol manufacturing plant were taken and spiked in laboratory scale experiments with high infectious titres of the rodent adapted scrapie strain ME 7 which served as model for BSE. After performing the respective process steps the output samples collected were tested in C57BL mice carrying the Sinc gene. An overall reduction of the infectious agent in the order of 18 log10 was observed, indicating a very high capacity of the Trasylol process for the inactivation/removal of the BSE/scrapie agent. The discussed safety strategy for the product leads to the conclusion that Trasylol is BSE safe.

Transmissible spongiform encephalopathies (TSE): minimizing the risk of transmission by biological/biopharmaceutical products: an industry perspective.

Several guidelines and recommendations have been published on assessing the potential risk of a biological product being contaminated with an agent causing a Transmissible Spongiform Encephalopathy (TSE). Basic principles which can be used during the manufacturing of biological products to minimize the risk of transmission of TSE agents include the following: (i) obtaining animals, tissues or animal-derived raw materials from countries in which the relevant TSE agent is reported to be absent; (ii) screening animal-derived material for appropriate animal husbandry, feeding practices, health certification, tissue procurement and processing practices, and human-derived material for appropriate medical history information and, if relevant, plasma donor exclusion criteria; (iii) selection of tissue source of raw material with reference to potential risk for harbouring or amplifying TSE agents; (IV) human tropism of TSE agent of concern; (v) quantity of raw material used to manufacture a dose of product; (vi) number of daily doses required for indication; (vii) route of administration; (viii) indication and age of patient; and (ix) clearance capabilities by the product purification scheme. A risk evaluation will be represented for Trasylol (Aprotinin) which is manufactured from bovine lung tissue. Trasylol is a protease inhibitor used in the control of blood loss during open heart surgery. Bovine Spongiform Encephalopathy (BSE) is a concern when a product is derived from a bovine source. Even though only bovine lung tissue from BSE-free countries is used to manufacture Trasylol, it was decided, based on the primary tissue source selection, to evaluate the potential of the purification process to clear a TSE agent. Duplicate "spiking experiments" were performed using a mouse-adapted strain of scrapie as the model for BSE. Four steps in the purification process were evaluated. Titration of "spiked" loading material and output samples was performed at dilutions of 10(-4) to 10(-7) and undiluted to 10(-7), respectively. The sum of the purification steps evaluated provided a clearance factor in excess of 18 log10 for a TSE agent. An overall safety factor of 30 is obtained using the notification document issued by the Federal Health Office (Germany), dated February 16, 1994, on "Safety Requirements for Medical Products Derived from Body Constituents of Cattle, Sheep, or Goats to Avoid Risk of Transmission of BSE or Scrapie". Based on a six-parameter risk assessment, this document considered a product of low-risk for transmitting TSE agents if obtaining or exceeding a score of 20. Principles for minimizing the risk of transmission of TSE agents in products derived from primary tissues are contrasted to strategies for biotechnology products.