Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Preserving or maintaining micro-organism
Reexamination Certificate
2001-07-12
2002-06-11
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Preserving or maintaining micro-organism
C514S635000, C514S642000, C424S078040, C424S201100, C424S202100, C424S204100, C424S209100, C424S211100, C424S210100, C435S236000
Reexamination Certificate
active
06403363
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of preventing or reducing microbial, and in particular, bacterial, contamination of viral vaccines such as influenza vaccines, during manufacture.
BACKGROUND OF THE INVENTION
Current influenza vaccines consist of either inactivated whole virus, disrupted virus (split vaccines) or purified preparations of the membrane glycoproteins haemagglutinin (HA) and neuraminidase (NA) sub-unit vaccines. Haemagglutinin and neuraminidase are the antigens to which protective antibody responses are directed, haemagglutinin being the major protective antigen. The haemagglutinin and neuraminidase antigens may be present in the vaccine in the form of rosettes, e.g. particles with a radius in the range 10 to 25 nanometer. One example of a commercially available haemagglutinin
euraminidase preparation is the “Fluvirin” product manufactured and sold by Evans Medical Limited of Speke, Merseyside, United Kingdom; see also S. Renfrey and A. Watts, Vaccine, 1994, Volume 12, Number 8, pp 747-752.
During the manufacture of viral vaccines such as the aforementioned influenza vaccines, preservatives can be used to reduce or prevent microbial contamination of the solutions isolated from the viral growth medium, and subsequent solutions containing partially purified or purified viral antigens. For example, with viral vaccines such as influenza vaccines in which eggs are used as the viral growth medium, a preservative can be added to the allantoic fluid harvested from the eggs after incubation with the virus. The purpose of the preservative is to reduce levels of contamination due to the inherent non-sterility of the egg, and also to reduce or prevent bacterial contamination during subsequent processing of the harvested allantoic fluid.
One preservative commonly used in vaccine production is the organo mercurial compound thiomersal, the full chemical name for which is sodium ethylmercurithiosalicylate. Thiomersal is generally effective as a preservative in vaccine production, but a major problem is that its use results in considerable quantities of mercury-containing waste being produced. In line with current and intended legislation, mercury-containing waste needs to be disposed of very carefully in order to avoid adverse effects on the environment.
In order to avoid releasing mercury-containing waste into the environment, there are several possible options. Firstly, the waste can be treated to remove mercury, and this approach is exemplified by U.S. Pat. Nos. 5,437,797 and 5,154,833. Another alternative is to discontinue the use of preservatives altogether, but a more preferable option in view of the difficulties in maintaining solution sterility in the absence of preservatives would be to find an alternative preservative which is at least as effective as thiomersal but which does not suffer from the same disposal and toxicity problems.
In order to be suitable for use in vaccine manufacture, a preservative must meet a number of very stringent criteria. Firstly, the preservative must be effective against the microbial species typically found in the vaccine production environment. Secondly, it must be compatible with the virus and the viral antigens and, if added during the viral growth phase, should not have any adverse effects on the growth of the virus in the medium. Thirdly, the preservative should be compatible with the production process and should not cause problems during the further processing of the vaccine composition. Fourthly, the preservative should be one which does not have an adverse effect on the environment, thereby minimising the need to take additional steps during its disposal.
It has now been found that the above criteria can be met using a polybiguanide preservative.
SUMMARY OF THE INVENTION
In a first aspect, the principles of the invention provide a method of preventing or reducing bacterial contamination of a viral vaccine, wherein the method comprises adding to a solution containing virus or virus antigen, an effective amount of a preservative composition containing polybiguanide.
Accordingly, in a first aspect, the invention provides a method of preventing or reducing bacterial contamination of a viral vaccine, which method comprises adding to a solution containing vaccine virus or virus antigen an effective preserving amount of a preservative composition containing polybiguanide.
In another aspect, the invention provides a preserved viral vaccine composition comprising a solution containing vaccine virus or virus antigen and an effective preserving amount of a preservative composition containing polybiguanide.
In one embodiment of the invention, the solution may be the final form of the vaccine immediately prior to or after filling into dosage containers such as vials, ampoules and the like, particularly multi-dose containers.
In another embodiment, the solution may be a process solution, the term “process solution” as used herein referring to any solution containing the vaccine virus or viral antigens derived from the vaccine virus up to the point at which the vaccine is filled into dosage containers.
Examples of “process solutions” are solutions of virus harvested from the medium in which the virus has been grown, such as the allantoic fluid from eggs, or the supernatant from a cell culture. Other examples include solutions containing disrupted virus and free antigens such as surface antigens, as well as partially purified and purified solutions of antigens. The term “process solution” can also include the viral growth medium itself, the preservative being added to the medium at the beginning of or during the growth phase of the virus.
The vaccine can contain a single strain of virus, or antigens from a single strain of virus, or it can contain a blend of antigens from different viral strains. For example, in the case of influenza vaccines, the vaccine can contain antigens from one or more strains of influenza A together with antigens from one or more strains of influenza B.
The polybiguanide is typically a polymeric compound containing the repeating unit:
—[NH—C(NH)—NH—C(NH)—NH—R]
n
—
wherein R is a divalent hydrocarbon chain, preferably having at least 2 carbon atoms; and n represents the number of repeating units and is at least 2.
More usually, n is in the range from 3 to 20, for example from 4 to about 16, preferably from 5 to 12, and more preferably from 5 to 7. The values given for n are the average values, since a given solution of a polybiguanide will frequently contain a mixture of molecules of differing chain lengths. For example, a solution of a polybiguanide can contain molecules in which n ranges from 1 to about 40. A preferred polybiguanide is one in which the average value for n is 5.5.
The molecular weight of the polymer, excluding the weight of any acid present in the form of acid addition salts of the polymer, may be up to 12,000 or more but is usually less than 5000, and is preferably in the range from about 750 to about 3000.
A presently preferred polybiguanide is poly(hexamethylene) biguanide, the INN for which is polyhexanide. One example of a proprietary product including poly(hexamethylenebiguanide) is “Cosmocil CQ” (RTM) manufactured by Zeneca PLC.
The polybiguanide can be presented in the form of an acid addition salt, and examples of such salts include the salts formed with hydrochloric acid, sulphuric acid, phosphoric acid and acetic acid, a presently preferred salt being the hydrochloride.
The amount of polybiguanide, as defined above, is an effective preserving amount, i.e. an amount which is at least sufficient to preserve the solution. Thus the amount is at least sufficient to provide a biostatic effect, but preferably is an amount sufficient to have a biocidal effect. The amount of polybiguanide is generally selected so as to give at least a one log reduction in the level of microbial contaminants during five hours. More preferably the amount is selected so as to give at least a two log reduction in microbial contaminants over 5 hours. The concentration of the polybiguanide, f
Greally Declan
Lawrence Michelle Irene Gregarach
Brown Stacy S.
Clement, Esq. Candice J.
Heslin Rothenberg Farley & & Mesiti P.C.
Medeva Europe Limited
Park Hankyel T.
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