EP3656218A1 - Procédé pour tester le résultat d'un processus de remplissage de flacons - Google Patents

Procédé pour tester le résultat d'un processus de remplissage de flacons Download PDF

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Publication number
EP3656218A1
EP3656218A1 EP18208057.2A EP18208057A EP3656218A1 EP 3656218 A1 EP3656218 A1 EP 3656218A1 EP 18208057 A EP18208057 A EP 18208057A EP 3656218 A1 EP3656218 A1 EP 3656218A1
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EP
European Patent Office
Prior art keywords
vial
dye
methselect
vials
drug product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
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EP18208057.2A
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German (de)
English (en)
Inventor
Roman Mathaes
Hanns-Christian Mahler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lonza AG
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Lonza AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lonza AG filed Critical Lonza AG
Priority to EP18208057.2A priority Critical patent/EP3656218A1/fr
Publication of EP3656218A1 publication Critical patent/EP3656218A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/18—Arrangements for indicating condition of container contents, e.g. sterile condition
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
    • B65B3/006—Related operations, e.g. scoring ampoules

Definitions

  • the invention relates to a method which employs a dye for testing the result of a filling process of vials with a liquid formulation, and to the use of a dye for testing the result of a filling process of vials with said liquid formulation.
  • Lyophilized formulations have become an important part of pharmaceutical development and production. In particular, lyophilized formulations offer significant advantages with respect to stability and storage over solutions or other liquid formulations.
  • the freeze-drying process itself can result in a deterioration of the properties of the formulation, in particular if the active agent is a protein.
  • Lyoprotectants such as certain sugars as well as surfactants are commonly added to the pharmaceutical formulation to avoid degradation of active agents and improve overall stability.
  • surfactants are typically used to ensure adequate drug product stability, processing and compatibility with administration materials and devices.
  • Surfactants within the meaning of the invention means any substance that shows surface activity, so the terms "surfactant” and "surface active agent” can be used synonymously within the meaning of the invention.
  • a liquid pharmaceutical formulation can creep up the inner surface of the walls of a container (e.g., a vial) above the meniscus of the liquid pharmaceutical formulation after it has been filled in.
  • This creeping results in an undesired appearance that is in essence a material causing the undesired appearance, for example, in the form of a contamination of the inner surface of the wall of a container above the meniscus and can take the form of a haze or cloud or fog or haziness of different patterns, or even of droplets, on the inner wall of the vial above the meniscus of the liquid pharmaceutical formulation.
  • the term “undesired appearance” encompasses also contamination or defect of the inner surface of the wall of a container above the meniscus of the content of the container, such as a liquid pharmaceutical formulation.
  • Another source of such a defect of the inner wall of the vial above the meniscus of the liquid pharmaceutical formulation can also be a "dirty" filling process or a shaking of the vial after filling, leaving splashes on the inner wall of the vial above the meniscus of the pharmaceutical formulation.
  • the defect takes on a form of a residue on the inner wall surface of the container. This residue may be considered a cosmetic defect, yet it is undesirable because it can impact the visual inspection of the containers and its appearance may be questioned by patients and doctors alike.
  • the creeping of the liquid on the container walls can for example occur, if the liquid formulation comprises a surfactant; however, it has also been observed for liquid formulations without surfactant.
  • the creeping can also depend on the properties of the glass container.
  • hydrophobic coatings e.g., siliconized coatings
  • glass containers have also been suggested to prevent creeping in glass vials of lyophilisates.
  • hydrophobic coatings e.g., siliconized coatings
  • the inventors found that not every container with a hydrophobic coating is equally suitable and such containers may introduce further quality defects, such as an increased amount of sub-visible particles.
  • the inventors found that, in particular, the difference between the actual surface tension of the liquid, compared to the actual surface energy of the glass container, is relevant for the avoidance of creeping.
  • the present invention is based on the finding that the use of a dye in a liquid drug formulation provides an accurate and reliable test method for determining whether material making up the defect occurs during the filling process of vials with a liquid drug formulation.
  • the method according to the invention allows one to determine both a vial and a filling process which avoids material making up the defect, thereby providing significant improvements in lyophilized drug formulation quality, in particular in mass production, and associated cost savings.
