Industrial aseptic distribution line qualification method and associated simulation products

Abstract

Method for qualifying an industrial aseptic distribution line and associated simulation products The present invention relates to the field of biological drugs, in particular the field of blood-derived drugs, and aims to provide a simulation product of such a drug comprising water, glycerin and polysorbate 80 in defined quantities, as well as the associated uses and methods. Figure for abstract: none

Description

Title of the invention: Method for qualifying an industrial aseptic distribution line and associated simulation products

[0001] The present invention relates to the field of biological drugs, in particular the field of blood-derived drugs, and aims to provide a product for simulating such a drug, as well as the associated uses and methods.

[0002] Biological drugs are generally produced by different techniques (recombination, transgenesis, but also by fractionation of plasma pools). However, once the active ingredient has been produced or collected, it is necessary to formulate and package it. On an industrial scale, this formulation and packaging are generally carried out via a production line, which aims to formulate and then distribute the product into final bottles.

[0003] A biological drug production line typically comprises tanks and at least one distribution line (for filling). This line must of course be qualified from a regulatory point of view in order to be used according to the constraints in force. Conventionally, the qualification of a biological drug production line, in particular blood-derived drugs, requires a significant quantity of these products.

[0004] However, given the high value of a batch of blood-derived drugs, there is a need for a product mimicking them ("simulation product"), and which has the same technical characteristics as these blood-derived drugs.

[0005] In addition, blood-derived drugs present specific technical constraints:

[0006] First, blood-derived drugs generally comprise the protein of interest but also other co-purified proteins. Therefore, homogenization in tanks is imperative. However, this homogenization can lead to undesired effects on blood-derived drugs, such as foaming or protein shearing (some proteins are very sensitive to this). This shearing can induce degradation of the protein of interest.

[0007] Furthermore, the presence of foam due to plasma proteins can complicate the distribution of products in the bottle, i.e. due to an incorrect filling volume. The viscosity and surface tension of the product are also parameters to be taken into account to adjust the filling parameters, control the filling flow rate and avoid overflows and / or drips at the edge of the bottle.

[0008] Finally, the simulation products used must meet a clearly identified and robust formulation, readily available in sufficient quantity for the qualification tests. They must be perfectly washable and / or cleanable: for obvious reasons of cleanliness, no residual traces must remain in the equipment. They must not present any adsorption phenomenon with respect to single-use assemblies. And they must of course be risk-free for handlers and equipment.

[0009] The present invention addresses this problem.

[0010] The Applicant has in fact developed simulation products capable of mimicking biological drugs, in particular blood-derived drugs, which can be used in a distribution line, in particular an aseptic one.

[0011] These simulation products are reliable and have properties similar to biological drugs, particularly blood-derived drugs. They are therefore of major interest for qualification, particularly for factory qualification or so-called FAT (Factory Acceptance Test) qualification or for the qualification of on-site equipment or so-called SAT (Site Acceptance Test) qualification, of a distribution line, particularly an aseptic one, because they thus minimize the use of expensive biological products.

[0012] The present invention thus relates to an aqueous solution comprising glycerin and polysorbate 80, in which the solution comprises, preferably consists of: a. an amount ranging from 26.0 to 34.0% by mass based on the total mass of glycerin solution, from 95 to 195 ppm of polysorbate 80, and the remainder being water, or b. an amount ranging from 34.1 to 42.8% by mass relative to the total mass of glycerin solution, from 5 to 70 ppm of polysorbate 80, and the remainder being water, or c. an amount ranging from 13.1 to 23.6% by mass relative to the total mass of glycerin solution, from 5 to 65 ppm of polysorbate 80, and the remainder being water.

[0013] The invention also relates to the use of an aqueous solution according to the invention, for the qualification, in particular for the FAT and / or SAT qualification, of a distribution line, in particular an aseptic one, for industrial biological medicines.

[0014] The invention also relates to the use of an aqueous solution according to the invention, for the parameterization of pharmaceutical equipment with a view to qualifying this equipment.

[0015] The invention also relates to a method for qualifying a distribution line, in particular an aseptic one, for biological medication comprising a distribution tank, comprising the following steps:

[0016] a first step of pouring an aqueous solution according to the invention into the distribution tank, then

[0017] a second step of distributing the aqueous solution from the distribution tank into conditioning units.

