Method for preparing injectable pharmaceutical composition

Abstract

The present invention relates to methods for preparing injectable pharmaceutical compositions wherein the particles present in these compositions are detected and analyzed and the acceptance of these compositions is determined based on the physical and chemical properties of these particles and the associated toxicological and patient risk.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980031064.9, application date April 2, 2019, and invention name “Method for Preparing Injectable Pharmaceutical Compositions”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 661,929, filed April 24, 2018, which is hereby incorporated by reference. Technical Field

[0004] The present invention relates to a method for preparing an injectable pharmaceutical composition. In particular, the present invention relates to a method for detecting and analyzing particles in an injectable pharmaceutical composition and determining whether the composition is acceptable. Background Art

[0005] Injectable pharmaceutical compositions include solutions suitable for intravenous, intramuscular, and subcutaneous administration. The manufacturing methods used to prepare these compositions may introduce particles from external sources (e.g., manufacturing environment, equipment, and packaging) and / or internal sources (e.g., excipients used to prepare the compositions) into the compositions. Because particles may pose potential health risks to patients (e.g., injection site reactions), particle control strategies have been implemented in the manufacturing methods based on current regulatory expectations. These include implementing particle control methods to reduce particle contamination during manufacturing, and inspecting and analyzing the presence of particles in the injectable pharmaceutical compositions at the end of the manufacturing method.

[0006] Particle control methods include reducing particles from manufacturing equipment and the manufacturing environment. Inspection and quality control strategies have been developed and adopted in the art to ensure that injectable pharmaceutical compositions meet acceptable particle levels. Once injectable pharmaceutical compositions are manufactured, the presence of particles in these compositions will be inspected. Standards for acceptable particle levels have also been adopted in the art. For example, the United States Pharmacopeia recommends that when inspected under specific conditions, no more than a specific number of drug product units are observed as determined by a statically reasonable sampling plan. However, current particle control and inspection strategies do not take into account safety or toxicology information related to particles. There is a need to develop a particle control strategy that takes into account the impact of particles on patient safety. Summary of the invention

[0007] Provided herein are methods for preparing injectable pharmaceutical compositions by utilizing particle information (e.g., particle size and material composition of particles) historically detected in injectable compositions and corresponding toxicology and safety evaluations performed on patients. In one aspect, the invention disclosed herein comprises a method for preparing an injectable pharmaceutical composition comprising etanercept, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the material contained in the particles, and accepting the injectable pharmaceutical composition if the size and mass of the largest particle of the one or more particles are within a certain range disclosed herein. In one embodiment, the invention disclosed herein comprises a method of preparing an injectable pharmaceutical composition comprising etanercept, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the injectable pharmaceutical composition if the length (L) of the largest particle of the one or more particles is not greater than about 19,200 μm, the width (W) is not greater than about 2,939 μm, and the mass (M) is not greater than about 97,200 μg; and wherein the one or more particles comprise acrylic, aluminum, aliphatic hydrocarbons, carbon, borosilicate glass, wool, silk, polyester (PET), polyurethane, polyetherether, polytetrafluoroethylene (PTFE), polyoxymethylene (POM), polystyrene, silicon carbide, or stainless steel. Also disclosed herein are the size and mass ranges of the largest particles that can be found in an injectable etanercept composition comprising each of these substances. In one embodiment, the injectable pharmaceutical composition is suitable for subcutaneous administration.

[0008] On the other hand, the invention disclosed herein comprises a method for preparing an injectable pharmaceutical composition comprising darbepoetin, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the composition if the L of the largest particle in the one or more particles is not greater than about 4,530 μm, W is not greater than about 8,890 μm, and M is not greater than about 21,190 μg; and wherein the one or more particles comprise acrylate, aluminum, cellulose, epoxy resin, keratin, hydrated aluminum silicate, magnesium, magnesium silicate, nitrocellulose, polyurethane, polytetrafluoroethylene (PTFE), stainless steel, zinc, borosilicate glass, iron, phosphate-containing iron-rich nickel-rich substances, polyamide, polyethylene, polyvinyl chloride (PVC), or titanium. The size and mass range of the largest particles found in an injectable darbepoetin composition comprising each of these substances are also disclosed herein. In one embodiment, the injectable pharmaceutical composition comprising darbepoetin is suitable for intravenous or subcutaneous administration.

[0009] On the other hand, the invention disclosed herein comprises a method for preparing an injectable pharmaceutical composition comprising pegfilgrastim, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the composition if the L of the largest particle of the one or more particles is not greater than about 3,500 μm, W is not greater than about 430 μm, and M is not greater than about 5,100 μg; and wherein the one or more particles comprise aluminum, calcium carbonate, iron, polytetrafluorocarbon, poly(ethylacrylate), polystyrene, polysulfone, poly(isobutylene)-butyl rubber, rubber, silicate, silicone, or stainless steel. Also disclosed herein are the size and mass ranges of the largest particles found in an injectable pegfilgrastim composition comprising each of these substances. In one embodiment, the injectable pharmaceutical composition comprising pegfilgrastim is suitable for subcutaneous administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 Particles comprising an acrylic acid material in an injectable composition comprising etanercept are shown.

[0011] Figure 2 Shown are particles comprising charcoal in an injectable composition comprising etanercept.

[0012] Figure 3 Particles comprising borosilicate glass are shown in an injectable composition comprising etanercept.

[0013] Figure 4 Particles comprising acrylate are shown in an injectable composition comprising darbepoetin.

[0014] Figure 5 Particles comprising aluminum in an injectable composition comprising darbepoetin are shown.

[0015] Figure 6 Particles comprising calcium carbonate are shown in an injectable composition comprising pegfilgrastim.

[0016] Figure 7 Particles comprising polystyrene are shown in an injectable composition comprising pegfilgrastim.

[0017] Figure 8 Particles comprising iron are shown in an injectable composition comprising pegfilgrastim. DETAILED DESCRIPTION

[0018] Disclosed herein is a method for preparing an injectable pharmaceutical composition comprising an active ingredient, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the composition if the size and mass of the largest particle of the one or more particles are within a certain range. The method disclosed herein is based on data compiled from particles historically observed in injectable pharmaceutical compositions (their size, mass, and composition), as well as toxicological evaluations and medical opinions of these particles for patients. It has been found that if the size and mass of the particles are within a certain range, the potential risk of these particles to patients is low to negligible.

[0019] As used herein, the term "injectable pharmaceutical composition" refers to a formulation comprising a therapeutically active ingredient and suitable for injection into a patient (e.g., a human) in need thereof. In certain embodiments, an injectable pharmaceutical composition is a solution that is substantially sterile and does not contain any agent that is excessively toxic or infectious to the recipient. Examples of injectable pharmaceutical compositions include compositions suitable for subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac, intraarticular, and intracavernous administration.

[0020] The therapeutically active ingredients contained in the injectable pharmaceutical composition refer to substances that are biologically active and have an effect on diagnosing, curing, alleviating, treating or preventing diseases or on restoring, correcting or adjusting the physiological functions of patients. The therapeutically active ingredients include, but are not limited to: small molecule compounds, polypeptides, antibodies, antigen-binding fragments, chemically modified polypeptides, polypeptides conjugated to chemical moieties, and antibodies conjugated to chemical moieties. In some embodiments, the therapeutically active ingredients contained in the injectable pharmaceutical composition are polypeptides, chemically modified polypeptides, polypeptides conjugated to chemical moieties, antibodies and antigen-binding fragments, more specifically polypeptides, polypeptides conjugated to chemical moieties, or antibodies. In certain embodiments, the therapeutically active ingredients contained in the injectable pharmaceutical composition are etanercept, erythropoiesis stimulating proteins (e.g., erythropoietin and darbepoietin), or pegfilgrastim.

