OA20106A - Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions - Google Patents

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

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Publication number
OA20106A
OA20106A OA1202100200 OA20106A OA 20106 A OA20106 A OA 20106A OA 1202100200 OA1202100200 OA 1202100200 OA 20106 A OA20106 A OA 20106A
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container
filling
solid
ioniser
ionisation
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OA1202100200
Inventor
Aduriz Ibón Gutierro
Amo Maria García
Miranda Elena Cebadera
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Laboratorios Farmacéuticos Rovi. S.A.
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Publication of OA20106A publication Critical patent/OA20106A/en

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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. 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

Field of the Invention
The présent invention falls within the field of filling and sealing under stérile conditions of pharmaceutical containers including syringes, vials, capsules, ampoules, single-dose devices or cartridges that hâve been filled with solid substances selected from the group formed by powder, granules, pellets, nanoparticles, or microparticles, obtaining the sealing of these solid substances. More particularly, the field of the invention relates to a procedure for the filling and sealing of pharmaceutical containers which hâve been filled with one or more stérile solid pharmaceutical substances or stérile excipients dispensed and prepared in an aseptie environment which avoids adhérence of the said substances to the sides of the pharmaceutical containers, thus ensuring the tightness of the container seal.
Background Art
In the pharmaceutical industry, the filling process of pharmaceutical containers is often carried out with liquid pharmaceutical substances and/or freeze-dried solids, as these are much easier to handle and involve fewer dosing problems than solids such as powders, granules, pellets, nanoparticles, microparticles, and others. The use of solids such as those mentioned above in the container filling process has the major drawback that these solids tend to adhéré to the walls or body ofthe containers, preventing or at least hindering the obtaining ofthe necessary tightness in the container seal. This adhérence to the walls or to the body, in addition to preventing the desired tightness, leads to contamination of the containers and loss of doses, as containers in which such adhérence to the walls is observed must be discarded because as part ofthe solid remains in the sealing area ofthe container walls, it is not possible to knowthe exact amount ofsolid that will be delivered to the patient. On the other hand, with regard to contamination, as the dispensed solid remams adliered to the walls of the sealing area, the stopper used to seal the container does not close hermetically, so it will not be able to prevent the entry of substances from the environment into the container and will not ensure the integrity of the product, such that its physico-chemical and microbiological properties may vary, affecting the quality ofthe médicinal product. This is the biggest drawback that the pharmaceutical industry can encounter in this field due to the strict conditions imposed by the régulations ofthe industry, which must also comply with the standards known as Good Manufacturing Practices (GMPs).
Another concem for the pharmaceutical industry is ensuring the integrity ofthe closure, which also affects safety, as small losses of the medicine can affect the safety of the healthcare workers 5 handling it. The term integrity here refers to the physic ability of a container closure system to maintain product sterility and quality of final stérile pharmaceutical, biological and vaccine products throughout their lifetime. A stérile product is also defined as a product free of microorganisms, whose composition is one or more of the éléments exposed to aseptie conditions and which ultimately make up the stérile finished pharmaceutical product. These éléments include the 10 containers, closures, and components of the finished pharmaceutical product.
When dosing powder into pharmaceutical containers, several factors affecting the cleanliness of the inner walls ofthe containers must be considered, as lack of cleanliness results in contamination. These factors are listed below:
- The static charge of the walls of the pharmaceutical containers used for filling, as well as the static charge of the solid that is dispensed into them: If the wall and solid loads hâve opposite charges, the dispensed solid will adhéré to the container walls.
- The kinetic energy that both the dispensed solid and the éléments in contact with it acquire when the solid falls into the containers: The greater the height from which the solid to be dispensed falls freely to the bottom ofthe containers, the greater the kinetic energy acquired by the solid and the éléments due to friction.
The length of the dispenser needles (also known as nozzles) used for dosing, as the longer the dispenser is and the closer it is to the top of the dispensed solid in the container, the less kinetic energy it will hâve. In addition, the dispenser conveys the dispensed solid to an area away from the wall surfaces ofthe container used. The idéal distance between the dispensed solid and the tip ofthe dispenser will dépend on the dispensing rate and the density ofthe solid dispensed.
- Redirection ofthe air displaced inside the containers. This phenomenon is related to the kinetic energy ofthe dispensed solid when it is released into the container. During dispensing, the inrush ofthe solid mto the container displaces the air inside the container upwards. This displaced air is full of suspended particles. Thus, the dispenser can be thought of as a chimney that moves the air stream away from the interior walls, preserving them from this contamination.
- The use of large airflow streams (unidirectional or turbulent régime) in filling cabins or filling sites as required by international Pharmacopoeias to ensure the removal of any foreign particles that may contaminate the final product from the aseptie filling and sealing process. The use of these airflow streams makes filling with solids quite difficult, as a disturbance is generated that causes the solid to adhéré to the walls of the container used for filling
In order to eliminate the adhérence of the solid to the walls of the container, one of the measures used is to perform a process of ionisation of both the container and the solid to be filled in it. In the présent invention, the terms process, stage and phase are used interchangeably, as well as the terms ionisation and deionisation or ioniser and deioniser.
Ionisation is a Chemical or physical phenomenon by which ions are produced. Ions are atoms or molécules that are electrically charged due to an excess or lack of électrons relative to a neutral atom or molécule. The Chemical species with more électrons than the neutral atom or molécule is called an anion, having a net négative charge, and the one with fewer électrons is called a cation, having a net positive charge.
The ionisation process employed in the présent invention is used both to neutralise the electrostatic charge ofthe pharmaceutical container to be filled with the pharmaceutical solid, and to neutralise the electrostatic charge of the solid to be dispensed, i.e., for both the container and the contents. This ionisation is also used to neutralise the éléments of the dosing and capping equipment that corne into contact with the container and/or the powder. For this purpose, the ioniser generates ions of both polarities which are projected onto the surface of the object to be neutralised, where ions of opposite signs are recombined and those of the same sign are rejected. Throughout this document, ioniser means any element or device which is capable of ionising the surrounding air molécules, so that they are then projected onto a surface which has static electrical charges that neutralise those charges, thereby ionising that surface.
However, with this ionisation process only it is not possible to avoid the serious problem of adhérence to the sides of the container during the process of filling the containers with solids, because when the solid is filled through the nozzle, the kinetic energy carried by the solid generates turbulence inside the container that eventually again causes part of the solid to stick to the walls or the body ofthe container.
As regards the prior art, the documents cited below describe the ionisation technique that results in the neutralisation of electrical charges applied to various situations:
In this regard, patent US 2016/0200461 Al filed by VANRX Pharmasystems INC. describes a method for volumétrie filling and aseptie sealing of containers such as vials, bottles, syringes and ampoules with a liquid pharmaceutical product (which can be subsequently lyophilised) in a controlled environment. This publication mentions concems about the materials from which the containers are made, whether glass or polymeric materials. On one hand, glass containers suffer from breakage, scratching, and particle émission due to collisions between them. On the other hand, containers made of polymeric materials are more résistant than those made of glass, although they suffer from cosmetic defects such as scratches, which can impair the quality of the pharmaceutical product due to collisions.
A substantial différence in the présent invention with respect to the document cited is that the compounds handled are solid substances that are much more difficult to dose, since they are highly charged and hâve a higher spécifie surface area. Moreover, in the above-mentioned document the sealing process comprises two stages, a partial stage and a second complété stage due to the need for freeze-drying after the first partial sealing, whereas in the présent invention the sealing process is carried out in a single stage with a complété sealing, without the need to resort to subséquent sealing stages.
In addition, it should be noted that the filling process of solid substances is much more complex due to the fact that the solid substances remain adhered to the walls of the pharmaceutical containers, impairing the précision of the dosage, which is more relevant in small calibre containers where it is necessary to dose small quantities of medicines in a very précisé way. This drawback is solved by the procedure proposed in the présent invention, since it must be taken into account that, in the pharmaceutical industry, an error in the filling ofthe active ingrédient may mean that patients will receive an incorrect dose of the product.
This is a serious drawback when filling containers with solids due to the problem ofthe adhérence ofthe solid to the body ofthe containers. For this reason, in most ofthe procedures used today in the pharmaceutical industry, certification of the equipment is mandatory to ensure that the dispensed quantity is adéquate. In addition, various in-process Controls are incorporated during packaging to verify the actual filling quantity of ail pharmaceutical containers. A common control is weighing the containers, which allows to rectify or discard containers in which the quantity of pharmaceutical substance, either drug or active ingrédient, does not meet the required weighing accuracy. In-process Controls canbe 100% or statistical; the latter are carried out from time to time to check the dosage. These Controls involve a high production and économie cost, which is necessary to control the précision of the product dosage.
As for the élimination of electrostatic charge, several types of ionisers are available for dealing with this problem. These ionisers corne in various shapes, such as ring, rod, gun, curtain, blade, barrel, needle, or fïlter ionisers, including isolators with an ioniser on the top of the isolator, among others. For the purpose of this invention, these ionisers can be installed on the machinery used for the filling process to produce ions ofboth polarities that neutralise the surface ofthe containers or products, or they can also be placed in the packaging areas, room or isolators, specifically on the ceiling of the isolators to produce an ionisation that neutralises both the environment and the air flow of the area, thereby eliminating the problem of static charges.
