Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions

Abstract

A sterile procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions; among these being syringes, vials, capsules, ampoules, single-dose devices or cartridges filled with solid substances selected from the group formed by powder, granules, pellets, nanoparticles or microparticles, obtaining the airtightness of said containers. The invention involves a procedure for filling pharmaceutical containers comprising the steps of a) providing a pharmaceutical container having walls and a bottom, b) dispensing the solid into a pharmaceutical container by means of a dispensing needle, gravimetrically checking the weight of solid dispensed into the container; and c) sealing the pharmaceutical container with a stopper, wherein in at least one of the steps, or plurality thereof, the static charges inside the container are neutralised by means of an ioniser such that the charge inside each container is less than 2000 volts, characterised in that between steps b) and c), an additional static charge is carried out inside the container. Conventional filling processes are susceptible to particles adhering to container walls or other nearby surfaces. The invention aims to solve this issue. More specifically, the procedure achieves the avoidance of the adherence of the aforementioned substances to the sides of the pharmaceutical containers, thus ensuring the airtightness of the seal of the container and likewise the exactitude of the weight of solid dispensed into the container.

Description

[0001] Procedure for filling solids into pharmaceutical containers and sealing them under sterile conditions

[0002] Field of invention

[0003] The present invention falls within the field of filling and sealing, under sterile conditions, pharmaceutical containers, including syringes, vials, capsules, ampoules, single-dose devices, or cartridges, filled with solid substances selected from the group consisting of powders, granules, pellets, nanoparticles, or microparticles, achieving a watertight seal. More particularly, the invention relates to a process for filling and sealing pharmaceutical containers filled with one or more sterile solid pharmaceutical substances or sterile excipients, dosed and prepared in an aseptic environment, which prevents the aforementioned substances from adhering to the sides of the pharmaceutical containers, thus ensuring a watertight seal.

[0004] State of the art.

[0005] In the pharmaceutical industry, the filling process for pharmaceutical containers is usually carried out with liquid and / or lyophilized solid pharmaceutical substances, as these are much easier to handle and present fewer problems during dosing than solids such as powders, granules, pellets, nanoparticles, or microparticles, among others. The use of solids like those mentioned above in the container filling process has the major drawback that these solids tend to adhere to the walls or body of the containers, preventing or at least hindering the creation of the necessary airtight seal.This adherence to the walls or body, besides preventing the desired airtight seal, leads to contamination of the containers and the loss of doses. Containers exhibiting such adherence to the walls must be discarded because, with some of the solid remaining in the sealing area of ​​the container walls, the exact amount of solid to be administered to the patient cannot be determined. Furthermore, regarding contamination, when the dosed solid adheres to the walls of this sealing area, the cap used to seal the container does not create a hermetic seal. Therefore, it cannot prevent the entry of substances from the environment into the container and does not ensure the integrity of the product, potentially altering its physicochemical and microbiological properties and affecting the quality of the medication.This is the biggest drawback that the pharmaceutical industry can encounter in this field due to the strict conditions imposed by the regulations of said industry, which must also comply with the standards known as Good Manufacturing Practices (GMPs).

[0006] Another concern for the pharmaceutical industry is ensuring the integrity of the closure, which also impacts safety, as even small leaks of the medication can affect the safety of healthcare personnel handling it. Integrity refers to the ability of a container's closure system to maintain the sterility and quality of the final sterile pharmaceutical, biological, and vaccine products throughout their shelf life. Similarly, a sterile product is defined as one free of microorganisms, whose composition includes one or more elements exposed to aseptic conditions and which ultimately comprise the finished sterile pharmaceutical product. These elements include containers, closures, and components of the finished pharmaceutical product.

[0007] When dispensing powder into pharmaceutical containers, several factors affecting the cleanliness of their interior walls must be considered, as a lack of cleaning leads to contamination. These factors are listed below:

[0008] -The static charge of the walls of the pharmaceutical containers used for filling, as well as the static charge of the solid that is dosed into them: If the charges of the walls and the solid are opposite, the dosed solid will adhere to the walls of the containers.

[0009] -The kinetic energy that both the dosed solid and the elements in contact with it acquire when the solid falls inside the containers: The greater the height from which the solid to be dosed falls in free fall to the bottom of the containers, the greater the kinetic energy that the solid and the elements in contact with it acquire due to friction with it.

[0010] The length of the dispenser needle (also called a "nozzle") used for dosing is important, as the longer the dispenser and the closer it is to the top of the solid being dispensed in the container, the less kinetic energy it will have. Furthermore, the dispenser directs the solid to an area away from the surface of the container walls. The ideal distance between the solid being dispensed and the dispenser tip will depend on the dosage, the dispensing speed, and the density of the solid being used.

[0011] -The redirection of displaced air inside the containers. This phenomenon is related to the kinetic energy of the dispensed solid as it is released inside the container. During dispensing, the solid's entry into the container displaces the air inside upwards. This displaced solid is full of suspended particles. Therefore, the dispenser can be considered a "chimney" that directs this airflow away from the inner walls, protecting them from this contamination.

[0012] The use of large airflow currents (unidirectional or turbulent) in filling booths or areas is required by international pharmacopoeias to ensure the removal of any particles foreign to the aseptic filling and sealing process that could contaminate the final product. However, the use of these airflow currents makes filling with solid substances quite difficult, as they create a disturbance that causes the solid to adhere to the walls of the filling container.

[0013] To eliminate the adhesion of the solid to the container walls, one of the measures to be taken is to carry out an ionization process of both the container and the solid to be filled into it. In the present invention, the terms “process,” “stage,” and “phase,” as well as the terms “ionization” and “deionization” or “ionizer” and “deionizer,” are used interchangeably.

[0014] Ionization is a chemical or physical phenomenon by which ions are produced. Ions are atoms or molecules that are electrically charged due to an excess or deficiency of electrons compared to a neutral atom or molecule. The chemical species with more electrons than the neutral atom or molecule is called an anion and has a net negative charge, while the one with fewer electrons is called a cation and has a net positive charge.

[0015] The ionization process employed in the present invention is used both to neutralize the electrostatic charge of the pharmaceutical container to be filled with the pharmaceutical solid and to neutralize the electrostatic charge of the solid to be dispensed; that is, both the container and the contents. Likewise, this ionization is also used to neutralize the components of the dispensing and capping equipment that come into contact with the container and / or the powder. To achieve this, the ionizer generates ions of both polarities, which are projected onto the surface of the object to be neutralized. There, ions of opposite charges recombine, and ions of the same charge are repelled.Throughout this document, “ionizer” will mean any element or device that is capable of ionizing the surrounding air molecules, so that they are then projected onto a surface that has static electrical charges in order to neutralize said charges, and consequently ionize said surface.

[0016] However, this ionization process alone cannot prevent the serious problem of adhesion to the sides of the container that occurs during the filling process with solids, since when the solid is filled through the nozzle, the kinetic energy of the solid generates turbulence inside the container which ultimately causes some of the solid to adhere to the walls or body of the container.

[0017] Regarding the state of the art, the documents cited below describe the ionization technique that causes a neutralization of electrical charges applied to various situations;

[0018] Thus, we find the publication of US patent 2016 / 0200481 A1, filed by VANRX Pharmasystems INC, which describes a method for the volumetric filling and aseptic sealing of containers such as vials, bottles, syringes, and ampoules with a liquid pharmaceutical product (which may be subsequently lyophilized) in a controlled environment. This publication addresses concerns regarding the materials used to manufacture the containers, whether glass or polymeric materials, as glass containers are susceptible to breakage, scratches, and particle emission due to collisions. On the other hand, polymeric containers are more resistant than glass, although they can suffer cosmetic defects such as scratches, which are potential defects that could compromise the quality of the pharmaceutical product due to collisions.

[0019] A substantial difference between the present invention and the cited document is that the compounds handled are solid substances that are much more difficult to dose because they are highly charged and have a larger specific surface area. Furthermore, in the cited document, the sealing process consists of two stages: a partial stage and a complete stage due to the need for lyophilization after the first partial sealing. In contrast, in the present invention, the sealing process is carried out in a single, complete stage, without the need for subsequent sealing steps.

[0020] Additionally, it should be noted that the filling process for solid substances is much more complex because the solids adhere to the walls of pharmaceutical containers, compromising dosage accuracy. This is particularly relevant in small-caliber containers where precise dosing of small quantities of medication is required. This issue is resolved by the procedure proposed in the present invention, as it is important to consider that, for the pharmaceutical industry, an error in filling the active ingredient can result in patients receiving an inadequate dose of the product.

[0021] This poses a serious problem when filling containers with solids due to the solid's adherence to the container body. For this reason, most procedures used today in the pharmaceutical industry require equipment qualification to ensure the correct dosage. Furthermore, various in-process controls are incorporated during packaging to verify the actual fill quantity of all pharmaceutical containers. One common control involves weighing the containers, allowing for the correction or disposal of those where the quantity of pharmaceutical substance, whether medication or active ingredient, does not meet the required weighing precision. In-process controls can be 100% or statistical; the latter are performed periodically to verify the dosage.These controls involve a high production and economic cost necessary to control the accuracy of the product dosage.

[0022] Regarding the elimination of electrostatic charge, several types of ionizers are available to address this problem. These ionizers come in various forms, such as rings, bars, guns, curtains, blades, cannons, needles, or ionizing filters. Isolators with an ionizer on their roof are also available, among others. For the purposes of this invention, these ionizers can be installed in the machinery used for the filling process, producing ions of both polarities to neutralize the surface of the containers or products. Alternatively, they can be placed in packaging areas, rooms, or insulators, specifically on their roofs, to produce ionization that neutralizes both the environment and the airflow in the area, thus eliminating the problem of static charges.Regarding the elimination of static charge from solids using ionizers, we found several documents cited below:.

[0023] European patent EP 2711096 A2, filed by TRINC Corporation, relates to a device for removing electrostatic charge and dirt from objects such as film, sheets, glass, clothing, paper, or similar materials. The device comprises a large container with an opening at the top and another at the bottom for drawing in and discharging dust, and a small, cylindrical or conical container within the larger container. This small container is designed to generate cyclone and tornado currents within it and includes at least one corona discharge ion generator. This ion generator consists of electrical discharge needles arranged either on top of or inside the small container.The small container consists of air injection openings through which compressed air is injected, as well as ultrasonic generators inside or outside the small container that vibrate the powder, allowing it to be separated from the desired object once it has been neutralized by the ion generator. This powder can then be collected by vacuum suction into the large container.