[0018] The aqueous solutions according to the invention comprise glycerin and polysorbate 80, in quantities as defined in (a) to (c).

[0019] Each of these solutions (a) to (c) is a simulation product within the meaning of the invention. In particular, each of these solutions (a) to (c) is a simulation product of a biological drug, preferably of a blood-derived drug.

[0020] In the invention, by "biological drug" (or biomedicine), we mean a pharmaceutically active biotechnological product synthesized by a biological source (i.e. living cell) or extracted from it, and not obtained by synthetic chemistry. A biological drug can be chosen from proteins (such as blood-derived drugs, hormones, cytokines or vaccines) and glycans (such as anticoagulants like heparin). A biological drug is a macromolecule that is generally very complex, in particular by its chemical formula, its size and / or its spatial configuration.

[0021] Preferably, the biological drug according to the invention is a blood-derived drug. By "blood-derived drug" (also called human plasma-derived drug (HPD)) is meant a plasma protein concentrate. Preferably, the blood-derived drug is chosen from albumin, immunoglobulins, coagulation factors, coagulation inhibitors, proteinase inhibitors and biological glues. Preferably, the biological drug according to the invention is human.

[0022] Preferably, the biological medicament according to the invention is chosen from human albumin, normal human immunoglobulins (which can be administered intravenously or subcutaneously; they are used in replacement therapy for immune deficiencies and in immunomodulatory treatment), specific immunoglobulins (which can be administered intravenously, intramuscularly or subcutaneously; for example anti-D, anti-varicella / zoster, anti-CMV, anti-HBS, anti-tetanus or anti-rabies), antihemophilic factors (factor VIII and factor IX), von Willebrand factor, prothrombin complex concentrates, fibrinogen, factor VII, factor XI, factor XIII, antithrombin, protein C, Cl esterase inhibitor, alpha-1 antitrypsin and biological glues.

[0023] Preferably, the biological drug or blood-derived drug is chosen from fibrinogen, albumin and immunoglobulins, preferably human.

[0024] Preferably, the aqueous solution according to the invention preferably comprises consists of: a. an amount ranging from 27 to 32% by mass relative to the total mass of glycerin solution, from 100 to 150 ppm of polysorbate 80, and the remainder being water, or b. an amount ranging from 35 to 40% by mass relative to the total mass of glycerin solution, from 7 to 60 ppm of polysorbate 80, and the remainder being water, or c. an amount ranging from 15 to 21% by mass relative to the total mass of glycerin solution, from 7 to 55 ppm of polysorbate 80, and the remainder being water.

[0025] Preferably, the aqueous solution according to the invention comprises, preferably consists of: a. an amount of 30% by mass relative to the total mass of glycerin solution, 100 ppm of polysorbate 80, and the remainder being water, or b. an amount of 40% by mass relative to the total mass of glycerin solution, 10 ppm of polysorbate 80, and the remainder being water, or

[0026] (c) an amount of 20% by mass relative to the total mass of solution of glycerin, 10 ppm polysorbate 80, and the remainder being water.

[0027] Glycerin (or glycerol) is a polyol generally of plant origin, very viscous and soluble in water; it is often used in the pharmaceutical and cosmetic industries.

[0028] Polysorbate 80 (or polyoxyethylene (20) sorbitan monooleate) is a non-ionic surfactant, derived from polyethoxylated sorbitan and oleic acid.

[0029] The water is preferably purified water.

[0030] In particular, solution (a) according to the invention is a product simulating immunoglobulins at 10%. Solution (b) according to the invention is a product simulating albumin at 20%. Finally, solution (c) according to the invention is a product simulating albumin at 4%, or simulating fibrinogen. This is shown in examples.

[0031] The aqueous solutions according to the invention are used for the qualification of a distribution line, in particular an aseptic one, for industrial biological drugs.

[0032] By "distribution line" within the meaning of the present invention, we mean all the equipment making it possible to transfer a batch of product in large quantity, stored in a tank (called distribution tank), to all the final packaging (such as bottle, pre-filled syringe, bag, etc.) constituting the final packaging unit of the finished pharmaceutical product.

[0033] The distribution line occurs at the end of the production line for a pharmaceutical product. It is part of what is generally called the “fill & finish” stages.