With regard to the removal of the static charge of solids by ionisers, several documents are cited below:
European patent EP 2711096 A2 applied for by TRINC Corporation relates to a device for the removal of electrostatic charge and dirt from objects such as film, foil, glass, dothing, paper or the like. The device comprises a large container with an opening at the top and an opening at the bottom for suctioning and discharging the powder and a small cylindrical or conical container inside the large container. This small container is designed to generate a cyclone current and tomado current within it, and comprises at least one corona discharge ion generator. This ion generator consists of electric discharge needles that are placed either on top of or inside the small container. The small container comprises air injection openings through which compressed air is injected, as well as ultrasound generators inside or outside the small container meant to make the powder vibrate so that it can be separated from the desired object once it has been neutralised by the ion generator. This powder can be collected by vacuum suction inside the large container.
The présent invention, instead, relates to the deionisation of both the container and the powder prior to packaging in order to prevent the powder from sticking to the container walls during the filling process and thus to achieve a complété seal. In addition, as a safety factor, deionisation is carried out on and/or inside the container to remove any remaining powder adhered to the walls of the sealing area.
The présent invention also uses an ioniser, whether in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of said isolator, to eliminate static electricity, but it does so both on the powdered solid and the container to be used, which is not done in European patent EP 2711096 A2, as this only ionises the powder and does not ionise the container. Another substantial différence of the présent invention with said document is based on the fact that said European patent EP 2711096 uses compressed air to facilitate suction, whereas the présent invention does not need an air stream and, if it does, it should be of a stérile carrier gas. Among stérile carrier gases, an ionised nitrogen stream has advantages which will be discussed below.
A characteristic drawback ofthe présent invention is the need to carry out the deionisation in stérile environments, making the use of stérile carrier gases necessary. It should be noted that this stérile condition ofthe carrier gas does not affect the deionisation process.
On the other hand, European patent EP 2711096 A2 differs from the présent invention in that, although in both it is important to eliminate the electrostatic charge ofthe solid, said document does not discuss in detail the method by which this is carried out, mentioning only the use of an ion generator such as discharge needles for deionisation, without mentioning the problem caused by the electric discharge needles when they approach any solid, namely the appearance of a combustion phenomenon buming the product, generating impurities and altering the physicochemical composition of the product.
Japanese patent JP 2005001818 A applied for by YMS KK refers to a powder supply device and an air conveying device capable of feeding easily-charged powder and charged powder. This device comprises a hopper equipped with aération means that are in tum equipped with a microporous diaphragm to aerate the powder in the hopper. The air for aération is pre-ionised by an ionisation device such as a corona discharge device. Compressed air supplied by an air compressor is used for aération. This compressed air is ionised by an air ionisation device comprising a corona discharge device or the like. When the aération is performed by ionised air, the ionised air neutralises or removes the surface charge ofthe powder, so that the surface charge of the charged powder disappears. In addition, when aération causes the powder in the hopper to inflate air and a layer of air forms between the powder and the inner wall of the hopper, the powder is prevented from becoming charged again. In addition, this document refers to a suction nozzle or needle made of conductive material that forms part of the air conveying device. This nozzle is never a dosing nozzle.
In the present invention, on the other hand, the solid substance is ionised on one band and the pharmaceutical container is ionised on the other hand, using a stérile carrier gas stream as the ionised gas, usually a stream of stérile nitrogen. Another différence of the present invention with this Japanese patent is 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 ioniser, whether in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator or of any other type, in order to neutralise the electrostatic charge of both the container to be fîlled and the solid to be dispensed, whereas the Japanese patent only mentions the use of a corona discharge ionising device or the like.
Chinese utility model CN 203265193U by Meech Static Eliminators Shanghai Co LTD makes reference to the technical field of static electricity and powder removal from the inner wall of bottles, prior to filling, for container cleaning, using for this purpose an ion needle with compressed air to eliminate static electricity and remove the powder adhering to the walls of the bottle. The device described in this utility model consists of a needle, a first tube connecting the needle and a second tube for connecting the electrical cable, the two ends of which hâve an internai thread or an extemal thread respectively. The needle tip and the second tube are screwed and fixed together, and the needle tip, the first tube and the second tube hâve an interconnected inner passage for the passage of air, and the second tube also has at least two threads, so that the passage thread is also connected to the inner bore ofthe first tube. The tube features uniformly spaced wire ho les between the inner and outer wall, each of these ho les forming an ion-generating end at one extreme ofthe second tube that fits into the first member of the tube. The ions can be introduced into the surface ofthe proposed object through the ion needle and with the help of compressed air.
In the present invention, instead, the ioniser can be of any type, as a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or even an ionising filter, among which can also be found isolators with an ioniser on the top of said isolator, without the need for it to be a needle as specifically mentioned in the Chinese utility model. Furthermore, this utility model is assisted by compressed air to displace the ions, whereas the présent invention may or may not use a stérile carrier gas stream, which may consist of stérile compressed nitrogen or air, not only to facilitate the ionisation process by aiding the dosing of the solid but also to maintain the necessary stérile conditions required for these procedures in the pharmaceutical industry by generating an inert atmosphère inside the containers. On the other hand, the utility model relates to cleaning bottles with powder prior to filling, whereas the présent invention relates to deionisation and cleaning of walls after filling and applies to smaller containers than bottles, such as syringes, vials, capsules, ampoules, single-dose, devices or cartridges, which are more difficult to fîll with a solid such as powder.
International patent 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 blister packs with powdered pharmaceutical material by vibration. This apparatus has a support for the pharmaceutical container, a tank containing pharmaceutical powder, this tank being in contact with a nozzle or filling needle in charge of filling the pharmaceutical container with the pharmaceutical powder, and a piezo-electric vibration device. This document relates to the advantage of using a cylinder comprising an electrically conductive material, which can be grounded through the weighing cell, thereby helping dissipate the static charge of plastic pharmaceutical containers to achieve a better 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 process for filling through the mouth ofthe container, so that the problem of sealing that occurs when filling from the back ofthe container would not arise.
The présent invention, on the other hand, concems a process for sealing pharmaceutical containers which are filled with pharmaceutical solids, wherein such filling is carried out under aseptie conditions without the need for terminal stérilisation, whereas said international patent WO 2016/185230 A2 describes filling through the mouth ofthe container as can be seen in figure 2. On the other hand, this international publication only mentions the filling of plastic pharmaceutical containers such as containers, whereas the présent invention includes ail types of materials, such as polymeric materials or glass, for the container. Furthermore, the international publication mentions a cylinder or puck with an electrically conductive material meant to dissipate the static charge ofthe pharmaceutical containers to be used, whereas, in the présent invention, the existence of a cylinder acting as a support for the container is an optional element, unrelated to the problem to be solved, and which is also intended for various other fonctions, such as:
- The use of such an element for the handling of the container without contact with same.
- The Cylinder protects the process from air streams by being part of the exclusion hood.
- It is an element for vertical support of the container on the weighing cell for accurate weighing
Furthermore, in the présent invention it is possible to use any ioniser, whatever form it may take, i.e. ring, bar, gun, curtain, blades, barrels, needle or nozzle, or an ionising filter, among which can also be isolators with an ioniser on the top of said isolator which can be installer! on the packaging equipment prior to filling, during filling and after filling, using or not a stérile carrier gas, whereas the invention described in said 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.
Summary of the Invention
Accordingly, the problem to be solved in the présent invention is to provide a procedure for filling pharmaceutical containers which may take the form of vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, sachets, bags, test tubes, Eppendorf® tubes and syringes. The syringes of the présent invention may hâve a needle, cathéter type cône, or Luer lock type cône, i.e. with an unthreaded tip or with female or male threaded tip, respectively. For the purpose of the présent invention, Luer cône refers to the cone-shaped tip invented by Wülfing Luer with atypical taper of 6%, which can be male or female depending on the coupling. Likewise, “Luer lock cône refers to the cone-shaped tip invented by the German Wülfing Luer with an airtight threaded closure.
The compounds ofthe containers ofthe présent invention are materials such as plastics of different composition, such as polyolefins and cyclopolyolefins, polypropylène, polybutadiene, polyethylene, polystyrène, polyvinyl chloride, polyacrylonitrile, polyamides, etc., polyesters (containing the ester functional group in their main chain: poly(ethylene terephthalate), polycarbonate), acrylic polymers (poly(methyl méthacrylate), polyacrylonitrile), thermoplastic resins (polyacetals and polyhaloethylenes), polyuréthanes, formaldéhyde resins (phénol resin, urea resin), phenoplasts, aminoplasts, thioplasts, duroplastic resins (unsaturated polyesters, polyuréthanes), polyvinylidene silicones, cellulose dérivatives, polycarbonates, and mixtures thereof, etc. Altematively, the container can also be made of métal, e.g. steel or titanium suitable for drug delivery, glass, etc., with solids in stérile 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 an airtight sealing of the container.
In tum, both the cylinder or puck, the hopper and the nozzle or needle will preferably be composed of various non-conductive materials such as various plastics, e.g. polyether etherketone (PEEK), glass, stone, resin, glass, but may also be composed of grounded conductive materials such as steel or titanium, etc.
Both the materials used for the container and the cylinder materials must be watertight, inert, not very permeable or imperméable, that do not absorb and/or adsorb the contained product, not rough, and free of particles.
The solution to the problem described in the présent invention is based on the fact that the inventors hâve found that such a problem can be satisfactorily solved by means of the following techniques, which can be applied independently or in any combination:
On the one hand, ionising both the solid and the pharmaceutical container where it is to be deposited, as well as ionising the éléments of the dosing and capping equipment that cornes into contact with the container and/or the powder, at one or more stages of the filling procedure, in order to prevent the solid from tending to adhéré to the walls of the container, as well as the walls of the container from tending to attract the solid particles, so that the only tendency of the solid is to fall to the bottom of the container and not be deposited on its walls. This deionisation technique can be applied to the container and the solid separately, as well as to the container with product inside. This deionisation can be applied as many times as there are filling and capping steps in the process;
On the other hand, by controlling the potential applied to the ionisers, which should be such that the resulting electrostatic charge on the container walls and/or the dispensed solid is preferably less than 2,000 V, more preferably less than 500 V, and most preferably less than 200 V.