[0024] The present invention, however, deals with the deionization of both the container and the powder prior to packaging to prevent the powder from adhering to the container walls during the filling process and thus achieve a complete seal. Furthermore, as a safety measure, deionization is performed on and / or inside the container to remove any remaining powder adhering to the walls of the sealing area.

[0025] The present invention also utilizes an ionizer—whether in the form of a ring, rod, gun, curtain, blades, cannon, needle, or nozzle—or an ionizing filter. Among these, insulators with an ionizer on their roof can also be found. This ionizer eliminates static electricity from both the powder and the container, unlike European patent EP 2711096 A2, which focuses solely on ionizing the powder and does not ionize the container. Another substantial difference between the present invention and this patent is that EP 2711096 uses compressed air to facilitate suction, while the present invention does not require an airflow, and if one is needed, it must be a sterile carrier gas. Among sterile carrier gases, ionized nitrogen offers advantages that will be discussed later.A key limitation of the present invention is the need to perform deionization in sterile environments, thus requiring the use of sterile carrier gases. It should be noted that this requirement of carrier gas sterility does not affect the deionization process.

[0026] On the other hand, European patent EP 2711096 A2 differs from the present invention in that, although for both it is important to eliminate the electrostatic charge of the solid, this publication does not mention in detail the method by which it carries it out, mentioning only the use of an ion generator such as discharge needles to deionize, without mentioning the problem caused by the electrical discharge needles when they approach any solid, which is that a combustion phenomenon occurs that burns the product generating impurities and altering the physicochemical composition of the product.

[0027] Japanese patent application JP 2005001818 A, filed by YMS KK, relates to a powder supply device and an air conveying device capable of feeding fluidized charged powder and charged powder. This device comprises a hopper equipped with aeration means, which in turn are equipped with a microporous diaphragm for aerating the powder in the hopper. The air for aeration is pre-ionized by an ionization device, such as a corona discharge device. Compressed air supplied by an air compressor is used for aeration. This compressed air is ionized by an air ionization device comprising a corona discharge device or similar. When aeration is performed by the ionized air, the ionized air neutralizes or eliminates the surface charge of the powder, so that the surface charge of the charged powder disappears.Furthermore, when aeration causes the powder in the hopper to inflate with air, forming an air layer between the powder and the hopper's inner wall, it prevents the powder from being refilled. On the other hand, this document refers to a nozzle or suction needle made of conductive material that is part of the air conveying device. The nozzle is never used for dosing.

[0028] In the present invention, on the contrary, ionization is carried out on one side of the solid substance and on the other side of the pharmaceutical container, for which a sterile carrier gas stream is used as the ionizing gas; generally a sterile nitrogen stream. Another difference between the present invention and this Japanese patent lies in the nozzle or needle: in the case of this Japanese patent, it refers to a suction nozzle made of conductive material, whereas in the present invention, the nozzle is a dispensing needle and is not made of conductive material.In contrast to this Japanese patent, the present invention also uses an ionizer, whether in the form of a ring, rod, gun, curtain, blades, cannon, needle or nozzle, or an ionizing filter, which may also include insulators with an ionizer on the roof of said insulator or any other type, to neutralize the electrostatic charge of both the container to be filled and the solid to be dosed, whereas the Japanese patent only mentions the use of a corona discharge ionizing device or similar.

[0029] The Chinese utility model CN ​​203265193U, issued by Meech Static Eliminators Shanghai Co., Ltd., relates to the technical field of static electricity and dust removal from the inner walls of bottles prior to filling, as a cleaning method. It uses an ion needle with compressed air to eliminate static electricity and remove dust adhering to the bottle walls. The device described in this utility model consists of a needle, a first tube connecting the needle, and a second tube connecting the electrical cable. The two ends of each tube have either an internal or external thread, respectively. The needle tip and the second tube are screwed and secured together. The needle tip, the first tube, and the second tube have an interconnected internal passage for airflow. The second tube also has at least two threads, such that the passage wire is also connected to the internal bore of the first tube.The tube has uniformly spaced wire holes between its inner and outer walls. Each of these holes forms an ion-generating end at one end of a second tube that fits into the first. Ions can be introduced onto the surface of the target object via the ion needle and with the aid of compressed air.

[0030] In the present invention, on the contrary, the ionizer can be of any type: ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or even an ionizing filter. Among these, isolators with an ionizer on their roof are also possible, and it is not necessary for it to be a needle ionizer, as specifically mentioned in the Chinese utility model. Furthermore, this utility model uses compressed air to move the ions, whereas the present invention may or may not use a sterile carrier gas stream, which can be sterile nitrogen or compressed air. This not only facilitates the ionization process by aiding in the dosing of the solid but also maintains the necessary sterile conditions required in these pharmaceutical industry procedures by generating an inert atmosphere inside the containers.On the other hand, the utility model refers to the cleaning of bottles with powder prior to filling; in contrast, the present invention refers to deionization and cleaning of walls after filling and applies to containers smaller than bottles such as syringes, vials, capsules, ampoules, single-dose devices or cartridges, which are more difficult to fill with a solid such as powder.

[0031] International patent publication WO 2016 / 185230 A2, filed by 3P Innovation Limited, describes an apparatus and method for filling pharmaceutical containers, such as syringes, vials, capsules, cartridges, and blisters, with powdered pharmaceutical material using vibration. This apparatus comprises a support for the pharmaceutical container, a reservoir for holding the powdered pharmaceutical substance (this reservoir is in contact with a nozzle or filling needle that fills the container with the powdered pharmaceutical substance), and a piezoelectric vibration device. The publication highlights the advantage of using a cylinder made of an electrically conductive material, which can be grounded via a weight cell. This grounding helps dissipate static charge from the plastic pharmaceutical containers, resulting in a more efficient powder filling process without compromising cleanliness.However, the invention described in that document would not require the material to be electrically conductive, since it is a filling procedure through the mouth of the container, so the problem of watertightness that occurs when filling is done from the back of said container would not occur.

[0032] The present invention, on the other hand, relates to a procedure for sealing pharmaceutical containers that are filled with solid pharmaceutical substances, and said filling is carried out under aseptic conditions without the need for terminal sterilization, whereas the international publication WO 2016 / 185230 A2 describes filling through the mouth of the container as can be seen in figure number 2. On the other hand, this international publication only mentions the filling of plastic pharmaceutical containers, while the present invention covers all types of materials, such as polymeric materials or glass, that make up the container.Furthermore, the international publication mentions a cylinder or puck with an electrically conductive material to dissipate the static charge of the pharmaceutical containers to be used, whereas, in the present invention, the existence of a cylinder that acts as a support for the container is an optional element, unrelated to the problem to be solved, and which is also directed to other various functions, such as: -The use of said element for the manipulation of the container without contact with it!.

[0033] -The cylinder protects the process from air currents by forming part of the "exclusion bell".

[0034] -This is a vertical support element for the container on the weighing cell to perform a precise weighing.

[0035] Furthermore, in the present invention it is possible to use any ionizer, whatever its form, i.e.: ring, rod, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which can also be found isolators with an ionizer on the roof of said isolator that can be installed in the packaging equipment prior to filling, during filling and after filling using or not a sterile carrier gas, whereas the invention described in the aforementioned international publication only deals with a cylinder (puck) with electrically conductive material that can dissipate the static charge of the plastic container used during filling.

[0036] Summary of the invention

[0037] Accordingly, the problem to be solved in the present invention is to provide a procedure for filling pharmaceutical containers that can take the form of vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, sachets, bags, test tubes, Eppendorf-type tubes ® and syringes. The syringes of the present invention may be with a needle or with a catheter-type cone, or a Luer lock cone, that is, with a threadless nozzle or with a female or male threaded nozzle, respectively. For the purposes of the present invention, “Luer cone” refers to the cone-type nozzle invented by Wülfing Luer with a typical taper of 6%, which may be male or female depending on the connection. Likewise, “Luer lock cone” refers to the cone-type nozzle invented by the German Wülfing Luer with a threaded locking mechanism.

[0038] The compounds of the containers of the present invention are materials such as plastics of different composition, such as polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, polyvinyl chloride, polyacrylonitrile, polyamides, etc., polyesters (containing the ester functional group in their main chain: poly(ethylene terephthalate), polycarbonate), acrylic polymers (poly(methyl methacrylate), polyacrylonitrile), thermoplastic resins (polyacetals and polyhalostyrenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenolics, aminoplastics, thioplastics, duroplastic resins (unsaturated polyester, polyurethanes), polyvinyldenic silicones, cellulose derivatives, polycarbonates, and mixtures of all of them, etc. Alternatively, the container can also be metallic, for example, made of steel or titanium suitable for drug administration, glass, crystal, etc., with solids in sterile conditions that overcome the problems existing in the state of the art, and in particular that prevent the solid from adhering to the walls of the container, while ensuring its airtight seal.

[0039] In turn, both the cylinder or puck, as well as the hopper and the nozzle or needle, will preferably be composed of various non-conductive materials such as different plastics, such as polyetheretherketone (PEEK), glass, stone, resin, crystal, although they can also be composed of grounded conductive materials such as steel or titanium, etc.

[0040] Both the materials used for the container and the materials of the cylinder must be watertight, inert, low permeability or impermeable, not absorb and / or adsorb the contained product, not rough and free of particles.

[0041] The solution to the problem set forth in the present invention is based on the fact that the inventors have found that such a problem can be satisfactorily solved by the following techniques, which can be applied independently or in any combination:

[0042] On the one hand, by ionizing both the solid and the pharmaceutical container where it will be deposited, as well as the elements of the dosing and capping equipment that come into contact with the container and / or the powder in one or more stages of the filling procedure, in order to prevent the solid from adhering to the container walls, and to prevent the container walls from attracting the solid particles, so that the only tendency of the solid is to fall to the bottom of the container and not to deposit on its walls. This deionization technique can be applied to the container and the solid separately, or to the container with the product inside. This latter form of deionization can be applied as many times as there are packaging and capping steps in the process.

[0043] On the other hand, by controlling the potential applied to the ionizers, which must be such that the resulting electrostatic charge on the walls of the container and / or the dispensed solid must be preferably less than 2,000 V, more preferably less than 500 V, and most preferably less than 200 V.

