Ronald Vance Mcintosh

Hepatitis C and haemophilia

EDITOR,--In her editorial on hepatitis C and haemophilia Christine A Lee states that recombinant factor VIII “cannot transmit bloodborne viruses.”1 Although this belief is widely held, it is not correct. All biological substances can harbour infectious agents, and consequently all biopharmaceutical …

The above letter was sent to Drs. Foster and Mclntosh, who offered the following reply

To the Editor: In their recent comment on Aronson’s review of the manufacture of factor VIII (FVIII) concentrate, Foster and McIntoshl seem to have ignored some fundamental aspects of pharmaceutical formulation and historical progression. It has traditionally been the objective of pharmaceutical research and clinical practice, when considering replacement therapy, to present the physician with the purest possible product to substitute for that missing in the patient. Notable examples are insulin, thyroid hormones, and growth hormone. To pretend that the enormous impurity load in intermediate-purity FVIII products is of no consequence, because a totality of data does not exist to confirm that pure products have an advantage, is unwise and a scientifically retrograde philosophy. It encourages a satisfaction with the status quo and inhibits progress. The argument that the addition of excipient to pure products reduces their purity is also invalid. There are many examples of pure drugs that are diluted with excipients of known purity and safety so as to stabilize, solubilize, or dilute to a specific potency. No one would equate such diluted products with the crude drug substance merely because of the presence of the excipient. In the case of FVIII preparations, the human albumin added is of known purity and composition and serves to prevent glass adsorption and to produce a visible powder in the vial. The nonclotting factor protein composition of less pure FVIII products is variable and unknown and can represent up to 99 percent of the product. Inevitably, newly developed products require time for clinical trials to establish all their perceived advantages. In the case of monoclonally purified FVIII and factor IX, this work is proceeding apace in centers throughout the world. Furthermore, manufacturing refinements will inevitably lead to improved yields as experience increases, so that the yield penalties that concern Foster and McIntosh will be very substantially reduced or even eliminated. Finally, I was disappointed to read the now largely irrelevant attempt to argue that payment of plasma donors contributes an automatic reduction in product quality and safety and the image of the paid donor of low socioeconomic class being the norm. Foster and McIntosh know that the fundamental safeguards for donated plasma and plasma-derived products are the sophistication of the screening process, good laboratory practice, and a well-proven virus inactivation procedure at the final product stage. Whether the donor receives payment, or other disguised remuneration, is not an issue.

Process Design for the Inactivation of Viruses in the Manufacture of Pharmaceutical Proteins

The transmission of viruses such as HIV-1 has made the inactivation of viral contaminants a major development area in the manufacture of pharmaceutical proteins from human blood plasma. The risk of infection from biological materials is also an important issue in the manufacture of cell culture derived products. The experience gained in developing different viral inactivation strategies in the production of blood products can be used to help design similar procedures for the production of pharmaceuticals from biosynthetic feed stocks. Ideally the inactivation process should be effective against a broad spectrum of viruses; it should not increase the toxicity or decrease the efficacy of the product; it should be reproducible and ensure that the treated product remains free from subsequent contaminantion. Methods which can be applied when products are sealed in the final container are most likely to fulfil all of these conditions.