[0021] Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75-kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of Etanercept contains the CH2 domain, CH3 domain, and hinge region, but does not contain the CH1 domain of IgG1. When expressed in mammalian cells, Etanercept forms a homodimeric complex with the two domains of the TNF receptor. Therefore, it is an artificial protein that is different from antibodies and soluble TNF receptors and undergoes a different degradation pathway than the above two. Etanercept as (Amgen Inc., Thousand Oaks, Calif.) is commercially available and is approved for the treatment of moderately to severely active rheumatoid arthritis, moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients aged 2 years and older, chronic moderate to severe plaque psoriasis (PsO) in adults, psoriatic arthritis (PsA) in adults, and active ankylosing spondylitis (AS). Etanercept is commercially available in a lyophilized formulation for reconstitution immediately prior to injection or as a solution in a prefilled syringe or cartridge.

[0022] Erythropoietin (also referred to as EPO) is a glycoprotein that stimulates erythropoiesis. As used herein, erythropoietin includes human erythropoietin purified from natural sources (e.g., urine), human erythropoietin (rHuEPO) (e.g., U.S. Patent No. 4,667,016, which is hereby incorporated by reference) produced by recombinant DNA technology in eukaryotic host cells, and its analogs with biological activity. Suitable eukaryotic hosts include yeast (e.g., Saccharomyces cerevisiae) and mammals (e.g., Chinese hamster ovary (CHO)) cells. Depending on the host used, the EPO expression product may be glycosylated by mammals or other eukaryotic carbohydrates, or may also be non-glycosylated.

[0023] Human erythropoietin has 166 amino acid residues. Human urine-derived erythropoietin and recombinant erythropoietin (expressed in mammalian cells) both have amino acids 1-165 of the amino acid sequence of human erythropoietin and contain three N-linked oligosaccharide chains and one O-linked oligosaccharide chain. N-linked glycosylation occurs on asparagine residues at positions 24, 38, and 83, while O-linked glycosylation occurs on a serine residue at position 126.

[0024] EPO analogs useful in practicing the present invention include those having one or more amino acid additions, substitutions, and / or deletions compared to EPO or rHuEPO of natural origin. Particularly useful analogs include substitution analogs, such as those disclosed in U.S. Patent No. 7,217,689 (which is hereby incorporated by reference), which provide additional sites for glycosylation compared to erythropoietin or rHuEPO of natural origin.

[0025] In one embodiment, the EPO analog is darbepoetin produced in CHO cells by recombinant DNA technology. Darbepoetin contains amino acid residues 1-165 of human erythropoietin and five N-linked oligosaccharide chains with a molecular weight of approximately 37,000 Daltons. The two additional N-glycosylation sites on darbepoetin are derived from amino acid substitutions on the human erythropoietin polypeptide. Darbepoetin is commercially available from Amgen Inc., Thousand Oaks, Calif., and is formulated as a sterile, colorless, preservative-free solution for intravenous or subcutaneous administration. Darbepoetin is approved for the treatment of anemia caused by chronic kidney disease or by chemotherapy received by cancer patients.

[0026] Pegfilgrastim is a covalent conjugate of recombinant methionylfilgrastim and monomethoxypolyethylene glycol. Filgrastim is a 175 amino acid human granulocyte colony stimulating factor (G-CSF) produced in Escherichia coli by recombinant DNA technology. The amino acid sequence of filgrastim is identical to the 174 amino acids of human G-CSF, with the addition of an N-terminal methionine essential for expression. The molecular weight of filgrastim is approximately 19 kilodaltons (kD).

[0027] Pegfilgrastim is produced by covalently linking a 20 kD monomethoxypolyethylene glycol molecule to the N-terminal methionine residue of filgrastim (e.g., as disclosed in U.S. Pat. Nos. 5,824,784 and 8,258,262, which are incorporated herein in their entirety). The average molecular weight of pegfilgrastim is approximately 39 kD. ANTI-PROPYLENE® (Amgen Inc., Thousand Oaks, CA) is commercially available and is formulated as a sterile, clear, colorless, preservative-free solution in a prefilled syringe or a syringe for subcutaneous administration.

[0028] Pegfilgrastim is approved to reduce the incidence of infections (as manifested by febrile neutropenia) in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs (associated with a clinically significant incidence of febrile neutropenia) and to improve survival in patients acutely exposed to myelosuppressive radiation doses.

[0029] As used herein, the term "particle" refers to a mobile and insoluble substance present in an injectable pharmaceutical composition (e.g., an injectable solution). In general, the particle can be described by its physical and chemical properties. Physical properties include the size (e.g., length, width, and height) and mass of the particle, while chemical properties include the substance contained in the particle. Particles of 50 μm or larger size are visible to the human eye. The methods disclosed herein are generally applicable to the detection and analysis of particles of all sizes, particularly visible particles.

[0030] The particles present in the injectable pharmaceutical composition may come from a variety of sources, including external sources and internal sources. External sources include the manufacturing environment, manufacturing equipment and packaging materials. Internal sources include excipients used to prepare the injectable pharmaceutical composition. In addition, therapeutically active ingredients (e.g., polypeptides and antibodies) can aggregate and form particles. It should be understood that the methods disclosed herein are particularly suitable for preparing injectable pharmaceutical compositions, wherein the particles come from external and / or internal sources, rather than from the therapeutically active ingredients contained in the composition.

[0031] Non-limiting exemplary materials from external and internal sources (which may be included in the particles) include acrylic materials, acrylates, aluminum, aluminum silicate, aliphatic hydrocarbons, borosilicate glass, calcium carbonate, cellulose, charcoal, epoxy resins, iron, phosphate-containing iron-rich and nickel-rich materials, hydrated aluminum silicates, keratin, magnesium, magnesium silicate, natural protein fibers (wool and silk), nitrocellulose, polyester (PET), polyamide, polyetheretherketone, polyethylacrylate, polyethylene, poly(isobutylene-butyl) rubber, polyoxymethylene (POM), polystyrene, polysulfone, polytetrafluorocarbon, polytetrafluoroethylene (PTFE), polyurethane, polyvinyl chloride (PVC), rubber, silicates, silicon carbide, silicone, stainless steel, titanium, and zinc. The particles may contain any one of these materials or a combination of these materials.

[0032] The method disclosed herein is based on data and information collected from particles found during inspections in injectable pharmaceutical compositions in the past, and investigations and evaluations of the potential safety risks of these particles to patients based on the data and information. Specifically, the data and information include identification information of the particles, including the product, the observed particles, the chemical and physical properties of the largest particles identified (e.g., the substances contained in the largest particles, their size and mass), and optionally representative images of the particles. The identification information is used in conjunction with evaluation criteria (e.g., the route of administration of the product, the potential source of the particles, the patient population, toxicological assessments, and medical opinions) to evaluate the potential risks of the particles to patient safety.

[0033] The chemical and physical properties of the particles (e.g., size, mass, and substances contained in the particles) can be measured and / or calculated using various methods known to those of ordinary skill in the art. These methods will be described below. Toxicological assessment determines the safety impact on patients from a toxicological perspective and is based on the substances contained in the particles and the particle mass. The medical opinion assessment elements include the results of the toxicological assessment, product dosage, route of administration, impact on sterility assurance, and possible sources of particles to determine the potential impact of the particles on patient safety.