  • Subject of the invention is a method METHTEST for testing the result of a filling process of vials with a liquid formulation DYE-FORM, comprising the steps (a), (b) and (c):
  • testing of a filling process of a vial comprises, for example, testing whether fogging occurs once a vial has been filled with liquid formulation. This can also be used to predict fogging, for example using a test liquid formulation to simulate the filling of an actual drug formulation. Furthermore, testing a filling process of a vial comprises verification that the filling of the vial with the liquid formulation was done in a clean way essentially keeping the inner surface of the wall above the meniscus of the liquid formulation in the vial in a clean state, for example, the filling of the vial was done without any splashing to the inner surface of the wall having occurred.
  • the result of the filling process of vials can be determined as being negative or unsatisfactory when any of the mentioned defects or undesired appearances occur, caused for example, when the filling process itself fails to meet expectations, such as when splashing occurs during the filling process, or caused for example when after the filling process for other reasons any of the mentioned defects or undesired appearances occur, such as due to fogging or creeping.
  • the vial is a glass vial.
  • one type of glass that is suitable is borosilicate glass.
  • Borosilicate glass vials are commercially available inter alia under the trade designations Duran®, Pyrex®, Ilmabor®, Simax®, Fiolax®, TopLyo®, Ompi Alba® and BORO-8330TM.
  • the surface of the glass can optionally be modified. Examples of modifications are hydrophobic coatings, siliconization or methylation of the surface.
  • the dye may be selected from the group consisting of fluorescein, methylene blue, rhodamine, Congo red, acridine orange, crystal violet, cyanine, methyl orange, Coomassie blue, methyl red, ethidium bromide, Victoria blue, Orange G, BODIPY, Alexa Fluor, Texas red, indocyanine green, cyanine, phtahlocyanine, and derivatives thereof.
  • the dye is a fluorescent dye.
  • the dye is fluorescein.
  • DYE-FORM comprises a surfactant.
  • component (2) of DYE-FORM can comprise the surfactant.
  • DYE-FORM comprises a surfactant
  • the surfactant is a polysorbate or a poloxamer.
  • the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80 and poloxamer 188.
  • DYE-FORM can be prepared by mixing the two components (1) and (2) in any order.
  • component (1) is added to component (2).
  • the dye is dissolved in component (2) thereby obtaining DYE-FORM with the dye in a dissolved state.
  • the dissolving can be done by any conventional means known to the skilled person in the art, such as shaking, stirring, application of ultrasonic sound.
  • Devices which can be used for the shaking, stirring or for application of ultrasonic sound are also known to the skilled person, stirring can for example be done with appliances such as stirring rods or magnetic stirrers.
  • the dissolving is performed during a time of from 1 second to 12 hours, more preferably of from 2 minutes to 6 hours, even more preferably of from 10 minutes to 4 hours, especially of from 30 minutes to 3 hours, more especially of form 1.5 hours to 2.5 hours.
  • the dissolving is done at a temperature of from 0°C to 100°C, more preferably of from 2°C to 80°C, even more preferably of from 5°C to 50°C, especially of from 10°C to 35°C, more especially of from 15°C to 25°C.
  • DYE-FORM can be filtered before it is filled into the vial, this is for example done to remove any undissolved particles, such as undissolved dye.
  • the filtering can be performed by any means known in the art.
  • the filtering may be performed using a PVDF filter.
  • the pore size can range preferably from 50 nm to 50 micrometer, more preferably from 100 nm to 10 micrometer, even more preferably from 100 nm to 5 micrometer. In one particular embodiment, the pore size is 0.2 micrometer.
  • the liquid is water.
  • the liquid formulation is an aqueous formulation.
  • the liquid formulation comprises a drug product.
  • the drug product can be any drug product known to the skilled person, such as small molecule drug products, large molecule drug products, such as proteins, antibodies, antibody-drug conjugates, peptides, RNA, DNA, oligonucleotides, or polynucleotides.
  • the liquid formulation is an aqueous formulation
  • it can comprise a buffer.
  • the buffer can, for example, be used to stabilize the pH of the solution.
  • liquid formulation is an aqueous formulation
  • it can have a pH of 2 to 12, preferably of 2.5 to 10, more preferably of 3.5 to 8, and even more preferably of 4 to 7.
  • Suitable buffers are well known in the art. Such buffers are for example histidine-buffers, citrate-buffers, succinate-buffers, acetate-buffers, phosphate-buffers, and mixtures thereof. Preferred buffers are citrate, L-histidine or mixtures of L-histidine and L-histidine hydrochloride.
  • the pH can be adjusted with an acid or a base known in the art, e.g. hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, sodium hydroxide or potassium hydroxide.
  • the liquid formulation can comprise, besides a drug product, further components typically found in pharmaceutical formulations, such as carriers, excipients, stabilizers, preservatives, lyoprotectants or other components.