[0044] Furthermore, the pharmaceutical container is preferably filled with the solid using a dispensing needle whose tip or dosing end is positioned, throughout the entire filling process, at a height of 1 to 3 mm above the surface of the solid deposited at the bottom of the container. This prevents turbulence that could lift the deposited solid against the walls. Even if some turbulence were to occur, the ionization of both the solid and the inner walls of the container would cause any lifted particles to settle back to the bottom, without substantial product loss on the container walls.

[0045] Accordingly, in a first aspect, the invention relates to a process for filling pharmaceutical containers with solids under sterile conditions, comprising the steps of: a) providing a pharmaceutical container (1) having walls and a bottom, b) dispensing the solid into the pharmaceutical container (1) by means of a dispensing needle (4), gravimetrically controlling the weight of solid dispensed into the container (1); and

[0046] sealing the pharmaceutical container by means of a stopper (6), characterized in that, in at least one of the steps a), b) and c), or a plurality of the same in any combination, the static electric charges existing on the inner walls of the container (1), on the solid dispensed inside the container and / or on any part in contact with the walls of the container or with the solid dispensed inside the container, are neutralized by means of an ionizer (2) to which an ionization potential is applied such that the electrostatic charge inside the container (1) after each ionization is less than 2,000 volts.This ionization prevents the solid dispensed inside the container from tending to adhere to the inner walls of the container (1), which can distort the amount of solid dispensed into the container, hinder the visual assessment of the dosed product level, or even cause an eventual incomplete administration of the product to the patient.

[0047] In a second aspect, the invention relates to a container (1) holding a solid product, wherein the solid product has been dispensed into the container using the described method. For ionization in the case of a rod / ring, it is preferably re-ionized with a needle, with or without a gas stream.

[0048] In general, throughout this description, filling is preferably done using a dispensing needle whose tip or dosing end is located, throughout the entire filling stage, at a height of 1 to 3 mm above the surface of the solid deposited at the bottom of the container, in order to avoid generating turbulence that could raise the solid towards the walls of the container.

[0049] This procedure offers two advantages. First, it ensures precise filling of substances into a single container, even when using two or more filling stations, by preventing solid substances from adhering to the container's sides. Second, it guarantees the integrity of the pharmaceutical container's seal, which is especially important for medications, as it prevents both the entry of foreign agents that could contaminate the product and the leakage of product that could affect the effective dose.

[0050] Additionally, the present invention also solves the problem of static charges produced by collisions generated by the containers used for filling, whether made of glass or polymeric material, in a sterile environment that is generally subject to laminar or turbulent flows, which increases the movement and dispersion of electrostatic charges.

[0051] Although the invention is generally applicable to powdered solid compounds of any nature, however, this procedure is particularly applicable to solids having the following particle size distribution:

[0052] He gave 20 miles

[0053] 70 mieras < Dso £ 110 mieras

[0054] 150 microns £ Dgo £ 215 microns where Dio indicates the mean particle size value that divides the population exactly into two equal halves, with 50% of the distribution above this value and 50% below. In general, throughout this descriptive report, a value called "d0,X" or "Dx" represents the mass fraction of the drug with particle sizes below the specified value, having a range of 0.0 to 1.0. According to this definition, a value of d0, 1 or Dio means that 10% of the total mass of the drug particles have a particle size equal to or less than 10 microns.

[0055] And it is optimally applicable to solids that have the following particle size distribution:

[0056] He gave 25 miles

[0057] 100 mieras < Dso £ 155 mieras

[0058] 245 mieras £ Dgo £ 325 mieras

[0059] Examples of this type of compound are rilsperidone, paliperidone, fentanyl, olanz, letrozole, aripiprazole, anastrozole, asen, brexiprazole, cariprazine, cloz, iloperidone, lurasidone, queti, ziprasidone, among others including any derivative, metabolite or sachet (such as pamoate or palmitate) alone or in combination.

[0060] Other examples of this type of compound are also biocompatible polymers of the polylactic acid type, (PLA), polyglycolic acid (PGA) and their copolymers polylactic-glycolic acid (PLGA) including any derivative or copolymer, alone or in combination.

[0061] Brief description of the figures

[0062] The figures accompanying this invention serve to illustrate its nature. These figures are included for illustrative purposes only and should not be interpreted as limitations on the invention claimed herein. With respect to the ionization phenomenon, the present invention proposes various methods, some of which are shown in Figures 1 to 7, described below. For the purpose of properly interpreting the figures, the ionization phenomenon is represented by alternating positive (+) and negative (-) signs, taking into account that this flow of ions of opposite charge may or may not be accompanied by a sterile carrier gas flow, although the latter is not explicitly shown in the figures.

[0063] Figure 1: Figure 1 illustrates a particular embodiment of the aseptic filling and sealing procedure according to the present invention, in which the pharmaceutical container shown is, in this case, a male syringe (1) that remains capped with a nozzle cap (8) throughout the process. The syringe (1) undergoes a first ionization stage (a) with the aid of an ionizer (2), which may be a ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof may also be included, although in this case, a needle-type ionizer is shown. The male syringe (1) then passes to the filling station (b). The procedure of the invention may include multiple filling stations, particularly if there are multiple solids to be filled into the syringe.At this station, the syringe, which may optionally be inserted into a cylinder (7), is weighed using a load cell (5) during filling, which takes place via a hopper (3) and a nozzle or dispensing needle (4). After filling, the male syringe (1) undergoes another ionization stage (c) using an ionizer (2) provided at this stage, which may be a ring, bar, gun, curtain, blades, cannons, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof may also be included, although in this case, a ring ionizer is shown. Finally, the male syringe (1) is transferred to a sealing station (d) where it is hermetically sealed at the top with a cap (6).

[0064] Figure 2: Another particular embodiment of the procedure of the present invention, in which the male syringe of Figure 1 has been replaced as a pharmaceutical container (1) by a female syringe.

[0065] Figure 3: Particular embodiment of the procedure of the present invention, in which the syringe has been replaced as a pharmaceutical container (1) by an Eppendorf type tube ®The material undergoes an ionization stage (a) thanks to the presence of an ionizer (2) in this stage, which may be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these options are also insulators with an ionizer on their roof; in this case, it is a needle ionizer. Subsequently, it is transferred to the filling station (b), of which there may be multiple. Each filling station contains an ionizer (2) in the form of a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these options are also insulators with an ionizer on their roof; in this case, it is an ionizing filter. In addition to the ionizer, this stage includes a weighing cell (5), a hopper (3), and a dispensing nozzle or needle (4). Finally, after filling, the Eppendorf tube... ®It is subjected to an ionization process by means of a ring, bar, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which are also insulators with an ionizer on the roof of said insulator, being in this case a bar ionizer (2) Figure 4: Particular embodiment of the procedure of the present invention in which the container represented is, in this case, a syringe with needle (1) pre-capped with the nozzle cap (8) during the entire sealing process, which is subjected to a first ionization process (a) with the help of an ionizer (2) which can be in the form of a ring, bar, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which are also insulators with an ionizer on the roof of said insulator, although in this case a needle ionizer is represented.Next, the syringe with needle (1) passes to the filling station (b). The procedure described in the present invention may have multiple filling stations, particularly if there are multiple solids to be filled into the syringe. At this station, the syringe with needle, which may optionally be inserted into a cylinder (7), is weighed by a weighing cell (5) during filling, which takes place via a hopper (3) and a nozzle or dispensing needle (4). After filling, the syringe with needle (1) undergoes another ionization stage (c) by means of an ionizer (2), which may be a ring, rod, gun, curtain, blade, cannon, needle, or nozzle ionizer, or an ionizing filter. Isolators with an ionizer on their roof may also be included, although in this case, a ring ionizer is shown.Finally, the syringe with needle (1) is transferred to a sealing station (d) where it will be hermetically sealed at the top with a plug (6), while it is subjected to an additional ionization phase by means of an ionizer (2) provided at that stage, which can be a ring, bar, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which there can also be insulators with an ionizer on the roof of said insulator, being on this occasion a bar ionizer.

[0066] Figure 5: Another particular embodiment of the procedure of the present invention in which the container shown is, in this case, a female syringe (1) plugged throughout the process with a nozzle cap (8), is subjected to a first ionization process (a) with the help of an ionizer (2) which can be in the form of a ring, rod, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which is also possible isolators with an ionizer on the roof of said isolator, although in this case a ring one is shown. Next, the female syringe (1) passes to the filling station (b), there being multiple filling stations in the procedure described in the present invention, in particular if there are multiple solids to be filled into the syringe.At this station, the syringe, which may optionally be inserted into a cylinder (7), is weighed with a weighing cell (5) during filling, which takes place via a hopper (3) and a nozzle or dispensing needle (4). After filling, the syringe undergoes an ionization process (c) using an ionizer (2) in the form of a ring, bar, gun, curtain, blades, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof are also available, although in this case, a needle-type ionizer is shown.Finally, the female syringe (1) is transferred to a sealing station (d) where it will be hermetically sealed at the top with a plug (8) while it is subjected to an additional deionization phase by means of an ionizer (2), provided at that stage, which can be a ring, bar, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which there can also be insulators with an ionizer on the roof of said insulator, in this case, it is a bar ionizer.

[0067] Figure 6: Another particular embodiment of the process of the present invention, in which the container shown is, in this instance, a cartridge (1), is subjected to a first ionization process (a) with the aid of an ionizer (2), which may be a ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Insulators with an ionizer on their roof may also be included, although in this case, a needle ionizer is shown. The cartridge (1) then passes to the filling station (b). The process described in the present invention may have multiple filling stations, particularly if there are multiple solids to be filled into the cartridge. At this station, the cartridge is weighed with a weighing cell (5) during filling, which takes place via a hopper (3) and a nozzle or dispensing needle (4).Finally, the cartridge (1), which may optionally be inserted into a cylinder (7), is moved to an ionization station where an ionizer (2) provided at that stage will act, which may be in the form of a ring, bar, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which isolators with an ionizer on the roof of said isolator can also be found, although in this case a bar ionizer is presented.

[0068] Figure 7: Particular embodiment of the procedure of the present invention, wherein the container shown is, in this case, a pre-capped female syringe (1) that is first subjected to an ionization process (a) with the aid of an ionizer (2) in the form of a ring, rod, gun, curtain, blades, cannon, needle, or nozzle, or an ionizing filter, which may also include insulators with an ionizer on the roof of said insulator, although in the present case a ring ionizer is shown. After this, the syringe, which is filled at its threaded end, is in the filling station (b). The procedure described in the present invention may have multiple filling stations, particularly if there are multiple solids to be filled into the syringe.At this station, the syringe, which may optionally be inserted into a cylinder (7), is weighed with a weighing cell (5) during filling, which takes place thanks to a hopper (3) and a nozzle or dispensing needle (4). After filling, the female syringe (1) is subjected to another ionization phase (o) by means of an ionizer (2) whether a ring, bar, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which there may also be isolators with an ionizer on the roof of said isolator, in this case being a bar ionizer).