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] It allows you to obtain: - either a liquid product in its stoppered packaging unit, which constitutes the finished pharmaceutical product, - either a liquid product in its stoppered packaging unit, which constitutes the intermediate product before the freeze-drying stage (in the case of finished pharmaceutical products in freeze-dried form). The distribution line is generally located in an aseptic environment, for example a clean room or a controlled atmosphere room. It may include or consist of an aseptic distribution unit under an isolator to completely isolate the distribution line and thus eliminate any risk of biological contamination. The distribution line can be fully automated to avoid human intervention and again minimize the risks of biological contamination. The distribution line generally includes the following equipment: - a distribution tank for storing bulk pharmaceutical products, - connectors such as pipes, tubes or tubing, connecting the distribution tank to the distribution system, - possibly a sterilizing filtration system between the distribution tank and the distribution system - a distribution system, equipped with one or more filling needles, allowing the bulk pharmaceutical product to be distributed into its packaging unit (bottle, syringe, bag), and - a container closure system (for example, a stopper and / or capping type). The distribution line equipment can be reusable equipment (after cleaning and sanitization) and / or single-use disposable equipment. Qualification is an operation intended to demonstrate that any material or equipment used for manufacturing, packaging or control functions correctly and gives expected results for the use for which it is intended. The qualification of equipment aims to demonstrate, through appropriate tests, complete documentation and records, that the equipment has been correctly put into service and that future uses will be reliable and will fall within the prescribed or specified limits of use. The qualification operation makes it possible to verify and guarantee the reliability of equipment, to establish operating procedures, to plan maintenance, servicing and / or the replacement of defective elements in order to ensure compliance with the standards or specifications defined and necessary for the quality of the manufactured products. It provides a certain control over the critical aspects of operations.

[0040] Preferably, the aqueous solution according to the invention is used for the qualification, in particular for the qualification of on-site equipment (or so-called S AT qualification for “Site Acceptance Test”) of a distribution line, in particular aseptic, of biological medicine.

[0041] The aqueous solution according to the invention can also be used for the parameterization of pharmaceutical equipment with a view to qualifying this equipment, in particular for the parameterization of pharmaceutical equipment with a view to validating a step in a process for preparing or packaging a pharmaceutical product.

[0042] Pharmaceutical equipment is typically any reusable equipment present on the distribution or packaging line of a pharmaceutical product. For example, it may be a tank.

[0043] The configuration of equipment concerns the addition, removal or modification of any element of equipment allowing the manufacture of a pharmaceutical product in accordance with the expected. For example, it may involve the addition of valves to control the transfer rate of a product.

[0044] The invention also relates to a method for qualifying a distribution line, in particular an aseptic line, for biological medication comprising a distribution tank, comprising the following steps:

[0045] a first step of pouring an aqueous solution according to the invention into the distribution tank, then

[0046] a second step of distributing the aqueous solution from the distribution tank into conditioning units.

[0047] The qualification of a distribution line, possibly including a parameterization of the pharmaceutical equipment used during the distribution step, ensures that the finished pharmaceutical product will conform to what is expected.

[0048] Annex 1 of the European Good Manufacturing Practices requires at least three consecutive successful process simulations to demonstrate the aseptic performance of a new installation or filling line.

[0049] The distribution line of the method according to the invention is a distribution line for a biological drug, preferably a blood-derived drug. It is preferably aseptic.

[0050] By "distribution tank" is meant a tank-type container allowing a large volume of bulk pharmaceutical product to be stored before its distribution (distribution) into the final packaging units (for example, such as bottles, syringes or bags) which constitute the finished distributed pharmaceutical product.

[0051] The distribution tank may be a single-use device, of the pocket type in single-use plastic, or more traditionally reusable equipment, for example stainless steel, which can be cleaned and sanitized before reuse.

[0052] The distribution tank may also comprise an internal device allowing the homogenization of the solution contained, for example such as a blade, a propeller or an agitator.

[0053] By "packaging unit" is meant a primary packaging unit. Primary packaging corresponds to the first "package". In the pharmaceutical industry, this packaging is not to be neglected: it is in direct contact with the product being produced. The choice of suitable primary packaging that is compatible with the drug is one of the prior regulatory requirements. The materials used for primary packaging meet the following technical criteria: - appropriate permeability: the packaging must be impermeable to external agents; - chemical inertia with respect to the product: the packaging must avoid exchanges between the container and the contents; - safety for the patient: the packaging must not be harmful or toxic for the patient; - minimum physical resistance: the packaging must be able to not break easily during storage and transport; - good neutrality: for example, the packaging must not give any taste to the product; and - an ability to undergo process treatments (for example, hot molding, heat sealing).