  • Carriers can be any carrier known to the skilled person in the art such as for example aqueous liquids; dextrose solutions; glycerol solutions; microemulsions; nanoparticles; liposomal suspensions; oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil; isopropyl alcohol, gaseous fluorocarbons, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, a gel-producing material, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, and methylcellulose; as well as combinations thereof.
  • oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil
  • isopropyl alcohol gaseous fluorocarbons
  • ethyl alcohol polyvinyl pyrrolidone
  • propylene glycol a gel-producing material
  • Excipients can be any excipient known to the skilled person in the art such as for example starch, glucose, lactose, sucrose, gelatin, silica gel, sodium stearate, glycerol, glycerol monostearate, talc, sodium chloride, propylene, glycol, and ethanol; as well as combinations thereof.
  • Stabilizers can be any stabilizers known to the skilled person in the art such as for example amino acids; ascorbic acid; surfactants such as a polyosorbate or a poloxamer; polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol and sucrose; as well as combinations thereof.
  • Preservatives can be any preservative known to the skilled person in the art, such as for example octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.
  • Lyoprotectants are pharmaceutically acceptable excipients which protect a labile active ingredient (e.g., a protein) against destabilizing conditions during the freeze-drying process, subsequent storage and reconstitution.
  • Lyoprotectants comprise, but are not limited to, the group consisting of sugars, polyols (e.g. sugar alcohols) and amino acids.
  • lyoprotectants are selected from the group consisting of sugars (such as sucrose, trehalose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, and neuraminic acid), amino sugars (such as lucosamine, galactosamine, and N-methylglucosamine (“Meglumine”)), polyols (such as mannitol and sorbitol), and amino acids (such as arginine and glycine).
  • sugars such as sucrose, trehalose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, and neuraminic acid
  • amino sugars such as lucosamine, galactosamine, and N-methylglucosamine (“Meglumine”)
  • polyols such as mannitol and sorbitol
  • hydrophilic polymers such as polyethylene glycol (PEG); monosaccharides; disaccharides; including mannose and trehalose; oligosaccharides, polysaccharides, and other carbohydrates including dextrins or dextrans; chelating agents such as EDTA; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and fatty acid esters, fatty acid ethers or sugar esters.
  • PEG polyethylene glycol
  • DYE-FORM comprises a surfactant
  • DYE-FORM preferably comprises the surfactant in an amount of from 0.000001 to 50%, more preferably from 0.000001 to 10%, even more preferably from 0.00001 to 1%, especially from 0.0001 to 0.5%, more especially from 0.00015 to 0.2%, even more especially from 0.001 to 0.1%, of surfactant; the percentages are weight of surfactant/volume of DYE-FORM.
  • DYE-FORM comprises from 0.01 to 100 mg/ml, more preferably from 0.05 to 50 mg/ml, even more preferably from 0.1 to 20 mg/ml, especially from 0.5 to 12 mg/ml, more especially from 1 to 10 mg/ml, even more especially from 2 to 8 mg/ml, of dye in DYE-FORM.
  • the vial is typically filled according to a pre-determined volume.
  • DYE-FORM fills 1 to 99%, more preferably 5 to 95%, even more preferably 10 to 90%, especially 15 to 80%, more especially 20 to 70%, even more especially 25 to 60%, in particular 30 to 60%, more in particular 40 to 60%, of the volume of the vial.
  • the filling of vials is preferably automated.
  • the period of time that the filled vial is allowed to stand upright may depend on the type of liquid or liquid formulation, on the type of vial and, in case a surfactant is present, on the type of surfactant.
  • the vial is allowed to stand upright for 1 second to 1 week, more preferably for 10 seconds to 1 day, even more preferably for 10 seconds to 12 hours, especially for 1 minute to 6 hours, more especially for 2 minutes to 3 hours, even more especially for 3 minutes to 1 hour, in particular for 5 minutes to 30 minutes.
  • the filled vials are allowed to stand upright for said period of time to observe potential creeping of DYE-FORM up the inner wall surface of the vials at a temperature of 0°C to 100°C, more preferably 2°C to 80°C, even more preferably 5°C to 50°C, especially 10°C to 35°C, more especially 15°C to 25°C.
  • step (c) of the method the meniscus line of the DYE-FORM is to be understood to correspond to the height which the DYE-FORM would be expected to reach in the vial based on the volume of DYE-FORM.
  • the determination of whether DYE-FORM is present on the inner wall surface of the filled vial above the meniscus line of the DYE-FORM can be made by a machine. In preferred embodiments, the determination of whether DYE-FORM is present on the inner wall surface of the filled vial above the meniscus line of the DYE-FORM is made by automated photographic analysis of the vial wall.
  • Another subject of the invention is a method METHSELECT for selecting a vial which shows no defects after the filling of the vial with a drug product, comprising the steps (a), (b), (c) and (d):
