Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2000-08-18
2003-11-18
Housel, James (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S006120, C435S034000, C435S091200, C536S025300
Reexamination Certificate
active
06649339
ABSTRACT:
The invention relates to a method for producing a pool of biological sample with assured quality with respect to the load of microorganisms, using nucleic acid amplification methods.
Biological samples, such as plasma donations or batches of cell culture supernatants, can be contaminated with undesired microorganisms, especially viruses or foreign DNA. These contaminations can lead to undesired reactions in preparations that are produced from such biological preparations and are administered to humans.
Above all, human plasma is of extraordinary clinical importance as a starting material for producing plasma derivatives, especially for substitution therapy in a hereditary or;acquired deficiency of plasma components. Pharmaceutical preparations of this kind as a rule are not produced from single donations, but rather from a plasma pool consisting of a very large number of individual donations.
However, when using human plasma care must be taken that it does not contain any infectious agents that could be transferred with the pharmaceutical preparation or with the plasma derivatives. Among infectious agents that could possibly be in the blood are above all viruses that can be transferred through the blood (hematogenic viruses), for example, HI-viruses or hepatitis viruses (A, B, C, D, E or G) as well as parvovirus.
Because of the great demand for drugs that contain plasma derivatives economical production of these drugs is possible only on an industrial scale.
Plasma is obtained from donors and pooled for the production of pharmaceutical preparations. A usual pool consists of about 2000-6000 individual plasma donations. Here there is the risk that the total plasma pool will become contaminated by a single virus-contaminated plasma donation. Although there was already success in processing human albumin to a virus-safe preparation by heating by the end of the first half of the 20
th
century, this was initially not possible with all other drugs obtainable from plasma because of their sensitivity to heat. To this day, although there have been millions of uses of adequately prepared albumin preparations, there have never been infections with viruses occurring in the blood in humans.
In contrast, several viral infections, especially with hepatitis viruses, have been reported with many other drugs produced from plasma and since the 1980s there have been increasing reports of infections with the AIDS virus.
Around 1980 heat treatments were carried out for the first time with the appropriately stabilized factor VIII concentrates with the intention of achieving inactivation of viral contaminants by this. However, at first one had to accept a large loss of factor VIII activity and the actual inactivation potential remained unknown, respectively.
Finally, through improvement of the heat inactivation methods and the use of other new inactivation methods it was possible to produce drugs from plasma that in most cases did not lead to viral infections in the receiver. This development also went hand in hand with improvement of the donor and donation selection with the goal of excluding every donor and donation in which the possibility of viremia and thus a virus-containing plasma existed.
Since a long time it has been attempted either through detection of antigens or antibodies to or against a certain virus in the blood to exclude those donations which give a positive result and not to introduce them into a larger plasma pool that is intended to serve as starting material for the production of blood products. In the case of individual donors who in all tests do not have any symptoms of disease or pathological test results even though certain viruses can be present in their blood even in high concentration for a prolonged period of time. Now the occurrence of such viremias by a specific virus can be unambiguously detected with the aid of an amplification method.
A single plasma donation contaminated with viruses does of course become diluted through the pooling of plasma units, but the detection of viral genome sequences with the aid of amplification reactions is so sensitive that even in these dilutions virus genomes or their sequences respectively are unambiguously determinable, and if they, as mentioned above, fall under a certain detection limit, then they no longer have any clinical relevance as far as the possibility of an infection is concerned.
The EC guideline in accordance with the “EEC Regulatory Document Note for Guidance,” Guidelines for Medicinal Products Derived from Human Blood and Plasma” (Biologicals 1992, 20: 159-164) proposes a quality assurance system for the control of plasma donors or plasma donations. Accordingly, every plasma donation has to be tested with validated tests for the absence of viral markers! such as hepatitis B antigen, HIV-1 and HIV-2 antibodies, since these are an indication of a corresponding viral infection of the plasma donor. Tests to exclude hepatitis C infection are also to be conducted.
According to the European Pharmacopoeia, special tests are supposed to be carried out to determine hepatitis B surface antigen, for hepatitis C virus antibody and for HIV antibodies in every donation (European Pharmacopoeia, 2
nd
Edition, Part II, 1994, pp. 853-4).
The FDA guideline of Mar. 14, 1995 provides a PCR (Polymerase-Chain-Reaction) testing of an end product (immunoglobulin product) as an additional safety factor.
In spite of the proposed tests, it is stressed in the EC guideline that the safety of individual plasma donations by a control of all these virus markers alone is not sufficient. Even if the absence of the said markers in a plasma sample is confirmed, viremia of the donor cannot be excluded. Viral antigens and the corresponding antibodies are not always immediately detectable after an infection. The first markers for a viral infection mostly do not arise until weeks or months after a contact with an infectious material. This critical period of time after an infection and before the occurrence of antibodies is generally characterized as a “window period.” The time after infection in which the first viral markers are detectable, however, varies from virus to virus.
Moreover, it is also known that for many drugs produced from plasma a depletion or inactivation occurs as part of the production process and such products themselves are virus safe to a great extent.
Although virus inactivation of plasma derivatives have been carried out extremely successfully on an industrial scale. Nevertheless in rare cases there have been transmissions of hematogenic viruses like AIDS, hepatitis A, B and C. Therefore it has to be,assumed that virus-contaminated products have been produced by the manufactures in a few production batches in spite of a constant production method (Lancet 340, 305-306 (1992); MMWR 43 (28), 505-509 (1994); Thromb. Haemost. 68, 781 (1992)). The cause of this should probably be sought in an extremely high contamination of certain starting batches. Since only indirect methods are available to exclude virus-contaminated plasma donations in producing the plasma, there is the possibility that the starting material will be so highly contaminated that the otherwise successful virus inactivation and virus depletion methods are no longer sufficient to produce virus-safe end products.
Since the human infectious dosage for most human pathogenic viruses is unknown and at the present is not even determinable in testing the plasma pool, it is desired to pick out every single contamination by identifying the contaminated individual samples. The nucleic acid amplification tests that are used therefore are indeed extremely sensitive, but very costly. So their use is justified with known human pathogenic viruses, while for other microorganisms of which either no human pathogenic effect is known or described or for which only a very high pathogen dosage is infectious, this expenses would not be necessary.
In particular, WO 96/35437 and U.S. Pat. No. 5,591,573—A describe test systems for plasma pools using nucleic acid amplification methods and/or anti
Gessner Matthias
Gross Patricia
Koettnitz Karl
Zerlauth Gerold
Baxter Aktiengesellschaft
Foley Shanon
Heller Ehrman White & McAuliffe
Housel James
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