[0069] Detailed description of the invention.

[0070] The filling of solid substances, either by volumetric or gravimetric filling, such as powders, granules, pellets, nanoparticles or microparticles, into small pharmaceutical containers such as vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, sachets, bags, test tubes, Eppendorf tubes ®and syringes (with female or male threaded nozzles, or without threads) and of different materials, such as plastics of different composition, such as polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, polyvinyl chloride, polyacrylonitrile, polyamides, etc., polyesters (containing the ester functional group in their main chain: poly(ethylene erephthalate), polycarbonate), acrylic polymers (poly(methyl methacrylate), polyacrylonitrile), thermoplastic resins (polyacetals and polyhydroxystyrenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenolics, aminoplastics, thioplastics, thermoplastic resins (unsaturated polyester, polyurethanes), polyvinyldenic silicones, cellulose derivatives, polycarbonates, and mixtures of all of them, etc.Alternatively, the container can also be metallic, for example, made of steel or titanium suitable for drug administration, or of glass, crystal, among others. Currently, the adhesion of these substances to the walls of the sealing area of ​​the containers used poses a serious problem for the pharmaceutical industry due to the significant drawback of their adherence. This adhesion presents considerable difficulties for the industry, as it must comply with the regulations specified in the various international pharmacopoeias, as well as with Good Manufacturing Practices (GMP). The present invention focuses on solving the problems related to the adhesion of these solid substances to the walls of the containers used for filling, since this adhesion hinders both the filling and aseptic sealing processes.For the aseptic filling and sealing process referred to in the present invention, only solid substances such as those mentioned above are used.

[0071] International pharmacopoeias require the presence of large airflow currents (unidirectional or turbulent) for aseptic filling and sealing to ensure the removal of any foreign particles that could contaminate the final product. The use of these airflow currents makes filling with solid substances quite difficult, as they create a disturbance that causes the solid to adhere to the walls of the filling container.

[0072] When the dispensed solid substances adhere to the walls of the container's sealing area, they are unable to bond at the container's opening, thus preventing the necessary airtight seal. This lack of airtightness leads to two serious problems: the loss of the dispensed solid substance and contamination of the container used for filling.

[0073] The loss of dose causes inaccuracy in the administration of the pharmaceutical product, since the solid substances remain adhered to the walls of the sealing area of ​​the container and are measured by the weighing cell indicating the precise amount of product that should be administered to the patient, but when the administration to said patient occurs, he will receive a lower dose than indicated because the solid substances adhered to the sides of the container will not be administered to the patient, remaining stuck to said sides.

[0074] Regarding contamination of the container used for filling, this is perhaps the most serious drawback resulting from a lack of airtightness caused by adherence to the walls of the sealing area. This affects the integrity of the medication and the health of the patient receiving the pharmaceutical product. When the container is sealed with the cap, if solid substances adhere to the container walls in the sealing area, these will remain there after the container is sealed. This means the cap cannot guarantee the integrity of the sealed product, as any type of foreign substance could enter after the capping process. Microbial contamination is a very serious issue for pharmaceutical companies, as their products provide ideal environments for the proliferation of microorganisms such as bacteria, fungi, and yeasts.A theoretically sterile but contaminated product can lead to deterioration, loss of its effectiveness, and pyrogenic reactions after administration to the patient, particularly in parenteral administration. This can also result in infection and colonization of the patient by microorganisms, with the risk of secondary infection. Any microorganism, whether pathogenic or non-pathogenic, present in a supposedly sterile pharmaceutical product poses a danger. Recognizing the significant problems caused by a lack of airtightness, the present invention offers a solution to the adhesion of solid substances to the sides of the sealing area of ​​the pharmaceutical container by achieving airtightness of said substance.To promote the sealing of solid substances, two methods are used: controlling the height of the dispensing needle and ionizing both the pharmaceutical container used for filling and the solid substance to be dosed, as well as ionizing the elements of the dosing and capping equipment that come into contact with the syringe and / or the powder.

[0075] As mentioned in the prior art, several factors affect the adhesion of solids to the inner walls of the container, including nozzle length. The longer the nozzle and the closer it is to the top of the powder in the container, the lower its kinetic energy will be. Furthermore, the nozzle directs the powder to an area away from the surface of the sealing walls. The inventors of the present invention have found that the ideal distance between the powder and the nozzle tip depends on the dosage, dosing rate, and powder density, although it is typically between 1 and 3 mm, more preferably around 2 mm. The present invention proposes several options regarding nozzle height:

[0076] The first method relies on having a nozzle with a precise height (h) relative to the bottom of the container. In this case, the filling process is carried out from the back of the container; that is, if the container is a syringe, at the opening or end with the larger diameter. A minimum height (h) of 2 mm must always be maintained between the solid being dispensed and the nozzle.

[0077] The second option involves always maintaining the nozzle at a minimum distance of h = 2 mm from the solid substance being dispensed into the container. This method would mean that the nozzle is not a fixed element, but rather a mobile one, able to move up and down as the filling process takes place, always maintaining the 2 mm distance from the solid substance.

[0078] An alternative to the above could be to equip the nozzle with a containment element to prevent powder from dispersing above the filling area during the process. Regarding ionization, it relies on a solution to eliminate electrostatic charges present in both the pharmaceutical container being filled and the solid substance. The container walls and the solid carry a static charge; if these charges are opposite, the solid will adhere to the container's inner walls. This is why ionization of both the container and the solid is performed.

[0079] There are two types of electrostatic charge: negative charges, which are electrons in the atoms of chemical elements, and positive charges, which are equivalent to the action of protons in the atomic nucleus deprived of the electrons in their outermost shell. Electrons on the surface of an insulating material cannot easily dissipate unless they have a conductive path to ground; this is why the cylinder is a conductive element, as mentioned earlier. Because they cannot circulate easily, they give rise to what is known as static electricity. Electrons are free to move from one molecule to another in conductors, but protons are inseparable from the atom and cannot move unless the atom itself moves.The magnitude of the electrostatic charge is related to the position or relative distance between the materials in the series and its sign is determined by the propensity of a material to give up or gain electrons, which is what the series actually indicates.

[0080] The present invention utilizes any type of ionizer, such as a ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these are also insulators with an ionizer in their roof. For example, a rod can be used to ionize and neutralize both the environment and the airflow, thus eliminating static charges. The ionizer can be implemented in practice using a sterile carrier gas stream, such as compressed air or nitrogen (N2), preferably nitrogen, which has the following functions and / or advantages:

[0081] This nitrogen stream acts as a carrier for the ions generated at the electrodes of the ionization elements, which ionize the surrounding air, producing ions that are carried along by the N2 current. These positive and negative ions are generated by supplying alternating current, which, through a transformer, is boosted to values ​​of up to 8,000 volts with a nearly negligible current (4 mA). Surfaces treated in this way end up with a neutral charge due to the recombination of opposite charges and the repulsion of like charges. It also generates an inert atmosphere inside containers by displacing the oxygen, thus protecting the product from its oxidative effects. The introduction of an inert gas into a container, known as inerting, is based on reducing the percentage of oxygen below the limiting oxygen concentration (L.O.C.).

[0082] -A sweeping effect medium inside the containers. The alternating generation of ions eliminates the static forces that adhere the powder to the container walls. This causes the solid to remain in its position, but without any adhesion to the container or to itself. A gentle airflow (0.1-0.8 l / min) then sweeps the now dispersed solid.

[0083] With respect to the ionization phenomenon, the present invention proposes different methods to be carried out, shown in the attached figures 1-7, in which the pharmaceutical container is represented in a non-limiting manner as a male or female type syringe, a syringe with needle, a cartridge or carpule or an Eppendorf type tube ®The use of ionizers can be carried out with any type of ionizer (with or without a sterile carrier gas stream), such as ring, bar, gun, curtain, blade, cannon, needle, or nozzle ionizers, or an ionizing filter. Isolators with an ionizer on their roof, such as a bar, can also be found, for ionizing and neutralizing both the environment and the airflow, thus eliminating static charges. In the case of isolators, and according to a preferred embodiment, prior to the dosing operation described in the present invention, sterilization with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide and peracetic acid is required.

[0084] As soon as the pharmaceutical container is removed from the tray, it has an extremely high electrostatic charge (over 30,000 volts). This is due to the continuous friction between the container and the tray. Therefore, as shown in the various figures, both before and after inserting the container into the cylinder, the containers are preferably exposed to an ionizer, regardless of the type, using a sterile carrier gas stream. This could be nitrogen, which carries ionized air molecules, or compressed air, which affects both the inside of the container and the sealing area to eliminate the electrostatic charge. Figure 1 shows a general aseptic container filling procedure consisting of several steps:

[0085] The container (1), optionally inserted into a support cylinder (7) and sealed with a nozzle cap (8), undergoes an ionization stage (a) using an ionizer (2) of any type, such as a ring, rod, gun, curtain, blade, cannon, needle, or nozzle ionizer, or an ionizing filter, including insulators with an ionizer on their roof, or any other type of ionizer. The ionizer (2) serves to eliminate the electrostatic charge of the container on both the inner walls and the sealing area. This ionizer may or may not be used in conjunction with a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although nitrogen carrying ionized air molecules is preferred.The nitrogen stream carrying ionized air molecules reaches both the inside of the container and the sealing area; with these two ionization processes (ionization with an ionizer and the optional application of a sterile gas stream) the electrostatic charges of the container are eliminated so that it can be filled.

[0086] Following the ionization process (a), the syringe (1) moves to the aseptic filling station (b). At this stage, the container (1) is aseptically filled with the solid substance. This process requires a hopper (3) containing the solid substance to be dispensed and a dispensing needle or nozzle (4) through which the solid substance is dispensed. A weighing cell (5) is also needed to accurately measure the amount of solid substance dispensed. This station may or may not contain a sterile carrier gas stream, such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen, which acts as a vehicle for the ions. There will be as many filling stations as there are products or combinations thereof to be filled.

