(19)
(11)EP 0 825 879 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
26.10.2005 Bulletin 2005/43

(21)Application number: 96919732.6

(22)Date of filing:  09.05.1996
(51)International Patent Classification (IPC)7A61L 2/02, B01D 61/14, A61K 9/00, A61K 9/08
(86)International application number:
PCT/EP1996/001953
(87)International publication number:
WO 1996/036370 (21.11.1996 Gazette  1996/51)

(54)

PROCESS FOR THE DEPYROGENATION OF INJECTABLE PHARMACEUTICAL SOLUTIONS

VERFAHREN ZUR DEPYROGENIERUNG INJIZIERBARER PHARMAZEUTISCHER LÖSUNGEN

PROCEDE DE DEPYROGENATION DE SOLUTIONS PHARMACEUTIQUES INJECTABLES


(84)Designated Contracting States:
DE FR GB IE IT

(30)Priority: 16.05.1995 IT MI950987

(43)Date of publication of application:
04.03.1998 Bulletin 1998/10

(73)Proprietor: BRACCO IMAGING S.p.A.
20134 Milano (IT)

(72)Inventors:
  • MORANDI, Ervino
    I-20134 Milano (IT)
  • GALLOTTI, Angelo
    I-20134 Milano (IT)

(74)Representative: Minoja, Fabrizio et al
Bianchetti Bracco Minoja S.r.l. Via Plinio, 63
20129 Milano
20129 Milano (IT)


(56)References cited: : 
EP-A- 0 113 040
WO-A-92/00132
GB-A- 2 269 166
EP-A- 0 312 104
WO-A-92/14539
US-A- 4 925 690
  
  • DATABASE WPI Week 9210 Derwent Publications Ltd., London, GB; AN 92-077012 XP002012908 & JP,A,04 022 491 (NOK CORP) , 27 January 1992
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] The present invention relates to the preparation of injectable solutions of pharmaceutical products and/or of diagnostic agents, characterized by an extremely high degree of purity as regards the low content of bacterial endotoxins.

[0002] It is known that injectable formulations of pharmaceutical products or of diagnostic agents must satisfy stringent criteria of sterility and of apyrogenicity, in order to be able to be administered to patients with acceptable margins of safety. Accordingly it is of fundamental importance to eliminate as completely as possible every pathogen and also the bacterial endotoxins, from the final formulation of the active principle before making-up, in order to avoid undesired and frequently hazardous reactions of the body to said toxic agents.

[0003] This requirement is all the more perceived in the preparation of diagnostic contrastographic formulations, where there is frequently the need of administering to the patient large volumes of highly concentrated solutions of said formulations.

[0004] Among the various diagnostic imaging techniques (X-ray, NMR, echography), it is worth mentioning, by way of example, the X-ray technique in which the opacifying contrastographic agent is preferably represented by a non-ionic iodine-containing aromatic compound.

[0005] To provide a sufficient contrast, the injectable solutions of these compounds are usually very concentrated, reaching approximately the value of 80% w/v, and, for example by the intravenous route, are administered in volumes which may reach 250 mL and above per single dose.

[0006] Another administration route adopted for these compounds is, for example, the intrathecal route for tests which concern the neural tissue and in this connection it is well known that this type of tissue proves to be very much more sensitive than the others to the toxic agents (up to 1000 times more sensitive).

[0007] It is accordingly clear that, especially in injectable solutions of these compounds, the presence of bacterial endotoxins must be as low as possible.

[0008] Among those techniques for the depyrogenation of liquids which are in common use industrially, the use of microporous filters and of ultrafiltration membranes has by now become widespread.

[0009] Such membranes are, at all events, widely used, with particularly satisfactory results, for the treatment of water or of dilute solutions.

[0010] Unfortunately, the situation proves to be very different when it is desired to subject to ultrafiltration solutions of contrast media, such as in particular non-ionic iodine-containing compounds, which are very concentrated and viscous.

[0011] The problem is that by reason of the characteristics of these solutions, there is a need for filtering surfaces which are very large, in order to remain within the range of practicable production times which are industrially acceptable. By contrast, smaller surfaces would excessively extend the filtration times.

[0012] Consequently, the plant required is bulky and characterized by significant dead volumes in which non-negligible quantities of unfiltered solution stagnate, which solution, at the end of each working cycle, has to be discarded or recovered and treated separately in a suitable smaller plant. All this has significant unfavourable effects on the total production costs and, potentially, also on the final quality of the product.

[0013] An obvious attempt at resolving this difficulty consisted in the use of spiral-wound membranes for tangential ultrafiltration (having a suitable porosity capable of blocking the passage of the bacterial endotoxins: for example, an average cut-off of 10,000 dalton) which are accomodated in cartridges of relatively restricted dimensions and capable of working under pressure, a possibility which for technical reasons is not applicable to other filtration systems, such as for example those formed by so-called string filters, used industrially in this field. In this way, it should have been possible to obtain substantial improvements in terms both of space and of process speed.