[0034] Based on investigations, assessments and evaluations, it has been found that particles having chemical and physical properties within certain parameters raise little toxicological concern and pose negligible safety risks when administered to patients. The presence of such particles in injectable pharmaceutical compositions is therefore considered acceptable. The invention disclosed herein utilizes the knowledge of potential patient safety risks associated with particles historically found in injectable pharmaceutical compositions to determine whether to accept the composition if particles are found in the injectable pharmaceutical composition at the time of inspection.

[0035] Thus, the invention disclosed herein provides a method for preparing an injectable pharmaceutical composition comprising a therapeutically active ingredient, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size and mass of the particles, and accepting the composition if the size (e.g., length (L), width (W), height (H), and mass (M)) of the largest particle of the one or more particles is within a certain range. In specific embodiments, the therapeutically active ingredient is etanercept, darbepoetin, or pegfilgrastim.

[0036] As used herein, the term "length (L)" refers to the longest dimension of a particle measured end to end. As used herein, the term "width (W)" refers to the second longest dimension of a particle measured end to end. As used herein, the term "height (H)" refers to the third longest dimension of a particle measured end to end. Mass is calculated based on the volume of the particle and the density of one or more substances contained in the particle. Methods for detecting the presence of particles in an injectable composition, measuring particle size, and calculating particle mass will be described below.

[0037] Injectable pharmaceutical composition comprising etanercept

[0038] In some embodiments, the injectable pharmaceutical composition comprises etanercept. In one embodiment, the particles that may be found in the etanercept composition comprise any of the following: acrylic, aluminum, aliphatic hydrocarbons, charcoal, borosilicate glass, natural protein fibers (wool and silk), polyester (PET), polyurethane, polyetheretherketone, polytetrafluoroethylene (PTFE), polyoxymethylene (POM), polystyrene, silicon carbide, and stainless steel. In one embodiment, the particles that may be found in the etanercept composition comprise any of acrylic, aluminum, aliphatic hydrocarbons, charcoal, borosilicate glass, charcoal, polyurethane, polytetrafluoroethylene (PTFE), silicon carbide, or stainless steel. In one embodiment, the particles that may be found in the etanercept composition comprise any of acrylic, charcoal, or borosilicate glass.

[0039] One or more particles may be found in an injectable etanercept composition. As long as the size (e.g., length, width) and mass of the largest particle of the one or more particles are within a certain range, the composition is acceptable. Exemplary sizes and masses of the largest particles acceptable in the etanercept composition include particles with L no greater than about 19,200 μm, W no greater than about 2,939 μm, and M no greater than about 39,300 μg; or particles with L no greater than about 6,154 μm, W no greater than about 2,454 μm, and M no greater than about 39,300 μg; or particles with L no greater than about 5,047 μm, W no greater than about 2,939 μm, and M no greater than about 97,200 μg; or particles with L no greater than about 1,200 μm, W no greater than about 2,939 μm, and M no greater than about 39,300 μg. L is not greater than about 700 μm, W is not greater than about 400 μm, and M is not greater than about 72 μg; or the L of the particle is not greater than about 257 μm, W is not greater than about 133 μm, and M is not greater than about 5.4 μg; or the L of the particle is not greater than about 176 μm, W is not greater than about 110 μm, and M is not greater than about 2.9 μg; or the L of the particle is not greater than about 420 μm, W is not greater than about 225 μm, and M is not greater than about 0.001 μg; or the L of the particle is not greater than about 131 μm, W is not greater than or particles having L no greater than about 19,200 μm, W no greater than about 50 μm, and M no greater than about 50 μg; or particles having L no greater than about 2,388 μm, W no greater than about 67 μm, and M no greater than about 14.7 μg; or particles having L no greater than about 359 μm, W no greater than about 306 μm, and M no greater than about 21 μg; or particles having L no greater than about 5,150 μm, W no greater than about 300 μm, and M no greater than about 2,330 μg; or particles with L no greater than about 700 μm, W no greater than about 250 μm, and M no greater than about 45.9 μg; or particles with L no greater than about 1,891 μm, W no greater than about 596.8 μm, and M no greater than about 1,010 μg; or particles with L no greater than about 359 μm, W no greater than about 306 μm, and M no greater than about 48.7 μg; or particles with L no greater than about 450 μm, W no greater than about 400 μm, and M no greater than about 72 μg.

[0040] In some embodiments, the invention disclosed herein comprises a method of preparing an injectable pharmaceutical composition comprising etanercept, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the injectable pharmaceutical composition if the L of the largest particle of the one or more particles is not greater than about 19,200 μm, W is not greater than about 2,939 μm, and M is not greater than about 97,200 μg; and the one or more particles comprise acrylic, aluminum, aliphatic hydrocarbons, charcoal, borosilicate glass, natural protein fibers (wool and silk), polyester (PET), polyurethane, polyetherether, polytetrafluoroethylene (PTFE), polyoxymethylene (POM), polystyrene, silicon carbide, or stainless steel. In some embodiments, the method comprises: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the injectable pharmaceutical composition if the largest particle of the one or more particles has an L of no greater than about 700 μm, a W of no greater than about 400 μm, and an M of no greater than about 72 μg; and the one or more particles comprise acrylic, aluminum, aliphatic hydrocarbons, carbon, polyurethane, polytetrafluoroethylene (PTFE), silicon carbide, or stainless steel. In some embodiments, the method comprises: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the injectable pharmaceutical composition if the largest particle of the one or more particles has an L of no greater than about 6,154 μm, a W of no greater than about 2,454 μm, and an M of no greater than about 39,300 μg; and wherein the one or more particles comprise polyetheretherketone, POM, or polystyrene.

[0041] In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 257 μm, a W of no greater than about 133 μm, and an M of no greater than about 5.4 μg; and the one or more particles comprise an acrylic material. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 5,047 μm, a W of no greater than about 2,939 μm, and an M of no greater than about 97,200 μg; and the one or more particles comprise borosilicate glass. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 176 μm, a W of no greater than about 110 μm, and an M of no greater than about 2.9 μg; and the one or more particles comprise charcoal. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 420 μm, a W of no greater than about 225 μm, and an M of no greater than about 0.001 μg; and the one or more particles comprise aluminum. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 131 μm, a W of no greater than about 64 μm, and an M of no greater than about 0.42 μg; and the one or more particles comprise an aliphatic hydrocarbon. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 19,200 μm, a W of no greater than about 50 μm, and an M of no greater than about 50 μg wool and no greater than about 50 μg silk; and the one or more particles comprise natural protein fibers (wool and silk). In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 2,388 μm, a W of no greater than about 67 μm, and an M of no greater than about 14.7 μg; and the one or more particles comprise polyester. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 359 μm, a W of no greater than about 306 μm, and an M of no greater than about 21 μg; and the one or more particles comprise polyurethane. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 5,150 μm, a W of no greater than about 300 μm, and an M of no greater than about 2,330 μg; and the one or more particles comprise polyetheretherketone.In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 700 μm, a W of no greater than about 250 μm, and an M of no greater than about 45.9 μg; and the one or more particles comprise PTFE. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 1,891 μm, a W of no greater than about 596.8 μm, and an M of no greater than about 1,010 μg; and the one or more particles comprise POM. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 6,154 μm, a W of no greater than about 2,454 μm, and an M of no greater than about 39,300 μg; and the one or more particles comprise polystyrene. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 359 μm, a W of no greater than about 306 μm, and an M of no greater than about 48.7 μg; and the one or more particles comprise silicon carbide. In some embodiments of the method, the injectable composition comprising etanercept is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 450 μm, a W of no greater than about 400 μm, and an M of no greater than about 72 μg; and the one or more particles comprise stainless steel.