[0087] After the container (1) is filled with the solid, it undergoes a deionization stage (c) using a deionizer (2), which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle type, or an ionizing filter. Isolators with an ionizer in their roof are also available. Along with the ionizer, a sterile carrier gas stream, such as compressed air or nitrogen containing ionized air molecules, may or may not be applied. Nitrogen, which contains ionized air molecules, is preferred to prevent the solid from adhering to the walls of the container's sealing area (1). Finally, the aseptic sealing station (d) is located, where the plug (6) is inserted to seal the container.In this last station, a sterile carrier gas stream such as compressed air or a nitrogen stream carrying preferably ionized air molecules may or may not be used.

[0088] Figure 2 shows another embodiment of the ionization process consisting of four stages:

[0089] The first stage involves an ionization process (a) similar to that shown in Figure 1, in which a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, may or may not be introduced into the container (1). The syringe has been previously sealed with the nozzle cap (8) and can optionally be inserted into the carrier cylinder (7). This sterile carrier gas stream is used in conjunction with an ionizer (2), which may be a ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof are also available. The stream and the ionizer (2) reach both the interior of the container (1) and the sealing area. In the figure shown, the sterile carrier gas stream used is preferably a nitrogen stream carrying ionized air molecules.After using this current, the container is free of electrostatic charges and ready to be filled.

[0090] For the second stage of the described process, the container (1) moves to the aseptic filling station (b) where the solid is aseptically filled. This station contains several components, including: a hopper (3) containing the solid substance to be dispensed, a dispensing needle or nozzle (4) responsible for dispensing the solid, and a weighing cell (5) to control the exact amount of solid dispensed. There will be as many filling stations as there are products to be filled or combinations thereof.To ensure the cleanliness of the sealing area, a third stage is used: an ionization stage (c). This stage employs an ionizer (2), which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof are also available. A sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air, may or may not be applied concurrently to eliminate the adhesion of the solid to the sides of the container in the sealing area. A nitrogen stream carrying ionized air molecules is preferred, as it acts as a carrier for the ions and as a sweeping agent, achieving the desired sealing effect at this stage.There will be a different number of ionization stations depending on the needs of each product.

[0091] This leads to the final stage, a sealing stage (d) in which the container is sealed with a stopper (6). In this stage, a sterile carrier gas stream, such as nitrogen carrying ionized air molecules, may or may not be used. Although the sealing area is free of solid substances, it is necessary to ensure the container is completely clean and that none of the dosed solid substances adhere to the sealing stopper or the container walls due to electrostatic charges created by friction when placing the container in the sealer.

[0092] Figure 3 shows another particular embodiment of the ionization procedure, which consists of the following steps:

[0093] The container (1) is subjected to an ionization process (a) by means of an ionizer (2) of any type, including ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof may also be included. This ionizer may or may not operate in conjunction with a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although nitrogen carrying ionized air molecules is preferred. The ionizer (2) serves to eliminate the electrostatic charge of the container, both on the interior walls and in the sealing area.On the other hand, the nitrogen stream carrying ionized air molecules reaches both the inside of the container and the sealing area; with these two ionization processes, the electrostatic charges of the container are eliminated so that it can be filled.

[0094] Subsequently, after this ionization phase (a), the container (1) moves to the aseptic filling station (b) where the aseptic filling with the solid takes place. This station contains several components, including a hopper (3) containing the solid substance to be dispensed, a dispensing needle or nozzle (4) for dispensing the solid, a weighing cell (5) to control the exact amount of solid dispensed, and an ionizer (2). The ionizer can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof are also an option. This station may or may not contain a sterile carrier gas stream, such as compressed air or nitrogen, which carries ionized air molecules. Nitrogen is preferred to carry the ions.This ensures that the dosed solid does not remain in the sealing zone. There will be as many filling stations as there are products or combinations thereof to be filled, and likewise, there will be as many ionization stages as necessary.

[0095] After the container (1) is filled with the solid at the filling station (b), the final stage, an ionization process (c), is carried out to ensure the cleanliness of the sealing area. This process utilizes an ionizer (2) in the form of a ring, bar, gun, curtain, blades, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof are also available, which may or may not operate in conjunction with a sterile carrier gas stream, such as nitrogen containing ionized air molecules or compressed air. This process eliminates the adhesion of the solid to the sides of the container in the sealing area. A nitrogen stream carrying ionized air molecules is preferred, as it acts as a carrier for the ions and as a sweeping agent, achieving the desired airtight seal at this station.There will be a different number of ionization stations depending on the needs of each product.

[0096] Figure 4 shows another particular embodiment of the procedure described in the present invention:

[0097] The container (1), optionally inserted into a support cylinder (7) and previously sealed with the nozzle cap (8), is subjected to an ionization process (a) by means of an ionizer (2) of any type, such as ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these, isolators with an ionizer on their roof may also be included. This ionizer may or may not be used in conjunction with a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although the nitrogen stream carrying ionized air molecules is preferred. The ionizer (2) serves to eliminate the electrostatic charge of the container, both on the inner walls and in the sealing area.On the other hand, the nitrogen stream carrying ionized air molecules reaches both the bottom of the container and the sealing area; with these two ionization processes, the electrostatic charges of the container are eliminated so that it can be filled.

[0098] Following this ionization phase (a), the container (1) moves to the aseptic filling station (b) where aseptic filling with the solid takes place. This process requires a hopper (3) containing the solid substance to be dispensed and a dispensing needle or nozzle (4) through which the solid substance is dispensed. A weighing cell (5) is also needed to accurately measure the amount of solid substance dispensed. This station may or may not contain a sterile carrier gas stream, such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen, which acts as a vehicle for the ions. There will be as many filling stations as there are products or combinations thereof to be filled.

[0099] After the container (1) is filled with the solid at the filling station (b), a third stage is performed to ensure the cleanliness of the sealing area. This stage involves an ionization process (c) using an ionizer (2), which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof are also available. This ionizer may or may not operate in conjunction with a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air, to eliminate the solid's adhesion to the sides of the container in the sealing area. A nitrogen stream carrying ionized air molecules is preferred, as it acts as a carrier for the ions and as a sweeping agent, achieving the desired airtight seal at this stage.There will be a different number of ionization stations depending on the needs of each product.

[0100] Finally, the container (1) passes to the sealing station (d) where it is sealed with a plug (6). At this stage, an ionizer (2) is used, which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these, isolators with an ionizer on the roof of the isolator can also be found. This ionizer may or may not operate in conjunction with a sterile carrier gas stream, such as nitrogen, which preferably carries ionized air molecules. Although the sealing area is free of solid substances, it is necessary to ensure the complete cleanliness of the container and that none of the dosed solid substances adhere to the plug used for sealing or to the container walls due to electrostatic charges created by friction when placing the container in the sealer.

[0101] Figure 5 shows another particular embodiment of the procedure described in the present invention.

[0102] The container (1), which has been sealed with the nozzle cap (8) and optionally inserted into a support cylinder (7), is subjected to an ionization process (a) by means of an ionizer (2) of any type, such as ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these options are also insulators with an ionizer on their roof, which may or may not be used in conjunction with a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although nitrogen carrying ionized air molecules is preferred. The ionizer (2) serves to eliminate the electrostatic charge of the container, both on the inner walls and in the sealing area.On the other hand, the nitrogen stream carrying ionized air molecules reaches both the inside of the container and the sealing area; with these two ionization processes, the electrostatic charges of the container are eliminated so that it can be filled.

[0103] Following this ionization process (a), the container (1) moves to the aseptic filling station (b) where the solid is aseptically filled. This station requires several components, including a hopper (3) containing the solid substance to be dispensed, a dispensing needle or nozzle (4) to dispense the solid, and a weighing cell (5) to control the exact amount of solid dispensed. This station may or may not use a sterile carrier gas stream, such as compressed air or nitrogen containing ionized air molecules, preferably nitrogen, to act as a vehicle for the ions. This ensures that the dispensed solid does not remain in the sealing area. There will be as many filling stations as there are products or combinations thereof to be filled.

[0104] Following this filling stage (b), the container is subjected to an ionization stage (c) in which the ionizer (2) can be found in the form of a ring, rod, gun, curtain, blades, cannons, needle or nozzle, or an ionizing filter, among which there can also be isolators with an ionizer on the roof of said isolator, which may or may not be found together with a sterile carrier gas stream such as nitrogen carrying ionized air molecules or as compressed air carrying ionized air molecules, although more preferably the nitrogen stream carrying ionized air molecules is used.

[0105] Finally, the container (1) passes to the sealing station (d) where it is sealed with a plug (6). At this stage, an ionizer (2) is also used, which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these, there are also isolators with an ionizer on the roof of said isolator that may or may not operate together with a sterile carrier gas stream such as compressed air or, preferably, nitrogen carrying ionized air molecules. This is because, although the sealing area is clean of solid substances, it is necessary to ensure the total cleanliness of the container and that none of the dosed solid substances adhere to the plug used for sealing and to the walls of the container due to the electrostatic charges created by friction when placing the container in the sealer.

[0106] Figure 6 consists of three stages:

[0107] In the first process, the container (1) is ionized by means of an ionization process (a) using an ionizer (2) of any type, such as ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these, isolators with an ionizer in their roof may also be found, with or without a sterile carrier gas stream such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although nitrogen carrying ionized air molecules is preferred. The ionizer (2) serves to eliminate the electrostatic charge of the container on both the interior walls and the sealing area.On the other hand, the nitrogen stream carrying ionized air molecules reaches both the inside of the container and the sealing area; with these two ionization processes, the electrostatic charges of the container are eliminated so that it can be filled.

[0108] After this ionization process (a), the container (1) is transferred to the aseptic filling station (b) where aseptic filling with the solid takes place. This process requires the use of a hopper (3) containing the solid substance to be dispensed and a dispensing needle or nozzle (4) through which the solid substance is dispensed. A weighing cell (5) is also needed to accurately measure the amount of solid substance dispensed. This station may or may not have a sterile carrier gas stream, such as compressed air or nitrogen carrying ionized air molecules, preferably nitrogen, to act as a vehicle for the ions. There will be as many filling stations as there are products to be filled or combinations thereof.

[0109] Finally, the container (1) passes to the ionization station. At this stage, an ionizer (2) is used, which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Among these, there are also isolators with an ionizer on the roof of said isolator, which may or may not operate in conjunction with a sterile carrier gas stream, such as nitrogen, which preferably carries ionized air molecules. This is because, although the sealing area is clean of solid substances, it is necessary to ensure the complete cleanliness of the container and that none of the dosed solid substances adhere to the container walls due to the electrostatic charges created by friction when placing the container in the sealer.

