Method for confirming and / or optimizing formula of filling equipment by adopting substitute liquid

Abstract

The invention belongs to the field of biological medicine. Specifically, the invention relates to a method for confirming and / or optimizing the formula of the filling equipment by using a substitute liquid, which is particularly suitable for the filling production of biological agents, in particular high-viscosity biological agents. The invention also relates to an alternative liquid useful in the method and to the use thereof.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine. Specifically, it relates to a method for confirming and / or optimizing the formulation of filling equipment using a replacement fluid. This method is particularly suitable for the filling production of biological preparations, especially high-viscosity biological preparations. The present invention also relates to a replacement fluid that can be used in this method and its use. Background Art

[0002] Formula validation for filling equipment for biologics (e.g., pharmaceutical preparations of proteins, peptides, nucleic acids, or their derivatives) typically requires consideration of avoiding issues such as dripping, splashing, and foaming during the filling process to achieve better filling accuracy and provide optimized filling parameters for production. However, for biologics, especially high-viscosity biologics, it is often difficult to obtain sufficient quantities of expensive stock solutions for formula validation of production-scale filling equipment during the early, rapidly progressing development and validation of biologic filling processes. Therefore, in the early stages of drug development, when stock solutions are scarce and progress needs to be rapidly accelerated, a traditional industry approach is to use water to validate the formula for production-scale filling equipment. However, although most biologics are aqueous solutions, their physical properties differ to varying degrees from those of water. Therefore, using water as a filling fluid has significant limitations when assessing filling accuracy and confirming the equipment formula for production-scale filling equipment. Especially when the product is a biological preparation with higher concentration and / or high viscosity, the filling parameters obtained by confirming the equipment formula with water often cannot avoid needle dripping, and are not representative in terms of filling accuracy and equipment process capability. Therefore, there are challenges in actual preparation filling production.

[0003] Another existing industry approach is to use small amounts of expensive stock solutions to confirm equipment formulations at the laboratory scale. However, since the filling needles at the laboratory scale are typically fixed in position, this is different from the filling process in large-scale production equipment, where the filling needles move with the conveyor, and to meet production capacity requirements, the conveyor speed is usually high. Therefore, the risks of dripping and splashing at the industrial scale are significantly different from those at the laboratory scale. Scaling up biologics, especially high-viscosity biologics, from laboratory scale to production scale presents challenges.

[0004] In view of this, the present invention aims to provide a simple, low-cost, and highly reliable method for confirming and / or optimizing the formula of filling equipment, which is particularly suitable for the filling production of biological preparations, especially high-viscosity biological preparations. Summary of the Invention

[0005] Summary of the Invention

[0006] In one aspect, a method for confirming and / or optimizing the formula of a filling equipment using a substitute liquid is provided, and the method is particularly suitable for biological preparations, especially high-viscosity biological preparations. Specifically, for filling operations, the performance of the process is affected by the physical properties of the filling liquid, such as density, viscosity, and surface tension. Based on the factors affecting the performance of the liquid used for filling biological preparations in the filling process, the inventors used a low-cost representative substitute liquid with the same or similar physical properties as the liquid as the filling liquid for filling in the production equipment, discovered and confirmed the factors that produce a linear relationship with the filling accuracy, and thus confirmed and / or optimized the parameters and settings of the filling equipment formula. The use of the substitute liquid significantly reduces the consumption of expensive drug stock solution, reduces the economic cost and time cycle of the confirmation and / or optimization of the filling equipment formula, and improves development efficiency. The use of the substitute liquid also reduces the risk of operators coming into contact with potentially harmful drug solutions, thereby improving safety. Moreover, the method of the present invention is simple, has high reliability and repeatability, can provide scientific and accurate data to guide and optimize the production of preparations under production scale, avoids problems such as dripping, splashing and foaming during the filling process, ensures filling accuracy, and avoids inconsistencies when scaling up from laboratory scale to production scale.

[0007] In another aspect, the present invention provides a method for guiding the formulation of a biologic.

[0008] In another aspect, the present invention provides a method for determining an upper limit on the production capacity of a production filling facility.

[0009] In another aspect, the present invention provides a replacement fluid that can be used in the method of the present invention.

[0010] In another aspect, the present invention provides the use of a replacement fluid of the present invention in a method of the present invention.

[0011] In another aspect, the present invention also provides a solid substitution composition that can be used to prepare the substitution fluid of the present invention.

[0012] In another aspect, the present invention provides the use of a solid replacement composition of the present invention in a method of the present invention.

[0013] Various aspects of the present invention and its embodiments, features and advantages are described in detail below. Other aspects and its embodiments, features and advantages not specifically described herein can be determined by those skilled in the art based on the description and subsequent claims without departing from the concept of the present invention. Detailed Description of the Invention

[0014] In one aspect, a method for confirming and / or optimizing a device formulation for biologics filling using a surrogate fluid is provided, comprising:

[0015] (a) providing a replacement fluid with physical properties identical or similar to the pharmaceutical fluid used to fill the biological product;

[0016] (b) using the replacement liquid of step (a) as the filling liquid, filling the filling liquid in a production filling machine at different recipe settings, and determining an acceptable or desired filling machine recipe based on the filling results, wherein the filling results include filling accuracy and, optionally, whether significant dripping, splashing, and foaming occur;

[0017] (c) optionally, performing data fitting analysis using the filling accuracy obtained in step (b) as a response and each formulation parameter in the formulation setting as a factor, thereby determining the formulation parameters that are the main factors affecting the accuracy and their influence mode; and

[0018] (d) Optionally, running the filling equipment at low or high levels of the formulation parameters that are the main accuracy influencing factors using the pharmaceutical liquid used for filling the biologic as the filling fluid to further confirm whether the equipment formulation is acceptable or desired.

[0019] In some embodiments, the physical property includes one or more of viscosity, density, and surface tension.

[0020] Therefore, in some embodiments, the replacement fluid has the same or similar viscosity, density, and / or surface tension as the pharmaceutical liquid used for the biologic filling. Preferably, the replacement fluid has the same or similar viscosity as the pharmaceutical liquid used for the biologic filling. More preferably, the replacement fluid has the same or similar viscosity, density, and surface tension as the pharmaceutical liquid used for the biologic filling. Methods or instruments for measuring the physical properties are known in the art or can be measured as described in the Examples.

[0021] In some embodiments, the physical properties, viscosity, density and / or surface tension of the replacement fluid are "the same as or similar to the pharmaceutical liquid used for filling the biologic" means that the values ​​of the physical properties, viscosity, density and / or surface tension of the replacement fluid are about 70%-130%, preferably about 80%-120%, more preferably about 90%-110%, and most preferably about 95%-105%, for example, about 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 110%, 120%, 130% or a range consisting of any two thereof, of the physical properties, viscosity, density and / or surface tension of the pharmaceutical liquid used for filling the biologic.

[0022] In some embodiments, the replacement fluid has a viscosity of about 1-25 cp, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 cp, or a range consisting of any two thereof. In some embodiments, the replacement fluid has a viscosity of about 1-20 cp or about 1-15 cp.

[0023] In some embodiments, the replacement fluid has a density of about 0.9-1.2 g / L, such as about 0.95-1.1 g / L, such as about 1 g / L.

[0024] In some embodiments, the replacement fluid has a surface tension of about 20-70 mN / m, such as about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 mN / m. In some embodiments, the replacement fluid has a surface tension of about 30-60 mN / m, about 30-50 mN / m, about 35-45 mN / m, or about 35-40 mN / m.

[0025] In some embodiments, the replacement fluid has a viscosity of about 1-25 cp, a density of about 0.9-1.2 g / L, and a surface tension of about 20-70 mN / m, preferably a viscosity of about 1-20 cp, a density of about 0.95-1.1 g / L, and a surface tension of about 35-45 mN / m, and more preferably a viscosity of about 1-15 cp, a density of about 0.95-1.1 g / L, and a surface tension of about 35-40 mN / m.

[0026] Typically, the replacement fluid can be prepared by dissolving a macromolecule (such as a polysaccharide) that is biocompatible and does not affect the compliance of a biologics GMP workshop in a solvent, and adding a viscosity modifier to adjust the viscosity and / or a surfactant to adjust the surface tension as appropriate. The replacement fluid may further comprise a filler (such as a sugar and / or a polyol) and any other suitable excipients. Therefore, in some embodiments, the replacement fluid comprises a macromolecule (such as a polysaccharide), an optional viscosity modifier, an optional surfactant, an optional filler, and a solvent.

[0027] In some embodiments, the macromolecule is a polysaccharide, such as a dextran, including but not limited to Dextran-10, Dextran-20, Dextran-40, Dextran-70, Dextran-110, Dextran-150, Dextran-250, Dextran-400, and Dextran-500. The amount of the macromolecule can be determined by one skilled in the art, for example, based on the physical properties (e.g., viscosity, density, and / or surface tension) of the pharmaceutical liquid used for filling the biologic. Generally, the macromolecule can be present in an amount of about 1-20% (w / v), such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% (w / v), or a range consisting of any two thereof. In some embodiments, the macromolecule may be present in an amount of about 1-15% (w / v), about 1-10% (w / v), about 2-8% (w / v), about 2-6% (w / v), for example about 4% (w / v).

[0028] In some embodiments, the replacement fluid comprises about 1-20% (w / v), about 1-15% (w / v), about 1-10% (w / v), about 2-8% (w / v), about 2-6% (w / v), for example, about 4% (w / v) dextran (e.g., Dextran-150).

[0029] In some embodiments, the viscosity modifier can be selected from cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylmethylcellulose. In some embodiments, the viscosity modifier is selected from sodium carboxymethylcellulose, methylcellulose, and hydroxypropylmethylcellulose. In some embodiments, the viscosity modifier is selected from sodium carboxymethylcellulose and methylcellulose. In some embodiments, the viscosity modifier is sodium carboxymethylcellulose. In some embodiments, the viscosity modifier is methylcellulose.

[0030] The amount of viscosity modifier can be determined by one skilled in the art, for example, based on the physical properties of the pharmaceutical liquid used for the biologic filling (e.g., viscosity, density, and / or surface tension), particularly the viscosity, and the viscosity modulating ability of the viscosity modifier itself. Typically, the viscosity modifier can be present in an amount of about 0.001-10% (w / v), for example, about 0.001, 0.005, 0.01, 0.02, 0.04, 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.6, 0.8, 1.0, 1.5, 2, 4, 6, 8, or 10% (w / v), or a range consisting of any two thereof. In some embodiments, the viscosity modifier may be present in an amount of about 0.001-6% (w / v), about 0.005-4% (w / v), about 0.01-3% (w / v), about 0.01-12% (w / v).

[0031] In some embodiments, the replacement fluid comprises about 0.01-0.1% (w / v) sodium carboxymethylcellulose. In other embodiments, the replacement fluid comprises about 0.4-5% (w / v), such as about 0.4-4% (w / v), about 0.4-3% (w / v), or about 0.4-1.2% (w / v) methylcellulose.