[0014] It was, however, unexpectedly found that the membranes which would theoretically have been best, especially with regard to the characteristics of strength and of service life, such as for example those which are polysulphone-based, not only became obstructed within more or less brief periods of time depending upon the characteristics of the pharmaceutical preparation to be filtered, but in addition showed the property of impairing the actual composition of the formulation of the contrast medium. In fact, the membrane partially rejected the saline excipient (especially when said excipient is EDTA.Ca2Na), preferentially transmitting the non-ionic iodine-containing agent. This phenomenon, which was entirely unexpected and, according to the actual supplier of the membrane, unforeseeable for pharmaceutical solutions of this type, made it impossible to apply this technique for the desired purpose.

[0015] Nor could the performance of the membrane be restored by the frequent use of detergents, for example after each working cycle, as the aforementioned phenomenon was already manifested after the passage of a few hundred litres of solution. Nor did it prove possible to resolve the problem in an acceptable manner by changing the type of filtering material. Finally, complex experimentation led to the identification of a class of membranes, in essence those which are cellulose-based, which enabled the desired pyrogen retention to be obtained without impairing to a substantial extent the composition of the formulation. However, it was not possible to prevent said membrane from becoming obstructed in short lengths of time.

[0016] The insertion of prefilters upstream of the ultrafiltration unit proved to be equally disappointing as, by reason of the particular characteristics of high concentration and viscosity of the solutions in question, in addition to the very fine microimpurities contained in these, said prefilters lost their effectiveness by becoming obstructed prematurely under the pressure conditions necessary for obtaining acceptable prefiltration times. It was possible to obviate this defect only by arranging a series of prefilters connected in parallel, where said filters were connected to one another by a complex bypass system the function of which was to switch the solution to be depyrogenated from one prefilter to the next, without having on each occasion to interrupt the process in order to replace the prefiltering cartridge which had become obstructed. All this involved the construction of a plant which was complex and bulky and the management of which was sophisticated and costly. Furthermore, the final yield of the process proved in every case to be suboptimal by reason of the dead spaces due to the prefiltration system. To demonstrate the situation in a clearer fashion, a diagrammatic description of the plant is shown in Fig. 1.

[0017] As indicated therein, the solution to be depyrogenated is driven from the feed-tank A through the prefilter to the collection tank D under pressure conditions such as to ensure total flow rates of 1200/1500 and even more L/h, irrespective of the prefilter used (a substantially lower flow rate would not be acceptable in the general economics of the process, involving excessively long total filtration time).

[0018] These conditions of high pressure, especially with highly viscous solutions, cause the rapid obstructing of the prefilter, which would need to be replaced on a plurality of occasions for each working cycle. As a consequence, there would be an extension of the overall time, loss of product and the possibility of contamination.

[0019] The adoption of a series of prefilters (C1, C2, C3) connected in parallel and controlled by a bypass (B) which diverts from one filter to the next the solution arriving from A permits the completion of the working cycle in the times and under the working conditions which are desired, without having to interrupt the process.

[0020] Naturally, the disadvantageous aspects of this process are connected with the complexity of the prefiltering system, with the space necessary to accommodate the same and the high maintenance costs, bearing in mind that exhausted filters have to be removed and replaced by new ones. These problems assume ever greater importance the more substantial is the batch to be purified, as the number of cartridges to be used for each cycle is dependent both upon the working conditions (for example, the pressure applied and the temperature), and also upon the total volume of the solution to be treated.

[0021] On the other hand, the possible alternatives consisted in the adoption either of a very much larger and bulkier prefilter or of substantially lower pressure values, both parameters not being applicable to industrial processes involving batches of at least 800-1500 L of formulation.

[0022] The prefiltered solution is collected in a second tank D, from which it is subsequently taken off and pumped to the filtering unit E in accordance with the procedures which are normally employed in ultrafiltration. The depyrogenated filtrate ends up in a suitable collector where, before being made up, it will be rehomogenized under agitation, while the residue, progressively enriched in pyrogens, is fed back to the tank D, being diluted, and then recycled to the filter E until such time as the entire process is completed.

[0023] Another process for the depyrogenation of solutions, especially containing drugs for hematic administration, is known from EP-A-0312104. It makes use of ultrafiltration membranes combined with a pyrogen adsorbent.

[0024] It has now unexpectedly been found that it is possible to solve in an optimal fashion the above discussed problems by virtue of a process which can be carried out by means of a very simple filtration plant, of modest dimensions, which plant can be managed in an economic fashion and is capable of giving a high total yield both in terms of quality and in terms of quantity.