[0110] Figure 7 shows a particular embodiment of the procedure described in the present invention.

[0111] The container (1), previously sealed with a plug (6) and optionally inserted into a cylinder (7), is ionized in an ionization stage (a) by means of an ionizer (2), which may be a ring, rod, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof may also be included. This station may or may not contain a sterile carrier gas stream, such as compressed air or nitrogen, carrying ionized air molecules; nitrogen is preferred to carry the ions.

[0112] Next, the container is placed in the aseptic filling station (b) where it is aseptically filled with the desired solid through the nozzle. This station requires several components, including a hopper (3) containing the solid substance to be dispensed, a dispensing needle or nozzle (4) to dispense the solid, and a weighing cell (5) to control the exact amount of solid dispensed. A sterile carrier gas stream, such as compressed air or nitrogen containing ionized air molecules, may or may not be present. Nitrogen, preferably, carries ionized air molecules to act as a vehicle for the ions. This ensures that the dispensed solid does not remain in the sealing area. There will be as many filling stations as there are products or combinations thereof to be filled.

[0113] After the container (1) is filled with the solid at the filling station (b), a final stage is performed to ensure the cleanliness of the sealing area. This stage involves an ionization process (c) using an ionizer (2), which can be a ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof may also be used. This process may or may not be accompanied by a sterile carrier gas stream, such as nitrogen carrying ionized air molecules or compressed air, to prevent the solid from adhering to the sides of the container in the sealing area. A nitrogen stream carrying ionized air molecules is preferred, as it acts as a carrier for the ions and as a sweeping agent, achieving the desired airtight seal at this station.The number of ionization stations will vary depending on the requirements of each product. In the preferred embodiments shown in the Figures, an additional ionization step of the container can be carried out after filling with the solid substance and just before sealing with the cap. Preferably, ionization should also be performed when the container is empty, before filling with the solid substance, and more preferably, ionizers should be present at each station of the filling and sealing process to ionize both the container and the solid substance, thus preventing its adhesion to the inner walls and ensuring the cleanliness of the container.These ionizers can be of any type, whether ring, bar, gun, curtain, blade, cannon, needle, or nozzle, or an ionizing filter. Isolators with an ionizer on their roof can also be found. To facilitate dosing, a sterile carrier gas stream, such as compressed air or nitrogen carrying ionized air molecules, can be used. Preferably, the stream is nitrogen carrying ionized air molecules, as it acts as a vehicle for ion displacement, generates an inert atmosphere, and serves as a sweeping medium. This nitrogen stream carrying ionized air molecules is used in ionization stations, along with an ionizer, and preferably, it is used in all stations of the aseptic filling and sealing process.

[0114] Examples

[0115] The following specific examples provided herein serve to illustrate the nature of the present invention. These examples are included for illustrative purposes only and are not to be construed as limitations on the invention claimed herein.

[0116] In these examples, cartridges or carpules, syringes with needles, catheter-type cones, Luer-type cones, or Luer-lock cones, all with male or female nozzles, and Eppendorf-type tubes have been used as containers. ® , as biocompatible polymer excipients of the type PLGA (lactic or gicholic acid) and PLA (polylactic acid), and as active compounds Risperidone and Letrozole respectively.

[0117] Example 1: Filling a 50 mg dose of Letrozole into a syringe with a male or male type nozzle.

[0118] In this example, the goal is to fill two products into a pharmaceutical container, specifically a syringe with a pre-capped glass male nozzle (8). The products to be filled are the excipient PLA and the active compound Letrozole, specifically a 50 mg dose. It is important to note that the filling process takes place within a rigid-walled aseptic isolator. Before starting the filling process, all equipment must be clean and sterile. Therefore, the equipment is first sterilized with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide and peracetic acid.

[0119] The isolator consists of two main sections: (i) the first is the transfer chamber (TC), which is a chamber that facilitates the loading of sterile materials to and from the working chamber of the isolator since all materials and tools that are loaded into the sterile isolator must be sterilized beforehand and (ii) the second is the working chamber (MC) which contains filling equipment for the excipient and for the active compound and a syringe capping or sealing unit.

[0120] To begin filling, start by taking the sterile male syringes (1) and stoppers (6) and handing them to the operator at the capping or sealing station (d) to be fed into the syringe sealing machine. There will be as many filling stations as there are products to be filled or combinations thereof.

[0121] Both the PLA used as an excipient and the Letrozole used as the active ingredient are delivered to the operators at the filling station (b), who load them into their respective hoppers (3). The male syringes (1) to be used for filling undergo an ionization process on the back of the syringes or on the collar using an ionizer (2) in the needle. This ionization (a) of the male syringes (1) eliminates the electrostatic charge inside and in the sealing area of ​​the syringe body. The male syringe (1) is then placed upside down inside a cylinder (7).

[0122] The cylinder (7) containing the ionized male syringe (1) is directed to the filling station (b) for filling with PLA. The male syringe (1) is placed on the weighing cell (5), and its weight is tared to zero. The filling of the male syringe (1) begins at the end closest to the collar with 90 mg ± 30% PLA. This filling is performed using a nozzle (4) or dispensing needle, both made of a non-conductive material. The male syringe (1) is continuously weighed during filling so that the system can be controlled to stop the filling precisely when the desired weight is reached, in this case, 90 mg ± 30%. After this process, the electrostatic charge inside the inner walls of the container (1) is measured, and the reading obtained is 1075 volts.

[0123] After filling station (b) with the PLA excipient, the male syringe (1) undergoes an ionization process (c) using a ring ionizer located on the outside of the syringe to ensure a leak-proof seal by preventing the PLA from adhering to the walls of the male syringe (1). During this process, a stream of nitrogen or sterile carrier gas with ionized air molecules is required to displace the ions and facilitate the powder sweeping effect.

[0124] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 775 volts.

[0125] Once the excipient has been filled and subsequently ionized, the cylinder (7) containing the PLA-filled male syringe (1) is placed in the filling station (b) to be filled with 50 mg ± 30% Letrozole. The cylinder with the male syringe (1) is then placed in the weighing cell (5) where it is tared before filling with the active product. The male syringe (1) is continuously weighed during filling so that the process can be stopped once the desired weight is reached.

[0126] Following the filling process of the male syringe (1), it undergoes another ionization process (c) using a ring ionizer (2) to prevent the excipient and active ingredient with which the male syringe (1) was filled from adhering to its walls. This process requires a stream of sterile nitrogen or carrier gas containing ionized air molecules to displace the ions and facilitate the powder removal process.

[0127] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 845 volts.

[0128] Once the cylinder (7) with the male syringe (1) has been filled with the active compound and subsequently ionized, it moves to the sealing station (d) where the cap (6) is placed. This process requires a stream of nitrogen or sterile carrier gas that carries ionized air molecules to displace the ions and act as a carrier.

[0129] Following this process, the electrostatic charge inside the inner walls of the container (1) is measured, yielding a reading of 375 volts. This method achieves the desired airtight seal and ensures the cleanliness of the sealing area inside the syringe body, at its distal end to the nozzle. Furthermore, it prevents both the PLA and the Letrozole from adhering to the sealing cap (8) and the container walls due to electrostatic charges generated by friction when placing the container in the sealer.

[0130] Once the male syringe has been filled and sealed, it can be placed in a tray with the other filled and sealed syringes.

[0131] or female syringe made of plastic material.

[0132] In this second example, PLA is also used as an excipient and Letrozole as the active compound, for a dose of 400 mg, and the filling process also takes place inside a rigid-walled aseptic isolator in the same way as in example 1.

[0133] Both the PLA used as an excipient and the Letrozole used as the active compound are delivered to the operators at the filling station (b), who load them into their respective hoppers (3), which in this case are not made of insulating material. The female syringes (1), pre-capped with the nozzle cap (8), which will be used for filling, are arranged under a stream of sterile nitrogen or carrier gas containing ionized air molecules. An ionizer (2) in the needle is added to this process, and in this way, the female syringes (a) are ionized to eliminate the electrostatic charge inside and in the sealing area.

[0134] The cylinder (7) containing the ionized female syringe (1) is directed to the PLA filling station (b). The female syringe (1) is placed in the weighing cell (5), and its weight is zeroed. The syringe (1) is then filled from the back or the collar with 500 mg ± 30% PLA using a nozzle (4) or dispensing needle, which is not made of insulating material. The syringe (1) is continuously weighed during filling so that the system can be controlled to stop the filling when the desired weight is reached, in this case, 500 mg ± 30%. During this process, a stream of nitrogen or sterile carrier gas with ionized air molecules is required to displace the ions and provide a sweeping effect.After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 1770 volts.

[0135] Subsequently, the cylinder (7) with the female syringe (1) filled with PLA undergoes an ionization process (c) before being filled in a second filling station (b) with the active compound Letrozole. A ring ionizer (2) is used for ionization, ionizing the PLA adhering to the walls of the syringe's sealing area (1). A stream of nitrogen or sterile carrier gas carrying ionized air molecules is also used to transport the ions and act as a sweeping medium, achieving the desired sealing effect during this ionization process.

[0136] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 975 volts.

[0137] Once ionization has taken place, the cylinder (7) with the female syringe (1) filled with PLA is placed in the filling station (b) containing 400 mg ± 30% of the active compound Letrozole. The cylinder (7) with the female syringe (1) is then placed in the weighing cell (5) where it is tared before filling with the active compound. Filling with Letrozole then begins. The syringe (1) is continuously weighed during filling so that the process can be stopped once the desired weight is reached.

[0138] It is then transferred to an ionization station (c) where a ring ionizer (2) is used to prevent both the excipient and the active ingredient from adhering to its walls.

[0139] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 895 volts, since both the dispensing needle and the hopper are not insulating materials.

[0140] Once the cylinder (7) is filled with the active compound and subsequently ionized, a plug (6) is inserted into the female syringe (1) (d). This process requires a stream of nitrogen or sterile carrier gas carrying ionized air molecules to displace the ions and carry away the powder. This method achieves the desired airtight seal and ensures the cleanliness of the sealing area inside the syringe body, leaving a clean area where the plug is inserted. It also prevents both the PLA and the Letrozole from adhering to the plug (6) used for sealing and to the container walls due to electrostatic charges created by friction when placing the container in the sealer. At this point, the electrostatic charge inside the inner walls of the container (1) is measured, and the reading obtained is 495 volts.

[0141] Once the syringe filling procedure is complete, and after sealing it, it can be placed in a tray with the rest of the filled and sealed syringes.