[0054] Preferably, the materials used for primary packaging are glasses, plastics, rubbers or certain metals.

[0055] Preferably, the packaging units are chosen from vials, syringes, ampoules and infusion bags. Preferably, the packaging units are made of glass.

[0056] The invention is now illustrated with the following examples.

[0057] Example 1: Development of simulation products (SPP) according to the invention

[0058] The simulation products (SPPs) developed are intended to be used in MPVP (Purified Bulk Raw Material) tanks and Distribution tanks, for the production of the following 4 blood-derived medicines:

[0059] • Immunoglobulins 10%,

[0060] • Albumin 20%,

[0061] • Fibrinogen, and

[0062] • Albumin 4%.

[0063] The objective of these PdS is to evaluate the capacity of MPVP tanks and Ré tanks partition to homogenize the MPVPs, while limiting the risks of shearing and the foaming effect induced by plasma products. The aim is also to evaluate the distribution lines (foam control, drop control and filling capacity).

[0064] 1 / The physicochemical characteristics to be investigated are as follows: viscosity, density, surface tension and foaming power.

[0065] For this purpose, these physicochemical characteristics were first determined for each plasma-derived product.

[0066] More precisely, the viscosity is measured using a rheometer (Mars III, Thermo Scientific) which will study the flow and deformation of the material under the effect of an applied stress (shear). Here, the dynamic viscosity is determined at 20°C via the measurement of a shear stress applied through a flow velocity gradient in the material, expressed in mPa.s.

[0067] The viscosity measurement results obtained at 20°C are as follows:

[0068] [Tables 1] Product Viscosity measurements at 20°C (mPa.s) - 3 different lots Albumin 20% 4.6; 4.6; 3.9 Immunoglobulins 10% 3.3; 3.2; 3.3 Albumin 4% 1.9; 2.2; 1.9 Fibrinogen 2.2; 2.5; 2.4

[0069] For information, the viscosity of water at 20°C is 1.0 mPa.s.

[0070] The density is measured at 20°C, on 3 different batches of each product. For information / reference, the density of water at 20°C is 1.000.

[0071] Density is measured using a densitometer (Anton PAAR DMA 500) using the oscillating U-tube method. The sample is injected into a borosilicate glass U-tube, which is oscillated at its characteristic frequency. The characteristic frequency varies depending on the sample's density (or specific gravity). The sample's density can be calculated by precisely determining the characteristic frequency. Density, or specific gravity, can be expressed either in units of mass per unit volume (e.g., g / cm3) or without units.

[0072] The density measurement results obtained at 20°C are as follows:

[0073] [Tables2] Product Density measurements at 20°C - 3 different lots Albumin 20% 1.055; 1.055; 1.055 Immunoglobulins 10% 1.033; 1.033; 1.033 Albumin 4% 1.014; 1.014; 1.014 Fibrinogen 1.021; 1.021; 1.020

[0074] Surface tension is measured using a Wilhelmy plate tensiometer (KRUSS, Germany) capable of measuring the surface tension of a liquid at equilibrium at 20°C, via a thin plate connected to a precision balance. The device measures the force exerted on this plate, which is perpendicular to the air-liquid or liquid-liquid interface. Surface tension is expressed in mN / m.

[0075] The surface tension results obtained at 20°C are as follows:

[0076] [Tables 3] Product Surface tension measurements at 20°C (mN / m) - 3 different lots Albumin 20% 48.9; 50.3; 49.5 Immunoglobulins 10% 42.7; 43.2; 42.7 Albumin 4% 51.0; 50.2; 51.5 Fibrinogen 56.3; 53.1; 56.4

[0077] For information, the surface tension of water is 73 mN / m, and that of an aqueous solution at 0.1% by weight of casein is 49 mN / m.

[0078] The foaming power is measured using a Foamscan (Teclis Scientific) which will form the foam by bubbling air into the solution studied at 20°C and at a flow rate of 200 mL / min for 30 seconds. The volume of foam generated (in mL) is then recorded.