[0032] In some embodiments, the surfactant may be an ionic or nonionic surfactant, preferably a nonionic surfactant. In some embodiments, the surfactant is a nonionic surfactant, for example, selected from: sorbitan fatty acid esters, including Tween and Span; polypropylene glycol ethylene oxide adducts, including poloxamer; polyoxyethylene alkyl ethers, including benzyl alcohol. In some embodiments, the surfactant is Tween (e.g., Tween 20, 40, 60, or 80) or poloxamer (e.g., poloxamer 188, poloxamer 407), preferably Tween 20, Tween 80, or poloxamer 188.

[0033] Typically, the concentration of the surfactant in the replacement fluid is about 0.001-0.1% (w / v), such as about 0.001, 0.005, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.06, 0.07, 0.08, 0.1% (w / v), or any two thereof. In some embodiments, the surfactant may be present at a concentration of about 0.005-0.1% (w / v), about 0.01-0.08% (w / v), or about 0.02-0.06% (w / v).

[0034] In some embodiments, the replacement fluid comprises about 0.001-0.1% (w / v), e.g., about 0.005-0.1% (w / v), about 0.01-0.08% (w / v), or about 0.02-0.06% (w / v), or about 0.04% (w / v) of Tween 20 or Tween 80, preferably Tween 80.

[0035] In some embodiments, described filler can be selected from sugar and / or polyol.In some embodiments, described sugar and / or polyol can be selected from sucrose, lactose, trehalose, maltose, fructose, inulin oligosaccharide, glucose, maltodextrin, cyclodextrin, dextran, glycerol, mannitol, sorbitol, xylitol, maltitol and ethylene glycol.In some embodiments, described sugar and / or polyol can be selected from sucrose, trehalose, glucose, mannitol, sorbitol and xylitol.In some embodiments, described sugar and / or polyol can be selected from sucrose, trehalose and mannitol, preferably selected from sucrose and mannitol.In some embodiments, described filler comprises or is sucrose.In some embodiments, described filler comprises or is the combination of sucrose and mannitol.

[0036] Typically, the concentration of the filler in the replacement fluid can be about 1-40% (w / v), for example, about 2% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), about 10% (w / v), about 12% (w / v), about 14% (w / v), about 16% (w / v), about 18% (w / v), about 20% (w / v), about 25% (w / v), about 30% (w / v), about 35% (w / v), about 40% (w / v), or a range consisting of any two thereof. In some embodiments, the filler can be present in a concentration of about 2-30% (w / v), about 3-25% (w / v), about 4-20% (w / v), about 5-15% (w / v), or about 6-10% (w / v). It will be understood that when a filler is included in a formulation, the concentration is provided by the plurality of fillers combined.

[0037] In some embodiments, the replacement solution comprises about 5-15% (w / v), such as about 6-10% (w / v), such as about 8% (w / v) sucrose. In addition, preferably, the replacement solution comprises about 2-10% (w / v) sucrose and about 1-6% (w / v) mannitol, about 4-8% (w / v) sucrose and about 1-4% (w / v) mannitol, such as 6% (w / v) sucrose and about 2% (w / v) mannitol.

[0038] In some embodiments, the solvent includes but is not limited to water (e.g., pure water, ultrapure water, Milli-Q water, water for injection, sterile water, double distilled water, etc.) or a physiologically acceptable solution (e.g., normal saline, Ringer's solution, glucose injection, etc.). Preferably, the solvent is water.

[0039] In some embodiments, the replacement fluid may further contain other excipients commonly used in biological preparations, such as stabilizers, buffers, osmotic pressure regulators, lyoprotectants, solubilizers, antioxidants, complexing agents, adsorption inhibitors, preservatives, local pain relievers, etc.

[0040] As stabilizers, examples include, but are not limited to, sugars or polyols, such as sucrose, trehalose, mannitol, sorbitol; amino acids and / or salts thereof, such as arginine or its salts, glycine, sodium aspartate, glutamic acid, lysine, etc.; complexing agents, such as edetic acid or its salts; polyethylene glycols, such as PEG200, PEG300, PEG400, PEG600, PEG1000, etc.; salts, such as sodium chloride, potassium chloride, etc.; glycerol; proteins, such as albumin, casein, mucopolysaccharide protein, etc.; cyclodextrins, such as hydroxypropyl β-cyclodextrin, etc.; and other macromolecular compounds, such as heparin, hydroxyethyl starch, polyvinyl pyrrolidone, etc.

[0041] Examples of the buffer include, but are not limited to, amino acids and / or salts thereof, such as histidine and / or salts thereof, glutamic acid and / or salts thereof; succinic acid and / or salts thereof, such as sodium succinate and potassium succinate; citric acid and / or salts thereof, such as sodium citrate and potassium citrate; phosphates, hydrogen phosphates and / or dihydrogen phosphates, such as sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate; acetates, such as sodium acetate and potassium acetate; tartaric acid and / or salts thereof , such as sodium tartrate, potassium tartrate; adipate; carbonate and / or bicarbonate, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; tris (hydroxymethylaminomethane) (Tris) buffer; HEPES (4-hydroxyethylpiperazineethanesulfonic acid) buffer; 2-(N-morpholino)ethanesulfonic acid (MES) buffer; 3-(N-morpholino)propanesulfonic acid (MOPS) buffer; or piperazine-N,N'-bis(2-ethanesulfonic acid) (Pipes) buffer.

[0042] Examples of the osmotic pressure regulator include, but are not limited to, fructose, glucose, sucrose, mannose, trehalose, sorbitol, xylitol, mannitol, glycerol, sodium chloride, calcium chloride, potassium chloride, magnesium chloride, ammonium sulfate, sodium nitrate, potassium nitrate, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, or calcium phosphate.

[0043] As the lyoprotectant, examples include, but are not limited to, sucrose, trehalose, glucose, lactose, maltose, xylose, mannitol, sorbitol, or dextran.

[0044] As the solubilizing agent, examples thereof include, but are not limited to, nonionic solubilizing agents such as polyoxyethylene sorbitan fatty acid ester (polysorbate), polyoxyethylene fatty acid ester (Myri), or polyoxyethylene fatty alcohol ether.

[0045] As the antioxidant, examples include, but are not limited to, methionine, ethylenediaminetetraacetic acid, ascorbic acid, gentisic acid, tocopherol, propyl gallate, butylated hydroxyanisole, sodium thiosulfate, sodium metabisulfite, sodium bisulfite and the like.

[0046] Examples of the complexing agent include, but are not limited to, edetic acid (EDTA) and / or its salts such as sodium salt, for example, disodium edetate or calcium sodium edetate.

[0047] Examples of the adsorption inhibitor include, but are not limited to, human serum albumin, lecithin, polyethylene glycol, and the like.

[0048] As the preservative, examples include, but are not limited to, benzyl alcohol, phenol, cresol, m-cresol, chlorocresol, resorcinol p-hydroxybenzoate, chlorobutanol and the like.

[0049] As the local pain-relieving agent, examples include, but are not limited to, benzyl alcohol, chlorobutanol, procaine hydrochloride and the like.

[0050] Preferably, the types and amounts of other excipients are substantially the same as or similar to the excipients and amounts contained in the pharmaceutical liquid used for filling the biological preparation.

[0051] In some embodiments, the replacement fluid comprises about 1-20% (w / v) dextran, 0.01-0.1% (w / v) sodium carboxymethylcellulose, about 0.001-0.1% (w / v) Tween 20 or 80, and about 5-15% (w / v) sucrose. Preferably, the replacement fluid comprises about 2-6% (w / v) dextran, 0.01-0.1% (w / v) sodium carboxymethylcellulose, about 0.02-0.06% (w / v) Tween 20 or 80, and about 6-10% (w / v) sucrose. For example, the replacement fluid comprises about 4% (w / v) dextran, 0.01-0.1% (w / v) sodium carboxymethylcellulose, about 0.04% (w / v) Tween 20 or 80, and about 8% (w / v) sucrose.

[0052] In some embodiments, the replacement fluid comprises about 1-20% (w / v) dextran, about 0.4-5% (w / v) methylcellulose, about 0.001-0.1% (w / v) Tween 20 or 80, about 2-10% (w / v) sucrose, and about 1-6% (w / v) mannitol. Preferably, the replacement fluid comprises about 2-6% (w / v) dextran, about 0.4-4% (w / v) methylcellulose, about 0.02-0.06% (w / v) Tween 20 or 80, about 4-8% (w / v) sucrose, and about 1-4% (w / v) mannitol. For example, the replacement solution comprises about 4% (w / v) dextran, about 0.4-1.2% (w / v) methylcellulose, about 0.04% (w / v) Tween 20 or 80, about 6% (w / v) sucrose, and about 2% (w / v) mannitol.

[0053] In some embodiments, in step (b), filling with different recipe settings in a production filling device comprises:

[0054] (b1) selecting a high level and a low level of a recipe parameter, respectively, and determining a corresponding center point (the center point represents an intermediate position between the low level and the high level); optionally, the recipe parameter includes pump acceleration and backsuction, preferably includes pump acceleration, pump deceleration, and backsuction, and more preferably includes pump acceleration, pump deceleration, backsuction acceleration, and backsuction stroke, for example, as shown in Table 1;

[0055] (b2) operating the filling equipment with different parameter recipes to obtain filling results for each of the parameter recipes, the filling results including filling accuracy and, optionally, whether obvious dripping, splashing, and foaming occur;

[0056] The parameter formula includes F1 to F5 as follows:

[0057] -F1: Pump acceleration, low level; Suction back, high level;

[0058] -F2: Pump acceleration, center point; Suction back, center point;

[0059] -F3: Pump acceleration, low level; Suction back, low level;

[0060] -F4: Pump acceleration, high level; Suction back, low level;

[0061] -F5: Pump acceleration, high level; Suction back, high level;

[0062] For example, the filling equipment pump acceleration and suckback settings are shown in Table 2.1;

[0063] Optionally, the parameter recipe includes the following F1 to F9:

[0064] -F1: Pump acceleration, low level; Pump deceleration, high level; Suction back, high level;

[0065] -F2: Pump acceleration, center point; Pump deceleration, center point; Suction back, center point;

[0066] -F3: Pump acceleration, high level; Pump deceleration, high level; Suction back, low level;

[0067] -F4: Pump acceleration, low level; Pump deceleration, low level; Suction back, low level;

[0068] -F5: Pump acceleration, high level; Pump deceleration, low level; Suction back, high level;

[0069] -F6: Pump acceleration, high level; Pump deceleration, low level; Suction back, low level;

[0070] -F7: Pump acceleration, low level; Pump deceleration, low level; Suction back, high level;

[0071] -F8: Pump acceleration, low level; Pump deceleration, high level; Suction back, low level;