[0025] The process of the invention comprises the following steps:
  • prefiltration of said solutions by means of a microfiltering unit,
  • passing of the solution deriving from the preceding step to the ultrafiltration unit, in which said ultrafiltration unit is equipped with tangential-ultrafiltration membranes having a porosity such as to deny passage to bacterial endotoxins and in which the retentate from said unit is directly recycled to the solution which emerges from the prefilter, while the permeate, complying with the limits set by the pharmacopoeia for the pyrogen content, is collected in a collector, where it is homogenized under agitation before being made up.


[0026] The process of the invention may conveniently be carried out using a plant, diagrammatically illustrated in Fig. 2, which is extremely compact as it uses only a single prefiltration unit C, and unexpectedly does not require a tank for collecting the prefiltrate. The prefilter may take various forms, for example one or more filtering cartridges of decreasing porosity connected in series with one another. By way of example, a preferred configuration may comprise two filtering cartridges, of 1 µ and 0.22 µ respectively. Equally preferred is for example a prefilter constituted by a single composite filtering cartridge, that is to say one having decreasing porosity, with an average porosity of 0.5 µ. In substance, the solution to be depyrogenated is driven through the prefilter C by virtue of a modest pressure applied from the exterior to the tank A (acceptable values range from 1 to 3 atm, preferably from 1.5 to 2.5 atm).

[0027] As it emerges from the prefilter, the solution is pumped directly to the ultrafiltration unit: the depyrogenated permeate is collected in a suitable collector provided with agitation and the retentate is recycled directly upstream of the pump which manages the ultrafiltration, to be admixed with the solution passing out from the prefilter. The ultrafiltering unit may be variously constituted: one of the preferred configurations may, for example, comprise a plurality of filtering modules (housings), in their turn comprising one or more filtering cartridges, said housings being capable of operating simultaneously or individually, depending upon the quantity of solution to be filtered. The membranes which are used are those which are capable of preventing a substantial impairment of the composition of the formulation during the process (for example, permitting the preferential passage of one or more constituents as compared with the others) and having a porosity such as to prevent the passage of bacterial endotoxins.

[0028] From this point of view, cellulose-based membranes have proved to be particularly preferred, especially those of regenerated cellulose, with an average cut-off of 10,000 dalton. An absolutely non-limiting example of these is represented by spiral-wound cartridges of regenerated cellulose S10Y10(R) and/or S40Y10(R) (Amicon).

[0029] The transmembrane pressure applied to the ultrafiltration unit varies, depending upon the type of filtering cartridge employed and upon the characteristics of the solution to be filtered (by way of example, a very important factor is the concentration and thus the viscosity of said solution).

[0030] As a general rule, entirely acceptable results are obtained by applying transmembrane pressures which are variable between 1 and 5 atm. Naturally, when it is necessary to depyrogenate less viscous solutions, it will be possible to obtain high flow rates (and therefore shorter times) when applying a lower transmembrane pressure.

[0031] The flow rates which are obtainable may normally vary between 4 L/h per m2 of filtering surface and 70 L/h·m2, preferably between 6 and 55 L/h·m2.

[0032] The operating temperature is another important parameter, and is dependent upon the thermal stability of the diagnostic formulation to be filtered and upon the limits imposed by the filtering material. In the case of cellulose-based membranes, particularly with those of regenerated cellulose, it is possible to operate at from 20° to 55°C, for example. Particularly preferred, in the case of highly concentrated and viscous solutions, is a temperature of approximately 50-54°C, preferably 52°C ± 2°C, while in the case of less viscous solutions it is preferred to operate at temperatures of approximately 30°C.

[0033] An absolutely non-limiting example is represented by the filtration of batches of 100-200 L of Iomeron(R) 150 (an injectable speciality containing the non-ionic iodine-containing contrast agent iomeprol in a concentration corresponding to a content of 150 mg/I per mL) in an AMICON SP150 + 52062 ultrafiltration unit equipped with S4010(R) ultrafiltering cartridges (Amicon) for a total filtering surface of approximately 11 m2. Working at a temperature of 45°C ± 5°C and applying a transmembrane pressure which is variable from batch to batch from 1 to ~4 atm, flow rates were obtained which were within the range between approximately 12 and 45 L/h per m2 with filtration times (for batches of 200 L) within the range between 0.4 and 1.5 h.

[0034] Another example of the invention may be represented by the depyrogenation of an industrial batch of 1,000 L of Iopamiro(R) 300 (an injectable speciality containing the non-ionic iodine-containing contrast agent iopamidol in a concentration corresponding to a content of 300 mg/I per mL) carried out in an Amicon SPM480 unit equipped with cartridges of regenerated cellulose for a total filtering surface of approximately 45 m2, average cut-off of 10,000 dalton. Working at a temperature of 52°C ± 2°C and applying a transmembrane pressure of 3.5 atm, a flow rate of ~11 L/h per m2 is obtained for a total filtration time of approximately 2 h.

