Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or... – Inactivation or attenuation; producing viral subunits
Reexamination Certificate
1996-05-14
2003-10-14
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
Inactivation or attenuation; producing viral subunits
C514S002600, C514S021800, C530S382000
Reexamination Certificate
active
06632648
ABSTRACT:
TECHNICAL FIELD
This invention relates to the field of sterilization of products derived from blood and other biological sources. The invention involves heating biologically active products in the presence of trehalose for a time and under conditions sufficient to kill viruses, particularly parvovirus.
BACKGROUND ART
The complete removal of viruses and other contaminants from biologically active products is essential to the production and use of a wide variety of therapeutic and prophylactic products. A number of methods are currently being used. Primarily, these are dry heat treatment, chromatography, solvent-detergent (SD) treatment and pasteurization. These methods all suffer from drawbacks and none has been successful in eliminating all known viruses. There may also be viruses that have not yet been characterized that are not inactivated by these methods. For review, see Cuthbertson et al. (1991)
Blood Separation and Plasma Fractionation
, Wiley-Liss, Inc. pp. 385-435; Mozen (1993)
J. Clin. Apheresis
8:126-130; Ingerslev (1994)
Haemostasis
24:311-323; Dorner et al. (1993)
Virological Safety Aspects of Plasma Derivatives
, Brown, ed., Dev. Biol. Stand., Basel, Karger, vol. 81, pp. 137-143; Mannucci (1993) Vox Sang. 64:197-203; and Hamman et al. (1 994) Vox Sang. 67:72-77.
A wide variety of products with therapeutic utility are derived from biological sources such as plasma and cell lines. Most of the plasma used for fractionation in the United States is obtained by plasmapheresis at collection centers distributed across the country. The centers provide plasma to commercial fractionators in the United States and Europe. About 9 million liters of plasma are collected per year from about 13 million donations. The Red Cross adds approximately 800,000 liters to this number.
Products from human plasma may be classified into several groups: the albumin products; the immune globulins; the cold insoluble globulins; the coagulation products; and the protease inhibitors. The albumin products, also termed fraction V products, are used primarily to restore colloidal osmotic pressure in conditions of shock such as burn, or hemorrhagic shock where fluid loss is a principal problem.
The immune globulins, or “gamma globulins,” are isolated from fraction II and contain a mixture of antibodies representative of the plasma pool source. A number of hyperimmune globulins used for passive immunization are isolated from donor plasma with high levels of protective antibody. The cold insoluble globulins include fibrinogen and von Willebrand's factor.
The coagulation products include the antihemophilic factor VIII and factor IX complex used for replacement therapy in hemophilia A and B, respectively. An activated form of factor IX complex called anti-inhibitor coagulant complex is prepared and used for treating patients with a factor VIII inhibitor. The protease inhibitors include &agr;-1-proteinase inhibitor, also known as &agr;-1-anti-trypsin which is used to treat a congenital deficiency. Antithrombin III is an inhibitor that is also congenitally deficient leading to thrombotic complications.
Other body fluids are the source of therapeutic products. For instance, erythropoietin was previously purified from the blood or urine of aplastic anemia patients. U.S. Pat. No. 4,677,195. High purity albumin has also been obtained from human placentas. Grandgeorge and Veron (1993)
Virological Safety Aspects of Plasma Derivatives
, Brown, ed. Dev. Biol. Stand. Basel, Karger, vol. 81, pp. 237-244. The production of recombinant proteins in the milk of transgenic animals is now a commercial reality.
Numerous therapeutic products are now obtained from cell cultures expressing recombinant proteins. The cell cultures are routinely grown in the presence of animal or human serum. The products are obtained from the cells or from the cell culture supernatant and thus may contain viruses, either from the media or the cells themselves. These products obtained include, but are not limited to, colony stimulating factors, monoclonal antibodies and derivatives thereof, growth factors such as erythropoietin, interleukins. Growth factors alone represent a multimillion dollar industry. For review, see, Erickson (1991)
Sci. Am
., February 1991 pp. 126-127.
Although the risk of viral contamination of proteins derived from cell culture is much less than that associated with plasma products, there is always the risk of viral contamination when dealing with cells. For this reason, products such as monoclonal antibodies are subject to heat treatment in order to inactivate viruses. Furthermore, the addition of human serum albumin (HSA) to stabilize formulations of recombinant proteins is common practice.
The major blood-borne viruses of clinical concern include the hepatitis B and C viruses and the HIV and HTLV retroviruses. With respect to blood derivatives, HTL VI and II and cytomegalovirus (CMB) appear to be cell-associated and thus do not present a risk in cell-free products.
As new viruses are discovered, inactivation protocols are changed to accommodate them. For instance, the finding that the human immunodeficiency virus (HIV) survived standard processing of factor VIII necessitated a change of protocol requiring the addition of HSA to stabilize the product under the new, more severe, conditions. Mozen (1993).
Methods to inactivate HIV and the hepatitis viruses in plasma fractions are known. As described above, heating at 60° C. for 10 hours in the presence of HSA inactivates HIV. Non-A, non-B hepatitis (NANBH) was found to be inactivated in factor VIII and IX preparations by heating at 80° C. for 72 hours in the freeze dried state. Study group of the UK Haemophilia Centre, Directors on Surveillance of Virus Transmission by Concentrates (1988)
Lancet
October 8, pp. 814-816.
In recent years, a few transfusion-transmissible diseases have been identified that, although uncommon from the public health perspective, have both real and potential transfusion impacts for the use of plasma and plasma derivatives as well as cellular products. These include transmission of parvovirus (B19). This etiologic agent appears to be resistant to the current methods used for viral inactivation. Sherwood (1993) Brown, ed.
Virological Safety Aspects of Plasma Derivatives
, Dev. Biol. Stand. Basel, Karger vol. 81, pp. 25-33.
The virus inactivation methods currently in use may also cause changes in the biological activity of the biological products obtained. Immunogenicity of the products is especially of concern where sterilization treatment may induce protein unfolding and/or aggregation. For instance, it has been found that factor VIII concentrates display evidence of FVIII activation, with higher one-stage than two-stage potencies, more rapid FXa generation, and increased lower molecular weight polypeptides. Viral inactivation procedures may also induce changes in non-FVIII components and these may be partly responsible for the immunosuppressive activity of some of these concentrates. Barrowcliffe (1993)
Virological Safety Aspects of Plasma Derivatives
Brown, ed. Dev. Biol. Stand. Basel, Karger, vol. 81, pp. 125-135.
Notable changes in immune system functions both in vitro and ex vivo have been found in patients frequently exposed to biologically derived products. In HIV-negative patients, changes include decreased numbers and functions of immune competent cells as assessed by their response to stimuli and in terms of markers of their cellular turnover. These changes are likely to occur when chronic viral disease is present. Furthermore denatured allogeneic protein impurities of factor concentrates and other contaminants may also be responsible for immunosuppression. See, Ingerslev (1994) for review.
Human parvovirus is a recently discovered agent that was given the code name B19. Cossart et al. (1975) Lancet 1:72-73. It is a very small (24 nm) single-stranded DNA virus with a very simple protein coat, but no lipid outer envelope. It causes a transient viraemia of 1-2 weeks but can achieve extraordinarily high circulating virus t
Alcock Robert A.
Kampinga Jaap
Elan Drug Delivery Limited
Saucier Sandra E.
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