Chemical apparatus and process disinfecting – deodorizing – preser – Process disinfecting – preserving – deodorizing – or sterilizing – Using direct contact with electrical or electromagnetic...
Reexamination Certificate
1998-03-23
2001-02-20
Jones, Deborah (Department: 1775)
Chemical apparatus and process disinfecting, deodorizing, preser
Process disinfecting, preserving, deodorizing, or sterilizing
Using direct contact with electrical or electromagnetic...
C422S186000, C422S186300, C250S492100, C250S455110
Reexamination Certificate
active
06190608
ABSTRACT:
The present application is the U.S. national phase under 35 U.S.C. § 371 of International Application No. PCT/BE96/00076, filed Jul. 15, 1996.
OBJECT OF THE INVENTION
The present invention relates to a method for inactivating contaminants in blood products, especially whole blood, plasma, fluids comprising cellular blood compounds, and blood derivatives such as clotting factors (factor VIII, factor IX, von Willebrand's factor and the like), fibrinogen, fibronectin, immunoglobulins, albumin, and the like, including nonnatural products obtained by biological engineering, as well as the apparatus for carrying out the said method.
The present invention also relates to blood products treated by the method of the invention as well as pharmaceutical and/or cosmetic compositions comprising the said blood products.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
The availability of blood products requires, for their use for therapeutic or nontherapeutic purposes, purification techniques which make it possible to obtain products of high purity, and preferably free of contaminants, in particular of viral contaminants.
In blood products, the viral contaminants may be enveloped viruses (HIV, hepatitis B, C, D, E and G viruses, and the like) or nonenveloped viruses (hepatitis A virus, parvovirus, and the like).
For many years, various international or national bodies have introduced increasingly strict standards for the preparation of blood products so as to prevent their application for therapeutic or nontherapeutic purposes when they contain viral contaminants (Council Directives 65/65 EEC, 75/319/EEC & 89/381 EEC).
At the European level, the CPMP standards (CPMP/BWT 268/95 and 269/95) require the use of certain treatments against enveloped or nonenveloped viruses.
It is in particular mentioned in these documents that an inactivation step using heat (dry or steam) or using pasteurization in the preparation of clotting factors is effective against the hepatitis A virus, but would not be very effective against other nonenveloped viruses, in particular parvoviruses.
On the other hand, a treatment comprising a chemical inactivation step (by addition of solvents-detergents) is effective for enveloped viruses but ineffective for treating nonenveloped viruses.
It is also known to use certain chemical agents such as beta-propiolactone, which is effective in the treatment of nonenveloped viruses but has the disadvantage of modifying the treated proteins.
It is also known that certain long treatments using pH modification, below pH 4, or the addition of proteases allows activation of some nonenveloped viruses such as parvoviruses. However, these treatments also modify the conformation and structure of the treated proteins.
Consequently, it is known that, to date, the majority of the physicochemical treatment steps capable of being used to obtain viral inactivation of blood products are either highly toxic, or unacceptably affect the conformation of the treated proteins, or are ineffective for treating nonenveloped viruses, in particular parvoviruses.
Parvoviruses are small nonenveloped DNA viruses which infect numerous animal species, including man (Handbook of Parvoviruses, Vol. 1, pp. 1-30, Disinfection, Sterilization and Preservation, Fourth Edition, Seymour S. Block, Ed. Lea & Febiger, Philadelphia-London). They are endemic in nature and cause a wide variety of diseases whose appearance largely depends on the state of development of the host.
Among these, parvovirus B19 is the only known member of the Parvoviridae family which is pathogenic for man. Likewise, murin parvovirus Hi can also infect man.
Parvovirus B19 infection in a healthy man may be asymptomatic or may induce benign diseases (example: fifth disease in children).
On the other hand, in immunodeficient patients or patients suffering from blood disorders, it may lead to chronic anaemias and to transient aplasias which may be associated with haemolytic anaemias.
Passing through the placenta, it may cause intrauterine death. It exhibits a remarkable tropism for the erythroid lines of human haematopoietic progenitor cells.
A recent epidemiological survey has shown that 50 to 60% of the adult French population and 36% of 1- to 15-year-old children have a positive parvovirus serology.
The process of viral DNA has been demonstrated by genetic amplification (PCR) in a number of batches of purified factor VIII concentrates, regardless of the methods of viral inactivation used.
This has been confirmed by the B19
+
serology detection, without clinical sign, in 85% of haemophilic children who have received, since birth, only highly purified factor VIII concentrate (FVIII THPSD) used in France since 1988, free of any contamination with enveloped viruses (HIV, HBV, HCV) (Y. Lauriau et al.,
1
er congrès de la Société Francaise de Transfusion [1st conference of the French Transfusion Company] (1994)).
This observation indeed demonstrates that, without new methods of viral inactivation, targeted at the selective elimination of parvoviruses, in particular of parvovirus B19, from blood products, the probability of contamination is high.
Parvoviruses are extremely resistant, even at high temperature. Their haemagglutination properties and their infectivity are not affected by chemical treatments, such as chloroform or various acids, and most resist enzymatic digestions using RNase, DNase, papain or trypsin.
STATE OF THE ART
International Patent Application WO95/00631 describes a method of viral inactivation of blood products comprising the addition to these blood products of products which are photoactivable by UVA radiation and which would become toxic for the viruses present in these blood products. This method comprises a step which makes it possible to isolate these toxic reagents from the blood products so that the latter are not contaminated with these toxic agents.
Among these toxic agents, psoralen may be mentioned in particular.
However, this method has the disadvantage that it cannot be guaranteed that the treated blood products will not be completely free of these photoactivable agents which would be capable of denaturing and/or inactivating the treated blood products and causing toxicity in man or animals when they are reinjected repeatedly, even at a low dose, with the treated blood products.
It is also known that it is possible to sterilize a large number of products by subjecting them to ultraviolet radiation. It is in particular known from the document “Sterilization by Ultraviolet Irradiation” (chapter 31, I L SHECHMEISTER) that ultraviolet radiation is capable of destroying contaminants such as viruses, mycoplasmas, bacteria and fungi. Such a radiation may be used in particular in media such as gases or liquids.
It is also known from the document by Chin S. et al. (Blood, volume 86, No. 11, December 1995, p. 4331-4336) to treat blood products with type C ultraviolet radiation in the presence or in the absence of antioxidants such as rutin and to obtain the inactivation of nonenveloped viruses, particularly parvoviruses.
In addition, the methods of viral inactivation of the state of the art can affect the integrity and the activity of blood products (in particular the three-dimensional conformation of clotting factors such as factor VIII) and consequently their activities.
Furthermore, the methods of viral inactivation of the state of the art often exhibit difficulties in relation to their validation, because they exhibit problems of reproducibility or of monitoring. Indeed, certain treatment parameters must be modified or cannot be easily maintained, in particular when the degree of humidity has to be monitored if a treatment is carried out with dry heat. Furthermore, it is difficult to control the various steps of the operating procedures.
AIMS OF THE INVENTION
The present invention aims to obtain a new method and an apparatus for inactivating contaminants present in blood products, which do not exhibit the disadvantages of the state of the art and which are simple, rapid, inexpensive and reproducible.
Another aim of
De Wael Luc
Di Giambattista Mario
Laub Ruth
Croix-Rouge de Beligique Departement Central de Fractionnement
Jones Deborah
Knobbe, Martens. Olson & Bear LLP
McNeil Jennifer
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