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Patent 1340737 Summary

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Claims and Abstract availability

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(12) Patent: (11) CA 1340737
(21) Application Number: 1340737
(54) English Title: PROCESS FOR THE PREPARATION OF PASTEURIZED IMMUNOGLOBULIN PREPARATION
(54) French Title: METHODE POUR L'OBTENTION D'UNE PREPARATION PASTEURISEE D'IMMUNOGLBULINE
Status: Term Expired - Post Grant
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61K 39/395 (2006.01)
  • A61K 38/00 (2006.01)
  • A61L 2/00 (2006.01)
  • A61L 2/16 (2006.01)
  • C07K 16/00 (2006.01)
  • G01N 33/531 (2006.01)
(72) Inventors :
  • MULLER, HANS (Germany)
  • GEIGER, HELMUT (Germany)
(73) Owners :
  • CSL BEHRING GMBH
(71) Applicants :
  • CSL BEHRING GMBH (Germany)
(74) Agent: SMART & BIGGAR LP
(74) Associate agent:
(45) Issued: 1999-09-14
(22) Filed Date: 1987-06-10
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
P 36 19 565.0 (Germany) 1986-06-11

Abstracts

English Abstract


A process for the production of a pasteurized immunoglobulin
preparation is described, which comprises heating a solution of
an immunoglobulin in the presence of a carboxylic acid or one
of its salts and/or of a saccharide until viable pathogens,
which may remain undetected in conventional tests, in particular
hepatitis viruses or HTLV III ("Aids") viruses, are inactivated
i.e. are rendered incapable of reproduction and/or of being
intracellularly or otherwise reproduced. A preparation of this
type can be used for therapy or prophylaxis or as component of
a diagnostic kit.


French Abstract

Est décrit un processus de production d’une préparation d’immunoglobulines pasteurisée, qui consiste à chauffer une solution d’une immunoglobuline en présence d’un acide carboxylique ou de l’un de ses sels ou d’un saccharide jusqu’à ce que les agents pathogènes viables, qui peuvent demeurer non détectés lors des tests classiques de chauffage, en particulier les virus de l’hépatite ou le virus HTLV-III (« sida »), soient inactivés, c’est-à-dire rendus incapables de reproduction ou d’être reproduits à l’intérieur des cellules ou autrement. Une préparation de ce type peut être utilisée pour le traitement ou la prophylaxie ou comme composante d’une trousse de diagnostic.

Claims

Note: Claims are shown in the official language in which they were submitted.


-14-
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a pasteurized
immunoglobulin preparation, which comprises heating a solution
containing up to 5% ethanol and an immunoglobulin in the
presence of one or both of a carboxylic acid or one of its
salts and of a saccharide until viable pathogens are
inactivated.
2. The process as claimed in claim 1, wherein the process
is performed in the presence of a carboxylic acid or one of
its salts and a saccharide.
3. The process as claimed in claim 1, wherein the carboxylic
acid is an aliphatic carboxylic acid which may be substituted.
4. The process as claimed in claim 1, wherein the carboxylic
acid is an aliphatic carboxylic acid which has two to ten
carbon atoms and is substituted with one or more of one or two
additional carboxyl groups, one or two amino groups and one
or more hydroxyl groups.
5. The process as claimed in claim 1, wherein the carboxylic
acid is glycine, glutamic acid, citric acid or tartaric acid.
6. The process as claimed in claim 1, wherein the saccharide
is a mono- or disaccharide.
7. The process as claimed in claim 1, wherein the saccharide
is glucose, fructose, galactose or sucrose.
8. The process as claimed in any one of claims 1 to 6,
wherein the viable pathogens are hepatitis viruses or HIV
viruses.

-15-
9. The use of an immunoglobulin preparation as claimed in
claim 1 for therapy or prophylaxis.
10. The use of an immunoglobulin preparation as claimed in
claim 1 in diagnostic reagent kits.

Description

Note: Descriptions are shown in the official language in which they were submitted.