[0079] The foaming power results obtained at 20°C are as follows:

[0080] [Tables4] Product Foaming power measurements at 20°C (mL) - 3 different lots Albumin 20% 135.5; 139.3; 136.1 Immunoglobulins 10% 138.1; 141.7; 144.9 Albumin 4% 136.2; 137.9; 144.7 Fibrinogen 143.3; 146.2; 141.9

[0081] For information, the foaming power of a 0.1% by mass aqueous solution of egg white protein is 120 mL.

[0082] The average results are as follows:

[0083] [Tables5] MPVP Viscosity (mPa.s) Density Surface tension (mN / m) Foaming power (mL) Albumin 20% 4.4 1.055 49.6 137 Immunoglobulins 10% 3.2 1.033 42.9 142 Fibrinogen 2.4 1.021 55.3 144 Albumin 4% 2.0 1.014 50.9 140

[0084] 2 / Then by playing on these four physicochemical characteristics (viscosity, density, surface tension and foaming power), the PdS in Table 6 were formulated.

[0085] Unless otherwise stated, the quantities are indicated as a percentage by mass relative to the total mass of the composition (% m / m).

[0086] [Tableauxô] Ingredient (% m / m) Weight No. 1 Weight No. 2 Weight No. 3 Glycerin 30 40 20 Polysorbate 80 (Tween 80) Quantity in ppm 100 ppm 10 ppm 10 ppm Purified water Qsp 100 Qsp 100 Qsp 100

[0087] They present values ​​close to those of blood-derived drugs (see table 7). In particular: - PdS No. 1 is a product simulating 10% immunoglobulins; - PdS No. 2 is a 20% albumin simulant product; and - PdS No. 3 is a product simulating 4% albumin and fibrinogen.

[0088] [Tables?] PdS Viscosity (mPa.s) Density Surface tension (mN / m) Foaming power (mL) PdS n°1 2.8 1.072 39.1 121 PdS n°2 3.9 1.098 55.0 130 PdS n°3 2.2 1.047 49.0 118

[0089] 3 / A robustness study is carried out to validate the choice of these 3 PdS.

[0090] The impact of a deviation from the target composition of the PdS was studied on their physicochemical behavior. A series of various PdS compositions was proposed using statistical software (Design Expert®), by varying the percentage of glycerin and polysorbate 80 (PS80). Thus, the deviations from the target composition, acceptable or not, were determined.

[0091] Setting up the study on Design Expert®:

[0092] 2 factors studied: A = % glycerin and B = log [PS 80]

[0093] 3 Answers are proposed for study:

[0094] - Viscosity,

[0095] - Surface Tension, and

[0096] - Foaming Power (Foaming).

[0097] Choice of the “Response Surface study” model and a “User-defined” design: implementation of a 5-level design (for factor A and factor B).

[0098] Plan with 25 different composition combinations.

[0099] At the end of the tests on the 25 compositions, each of the responses was studied and graphically mapped.

[0100] The “Viscosity” response is mainly determined by the glycerin load, here studied between 5 and 45% m / m, a space in which it is possible to see that the viscosity evolves from less than 2 mPa.s to more than 4 mPa.s.

[0101] The surface tension depends rather on the PS80 charge. Between 0.7 and 2.3 log of the PS80 concentration, corresponding to 5 to 200 ppm, the surface tension evolves from 55 to less than 45 mN / m.

[0102] Finally, the “Foaming” response appears to demonstrate a rather “hybrid” behavior, depending on both the PS80 and glycerin loading. Generally speaking, the product is likely to foam a lot when the PS80 loading is high with relatively little glycerin.

[0103] Once the Responses are studied in the corresponding design space, acceptance criteria are set on each Response for all the PdS.