[0042] As used herein, the term "about" should be understood to mean that there may be variations from a given value, including ranges of 5%, 10%, 15%, or 20% above and below the given value.

[0043] Particles containing different materials may have acceptable maximum particles of different sizes and mass ranges. For example, the L, W, and M of the acceptable maximum particles of acrylic acid materials that may be found in an etanercept composition may be no greater than about 257 μm, about 133 μm, and about 5.4 μg, respectively, while the L, W, and M of the acceptable maximum particles of charcoal that may be found in an etanercept composition may be no greater than about 176 μm, about 110 μm, and about 2.9 μg, respectively. Specific examples of the types of particles that may be found in an etanercept injectable composition, the size and mass of the acceptable maximum particles in each type, and the toxicological evaluation and medical opinion of the acceptable maximum particles in each type are shown in Example 1 below.

[0044] In some embodiments of the method, different particles of one or more particles identified in the composition comprising etanercept may comprise different types of materials, for example, some of the one or more particles comprise an acrylic material and some of the one or more particles comprise carbon; and the composition is acceptable if the L, W, and M of the largest particle of each type are within the ranges disclosed herein for that each type of particle (e.g., the largest acrylic material particle has L not greater than about 257 μm, W not greater than about 133 μm, and M not greater than about 5.4 μg, and the largest carbon particle has L not greater than about 176 μm, W not greater than about 110 μm, and M not greater than about 2.9 μg).

[0045] In one embodiment, the injectable pharmaceutical composition comprising etanercept is a lyophilized formulation that is reconstituted immediately prior to subcutaneous administration. In another embodiment, the injectable pharmaceutical composition comprising etanercept is a solution in a disposable vial, or a prefilled syringe or cartridge. In another embodiment, the injectable pharmaceutical composition comprising etanercept comprises a buffer. In another embodiment, the injectable pharmaceutical composition comprising etanercept is a buffer-free formulation.

[0046] Injectable pharmaceutical composition comprising darbepoetin

[0047] In some embodiments, the injectable pharmaceutical composition comprises darbepoetin. In one embodiment, the particles that can be found in the darbepoetin composition include any one of acrylate, aluminum, borosilicate glass, cellulose, epoxy resin, keratin, hydrated aluminum silicate, iron, phosphate-containing iron-rich nickel-rich material, magnesium, magnesium silicate, nitrocellulose, polyurethane, polytetrafluoroethylene (PTFE), polyamide, polyethylene, polyvinyl chloride (PVC), stainless steel, zinc, or titanium. In one embodiment, the particles that can be found in the darbepoetin composition include any one of acrylate, aluminum, cellulose, epoxy resin, keratin, hydrated aluminum silicate, magnesium, magnesium silicate, nitrocellulose, polyurethane, polytetrafluoroethylene (PTFE), iron, phosphate-containing iron-rich nickel-rich material, stainless steel, or zinc. In one embodiment, the particles that can be found in the darbepoetin composition include any one of acrylate, aluminum, cellulose, epoxy resin, hydrated aluminum silicate, magnesium, nitrocellulose, polytetrafluoroethylene (PTFE), iron, phosphate-containing iron-rich nickel-rich material, stainless steel, or zinc. In one embodiment, particles that may be found in darbepoetin compositions comprise any of acrylate, aluminum, or cellulose.

[0048] One or more particles may be found in an injectable darbepoetin composition. As long as the size (eg, length and width) and mass of the largest particle among the one or more particles are within a certain range, the composition is acceptable.Exemplary sizes and masses of the largest particles acceptable in the darbepoetin composition include particles with L no greater than about 4,530 μm, W no greater than about 8,890 μm, and M no greater than about 21,190 μg; or particles with L no greater than about 904 μm, W no greater than about 509 μm, and M no greater than about 398 μg; or particles with L no greater than about 836 μm, W no greater than about 390 μm, and M no greater than 64.2 μg; or particles with L no greater than about 775 μm, W no greater than about 184 μm, and M no greater than about 212 μg; or particles with L no greater than about 302 μm, W no greater than about 184 μm, and M no greater than 11 μg; or particles with L no greater than about 74 μm, W no greater than about 28 μm, and M is not greater than 0.14 μg; or the L of the particle is not greater than about 775 μm, W is not greater than about 43 μm, and M is not greater than 1.7 μg; or the L of the particle is not greater than about 442 μm, W is not greater than about 237 μm, and M is not greater than about 60 μg; or the L of the particle is not greater than about 2,304 μm, W is not greater than about 1,790 μm, and M is not greater than about 21,190 μg; or the L of the particle is not greater than about 904 μm, W is not greater than about 10 μm, H is not greater than 412 μm, and M is not greater than about 3 μg iron, not greater than about 19 μg nickel and not greater than about 6.6 μg phosphate; or the L of the particle is not greater than about 81 μm, W is not greater than about 44 μm, and M is not greater than about 212 μg; or the L of the particle is not greater than about 51 5μm, W is not greater than about 509μm, and M is not greater than about 357.8μg; or the L of the particle is not greater than about 74μm, W is not greater than about 28μm, and M is not greater than about 0.14μg; or the L of the particle is not greater than about 836μm, W is not greater than about 120μm, and M is not greater than about 1μg; or the L of the particle is not greater than about 681μm, W is not greater than about 390μm, and M is not greater than about 398μg; or the L of the particle is not greater than about 471μm, W is not greater than about 333μm, and M is not greater than about 64.2μg; or the L of the particle is not greater than about 1,331μm, W is not greater than about 293μm, and M is not greater than about 130μg; or the L of the particle is not greater than about 570μm, W is not greater than about 321μm, and M or particles having L no greater than about 4,530 μm, W no greater than about 8,890 μm, and M no greater than about 764 μg; or particles having L no greater than about 129 μm, W no greater than about 93 μm, and M no greater than about 2.4 μg; or particles having L no greater than about 1,265 μm, W no greater than about 322 μm, and M no greater than about 181 μg; or particles having L no greater than about 254 μm, W no greater than about 190 μm, and M no greater than about 72.9 μg; or particles having L no greater than about 1,331 μm, W no greater than about 174 μm, and M no greater than about 926 μg; or particles having L no greater than about 836 μm, W no greater than about 120 μm, and M no greater than about 4.3 μg.

[0049] In some embodiments, the invention disclosed herein comprises a method of preparing an injectable pharmaceutical composition comprising darbepoetin, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the injectable pharmaceutical composition if the L of the largest particle of the one or more particles is not greater than about 4,530 μm, W is not greater than about 8,890 μm, and M is not greater than about 21,190 μg; and the one or more particles comprise acrylate, aluminum, cellulose, epoxy resin, keratin, hydrated aluminum silicate, magnesium, magnesium silicate, nitrocellulose, polyurethane, polytetrafluoroethylene (PTFE), stainless steel, zinc, borosilicate glass, iron, phosphate-containing iron-rich and nickel-rich materials, polyamide, polyethylene, polyvinyl chloride (PVC), or titanium. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of the one or more particles is not greater than about 904 μm, W is not greater than about 509 μm, and M is not greater than about 398 μg; and the one or more particles comprise acrylate, aluminum, cellulose, epoxy resin, keratin, hydrated aluminum silicate, magnesium, magnesium silicate, nitrocellulose, polyurethane, polytetrafluoroethylene (PTFE), stainless steel, zinc, iron, or phosphate-containing iron-rich and nickel-rich substances. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of the one or more particles is not greater than about 836 μm, W is not greater than about 390 μm, and M is not greater than about 64.2 μg; and the one or more particles comprise acrylate, aluminum, cellulose, epoxy resin, magnesium, nitrocellulose, polytetrafluoroethylene (PTFE), stainless steel, iron, or zinc.

