EP4665763A1

EP4665763A1 - Stable protein compositions of anti-pd1 antibody

Info

Publication number: EP4665763A1
Application number: EP24706511.3A
Authority: EP
Inventors: Bhavik Kumar SHAH; Manish Sharma; Viralkumar Vinodlal JOGANI; Ajay Jaysingh Khopade; Ravishankara Madavati NAGARAJA; Pankaj Singh Chouhan
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2023-02-16
Filing date: 2024-02-14
Publication date: 2025-12-24
Also published as: WO2024171082A1; AU2024221025A1; IL322410A; MX2025009448A

Abstract

The invention relates to stable compositions of an antibody against human programmed death receptor PD-1, or antigen binding fragments thereof. The invention further provides methods for treating various cancers with stable formulations of the invention. The present invention relates to pharmaceutical compositions of an anti-PD1 antibody comprising a buffer, a sugar or sugar alcohol and a surfactant. In some embodiments of the invention, the formulations may be administered to a subject by intravenous or subcutaneous administration.

Description

STABLE PROTEIN COMPOSITIONS OF ANTI-PD1 ANTIBODY FIELD OF THE INVENTION [0001] The present invention relates generally to the preparation of a stable anti-PD1 antibody compositions and its application in a medicine. The present invention relates to a pharmaceutical composition comprising of an anti-PD1 antibody, a buffer, a sugar or sugar alcohol and a surfactant. BACKGROUND OF THE INVENTION [0002] Programmed cell death protein 1 (PD-1) is a 288 amino acid, cell surface molecule that has been designated as a membrane protein of the immunoglobulin superfamily in humans. This protein is expressed on T cells, pro-B cells, and myeloid-derived dendritic cells, leading to negative regulation of the proliferation and activity of these cells (Yamane, Hiromichi et al. American journal of cancer research vol.5,41553-7.15 Mar.2015). [0003] Several anti PD1 and PDL1 antibodies targeting either PD-1 or PD-L1 have been approved and marketed. There are published documents that disclose anti PD1 formulations, for example: [0004] US9220776B2 and its equivalent families discloses liquid and lyophilized formulations of pembrolizumab comprising a histidine buffer, polysorbate 80 and sucrose; [0005] WO2021123202A1 discloses liquid pharmaceutical compositions comprising: an anti- human PD1 antibody, trehalose or a sugar alcohol; a non-ionic surfactant; and histidine buffer; [0006] US10786567B2 and its equivalent families discloses formulations of an anti-PD1 antibody containing sodium acetate, α,α-trehalose dihydrate and polysorbate 20, pH 5.2; [0007] WO 2018/028383 A1 describes a pharmaceutical formulation comprising an anti-PD1 antibody, citrate, histidine, mannitol, sodium chloride, edetate and polysorbate 20 or polysorbate 80, with a pH 5.5 to 6.5; [0008] WO 2018/187057 A1 discloses a pharmaceutical composition comprising an anti-PD1 antibody, histidine, sucrose, proline and polysorbate 80, with a pH 6.0; [0009] WO 2018/204368 A1 describes formulations of an anti-PD1 antibody comprising a buffer, a stabilizer, a non-ionic surfactant and an anti-oxidant; 1 [0010] WO 2019/142149 discloses a pharmaceutical composition comprising an anti-PD1 antibody, histidine, sucrose, polysorbate 20 and EDTA, with a pH 6.5; and [0011] WO 2019/171253 A1 describes a pharmaceutical composition comprising an anti-PD1 antibody, a disaccharide, a buffer, a chelating agent and a polysorbate, with a pH 4.5 to 5.5. [0012] The present inventors have conducted intensive studies in an effort to solve an unmet need for a stable composition of anti-PD1 antibodies and found that a combination of a buffer, a sugar or sugar alcohol and a surfactant in the correct proportions unexpectedly result in a composition that is stable and convenient for clinical use. SUMMARY OF THE INVENTION [0013] One object of the present invention is to provide a stable anti-PD-1 antibody composition. [0014] Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar, for example, a non-reducing sugar; (c) a buffer; and (d) a non-ionic surfactant. [0015] Yet another object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the antiPD1 antibody is at a concentration in the range of about 5 mg/mL to about 30 mg/mL. [0016] Still yet another object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the non-reducing sugar is sucrose, trehalose or mannitol, preferably trehalose, more preferably α,α-trehalose dihydrate. [0017] Yet another object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the buffer comprises a citrate, L-Histidine, DiSodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Glacial acetic acid, Citric acid monohydrate and/or adipic acid, preferably L-Histidine, L-Histidine HCl monohydrate, and/or Succinic Acid. One object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the non-ionic surfactant is Sodium Chloride, Edetate disodium 2 dehydrate, Polysorbate 20, Polysorbate 80 or Poloxamer 188, preferably, Edetate disodium dihydrate or Polysorbate 80. [0018] One object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the anti-PD-1 antibody is Nivolumab or Pembrolizumab, preferably Pembrolizumab. [0019] Another object of the present invention is to provide a stable liquid pharmaceutical composition wherein the sugar is present at a concentration of about 50 mg/ml to about 150 mg/ml. [0020] Yet another object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the buffer is present at a concentration of about 0.05 mM to about 50 mM, preferably 0.05mM to 25 mM. [0021] Still yet another object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the one non-ionic surfactant is present at a concentration in the range of about 0.01 mg/ml to about 2.0 mg/ml. [0022] One object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the composition has a pH of about 5.2 to about 6.5. [0023] One object of the present invention