[0072] -F9: Pump acceleration, high level; Pump deceleration, high level; Suction back, high level;

[0073] For example, the acceleration, deceleration, and suckback settings for the filling equipment pump are shown in Table 2.2;

[0074] Optionally, the parameter recipe includes the following F1 to F9:

[0075] -F1: Pump acceleration, high level; Pump deceleration, low level; Back-suction acceleration, high level; Back-suction stroke, low level; -F2: Pump acceleration, high level; Pump deceleration, high level; Back-suction acceleration, low level; Back-suction stroke, low level; -F3: Pump acceleration, low level; Pump deceleration, high level; Back-suction acceleration, low level; Back-suction stroke, high level; -F4: Pump acceleration, center point; Pump deceleration, center point; Back-suction acceleration, center point; Back-suction stroke, center point; -F5: Pump acceleration, low level; Pump deceleration, low level; Back-suction acceleration, high level; Back-suction stroke, high level Level; -F6: Pump acceleration, high level; Pump deceleration, low level; Back-suction acceleration, low level; Back-suction stroke, high level; -F7: Pump acceleration, low level; Pump deceleration, low level; Back-suction acceleration, low level; Back-suction stroke, low level; -F8: Pump acceleration, high level; Pump deceleration, high level; Back-suction acceleration, high level; Back-suction stroke, high level; -F9: Pump acceleration, low level; Pump deceleration, high level; Back-suction acceleration, high level; Back-suction stroke, low level; For example, the settings of pump acceleration, pump deceleration, back-suction acceleration and back-suction stroke of filling equipment are shown in Table 2.3:

[0076] (b3) determining a filling equipment formulation for filling the pharmaceutical liquid for filling the biological agent based on the filling results obtained in step (b2), or adjusting the physical properties of the biological agent and optionally repeating steps (a) and (b) (including steps b1 to b3).

[0077] Table 1. High and low levels of various parameters in filling equipment recipes

[0078] Recipe parameters Low level high level Pump acceleration － + Pump deceleration － + Suction acceleration － + Suction stroke － +

[0079] Table 2.1. Filling equipment recipe settings (pump acceleration and suckback)

[0080] formula Pump acceleration Suction Back F1 － + F2 0 0 F3 － － F4 + － F5 + +

[0081] Table 2.2. Settings for filling equipment recipes (pump acceleration, pump deceleration and suckback)

[0082] formula Pump acceleration Pump deceleration Suction Back F1 － + + F2 0 0 0 F3 + + － F4 － － － F5 + － + F6 + － － F7 － － + F8 － + － F9 + + +

[0083] Table 2.3. Settings for filling machine recipes F1 to F9 (pump acceleration, pump deceleration, suction acceleration and suction stroke)

[0084] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke F1 + － + － F2 + + － － F3 － + － + F4 0 0 0 0 F5 － － + + F6 + － － + F7 － － － － F8 + + + + F9 － + + －

[0085] Note: 0 represents the center point.

[0086] In some embodiments, in step (b1), the high and low levels of the recipe parameter are set according to the filling equipment parameter range. In some embodiments, the high and low levels of the recipe parameter are set to the upper and lower limits, respectively, of the acceptable range of the filling equipment parameter. The acceptable range of the filling equipment parameter is generally determinable by those skilled in the art. As a non-limiting example, the high and low levels of the recipe parameters for a filling machine (Syntegon, model FLC3080) can be selected as follows: the low level of pump acceleration is 0.3, the high level is 3 (the filling machine gear range is 0.1-10, and the acceptable gear range is 0.3 to 3); the low level of pump deceleration is 1, the high level is 10 (the filling machine gear range is 0.1-10, and the acceptable gear range is 1-10); the low level of suck-back acceleration is 1, the high level is 10 (the filling machine gear range is 1-10, and the acceptable gear range is 1-10); the low level of suck-back stroke is 0.1, the high level is 10 (the filling machine gear range is 0.1-10, and the acceptable gear range is 0.1-10). The higher the pump acceleration, the greater the impact of the liquid, which can easily cause liquid to splash onto the vial or filling needle. Therefore, the high level of pump acceleration is preferably 3.

[0087] Typically, the acceptable range for filling accuracy is ±5%, preferably ±3%. Therefore, when the absolute value of the filling accuracy is ≤5%, preferably ≤3%, the filling result is acceptable. Furthermore, when the absolute value of the filling accuracy is ≤5%, preferably ≤3%, and no significant dripping, splashing, or foaming is observed, the filling result is acceptable. Unacceptable filling results include: an absolute value of the filling accuracy greater than 5%, preferably greater than 3%, and / or significant dripping, splashing, or foaming is observed.

[0088] Therefore, in some embodiments, in step (b3), based on the filling result obtained in step (b2), when the filling result is acceptable (i.e., the absolute value of the filling accuracy is ≤5%, preferably ≤3%, and optionally further, no obvious dripping, splashing and foaming are observed), the corresponding equipment formula is determined to be the equipment formula that can be used to fill the medicinal liquid.

[0089] In some embodiments, when the filling results of each formulation obtained in step (b2) are all unacceptable, the physical properties of the biologic are adjusted (e.g., viscosity is reduced), and steps (a) and (b) (including steps b1 to b3) are optionally repeated. In some embodiments, the adjustment of the physical properties of the biologic is to reduce viscosity, for example, by adjusting the formulation of the biologic, such as reducing the amount of a viscosity modifier or replacing it with another viscosity modifier with lower viscosity, reducing the concentration of the bioactive molecule, etc.

[0090] In some embodiments, in step (b), the filling equipment is operated at a maximum filling speed.

[0091] In some embodiments, in step (b), the filling equipment activates online weighing during operation to determine the filling accuracy.

[0092] In some embodiments, in step (b), the filling equipment runs at least 6 sets for each formulation.

[0093] In some embodiments, in step (c), the recipe parameters include or are pump acceleration and suckback, preferably include or are pump acceleration, pump deceleration and suckback, and more preferably include or are pump acceleration, pump deceleration, suckback acceleration and suckback stroke.

[0094] In some embodiments, in step (c), the data fitting analysis is a JMP data fitting analysis.

[0095] In some embodiments, in step (c), the effect of each formulation parameter on filling accuracy is determined by data fitting analysis (e.g., JMP data analysis). In some embodiments, the determination includes determining which parameter(s) have a significant effect and determining the effect mode of the parameter(s) (factors), such as whether the value of the parameter(s) (factors) is better when it is larger or smaller, or whether there is an interaction effect (e.g., when certain factors are larger, another factor is smaller, etc.).

[0096] In some embodiments, the factor p-value calculated by data fitting analysis (e.g., JMP data analysis) is used to determine whether the factor effect is significant. Typically, when p≤0.05, the effect of the factor (parameter) is significant (as a major accuracy influencing factor).

[0097] In some embodiments, through data fitting analysis (e.g., JMP data analysis), the precision value is set as the response, the response goal is to minimize, and the prediction information is retrieved to confirm how the factor affects the response, that is, whether the larger the factor, the larger the response value, or the smaller the factor, the larger the response value.

[0098] In some embodiments, data fitting analysis (e.g., JMP data analysis) is used to determine that the influence of backsuck on precision is significant or significant. In some embodiments, data fitting analysis is used to determine that the backsuck acceleration and backsuck stroke, and in particular, the backsuck acceleration, are significant or significant factors affecting precision. Preferably, in step (c), backsuck is determined to be the primary factor affecting precision. More preferably, in step (c), backsuck acceleration is determined to be the primary factor affecting precision.

[0099] In some embodiments, the influence of the back-suck acceleration is determined by data fitting (e.g., JMP data analysis) in the following manner: the greater the back-suck acceleration, the greater the precision value. Considering that the response goal is to minimize, the smaller the back-suck acceleration, the smaller the precision value, and the closer to the target.

[0100] In some embodiments, in step (d), the equipment parameters of the filling equipment are set based on the main accuracy influencing factors (i.e., factors with significant influence) and their influence modes determined in step (c). For example, if a parameter (factor) is determined to be more conducive to filling as it decreases, then the parameter is set to the minimum value of the parameter range for the production filling equipment.

[0101] In some embodiments, in step (d), when the main accuracy influencing factor affects the response (e.g., accuracy) in such a manner that the smaller the main accuracy influencing factor, the smaller the response, the filling equipment is operated at a low level of the recipe parameter that is the main accuracy influencing factor, and conversely, the filling equipment is operated at a high level.

[0102] In some embodiments, in step (d), it is determined that suck-back acceleration is the main accuracy-affecting factor and that it affects the response (e.g., accuracy) in such a way that the smaller the suck-back acceleration, the smaller the response, and the filling apparatus is operated with a low level of suck-back acceleration.

[0103] In some embodiments, in step (d), whether the formulation is acceptable or desired is determined by the filling results of the pharmaceutical liquid under the formulation. In some embodiments, when the filling results of the pharmaceutical liquid under the formulation are acceptable (e.g., the absolute value of the filling accuracy is ≤5%, preferably ≤3%, and optionally further, no obvious dripping, splashing, and foaming are observed), the corresponding formulation is determined to be the optimized equipment formulation that can be used to fill the pharmaceutical liquid.

[0104] Preferably, when the absolute value of the filling accuracy of the drug liquid under the formula is ≤5%, preferably ≤3% and the drug liquid does not show obvious dripping, splashing and foaming, the corresponding equipment formula is determined to be the optimized equipment formula that can be used to fill the drug liquid.

[0105] In some embodiments, in step (d), the filling equipment is operated at a maximum filling speed.

[0106] In some embodiments, in step (d), the filling equipment activates online weighing during operation to determine the filling accuracy.

[0107] In some embodiments, in step (d), the filling equipment runs at least 6 sets for each recipe setting.

[0108] In another aspect, a method for guiding the formulation of a biologic is provided, the method comprising:

[0109] (a) providing a replacement fluid with physical properties identical or similar to the pharmaceutical fluid used to fill the biological product; and

[0110] (b) using the replacement liquid of step (a) as the filling liquid, filling the filling liquid in the production filling equipment with different formulation settings, and determining an acceptable or desired filling equipment formulation based on the filling results;

[0111] Wherein, in step (b), when the filling results are unacceptable under all formulation settings, the prescription of the biological preparation is adjusted to change the physical properties of the drug liquid used for filling the biological preparation, and then steps (a) and (b) are repeated one or more times until an acceptable filling result is obtained.

[0112] Any content described above in relation to the method for confirming and / or optimizing the formulation of a device for filling a biologic using a surrogate fluid, in particular any content described in relation to steps (a) and (b), including embodiments and features, etc., also applies to the method described herein, unless the context clearly contradicts or indicates otherwise.

[0113] In some embodiments, adjusting the formulation of the biologic comprises adjusting the concentration of the bioactive molecule, adjusting the type and / or amount of the viscosity modifier.