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In addition, the filling of the pharmaceutical container with the solid is preferably carried out using a dispensing needle whose tip or dispensing end is located, throughout the filling stage, at a height between 1 to 3 mm above the surface of the solid deposited on the bottom of the container, so as to avoid turbulence that could lift the deposited solid towards the walls. Even if this turbulence 5 phenomenon were to occur to some extent, ionisation of both the solid and the inner walls of the container will make said lifted particles settle back on the bottom of the container, without substantial loss of product on the container walls.
Consequently, in a first aspect the invention relates to a process for filling under stérile conditions 10 pharmaceutical containers with solids, 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 checking the weight of solid dispensed into the container (1); and
c) sealing the pharmaceutical container with a stopper (6), characterised m that, m at least one of steps a), b) and c), or a plurality thereof in any combination, the static electric charges on the inside walls of the container (1), on the solid dispensed inside the container, and/or on any parts in contact with the container walls or with the solid dispensed inside 20 the container, are neutralised by means of an ioniser (2) to which an ionisation potential is applied such that the electrostatic charge inside the container (1) after each ionisation is less than 2,000 volts. This ionisation prevents the solid dispensed into the container from tending to adhéré to the inner walls of the container (1), which may distort the amount of solid dispensed into the container, hinder a visual assessment of the level of product dispensed, or even cause incomplète 25 administration of the product to the patient.
In a second aspect, the invention relates to a container (1) containing a solid product, wherein the solid product has been dispensed into the container using the described method.
In the case of ionisation in the rod/ring case, re-ionisation will be performed preferably with a needle with or without a gas stream.
In general, throughout the présent description, filling is preferably carried out by means of a dispensing needle whose tip or dispensing end is located, throughout the filling stage, at a height of 1 to 3 mm above the surface of the solid deposited on the bottom of the container, in order to prevent generating turbulence that could lift the solid towards the walls of the container.
This procedure has two advantages: On the one hand, achieving accuracy in the filling of substances into a single container even when two or more filling stations are used, by preventing the solid substances from sticking to the sides of the container. On the other hand· ensuring the integrity of the seal of the pharmaceutical container, which is especially important in the case of médicinal products as it prevents both the entry of foreign agents into the container that would contaminate the product, and the leakage of the product to the outside affecting the effective dose of the product.
Additionally, the présent invention also solves the problem of static charges generated by collisions between the containers used for filling, whether they are made of glass or polymeric material, in a stérile environment that is generally subject to laminar or turbulent flows which increase the movement and dispersion of electrostatic charges.
Although the invention is generally applicable to powdered solid compounds of any nature, this procedure is particularly applicable to solids having the following particle size distribution:
Dio > 20 microns microns < D50 <110 microns
150 microns < D90 <215 microns where Dw is the mean value ofthe particle size that divides the population into exactly two equal halves, with 50% ofthe distribution being above this value, and 50% below. In general, throughout this spécification, a value denoted as dO.X or Dx represents the mass fraction ofthe drug with particle sizes below the specified value, having a range of 0.0 to 1.0. According to this définition, a value of dO. 1 or Dw means that 10% of the total mass of the drug particles has a particle size of 10 microns or less.
This is ideally applicable to solids having the following particle size distribution:
Dw > 25 microns
100 microns < D50 <155 microns
245 microns < D90 < 325 microns
Examples of such compounds are rispéridone, paliperidone, fentanyl, olanzcompound activone, letrozole, aripiprazole, anastrozole, asencompound activone, brexiprazole, cariprazine, clozcompound activone, iloperidone, lurasidone, queticompound activone, ziprasidone, among others including any dérivatives, métabolites or salts (such as pamoate or palmitate) alone or in combination.
Other examples of such compounds are also biocompatible polymers of the polylactic acid (PLA), polyglycolic acid (PGA) types and their copolymers polylactic co-glycolic acid (PLGA) including any dérivatives or copolymers, alone or in combination.
Brief description of the figures
The figures accompanying the présent invention serve to illustrate the nature of the invention. These figures are included for purposes of illustration only and should not be understood as limiting the invention claimed herein. With respect to the ionisation phenomenon, the présent invention proposes different methods, some of which are shown in figures 1 to 7 described below. In order to properly interpret the figures, the ionisation phenomenon is represented by the altemating positive (+) and négative (-) signs, bearing in mind that this stream of ions of different signs may or may not be accompanied by a stream of stérile carrier gas, although the latter is not represented as such in the figures.
Figure 1: Figure 1 shows a particular embodiment of the aseptie filling and sealing process according to the présent invention, wherein the pharmaceutical container depicted is, in this case, a male syringe ( 1 ) which remains capped with a nozzle cap (8) throughout the process. The syringe (1) is subjected to a first ionisation stage (a) with the aid of an ioniser (2), with either a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator, although in this case a needle ioniser is shown. The male syringe ( 1 ) then passes to the filling station (b), where the procedure ofthe invention may comprise multiple filling stations, in particular if there are multiple solids to be filled into the syringe. In this station, the syringe, which may optionally be inserted in a cylinder (7), is weighed by a weighing cell (5) during filling, which takes place by means of a hopper (3) and a nozzle or dispensing needle (4). After filling, the male syringe (1) is subjected to another ionisation stage (c) by means of an ioniser (2) provided at this stage either by a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising filter, among which isolators with an ioniser on the top of the isolator can also be found, although in this case a ring ioniser is shown. Finally, the male syringe (1) is transferred to a sealing station (d) where it is hermetically sealed at the top with a stopper (6).
Figure 2: Shows another particular embodiment of the process of the présent invention, where the male syringe of Figure 1 has been replaced by a female syringe as the pharmaceutical container (1).
Figure 3: Shows a particular embodiment ofthe process ofthe présent invention, where the syringe has been replaced as the pharmaceutical container (1) by an Eppendorf® tube, which is subjected to an ionisation stage (a) thanks to the presence in said stage of an ioniser (2) whether it be a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising filter, among which can also be found isolators with an ioniser on the top of said isolator, in this case a needle ioniser. It is then transferred to the filling station (b) (there may be multiple filling stations) where there is an ioniser (2) with a ring, bar, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, among which there may also be isolators with an ioniser on the top of the isolator, in this case an ionising filter. In addition to the ioniser, this stage contains a weighing cell (5), a hopper (3), and a nozzle or dispensing needle (4). Finally, after filling, the Eppendorf® tube is subjected to an ionisation process by means of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, which may also include isolators with an ioniser on the top of the isolator, in this case a rod ioniser (2).
Figure 4: Shows a particular embodiment of the procedure of the présent invention in which the container represented is, in this case, a syringe with needle (1) pre-capped with the nozzle cap (8) throughout the sealing process, which is subjected to a first ionisation process (a) with the aid of an ioniser (2) which may be in the form of a ring, bar, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, among which can also be found isolators with an ioniser on the top of said isolator, although in this case a needle ioniser is shown. The syringe with needle (1) then passes to the filling station (b), where in the procedure described in the présent invention there may be multiple filling stations, in particular if there are multiple solids to be filled into the syringe. In said station, the syringe with needle, which may optionally be inserted in a cylinder (7), is weighed by a weighing cell (5) during filling, which takes place by means of a hopper (3) and a nozzle or dispensing needle (4). After filling, the syringe with needle (1) is subjected to a further ionisation step (c) by means of an ioniser (2), with either a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator, although in this case a ring ioniser is shown. Finally, the syringe with needle (1) is transferred to a sealing station (d) where it is hermetically sealed at the top with a stopper (6), while it is subjected to an additional ionisation stage by means of an ioniser (2) provided at this step, with either a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising filter, among which isolators with an ioniser on the top of said isolator can also be found, in this case a rod ioniser.
Figure 5: Shows another particular embodiment of the procedure of the présent invention in which the container depicted is, in this case, a female syringe (1) capped throughout the process with a nozzle cap (8), which is subjected to a first ionisation process (a) with the aid of an ioniser (2) with either a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter. Next, the female syringe (1) passes to the filling station (b), where in the procedure described in the présent invention there may be multiple filling stations, in particular if there are multiple solids to be filled into the syringe. In said station, the syringe, which may optionally be inserted in a cylinder (7), is weighed by a weighing cell (5) during filling, which takes place by means of a hopper (3) and a nozzle or dispensing needle (4). Aller filling, the syringe undergoes an ionisation process (c) by means of an ioniser (2) in the form of a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator, although in this case a needle ioniser is shown. Finally, the female syringe (1) is transferred to a sealing station (d) where it is hermetically sealed at the top with a stopper (6) while it is subjected to an additional deionisation phase by means of an ioniser (2), provided at this stage, with either a ring, rod, gnn, curtain, blade, barrel, needle or nozzle, or a filter ioniser, among which there may also be isolators with an ioniser on the top of the isolator, in this case, a rod ioniser.