is to provide a stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar, for example, a non-reducing sugar; (c) a buffer; and (d) a non-ionic surfactant, wherein: the non-reducing sugar is sucrose or trehalose or mannitol; the buffer comprises a citrate, L-Histidine, Di Sodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Citric acid monohydrate or adipic acid; and the non-ionic surfactant is Edetate disodium dehydrate, Polysorbate 20, Polysorbate 80 or Poloxamer 188. [0024] Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30 mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, L-histidine at a concentration of about 0.5 mM to about 5 mM, L- 3 Histidine HCl monohydrate at a concentration of about 5 mM to about 15 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, and pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0025] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL , Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 5 mM to about 25 mM, Edetate disodium dihydrate at a concentration of about 0.01 mg/ml to about 1.0 mg/ml, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0026] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 0.05 mM to about 2 mM, DiSodium Succinate Hexahydrate at a concentration of about 0.5 mM to about 10 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml , a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0027] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, sucrose at a concentration of about 50 mg/ml to about 100 mg/ml , Glacial acetic acid at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0028] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Mannitol at a concentration of about 5 mg/ml to about 15mg/ml, Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml , Citric acid monohydrate at a concentration of about 0.5 mM to about 5 mM, adipic acid at a concentration of about 5 mM to about 50 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. 4 [0029] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Mannitol at a concentration of about 5 mg/ml to about 15 mg/ml, Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml , Sodium citrate at a concentration of about 0.1 mM to about 5 mM, Citric acid monohydrate at a concentration of about 3 mM to about 15 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0030] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, L-Histidine at a concentration of about 5 mM to about 15 mM, sodium chloride at a concentration of about 5 mg/ml to about 10 mg/ml , polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml , a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0031] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, L-Histidine at a concentration of about 0.5 mM to about 5 mM, L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 20 at a concentration in the range of about 0.05% mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0032] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, L-Histidine at a concentration of about 0.5 mM to about 5 mM, L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM, Poloxamer 188 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0033] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30 mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM, Sodium acetate trihydrate 5 at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0034] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to 5 mM, Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml , a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0035] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 1 mM to about 10 mM, Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0036] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to about 5 mM, Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0037] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM, Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. 6 [0038] The present invention also provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 1 mM to about 10 mM, Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0039] Another object of the present invention is to provide an anti-PD-1 antibody composition wherein the composition may be administered by an intravenous administration or by a subcutaneous administration, or a combination thereof. [0040] In one embodiment, the composition and methods of the invention include high concentrations of an anti-PD1 antibody, or antigen binding portions thereof, and (a) a sugar, for example, a non-reducing sugar; (b) a buffer; and (c) a non-ionic surfactant. [0041] A stable anti-PD-1 antibody composition of the present invention can be used for the prophylaxis or treatment of a PD-1 mediated disease or disorder, wherein the disease or disorder is preferably cancer; more preferably PD-L1 expressing cancer; wherein the disease or disorder is most preferably breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, melanoma; most preferably non-small cell lung cancer, melanoma and kidney cancer. SUMMARY OF THE INVENTION [0042] One object of the present invention is to provide a stable anti-PD-1 antibody composition. [0043] Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar, for example, a non-reducing sugar; (c) a buffer; and 7 (d) a non-ionic surfactant. [0044] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the antiPD1 antibody is present at a concentration in the range of about 5 mg/mL to about 30 mg/mL. [0045] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the non-reducing sugar is sucrose, trehalose or mannitol, preferably trehalose, more preferably α,α-trehalose dihydrate. [0046] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the buffer comprises a citrate, L-Histidine, Disodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Glacial acetic acid, Citric acid monohydrate and/or adipic acid, preferably L-Histidine, L-Histidine HCl monohydrate, and/or