[0142] Example 3: Filling a 50 mq dose of Letrozole into Eppendorf-type tubes ® .

[0143] In this example, PLA is used as an excipient and Letrozole as the active ingredient, for a dose of 50 mg. It should be noted that the filling process takes place inside a rigid-walled aseptic isolator, just as in the previous examples.

[0144] Both the PLA used as an excipient and the Letrozole used as the active compound are delivered to the operators at the filling station (b), who load them into their respective hoppers (3). Eppendorf-type tubes ®(1) that are to be used for filling are arranged under a stream of nitrogen or sterile carrier gas that carries ionized air molecules, to this process is added a needle ionizer (2) and in this way the ionization of the Eppendorf type tubes is carried out ® (1) to achieve the elimination of the electrostatic charge inside and in the sealing area.

[0145] At this point the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 695 volts, since the tube is made of insulating material and its dimensions are significantly different from the syringes, as they are wider and shorter than the syringes in examples 1 and 2.

[0146] The Eppendorf type tube ® (1) Ionized material is directed to the filling station with 50 mg ± 30% Letrozole. The Eppendorf-type tube ®(1) is placed in the weighing cell (5), taring its weight to zero. After this, the filling of the Eppendorf tube begins. ® (1) with the active compound through a nozzle (4) of insulating material. The Eppendorf-type tube ® (1) It is weighed continuously during filling, so that the system can be controlled to stop filling when the desired weight is reached. While filling with Letrozole, it is necessary to use an ionization filter (2) to prevent it from adhering to the walls of the sealing area.

[0147] After the filling stage (b), it is subjected again to the Eppendorf-type tube ®(1) to an ionization process (c) with the help of a bar ionizer (2), in order to ensure that no residue of active compound remains adhered to the walls of the container (1). The electrostatic charge inside the inner walls of the container (1) is measured again and the measurement obtained is 700 volts.

[0148] Once filled with the active compound, the Eppendorf-type tube ® (1) The Letrozoi-filled tube is placed in the second filling station (b), this time with 90 ± 30% of the PLA excipient. The Eppendorf-type tube ® (1) is placed in the weighing cell (5) where it is tared before proceeding to filling with said excipient, after which filling with PLA begins. The Eppendorf type tube ®(1) It is weighed continuously during filling, so that filling can be stopped once the desired weight is reached. During this process, the use of an ionization filter (2) is necessary to prevent both the Letrozoi and the PLA from adhering to the sealing area.

[0149] After this Eppendorf-type tube filling process ® (1), this is subjected to another ionization process (c) with the help of a bar ionizer (2) to prevent both the excipient and the active ingredient with which the Eppendorf type tube ®(1) has been filled so that they adhere to the walls of said container (1). The presence of a current of nitrogen or sterile carrier gas carrying ionized air molecules is also necessary to displace the ions and act as a drag. By means of these two means, the electrostatic charge inside the inner walls of the container (1) is achieved to be about 595 volts, achieving the desired sealing phenomenon and ensuring the cleanliness of the sealing area. In addition, it is possible to prevent both the PLA and the Letrozoi from adhering to the plug (8) used for sealing and to the walls of the container due to the electrostatic charges created by friction when placing the container in the sealer.

[0150] Example 4. Filling a 75 mq dose of a in a syringe with a needle or syringe with a plastic material tube.

[0151] In this example, PLGA is used as the excipient and Risperidone as the active ingredient, for a dose of 75 mg. The filling process also takes place inside a rigid-walled aseptic isolator using the same material sterilization procedure as in the previous examples.

[0152] The syringes with needles (1) to be used for filling are capped by the nozzle cap (8) and undergo an ionization process using a needle ionizer (2). This ionization process (a) eliminates the electrostatic charge inside the syringes (1) and in the sealing area. The cylinder (7) containing the ionized syringe with needle (1) is made of an insulating material. The syringe (1) is placed in the weighing cell (5) and its weight is zeroed. The male syringe (1) is then filled with 75 mg ± 30% PLGA using an insulating nozzle (4). The syringe (1) is continuously weighed during filling so that the system can be monitored and stopped when the desired weight is reached, in this case, 75 g ± 30%.

[0153] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 775 volts.

[0154] After the syringe with needle (1) is filled with the excipient, it is subjected to an ionization process (c) thanks to a ring ionizer (2) thus preventing the PLGA from adhering to the walls of the sealing area of ​​the container (1).

[0155] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 550 volts.

[0156] Once the cylinder has been filled with the excipient and subsequently ionized, the cylinder (7) containing the syringe (1) filled with PLGA is placed in the next filling station (b) for the active compound risperidone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5) where it is tared before filling with the active compound, after which the filling with risperidone begins. The syringe (1) is weighed continuously during filling so that the filling process can be stopped once the target weight is reached.

[0157] Once filled with the active compound, the cylinder (7) with the syringe and needle (1) is subjected to another ionization process. Using a ring ionizer (2), the active compound and the excipient are prevented from adhering to the walls of the sealing area of ​​the male syringe (1). After this process, the electrostatic charge inside the inner walls of the container (1) is measured, yielding a reading of 470 volts.

[0158] Following this ionization process, the male syringe (1) passes to the sealing station (d) where a cap (6) is placed and where it undergoes another ionization process. This process requires a bar ionizer (2) that ionizes the PLGA and Risperidone adhering to the walls of the sealing area.

[0159] Following this process, the electrostatic charge inside the inner walls of the container (1) is measured, yielding a reading of 199 volts. The ionization process achieves optimal sealing and ensures complete cleanliness of the sealing area. Furthermore, it prevents both PLGA and Risperidone from adhering to the sealing cap (6) and the container walls due to electrostatic charges generated by friction when placing the container in the sealer.

[0160] Example 5: Filling a 100 mg dose of Risperidone into a syringe with a female nozzle or a female syringe made of plastic material.

[0161] In this example, PLGA is used as the excipient and Risperidone as the active ingredient, for a dose of 100 mg. The filling process also takes place inside a rigid-walled aseptic isolator using the same material sterilization procedure as in the previous examples.

[0162] The pre-filled female syringes (1) with nozzle caps (8) undergo an ionization process using a ring ionizer (2). This ionization process (a) eliminates the electrostatic charge inside the syringes and in the sealing area. The cylinder (7) containing the ionized syringe (1) is made of an insulating material. The syringe (1) is placed in the weighing cell (5) and its weight is zeroed. The syringe (1) is then filled with 100 g ± 30% PLGA using an insulating nozzle (4). The syringe (1) is continuously weighed during filling, allowing the system to stop the filling process when the desired weight is reached, in this case, 100 mg ± 30%.

[0163] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 785 volts.

[0164] After filling the female syringe (1) with the excipient, it is subjected to an ionization process (c) thanks to a needle ionizer (2), thus preventing the PLGA from adhering to the walls of the sealing area of ​​the container (1).

[0165] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 580 volts.

[0166] Once the cylinder has been filled with the excipient and subsequently ionized, the cylinder (7) containing the syringe (1) filled with PLGA is placed in the next filling station (b) for the active compound risperidone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5) where it is tared before filling with the active compound, after which the filling with risperidone begins. The syringe (1) is weighed continuously during filling so that the filling process can be stopped once the target weight is reached.

[0167] Once filled with the active compound, the cylinder (7) with the syringe (1) is subjected to another ionization process. Using a needle ionizer (2), the active compound and the excipient are prevented from adhering to the walls of the syringe's sealing area (1). After this process, the electrostatic charge inside the inner walls of the container (1) is measured, yielding a reading of 440 volts.

[0168] Following this ionization process, the syringe (1) moves to the sealing station (d) where the cap (6) is applied and where it undergoes another ionization process. This process requires a bar ionizer (2) to ionize the PLGA and Risperidone adhering to the walls of the sealing area. After this process, the electrostatic charge inside the inner walls of the container (1) is measured, and the reading obtained is 197 volts.

[0169] The ionization process achieves optimal sealing and ensures complete cleanliness of the sealing area. It also prevents both PLGA and Risperidone from adhering to the cap (8) used for sealing and to the container walls due to electrostatic charges created by friction when placing the container in the sealer.

[0170] Example 8: Filling a 75 mq dose of Risperidone into cartridges or carpules.

[0171] In this other example, PLGA is used as an excipient and Risperidone as the active ingredient, for a dose of 75 mg. The filling process also takes place inside a rigid-walled aseptic isolator using the same material sterilization procedure as in the previous examples.

[0172] Both the PLGA used as an excipient and the Risperidone used as the active compound, as well as the cartridges, are delivered to the operators at the filling station (b), who load them into their respective hoppers (3). The cartridges (1) to be used for filling are arranged under a stream of nitrogen or sterile carrier gas containing ionized air molecules. A needle ionizer (2) is added to this process, ionizing the cartridges (1) to eliminate the electrostatic charge inside.

[0173] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 1285 volts.

[0174] The ionized cartridge (1) is directed to the filling station (b) containing 75 mg ± 30% risperidone. The cartridge (1) is placed face up in the weighing cell (5), and its weight is tared to zero. The cartridge (1) is then filled with risperidone through its nozzle using a nozzle (4) or dispensing needle made of insulating material. The cartridge (1) is continuously weighed during filling so that the system can be monitored and stopped when the desired weight is reached.

[0175] Once the cartridge (1) has been filled with the active ingredient, it is placed in the second filling station (b), this time with 100 g ± 30% of the PLGA excipient. The cartridge (1) is then placed in the weighing cell (5) where it is tared before filling with the active ingredient. Filling with PLGA then begins, also through the nozzle. The cartridge (1) is weighed continuously during filling so that the process can be stopped once the desired weight is reached.

[0176] Once filled with the PLGA excipient, the cartridge (1) undergoes another ionization process using a bar ionizer (2). Additionally, a stream of sterile nitrogen or carrier gas is present, carrying ionized air molecules to displace the ions and facilitate the insertion of the cartridge nozzle cover. Both processes prevent the excipient and the active compound from adhering to the cartridge walls, thus achieving the desired effect.

[0177] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 1085 volts.

[0178] Example 7. Filling a 400 mq dose of Risperidone into a pre-capped female syringe.

[0179] In this example, PLGA is used as the excipient and Risperidone as the active ingredient, for a dose of 400 g. The filling process also takes place inside a rigid-walled aseptic isolator using the same material sterilization procedure as in the previous examples.