Figure 6: Shows another particular embodiment of the procedure of the présent invention in which the container represented is, on this occasion, a cartridge (1), is subjected to a first ionisation process (a) with the aid of an ioniser (2) with either a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, among which can also be found isolators with an ioniser on the top of said isolator, although in the présent case a needle ioniser is represented. The cartridge (1) then passes to the filling station (b), where in the procedure described in the présent invention there may be multiple filling stations, particularly if there are multiple solids to be filled into the cartridge. In this station, the cartridge is weighed by a weighing cell (5) during filling, which takes place by means of a hopper (3) and a nozzle or dispensing needle (4). Finally, the cartridge (1), which may optionally be inserted in a cylinder (7), is transferred to an ionisation station where an ioniser (2) will act, with either a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising fîlter, or an isolator with an ioniser on the top of the isolator, where in this case a rod ioniser is shown.
Figure 7: Shows a particular embodiment of the process of the présent invention in which the container represented is, in this case, a pre-filled female syringe (1) which is first subjected to an ionisation process (a) with the aid of an ioniser (2) with a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising fîlter, among which can also be found isolators with an ioniser on the top of said isolator, although in the présent case one with a ring is represented. Afîer this the syringe, which is filled at its threaded end, is located in the filling station (b), where in the process described in the présent invention there may be multiple filling stations, particularly if there are multiple solids to be filled into the syringe. In this station, the syringe, which may optionally be inserted in a cylinder (7), is weighed by a weighing cell (5) during filling, which takes place by means of a hopper (3) and a nozzle or dispensing needle (4). After filling, the female syringe (1) is subjected to a further ionisation phase (c) by means of an ioniser (2) with either a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising fîlter, which may also include isolators with an ioniser on the top of the isolator (in this case a rod ioniser).
Detailed description of the invention
Filling of solid substances either by volumétrie or gravimétrie filling such as powder, granules, pellets, nanoparticles or microparticles in small pharmaceutical containers such as vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, sachets, bags, test tubes, Eppendorf® type tubes and syringes (with male or female, threaded or non-threaded nozzles) and of different materials, such as plastics of different composition, such as polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrène, polyvinyl chloride, polyacrylonitrile, polyamides, etc., polyesters (containing the ester functional group in its main chain), poly(ethylene terephthalate), polycarbonate), acrylic polymers (poly(methyl méthacrylate), polyacrylonitrile), thermoplastic resins (polyacetals and polyhaloethylenes), polyuréthanes, formaldéhyde resins (phénol resin, urea resin), phenoplasts, aminoplasts, thioplasts, duroplastic resins (unsaturated polyester, polyuréthanes), polyvinylidene silicones, cellulose dérivatives, polycarbonates, and mixtures thereof, etc., where also alternatively the container can be made of métal, e.g. steel or titanium suitable for drug administration, or glass, among others, is currently a serious problem for the pharmaceutical industry due to the great drawback of adhérence of these substances to the walls of the sealing area of the containers used. This adhérence results in significant inconveniences for the cited industry, as it must comply with the régulations indicated in the various international Pharmacopoeias, in addition to complying with good manufacturing practices (GMP). The présent invention addresses the drawbacks related to the adhesion of said solid substances to the walls of containers used for filling, as this adhesion binders both the filling and the aseptie sealing processes. For the aseptie filling and sealing process referred to in the présent invention, only solid substances such as those mentioned above are used.
The international Pharmacopoeias require for aseptie filling and sealing the presence of large air flow streams (unidirectional or turbulent régime) to ensure the removal of any extraneous particles that may contaminate the final product. The use of these airflow streams makes filling with solids quite difficult, as a disturbance is generated that causes the solid to adhéré to the walls of the container used for filling.
As the solid substances dispensed adhéré to the walls of the container sealing area, they are not able to coalesce in the mouth area of the container, thus preventing the necessary sealing from being achieved. This lack of sealing leads to two serious problems: the loss of doses ofthe solid substance dispensed and the contamination of the container used for filling.
The loss of doses leads to inaccuracy in the administration of the pharmaceutical product, as the solid substances adhering to the walls of the container sealing area will be measured by the weighing cell indicating the précisé amount of product to be administered to the patient, but when it is administered to the patient, they will receive a lower dose than indicated, as the solid substances adhering to the sides of the container will not be administered and will remain stuck to the sides of the container.
With regard to the contamination of the container that has been used for filling, this is perhaps the most serious of the drawbacks that can resuit from the lack of airtightness caused by substance adhering to the walls ofthe sealing area, as it affects the integrity ofthe médicinal product and has an impact on the health of the patient receiving the pharmaceutical product. When sealing the container with the stopper, ifthe walls ofthe container hâve solid substances adhered to the sealing area, these substances will remain in this area after the container is sealed, which means that the stopper cannot ensure the integrity of the sealed product, as any kind of substance from the environment could enter the product after the capping stage. Microbial contamination is a very serious issue for pharmaceutical companies, as their products are idéal breeding grounds for microorganisms such as bacteria, fungi or yeasts. A theoretically stérile but contaminated product can lead to détérioration of the product, loss of the product's potential, pyrogenic reactions after administration to the patient, particularly in parentéral administration, infection and colonisation of micro-organisms in the patient, with the risk of secondary infection. Any micro-organism, whether pathogenic or non-pathogenic, found in a supposedly stérile pharmaceutical product is a hazard.
In view of the significant problems caused by the lack of sealing, the présent invention offers a solution to the adhérence of solid substances to the sides of the sealing area of the pharmaceutical container by achieving the sealing of said substance. Two methods are used to promote the sealing ofthe solid substances, namely the control ofthe height ofthe dispensing needle and the ionisation of both the pharmaceutical container used for filling and the solid substance to be dispensed, as well as the ionisation of the éléments of the dispensing and capping equipment that corne into contact with the syringe and/or the powder.
As mentioned in the section on the prior art, there are a number of factors that affect the adhesion of solids to the inner walls of the container, among which is the length of the nozzle. The longer the nozzle and the doser it is to the top level of powder in the container, the less kinetic energy it will hâve. In addition, the nozzle carries the powder away from the surface of the sealing walls. The inventors of the présent invention hâve found that the idéal distance between the powder and the nozzle tip dépends on the dosage, dispensing rate and density of the powder, although typically it is between 1 and 3 mm, more preferably around 2mm. The présent invention proposes several options regarding the height of the nozzle:
-The first of these is based on having a nozzle with an exact height (h) of the nozzle measured from the bottom ofthe container. In this case, the filling process is carried out at the rear ofthe container, i.e. when the container is a syringe, at the mouth or end with the largest diameter. A minimum height h between the solid to be dispensed and the nozzle must always be kept, specifïcally 2 mm.
-The second option is to always keep 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 would not be a fixed element, but instead be mobile and could be raised and lowered as the filling process takes place, always maintaining a distance of 2 mm from the solid substance.
-An alternative to the above could be that the nozzle be provided with a contaminent element to prevent the powder from dispersing, during filling, above the area being fïlled.
With regard to the ionisation, the approach relies on the solution for preventing electrostatic charges contained in both the pharmaceutical container to be fïlled and in the solid substance that will be used to fill it. The container walls and the solid hâve static charges. If these charges are of opposite signs, the solid will adhéré to the inner walls of the container. For this reason, both the container and the solid are ionised.
There are two types of electrostatic charges, négative charges which are électrons of the atoms of the Chemical éléments, and positive charges which are équivalent to the action of the protons of the atomic nucléus deprived of the électrons of the last shell. Electrons on the surface of an insulating material cannot be easily dissipated unless they hâve a conductive pathto ground, which is why the cylinder is a conductive element as mentioned above. As they cannot circulate easily, they give rise to what is known as static electricity. Electrons are free to move from molécule to molécule in conductors, but protons are inséparable from the atom and cannot move unless the atom itself moves. The amount of electrostatic charge dépends on the position or distance relative to each other ofthe materials in the sériés and its sign is determined by the propensity ofa material to give up or gain électrons, which is what the sériés actually indicates.
The présent invention uses any type of ioniser, such as a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top ofthe isolator. For example, a rod can be used to ionise and neutralise both the environment and the air flow, thus eliminating static charges. The ioniser can be implemented in practice by means ofa stérile carrier gas stream, such as compressed air or nitrogen N2, preferably using a nitrogen stream, which has the following functions and/or advantages:
-This nitrogen current serves as a vehicle for displacing the ions generated at the électrodes ofthe ionisation éléments that ionise the surrounding air, producing ions that are carried away by the N2 current. These positive and négative ions are generated by supplying altemating current which, via a transformer, reaches values of up to 8,000 volts with an almost negligible current (4mA).
Surfaces treated in this way end up having a neutral charge due to the recombination of charges of different signs and repulsion of charges of like sign.
-Génération of an inert atmosphère inside the containers by displacing the oxygen inside the containers, thus preserving the product from the oxidative effect thereof. The introduction of an inert gas into a vessel, known as inerting, is based on the réduction of the percentage of oxygen below the limiting oxygen concentration (LOC),
-Carrying means in the sweeping effect inside the containers. Altemating ion génération éliminâtes the static forces that adhéré the powder to the container walls. This makes the solid remain in its position without adhering to the container or between the solid particles themselves. Then a slight air flow (0.1-0.8 1/min) performs a sweeping effect with the now disaggregated solid.
With respect to the ionisation phenomenon, the présent invention proposes different methods for carrying it out, shown in the accompanying figures 1-7, in which the pharmaceutical container is represented in a non-limiting manner as a male or female syringe, a syringe with needle, a cartridge or carpule, or an Eppendorf® tube. lonisers can be used with any type of ioniser (whether or not accompanied by a stream of stérile carrier gas), such as a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top ofthe isolator, such as a rod, to ionise and neutralise 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 présent invention, stérilisation with nebulised or vaporised hydrogen peroxide or a mixture of hydrogen peroxide with peracetic acid is required.