[0114] In some embodiments, the change in the physical properties of the drug liquid used for filling the biological agent is to reduce the viscosity of the drug liquid, which can be achieved, for example, by reducing the concentration of the bioactive molecule, reducing the amount of the viscosity regulator, or replacing it with other viscosity regulators with lower viscosity properties.

[0115] In another aspect, a method for determining an upper limit of production capacity of a production filling device is provided, the method comprising: (i) providing a series of replacement fluids having different physical properties (e.g., viscosity, density, and / or surface tension);

[0116] (ii) using the replacement liquid of step (i) as the filling liquid, filling the filling liquids in the production filling equipment in sequence with different formula settings, and obtaining the filling results of each filling liquid under each formula setting;

[0117] (iii) determining the upper limit of the physical properties of the biopharmaceutical liquid that can be filled using the production filling equipment based on the filling results obtained in step (ii).

[0118] In some embodiments, the series of surrogate liquids of step (i) have substantially the same density and surface tension and increasing viscosity. In some embodiments, the series of surrogate liquids of step (i) each have a density of about 0.9-1.2 g / L, for example about 0.95-1.1 g / L, for example about 1 g / L. In some embodiments, the series of surrogate liquids of step (i) each have a surface tension of about 20-70 mN / m, preferably about 30-60 mN / m, about 30-50 mN / m, about 35-45 mN / m, or about 35-40 mN / m, for example about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 mN / m. In some embodiments, the series of surrogate liquids of step (i) have increasing viscosity in the range of about 1-50 cp, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50 cp, or a range defined by any two of these.

[0119] The surrogate liquids can be prepared as described herein, for example as described above, which is not repeated here.

[0120] In some embodiments, the filling in step (ii) in the production filling apparatus at different formulation settings is performed as described above for step (b).

[0121] Generally, if the filling result of a certain surrogate liquid at a certain formulation setting is acceptable, the production filling apparatus is deemed to be capable of being used for filling of a drug solution having the physical properties of the surrogate liquid. If the filling result of a certain surrogate liquid at all formulation settings is unacceptable, the production filling apparatus is deemed to be incapable of being used for filling of a drug solution having the physical properties of the surrogate liquid. In this case, the prescription of the biopharmaceutical should be adjusted to accommodate the production filling apparatus.

[0122] In some embodiments, the maximum viscosity in the surrogate liquid that can achieve an acceptable filling result when filled in the production filling apparatus is determined as the upper limit of the production capacity of the production filling apparatus. It is understood that it is not required that the surrogate liquid achieve an acceptable filling result at all formulation settings, but it is sufficient that an acceptable filling result can be achieved at at least one formulation setting.

[0123] Any of the above description, including embodiments and features, etc., of the "method for confirming and / or optimizing formulation of a device for filling of a biopharmaceutical using surrogate liquids" applies to the method described herein, unless the context clearly contradicts or otherwise indicates.

[0124] In another aspect, the present invention provides a surrogate fluid having the same or similar physical characteristics (e.g., viscosity, density, and / or surface tension) as the pharmaceutical liquid used for biologic filling. Preferably, the surrogate fluid is as defined herein. The surrogate fluid can be used in the methods of the present invention, including methods for confirming and / or optimizing equipment formulations for biologic filling, methods for guiding biologic preparation, and methods for determining the upper limit of production capacity of production filling equipment.

[0125] In another aspect, the present invention provides the use of a replacement fluid of the present invention for use in a method of the present invention. Preferably, the replacement fluid is as defined herein, and / or the method is as defined herein.

[0126] In another aspect, the present invention provides a solid replacement composition that can be used to prepare a replacement fluid of the present invention. In some embodiments, the solid replacement composition has the same composition as a composition obtained by removing a solvent, such as water, from a replacement fluid of the present invention. In some embodiments, the components of the solid replacement composition are in the same composition, or in two or more packages (e.g., in the form of a kit).

[0127] In some embodiments, the replacement liquid of the present invention can be obtained by dissolving the solid replacement composition of the present invention with a solvent such as water. The amount of solvent is the amount that can obtain the composition of the replacement liquid of the present invention, which can be easily determined by those skilled in the art.

[0128] In another aspect, the present invention provides a use of the solid replacement composition of the present invention in the method of the present invention. In some embodiments, the solid replacement composition of the present invention is dissolved in a solvent such as water to obtain the replacement solution of the present invention, and then the method of the present invention is performed.

[0129] It is understood that the various aspects and their embodiments, features, and advantages described herein are equally applicable to the other aspects of the present invention, including aspects not directly described, and their various embodiments, features, and advantages. Without departing from the concept of the present invention, other aspects and their embodiments, features, and advantages not specifically described herein can be determined by those skilled in the art based on the description and subsequent claims, and these are also included in the scope of the present invention.

[0130] definition

[0131] It should be understood that the terms used herein are only for the purpose of describing embodiments of the present invention, and are not intended to limit the scope of the present invention. The terms used in this application have the meanings defined below, unless otherwise specified or the context clearly contradicts. The terms not clearly defined in this application have the meanings generally understood by those skilled in the art. Other features, objects and advantages of the present invention will be apparent from this specification and the accompanying drawings and from the appended claims.

[0132] As used in this application, the terms "a," "an," "the" and similar referents are to be construed to cover both the singular and the plural, unless otherwise indicated or clearly contradicted by context.

[0133] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5%, 4%, 3%, 2% or 1% less than the specified numerical value and an upper limit that is 5%, 4%, 3%, 2% or 1% greater than the specified numerical value.

[0134] As used herein, the term "and / or" means any one of the alternatives or two or more or all of the alternatives.

[0135] As used herein, the terms "comprising" or "including" are intended to include the recited elements, integers, or steps, but not to exclude any other elements, integers, or steps. Herein, when the terms "comprising" or "including" are used, unless otherwise indicated, both the case of consisting essentially of the recited elements, integers, or steps and the case of consisting of the recited elements, integers, or steps are encompassed. For example, when reference is made to an antibody variable region "comprising" a particular sequence, it is intended to encompass an antibody variable region consisting of the particular sequence.

[0136] The term "consisting essentially of" means that other than the defined components, no other components are present in significant amounts, e.g., the amount of said other components is less than 10% w / w, preferably less than 5% w / w, more preferably less than 3% w / w, most preferably less than 1% w / w.

[0137] The term "w / w" means weight ratio.

[0138] The term "% (w / v)" means the concentration by mass volume percentage, ie, the number of grams of solute per 100 milliliters of solution (g / 100 mL).

[0139] The term "biologic," also referred to as "biotech drug formulation," refers to a pharmaceutical formulation comprising a biopharmaceutical molecule, optionally comprising one or more excipients. The biologic can be in liquid or powder form (e.g., spray-dried powder or freeze-dried powder). Preferably, the biologic is an injectable biologic, for example, administered by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intraperitoneal, abdominal, spinal, joint, intracardiac, thoracic, intrathecal, or intravitreal route.

[0140] The term "biopharmaceutical molecule" refers to a biotechnology drug molecule that can produce a therapeutic or preventive effect, for example, a protein, a polypeptide, a nucleic acid, or any derivative thereof (e.g., a fusion or conjugate). For example, the biopharmaceutical molecule can be selected from an antibody (e.g., a monoclonal antibody or a polyclonal antibody) or an antigen-binding fragment thereof, a fusion protein, a biopharmaceutical conjugate (XDC) such as an antibody-drug conjugate (ADC), a polypeptide, or a small nucleic acid drug. The biopharmaceutical molecule is susceptible to aggregation or denaturation under the action of shear forces.

[0141] The term "protein" refers to a biological macromolecule composed of amino acids linked by peptide bonds to form a polypeptide chain, which further folds and coils to form a specific spatial structure. Protein molecules are generally prone to aggregation or denaturation under the influence of shear forces.

[0142] As used herein, the term "antibody" is used in the broadest sense and encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity. A complete antibody will generally comprise at least two full-length heavy chains and two full-length light chains, but may comprise fewer chains in certain circumstances, e.g., antibodies naturally occurring in camels may comprise only heavy chains.

[0143] The term "antigen-binding fragment" means a molecule different from an intact antibody, which comprises a portion of an intact antibody and is capable of binding to the antigenic epitope to which the intact antibody binds. Examples of antigen-binding fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; single-chain antibodies (e.g., scFv); single-domain antibodies; camelid antibodies (heavy-chain antibodies). Antigen-binding fragments can be prepared by recombinant DNA technology, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise specified herein or clearly contradicted by the context, the term "antibody" herein is equivalent to "antibody or antigen-binding fragment thereof."

[0144] The term "antibody-drug conjugate" or "ADC" refers to a substance obtained by coupling a small molecule drug toxin (payload) to an antibody or its antigen-binding fragment (responsible for targeting function and sometimes also having biological activity) via a linker. As used herein, the term "antibody-drug conjugate" or "ADC" includes pharmaceutically acceptable salts or esters, solvates, isotopically labeled substances (such as deuterated derivatives), stereoisomers, tautomers, and other equivalent forms thereof, unless otherwise indicated or clearly contradicted by the context.

[0145] The term "drug liquid for filling the biologic" refers to the liquid used to fill a packaging container (e.g., a vial, prefilled syringe, etc.) during the biologic's production process. This liquid comprises an effective amount of the biopharmaceutical molecule and pharmaceutically acceptable excipients (e.g., fillers, buffers, stabilizers, surfactants, etc.) dissolved in a solvent (e.g., water). After filling, the liquid in the packaging container can optionally be further manipulated, such as freeze-dried, to produce a lyophilized formulation.

[0146] The term "substitute fluid" means a substitute solution that is identical or similar in physical properties to the pharmaceutical liquid actually used for filling the biologic.

[0147] The term "solid replacement composition" means a solid composition that can be dissolved in a solvent such as water to prepare a replacement solution, for example, in the form of a powder or granules, preferably a powder. The solid composition can be a single composition or a combination of two or more packages (each package containing one or more components of the composition).

[0148] The term "parameter" or "equipment parameter" refers to a specific value or condition that is adjustable during equipment operation and controls equipment operation, performance, or production processes. Parameter values ​​or levels can be adjusted and set to meet specific production requirements and goals. For some filling equipment, these parameters may include pump acceleration, pump deceleration, and suckback. For other filling equipment, these parameters may include pump acceleration, pump deceleration, suckback acceleration, and suckback stroke.

[0149] The term "recipe" or "equipment recipe" refers to a collection of various parameter settings used to control the operation of equipment during a production process to achieve a specific production goal. For a filling device, the recipe may include a collection of one or more parameters of pump acceleration, pump deceleration, and backsuction (e.g., backsuction acceleration and backsuction stroke). For example, the recipe for a filling device includes a collection of pump acceleration and backsuction. Preferably, the recipe for a filling device includes a collection of pump acceleration, pump deceleration, and backsuction. More preferably, the recipe for a filling device includes a collection of pump acceleration, pump deceleration, backsuction acceleration, and backsuction stroke.