[0050] In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 302 μm, W is no greater than about 184 μm, and M is no greater than 11 μg; and the one or more particles comprise acrylate. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 74 μm, W is no greater than about 28 μm, and M is no greater than 0.14 μg; and the one or more particles comprise aluminum. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 479 μm, W is no greater than about 127 μm, and M is no greater than 11.6 μg; and the one or more particles comprise cellulose. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 442 μm, a W of no greater than about 237 μm, and an M of no greater than about 60 μg; and the one or more particles comprise an epoxy resin. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 2,034 μm, a W of no greater than about 1,790 μm, and an M of no greater than about 21,190 μg; and the one or more particles comprise borosilicate glass. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 904 μm, a W of no greater than about 10 μm, an H of no greater than about 412 μm, and M of no greater than about 3 μg iron, no greater than about 19.1 μg nickel, and no greater than about 6.6 μg phosphate; and the one or more particles comprise an iron-rich and nickel-rich material containing phosphate. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 81 μm, a W of no greater than about 44 μm, and M of no greater than about 212 μg; and the one or more particles comprise keratin. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 515 μm, a W of no greater than about 509 μm, and an M of no greater than about 357.8 μg; and the one or more particles comprise hydrated aluminum silicate. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 74 μm, a W of no greater than about 28 μm, and an M of no greater than about 0.05 μg; and the one or more particles comprise iron.In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 836 μm, W is no greater than about 120 μm, and M is no greater than about 1 μg; and the one or more particles comprise magnesium. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 681 μm, W is no greater than about 390 μm, and M is no greater than about 398 μg; and the one or more particles comprise magnesium silicate. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 471 μm, W is no greater than about 333 μm, and M is no greater than about 64.2 μg; and the one or more particles comprise nitrocellulose. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is not greater than about 1,331 μm, W is not greater than about 293 μm, and M is not greater than about 130 μg; and the one or more particles comprise polyamide. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is not greater than about 570 μm, W is not greater than about 321 μm, and M is not greater than about 130 μg; and the one or more particles comprise polyurethane. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is not greater than about 4,530 μm, W is not greater than about 8,890 μm, and M is not greater than about 764 μg; and the one or more particles comprise polyethylene. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 129 μm, W is no greater than about 93 μm, and M is no greater than about 2.4 μg; and the one or more particles comprise PTFE. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 1,265 μm, W is no greater than about 322 μm, and M is no greater than about 181 μg; and the one or more particles comprise PVC. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 254 μm, W is no greater than about 190 μm, and M is no greater than about 72.9 μg; and the one or more particles comprise stainless steel.In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 1,331 μm, a W of no greater than about 174 μm, and an M of no greater than about 926 μg; and the one or more particles comprise titanium. In some embodiments of the method, the injectable composition comprising darbepoetin is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 836 μm, a W of no greater than about 120 μm, and an M of no greater than about 4.3 μg; and the one or more particles comprise zinc.

[0051] Particles containing different materials may have acceptable maximum particles of different sizes and mass ranges. For example, the L, W, and M of the acceptable maximum particles containing acrylic acid materials that can be found in the darbepoetin composition can be no more than about 302 μm, about 184 μm, and about 11 μg, respectively, while the L, W, and M of the acceptable maximum particles containing cellulose that can be found in the darbepoetin composition can be no more than about 479 μm, about 127 μm, and about 11.6 μg, respectively. Specific examples of the types of particles that can be found in the darbepoetin composition, the size and mass of the acceptable maximum particles in each type, and the toxicological evaluation and medical opinion of the acceptable maximum particles in each type are shown in Example 2 below.

[0052] In some embodiments of the method, different particles of the one or more particles identified in the composition comprising darbepoetin may comprise different types of materials, e.g., some of the one or more particles comprise acrylate and some of the one or more particles comprise aluminum; and the composition is acceptable if the L, W, and M of the largest particle of each type are within the ranges disclosed herein for that each type of particle (e.g., the largest acrylate particle has L no greater than about 302 μm, W no greater than about 184 μm, and M no greater than 11 μg, and the largest aluminum particle has L no greater than about 74 μm, W no greater than about 28 μm, and M no greater than about 0.14 μg).

[0053] In one embodiment, the injectable pharmaceutical composition comprising darbepoetin is a solution for subcutaneous administration. In another embodiment, the injectable pharmaceutical composition comprising darbepoetin is a solution for intravenous administration. Injectable pharmaceutical composition comprising pegfilgrastim

[0054] In some embodiments, the injectable pharmaceutical composition comprises pegfilgrastim. In one embodiment, the particles that can be found in the pegfilgrastim composition comprise any of the following: aluminum silicate, calcium carbonate, iron, polytetrafluorocarbon and poly(ethyl acrylate), polystyrene, polysulfone, poly(isobutylene)-butyl rubber, rubber, silicate, silicone, or stainless steel. In one embodiment, the particles that can be found in the pegfilgrastim composition can comprise any of aluminum silicate, calcium carbonate, iron, polytetrafluorocarbon and poly(ethyl acrylate), polystyrene, polysulfone, poly(isobutylene)-butyl rubber, rubber, silicate, or silicone. In one embodiment, the particles that can be found in the pegfilgrastim composition comprise any of aluminum, calcium carbonate, or polystyrene.

[0055] One or more particles may be found in the injectable pegfilgrastim composition. As long as the size (eg, length and width) and mass of the largest particle among the one or more particles are within a certain range, the composition is acceptable. Exemplary sizes and masses of the largest particles acceptable in the pegfilgrastim composition include particles with L no greater than about 3,547 μm, W no greater than about 430 μm, and M no greater than about 5,160 μg; or particles with L no greater than about 931 μm, W no greater than about 319 μm, and M no greater than about 278 μg; or particles with L no greater than about 488 μm, W no greater than about 262 μm, and M no greater than about 35.5 μg; or particles with L no greater than about 931 μm, W no greater than about 319 μm, and M no greater than about 144 μg; or particles with L no greater than about 137 μm, W no greater than about 108 μm, and M no greater than about 3.5 μg; or particles with L no greater than about 137 μm, W no greater than about 108 μm, and M no greater than about 3.5 μg. m, and M is not greater than about 1.8 μg; or the L of the particle is not greater than about 209 μm, W is not greater than about 79 μm, and M is not greater than about 0.34 μg; or the L of the particle is not greater than about 209 μm, W is not greater than about 79 μm, and M is not greater than about 1.1 μg; or the L of the particle is not greater than about 488 μm, W is not greater than about 262 μm, and M is not greater than about 35.5 μg; or the L of the particle is not greater than about 122 μm, W is not greater than about 105 μm, and M is not greater than about 1.7 μg; or the L of the particle is not greater than about 486 μm, W is not greater than about 312 μm, and M is not greater than about 54.5 μg; or the L of the particle is not greater than about 978 μm, W is not greater than about 166 μm, and M is not greater than about 1,246.6 μg.