[0035] The plant constructed proved to be surprisingly efficient, especially as, with the elimination of the tank D (typical of an ultrafiltration process: as a common practice, where there are no prefiltration problems, the residue is directly recycled, becoming diluted, to the feed tank, something which is obviously not possible in the present situation), the retentate c, becoming admixed directly with the flow arriving from the prefilter, causes an almost immediate increase in the concentration of toxins in the solution to be filtered. This fact should obviously impair the efficiency of the filtering unit.

[0036] However, the efficiency of the process proves to be optimal and the actual life of the cellulose filter proves to be surprisingly long, whereas its greater structural delicacy had initially greatly discouraged the continuous use thereof for the filtration of highly viscous solutions, such as for example X-ray diagnostic solutions, and especially at temperatures which are very close to the operating limits prescribed for said filter.

[0037] The fact that the process is a single-stage process eliminates the time wasted in collecting the prefiltrate in the tank D of Fig. 1. It further proves to be possible to operate at moderate operating pressures, with obvious benefits regarding the safety of the plant.

[0038] There is thus created a single-stage process (on the contrary the one illustrated in Fig. 1 is in essence a two-stage process) which is economic, is in full compliance with the most stringent regulatory standards, is highly efficient and is also entirely in line with the requirement to show care for the environment because it eliminates the need to use detergents to clean and restore the filtering surfaces (a simple step of sanitizing said surfaces, for example with soda, is sufficient). This gives a drastic improvement from the point of view of the impact on the environment. Furthermore, this also removes the need to eliminate every residual trace of detergent and the need then to analytically certify its absence. All this brings clear benefits in terms of costs and quality of the finished product as well.

[0039] If required, it is also possible to insert at the outlet, preferably downstream of the collector/mixer of the filtrate (not indicated in Fig. 2), a further sterilizing filter of 0.2 µ or even less (F, indicated in the outlined zone of Fig. 2), thus obtaining a final solution which is homogeneous and entirely sterile, ready to be made up.

[0040] The flow rate remains substantially constant throughout the entire duration of the process. In this way, it remains possible to treat preparations up to 800-1,500 L in modest times (1.5-5 h) with yields of up to 97-98%, obtaining a product which is in full compliance with the most stringent pharmacopoeia limits.

[0041] The plant of Fig. 2 has proved to be particularly useful for the depyrogenation of diagnostic injectable pharmaceutical formulations. Radio-opaque diagnostic formulations comprising as contrast agent a non-ionic iodine-containing compound or a mixture of iodine-containing compounds, either or monomeric or of dimeric type, have proved to be particularly preferred.

[0042] Absolutely non-limiting examples of iodine-containing radio-opaque contrast agents, injectable formulations of which can be depyrogenated by means of the process and the plant of the invention, may be selected from among the following monomeric and dimeric compounds and mixtures thereof: iopamidol, iomeprol, iohexol, ioversol, iopentol, iopromide, ioxilan, iotriside, iobitridol, iodixanol, iofratol, iotrolan, iodecimol, iopirol, iopiperidol.

[0043] Equal preference has proved to be ascribable to the injectable formulations of contrast agents for NMR imaging, usually comprising, as contrastographic ingredients, chelates of paramagnetic metal ions (such as for example Gd3+, Mn2+, Fe3+, Eu3+, Dy3+ etc.) with chelating agents of various types (such as for example linear or cyclic polycarboxylic polyamino acids, and derivatives or salts thereof, polyaminophosphonic or polyaminophosphinic acids and derivatives thereof etc.).

[0044] Absolutely non-limiting examples of contrast agents of this type may be selected from among the following: chelate of Gd3+ with diethylenetriamine pentaacetic acid (Gd-DTPA), chelate of Gd3+ with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid (Gd-DOTA), chelate of Gd3+ with [10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclodecan-1,4,7-triacetic acid (Gd-HPD03A), chelate of Gd3+ with 4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oic acid (Gd-BOPTA), chelate of Gd3+ with N-[2-[bis(carboxymethyl)amino]-3-(4-ethoxyphenyl)propyl]-N-(2-[bis(carboxymethyl)amino]ethylglycine (Gd-EOB-DTPA), chelate of Gd3+ with N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]-glycine (Gd-DTPA-BMA), chelate of Gd3+ with (α,α',α"',α"')-tetramethyl-1,4,7,10-tetraazocyclododecan-1,4,7,10-tetraacetic acid (Gd-DOTMA), chelate of Mn2+ with N,N'-bis(pyrodoxal-5-phosphate)ethylene-diamine-N,N'-diacetic acid (Mn-DPDP) and salts or derivatives thereof, such as for example those of amide or ester type.