[0150] The term "pump acceleration" refers to the rate at which a filling pump gradually increases from a stationary state to a set constant speed during startup. Properly increasing pump acceleration can shorten filling time. However, excessive pump acceleration can easily cause splashing or foaming of the filling liquid.

[0151] The term "pump deceleration" refers to the rate at which the filling pump gradually slows down from a constant speed to a standstill near the end of the filling process. Proper pump deceleration ensures that the filling liquid stops smoothly at the end of the filling process.

[0152] The term "suction-back acceleration" refers to the rate at which the filling pump or needle accelerates during the suction-back operation at the end of a fill. Rapid suction pulls the liquid back from the needle tip, preventing it from dripping onto the outside of the bottle neck. Appropriate suction-back acceleration reduces residual liquid at the end of a fill, improving filling accuracy and reducing the risk of contamination.

[0153] The term "suction stroke" refers to the distance the filling pump or needle moves during the suction operation. Proper suction stroke prevents dripping or residual filling liquid, ensures accurate filling volume, and reduces the risk of contamination.

[0154] The term "filling accuracy" or "precision" refers to the degree of deviation between the actual filling volume and the nominal filling volume during the filling process of the filling equipment. It reflects the stability and consistency of the filling volume of the filling equipment during the filling operation.

[0155] During the filling process, improper equipment formulation can easily lead to problems such as dripping, splashing, and foaming. The term "dripping" refers to the phenomenon of filling liquid accidentally dripping or leaking from the filling equipment (such as filling needles, etc.) during the filling process. The term "splashing" refers to the phenomenon of filling liquid splashing due to external force during the filling process, for example, too fast filling speed can cause liquid splashing. The term "foaming" refers to the phenomenon of filling liquid generating bubbles due to gas mixing during the filling process, which can be caused by too fast filling liquid flow speed during the filling process, leading to air entrainment in the filling liquid to form bubbles. Obvious dripping, splashing, and foaming not only affect the filling accuracy, but also can cause product contamination and waste. Therefore, it is necessary to optimize the equipment formulation during the filling process to reduce the occurrence of dripping, splashing, and foaming.

[0156] The term "data fitting analysis" refers to the analysis and statistical modeling of data to reveal the relationship between variables for prediction and optimization.

[0157] The term "response" refers to the output variable that is intended to be measured or observed in an experiment or study. It is usually the dependent variable, whose value is affected by other variables (factors).

[0158] The term "factor" refers to an input variable that can affect the response variable in an experiment or study. It is usually the independent variable, whose value can be set or observed.

[0159] The term "primary precision influencing factor" refers to the factor that has a significant effect (p≤0.05) on the filling accuracy during the filling process.

[0160] The term "filling speed" refers to the rate at which filling liquid is filled into a container during the filling process. It is an important indicator of filling efficiency and production capacity, usually expressed in terms of volume or weight of filling liquid per unit time. The maximum filling speed is usually determined based on equipment stability (e.g., no bottle tipping, broken bottle, etc.) and aseptic process requirements (e.g., compliance), through equipment validation and aseptic process simulation validation, which is within the ability of those skilled in the art.

[0161] The term "method of the present invention" includes the method of identifying and / or optimizing the equipment formulation for biologic filling, the method for guiding biologic formulation, and the method for determining the upper limit of production capacity of the filling equipment, as described herein, as well as equivalent methods that can be determined by those skilled in the art according to the description in the specification, although not specifically described in the present application. BRIEF DESCRIPTION OF DRAWINGS

[0162] Figure 1 is the predicted profiler result obtained in JMP data analysis for the filling results of the alternative liquid in Example 1.

[0163] Figure 2 This is the prediction profiler result obtained from the JMP data analysis of the filling results of the replacement solution in Example 2.

[0164] Figure 3 This is the prediction profiler result obtained from the JMP data analysis of the filling results of the replacement solution in Example 3.

[0165] Figure 4 This is the prediction profiler result obtained from the JMP data analysis of the filling results of the replacement solution in Example 4.

[0166] Figure 5 This is the prediction profiler result obtained from the JMP data analysis of the filling results of the replacement solution in Example 6.

[0167] Figure 6 This is the prediction profiler result obtained from the JMP data analysis of the filling results of the replacement solution in Example 7. Example

[0168] The following examples are provided to further illustrate the present invention. It should be understood that these examples are only for a better understanding of the present invention and are not intended to limit the scope of the present invention in any way. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included within the scope of the present invention.

[0169] Except as specifically mentioned below, the processes, conditions, methods, etc. for implementing the present invention are all common knowledge and common common sense in the art, and the present invention is not particularly limited. The materials and reagents used in the examples can be obtained from commercial channels or prepared according to methods known in the art unless otherwise specified. Specifically, dextran 150 was purchased from Xibao Bio, sucrose was purchased from Merck KGaA-4, mannitol was purchased from Huaxu Pharmaceutical, sodium carboxymethyl cellulose was purchased from Myrel, methylcellulose was purchased from Sinopharm Suzhou, Tween 80 and Tween 20 were both purchased from Nanjing Well, and poloxamer 188 was purchased from Hunan Erkang.

[0170] In the examples, % represents the concentration by mass / volume percentage, i.e., the number of grams of solute per 100 ml of solution, unless otherwise specified or clearly contradicted by the context.

[0171] In the examples, the density is measured using a METTLER TOLEDO D4 densitometer, the viscosity is measured using a Brookfield DV2T viscometer, and the surface tension is measured using a KRUSSDSA30 tensiometer.

[0172] Example 1

[0173] A surrogate solution was prepared with the physical properties (density, viscosity, and surface tension) of the drug solution, consisting of 4% dextran 150, 8% sucrose, 0.01% sodium carboxymethylcellulose, and 0.04% Tween 80. The density of the surrogate solution was measured to be 1.029 g / L (25°C), the viscosity was 3 cp (25°C), and the surface tension was 39 mN / m. The surrogate solution was placed in the reservoir of a filler (Syntegon, model FLC3080) and connected to the tubing. The pump tubing dimensions were 1.2 mm ID x 4.4 mm OD, and the fill volume was set to 1 mL. The two levels of each recipe parameter (pump acceleration, pump deceleration, backdraft acceleration, and backdraft stroke) were selected as shown in Table 3, and the recipe was set according to Table 4. The filler was operated automatically at maximum speed, with online weighing activated during operation. Run at least 6 groups of each formula (8 vials per group), record the dripping, splashing and foaming of the filling liquid under each formula, and calculate the filling accuracy of each formula. The filling accuracy is calculated as follows:

[0174]

[0175] Where Q is the filling accuracy (%); P is the measured net weight (net value after tare), in g; and N is the nominal value, in g. The filling accuracy of each vial is calculated using the maximum (i.e., worst-case) value of all accuracy data in each formulation experiment as the filling accuracy for that formulation, as all other accuracy data are included in this filling accuracy.

[0176] The filling accuracy results are shown in Table 4. As can be seen, the filling accuracy of all formulations was within the acceptable range. No significant dripping, splashing, or foaming was observed for these formulations.

[0177] In JMP software, data fitting analysis was performed using filling accuracy as the response. The effects of four factors (pump acceleration, pump deceleration, back-suction acceleration, and back-suction stroke) on the accuracy response were examined. The factors with significant influence were determined through JMP fitting calculations. The prediction profiler results are shown in Figure 1 The results show that for products with the tested physical properties (density, viscosity, and surface tension), the significant effect of pump acceleration and deceleration on accuracy is relatively small, while backsuck has a greater impact on accuracy. Backsuck acceleration is the primary factor affecting accuracy (p=0.04), and the smaller the backsuck acceleration, the higher the accuracy.

[0178] Therefore, while all formulations were within acceptable limits, further optimization was possible. Using the original liquid as the filling fluid, a smaller suction acceleration and stroke, which could be set by the production equipment, were selected as the predicted optimized parameters for confirmation. The optimized formulation was: pump acceleration 1, pump deceleration 1, suction acceleration 1, and suction stroke 0.1. Six runs of this formulation were conducted for confirmation. The confirmed accuracy was ±0.50%, meeting the filling requirements. There was no leakage, splashing, or foaming, and the filling needle was not susceptible to clogging. Therefore, these filling parameters can be used for subsequent production of pharmaceutical liquids with the same or similar physical properties as the surrogate fluid.

[0179] Table 3. Two levels of each factor of filling machine recipe parameters

[0180] Recipe parameters Low level high level Pump acceleration 0.3 3 Pump deceleration 1 10 Suction acceleration 1 10 Suction stroke 0.1 10

[0181] Table 4. Recipe settings and filling accuracy results

[0182] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke Filling accuracy F1 3 1 10 0.1 ±0.83％ F2 3 10 1 0.1 ±0.61％ F3 0.3 10 1 10 ±0.61％ F4 1.65 5.5 5.5 5.05 ±0.73％ F5 0.3 1 10 10 ±0.84％ F6 3 1 1 10 ±0.62％ F7 0.3 1 1 0.1 ±0.55％ F8 3 10 10 10 ±0.83％ F9 0.3 10 10 0.1 ±0.82％

[0183] Example 2

[0184] A surrogate solution was prepared with the physical properties (density, viscosity, and surface tension) of the drug solution, consisting of 4% dextran 150, 8% sucrose, 0.025% sodium carboxymethylcellulose, and 0.04% Tween 80. The density of the surrogate solution was measured to be 1.029 g / L (25°C), the viscosity was 6 cP (25°C), and the surface tension was 39 mN / m. The surrogate solution was placed in the reservoir of a filling machine (Syntec, model FLC3080) and connected to the tubing. The pump tubing dimensions were 1.2 mm ID x 4.4 mm OD, and the fill volume was set to 1 mL. The two levels of each formulation parameter (pump acceleration, pump deceleration, backdraft acceleration, and backdraft stroke) were selected as shown in Table 3, and the formulation was set according to Table 5. The filling machine was automatically operated at maximum speed, with at least six groups of eight vials per formulation run. Any leakage, splashing, and foaming of the filling solution during each formulation run was recorded, and the filling accuracy of each formulation was statistically analyzed. The filling accuracy statistics were as described in Example 1.

[0185] The filling accuracy results are shown in Table 5. As can be seen, the filling accuracy of all formulas is within the acceptable range. No obvious dripping, splashing, or foaming was observed in any formula. In JMP software, data fitting analysis was performed with filling accuracy as the response. The effects of four factors (pump acceleration, pump deceleration, back-suction acceleration, and back-suction stroke) on the accuracy response were examined. The factors with significant influence were determined through JMP fitting calculations. The prediction profiler results are shown in Table 5. Figure 2The results show that for products with the tested physical properties (density, viscosity, and surface tension), pump acceleration and deceleration have a smaller impact on accuracy, while backsuck has a greater impact on accuracy, with backsuck acceleration being the primary factor affecting accuracy (p=0.04).