Succinic Acid. One object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the non-ionic surfactant is Sodium Chloride, Edetate disodium dehydrate, Polysorbate 20, Polysorbate 80 or Poloxamer 188, preferably, Edetate disodium dihydrate or Polysorbate 80. [0047] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the anti-PD-1 antibody is Nivolumab or Pembrolizumab, preferably Pembrolizumab. [0048] In an embodiment, the present invention provides a stable liquid pharmaceutical composition wherein the sugar is present at a concentration of about 50 mg/ml to about 150 mg/ml. [0049] Yet another embodiment of the present invention is to provide a stable anti-PD-1 antibody composition wherein the buffer is present at a concentration of about 0.05 mM to about 50 mM, preferably 0.05mM to 25 mM. [0050] Still yet another embodiment of the present invention is to provide a stable anti-PD-1 antibody composition wherein the one non-ionic surfactant is present at a concentration in the range of about 0.01 mg/ml to about 2.0 mg/ml. [0051] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the composition has a pH of about 5.2 to about 6.5. 8 [0052] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar, for example, a non-reducing sugar; (c) a buffer; and (d) a non-ionic surfactant, wherein: the non-reducing sugar is sucrose or trehalose or mannitol; the buffer comprises a citrate, L-Histidine, Di Sodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Citric acid monohydrate or adipic acid; and the non-ionic surfactant is Edetate disodium dehydrate, Polysorbate 20, Polysorbate 80 or Poloxamer 188. [0053] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30 mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, L-histidine at a concentration of about 0.5 mM to about 5 mM, L- Histidine HCl monohydrate at a concentration of about 5 mM to about 15 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, and pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0054] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 5 mM to about 25 mM, Edetate disodium dihydrate at a concentration of about 0.01 mg/ml to about 1.0 mg/ml, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0055] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 0.05 mM to about 2 mM, Disodium Succinate Hexahydrate at a concentration of about 0.5 mM to about 10 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. 9 [0056] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Glacial acetic acid at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0057] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Mannitol at a concentration of about 5 mg/ml to about 15mg/ml, Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml , Citric acid monohydrate at a concentration of about 0.5 mM to about 5 mM, adipic acid at a concentration of about 5 mM to about 50 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0058] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Mannitol at a concentration of about 5 mg/ml to about 15 mg/ml, Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml, Sodium citrate at a concentration of about 0.1 mM to about 5 mM, Citric acid monohydrate at a concentration of about 3 mM to about 15 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0059] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, L-Histidine at a concentration of about 5 mM to about 15 mM, sodium chloride at a concentration of about 5 mg/ml to about 10 mg/ml, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0060] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, L-Histidine at a concentration of about 0.5 mM to about 5 mM, L-Histidine HCl 10 monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 20 at a concentration in the range of about 0.05% mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0061] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, L-Histidine at a concentration of about 0.5 mM to about 5 mM, L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM, Poloxamer 188 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0062] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30 mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM, Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab [0063] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to 5 mM, Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0064] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 1 mM to about 10 mM, Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. 11 [0065] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to about 5 mM, Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0066] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM, Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0067] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 1 mM to about 10 mM, Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0068] Another embodiment of the present invention is to provide an anti-PD-1 antibody composition wherein the composition may be administered by an intravenous administration or by a subcutaneous administration, or a combination thereof. [0069] In one embodiment, the composition and methods of the invention include high concentrations of an anti-PD1 antibody, or antigen binding portions thereof, and (a) a sugar, for example, a non-reducing sugar; (b) a buffer; and (c) a non-ionic surfactant. 