1340737
A process for the preparation of a pasteurized
immunoglobulin preparation
The invention :relates to a process for the production of
an immunoglobu:Lin preparation, in which, for the purpose
of inactivation of pathogens, a solution of an immunoglo-
bulin is heated in the presence of stabilizers and is,
if necessary, subsequently purified.
A process is neseded which permits inactivation of
pathogens, such as viruses, by pasteurization of immuno-
globulin preparations; thereby the full activity of the
immunoglobulin must be retained. In general, when
immunoglobulins are prepared by conventional processes
there is a reduction in the potential risk of infection
to such an extent that the content of viruses or viral
antigens is often merely reduced to below the detection
limit of the test system used. However, the detection
limit is either usually inadequate to unambiguously rule
out a risk of ~:nfection; or further, there are not test
systems appropriate for detecting certain contamination
viruses. Hence a heat treatment is expedient. It is
claimed that the inactivation renders the infectious
agent incapable of reproduction and/or of being intra-
cellularly or otherwise reproduced.
To avoid their denaturation it is necessary to stabilize
the immunoglobulins during their prolonged exposure to
heat. To inactivate viruses it is indispensable to heat
at the highest permissable temperature for a prolonged
period.

1340'37
- 2 -
A process is described in EP-A-0 124 506, in which
ammonium sulfas=a is added to an immunglobulin solution,
and the suspension is heated at 60°C for 10 hours.
However, when an immunoglobulin solution is treated
as described in Example 16 of that patent application,
the formation of polymeric immunoglobulin occurs. A
maximum limit o f 10$ of polymeric immunoglobulin is
permitted in the European Pharmacopoea in an immuno-
globulin solution for intramuscular administration.
In EP-A-0 144 714 it is described that a Cohn fraction
II+III (J. Am.Chem.Soc. (1946) 68, 459) can be pasteuriz-
ed only under mild conditions, preferably at 52°C for
about 30 minute's; even when there has been previous
removal of the euglobulins and dialysis of the solution
to remove ethanol, aggregates are nevertheless produced.
It is doubtful whether absolute virus inactivation is
reliable under these conditions.
In The Lancet, of November 19, 1983, pages 1198-99,
there is a description of a process in which human
immunoglobulin was heated to 60°C for 10 h in solution
containing 45$ (w: v) sorbitol and 15~ (w: v) glycine.
Afterwards neither a loss of activity nor an increase in
the aggregate content was observed.
A process for t:he pasteurization of human plasma with
the addition of sugar alcohols, amino acids or saccha-
rides is described in EPatent-A-0 139 975. In the
pasteurization of plasma the immunoglobulin is protected
by the other plasma proteins. The stabilizing effect of
albumin on IgG is known.
The present invention relates to a process for the
preparation of a pasteurized immunoglobulin preparation,
which comprise; heating a solution of an immunoglobulin

1340737
- 3 -
in the presence of a carboxylic acid or one of its salts
and/or of a sac:charide until pathogens in particular
hepatitis viruses or HTLV III ("Aids") viruses, are
inactivated (i,.e. rendered incapable of reproduction or
of being intrac:ellularly or otherwise reproduced).'
Conditions suitable for such inactivation are known to
the expert. It is customary to heat at about 60°C for
about 10 hours.
This carboxylic' acid is preferably an aliphatic carboxy-
lic acid which can preferably be substituted with one or
more additional. carboxyl groups or one or more amino
groups or one or more hydroxyl groups. It preferably
contains two to ten carbon atoms. This carboxylic acid
is preferably g~lycine, glutamic acid, citric acid or
tartaric acid.
A preferred salt of a carboxylic acid is a soluble metal
salt, in particular an alkali metal or alkaline earth
metal salt, especially the sodium or magnesium salt.
The salt of glutamic acid which is used is preferably an
alkali metal salt, especially the monosodium salt (sodium
glutamate).
The carboxylic acids or their salts can be added in an
amount up to or exceeding the saturation limit, preferab-
ly from 0.4 to 0.6 g per milliliter of the immunoglobu-
lin solution which is to be stabilized.
The saccharide which is preferably used is a mono- or
disaccharide, with particular preference for sucrose.
These saccharides are preferably added in an amount of
0.5 to 1.0 g per milliliter of the immunoglobulin
solution which is to be stabilized.