  • kit KITDYE for analyzing the susceptibility to fogging of a vial containing a component (2), wherein the kit comprises a component (1); with component (1) and component (2) as defined herein, also with all their embodiments.
  • the kit additionally comprises a member selected from the group consisting of:
  • component (1) is present in the kit in the form of a solution, preferably in the form of an aqueous solution.
  • the positive control vial can be a vial type which has been tested by METHTEST, and for which it has been determined that DYE-FORM is present on the inner wall surface of the filled vial above the meniscus line of the DYE-FORM;
  • the negative control vial can be a vial type which has been tested by METHTEST, and for which it has been determined that DYE-FORM is not present on the inner wall surface of the filled vial above the meniscus line of the DYE-FORM; with METHTEST as defined herein, also with all its embodiments.
  • Another subject of the invention is a method METHCOMP for increasing patient compliance, wherein a drug product is provided to the patient in a vial selected by METHSELECT, with METHSELECT as defined herein, also with all its embodiments.
  • METHCOMP is for increasing patient compliance for a patient who is self-administering a drug product.
  • Another subject of the invention is a method METHRED for reducing waste of drug product dosed from a vial and/or for reducing waste of vials, comprising selecting the vial by METHSELECT, with METHSELECT as defined herein, also with all its embodiments.
  • Another subject of the invention is a method METHSTAND for standardizing the dosage and/or administration of drug product administered to a patient from a vial, comprising filling a vial with drug product, wherein said vial is selected by METHSELECT, with METHSELECT as defined herein, also with all its embodiments.
  • Another subject of the invention is the use of a dye in METHTEST, KITDYE, METHSELECT, METHCOMP, METHRED, and/or METHSTAND, with METHTEST, KITDYE, METHSELECT, METHCOMP, METHRED, and METHSTAND as defined herein, also with all their embodiments.
  • a simulated "dirty" fill-in procedure causing creeping of non-lyophilized formulations was performed to evaluate the extent of solution creeping up the inner vial surface, before actual freeze drying.
  • the filling process and any material making up the defect was characterized through the use of a fluorescent dye.
  • the obtained aqueous solution was subsequently filtered using a Millipore 0.22 micrometer PVDF (polyvinylidene difluoride) filter.
  • SCHOTT TopLyo® vials (size 2R, ca. 2 mL of volume) were filled with 0.7 mL of this filtered aqueous solution.
  • the vials were allowed to stand for 10 min at ambient temperature before being assessed for any changes on the inner wall of the vials above the meniscus of the aqueous solution.
  • the assessment was conducted in an Apollo II liquid viewer (Adelphi manufacturing, Haywards heath, UK) with the least possible movement of the vials during assessment.
  • the other 15 vials of the 50 vials showed dots or small droplets on the inner wall surface above the meniscus of the aqueous solution. This can be seen from Figure 2 , which is a representative photograph of the 15 vials with such small droplets on the inner wall surface above the meniscus of the aqueous solution. These small droplets remained on the inner wall surface and did not flow down back into the solution.
  • the obtained aqueous solution was subsequently filtered using a Millipore 0.22 micrometer PVDF filter.
  • 10 SCHOTT Fiolax® vials (size 2R, ca. 2 mL of volume) were filled with 0.7 mL of this filtered aqueous solution.
  • the vials were allowed to stand for 10 min at ambient temperature before being assessed for any changes on the inner wall of the vials above the meniscus of the aqueous solution.
  • the assessment was conducted in an Apollo II liquid viewer (Adelphi manufacturing, Haywards heath, UK) with the least possible movement of the vials during assessment.
  • both formulations contained a model protein (BSA) at a concentration of 20 mg/ml.
  • BSA model protein
  • PS20 polysorbate 20
  • PS80 polysorbate 80
  • Formulation 1 20 mg/ml BSA, 0.03% w/v PS20, 248 mM Sucrose, 20 mM Histidine/Histidine HCI at pH 5.75.
  • Formulation 2 20 mg/ml BSA, 0.03% w/v PS80, 248 mM Sucrose, 20 mM Histidine/Histidine HCI at pH 5.75.
  • the vials used were the following: Two types of vials were used, each in a 2 ml configuration. For vial type 1 a Fiolax® vial (SCHOTT AG, Germany) was used, which had a hydrophilic inner wall glass surface. For vial type 2 a TopLyo® vial (SCHOTT AG, Germany) was used, which had a hydrophobic inner wall glass surface. Prior to filling, vials type 1 and 2 were washed with a Belimed PH810 vial washer (Belimed AG, Switzerland) at 80°C using deionized water.
  • a Belimed PH810 vial washer Belimed PH810 vial washer
  • Fluorescein was added to formulations 1 and 2 in a concentration of 5 mg/ml and the formulations were stirred for 2 h at room temperature and subsequently filtered using a Millipore 0.22 micrometer PVDF filter. The filtered aqueous solutions were used for simulated fogging.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
EP18208057.2A 2018-11-23 2018-11-23 Procédé pour tester le résultat d'un processus de remplissage de flacons Withdrawn EP3656218A1 (fr)