[0186] Further confirmation was conducted using the original liquid as the filling fluid, with a smaller backdraft acceleration and stroke, based on the predicted optimized parameter range. The optimized formula was: pump acceleration 1, pump deceleration 1, backdraft acceleration 1, and backdraft stroke 0.1. Six runs using this formula were conducted for confirmation. The accuracy was confirmed to be ±1.20%, meeting the filling requirements, with no leakage, splashing, or foaming. Therefore, these filling parameters can be used in subsequent production for pharmaceutical liquids with the same or similar physical properties as the surrogate liquid.

[0187] Table 5. Recipe settings and their accuracy results

[0188] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke Accuracy F1 3 1 10 0.1 ±2.67％ F2 3 10 1 0.1 ±1.24％ F3 0.3 10 1 10 ±1.27％ F4 1.65 5.5 5.5 5.05 ±2.05％ F5 0.3 1 10 10 ±2.80％ F6 3 1 1 10 ±1.28％ F7 0.3 1 1 0.1 ±1.15％ F8 3 10 10 10 ±2.93％ F9 0.3 10 10 0.1 ±2.62％

[0189] Example 3

[0190] A surrogate solution was prepared with the physical properties (density, viscosity, and surface tension) of the drug solution, consisting of 4% dextran 150, 8% sucrose, 0.05% sodium carboxymethylcellulose, and 0.04% Tween 80. The density of the surrogate solution was measured to be 1.029 g / L (25°C), the viscosity was 10 cp (25°C), and the surface tension was 39 mN / m. The surrogate solution was placed in the reservoir of a filling machine (Syntec, model FLC3080) and connected to the tubing. The pump tubing dimensions were 1.2 mm ID x 4.4 mm OD, and the fill volume was set to 1 mL. The two levels of each formulation parameter (pump acceleration, pump deceleration, backdraft acceleration, and backdraft stroke) were set as shown in Table 3, and the formulation was set according to Table 6. The filling machine was automatically operated at maximum speed, with at least six groups of eight vials per formulation run. Any leakage, splashing, and foaming of the filling solution during each formulation run was recorded, and the filling accuracy of each formulation was statistically analyzed. The filling accuracy statistics were as described in Example 1.

[0191] The filling accuracy results are shown in Table 6. It can be seen that when filling the alternative liquid with this physical property, the absolute value of the filling accuracy of the formula that produces more dripping liquid is larger, which is likely to exceed the acceptable range. In JMP software, data fitting analysis was performed using filling accuracy as the response, and the influence of four factors on the accuracy response was examined. The factors with significant influence were determined through JMP fitting calculations. The prediction profiler results are shown in Figure 3The results show that for products with the above physical characteristics, pump acceleration and pump deceleration have little effect on accuracy, while backsuck has a greater impact on accuracy, with backsuck acceleration being the main factor affecting accuracy (p=0.03).

[0192] Further confirmation was conducted using the original liquid as the filling fluid, with a smaller backdraft acceleration and stroke, based on the predicted optimized parameter range. The optimized formula was: pump acceleration 0.3, pump deceleration 1, backdraft acceleration 1, and backdraft stroke 0.1. This formula was used for six runs for confirmation. The confirmed accuracy was ±2.66%, meeting the filling requirements, with no leakage, splashing, or foaming. Therefore, these filling parameters can be used in subsequent production for pharmaceutical liquids with the same or similar physical properties as the surrogate liquid.

[0193] Table 6. Recipe settings and their accuracy results

[0194] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke Accuracy F1 3 1 10 0.1 ±4.32％ F2 3 10 1 0.1 ±2.88％ F3 0.3 10 1 10 ±3.00％ F4 1.65 5.5 5.5 5.05 ±3.56％ F5 0.3 1 10 10 ±5.08％ F6 3 1 1 10 ±2.92％ F7 0.3 1 1 0.1 ±2.64％ F8 3 10 10 10 ±5.72％ F9 0.3 10 10 0.1 ±3.88％

[0195] Example 4

[0196] A surrogate solution was prepared with a composition consisting of 4% dextran 150, 8% sucrose, 0.1% sodium carboxymethylcellulose, and 0.04% Tween 80, with physical properties (density, viscosity, and surface tension) that were essentially identical to the drug solution. The density of the surrogate solution was measured to be 1.030 g / L (25°C), the viscosity was 15 cp (25°C), and the surface tension was 39 mN / m. The surrogate solution was placed in the reservoir of a filling machine (Syntec, model FLC3080) and connected to the tubing. The pump tubing dimensions were 1.2 mm ID x 4.4 mm OD, and the fill volume was set to 1 mL. The two levels of each formulation parameter (pump acceleration, pump deceleration, backdraft acceleration, and backdraft stroke) were selected as shown in Table 3, and the formulation was set according to Table 7. The filling machine was automatically operated at maximum speed, with at least six groups of eight vials per formulation run. Any leakage, splashing, and foaming of the filling solution during each formulation run was recorded, and the filling accuracy of each formulation was statistically analyzed. The filling accuracy statistics were as described in Example 1.

[0197] The results are shown in Table 7. It can be seen that for the filling of the alternative liquid with this physical property, the filling accuracy of all formulas exceeds the acceptable range of ±3%, and the absolute value of the filling accuracy of the formula that produces more dripping liquid is larger, but some formulas can control the filling accuracy within the range of ±5%. Considering that the accuracy of ±5% can meet the needs of some products, especially high-viscosity products, for products with an acceptable range of ±5% filling accuracy, subsequent research can be conducted based on the acceptable range of ±5%. In the JMP software, data fitting analysis was performed with filling accuracy as the response to examine the influence of four factors on the accuracy response. The factors with significant influence were determined through JMP fitting calculations, and the prediction profiler results are shown in Figure 4 The results show that for products with this physical property, pump acceleration and pump deceleration have a smaller impact on accuracy, while back suction has a greater impact on accuracy, with back suction acceleration being the main factor affecting accuracy (p=0.01).

[0198] Further confirmation was conducted using the original liquid as the filling fluid, selecting a smaller backdraft acceleration and a smaller backdraft stroke within the predicted optimized parameter range. The optimized formula was: pump acceleration 1, pump deceleration 1, backdraft acceleration 1, and backdraft stroke 0.1. This formula was run for 10 cycles for confirmation. The confirmed accuracy was ±3.45%, meeting the acceptable filling accuracy range of ±5%, with no leakage, splashing, or foaming. Therefore, for pharmaceutical liquids with the same or similar physical properties as the surrogate liquid within an acceptable filling accuracy range of ±5%, these filling parameters can be used for subsequent production.

[0199] Table 7. Recipe settings and their accuracy results

[0200]

[0201]

[0202] Example 5

[0203] Substitute fluid A was prepared with a composition of 4% dextran 150, 8% sucrose, 0.2% sodium carboxymethylcellulose, and 0.04% Tween 80. The density of Substitute fluid A was determined to be 1.032 g / L (25°C), the viscosity was 30 cp (25°C), and the surface tension was 39 mN / m. Substitute fluid B was prepared with a composition of 4% dextran 150, 8% sucrose, 0.3% sodium carboxymethylcellulose, and 0.04% Tween 80. The density of Substitute fluid B was determined to be 1.031 g / L (25°C), the viscosity was 60 cp (25°C), and the surface tension was 39 mN / m.

[0204] Substitute A was placed in the reservoir bottle of the filling machine (Standex, Model FLC3080), the tubing was connected, the pump tubing size was ID*OD 1.2mm*4.4mm, and the fill volume was set to 1 mL. Two levels of each parameter (pump acceleration, pump deceleration, suckback acceleration, and suckback stroke) in the formula were set as shown in Table 3, and the formula was set according to Table 8. The filling machine was automatically run at the maximum operating speed, at least 6 groups were run for each formula, the dripping, splashing, and foaming of the filling liquid were recorded under each formula, and the filling accuracy of each formula was counted, and the filling accuracy was counted as described in Example 1. If the experimental results of Substitute A can predict better parameters, then further use Substitute B with higher viscosity to optimize the parameters according to the above experimental steps.

[0205] The experimental results are shown in Table 8. It can be seen that for the filling of Substitute A, all formulas produced dripping, and the filling accuracy was far beyond the acceptable range (>5%). It shows that the existing filling equipment is not suitable for the filling of drug liquids with such physical properties, and at this time the equipment capacity limit has been reached, that is, the limit of the equipment capacity can be investigated in this way. Therefore, Substitute B with higher viscosity is no longer used for experiments. The experimental results show that for drug liquids with similar physical properties to Substitute A or higher viscosity drug liquids, the viscosity should be reduced to within the equipment capacity range first, and then the parameters are optimized to meet the production requirements. The equipment capacity range described above can be investigated by the method of preparing substitute liquids with different viscosities to investigate the equipment capacity of different filling machines.

[0206] Table 8. Formula settings and their accuracy results

[0207] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke Accuracy F1 3 1 10 0.1 ±9.44％ F2 3 10 1 0.1 ±6.82％ F3 0.3 10 1 10 ±6.45％ F4 1.65 5.5 5.5 5.05 ±7.51％ F5 0.3 1 10 10 ±9.73％ F6 3 1 1 10 ±6.65％ F7 0.3 1 1 0.1 ±6.21％ F8 3 10 10 10 ±9.63％ F9 0.3 10 10 0.1 ±9.41％

[0208] Example 6

[0209] A surrogate solution was prepared with the physical properties (density, viscosity, and surface tension) of the drug solution, consisting of 4% dextran 150, 6% sucrose, 2% mannitol, 0.4% methylcellulose, and 0.04% Tween 20. The density of the surrogate solution was measured to be 1.031 g / L (25°C), the viscosity was 2 cp (25°C), and the surface tension was 35 mN / m. The surrogate solution was placed in the reservoir of a filler (Synteko, model FLC3080) and connected to the tubing. The pump tubing dimensions were 1.2 mm ID x 4.4 mm OD, and the fill volume was set to 1 mL. The two levels of each formulation parameter (pump acceleration, pump deceleration, backdraft acceleration, and backdraft stroke) were selected as shown in Table 3, and the formulation was set according to Table 9. The filling machine was automatically operated at maximum speed, with at least six groups of eight vials per formulation run. Any leakage, splashing, and foaming of the filling solution during each formulation run was recorded, and the filling accuracy of each formulation was statistically analyzed. The filling accuracy statistics were as described in Example 1.

[0210] The results are shown in Table 9. As can be seen, the accuracy of all formulas is within the acceptable range, with no obvious dripping, splashing, or foaming. In JMP software, data fitting analysis was performed with filling accuracy as the response, examining the effects of the four factors on the accuracy response. The factors with significant influence were determined through JMP fitting calculations, and the prediction profiler results are shown in Table 9. Figure 5 The results show that for products with these physical properties (density, viscosity, and surface tension), the suction acceleration is the main factor affecting the accuracy (p = 0.05).