[0180] The female syringes (1) used for filling undergo an ionization process using a ring ionizer (2). This ionization process (a) eliminates the electrostatic charge inside the syringe (1) and in the sealing area. The cylinder (7) containing the ionized syringe (1) is made of an insulating material. The syringe (1) is placed upside down in the weighing cell (5), as it is already capped with a plug (8), and its weight is zeroed. The syringe (1) is then filled through the nozzle with 100 mg ± 30% PLGA using an insulating nozzle (4). The syringe (1) is continuously weighed during filling, allowing the system to stop the filling process when the desired weight is reached, in this case, 100 mg ± 30%.

[0181] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 735 volts.

[0182] After filling the female syringe (1) with the excipient, it is subjected to an ionization process (c) thanks to a bar ionizer (2) thus preventing the PLGA from adhering to the walls of the container (1) near the nozzle.

[0183] After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 530 volts.

[0184] Once the cylinder has been filled with the excipient and subsequently ionized, the cylinder (7) containing the syringe (1) filled with PLGA is placed in the next filling station (b) for the active compound Risperidone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5) where it is tared before filling with the active compound. Filling with Risperidone then begins. The syringe (1) is weighed continuously during filling so that the process can be stopped once the target weight is reached.

[0185] Once filled with the active compound, the cylinder with the syringe (1) is subjected to another ionization process. Using a bar ionizer (2), the active compound and the excipient are prevented from adhering to the walls of the syringe (1). After this process, the electrostatic charge inside the inner walls of the container (1) is measured, and the reading obtained is 215 volts.

[0186] The ionization process achieves the optimal sealing phenomenon and the precise dose required.

Claims

CLAIMS 1. Procedure for filling pharmaceutical containers (1) with at least one solid and sealing the same under sterile conditions, comprising the steps of: a) provide a pharmaceutical container (1) having walls and a bottom, b) dispensing the solid into the pharmaceutical container (1) using a dispensing needle (4), gravimetrically controlling the weight of solid dispensed into the container (1); and c) sealing the pharmaceutical container by means of a stopper (6), characterized in that, in at least one of the steps a), b) i) or a plurality thereof in any combination, the static electric charges existing on the inner walls of the container (1), on the solid dispensed inside the container, and / or on any part in contact with the walls of the container or with the solid dispensed inside the container, are neutralized by means of an ionizer (2) to which an ionization potential is applied such that the electrostatic charge inside the container (1) after each ionization is less than 2000 volts 2. Method according to claim 1, wherein, between step b) and step c), an additional ionization of static electric charges is carried out inside the pharmaceutical container (1).

3. A method according to claim 1 or 2, wherein, in step a), the ionization is carried out with the pharmaceutical container (1) empty 4. Method according to any one of claims 1 to 3, wherein the ionizer(s) (2) are located on the outside or inside of the pharmaceutical container (1), in any combination.

5. Method according to any of claims 1 to 4, wherein, in step c), ionization is carried out before and / or during sealing 6. A process according to any of the preceding claims, characterized in that the static electric charges are less than 1000 volts.

7. A process according to any of the preceding claims, characterized in that the static electric charges are less than 500 volts.

8. A process according to any of the preceding claims, characterized in that the static electric charges are less than 200 volts.

9. A method according to any of the preceding claims, wherein step b) is carried out under vibration of the dispensing needle (4) to assist in the homogeneous dosing of the solid.

10. A method according to any one of the preceding claims, wherein step b) is repeated a certain number of times.

11. A method according to any of the preceding claims wherein, in step b), the tip of the dosing end of the dispensing needle (4) is at a height h of 1 to 3 mm above the surface of the solid deposited at the bottom of the container (1).

12. A method according to any of the preceding claims, wherein, in step b), the container (1) is in a fixed position throughout the filling step, while the dispensing needle (4) is a movable element that moves upwards as the filling step progresses, in order to maintain the distance h between the dosing end of the dispensing needle and the surface of the solid deposited at the bottom of the container (1).

13. A method according to any of claims 1 to 11, wherein, in step b), the dispensing needle (4) is in a fixed position throughout the filling step, while the container (1) is a movable element that moves downwards as the filling step progresses, in order to maintain the distance h between the dosing end of the dispensing needle and the surface of the solid deposited at the bottom of the container (1).

14. A method according to any of claims 1 to 11, wherein, in step b), both the dispensing needle (4) and the container (1) are movable elements that move synchronously with each other during the filling step, in order to maintain the distance h between the dosing end of the dispensing needle (4) and the surface of the solid deposited at the bottom of the container (1).

15. A method according to any of the preceding claims, wherein, in step b), the container (1) is filled from the distal part to the container collar when the container is a syringe or cartridge.

16. A method according to any of claims 1 to 14 above, wherein, in step b), the container (1) is filled from the distal part to the container nozzle when the container is a syringe or cartridge.

17. A process according to any one of the preceding claims, wherein step c) is carried out under vacuum 18. A method according to any one of the preceding claims, wherein, in at least one of steps a), b) and c) or in a plurality of the same in any combination, a sterile carrier gas stream such as N2 or sterile compressed air is applied inside the pharmaceutical container (1).

19. A method according to any one of the preceding claims, wherein the ionizer (2) is selected from the group consisting of ring, rod, gun, curtain, blade, cannon, needle or filter ionizer ionizers, and insulators with an ionizer on the ceiling thereof.

20. A method according to any one of the preceding claims, wherein a dispensing needle (d) dispenses the solid contained in a hopper (c), and both the hopper (c) and the dispensing needle (d) are made of a non-conductive material.

21. A method according to any one of the preceding claims wherein the pharmaceutical container (1) is inserted into a cylinder made of an electrically conductive material and is grounded to help dissipate static charge from the pharmaceutical container.

22. A method according to any one of claims 1 to 20 above, wherein the pharmaceutical container (1) is inserted into a cylinder of an electrically non-conductive material, to help dissipate the static charge of the pharmaceutical container.

23. A method according to any one of the preceding claims wherein the pharmaceutical container (1) is made of an electrically non-conductive material.

24. A method according to any one of the preceding claims wherein the pharmaceutical container (1) is selected from the group consisting of a male syringe, a female syringe, a syringe with needle, a vial, a capsule, an ampoule, a single-dose device, a cartridge, an inhaler, a bottle, a blister pack, a sachet, a bag, a test tube, and an Eppendorf®-type tube.

25. A method according to any one of the preceding claims wherein the pharmaceutical container (1) is composed of glass, crystal, metal such as steel or titanium suitable for drug administration, or plastic-type materials.

28. A process according to claim 25, wherein the plastic-type materials are selected from polyolefins, cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polyetheretherketone, polystyrene, polyvinyl chloride, polyacrylonitrile, polyamides, polyesters such as poly(ethylene terephthalate), polycarbonate, acrylic polymers such as poly(methyl methacrylate), polyacrylonitrile, thermoplastic resins such as polyacetates and polyhalostyrenes, polyurethanes, formaldehyde resins such as phenol resin and urea resin, phenolics, aminoplasts, thioplasts, thermoplastic resins such as unsaturated polyesters and polyurethanes, polyvinylidene silicones, cellulose derivatives, polycarbonates, and combinations thereof.

27. Method according to any one of the preceding claims wherein the pharmaceutical container (1) has a diameter between 9 and 80 mm.

28. A method according to any one of the preceding claims, wherein the dispensing needle (4) is provided with a containment element to prevent the powder from being dispersed above the level of the dosing tip or end of the needle during filling.

29. A method according to any one of the preceding claims, wherein the solid product to be dispensed into the container (1) has the following particle size distribution: -no more than 10% of the total particle volume is less than or equal to 20 microns, -no more than 10% of the total particle volume is greater than or equal to 230 microns or less than or equal to 14G microns, -a d0.5 value in the range of 80-180 miles, where d0,5 indicates the mean particle size value that divides the population exactly into two equal halves, with 50% of the distribution above this value and 50% below it.

30. A method according to any one of claims 1 to 28 above, wherein the solid product to be dispensed into the container (1) has the following particle size distribution: -no more than 10% of the total particle volume is less than or equal to 20 microns, -no more than 10% of the total particle volume is greater than or equal to 325 microns or less than or equal to 245 microns, -a d0.5 value in the range of 100-155 miles, 31. A method according to any one of the preceding claims, wherein the solid product to be dispensed into the container (1) is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, alone or in combination.

32. A method according to any one of the preceding claims, wherein the solid product to be dispensed into the container (1) is selected from the group consisting of biocompatible polymers of the type polylactic acid, (PLA), polyglycolic acid (PGA) and their copolymers polylactic-co-glycolic acid (PLGA) including any derivative or copolymer, alone or in combination.

33. A procedure according to any one of the preceding claims, characterized in that it is carried out in an aseptic environment in an area with unidirectional airflow.

34. A procedure according to any one of the preceding claims, characterized in that it is carried out in an insulator.

35. A process according to any one of the preceding claims, characterized in that prior to step b) sterilization of the insulator with nebulized or vaporized hydrogen peroxide, or mixture of hydrogen peroxide with peracetic acid.

36. A method according to any one of the preceding claims that is implemented in computer executable software.

37. Container (1) containing a solid product, wherein the solid product has been dispensed into the container (1) using the method described in any one of claims 1 to 36 above.

38. Container (1) containing a solid product according to claim 37, wherein the solid product has the following particle size distribution: -no more than 10% of the total particle volume is less than or equal to 20 microns, -no more than 10% of the total particle volume is greater than or equal to 230 microns or less than or equal to 140 microns, -a d0.5 value in the range of 60-160 microns, where d0.5 indicates the average particle size value that divides the population exactly into two equal halves, with 50% of the distribution above this value and 50% below it.

39. Container (1) containing a solid product according to claim 37, wherein the solid product has the following particle size distribution: -no more than 10% of the total particle volume is less than or equal to 20 microns, -no more than 10% of the total particle volume is greater than or equal to 325 microns or less than or equal to 245 microns, -a d0.5 value in the range of 100-155 miles.

40. Container (1) containing a solid product according to any one of claims 37 to 39, wherein the solid product is a medicament.

41. Container (1) containing a solid product according to claim 40, wherein the medicament is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, alone or in combination.

42. Container (1) containing a solid product according to any one of claims 37 to 39, wherein the solid product is a biocompatible polymer.

43. Container (1) containing a solid product according to claim 42, wherein the biocompatible polymer is selected from the group consisting of biocompatible polymers of the polylactic acid (PLA) type, polyglycolic acid (PGA) and their polylactic-co-glycolic acid (PLGA) copolymers, including any derivative or copolymer, alone or in combination.

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