Claims

1. A single-stage process for the depyrogenation of an injectable solution of contrast agent for diagnostic imaging, said process operating on solution volumes of up to 800-1500 L and comprising the following steps:

a) prefiltering the solution by means of a microfiltering unit,

b) passing the solution from step a) through an ultrafiltration unit consisting of one or more filtration modules which are capable of operating simultaneously or individually, said modules being equipped with cellulose-based tangential-ultrafiltration membranes having an average cut-off of 10000 Dalton to prevent passage of bacterial endotoxins, whereby a retentate and a permeate complying with the limits set by the pharmacopoeia for the pyrogen content are obtained;

c) recycling the retentate from said ultrafiltration unit directly to the solution from step a), and

d) collecting the permeate in a collector, where it is homogenized under agitation before being made up.


 
2. Process according to Claim 1, in which the injectable solution is passed through the prefilter under a pressure between 1 and 3 atm.
 
3. Process according to Claim 2, in which the injectable solution is passed through the prefilter under a pressure between 1.5 and 2.5 atm.
 
4. Process according to Claim 1, in which the prefilter comprises 1 or more filtering cartridges of decreasing porosity connected in series with one another.
 
5. Process according to Claim 4, in which the prefilter comprises two filtering cartridges which are connected in series, of 1 µ to 0.22 µ porosity, respectively.
 
6. Process according to Claim 4, in which the prefilter comprises a single filtering cartridge of decreasing porosity, having an average porosity of 0.5 µ.
 
7. Process according to Claim 1, in which said ultrafiltration membranes are of regenerated cellulose.
 
8. Process according to Claim 1, in which the transmembrane pressure applied to the ultrafiltration unit permits an outflow rate of the permeate ranging from 4 to 70 L/h per m2.
 
9. Process according to claim 8, wherein said outflow rate of the permeate is between 6 and 55 L/m2
 
10. Process according to Claim 8, in which said transmembrane pressure ranges from 1 to 5 atm.
 
11. Process according to Claim 1, in which the operating temperature ranges from 20° to 55°C throughout the entire process.
 
12. Process according to Claim 1, in which said injectable solution comprises, as active principle, at least one non-ionic iodine-containing radio-opaque agent.
 
13. Process according to Claim 12, in which said radio-opaque agent is iopamidol.
 
14. Process according to Claim 12, in which said radio-opaque agent is iomeprol.
 
15. Process according to Claim 12, in which said injectable solution comprises a mixture of monomeric and dimeric non-ionic iodine-containing radio-opaque agents.
 
16. Process according to Claim 1, in which said injectable solution comprises, as active principle, at least one contrastographic agent for NMR imaging.
 
17. Process according to Claim 16, in which said contrastographic agent is a chelate of the ion of a paramagnetic metal.
 
18. Process according to Claim 17, in which said paramagnetic chelate is selected from Gd-BOPTA and Gd-HPDO3A and salts thereof.
 
19. A plant for depyrogenating an injectable solution of contrast agent for diagnostic imaging, operating on batches of at least 800-1500 L of solution and comprising:

- a feed tank (A), containing said solution;

- one prefiltration microfiltering unit (C), through which said solution from (A) is passed;

- pumping means for pumping the solution emerging from (C) into an ultrafiltration unit (E);

- an ultrafiltration unit (E), which consists of one or more filtration modules capable of operating simultaneously or individually, said modules being equipped with cellulose-based tangential ultrafiltration membranes having an average cut-off of 10000 Dalton to prevent passage of bacterial endotoxins, whereby a retentate and a depyrogenated permeate are obtained;

- means for recycling the retentate from said unit (E), said retentate being enriched in pyrogens, directly into the solution emerging from (C), upstream of said pumping means;

- a collector, provided with agitation means, where the depyrogenated permeate from unit (E) is collected and homogenised before being made up.


 
20. A plant according to claim 19, wherein the solution from tank (A) is passed through the microfiltering unit (C) under a pressure of between 1 and 3 atm.
 
21. A plant according to claim 20, wherein said pressure is between 1,5 and 2.5 atm.
 
22. A plant according to claim 19, wherein the prefiltration unit (c) comprises one or more filtering cartridges of decreasing porosity connected in series with one another.
 
23. A plant according to claim 22, wherein said prefiltration unit (c) comprises two filtering cartrdidges, which are connected in series, of 1µ and 0.22 µ porosity, respectively.
 
24. A plant according to claim 22, wherein said prefiltration unit (c) comprises a single composite filtering cartridge of decreasing porosity, having an average porosity of 0.5 µ.
 
25. A plant according to claim 19, in which said tangential-ultrafiltration membranes of said ultrafiltration unit (E) are of regenerated cellulose.
 
26. A plant according to claim 19, wherein a sterilizing filter (F) of porosity 0.2µm or less is located downstream of said collector, whereby the final depyrogenated and homogenised injectable solution is entirely sterilised before being packaged.
 