12 [0070] A stable anti-PD-1 antibody composition of the present invention can be used for the prophylaxis or treatment of a PD-1 mediated disease or disorder, wherein the disease or disorder is preferably cancer; more preferably PD-L1 expressing cancer; wherein the disease or disorder is most preferably breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, melanoma; most preferably non-small cell lung cancer, melanoma and kidney cancer. DESCRIPTION OF THE INVENTION [0071] It is to be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. [0072] Although any methods and materials similar or equivalent to those described herein may be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used. [0073] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like. [0074] The transitional terms “comprising”, “consisting essentially of”, and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including”, “containing”, or “characterized by”, is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps“ and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.” [0075] The pharmaceutical composition of the present invention may comprise a human antibody, or an antigen-binding fragment thereof, that binds specifically to human PD-1. As used herein, the term "PD-1" means human programmed death -1 protein. An example 13 of a human PD-1 antibody is Merck’s Keytruda®. However, the composition as described herein can be used for other PD-1 antibodies. [0076] The term "antibody", as used herein, is generally intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM); however, immunoglobulin molecules consisting of only heavy chains (i.e., lacking light chains) are also encompassed within the definition of the term "antibody". Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CHI, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementary determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino- terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. [0077] Unless specifically indicated otherwise, the term "antibody", as used herein, shall be understood to encompass complete antibody molecules as well as antigen-binding fragments thereof. The term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or simply "antibody portion" or "antibody fragment"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to human PD-1 or an epitope thereof. [0078] The high antibody composition and methods of the invention not only overcome a number of known challenges for pharmaceutical composition, including high concentrations in a stable composition. [0079] The term Reference Listed Drug (RLD), as used herein is an approved drug product to which new generic versions are compared to show that they are bioequivalent. A drug company seeking approval to market a generic equivalent must refer to the Reference Listed Drug in an Abbreviated New Drug Application (ANDA). By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. 14 [0080] Reference will now be made in detail to the exemplary embodiments of the present disclosure, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or like parts. [0081] One object of the present invention is to provide a stable anti-PD-1 antibody composition. [0082] Another object of the present invention is to provide a stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar, for example, a non-reducing sugar; (c) a buffer; and (d) a non-ionic surfactant. [0083] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the antiPD1 antibody is present at a concentration in the range of about 5 mg/mL to about 30 mg/mL. [0084] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the non-reducing sugar is sucrose, trehalose or mannitol, preferably trehalose, more preferably α,α-trehalose dihydrate. [0085] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the buffer comprises a citrate, L-Histidine, DiSodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Glacial acetic acid, Citric acid monohydrate and/or adipic acid, preferably L-Histidine, L-Histidine HCl monohydrate, and/or Succinic Acid. One object of the present invention is to provide a stable anti-PD-1 antibody composition wherein the non-ionic surfactant is Sodium Chloride, Edetate disodium dehydrate, Polysorbate 20, Polysorbate 80 or Poloxamer 188, preferably, Edetate disodium dihydrate or Polysorbate 80. [0086] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the anti-PD-1 antibody is Nivolumab or Pembrolizumab, preferably Pembrolizumab. 15 [0087] In an embodiment, the present invention provides a stable liquid pharmaceutical composition wherein the sugar is present at a concentration of about 50 mg/ml to about 150 mg/ml. [0088] Yet another embodiment of the present invention is to provide a stable anti-PD-1 antibody composition wherein the buffer is present at a concentration of about 0.05 mM to about 50 mM, preferably 0.05mM to 25 mM. [0089] Still yet another embodiment of the present invention is to provide a stable anti-PD-1 antibody composition wherein the one non-ionic surfactant is present at a concentration in the range of about 0.01 mg/ml to about 2.0 mg/ml. [0090] In an embodiment, the present invention provides a stable anti-PD-1 antibody composition wherein the composition has a pH of about 5.2 to about 6.5. [0091] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar, for example, a non-reducing sugar; (c) a buffer; and (d) a non-ionic surfactant, wherein: the non-reducing sugar is sucrose or trehalose or mannitol; the buffer comprises a citrate, L-Histidine, Di Sodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Citric acid monohydrate or adipic acid; and the non-ionic surfactant is Edetate disodium dehydrate, Polysorbate 20, Polysorbate 80 or Poloxamer 188. [0092] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30 mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, L-histidine at a concentration of about 0.5 mM to about 5 mM, L- Histidine HCl monohydrate at a concentration of about 5 mM to about 15 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, and pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0093] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 16 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 5 mM to about 25 mM, Edetate disodium dihydrate at a concentration of about 0.01 mg/ml to about 1.0 mg/ml, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0094] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 0.05 mM