1340737
- 4 -
The carboxylic acids or their salts or the saccharides
can be added i:n an amount up to or exceeding the satur-
ation limit of the immunoglobulin solution which is to
be stabilized.
The addition of these substances may cause a precipitat-
ion of the immunoglobulins. In this case, the resulting
suspension is nevertheless heated without detrimental
effect on the :immunoglobulin.
The pH-value i:a adjusted to 5-8.5, preferably 6.5-7.5,
for the heating process.
Using the clairned process it is possible to obtain
pasteurized imnnunoglobulin solutions whose polymer
content is below 10$. In the preferred embodiments the
polymer content: remains unchanged, within the range of
experimental error variation of the method, compared
with that of the unheated immunoglobulin solution.
The starting material for the process according to the
present invention can be a purified immunoglobulin
which, in the literature is called gamma-globulin, IgG,
imunoglobulin Gr or fraction II based on J.Am.Chem.Soc.
71, 541 (1949). Immunoglobulins of this type are mainly
derived from the step-wise precipitation which result
from the fractionation of plasma. Immunoglobulin-con-
taining precipitates are the fraction A of Vox.Sang. 7,
414 (1962), or fraction II and III of J.Am.Chem.Soc. 68,
459 (1946).
It is also possible to use modified immunogloblins as
starting materials. Immunoglobulins of this type can be
modified by chemical modification, for example sulfito-
lysis, or enzymatic treatment, for example peptic
elimination of the Fc portion. Proteolytic cleavage of
the immunoglobulin molecule with pepsin at pH 4 results

,~- - 5 -
1340737
mainly in F(ab)2 fragments with a molecular weight of
about 100,000 and a sedimentation coefficient determined
in the analytical ultracentrifuge of about 5 S (S =
Svedberg unit).
Products of this type contain uncleaved immunoglobulin
of 7 S (molecular weight about 150,000) but virtually no
immunoglobulin polymers. However, more extensively
fragmented portions with a molecular weight below 5 S
are observed at concentrations below 10~.
It has been surprisingly found, that the claimed process
is also suitab:Le for solutions of immunoglobulins which
contain ethano:L .
When purified :immunoglobulins are obtained using etha-
nol, often the final concentration step of the product-
ion process consists of a complete precipitation of the
immunoglobulins with ethanol and the subsequent removal
of the precipitate by centrifugation.
Dissolution of the precipitate to an approximate 10$
solution resulta in a residual alcohol content which
amounts to about 4~ by volume. The ethanol is usually
removed by freeze-drying or ultrafiltration. If the
heating were to be carried out in the alcohol-free
solution, for example after ultrafiltration, in the
presence of stabilizers it would be necessary to repeat
the ultrafiltration to remove these additives subsequent-
ly. Thus, to e~;pedite and economize the processing it is
advantageous to perform the heating in the presence of
ethanol.
It was surprisingly found, that, upon addition of
carboxylic acid., no increase in aggregation was observed
when the immunoglobulins were heated in the presence of
ethanol at 60°C' for prolonged periods, for example 40 h.