[0104] The acceptance criteria are as follows:

[0105] [Tables8] PdS Target Viscosity (mPa.s) Viscosity Criteria Min - Max Surface Tension (mN / m) Surface Tension Criteria Min - Max PdS No. 1 2.8 2.5 - 3.2 Approx. 40 37-43 PdS No. 2 3.9 3.6-4.4 Approx. 52 44-60 PdS No. 3 2.2 2.0 - 2.4 Approx. 52 44-60

[0106] Final acceptance criteria for PdS 1

[0107] [Tables9] Criterion Parameter Range Minimum Maximum Viscosity Glycerin (% w / w) PS80 (ppm) 26.0 5 34.0 200 Surface tension Glycerin (% w / w) PS80 (ppm) 5 10198=95 ppm 45 102.29 = 195 ppm Endpoint Glycerin (% w / w) PS80 (ppm) 26.0 95 34.0 195

[0108] Final acceptance criteria for PdS2

[0109] [TableauxlO] Criterion Parameter Range Minimum Maximum Viscosity Glycerin (% w / w) PS80 (ppm) 34.1 5 42.8 200 Surface tension Glycerin (% w / w) PS80 (ppm) 5 10°71 = 5 ppm 45 10185= 70 ppm Final criterion Glycerin (% w / w) PS80 (ppm) 34.1 5 42.8 70

[0110] Final acceptance criteria for PdS3 [YES] [Tableauxll] Criterion Parameter Range Minimum Maximum Viscosity Glycerin (% w / w) PS80 (ppm) 13.1 5 23.6 200 Surface tension Glycerin (% w / w) PS80 (ppm) 5 10071 = 5 ppm 45 10181 = 65 ppm Endpoint Glycerin (% w / w) PS80 (ppm) 13.1 5 23.6 65

[0112] Based on these results, PdS Nos. 1, 2 and 3 may comprise glycerin and polysorbate 80 in the following ranges:

[0113] [Tablesl2] % w / w Glycerin ppm Polysorbate 80 Weight No. 1 26.0 - 34.0 95 - 195 Weight No. 2 34.1-42.8 5-70 Weight No. 3 13.1-23.6 5-65

Claims

Claims

1. An aqueous solution comprising glycerin and polysorbate 80, wherein the solution comprises, preferably consists of: a. an amount ranging from 26.0 to 34.0% by mass based on the total mass of glycerin solution, from 95 to 195 ppm of polysorbate 80, and the remainder being water, or b. an amount ranging from 34.1 to 42.8% by mass relative to the total mass of glycerin solution, from 5 to 70 ppm of polysorbate 80, and the remainder being water, or c. an amount ranging from 13.1 to 23.6% by mass relative to the total mass of glycerin solution, from 5 to 65 ppm of polysorbate 80, and the remainder being water.

2. An aqueous solution according to claim 1, which preferably comprises: a. an amount of 27 to 32% by mass relative to the total mass of glycerin solution, 100 to 150 ppm of polysorbate 80, and the remainder being water, or b. an amount of 35 to 40% by mass relative to the total mass of glycerin solution, 7 to 60 ppm of polysorbate 80, and the remainder being water, or c. an amount of 15 to 21% by mass relative to the total mass of glycerin solution, 7 to 55 ppm of polysorbate 80, and the remainder being water.

3. An aqueous solution according to claim 1 or 2, which comprises, preferably consists of: an amount of 30% by mass relative to the total mass of glycerin solution, 100 ppm of polysorbate 80, and the remainder being water, or an amount of 40% by mass relative to the total mass of glycerin solution, 10 ppm of polysorbate 80, and the remainder being water, or an amount of 20% by mass relative to the total mass of glycerin solution, 10 ppm of polysorbate 80, and the remainder being water.

4. Use of an aqueous solution according to one of claims 1 to 3, for qualification, in particular for factory qualification or FAT (Factory Acceptance Test) qualification and / or for qualification on site (or qualification known as SAT for “Site Acceptance Test”), of a distribution line, in particular aseptic, industrial biological drug distribution.

5. Use of an aqueous solution according to one of claims 1 to 3, for the parameterization of pharmaceutical equipment with a view to qualifying this equipment.

6. Method for qualifying a distribution line, in particular an aseptic one, for biological medication comprising a distribution tank, comprising the following steps: a first step of pouring an aqueous solution according to one of claims 1 to 3 into the distribution tank, then a second step of distributing the aqueous solution from the distribution tank into packaging units.

7. A method according to claim 6, characterized in that the distribution line is a distribution line of a blood-derived drug.

8. Method according to claim 6 or 7, characterized in that the biological drug or the blood-derived drug is chosen from fibrinogen, albumin and immunoglobulins, preferably human.

9. Method according to one of claims 6 to 8, characterized in that the packaging units are chosen from bottles, ampoules and infusion bags.

10. Method according to one of claims 6 to 9, characterized in that the packaging units are made of glass.