When the pharmaceutical container is removed from the tray, it has a very high electrostatic charge (more than 30,000 Volts). This is due to the constant friction between the container and the tray. That is why, as shown in the various figures, both before the container is inserted into the cylinder and after it has been inserted, the containers are preferably exposed to an ioniser of any type and to a stream of stérile carrier gas. This gas can be nitrogen, which carries ionised air molécules, or compressed air, which hits the inside of the container as well as the sealing area in order to suppress the electrostatic charge they hâve.
Figure 1 shows a general procedure for aseptie filling of a container comprising several steps:
The container (1), optionally inserted in a supporting cylinder (7) and capped with a nozzle cap (8), is subjected to an ionisation stage (a) by means of an ioniser (2), of any type, e.g. ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, which may also include isolators with an ioniser on the top of the isolator, or any other type of ioniser. The ioniser (2) is used to remove the electrostatic charge from the container both on the inside walls and in the sealing area. This ioniser may or may not be applied together with a stérile stream of a carrier gas such as nitrogen, carrying ionised air molécules, or compressed air carrying ionised air molécules, although more preferably a nitrogen stream carrying ionised air molécules is used. The nitrogen stream carrying ionised air molécules that is used reaches both the inside of the container and the sealing area. By these two ionisation processes (ionisation with ioniser and the optional application of a stérile gas stream), the electrostatic charges in the container are removed so that the container can be filled.
After the ionisation process (a), the syringe (1) passes to the aseptie filling station (b). In this stage the aseptie filling ofthe container (1) with the solid substance is carried out. 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 required to measure accurately the amount of solid substance that is dispensed. This station may or may not hâve a stream of a stérile carrier gas, such as compressed air or nitrogen, that carries ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions. There are as many filling stations as products or combinations thereof will be filled.
After filling the container (1) with the solid, it is subjected to a deionisation stage (c) by means of a deioniser (2), which may be a ring, rod, gun, curtain, blades, barrels, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator. Together with the ioniser, a stream of a stérile carrier gas such as compressed air or nitrogen carrying ionised air molécules may or may not be applied; preferably, nitrogen carrying ionised air molécules is used to prevent the solid from adhering to the walls of the sealing area of the container (1).
Finally, there is the aseptie sealing station (d), where the stopper (6) is inserted to seal the container. The latter station may or may not use a stream of a stérile carrier gas such as compressed air or nitrogen, preferably carrying ionised air molécules.
Figure 2 shows another embodiment ofthe ionisation process consisting of four stages:
The first stage consists in an ionisation process (a) similar to that shown in figure 1, in which a stream of a stérile carrier gas, such as nitrogen carrying ionised air molécules or compressed air carrying ionised air molécules, may or may not be introduced into the container (1), the syringe having been previously capped with the nozzle cap (8) and optionally introduced into the carrier cylinder (7). This stérile carrier gas stream is used in conjunction with an ioniser (2), whether in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, which may also include isolators with an ioniser on the top of the isolator. The stream and ioniser (2) reach both the bottom of the container (1) and the sealing zone; in the présent figure, the stérile carrier gas stream used is preferably a nitrogen stream carrying ionised air molécules. After applying this stream, the container is free of electrostatic charges in order to start filling.
In the second stage of the described process, the container (1) passes to the aseptie filling station (b) where aseptie filling with the solid is carried out. In this station there are several éléments such as: a hopper (3) in which the solid substance to be dispensed is located, a dispensing needle or nozzle (4) in charge of dispensing the solid, and a weighing cell (5) to control the exact amount of solid that is dispensed. There are as many filling stations as products or combinations thereof will be filled. In order to ensure the cleanliness of the sealing zone, a third stage is used which consists in an ionisation stage (c) where an ioniser (2) is used, which may be a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, among which there may also be isolators with an ioniser on the top of the isolator, where a stream of stérile carrier gas such as nitrogen carrying ionised air molécules or compressed air may or may not be applied as well in order to break the adhesion of the solid to the sides of the container in the sealing zone. Preferably, a nitrogen stream carrying ionised air molécules is used to serve as a vehicle for ion displacement and as a carrier means in the sweeping effect, thus obtaining the desired sealing phenomenon in this station. There will be different numbers of ionisation stations according to the needs of each product.
Finally, the last stage consists in a sealing stage (d) in which the container is sealed with a stopper (6). A stérile carrier gas stream such as nitrogen, preferably carrying ionised air molécules, may or may not be used at this stage, because although the sealing area is clean of solids, it is necessary to ensure that the container is completely clean and that none of the dispensed solids adhéré to the stopper used for sealing and to the container walls due to the electrostatic charges created by the friction when the container is placed in the sealer.
Figure 3 shows another particular réalisation of the ionisation process, comprising the following steps:
The container (1) is subjected to an ionisation process (a), by means of an ioniser (2) which can be a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator. This ioniser may or may not be applied together with a stérile carrier gas stream such as nitrogen carrying ionised air molécules or compressed air carrying ionised air molécules, although more preferably a nitrogen stream carrying ionised air molécules is used. The ioniser (2) is used to remove the electrostatic charge from the container both on the inside walls and in the sealing area. In addition, the nitrogen stream carrying ionised air molécules used reaches both the inside of the container and the sealing area; with these two ionisation processes, the electrostatic charges on the container are eliminated so that it can then be fïlled.
Subsequently, after this ionisation phase (a), the container (1) passes to the aseptie filling station (b) where it is aseptically filled with the solid. In this station there are several éléments such as a hopper (3) where the solid substance to be dispensed is located, a dispensing needle or nozzle (4) in charge of dispensing the solid, a weighing cell (5) to control the exact amount of solid that is dispensed and an ioniser (2) which can be a ring, bar, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, among which there can also be isolators with an ioniser on the top of the isolator. This station may or may not hâve a stream of a stérile carrier gas, such as compressed air or nitrogen, that carries ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions. This ensures that the dispensed 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, as well as as many ionisation stages as necessary.
After the container (1) has been filled with the solid in the filling station (b), in order to ensure the cleanliness of the sealing area of the container the last stage is carried out, which is an ionisation process (c) using an ioniser (2) either in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top ofthe isolator which may or may not act in conjunction with a stream of stérile carrier gas such as nitrogen carrying ionised air molécules or compressed air in order to break the adhesion ofthe solid to the sides of the container in the sealing zone. Preferably, a nitrogen stream carrying ionised air molécules is used to serve as a vehicle for ion displacement and as a carrier means in the sweeping effect, thus obtaining the desired sealing phenomenon in this station. There will be different numbers of ionisation stations according to the needs of each product.
Figure 4 shows another particular embodiment of the procedure described in the présent invention:
The container (1), optionally inserted in a supporting cylinder (7) and capped with the nozzle cap (8), is subjected to an ionisation process (a) by means of an ioniser (2), of any type in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising fîlter, which may also include isolators with an ioniser on the top of the isolator, or any other type of ioniser. This ioniser may or may not be applied together with a stérile carrier gas stream such as nitrogen carrying ionised air molécules or compressed air carrying ionised air molécules, although more preferably a nitrogen stream carrying ionised air molécules is used. The ioniser (2) is used to remove the electrostatic charge from the container both on the inside walls and in the sealing area. In addition, the nitrogen stream carrying ionised air molécules used reaches both the inside of the container and the sealing area; with these two ionisation processes, the electrostatic charges on the container are eliminated so that it can then be filled.
After this ionisation phase (a), the container (1) passes to the aseptie filling station (b) where it is aseptically filled with the solid. 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 required to measure accurately the amount of solid substance that is dispensed. This station may or may not hâve a stream of a stérile carrier gas, such as compressed air or nitrogen, that carries ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions. There are as many filling stations as products or combinations thereof will be filled.
After the container (1) has been filled with the solid in the filling station (b), in order to ensure that the sealing area of the container is clean, a third stage is carried out, which is an ionisation process (c) in which an ioniser (2) is used, either in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising fîlter, among which isolators with an ioniser on the top of the isolator can also be found. This ioniser may or may not act together with a stream of a stérile carrier gas such as nitrogen carrying ionised air molécules or compressed air, in order to break the adhesion ofthe solid to the sides ofthe container in the sealing area. Preferably, a nitrogen stream carrying ionised air molécules is used to serve as a vehicle for ion displacement and as a carrier means in the sweeping effect, thus obtaining the desired sealing phenomenon in this station. There will be different numbers of ionisation stations according to the needs of each product.
Finally, the container (1) passes to the sealing station (d) where it is sealed with a stopper (6). In this stage an ioniser (2) is used which may be in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, among which there may also be isolators with an ioniser on the top ofthe isolator which may or may not act together with a stream of stérile carrier gas such as nitrogen, preferably carrying ionised air molécules, because, although the sealing area is clean of solid substances, it is necessary to ensure that the container is completely clean and thaï none ofthe dispensed solid substances adhères to the stopper used for sealing and to the walls ofthe container due to the electrostatic charges created by friction when the container is placed in the sealing machine.
Figure 5 shows another particular embodiment ofthe procedure described in the present invention.
The container (1) which has been capped with the nozzle cap (8) and optionally inserted into a support cylinder (7) is subjected to an ionisation process (a) by means of an ioniser (2), whether in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator, which may or may not be in conjunction with a stérile carrier gas stream such as nitrogen carrying ionised air molécules or compressed air carrying ionised air molécules, but more preferably nitrogen carrying ionised air molécules. The ioniser (2) is used to remove the electrostatic charge from the container both on the inside walls and in the sealing area. In addition, the nitrogen stream carrying ionised air molécules used reaches both the inside of the container and the sealing area; with these two ionisation processes, the electrostatic charges on the container are eliminated so that it can then be fîlled.
