Classifications

• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F26—DRYING
  • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
  • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
  • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
  • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

• the invention relates to a method for freeze drying under sterile conditions and a container for carrying out the method.
• the invention particularly relates to the drying of biological and / or pharmaceutical material.
• Freeze-drying of biological and pharmaceutical substances is generally known (see also Ullmanns Enzyklopadie der Technischen Chemie, 3rd edition, Vol. I, p. 556 ff.). In order to avoid contamination of the dried goods with germs and other impurities, complex equipment and process engineering measures are taken.
• the procedure is such that vials containing the frozen good are provided with a bacterial filter and the good in the vial is dried in a first drying step until sublimation of the frozen solvent is complete is.
• the so-called post-drying or residual drying the goods remaining moisture removed. Since this second drying step is usually carried out in a special apparatus, the ampoules or vials must be removed from the first drying apparatus in a further contamination-sensitive operation and introduced into the second drying apparatus.
• the bacterial filter is removed and replaced by an aluminum cap with a rubber diaphragm and a hollow needle.
• the drying room is filled with an inert gas and with a slight overpressure and the diaphragm opening is sealed as vapor-tight as possible by a sealing compound.
• freeze-drying of biological and pharmaceutical material is also carried out on plates under sterile conditions.
• a solution of the material to be dried is first sterilized, for example by filtration through a sterile filter, then poured onto plates under sterile conditions and freeze-dried using known methods.
• this method presupposes that the entire freeze dryer can be sterilized. It is also necessary to keep the area around the drying plant germ-free.
• the aim of the invention is to overcome the disadvantages indicated above and to provide a simple method by means of which a sterile, freeze-dried material can be obtained without the complex sterility requirements for the drying system and the space surrounding it.
• the material to be dried is introduced under sterile conditions into a germ-tight sealable container, the boundary wall surfaces of which at least partially consist of a germ-tight, porous, water-vapor-permeable hydrophobic membrane, that the container is sealed germ-tight and pressure-tight, in particular glued or welded, and the material is freeze-dried directly in the closed container under usual conditions.
• the invention is based on the surprising finding that, contrary to expectations, the steam flow resulting from the sublimation of solvent molecules, in particular water molecules, which flows from the material to be dried to the condenser, is only hindered to a small extent by the membrane used in the process according to the invention.
• the freeze-drying of material that is enclosed by the membrane takes place almost as quickly as the freeze-drying of the same open, non-packaged material.
• the membranes used according to the invention are hydrophobic membranes, the pores contain, on the one hand permeable to water vapor, but on the other hand are so small that they can no longer be passed by microorganisms. Such pores preferably have a size of ⁇ 0.5 ⁇ m, in particular of ⁇ 0.2 ⁇ m.
• membranes are preferably used which are still tear-resistant even under the respective process conditions when wet.
• the method according to the invention can also be carried out with less stable membranes, provided that these are reinforced with a carrier material or are not subjected to excessive mechanical stress.
• the proportion of the membrane on the wall surface of the container used in the method according to the invention depends on the respectively selected conditions and the drying time and can easily be found out by a person skilled in the art by simply trying it out.
• the entire wall surface consists of the membrane film, in a further preferred embodiment approximately half.
• the method according to the invention can also advantageously be carried out even if the wall surface consists of only 10% of the membrane film.
• cellulose and conventional cellulose derivatives are particularly suitable.
• membranes made of films of polymer compounds, such as polytetrafluoroethylene or polypropylene, are also preferably used.
• Goretex and similar membranes are also available Usual film tubes used, such as those sold by Vihuri OY, Wipack, Finland, under the name "Mediplast".
• any film membrane can be used regardless of its constituents, provided that it fulfills the requirements specified in DIN standard 58 953 with regard to germ density, air permeability and, in particular, strength.
• the method according to the invention is carried out with a bag or tube, which preferably consists of two walls which are tightly and pressure-tightly connected at their edges, of which one wall consists of liquid-tight material and the other wall is formed by the membrane.
• the membrane is preferably welded or glued to the vessel.
• Troughs are particularly suitable as vessels according to the invention.
• the trough consists of liquid-tight plastic and preferably has a wall thickness of 0.5 to 1 mm.
• drying conditions such as pressure, temperature and quantity, depend on the material to be dried, the thickness of the membrane as well as the size and number of its pores and have to be determined for the respective material and the packaging by usual and simple trials.
• the test of the germ density of a membrane was carried out in accordance with DIN 58 953 in such a way that microorganisms in water drops were placed on the test pieces and after the water drops had dried on it was examined whether microorganisms had passed through on the underside of the test pieces.
• the membrane film to be tested was cut into squares with an edge length of approximately 50 mm.
• the test pieces were sterilized and dried. Each test piece of the sterilized membrane was placed with the side that can be contaminated during use upwards on a sterilized surface and inoculated with 5 drops of 0.1 ml (corresponding to 107 to 107 germs).
• the test pieces were stored at room temperature from 20 to 25 ° C under a relative humidity of 40 to 60%. The drops must be completely dry within 6 hours.
• Each specimen was placed with the inoculated area up on the surface of a blood agar plate (1.5% agar) so that the entire film area came into contact with the agar. After 5 to 6 seconds the paper was removed.
• the plates were incubated at 37 ° C for 16 to 25 h. If the agar plates treated with such film samples show no growth, the film is considered to be sufficiently germ-tight. Further information on testing the germ tightness of membranes, in particular the production of test microbial suspensions, can be found in part 6 of DIN standard 58 953.
• a nutrient solution was prepared which consisted of 10 g peptone, 5 g glucose, 5 g NaCl, 0.084 g KH2PO4, 0.187 g Na2-HPO4x2H2O and pyrogen-free water ad 1.0 l existed and which was adjusted to pH 7.0. It was then sterilized in a closed vial.
• a transparent sterile bag consisting of a transparent film and a suitable paper was prepared to hold the sterile nutrient solution to be lyophilized.
• the commercially available transparent sterilization pouch film from Wipak Medical, type Steri-King R 47, which is tubular, i.e. welded on both sides, otherwise open, located on a roll (width of the roll 400 mm), cut off a piece with a length of 800 mm. This tube was sealed on the two open sides to a bag with a commercially available film device.
• This bag was then sterilized in an autoclave with a filter program at 123 ° C and 2 bar steam pressure, the sterile bag with the transparent film facing downwards for better handling in an unsterile sheet tray (VA sheet, dimensions: length 800 mm, width 400 mm, height 30 mm) and opened in a laminar flow box under sterile conditions with disinfected scissors by cutting off a corner. Through this opening of approximately 30 mm between the film and paper, 1.5 l of the sterile nutrient solution were introduced via a sterile tube pushed into the opening. The bag filled in this way was sealed in the laminar flow box under sterile conditions by means of a commercially available film sealing device by corner sealing.
• the entire arrangement (sheet tray, bag and sterile solution) was placed on a plate pre-cooled to -45 ° C in a commercially available, non-sterilizable freeze drying system from Edwards + Kniese a total floor space of 1.5 m2 and the solution frozen.
• freeze-drying was carried out at a pressure of 10 ⁇ 1 torr and a plate temperature of 22 ° C and the product was dried at 10 ⁇ 3 torr, also under non-sterile conditions.
• the total drying time was approx. 72 h.
• the freeze-dried material thus obtained which was present as a light brown powder in the transparent sterilization bag, was placed in a laminar flow box including the bag and dissolved in 1.5 l of sterile water.
• the intended puncture site on the paper side was disinfected with alcohol, a total of 1.5 l of sterile water was added to the bag using a sterile cannula and a suitable sterile syringe, the dried material was dissolved and the solution was transferred to a sterile bottle. This solution was incubated for 4 days at 37 ° C. and the germ count of the incubated solution was then determined using the membrane filter method.