27. The use of a plant according to Claim 19 for the depyrogenation of radio-opaque injectable diagnostic solutions.
 
28. The use of a plant according to Claim 19 for the depyrogenation of injectable diagnostic solutions for NMR imaging.
 


Ansprüche

1. Einstufiges Verfahren für die Depyrogenierung einer injizierbaren Lösung eines Kontrastmittels für die diagnostische Bildgebung, wobei das genannte Verfahren bei Lösungsvolumen von bis zu 800 - 1500 L betrieben wird und die folgenden Schritte aufweist:

a) Vorfiltrierung der Lösung mittels Mikrofiltriereinheit;

b) Durchlauf der Lösung von Schritt a) durch eine Ultrafiltrationseinheit, die aus einem oder mehreren Filtrationsmodulen besteht, die sich zum simultanen oder individuellen Betrieb eignen, wobei die genannten Module mit Tangential-Ultrafiltrationsmembranen auf Cellulosebasis mit einer mittleren Ausschlussgrenze von 10000 Dalton ausgestattet sind, um den Durchgang bakterieller Endotoxine zu verhindern, wodurch ein Retentat und ein Permeat erhalten werden, das den Grenzen, die durch das Arzneibuch für den Pyrogengehalt vorgeschrieben sind, entspricht;

c) Rückführung des Retentats von der genannten Ultrafiltrationseinheit unmittelbar zur Lösung von Schritt a), und

d) Sammeln des Permeats in einem Sammelbehälter, wo es unter Rühren homogenisiert wird, bevor es aufgearbeitet wird.


 
2. Verfahren gemäß Anspruch 1, in der die injizierbare Lösung den Vorfilter bei einem Druck zwischen 1 und 3 atm durchläuft.
 
3. Verfahren gemäß Anspruch 2, in der die injizierbare Lösung den Vorfilter bei einem Druck zwischen 1,5 und 2,5 atm durchläuft.
 
4. Verfahren gemäß Anspruch 1, bei dem der Vorfilter ein oder mehrere Filtereinsätze mit abnehmender Porosität, die in Reihe miteinander verbunden sind, umfasst.
 
5. Verfahren gemäß Anspruch 4, bei dem der Vorfilter zwei Filtereinsätze, die in Reihe miteinander verbunden sind, mit einer Porosität von 1 µ beziehungsweise 0,22 µ umfasst.
 
6. Verfahren gemäß Anspruch 4, bei dem der Vorfilter einen einzelnen Filtereinsatz mit abnehmender Porosität, der eine mittlere Porosität von 0,5 µ aufweist, umfasst.
 
7. Verfahren gemäß Anspruch 1, bei dem die genannten Ultrafiltrationsmembranen aus regenerierter Cellulose sind.
 
8. Verfahren gemäß Anspruch 1, bei dem der transmembrane Druck, der an der Ultrafiltrationseinheit anliegt, eine Ausflussrate des Permeats im Bereich 4 bis 70 L/h pro m2 ermöglicht.
 
9. Verfahren gemäß Anspruch 8, bei dem die genannte Ausflussrate des Permeats zwischen 6 und 55 L/h pro m2 liegt.
 
10. Verfahren gemäß Anspruch 8, bei dem der genannte transmembrane Druck im Bereich von 1 bis 5 atm liegt.
 
11. Verfahren gemäß Anspruch 1, bei dem die Betriebstemperatur während des gesamten Verfahrens im Bereich von 20° bis 55°C liegt.
 
12. Verfahren gemäß Anspruch 1, bei dem die genannte injizierbare Lösung als aktiven Grundbestandteil wenigstens ein nichtionisches, jodhaltiges röntgenkontrastgebendes Mittel umfasst.
 
13. Verfahren gemäß Anspruch 12, bei dem das genannte röntgenkontrastgebende Mittel Iopamidol ist.
 
14. Verfahren gemäß Anspruch 12, bei dem das genannte röntgenkontrastgebende Mittel Iomeprol ist.
 
15. Verfahren gemäß Anspruch 12,bei dem die genannte injizierbare Lösung eine Mischung aus monomeren und dimeren nichtionischen, jodhaltigen, röntgenkontrastgebenden Mitteln umfasst.
 
16. Verfahren gemäß Anspruch 1, bei dem die genannte injizierbare Lösung als aktiven Grundbestandteil wenigstens ein kontrastographisches Mittel für die NMR-Bildgebung umfasst.
 
17. Verfahren gemäß Anspruch 16, bei dem das genannte kontrastographische Mittel ein Chelat des Ions eines paramagnetischen Metalls ist.
 
18. Verfahren gemäß Anspruch 17, bei dem das genannte paramagnetische Chelat aus Gd-BOPTA und GD-HPD03A und deren Salzen ausgewählt ist.
 
