Immunoglobulin Preparation and Storage System for an Immunoglobulin Preparation

Abstract

The present invention relates to an immunoglobulin preparation comprising immunoglobulin in a mass-volume percentage of at least 4%, wherein the concentration of oxygen dissolved in the preparation at room temperature is less than 40 μmol/l.

Claims

1.-18. (canceled)

19. A storage system for a ready-to-use liquid immunoglobulin preparation for intravenous or subcutaneous administration comprising a container having an interior, a first portion of said interior being occupied by the ready-to-use liquid immunoglobulin preparation, wherein the ready-to-use liquid immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of at least 4%, wherein the concentration of oxygen dissolved in the preparation at room temperature is less than 150 μmol/l, wherein the absorbance at 350 nm minus the absorbance at 500 nm (absorbance A.sub.350-500 nm) of the immunoglobulin preparation remains below 0.28 upon storage for 24 months at 25° C. in the dark, and the remaining portion of said interior forming a headspace and being occupied by a gas other than air, wherein the content of oxygen in the gas of the headspace remains less than 20 vol-% during said storage.

20. The storage system according to claim 19, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of at least 10%.

21. The storage system according to claim 19, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of 14-20%.

22. The storage system according to claim 19, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of at least 18%.

23. The storage system according to claim 19, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of at least 20%.

24. The storage system according to claim 19, wherein the preparation has a mean increase in absorbance A350-500 nm of less than 0.2 upon storage of 6 months at 37° C. in the dark.

25. The storage system according to claim 19, wherein the immunoglobulin comprised in the immunoglobulin preparation consists essentially of IgG.

26. The storage system according to claim 19, wherein the absorbance at 350 nm minus the absorbance at 500 nm (absorbance A350-500 nm) of the immunoglobulin preparation remains below 0.28 upon storage for 36 months at 25° C. in the dark.

27. The storage system according to claim 19, wherein the concentration of oxygen dissolved in the preparation at room temperature is less than 125 μmol/l.

28. The storage system according to claim 27, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of at least 10%.

29. The storage system according to claim 27, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of 14-20%.

30. The storage system according to claim 27, wherein the absorbance at 350 nm minus the absorbance at 500 nm (absorbance A350-500 nm) of the immunoglobulin preparation remains below 0.28 upon storage for 36 months at 25° C. in the dark.

31. The storage system according to claim 19, wherein the concentration of oxygen dissolved in the preparation at room temperature is less than 100 μmol/l.

32. The storage system according to claim 31, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of at least 10%.

33. The storage system according to claim 31, wherein the immunoglobulin preparation comprises immunoglobulin in a mass-volume percentage of 14-20%.

34. The storage system according to claim 31, wherein the absorbance at 350 nm minus the absorbance at 500 nm (absorbance A350-500 nm) of the immunoglobulin preparation remains below 0.28 upon storage for 36 months at 25° C. in the dark.

35. The storage system of claim 19, wherein the immunoglobulin is a polyvalent human IgG derived from a pool of human plasma.

36. The storage system of claim 21, wherein the immunoglobulin is a polyvalent human IgG derived from a pool of human plasma.

37. The storage system of claim 23, wherein the immunoglobulin is a polyvalent human IgG derived from a pool of human plasma.

38. The storage system of claim 33, wherein the immunoglobulin is a polyvalent human IgG derived from a pool of human plasma.

Description

[0057] FIG. 1 is a graphical representation of the optical density (absorbance) A.sub.350-500 nm of the Ig preparation stored as a function of storage time after storage at 5° C. under light without inert gassing of the headspace (diamonds), using a gas in the headspace having an oxygen content of 16 vol-% (squares), 12 vol-% (triangles), 10 vol-% (crosses), 7 vol-% (stars) and less than 7 vol-% (circles), respectively; and

[0058] FIG. 2 is a graphical representation of the optical density (absorbance) A.sub.350-500 nm of the Ig preparation stored as a function of storage time after storage at 37° C. in the dark without inert gassing of the headspace (diamonds) and using a gas in the headspace having an oxygen content of at most 7 vol-% (squares), respectively, and

[0059] FIG. 3 is a graphical representation of the mean optical density (absorbance) A.sub.350-500 nm of a number of samples of the Ig preparation as a function of storage time when stored at 25° C. in the dark using a gas in the headspace having an oxygen content of less than 7 vol-%.

[0060] As can be seen from FIG. 1, yellowing of the immunoglobulin preparation over time is reduced by using a gas having a reduced oxygen content (and thus also a reduced oxygen partial pressure) in the headspace. Specifically, by using a gas having an oxygen content of less than 7 vol-%, the optical density A.sub.350-500 nm is less than 0.35 even after storage for 6 months, thus fully complying with the requirements of the European Pharmacopoeia after prolonged storage. The concentration of oxygen dissolved in the respective sample at room temperature is less than 100μmol/l.

[0061] Referring to FIG. 2, a mean increase of the optical density A.sub.350-500 nm of only about 0.18 can be achieved according to the present invention when stored over 6 months at 37° C. in the dark using a gas in the headspace having an oxygen content of at most 7 vol-%. This is in clear contrast to the mean increase for an Ig preparation stored without gassing of the headspace, said increase being about

[0062] As shown in FIG. 3, a mean increase of the mean optical density A.sub.350-500 nm of only about 0.1 can be achieved according to the present invention when stored over 24 months at 25° C. in the dark.

[0063] As shown in Table 1 below, the mean optical density is still below 0.355 even after storage over 36 months at 25° C. in the dark, and even lower if stored at 5° C. in the dark. The values of 6 different lots are shown.

TABLE-US-00001 TABLE 1 25° C. 5° C. 30 months 36 months 30 months 36 months O.sub.2 O.sub.2 O.sub.2 O.sub.2 μmol/L % O.sub.2 A.sub.350 μmol/L % O.sub.2 A.sub.350 μmol/L % O.sub.2 A.sub.350 μmol/L % O.sub.2 A.sub.350 79.2 6.3 0.270 83.5 6.6 0.319 61.3 4.8 0.156 58.4 4.6 0.158 75.8 6.0 0.229 79.9 6.3 0.249 56.0 4.4 0.132 54.8 4.3 0.130 82.4 6.5 0.297 86.3 6.8 0.332 65.3 5.1 0.181 62.4 4.9 0.186 53.3 4.2 0.298 54.3 4.3 0.289 66.0 5.2 0.155 62.3 4.9 0.159 55.7 4.4 0.231 57.3 4.5 0.244 62.3 4.9 0.133 58.5 4.6 0.131 54.7 4.3 0.290 56.3 4.4 0.318 63.5 5.0 0.180 59.8 4.7 0.179

[0064] Table 2 shows the mean monthly increase in absorbance A.sub.350-500 nm in different storage conditions. For all conditions tested, keeping the oxygen concentration below 100 μmol/l, or below 7% oxygen in the headspace, leads to significantly lower increase in absorbance, indicating significantly higher stability of the IgG preparation. All samples were stored in the dark. Data were collected for 24 or 36 months: during this time, the increase of absorbance over time was about linear.

TABLE-US-00002 TABLE 2 Storage Oxygen in Mean monthly A.sub.350-500 nm reduction temperature headspace increase in A.sub.350-500 nm by O2 reduction 37° C. <7% 0.030 42.5% 20% (air) 0.052 25° C. <7% 0.0042 19.9% 20% (air) 0.0052  5° C. <7% 0.00037 47.8% 20% (air) 0.00071