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EP18208057.2A EP3656218A1 (fr) 2018-11-23 2018-11-23 Procédé pour tester le résultat d'un processus de remplissage de flacons

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EP18208057.2A EP3656218A1 (fr) 2018-11-23 2018-11-23 Procédé pour tester le résultat d'un processus de remplissage de flacons

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172587A1 (fr) * 2022-03-07 2023-09-14 Opus Life Sciences Llc Formulations de fluorescéine et kits

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003169694A (ja) * 2001-12-10 2003-06-17 Wako Pure Chem Ind Ltd グラム染色用試液並びに試薬キット及びこれを用いたグラム染色法
WO2010115728A2 (fr) 2009-03-30 2010-10-14 F. Hoffmann-La Roche Ag Procédé permettant d'éviter la condensation du verre
US20130203173A1 (en) * 2012-02-03 2013-08-08 Thermo Fisher Scientific Oy Method for determining the concentration of beta-D-glucan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003169694A (ja) * 2001-12-10 2003-06-17 Wako Pure Chem Ind Ltd グラム染色用試液並びに試薬キット及びこれを用いたグラム染色法
WO2010115728A2 (fr) 2009-03-30 2010-10-14 F. Hoffmann-La Roche Ag Procédé permettant d'éviter la condensation du verre
US20130203173A1 (en) * 2012-02-03 2013-08-08 Thermo Fisher Scientific Oy Method for determining the concentration of beta-D-glucan

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABDUL-FATTAH, A.M. ET AL., EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 85, 2013, pages 314 - 326
ABDUL-FATTAH, A.M. ET AL., EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 85, 2013, pages 314 - 326, XP002789312 *
DOUGLAS ROBY: "New Mexico Wastewater Laboratory Certification Study Guide. Version I", UTILITY OPERATORS CERTIFICATION PROGRAM, 1 July 2016 (2016-07-01), pages 296 pp., XP055562614, Retrieved from the Internet <URL:https://www.env.nm.gov/wp-content/uploads/2016/07/New-Mexico-Wastewater-Laboratory-Certification-Study-Guide.pdf> *
RODEL, E. ET AL., PHARM. IND., vol. 75, 2013, pages 328 - 332

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172587A1 (fr) * 2022-03-07 2023-09-14 Opus Life Sciences Llc Formulations de fluorescéine et kits

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