[0211] Therefore, while all formulations were within acceptable limits, further optimization was possible. Using the original solution as the filling fluid and selecting a smaller backdraft acceleration, the optimized parameters were then confirmed within the predicted optimized parameter range. The optimized formulation was: pump acceleration 1, pump deceleration 1, backdraft acceleration 1, and backdraft stroke 0.1. Six runs using this formulation were conducted for confirmation. The confirmed accuracy was ±0.52%, meeting filling requirements, with no leakage, splashing, or foaming. Therefore, these filling parameters can be used in subsequent production for pharmaceutical liquids with the same or similar physical properties as the surrogate fluid.

[0212] Table 9. Recipe settings and their accuracy results

[0213] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke Accuracy F1 3 1 10 0.1 ±0.84％ F2 3 10 1 0.1 ±0.67％ F3 0.3 10 1 10 ±0.64％ F4 1.65 5.5 5.5 5.05 ±0.77％ F5 0.3 1 10 10 ±0.88％ F6 3 1 1 10 ±0.68％ F7 0.3 1 1 0.1 ±0.55％ F8 3 10 10 10 ±0.89％ F9 0.3 10 10 0.1 ±0.86％

[0214] Example 7

[0215] A surrogate solution was prepared with a composition consisting of 4% dextran 150, 6% sucrose, 2% mannitol, 1.2% methylcellulose, and 0.04% Tween 20, with physical properties (density, viscosity, and surface tension) that were essentially identical to the drug solution. The density of the surrogate solution was measured to be 1.032 g / L (25°C), the viscosity was 5 cP (25°C), and the surface tension was 36 mN / m. The surrogate solution was placed in the reservoir of a filling machine (Syntec, model FLC3080) and connected to the tubing. The pump tubing dimensions were 1.2 mm ID x 4.4 mm OD, and the fill volume was set to 1 mL. The two levels of each formulation parameter (pump acceleration, pump deceleration, backdraft acceleration, and backdraft stroke) were selected as shown in Table 3, and the formulation was set according to Table 10. The filling machine was automatically operated at maximum speed, with at least six groups of eight vials per formulation run. Any leakage, splashing, and foaming of the filling solution during each formulation run was recorded, and the filling accuracy of each formulation was statistically analyzed. The filling accuracy statistics were as described in Example 1.

[0216] The experimental results are shown in Table 10. It can be seen that the accuracy of all formula groups is within the acceptable range, and no obvious dripping, splashing, or foaming is observed. In JMP software, data fitting analysis is performed with filling accuracy as the response, and the influence of four factors on the accuracy response is examined. The factors with significant influence are determined through JMP fitting calculations. The prediction profiler results are shown in Figure 6 The results show that for products with these physical properties (density, viscosity, and surface tension), the suction acceleration is the main factor affecting the accuracy (p = 0.01).

[0217] Therefore, further confirmation was conducted using the original liquid as the filling fluid, selecting a smaller backdraft acceleration and stroke within the predicted optimized parameter range. The optimized formula was: pump acceleration 1, pump deceleration 1, backdraft acceleration 1, and backdraft stroke 0.1. This formula was used for six runs for confirmation. The confirmed accuracy was ±1.20%, meeting the filling requirements, with no leakage, splashing, or foaming. Therefore, these filling parameters can be used in subsequent production for pharmaceutical liquids with the same or similar physical properties as the surrogate liquid.

[0218] Table 10. Recipe settings and their accuracy results

[0219] formula Pump acceleration Pump deceleration Suction acceleration Suction stroke Accuracy F1 3 1 10 0.1 ±2.20％ F2 3 10 1 0.1 ±1.40％ F3 0.3 10 1 10 ±1.50％ F4 1.65 5.5 5.5 5.05 ±1.88％ F5 0.3 1 10 10 ±2.54％ F6 3 1 1 10 ±1.46％ F7 0.3 1 1 0.1 ±1.30％ F8 3 10 10 10 ±2.90％ F9 0.3 10 10 0.1 ±1.90％

[0220] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the appended claims.

[0221] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Any or all features of the foregoing can be combined in various embodiments of the application. Furthermore, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

Claims

1. A method for confirming and / or optimizing a device formulation for filling a biologic using a surrogate fluid, comprising: (a) providing a replacement fluid with physical properties identical or similar to the pharmaceutical fluid used to fill the biological product; (b) using the replacement liquid of step (a) as the filling liquid, filling the filling liquid in a production filling machine at different recipe settings, and determining an acceptable or desired filling machine recipe based on the filling results, wherein the filling results include filling accuracy and, optionally, whether significant dripping, splashing, and foaming occur; (c) Optionally, using the filling accuracy obtained in step (b) as a response and each recipe parameter in the recipe setting as a factor, performing data fitting analysis to determine the recipe parameters that are the main factors affecting the accuracy and their influence mode; and (d) Optionally, running the filling equipment at low or high levels of the formulation parameters that are the main accuracy influencing factors using the pharmaceutical liquid used for filling the biologic as the filling fluid to further confirm whether the equipment formulation is acceptable or desired.

2. The method according to claim 1, wherein the physical properties include one or more of viscosity, density and surface tension; optionally wherein, The replacement fluid has the same or similar viscosity as the drug liquid used for filling the biological agent, and preferably has the same or similar viscosity, density and surface tension as the drug liquid used for filling the biological agent; Optionally, the values ​​of the physical properties (including viscosity, density and / or surface tension) of the replacement fluid are about 70%-130%, such as about 80%-120%, preferably about 90%-110%, and more preferably about 95%-105% of the physical properties (viscosity, density and / or surface tension) of the pharmaceutical liquid used for filling the biological preparation.

3. The method according to any of the preceding claims, wherein the replacement fluid has a viscosity of about 1-25 cp, such as about 1-20 cp or about 1-15 cp; and / or the replacement fluid has a density of about 0.9-1.2 g / L, such as about 0.95-1.1 g / L, such as about 1 g / L; and / or the replacement fluid has a surface tension of about 20-70 mN / m, such as about 30-60 mN / m, about 30-50 mN / m, about 35-45 mN / m, or about 35-40 mN / m; Optionally, the replacement fluid has a viscosity of about 1-25 cp, a density of about 0.9-1.2 g / L, and a surface tension of about 20-70 mN / m, preferably has a viscosity of about 1-20 cp, a density of about 0.95-1.1 g / L, and a surface tension of about 35-45 mN / m, and more preferably has a viscosity of about 1-15 cp, a density of about 0.95-1.1 g / L, and a surface tension of about 35-40 mN / m.

4. The method according to any one of the preceding claims, wherein the replacement fluid comprises a macromolecule (such as a polysaccharide), an optional viscosity modifier, an optional surfactant, an optional filler and a solvent; Optionally, the macromolecule is a polysaccharide, such as dextran, optionally the macromolecule is present in an amount of about 1-20% (w / v), such as about 1-15% (w / v), about 1-10% (w / v), about 2-8% (w / v), about 2-6% (w / v), such as about 4% (w / v); Optionally, the viscosity modifier is selected from cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylmethylcellulose; preferably, the viscosity modifier is selected from sodium carboxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose, preferably selected from sodium carboxymethylcellulose and methylcellulose, for example, sodium carboxymethylcellulose or methylcellulose; optionally, the viscosity modifier is present in an amount of about 0.001-10% (w / v), for example, about 0.001-6% (w / v), about 0.005-4% (w / v), about 0.01-3% (w / v), about 0.01-12% (w / v); Optionally, the surfactant is an ionic or nonionic surfactant, preferably a nonionic surfactant, for example, selected from: sorbitan fatty acid esters, including Tween and Span; polypropylene glycol ethylene oxide adducts, including poloxamer; polyoxyethylene alkyl ethers, including benzyl alcohol; preferably, the surfactant is Tween (e.g., Tween 20, 40, 60 or 80) or poloxamer (e.g., poloxamer 188, poloxamer 407), preferably Tween 20, Tween 80 or poloxamer 188; optionally, the concentration of the surfactant in the replacement fluid is about 0.001-0.1% (w / v), for example, about 0.005-0.1% (w / v), about 0.01-0.08% (w / v), or about 0.02-0.06% (w / v); Optionally, the filler is selected from sugars and / or polyols, for example, selected from sucrose, lactose, trehalose, maltose, fructose, inulin oligosaccharides, glucose, maltodextrin, cyclodextrin, dextran, glycerol, mannitol, sorbitol, xylitol, maltitol and ethylene glycol; preferably, the sugar and / or polyol is selected from sucrose, trehalose, glucose, mannitol, sorbitol and xylitol, more preferably selected from sucrose, trehalose and mannitol, most preferably selected from sucrose and mannitol; for example, the filler comprises or is sucrose, or comprises or is a combination of sucrose and mannitol; optionally, the concentration of the filler in the replacement fluid can be about 1-40% (w / v), for example, about 2-30% (w / v), about 3-25% (w / v), about 4-20% (w / v), about 5-15% (w / v), or about 6-10% (w / v); Optionally, the vehicle is water or a physiologically acceptable solution.

5. A method according to any one of the preceding claims, wherein The replacement fluid comprises about 1-20% (w / v), about 1-15% (w / v), about 1-10% (w / v), about 2-8% (w / v), about 2-6% (w / v), such as about 4% (w / v) dextran; and / or The replacement fluid comprises about 0.01-0.1% (w / v) sodium carboxymethylcellulose, or about 0.4-5% (w / v), such as about 0.4-4% (w / v), about 0.4-3% (w / v), about 0.4-1.2% (w / v) methylcellulose; and / or The replacement fluid comprises about 0.001-0.1% (w / v), such as about 0.005-0.1% (w / v), about 0.01-0.08% (w / v), or about 0.02-0.06% (w / v), or about 0.04% (w / v) of Tween 20 or Tween 80, preferably Tween 80; and / or The replacement fluid contains about 5-15% (w / v), such as about 6-10% (w / v), such as about 8% (w / v) sucrose, or the replacement fluid contains about 2-10% (w / v) sucrose and about 1-6% (w / v) mannitol, about 4-8% (w / v) sucrose and about 1-4% (w / v) mannitol, or 6% (w / v) sucrose and about 2% (w / v) mannitol.