1340737
- 6 -
It is known that ethanol normally denatures immunoglobu-
lins at elevated temperatures. Accordingly, heating of
immunoglobulins even in the presence of carboxylic acids
or their salts as stabilizers did produce a higher
content of polymers in the presence of alcohol, than in
a procedure without alcohol.
An example of an ethanol-containing immunoglobulin
solution is a fraction containing gamma-globulin called
fraction II+III: by Cohn et al., J.Am.Chem.Soc. (1946),
68, pages 459 e:t seq., or fraction A by Nitschmann
(Kistner and Ni.tschmann, Vox Sang. (1962), 7, 414).
Fractions of this type contain not only gamma-globulins
but also lipoproteins, euglobulins, alpha- and beta-glo-
bulins and minor amounts of albumin. The gamma-globulin
content is about 40-80 g in 100 g total protein. When
100 g of fraction II+III are dissolved in 250 ml of
distilled water, the alcohol content of the solution is
4-5 ml/100 ml. A fraction II+III of this type can there-
fore be pasteurized in the manner according to the
invention.
Table 1 shows the contents of polymeric immunglobulin
after application of the process described, compared
with the state of the art. In each case, heating at 60°C
was continued for 10 hours. The immunglobulin content
was 10-11 g of protein per 100 ml of solution. The pH
was 7.

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The table showa that, after application of the claimed
process, the undesired increase in polymers of immuno-
globulin is, as a rule, very low even in the presence of
alcohol. This :Finding is, moreover, confirmed by other
test methods, j_or example by determination of the
anticomplementary activity.
The contents of: the higher molecular weight portions
resulting from the heating can be further reduced by
known processes;.
To this end it is advantageous to replace the added
stabilizer, for example by ultrafiltration, by an ionic
medium which is suitable for the chosen purification
process.
The duration of heating can be varied within certain
limits.
To test the efficacy of the process which has been
described, an i:mmunoglobulin in solution containing 9.9
g of protein per 100 ml and 3.6 g of ethanol per 100 ml
was mixed with 1 g of sucrose and 0.15 g of glycine per
1 ml of solution. Rous sarcoma virus (RSV) was added in
a concentration of 1 x 104 infectious RSV units/ml
(U/ml) and then the solution was heated at 60°C. After
heating for one hour, the virus content had decreased
below the detection limit.
It is evident from Table 2 that the heating which has
been described lead no effect on the antibody acitivity.

1340737
- 9 -
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'- ~. 1340737
- 10 -
The examples w'.hich follow illustrate the invention:
Example 1
Heating of an :immunoglo~bulin in solution with sodium
glutamate
200 ml of a virtually pure solution of immunoglobulin
with a protein concentration of 90 g/1 were stirred
while 120 g of sodium glutamate (monosodium salt of
glutamic acid) were adeed. This resulted in the preci-
pitation of the' immunoglobulin. The pH-value of the
suspension was adjusted to 7; it was then heated and
stirred at 60°C: for 10 hours. The mixture was cooled to
room temperature and then the precipitate was removed by
filtration or centrifugation. The precipitate was
dissolved in distilled water. The glutamate was removed
by dialysis or ultrafiltration. The solution was ad-
justed to the desired protein content and made isotonic.
Herefrom 110 m7. with a protein concentration of 155 g/1
were obtained. The polymer content was 1.6% (1.2%
unheated).
Example 2
Heating of an i.mmunoglobulin solution with sucrose and
glycine
89 kg of sucrose and 13.3 kg of glycine were added to 89
1 of immunoglobulin solution which had a sodium chloride
concentration of 1 g/1, a protein concentration of 97
g/1 and 3.6% ethanol by volume. The pH-value was adjust-
ed to 7 and then the mixture was heated and stirred at
60°C for 10 hours. The solution was diluted with 100 1