After this ionisation process (a), the container (1) passes to the aseptie filling station (b) where it is aseptically fîlled with the solid. In this station it is necessary to use several éléments such as a hopper (3) where the solid substance to be dispensed is located, a dispensing needle or nozzle (4) in charge of dispensing the solid, and a weighing cell (5) to control the exact amount of solid that is dispensed. This station may or may not hâve a stream of a stérile carrier gas, such as compressed air or nitrogen, that carries ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions. This ensures that the dispensed solid does not remain in the sealing zone. There are as many filling stations as products or combinations thereof will be filled.
After this filling stage (b), the container is subjected to an ionisation stage (c) in which the ioniser (2) may be in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, which may also include isolators with an ioniser on the top of the isolator, which may or may not be in conjunction with a stérile carrier gas stream such as nitrogen carrying ionised air molécules or compressed air carrying ionised air molécules, although more preferably the nitrogen stream carrying ionised air molécules is used.
Finally, the container (1) passes to the sealing station (d) where it is sealed with a stopper (6). In this stage an ioniser (2) is also used which may be in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, among which there may also be isolators with an ioniser on the top of the isolator which may or may not act together with a stream of stérile carrier gas such as compressed air or preferably nitrogen carrying ionised air molécules, because, although the sealing area is clean of solid substances, it is necessary to ensure that the container is completely clean and that none of the dispensed solid substances adhères to the stopper used for sealing and to the walls of the container due to the electro static charges created by friction when the container is placed in the sealing machine.
Figure 6 shows three stages:
In the first stage the container (1) is subjected to an ionisation process (a) by means of an ioniser (2), whether in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, including isolators with an ioniser on the top of the isolator, which may or may not be in conjunction with a stérile carrier gas stream such as nitrogen carrying ionised air molécules or compressed air carrying ionised air molécules, although more preferably nitrogen carrying ionised air molécules is used. The ioniser (2) is used to remove the electrostatic charge from the container both on the inside walls and in the sealing area. In addition, the nitrogen stream carrying ionised air molécules used reaches both the inside of the container and the sealing area; with these two ionisation processes, the electrostatic charges on the container are eliminated so that it can then be filled.
After this ionisation process (a), the container (1) passes to the aseptie filling station (b) where it is aseptically filled with the solid. This process requires the use of a hopper (3) containing the solid substance to be dispensée! and a dispensing needle or nozzle (4) through which the solid substance is dispensed. A weighing cell (5) is also required to measure accurately the amount of solid substance that is dispensed. This station may or may not hâve a stream of a stérile carrier gas, such as compressed air or nitrogen, that cames ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions. There are as many filling stations as products or combinations thereof will be filled.
Lastly, the container (1) passes to the ionisation station. In this stage an ioniser (2) is used which may be in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, among which there may also be isolators with an ioniser on the top of the isolator which may or may not act together with a stream of stérile carrier gas such as nitrogen, preferably carrying ionised air molécules, because, although the sealing area is clean of solid substances, it is necessary to ensure that the container is completely clean and that none of the dispensed solid substances adhères to the stopper and to the walls of the container due to the electrostatic charges created by friction when the container is placed in the sealing machine.
Figure 7 shows a particular embodiment ofthe procedure described in the présent invention:
The container (1) already capped with a stopper (6) and optionally inserted in a cylinder (7) is ionised in an ionisation stage (a) by means of an ioniser (2) in the form of a ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, among which can also be isolaters with an ioniser on the top of said isolator. This station may or may not hâve a stream of a stérile carrier gas, such as compressed air or nitrogen, that carries ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions.
The container is then placed in the aseptie filling station (b), where it is aseptically filled with the desired solid with the nozzle part. In this station it is necessary to use several éléments, such as a hopper (3) where the solid substance to be dispensed is located, a dispensing needle or nozzle (4) m charge of dispensing the solid, and a weighing cell (5) to control the exact amount of solid that is dispensed. There may or may not be a stream of a stérile carrier gas, such as compressed air or nitrogen, that carries ionised air molécules, preferably nitrogen carrying ionised air molécules to provide a vehicle for the ions. This ensures that the dispensed solid does not remain in the sealing zone. There are as many filling stations as products or combinations thereof will be filled
After the container (1) has been filled with the solid in the filling station (b), in order to ensure that the sealing area ofthe container is clean, a final stage is carried out, which is an ionisation process (c) in which an ioniser (2) is used, either in the form of a ring, rod, gun, curtain, blades, barrel, needle or nozzle, or an ionising filter, among which isolators with an ioniser on the top of the isolator can also be found. This ioniser may or may not be next to a stream of a stérile carrier gas such as nitrogen carrying ionised air molécules or compressed air, in order to break the adhesion of the solid to the sides of the container in the sealing area. Preferably, a nitrogen stream carrying ionised air molécules is used to serve as a vehicle for ion displacement and as a carrier means in the sweeping effect, thus obtaining the desired sealing phenomenon in this station. There will be different numbers of ionisation stations according to the needs of each product.
In the preferred embodiments shown in the figures, an additional ionisation stage ofthe container can be executed after filling with the solid substance and immediately prior to sealing with the stopper. Preferably, the ionisation must be performed also when the container is empty, before it is filled with the solid substance, and more preferably every station ofthe filling and sealing station must include ionisers to ionise both the container and the solid substance, thereby preventing adhérence of the latter to the inner walls and ensuring the cleanliness of the container. These ionisers may be of any type, such as ring, rod, gun, curtain, blade, barrel, needle or nozzle, or an ionising filter, among which can also be isolators with an ioniser on the top of said isolator. To aid the dosing, a stream can be used of a stérile carrier gas such as compressed air or nitrogen, carrying ionised air molécules, as it provides a vehicle for displacement of the ions, generates an inert atmosphère, and provides a carrier means in the sweeping effect. This nitrogen current carrying ionised air molécules is used in the ionisation stations together with an ioniser. More preferably, it is used in ail the stations of the aseptie filling and sealing process.
Examples
The following spécifie examples are provided to illustrate the nature of the présent invention. These examples are included for purposes of illustration only and should not be understood as limiting the invention claimed herein.
These examples use as containers cartridges or carpules, syringes with a needle or with a cathéter cône, Luer cône, or Luer lock cône; ail of them with a male tip or female tip and Eppendorf® tubes, as excipients biocompatible polymers of the PLGA (lactic or glycolic acid) and PLA (poly(lactic acid)) type, and as active ingrédients Rispéridone and Letrozole respectively.
Example 1 : Filling of a 50 mg dose of Rispéridone in a syringe with a male nozzle or male syringe.
In this example, two products must be filled in a pharmaceutical container, specifically in a glass syringe with a male nozzle that has been precapped with the nozzle cap (8). The products to be filled are the excipient PLA and the active ingrédient Letrozol, specifically a 50 mg dose. It should be noted that the filling process takes place inside a rigid-walled aseptie isolator. Before starting the filling process, ail the equipment must be clean and stérile. For this purpose the equipment is previously sterilised with nebulised or vaporised hydrogen peroxide, or with a mixture of hydrogen peroxide and peracetic acid.
The isolator comprises two main sections: (i) the transfer chamber (TC), which is a chamber that facilitâtes loading stérile materials to and from the working chamber of the isolator, as ail the materials and tools loaded in the stérile isolator must be previously sterilised; and (ii) the working chamber (MC), which contains filling equipment for the excipient and the active ingrédient, and a syringe capping or sealing unit.
To start the filling the male syringes (1) and the caps (6) are taken, both stérile, delivering said caps to the operator in the capping or sealing station (d) so that they are inserted in the syringe sealing machine. There are as many filling stations as products or combinations thereof will be filled.
Both the PLA used as excipient and the Letrozole used as active ingrédient are delivered to the operators at the filling station (b), who load them in their respective hoppers (3). The male syringes (1) that will be used for filling undergo an ionisation process from the rear part ofthe syringes or from the collar ofthe syringes using a needle ioniser (2). In this way the male syringes (1) are lonised (a) to eliminate the electrostatic charge inside them and in the sealing area ofthe syringe body. The male syringe (1) is then placed upside down inside a cylinder (7).
The cylinder (7) containing the ionised male syringe (1) is directed towards the filling station (b) to fîll with PLA. The male syringe (1) is placed in the weighing cell (5), taring its weight to zéro. After this, the male syringe (1) is filled at the end proximal to the collar with 90 mg ± 30% of PLA. Filling is carried out with a dispensing needle or nozzle (4), both made from a non-conducting material. The male syringe (1) is continuously weighed during filling so that the System can be controlled to stop filling when the desired weight is precisely reached, in this case between 90 mg ± 30%.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 1075 volts.
After the filling station (b) with the PL A excipient, the male syringe (1) is subjected to an ionisation process (c) using a ring ioniser located on the outside of the syringe to facilitate sealing by preventing the PLA from adhering to the walls of the male syringe (1). During this process, the presence of a stream of nitrogen or stérile carrier gas with ionised air molécules is necessary to displace the ions and act as a carrier for the powder sweeping effect.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 775 volts.
Once the excipient has been fïlled and ionised, the cylinder (7) with the male syringe (1) filled with PLA is placed in the filling station (b) in order to fîll it with 50 mg ± 30% of Letrozole. The cylinder with the male syringe (1) is 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 filling can be stopped once the desired weight has been reached.