19. Anlage zur Depyrogenierung einer injizierbaren Lösung eines Kontrastmittels für die Diagnosebildgebung, welche mit Chargen von wenigstens 800 - 1500 L einer Lösung betrieben wird und umfasst:

- einen Zuführtank (A), der die genannte Lösung enthält;

- eine Vorfiltration-Mikrofiltriereinheit (C), die die Lösung aus (A) durchläuft;

- Pumpeinrichtung zum Pumpen der aus (C) austretenden Lösung in eine Ultrafiltrationseinheit (E);

- Ultrafiltrationseinheit (E), die aus einem oder mehreren Filtrationsmodulen besteht, die sich zum simultanen oder individuellen Betrieb eignen, wobei die genannten Module mit Tangential-Ultrafiltrationsmembranen auf Cellulosebasis mit einer mittleren Ausschlussgrenze von 10000 Dalton ausgestattet sind, um den Durchgang bakterieller Endotoxine zu verhindern, wodurch ein Retentat und ein depyrogeniertes Permeat erhalten werden;

- Mittel zur Rückführung des Retentats von der genannten Einheit (E), wobei das genannte Retentat mit Pyrogenen angereichert ist, unmittelbar in die Lösung, die aus (C) austritt, stromaufwärts der genannten Pumpeinrichtung;

- ein Sammelbehälter, der mit Rührmitteln versehen ist, worin das depyrogenierte Permeat aus der Einheit (E) gesammelt und homogenisiert wird, bevor es aufgearbeitet wird.


 
20. Anlage gemäß Anspruch 19, in der die Lösung aus Tank (A) die Mikrofiltriereinheit (C) bei einem Druck zwischen 1 und 3 atm durchläuft.
 
21. Anlage gemäß Anspruch 20, in der genannte Druck zwischen 1,5 und 2,5 atm liegt.
 
22. Anlage gemäß Anspruch 19, in der die Vorfiltrationseinheit (C) einen oder mehrere Filtereinsätze mit abnehmender Porosität, die in Reihe miteinander verbunden sind, umfasst.
 
23. Anlage gemäß Anspruch 22, bei der die genannte Vorfiltrationseinheit (C) zwei Filtereinsätze, die in Reihe miteinander verbunden sind, mit einer Porosität von 1 µ beziehungsweise 0,22 µ umfasst.
 
24. Anlage gemäß Anspruch 22, bei der die genannte Vorfiltrationseinheit (C) einen einzelnen Filtereinsatz mit abnehmender Porosität, der eine mittlere Porosität von 0,5 µ aufweist, umfasst.
 
25. Anlage gemäß Anspruch 19, bei der die genannten Tangential-Ultrafiltrationsmembranen aus regenerierter Cellulose sind.
 
26. Anlage gemäß Anspruch 19, in der ein Sterilisierfilter (F) mit einer Porosität von 0,2 µm oder weniger stromabwärts des genannten Sammelbehälters angeordnet ist, wobei die depyrogenierte und homogenisierte, injizierbare Fertiglösung vollständig vor der Verpackung sterilisiert wird.
 
27. Verwendung der Anlage gemäß Anspruch 19 für die Depyrogenierung von röntgenkontrastgebenden, injizierbaren, diagnostischen Lösungen.
 
28. Verwendung der Anlage gemäß Anspruch 19 für die Depyrogenierung von injizierbaren, diagnostischen Lösungen für die NMR-Bildgebung.
 


Revendications

1. Procédé à un seul stade pour la dépyrogénation d'une solution injectable d'un agent de contraste pour imagerie diagnostique, ledit procédé fonctionnant sur des volumes de solution allant jusqu'à 800-1 500 litres et comprenant les étapes suivantes :

a) pré-filtration de la solution au moyen d'une unité de microfiltration,

b) passage de la solution obtenue dans l'étape a) au travers d'une unité d'ultrafiltration constituée d'un ou plusieurs modules filtrante qui sont capables de fonctionner simultanément ou individuellement, lesdits modules étant équipés de membranes d'ultrafiltration tangentielle à base de cellulose ayant un seuil de coupure moyen de 10 000 Daltons pour empêcher le passage d'endotoxines bactériennes, ce par quoi un rétentat et un perméat respectant les limites fixées par la pharmacopée pour la teneur en substances pyrogènes sont obtenus ;

c) recyclage du rétentat provenant de ladite unité d'ultrafiltration, directement vers la solution obtenue dans l'étape a), et

d) collecte du perméat dans un collecteur, où il est homogénéisé sous agitation avant d'être complété.


 
2. Procédé selon la revendication 1, dans lequel la solution injectable est amenée à passer au travers du pré-filtre sous une pression comprise entre 1 et 3 atm.
 
3. Procédé selon la revendication 2, dans lequel la solution injectable est amenée à passer au travers du pré-filtre sous une pression comprise entre 1,5 et 2,5 atm.
 
4. Procédé selon la revendication 1, dans lequel le pré-filtre comprend une ou plusieurs cartouches filtrantes de porosité décroissante reliées en série les unes aux autres.
 
5. Procédé selon la revendication 4, dans lequel le pré-filtre comprend deux cartouches filtrantes qui sont reliées en série, ayant des porosités respectives de 1 µ à 0,22 µ.
 