[0056] In some embodiments, the invention disclosed herein comprises a method of preparing an injectable pharmaceutical composition comprising pegfilgrastim, the method comprising: detecting the presence of one or more particles in the composition, analyzing the size of the particles and the substances contained in the particles, and accepting the injectable pharmaceutical composition if the largest particle of the one or more particles has an L of no greater than about 3,547 μm, a W of no greater than about 430 μm, and an M of no greater than about 5,160 μg; and the one or more particles comprise aluminum, calcium carbonate, iron, polytetrafluorocarbon and poly(ethylacrylate), polystyrene, polysulfone, poly(isobutylene)-butyl rubber, rubber, silicate, silicone, or stainless steel. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 930 μm, a W of no greater than about 320 μm, and an M of no greater than about 280 μg; and the one or more particles comprise aluminum, calcium carbonate, iron, polytetrafluorocarbon and poly(ethylacrylate), polystyrene, polysulfone, poly(isobutylene)-butyl rubber, rubber, silicate, or silicone.

[0057] In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 209 μm, a W of no greater than about 79 μm, and an M of no greater than about 0.34 μg; and the one or more particles comprise aluminum silicate. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 931 μm, a W of no greater than about 319 μm, and an M of no greater than about 278 μg; and the one or more particles comprise calcium carbonate. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 3,547 μm, a W of no greater than about 430 μm, and an M of no greater than about 5,160 μg; and the one or more particles comprise iron. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 137 μm, a W of no greater than about 108 μm, and M of no greater than about 3.5 μg polytetrafluorocarbon and no greater than about 1.8 μg poly(ethylacrylate); and the one or more particles comprise polytetrafluorocarbon and poly(ethylacrylate). In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 488 μm, a W of no greater than about 262 μm, and M of no greater than about 35.5 μg; and the one or more particles comprise polystyrene. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 122 μm, a W of no greater than about 105 μm, and M of no greater than about 1.7 μg; and the one or more particles comprise polysulfone. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 209 μm, W is no greater than about 79 μm, and M is no greater than about 1.1 μg; and the one or more particles comprise poly(isobutylene)-butyl rubber. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 931 μm, W is no greater than about 319.4 μm, and M is no greater than about 144 μg; and the one or more particles comprise rubber. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the L of the largest particle of one or more particles found in the composition is no greater than about 931 μm, W is no greater than about 319 μm, and M is no greater than about 144 μg; and the one or more particles comprise silicate.In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 486 μm, a W of no greater than about 312 μm, and an M of no greater than about 54.5 μg; and the one or more particles comprise silicone. In some embodiments of the method, the injectable composition comprising pegfilgrastim is acceptable if the largest particle of one or more particles found in the composition has an L of no greater than about 978 μm, a W of no greater than about 166 μm, and an M of no greater than about 1246.6 μg; and the one or more particles comprise stainless steel.

[0058] Particles containing different materials may have acceptable maximum particles of different sizes and mass ranges. For example, the L, W and M of the acceptable maximum particles containing calcium carbonate that can be found in the pegfilgrastim composition can be no more than about 931 μm, about 319 μm and about 278 μg, respectively, while the L, W and M of the acceptable maximum particles containing iron that can be found in the pegfilgrastim composition can be no more than about 3,547 μm, about 430 μm and about 5,160 μg, respectively. Specific examples of the types of particles that can be found in the pegfilgrastim composition, the size and mass of the acceptable maximum particles in each type, and the toxicological evaluation and medical opinion of the acceptable maximum particles in each type are shown in Example 3 below. In one embodiment, the injectable pharmaceutical composition containing pegfilgrastim is a solution for subcutaneous administration.

[0059] In some embodiments of the method, different particles of the one or more particles identified in the composition comprising pegfilgrastim may comprise different types of materials, e.g., some of the one or more particles comprise aluminum silicate and some of the one or more particles comprise calcium carbonate; and the composition is acceptable if the L, W, and M of the largest particle of each type are within the ranges disclosed herein for that each type of particle (e.g., the largest aluminum silicate particle has L not greater than about 209 μm, W not greater than about 79 μm, and M not greater than 0.3 μg, and the largest calcium carbonate particle has L not greater than about 931 μm, W not greater than about 319 μm, and M not greater than about 278 μg).

[0060] Injectable pharmaceutical compositions can be prepared by methods known in the art and established. For example, the polypeptide or antibody contained in the injectable pharmaceutical composition can be synthesized by techniques known in the art, including recombinant techniques, peptide synthesis, separation from endogenous sources of protein, or a combination thereof. In one embodiment, the polypeptide or antibody is synthesized by recombinant techniques, which are included in prokaryotic cells (e.g., Escherichia coli) or eukaryotic cells (e.g., CHO) for expression. Various purification steps are then used to purify polypeptides or antibodies from a heterogeneous protein mixture, which purification steps include one or more of the following: a viral inactivation step, a plurality of chromatography and filtration steps, including affinity chromatography, cation exchange chromatography, anion exchange chromatography, hydrophobic interaction chromatography, multivariate chromatography, hydroxyapatite chromatography, ultrafiltration and diafiltration, single tangential flow filtration (SPTFF) and deep filtration, to remove impurities such as host cell proteins. The purified polypeptide or antibody is formulated with a suitable excipient to prepare a final formulation, and then filled into a suitable container (e.g., vial, ampoule, syringe or autoinjector) for inspection and analysis of particles. Method for detecting particles in injectable pharmaceutical compositions

[0061] Particles in an injectable pharmaceutical composition can be detected or identified by methods known and established in the art, including manual methods and automated methods. In one embodiment, particles in an injectable pharmaceutical composition are detected or identified by manual inspection of the injectable composition. USP <790> (which is incorporated herein by reference) specifically specifies the conditions for manual inspection. If the composition is stored in a temperature-controlled environment, it is kept at room temperature until the outer surface of the container containing the composition becomes clear and non-condensing, and then the inspection is started. Before inspection, dust and / or stains are removed from the outer surface of the container using a suitable wipe (e.g., a low-particle wipe dried or moistened with 70% isopropyl alcohol). In particular, in manual inspection, the injectable pharmaceutical composition is inspected at a light intensity of 2,000 to 3,750 lux. In one embodiment, the light intensity used for inspection is between 3,500 and 3,750 lux. This can be achieved by using two 13-W or 15-W fluorescent lamps (e.g., F13 / T5 or F15 / T8). Other light sources (e.g., incandescent lamps, LEDs) can also be used, provided that they can provide illumination of a specific intensity range at the inspection point. The sample is then inspected against a black background and a white background without magnification, for at least five (5) seconds on each background. During the inspection process, the sample can be inverted and / or vortexed slowly (to avoid the creation of air bubbles) and the presence of particles observed in each background.

[0062] In one embodiment, a semi-automatic method or an automatic method (e.g., a commercially available semi-automatic system or automatic system for identifying particles in a pharmaceutical composition) is used to detect or identify particles in an injectable pharmaceutical composition. Semi-automatic inspection systems that can be used to detect particles in an injectable pharmaceutical composition include Seidenader semi-automatic inspection machines. Automatic systems that can be used for this purpose include Seidenader De- / Re-Nester DE.SY.RE, Seidenader VI series, Seidenader MS series, Seidenader ES series, Seidenader CS series, and Seidenader MS-S / VI-S series machines. Other instruments or devices that can be used to detect particles in an injectable pharmaceutical composition include particle counting systems, such as APSS200 particle counting systems (e.g., LiQuilaz particle counters), ParticleScope TM Particle measurement system (Phoenix Imaging, Ltd.), and Coulter sizer (Multisizer 3 Coulter sizer from Beckman Coulter Life Sciences).