After this filling process of the male syringe (1), it is subjected to another ionisation process (c) with the help of a ring ioniser (2) to prevent both the excipient and the active ingrédient with which the male syringe (1) has been filled from adhering to the walls ofthe male syringe (1). This process requires the presence of a stream of nitrogen or stérile carrier gas with ionised air molécules to displace the ions and act as a carrier for the powder sweeping effect.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 645 volts.
After filling with the active ingrédient and subséquent ionisation, the cylinder (7) with the male syringe (1) passes to the sealing station (d) where the stopper (6) is fitted. This process requires the presence of a stream of nitrogen or stérile carrier gas carrying ionised air molécules to displace the ions and act as a carrier.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 375 volts.
In this way the desired sealing phenomenon is achieved and the cleanliness of the sealing area inside the syringe body at the distal end ofthe nozzle thereof is ensured. It also prevents both PL A and Letrozole from sticking to the stopper (6) used for sealing and to the walls ofthe container due to the electrostatic charges created by the friction created when the container is placed in the sealer.
Once the male syringe has been filled and sealed, it can be placed on a tray with the rest of the filled and sealed syringes.
or female syringe of plastic material.
In this second example, PLA is also used as excipient and Letrozole as active ingrédient for a dose of400 mg, and the filling process also takes place inside a rigid-walled aseptie isolator in the same way as in example 1.
Both the PLA used as excipient and the Letrozole used as active ingrédient are delivered to the operators at the filling station (b), who load them into their respective hoppers (3), in this case without the hoppers being made of insulating material. The female syringes (1), pre-capped with the nozzle cap (8), that will be used for filling are arranged under a stream of nitrogen or stérile carrier gas carrying ionised air molécules; a needle ioniser (2) is added to this process, such that the female syringes are ionised (a) to elnninate the electrostatic charge inside them and in the sealing zone.
The cylinder (7) containing the ionised female syringe (1) is directed towards the filling station (b) with PLA. The female syringe (1) is placed in the weighing cell (5), taring its weight to zéro. After this, the syringe (1) is filled from the back of the syringes or from the collar part ofthe syringes with an amount of 500 mg + 30% PLA, this filling is done by means of 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 filling when the desired weight, in this case between 500 mg + 30%, is reached. During this process the presence of a stream of nitrogen or stérile carrier gas with ionised air molécules is required to displace the ions and provide a carrier in the 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.
Subsequently, the cylinder (7) with the female syringe (1) filled with PLA undergoes an ionisation process (c) before being filled in a second filling station (b) with the active ingrédient Letrozole.
For the ionisation, a ring ioniser (2) is used to ionise the PLA adhering to the walls of the sealing area of the syringe (1). A stream of nitrogen or stérile carrier gas carrying ionised air molécules is also used to serve as a vehicle for the displacement of the ions and as a carrier in the sweeping effect, thus achieving the desired sealing phenomenon in this ionisation process.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 975 volts.
After ionisation, the cylinder (7) with the female syringe (1) filled with PLA is placed in the filling station (b) with 400 mg ± 30% of the active ingrédient Letrozole. The cylinder (7) with the female 20 syringe (1) is placed in the weighing cell (5) where it is tared before filling with the active ingrédient, and then filling with Letrozole begins. The syringe (1) is continuously weighed during filling so that filling can be stopped once the desired weight has been reached.
It is then transferred to an ionisation station (c) in which a ring ioniser (2) is used to prevent 25 adhérence of both the excipient and the active substance to its walls.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 895 volts, as both the dispensing needle and the hopper are not insulating materials.
After filling with the active ingrédient and subséquent ionisation, the cylinder (7) with the female syringe (1) (d) is filled with the active ingrédient and a stopper (6) is fitted in it. This process requires the presence of a stream of nitrogen or stérile carrier gas carrying ionised air molécules to displace the ions and act as a carrier for the powder. By this means, the desired sealing phenomenon is achieved and the cleaning ofthe sealing area inside the syringe body is ensured to leave a clean area in which the stopper is inserted. Furthermore, it prevents both PLA and Letrozole from adhering to the stopper (6) used for sealing and to the walls of the container due to the electrostatic charges created by friction when the container is placed in the sealer.
At this point, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 495 volts.
Once the syringe filling process is completed and it has been sealed, the syringe can be placed on 10 a tray with the rest of the filled and sealed syringes.
Example 3: Filling of a 50 mg dose of Letrozole in Eppendorf® tubes.
In this example PLA is used as excipient and Letrozole as active ingrédient, for a dose of 50 mg. 15 It should be noted that the filling process takes place inside a rigid-walled aseptie isolator, as in the previous examples.
Both the PLA used as excipient and the Letrozole used as active ingrédient are delivered to the operators at the filling station (b), who load them in their respective hoppers (3). The Eppendorf© 20 tubes ( 1 ) to be used for filling are arranged under a stream of nitrogen or stérile carrier gas carrying ionised air molécules; a needle ioniser (2) is added to this process and the Eppendorf® tubes (1) are ionised to remove the electrostatic charge inside them and in the sealing zone.
At this point the electrostatic charge inside the inner walls ofthe container (1) is measured and the 25 measurement obtained is 695 volts, as the tube is made of insulating material and the dimensions ofthe tube are significantly different from the syringes, as they are wider and shorter than the syringes of examples 1 and 2.
The ionised Eppendorf® tube (1) is led to the filling station with 50 mg ± 30% Letrozole. The 30 Eppendorf® tube (1) is placed in the weighing cell (5), taring its weight to zéro. The Eppendorf® tube (1) is then filled with the active ingrédient by means of a nozzle (4) made of insulating material. The Eppendorf® tube (1) is continuously weighed 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 ionisation fîlter (2) to prevent it from sticking to the walls ofthe sealing area.
After the filling stage (b), the Eppendorf® tube (1) is again subjected to an ionisation process (c) with the aid of a rod ioniser (2), to ensure that no active ingrédient remains adhering to the walls of the container (1).
Again, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 700 volts.
After filling with the active ingrédient, the Eppendorf© tube (1) filled with Letrozole is placed in the second filling station (b), this time with 90 ± 30% ofthe excipient PLA. The Eppendorf® tube (f ) is placed in the weighing cell (5) where it is tared before filling with the excipient, after which filling with PLA begins. The Eppendorf® tube (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached. During this process, the use of an ionisation filter (2) is necessary to prevent both Letrozole and PLA from adhering to the sealing area.
After this filling process of the Eppendorf® tube (1), the tube is subjected to another ionisation process (c) with the aid of a rod ioniser (2) to prevent both the excipient and the active ingrédient with which the Eppendorf® tube (f) has been filled from adhering to the walls ofthe container (1). The presence of a stream of nitrogen or stérile carrier gas carrying ionised air molécules is also necessary to displace ions and act as a carrier. These two means ensure that the electrostatic charge on the inside of the inner walls of the container (1) is about 595 volts, thus achieving the desired sealing phenomenon and ensuring the cleanliness of the sealing area, as well as preventing both PLA and Letrozole from adhering to the stopper (6) used for sealing and to the walls ofthe container due to the electrostatic charges created by friction when the container is placed in the sealing machine.
Example 4. Filling of a 75 mg dose of Rispéridone in a syringe with needle or syringe with needle made of plastic material.
In this example, PLGA is used as excipient and Rispéridone as active ingrédient, for a dose of 75 mg. The filling process also takes place inside a rigid-walled aseptie isolator using the same material stérilisation operation as in the previous examples.
The syringes with needle (1) to be used for filling are closed with the nozzle cap (8) and are subjected to an ionisation process with a needle ioniser (2), thereby ionising (a) the syringes (1) in order to eliminate the electrostatic charge inside them and in the sealing area. The cylinder (7) containing the syringe with the ionised needle (1) is made in this case of an insulating material.
The syringe (1) is placed in the weighing cell (5), taring its weight to zéro. After this, the male syringe (1) is filled with 75 mg ± 30% of PLGA by means of a nozzle (4) made of insulating material. The syringe (1) is continuously weighed during filling so that the System can be controlled to stop filling when the desired weight, in this case between 75 mg ± 30%, is reached.
After this process, the electrostatic charge inside the inner walls ofthe container (1) is measured and the measurement obtained is 775 volts.
After filling the needle syringe (1) with the excipient, it is subjected to an ionisation process (c) by means of a ring ioniser (2), thus preventing the PLGA from adhering to the walls ofthe sealing 15 area of the container ( 1 ).
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 550 volts.
After filling with the excipient and subséquent ionisation, the cylinder (7) with the syringe (1) filled with PLGA is placed in the next filling station (b) with the active ingrédient Rispéridone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5), where it is tared before filling with the active ingrédient, and then filling with Rispéridone begins. The syringe (1) is continuously weighed during filling so that filling can be stopped once the desired weight has been 25 reached.
After filling with the active ingrédient, the cylinder (7) with the needle syringe (1) is again subjected to an ionisation process, where with the aid of a ring ioniser (2), both the active ingrédient and the excipient are prevented from adhering to the walls ofthe sealing area ofthe 30 male syringe (1). After this process, the electrostatic charge inside the inner walls ofthe container (1) is measured and the measurement obtained is 470 volts.
After this ionisation process, the male syringe (1) passes to the sealing station (d) where it is fitted with a stopper (6) and undergoes a further ionisation process. This process requires a rod ioniser ( 2) to ionise the PLGA and Rispéridone that are adhered 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 measurement obtained is 199 volts.