6. Procédé selon la revendication 4, dans lequel le pré-filtre comprend une seule cartouche filtrante de porosité décroissante, ayant une porosité moyenne de 0,5 µ.
 
7. Procédé selon la revendication 1, dans lequel lesdites membranes d'ultrafiltration sont en cellulose régénérée.
 
8. Procédé selon la revendication 1, dans lequel la pression transmembranaire appliquée à l'unité d'ultrafiltration permet un débit du perméat situé dans la plage allant de 4 à 70 l/h par m2.
 
9. Procédé selon la revendication 8, dans lequel ledit débit du perméat est compris entre 6 et 55 l/m2.
 
10. Procédé selon la revendication 8, dans lequel ladite pression transmembranaire est située dans la plage allant de 1 à 5 atm.
 
11. Procédé selon la revendication 1, dans lequel la température de fonctionnement est située dans la plage allant de 20 °C à 55 °C tout au long du procédé.
 
12. Procédé selon la revendication 1, dans lequel ladite solution injectable comprend, en tant que principe actif, au moins un agent radio-opaque iodé non ionique.
 
13. Procédé selon la revendication 12, dans lequel ledit agent radio-opaque est l'iopamidol.
 
14. Procédé selon la revendication 12, dans lequel ledit agent radio-opaque est l'ioméprol.
 
15. Procédé selon la revendication 12, dans lequel ladite solution injectable comprend un mélange d'agents radio-opaques iodés non ioniques monomère et dimère.
 
16. Procédé selon la revendication 1, dans lequel ladite solution injectable comprend, en tant que principe actif, au moins un agent de contraste pour une imagerie RMN.
 
17. Procédé selon la revendication 16, dans lequel ledit agent de contraste est un chélate de l'ion d'un métal paramagnétique.
 
18. Procédé selon la revendication 17, dans lequel ledit chélate paramagnétique est choisi parmi Gd-BOPTA et Gd-HPD03A et des sels de ceux-ci.
 
19. Installation pour la dépyrogénation d'une solution injectable d'un agent de contraste pour une imagerie diagnostique, fonctionnant sur des lots d'au moins 800 à 1 500 litres de solution et comprenant :

- un réservoir d'alimentation (A) contenant ladite solution ;

- une unité de microfiltration de préfiltration (C), par laquelle est amenée à passer ladite solution provenant de (A) ;

- un moyen de pompage pour pomper la solution qui émerge de (C) dans une unité d'ultrafiltration (E) ;

- une unité d'ultrafiltration (E) qui est constituée d'un ou de plusieurs modules filtrante capables de fonctionner simultanément ou individuellement, lesdits modules étant équipés de membranes d'ultrafiltration tangentielle à base de cellulose ayant un seuil de coupure moyen de 10 000 Daltons pour empêcher le passage d'endotoxines bactériennes, ce par quoi on obtient un rétentat et un perméat dépyrogéné ;

- un moyen pour recycler le rétentat provenant de ladite unité (E), ledit rétentat étant enrichi en pyrogènes, directement dans la solution émergeant de (C), en amont dudit moyen de pompage ;

- un collecteur, pourvu de moyens d'agitation, où le perméat dépyrogéné provenant de l'unité (E) est collecté et homogénéisé avant d'être complété.


 
20. Installation selon la revendication 19, dans laquelle la solution provenant du récipient (A) est amenée à passer au travers de l'unité de microfiltration (C) sous une pression comprise entre 1 et 3 atm.
 
21. Installation selon la revendication 20, dans laquelle ladite pression est comprise entre 1,5 et 2,5 atm.
 
22. Installation selon la revendication 19, dans laquelle l'unité de préfiltration (C) comprend une ou plusieurs cartouches filtrantes de porosité décroissante reliées en série les unes aux autres.
 
23. Installation selon la revendication 22, dans laquelle ladite unité de préfiltration (C) comprend deux cartouches filtrantes, qui sont reliées en série, ayant des porosités respectives de 1 µ et 0,22 µ.
 
24. Installation selon la revendication 22, dans laquelle ladite unité de préfiltration (C) comprend une seule cartouche filtrante composite de porosité décroissante, ayant une porosité moyenne de 0,5 µ.
 
25. Installation selon la revendication 19, dans laquelle lesdites membranes d'ultrafiltration tangentielle de ladite unité d'ultrafiltration (E) sont en cellulose régénérée.
 
26. Installation selon la revendication 19, dans laquelle un filtre de stérilisation (F) ayant une porosité de 0,2 µm ou moins est situé en aval dudit collecteur, de sorte que la solution injectable dépyrogénée et homogénéisée finale soit entièrement stérilisée avant d'être conditionnée.
 
27. Utilisation d'une installation selon la revendication 19 pour la dépyrogénation de solutions diagnostiques injectables radio-opaques.
 
28. Utilisation d'une installation selon la revendication 19 pour la dépyrogénation de solutions diagnostiques injectables pour imagerie RMN.
 




Drawing