i3~~'~3~
- 11 -
of 0.3 g/100 ml sodium chloride solution and was steri-
lized by filtration. The stabilizers were removed by
ultrafiltration in a known manner. The solution was then
made isotonic and adjusted to a protein concentration of
160 g/1.
Consequently 51 1 of solution with a polymer content of
2.6% (2% in the unheated solution) were obtained. The
residual sucrose concentration was 0.04 g/l.
Example 3
100 g of sucrose and 15 g of glycine were added to 100
ml of sulfonatE:d immunoglobulin with a protein concen-
tration of 100 g/1 and a sodium chloride concentration
of 3 g/1. The pH-value was adjusted to 7.3 and then the
mixture was heated and stirred at 60°C for 10 hours.
The solution was then cooled to room temperature and
diluted with 1'l0 ml of 0.3 g/100 ml sodium chloride
solution. The stabilizers were removed by ultrafiltrat-
ion. The solvent was replaced by a 0.3 g/100 ml sodium
chloride solution. The solution of the immunoglobulin
was made isotonic and adjusted to a protein concentrat-
ion of 50 g/1.
195 ml of solution with a polymer content of 5.6% (5.8%
in the unheated solution) were obtained by this proce-
dure.
Example 4
13.7 1 of an inununoglobulin solution which had undergone
peptic cleavage (with a protein concentration of 180 g/1
and a sodium chloride concentration of 3.2 g/1) were

1340'~3'~
7
- 12 -
diluted with 13.5 1 of a 0.3 g/100 ml sodium chloride
solution. Then 27.2 kg of sucrose and 4.08 kg of glycine
were added. At pH 7 the mixture was then heated to 60°C
and stirred fo:r 10 hours. The solution was then cooled
to room temperature and diluted with 45 1 of 0.3 g/100
ml sodium chloride solution. Sterilization by filtration
was followed b:y substantial removal of the added stabi-
lizers by ultrafiltration. The solution was then made
isotonic and adjusted to a protein concentration of 50
g/1. 48 1 of solution with a residual sucrose concen-
tration of O.O:L g/1 were obtained. The content of
components of <iefined molecular weights was determined
in an analytical ultracentrifuge as follows:
Starting material: S less than 5 = 8.8%
S about 5 = 75.5%
S about 7 = 15.7%
S greater than 7 = 0 %
Heating final product: S less than 5 = 8.1%
S about 5 = 77.5%
S about 7 = 14.4%
S greater than 7 = 0 %
Example 5
Heating of a dissolved ethanol-containing fraction
II+III in the presence of ethanol
200 g of fraction II+III were dissolved under stirring
in 500 ml of distilled water. To the solution (about 700
ml) 700 g of sucrose and 0.3 to 0.2 mol/1 glycine were
added. The pH-value was adjusted to about 7 and the
solution was then heated and stirred at 60°C for 10
hours. The heated solution was then fractionated. 304 ml
of immunoglobulin solution with a protein concentration
of 66 g/1 were obtained. The polymer content was 1.1%.

1340'~3~
- 13 -
For comparison an unheated treatment also using 200 g of
fraction II+III produced 208 ml of immunoglobulin
solution with a protein concentration of 96.8 g/1. The
polymer content was 2.0$.

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Administrative Status

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Event History

Description Date
Inactive: Expired (old Act Patent) latest possible expiry date 2016-09-14
Inactive: Correspondence - Transfer 2007-05-10
Letter Sent 2007-04-03
Letter Sent 2007-04-03
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Letter Sent 2004-11-05
Inactive: Multiple transfers 2004-10-01
Letter Sent 2000-08-04
Inactive: Multiple transfers 2000-06-12
Inactive: Cover page published 1999-09-30
Inactive: IPC assigned 1999-09-27
Inactive: First IPC assigned 1999-09-27
Inactive: CPC assigned 1999-09-27
Inactive: IPC assigned 1999-09-27
Grant by Issuance 1999-09-14

Abandonment History

There is no abandonment history.

Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
CSL BEHRING GMBH
Past Owners on Record
HANS MULLER
HELMUT GEIGER
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Claims 1999-09-30 2 46
Cover Page 1999-09-30 1 19
Abstract 1999-09-30 1 20
Descriptions 1999-09-30 13 422
Correspondence 2007-05-10 2 80
Examiner Requisition 1991-05-14 1 60
Prosecution correspondence 1991-09-13 5 222
Examiner Requisition 1993-02-24 2 125
Prosecution correspondence 1993-05-25 3 96
Examiner Requisition 1997-05-23 2 65
PCT Correspondence 1999-07-29 1 47
Prosecution correspondence 1997-11-18 2 62