Landscapes

• Engineering & Computer Science (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Molecular Biology (AREA)
• Mechanical Engineering (AREA)
• General Engineering & Computer Science (AREA)
• Medical Preparation Storing Or Oral Administration Devices (AREA)
• Drying Of Solid Materials (AREA)
• Freezing, Cooling And Drying Of Foods (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)
• Separation Using Semi-Permeable Membranes (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (3)

Family

ID=6355171

Family Applications (1)

Country Status (13)

Cited By (16)

Families Citing this family (4)

Citations (4)

Family Cites Families (2)

• 1988
  • 1988-05-26 DE DE3817906A patent/DE3817906A1/de not_active Withdrawn
• 1989
  • 1989-05-11 IE IE154189A patent/IE61012B1/en not_active IP Right Cessation
  • 1989-05-19 CA CA000600212A patent/CA1337974C/fr not_active Expired - Lifetime
  • 1989-05-23 EP EP89109246A patent/EP0343596B1/fr not_active Expired - Lifetime
  • 1989-05-23 DE DE8989109246T patent/DE58900902D1/de not_active Expired - Lifetime
  • 1989-05-23 AT AT89109246T patent/ATE73226T1/de not_active IP Right Cessation
  • 1989-05-23 ES ES198989109246T patent/ES2030556T3/es not_active Expired - Lifetime
  • 1989-05-24 DD DD89328870A patent/DD283864A5/de not_active IP Right Cessation
  • 1989-05-24 DK DK198902525A patent/DK173643B1/da not_active IP Right Cessation
  • 1989-05-24 PL PL1989279609A patent/PL159938B1/pl unknown
  • 1989-05-25 HU HU892683A patent/HU204126B/hu unknown
  • 1989-05-25 FI FI892563A patent/FI91442C/fi not_active IP Right Cessation
  • 1989-05-26 JP JP1131693A patent/JPH0229256A/ja active Granted
• 1992
  • 1992-05-13 GR GR920400224T patent/GR3004584T3/el unknown

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events