[0063] Particle characterization

[0064] Once the particles from statistical sampling are identified in the injectable composition and confirmed to exist, the method established and known in the art is used to characterize them to determine their physical and chemical properties. Microscopic tools (such as high-power microscopes and scanning electron microscopes (SEM)) can be used to characterize the physical properties (e.g., L, W and H) of the particles. Specifically, the particles are removed or separated from the injectable composition using a clean probe, or filtered onto a filter, and then observed with the naked eye using a high-power microscope or SEM connected to a computer equipped with a suitable software package. Microscopes are used to obtain particle images, and software packages are used to measure particle size. Typically, the longest dimension of the particle end-to-end is designated as length, the second longest dimension of the particle end-to-end is designated as width, and the third longest dimension of the particle end-to-end is designated as height. The size measurement of the report particle is together with the image.

[0065] The chemical properties of the particles (e.g., the substances contained in the particles) are usually characterized using various spectral analysis methods (which provide characteristic spectra reflecting one or more substances contained in the particles). This characteristic spectrum is then compared with a spectral library of known substances to determine the properties of the one or more substances contained in the particles. Non-limiting spectral analysis methods that can be used to characterize the chemical properties of the particles include SEM, Fourier transform infrared spectroscopy (FTIR), Raman imaging, and laser induced breakdown spectroscopy (LIBS). Standard spectral libraries of known substances and algorithm software for comparing and identifying substances contained in particles are readily available in the art (e.g., provided by spectral machine manufacturers or third-party software suppliers).

[0066] By way of illustration, to identify the chemical composition of particles found in an injectable pharmaceutical composition, the particles are analyzed using a spectroscopic method (e.g., FTIR) to generate a characteristic spectrum reflecting the substances contained in the particles. This characteristic spectrum is then compared to a library of FTIR spectra of known substances and found to match the spectrum of cellulose. Based on the match, the particles are identified as containing cellulose.

[0067] Calculation of particle mass

[0068] The mass of the particle is calculated based on the physical and chemical properties of the particle. Specifically, the mass of the particle is calculated based on the volume of the particle and the density of one or more substances contained in the particle. The volume of the particle is calculated based on the size of the particle. Because the shape of the particles is usually irregular, a worst-case geometry is assumed when calculating the volume of the particle. Specifically, if the particle is identified as having a fibrous morphology, a right circular cylinder is assumed as the worst-case geometry. The volume of the particle is calculated using the following formula: Volume (V) = (3.1416) x (d / 2) 2 xh, where "h" is equivalent to the particle length (L), "d" is equivalent to the particle width (W), and "V" is expressed in cubic micrometers (μm 3 )express.

[0069] If the particle is identified as having a non-fibrous morphology (e.g., residue, flat particle, or isodiameter particle), a cube or rectangular prism is assumed as the worst-case geometry. The volume of the particle is calculated using the following formula: Volume (V) = Length (L) x Width (W) x Height (H), where the height is equivalent to W if H is not available, and "V" is expressed in cubic micrometers (μm 3 )express.

[0070] If the particle is identified as a cone, the volume of the particle is calculated using the following formula: Volume (V) = (3.1416) x (r) 2xh / 3, where "r" is equal to half the particle width, "h" is equal to the particle length, and "V" is expressed in cubic micrometers (μm 3 )express.

[0071] The mass of a particle can be calculated by converting cubic micrometers to cubic centimeters: 1x 10 -12 cm 3 =1μm 3 .

[0072] Density values ​​for various substances are known in the art and can be found in scientific sources. Sources providing density values ​​for substances include: Polymer Handbook (Brandrup J. et al., ed., 1999), CRC Handbook of Chemistry and Physics (e.g., Internet version 2005, available from hbcponline), and Hazardous Substance Database (HSDB) from the US National Library of Medicine. Table 1 below lists density values ​​for exemplary substances that may be found in the injectable pharmaceutical compositions disclosed herein.

[0073] Table 1. Density of exemplary substances

[0074]

[0075]

[0076] The mass of a particle is calculated using the following formula: Mass (M) = V x D, where "V" is the volume of the particle and "D" is the density of the substance contained in the particle. If a particle is identified as containing a single substance, the particle is considered to be composed of 100% of the identified substance, and the mass is calculated using the density of that substance. If a particle is identified as containing multiple substances, the particle is considered to be composed of 100% of each identified substance, and the mass is calculated using the density of each substance. If a particle is identified as multiple fragments of a single substance, the mass is the sum of the masses of each fragment, where the mass of each fragment is calculated using the volume of the fragment and the density of the substance.

[0077] The methods disclosed herein can be used to inspect or detect the presence of one or more particles in an injectable pharmaceutical composition, analyze the size and the material contained in the particles, calculate the mass of the particles, and accept the composition if the size and mass of the largest particle of the one or more particles are within the ranges disclosed herein.

[0078] The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention.

[0079] Examples

[0080] Example 1. Compilation of particles historically detected in injectable compositions containing etanercept

[0081] Table 2 below lists the largest particles detected in the visual inspection of the injectable pharmaceutical composition containing etanercept, their physical and chemical characteristics (e.g., size, material composition, mass), and toxicological evaluation and medical opinion on the particles. As shown in the table, it can be concluded that each of these particles, when administered to patients, raises little toxicological concern and poses a negligible safety risk. An etanercept composition containing one or more particles is acceptable provided that the size and mass of the largest particle of each type of the one or more particles is no greater than about the size and mass of the corresponding largest particle shown in Table 2.

[0082] Table 2. Largest particles identified in injectable compositions containing etanercept

[0083]

[0084]

[0085] Example 2. Compilation of particles historically detected in injectable compositions containing darbepoetin

[0086] Table 3 below lists the largest particles detected in the visual inspection of the injectable pharmaceutical composition containing darbepoetin, their physical and chemical characteristics (e.g., size, material composition, mass), and toxicological evaluation and medical opinion on the particles. As shown in the table, it can be concluded that each of these particles, when administered to a patient, raises little toxicological concern and poses a negligible safety risk. Darbepoetin compositions containing one or more particles are acceptable provided that the size and mass of the largest particle of each type of the one or more particles is not greater than about the size and mass of the corresponding largest particle in Table 3.

[0087] Table 3. Largest particles identified in injectable compositions containing darbepoetin

[0088]

[0089]

[0090]

[0091] Example 3. Compilation of particles historically detected in injectable compositions containing pegfilgrastim

[0092] Table 4 below lists the largest particles detected in the visual inspection of the injectable pharmaceutical composition containing pegfilgrastim, their physical and chemical characteristics (e.g., size, material composition, mass), and toxicological evaluation and medical opinion on the particles. As shown in the table, it can be concluded that each of these particles, when administered to a patient, raises little toxicological concern and poses a negligible safety risk. The pegfilgrastim composition containing one or more particles is acceptable provided that the size and mass of the largest particle of each type of the one or more particles is not greater than about the size and mass of the corresponding largest particle in Table 4.