The ionisation process ensures an optimum sealing and the total cleanliness of the sealing area, as well as preventing both PLGA and Rispéridone from adhering to the stopper (6) used for sealing and to the walls of the container due to the electrostatic charges created by the friction created when the container is placed in the sealer.
Example 5: Filling of a 100 mg dose of Rispéridone in a syringe with a female nozzle or a female syringe made of plastic material.
In this example, PLGA is used as excipient and Rispéridone as active ingrédient, for a dose of 100 mg. The filling process also takes place inside a rigid-walled aseptie isolator using the same material stérilisation operation as in the previous examples.
The female syringes (1) pre-capped with the nozzle cap (8) to be used for filling are subjected to an ionisation process by a ring ioniser (2), thus ionising (a) the syringes (1) to remove the electrostatic charge inside them and in the sealing area. The cylinder (7) containing the ionised syringe (1) in this case is made of an insulating material. The syringe (1) is placed in the weighing cell (5), taring its weight to zéro. Then the syringe (1) is filled with 100 mg ± 30% of PLGA by means of a nozzle (4) made of insulating material. The syringe (1) is continuously weighed during filling so that the System can be controlled to stop filling when the desired weight, in this case between 100 mg ± 30%, is reached.
After this process, the electrostatic charge inside the inner walls ofthe container (1) is measured and the measurement obtained is 785 volts.
After filling the female syringe (1) with the excipient, it is subjected to an ionisation process (c) using a needle ioniser (2), thus preventing the PLGA from adhering to the walls ofthe sealing area ofthe container (1).
After this process, the electrostatic charge inside the inner walls ofthe container (1) is measured and the measurement obtained is 580 volts.
After filling with the excipient and subséquent ionisation, the cylinder (7) with the syringe (1) filled with PLGA is placed in the next filling station (b) with the active ingrédient Rispéridone.
The cylinder (7) with the syringe (1) is placed in the weighing cell (5), where it is tared before filling with the active ingrédient, and then filling with Rispéridone begins. The syringe (1) is continuously weighed during filling so that filling can be stopped once the desired weight has been reached.
After filling with the active ingrédient, the cylinder (7) with the syringe (1) is again subjected to an ionisation process, where with the help of a needle ioniser (2), both the active ingrédient and the excipient are prevented from adhering to the walls of the sealing area of the syringe (1). After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 440 volts.
After this ionisation process, the syringe (1) passes to the sealing station (d) to be fitted with the stopper (6) and undergoes a further ionisation process. This process requires a rod ioniser (2) to ionise the PLGA and Rispéridone that are adhered 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 20 measurement obtained is 197 volts.
The ionisation process ensures an optimum sealing and the total cleanliness of the sealing area, as well as preventing both PLGA and Rispéridone from adhering to the stopper (6) used for sealing and to the walls of the container due to the electrostatic charges created by the friction created 25 when the container is placed in the sealer.
Example 6; Filling of a 75 mg dose of Rispéridone in cartridges or carpules.
In this other example, PLGA is used as excipient and Rispéridone as active ingrédient, for a dose 30 of 75 mg. The filling process also takes place inside a rigid-walled aseptie isolator using the same material stérilisation operation as in the previous examples.
Both the PLGA used as excipient and the Rispéridone used as active ingrédient, as well as the cartridges, are delivered to the operators at the filling station (b) and loaded into their respective hoppers (3). The cartridges or carpules (1) to be used for filling are arranged under a stream of nitrogen or stérile carrier gas carrying ionised air molécules, a needle ioniser (2) is added to this process, and the cartridges or carpules (1) are ionised to eliminate the electrostatic charge inside them.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 1285 volts.
The ionised cartridge or carpule (1) is directed to the filling station (b) with 75 mg ± 30% Rispéridone. The cartridge (1) is placed in the weighing cell (5) face up, taring its weight to zéro. Then the cartridge (1) is filled with Rispéridone through the nozzle of the cartridge 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 controlled to stop filling when the desired weight is reached.
Once the cartridge (1) has been filled with the active ingrédient, it is placed in the second filling station (b), this time with 100 mg ± 30% of the excipient PLGA. The cartridge (1) is placed in the weighing cell (5) where it is tared before being filled with this active ingrédient, after which the filling with PLGA also starts from the nozzle. The cartridge (1) is continuously weighed during filling, so that filling can be stopped once the desired weight has been reached.
After filling with the PLGA excipient, the cartridge (1) undergoes a further ionisation process using a rod ioniser (2) and a stream of nitrogen or stérile carrier gas carrying ionised air molécules to displace the ions and act as a carrier for the insertion of the cartridge nozzle cover. These two processes prevent both the excipient and the active ingrédient from adhering to the walls, thus achieving the sealing phenomenon.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 1085 volts.
Example 7, Filling of a 400 mg dose of Rispéridone in a pre-capped female syringe.
In this example, PLGA is used as excipient and Rispéridone as active ingrédient, for a dose of 400 mg· The filling process also takes place inside a rigid-walled aseptie isolator using the same material stérilisation operation as in the previous examples.
The female syringes (1) to be used for filling are subjected to an ionisation process by means of a ring ioniser (2), so that the syringes (1) are ionised (a) to eliminate the electrostatic charge inside them and in the sealing area. The cylinder (7) containing the ionised syringe (1) in this case is 5 made of an insulating material. The syringe (1) is placed in the weighing cell (5) upside down since it is previously closed with a stopper (6), taring its weight to zéro. After this, the syringe (1) is filled through the nozzle with 100 mg + 30% PLGA, using a nozzle (4) made of insulating material. The syringe (1) is continuously weighed during filling so that the system can be controlled to stop filling when the desired weight, in this case between 100 mg ± 30%, is reached. 10
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 735 volts.
After filling the female syringe (1) with the excipient, it is subjected to an ionisation process (c) 15 using a rod ioniser (2), thus preventing the PLGA from adhering to the walls ofthe container (1) near the nozzle.
After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the measurement obtained is 530 volts.
After filling with the excipient and subséquent ionisation, the cylinder (7) with the syringe (1) filled with PLGA is placed in the next filling station (b) with the active ingrédient Rispéridone. The cylinder (7) with the syringe (1) is placed in the weighing cell (5), where it is tared before filling with the active ingrédient, and then filling with Rispéridone begins. The syringe (1) is 25 continuously weighed during filling so that filling can be stopped once the desired weight has been reached.
After filling with the active ingrédient, the cylinder with the syringe (1) is again subjected to an ionisation process, where, with the help of a rod ioniser (2), both the active ingrédient and the 30 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 measurement obtained is 215 volts.
The ionisation process provides an optimum sealing and the précisé dosage required.

Claims (5)

1. A procedure for filling pharmaceutical containers (1) with at least one solid and sealing them under stérile 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 checking the weight of solid dispensed into the container (1); and
c) sealing the pharmaceutical container with a stopper (6), characterised in that, in at least one of steps a), b) and c), or in a plurality thereof in any combination, the static electric charges on the inside walls of the container (1), on the solid dispensed inside the container, and/or on any parts in contact with the container walls or with the solid dispensed inside the container, are neutralised by means of an ioniser (2) to which an ionisation potential is applied such that the electrostatic charge inside the container (1) after each ionisation is less than 2000 volts.
2. A procedure according to claim 1, wherein, between step b) and step c), an additional static electric charge ionisation is carried out inside the pharmaceutical container (1).
3. A procedure according to claim 1 or 2, wherein in step a) the ionisation is carried out with the pharmaceutical container (1) empty.
4 1
8. A procedure according to any one ofthe preceding claims, wherein in at least one of steps a), b) and c) or in a plurality thereof in any combination, a stérile carrier gas stream such as N2 or stérile compressed air is applied inside the pharmaceutical container (1).
9. A procedure according to any one of the preceding claims, wherein the 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.
10. A procedure according to any one of the preceding claims, wherein the pharmaceutical container (1) is inserted into a cylinder of an electrically conductive material that is grounded, to help dissipate the static charge of the pharmaceutical container.
H. A procedure according to any one of the preceding claims 1 to 9, 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.
12. A procedure according to any one of the preceding claims, wherein the pharmaceutical container (1) is made of an electrically non-conductive material.
13. A procedure 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 less than or equal to 20 microns,
- no more than 10% ofthe total particulate volume greater than or equal to 230 microns or less than or equal to 140 microns,
- a d0.5 value in the range 60-180 microns, where d0.5 indicates the mean value of the particle size that divides the population into exactly two equal halves, with 50% ofthe distribution being above this value and 50% below.
14. A procedure according to any one of the preceding claims 1 to 12, wherein the solid product to be dispensed into the container (1) has the following particle size distribution:
- no more than 10% ofthe total particle volume less than or equal to 20 microns,
- no more than 10% of the total particle volume greater than or equal to 325 microns or less than or equal to 245 microns, a d0.5 value in the range 100-155 microns.
15. A 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 14 above.
4. A procedure according to any one of the preceding claims, wherein step b) is carried out under vibration of the dispensing needle (4) to assist homogeneous dosing of the solid.
5. A procedure according to any one of the preceding claims, wherein step b) is repeated a number of times.
6. A procedure according to any one of the preceding claims wherein, in step b), the tip of the dispensing end of the dispensing needle (4) is at a height h of 1 to 3 mm above the surface of the solid deposited on the bottom of the container (1).
7. A procedure according to any one of the preceding claims, wherein step c) is carried out under vacuum.
5 —__............__
OA1202100200 2018-11-02 2019-10-30 Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions OA20106A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
ESP201831060 2018-11-02

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Publication Number Publication Date
OA20106A true OA20106A (en) 2021-12-13

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