6. A method according to any one of the preceding claims, wherein The replacement fluid comprises about 1-20% (w / v) dextran, 0.01-0.1% (w / v) sodium carboxymethylcellulose, about 0.001-0.1% (w / v) Tween 20 or 80, and about 5-15% (w / v) sucrose; preferably, the replacement fluid comprises about 2-6% (w / v) dextran, 0.01-0.1% (w / v) sodium carboxymethylcellulose, about 0.02-0.06% (w / v) Tween 20 or 80, and about 6-10% (w / v) sucrose; more preferably, the replacement fluid comprises about 4% (w / v) dextran, 0.01-0.1% (w / v) sodium carboxymethylcellulose, about 0.04% (w / v) Tween 20 or 80, and about 8% (w / v) sucrose; or The replacement solution comprises about 1-20% (w / v) dextran, about 0.4-5% (w / v) methylcellulose, about 0.001-0.1% (w / v) Tween 20 or 80, about 2-10% (w / v) sucrose and about 1-6% (w / v) mannitol; preferably, the replacement solution comprises about 2-6% (w / v) dextran, about 0.4-4% (w / v) methylcellulose, about 0.02-0.06% (w / v) Tween 20 or 80, about 4-8% (w / v) sucrose and about 1-4% (w / v) mannitol; more preferably, the replacement fluid comprises about 4% (w / v) dextran, about 0.4-1.2% (w / v) methylcellulose, about 0.04% (w / v) Tween 20 or 80, about 6% (w / v) sucrose and about 2% (w / v) mannitol.

7. The method according to any one of the preceding claims, wherein in step (b), filling with different recipe settings in a production filling device comprises: (b1) selecting a high level and a low level of a recipe parameter, respectively, and determining the corresponding center point; optionally, the recipe parameter includes pump acceleration and backsuction, preferably includes pump acceleration, pump deceleration and backsuction, and more preferably includes pump acceleration, pump deceleration, backsuction acceleration and backsuction stroke; (b2) operating the filling equipment with different parameter recipes to obtain filling results for each of the parameter recipes, the filling results including filling accuracy and, optionally, whether obvious dripping, splashing, and foaming occur; the parameter recipes include the following F1 to F5: -F1: Pump acceleration, low level; Suction back, high level; -F2: Pump acceleration, center point; Suction back, center point; -F3: Pump acceleration, low level; Suction back, low level; -F4: Pump acceleration, high level; Suction back, low level; -F5: Pump acceleration, high level; Suction back, high level; Optionally, the parameter recipe includes the following F1 to F9: -F1: Pump acceleration, low level; Pump deceleration, high level; Suction back, high level; -F2: Pump acceleration, center point; Pump deceleration, center point; Suction back, center point; -F3: Pump acceleration, high level; Pump deceleration, high level; Suction back, low level; -F4: Pump acceleration, low level; Pump deceleration, low level; Suction back, low level; -F5: Pump acceleration, high level; Pump deceleration, low level; Suction back, high level; -F6: Pump acceleration, high level; Pump deceleration, low level; Suction back, low level; -F7: Pump acceleration, low level; Pump deceleration, low level; Suction back, high level; -F8: Pump acceleration, low level; Pump deceleration, high level; Suction back, low level; -F9: Pump acceleration, high level; Pump deceleration, high level; Suction back, high level; Optionally, the parameter recipe includes the following F1 to F9: -F1: Pump acceleration, high level; Pump deceleration, low level; Suction acceleration, high level; Suction stroke, low level; -F2: Pump acceleration, high level; Pump deceleration, high level; Suction acceleration, low level; Suction stroke, low level; -F3: Pump acceleration, low level; Pump deceleration, high level; Suction acceleration, low level; Suction stroke, high level; -F4: Pump acceleration, center point; Pump deceleration, center point; Suction acceleration, center point; Suction stroke, center point; -F5: Pump acceleration, low level; Pump deceleration, low level; Suction acceleration, high level; Suction stroke, high level; -F6: Pump acceleration, high level; Pump deceleration, low level; Suction acceleration, low level; Suction stroke, high level; -F7: Pump acceleration, low level; Pump deceleration, low level; Suction acceleration, low level; Suction stroke, low level; -F8: Pump acceleration, high level; Pump deceleration, high level; Suction acceleration, high level; Suction stroke, high level; -F9: Pump acceleration, low level; Pump deceleration, high level; Suction acceleration, high level; Suction stroke, low level; (b3) determining a filling equipment formulation for filling the pharmaceutical liquid for filling the biological agent based on the filling results obtained in step (b2), or adjusting the physical properties of the biological agent and optionally repeating steps (a) and (b).

8. A method according to any of the preceding claims, wherein in step (b1), the high level and the low level of the recipe parameter are set according to the filling equipment parameter gear; preferably, the high level and the low level of the recipe parameter are set to the upper limit and the lower limit of the acceptable gear range of the filling equipment parameter, respectively.

9. The method according to any one of the preceding claims, wherein in step (b3), based on the filling result obtained in step (b2), when the filling result is acceptable (i.e., the absolute value of the filling accuracy is ≤5%, preferably ≤3%, and optionally further, no obvious dripping, splashing and foaming are observed), the corresponding equipment formula is determined to be the equipment formula that can be used to fill the drug liquid; when the filling results of each formula obtained in step (b2) are all unacceptable, the physical properties of the biological preparation are adjusted (for example, the viscosity is reduced), and steps (a) and (b) are optionally repeated.

10. The method according to any of the preceding claims, wherein in step (b), the filling device is operated at maximum filling speed, and / or the filling device activates online weighing during operation to determine the filling accuracy, and / or the filling device runs at least 6 groups for each recipe.

11. The method according to any of the preceding claims, wherein in step (c), the recipe parameters include or are pump acceleration and suckback, preferably include or are pump acceleration, pump deceleration and suckback, and more preferably include or are pump acceleration, pump deceleration, suckback acceleration and suckback stroke.

12. The method according to any one of the preceding claims, wherein in step (c), the data fitting analysis is a JMP data fitting analysis; optionally, in step (c), the effect of each formulation parameter on filling accuracy is determined by data fitting analysis (e.g., JMP data analysis), such as determining which parameter(s) have a significant effect and determining the influence mode of the parameter(s) (factors); Optionally, the p-value of the factor calculated by data fitting analysis (e.g., JMP data analysis) is used to determine whether the effect of the factor is significant. When p≤0.05, the effect of the factor (parameter) is significant (serving as the main factor affecting accuracy). Optionally, through data fitting analysis, the precision value is set as the response, the response goal is to be minimized, and the prediction information is retrieved to confirm how the factor affects the response, that is, whether the larger the factor, the larger the response value, or the smaller the factor, the larger the response value.

13. The method according to any one of the preceding claims, wherein in step (c), the back-suction, preferably the back-suction acceleration, is determined to be the main accuracy influencing factor; further, the influence of the back-suction acceleration is determined in such a way that the greater the back-suction acceleration, the greater the accuracy value.

14. The method according to any one of the preceding claims, wherein in step (d), the equipment parameters of the filling equipment are set according to the main accuracy influencing factors and their influence patterns determined in step (c); optionally, when the main accuracy influencing factors affect the response (e.g., accuracy) in such a manner that the smaller the main accuracy influencing factors, the smaller the response, the filling equipment is operated at a low level of the recipe parameter serving as the main accuracy influencing factor, and vice versa, the filling equipment is operated at a high level; Optionally, in step (d), it is determined that suck-back acceleration is the main accuracy influencing factor and that its effect on response (eg, accuracy) is such that the smaller the suck-back acceleration, the smaller the response, and the filling apparatus is operated with a low level of suck-back acceleration.

15. The method according to any one of the preceding claims, wherein in step (d), whether the formulation is acceptable or desired is confirmed by the filling result of the drug liquid under the formulation; Preferably, when the filling result of the medicinal liquid under the formula is acceptable (for example, the absolute value of the filling accuracy is ≤5%, preferably ≤3%, and optionally further, no obvious dripping, splashing and foaming are observed), the corresponding formula is determined to be the optimized equipment formula that can be used to fill the medicinal liquid. More preferably, when the absolute value of the filling accuracy of the drug liquid under the formula is ≤5%, preferably ≤3% and the drug liquid does not show obvious dripping, splashing and foaming, the corresponding equipment formula is determined to be the optimized equipment formula that can be used to fill the drug liquid.

16. The method according to any of the preceding claims, wherein in step (d), the filling device is operated at maximum filling speed, and / or the filling device activates online weighing during operation to determine filling accuracy, and / or the filling device runs at least 6 sets for each recipe setting.

17. A method for guiding the preparation of a biological agent, the method comprising: (a) providing a replacement fluid with physical properties identical or similar to the pharmaceutical fluid used to fill the biological product; and (b) using the replacement liquid of step (a) as the filling liquid, filling at different recipe settings in a production filling device, and determining an acceptable or desired filling device recipe based on the filling results; wherein, in step (b), when the filling results are unacceptable under all formulation settings, the formulation of the biologic is adjusted to change the physical properties of the drug liquid used for filling the biologic, and then steps (a) and (b) are repeated one or more times until an acceptable filling result is obtained; Optionally, steps (a) and (b) are performed as described in any one of claims 2-10.

18. The method according to claim 17, wherein the changing of the physical properties of the drug liquid used for the filling of the biological preparation is to reduce the viscosity of the drug liquid, which can optionally be achieved by reducing the concentration of the bioactive molecule, reducing the amount of the viscosity regulator, or replacing it with another viscosity regulator with lower viscosity properties.

19. A method for determining the upper limit of production capacity of a production filling equipment, the method comprising: (i) providing a range of alternative fluids with different physical properties (e.g., viscosity, density and / or surface tension); (ii) using the replacement liquid of step (i) as the filling liquid, filling the filling liquids in the production filling equipment in sequence with different formula settings, and obtaining the filling results of each filling liquid under each formula setting; (iii) determining the upper limit of the physical properties of the biopharmaceutical liquid that can be filled using the production filling equipment based on the filling results obtained in step (ii); Optionally, the filling in step (ii) is carried out in a production filling device with different recipe settings as described in any one of claims 7 to 10 for step (b).

20. The method of claim 19, wherein the series of replacement fluids of step (i) have substantially the same density and surface tension and increasing viscosity; Optionally, the series of replacement fluids of step (i) all have a density of about 0.9-1.2 g / L, such as about 0.95-1.1 g / L, such as about 1 g / L, a surface tension of about 20-70 mN / m, such as about 30-60 mN / m, about 30-50 mN / m, about 35-45 mN / m or about 35-40 mN / m, and an increasing viscosity in the range of about 1-50 cp; Optionally, the replacement fluid is as defined in claim 4.

21. The method according to any one of claims 19-20, wherein the maximum viscosity of the substitute liquid that can obtain an acceptable filling result when filling in the production filling equipment is determined as the upper limit of the production capacity of the production filling equipment.

22. A replacement fluid having the same or similar physical characteristics (such as viscosity, density and / or surface tension) as the pharmaceutical liquid used for filling the biological preparation; optionally, the replacement fluid is defined in any one of claims 2 to 6.

23. Use of the substitution fluid according to claim 22 in the method according to any one of claims 1 to 21.

24. A solid replacement composition having the same composition as that obtained by removing a solvent such as water from the replacement liquid according to claim 22.

25. Use of the solid substitute composition according to claim 24 in the method according to any one of claims 1 to 21, wherein the solid substitute composition is dissolved in a solvent such as water to obtain a substitute solution, and then the method according to any one of claims 1 to 21 is carried out.

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