[0093] Table 4. Largest particles identified in injectable pharmaceutical compositions containing pegfilgrastim

[0094]

[0095]

[0096] Example 4. Identification and Characterization of Particles Detected in Injectable Pharmaceutical Compositions Containing Etanercept

[0097] Using the manual inspection method disclosed herein, particles in an injectable composition containing etanercept in a syringe were identified. The physical and chemical properties of the particles in the syringe were investigated and analyzed. The particles were imaged, measured, and identified as acrylic material. The dimensions of the particles were found to be as follows: a) length (L) = 200 μm, and b) width (W) = 100 μm. To calculate the volume of the particle, the worst-case geometry of the particle was assumed to be a rectangular prism. Because no information was obtained on the height of the particle, its third dimension was considered to be equivalent to its width: height (H) = 100 μm.

[0098] Therefore, the volume of the particle is calculated using the following formula: Volume (V) = L x W x H, i.e. 200 μm x 100 μm x 100 μm = 2 x 10 6 μm 3 =2x 10 -6 cm 3 Since the density of acrylic acid (d) is 1.2 g / cm 3 , so the mass of the particle is calculated as mass (M) = V xd = 2 x 10 -6 cm 3 x 1.2g / cm 3 =2.4μg.

[0099] Table 2 above indicates that for the acrylic material particles found in the injectable pharmaceutical composition containing etanercept, the size of the largest particle was L: 257 μm and W: 133 μm, and the calculated mass was 5.4 μg. In addition, this largest particle is considered to not cause toxicological concerns, and its risk to patients is very low. Because the size and mass of the particles identified in this case are smaller than the size and mass of the largest acrylic material particles, the overall risk to patients is considered low. Therefore, the etanercept composition in the syringe is considered acceptable.

Claims

1. A method for preparing an injectable pharmaceutical composition comprising darbepoetin, the method comprising: detecting the presence of one or more particles in the composition, Analyze the size of these particles and the substances contained in these particles, and If the largest particle of the one or more particles has L no greater than about 4,530 μm, W no greater than about 8,890 μm, and M no greater than about 21,190 μg, then the injectable pharmaceutical composition is accepted, The one or more particles comprise acrylate, aluminum, cellulose, epoxy resin, keratin, hydrated aluminum silicate, magnesium, magnesium silicate, nitrocellulose, polyurethane, polytetrafluoroethylene (PTFE), stainless steel, zinc, borosilicate glass, iron, phosphate-containing iron-rich and nickel-rich materials, polyamide, polyethylene, polyvinyl chloride (PVC), or titanium.

2. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 302 μm, a W of no greater than about 184 μm, and an M of no greater than 11 μg, and the one or more particles comprise an acrylate.

3. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 74 μm, a W of no greater than about 28 μm, and an M of no greater than about 0.14 μg, and the one or more particles comprise aluminum.

4. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 479 μm, a W of no greater than about 127 μm, and an M of no greater than about 11.6 μg, and the one or more particles comprise cellulose.

5. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 442 μm, a W of no greater than about 237 μm, and an M of no greater than about 60 μg, and the one or more particles comprise an epoxy resin.

6. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 2,034 μm, W no greater than about 1,790 μm, and M no greater than about 21,190 μg, and the one or more particles comprise borosilicate glass.

7. The method of claim 1, wherein the L of the largest particle of the one or more particles is not greater than about 904 μm, W is not greater than about 10 μm, H is not greater than about 412 μm, and M is not greater than about 3 μg iron, not greater than about 19.1 μg nickel, and not greater than about 6.6 μg phosphate, and the one or more particles comprise an iron-rich and nickel-rich material containing phosphate.

8. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 81 μm, a W of no greater than about 44 μm, and an M of no greater than about 212 μg, and the one or more particles comprise keratin.

9. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 515 μm, a W of no greater than about 509 μm, and an M of no greater than about 357.8 μg, and the one or more particles comprise hydrated aluminum silicate.

10. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 836 μm, W no greater than about 120 μm, and M no greater than about 1 μg, and the one or more particles comprise magnesium.

11. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 681 μm, W no greater than about 390 μm, and M no greater than about 398 μg, and the one or more particles comprise magnesium silicate.

12. The method of claim 1, wherein the largest particle of the one or more particles has an L of no greater than about 471 μm, a W of no greater than about 333 μm, and an M of no greater than about 64.2 μg, and the one or more particles comprise nitrocellulose.

13. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 1,331 μm, W no greater than about 293 μm, and M no greater than about 130 μg, and the one or more particles comprise polyamide.

14. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 570 μm, W no greater than about 321 μm, and M no greater than about 130 μg, and the one or more particles comprise polyurethane.

15. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 4,530 μm, W no greater than about 8,890 μm, and M no greater than about 764 μg, and the one or more particles comprise polyethylene.

16. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 129 μm, W no greater than about 93 μm, and M no greater than about 2.4 μg, and the one or more particles comprise PTFE.

17. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 1,265 μm, W no greater than about 322 μm, and M no greater than about 181 μg, and the one or more particles comprise PVC.

18. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 254 μm, W no greater than about 190 μm, and M no greater than about 72.9 μg, and the one or more particles comprise stainless steel.

19. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 1,331 μm, W no greater than about 174 μm, and M no greater than about 926 μg, and the one or more particles comprise titanium.

20. The method of claim 1, wherein the largest particle of the one or more particles has L no greater than about 836 μm, W no greater than about 120 μm, and M no greater than about 4.3 μg, and the one or more particles comprise zinc.

21. The method of claim 1, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration.

22. A method for preparing an injectable pharmaceutical composition comprising pegfilgrastim, the method comprising: detecting the presence of one or more particles in the composition, Analyze the size of these particles and the substances contained in these particles, and If the largest particle of the one or more particles has L no greater than about 3,500 μm, W no greater than about 430 μm, and M no greater than about 5,100 μg, the composition is accepted, Wherein the one or more particles comprise aluminum, calcium carbonate, iron, polytetrafluorocarbon, poly(ethyl acrylate), polystyrene, polysulfone, poly(isobutylene)-butyl rubber, rubber, silicate, silicone, or stainless steel.

23. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 209 μm, W no greater than about 79 μm, and M no greater than about 0.34 μg, and the one or more particles comprise aluminum silicate.

24. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 931 μm, W no greater than about 319 μm, and M no greater than about 278 μg, and the one or more particles comprise calcium carbonate.

25. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 3,547 μm, W no greater than about 430 μm, and M no greater than about 5,160 μg, and the one or more particles comprise iron.

26. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 137 μm, W no greater than about 108 μm, and M no greater than about 3.5 μg polytetrafluorocarbon and no greater than about 1.8 μg poly(ethyl acrylate), and the one or more particles comprise polytetrafluorocarbon and poly(ethyl acrylate).

27. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 488 μm, W no greater than about 262 μm, and M no greater than about 35.5 μg, and the one or more particles comprise polystyrene.

28. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 122 μm, W no greater than about 105 μm, and M no greater than about 1.7 μg, and the one or more particles comprise polysulfone.

29. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 209 μm, W no greater than about 79 μm, and M no greater than about 1.1 μg, and the one or more particles comprise poly(isobutylene)-butyl rubber.

30. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 931 μm, W no greater than about 319.4 μm, and M no greater than about 144 μg, and the one or more particles comprise rubber.

31. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 931 μm, W no greater than about 319 μm, and M no greater than about 144 μg, and the one or more particles comprise silicate.

32. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 486 μm, W no greater than about 312 μm, and M no greater than about 54.5 μg, and the one or more particles comprise silicone.

33. The method of claim 22, wherein the largest particle of the one or more particles has L no greater than about 978 μm, W no greater than about 166 μm, and M no greater than about 1246.6 μg, and the one or more particles comprise stainless steel.

34. The method of claim 22, wherein the composition is suitable for subcutaneous administration.

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