to about 2 mM, Disodium Succinate Hexahydrate at a concentration of about 0.5 mM to about 10 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0095] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Glacial acetic acid at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0096] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Mannitol at a concentration of about 5 mg/ml to about 15mg/ml, Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml, Citric acid monohydrate at a concentration of about 0.5 mM to about 5 mM, adipic acid at a concentration of about 5 mM to about 50 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0097] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Mannitol at a concentration of about 5 mg/ml to about 15 mg/ml, Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml, Sodium citrate at a concentration of about 0.1 mM to about 5 mM, Citric acid monohydrate at a concentration of about 3 mM to about 15 mM, polysorbate 80 at a concentration in the 17 range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0098] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, L-Histidine at a concentration of about 5 mM to about 15 mM, sodium chloride at a concentration of about 5 mg/ml to about 10 mg/ml, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [0099] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, L-Histidine at a concentration of about 0.5 mM to about 5 mM, L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 20 at a concentration in the range of about 0.05% mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00100] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, L-Histidine at a concentration of about 0.5 mM to about 5 mM, L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM, Poloxamer 188 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00101] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30 mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM, Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00102] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 18 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml, Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to 5 mM, Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00103] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, Sucrose at a concentration of about 50mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 1 mM to about 10 mM, Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00104] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to about 5 mM, Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00105] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM, Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM, polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00106] In an embodiment, the present invention provides a stable liquid pharmaceutical composition comprising an anti-PD-1 antibody at a concentration in the range of about 5 mg/mL to about 30mg/mL, α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml, Succinic Acid at a concentration of about 1 mM to about 10 mM, Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM, polysorbate 80 19 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, a pH of about 5.2 to about 6.5, and wherein the anti-PD-1 antibody is Pembrolizumab. [00107] Another embodiment of the present invention is to provide anti-PD-1 antibody composition wherein the composition may be administered by an intravenous administration or by a subcutaneous administration, or a combination thereof. [00108] In one embodiment, the composition and methods of the invention include high concentrations of an anti-PD1 antibody, or antigen binding portions thereof, and (a) a sugar, for example, a non-reducing sugar; (b) a buffer; and (c) a non-ionic surfactant. [00109] A stable anti-PD-1 antibody composition of the present invention can be used for the prophylaxis or treatment of a PD-1 mediated disease or disorder, wherein the disease or disorder is preferably cancer; more preferably PD-L1 expressing cancer; wherein the disease or disorder is most preferably breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, melanoma; most preferably non-small cell lung cancer, melanoma and kidney cancer. EXAMPLES [00110] The following examples are presented so as to provide those of ordinary skill in the art with a disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but as known to those of ordinary skill in the art some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by mole, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric pressure. Development of stable anti-PD-1 antibody compositions Screening of different compositions. 20 [00111] For screening, different compositions were exposed to stress conditions as follows. ^ Photo stress 1 cycle (Exposure to light) ^ Photo stress 1 cycle + 50°C for 6 Days (Exposure to light followed by heat) ^ Photo stress 3 cycles (Exposure to excessive light) The above-considered stress conditions were shortlisted based on previous degradation studies conducted with the RLD. [00112] Compositions of the present invention (1-15 set forth below) were exposed to the above noted stress conditions and then subjected to analysis by (SEC)-HPLC size exclusion chromatography, Monomer, Hydrophobic interaction chromatography (HIC), Ion exchange (IEX)-chromatography, and protein A HPLC. The results of which are set forth in studies A-J below. PD1 Compositions (1-6) Compositions Name of Ingredients 1 2 3 4 5 6 mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml Pembrolizumab 25 25 25 25 25 25 Polysorbate 80 0.2 0.2 0.2 0.2 0.2 0.2 L-Histidine - - - - - 9.99 mM Sucrose 70 70 70 - - - DiSodium Succinate H_exahydrate ^{- 4.48 mM - - - -} Succinic Acid 19.98 mM 0.51 mM - - - - Sodium Chloride - - - 6.16 6.16 9 Mannitol - - - 12.0 12.0 - Sodium citrate dihydrate - - - - 1.02 mM - Citric acid monohydrate - - - 1.22 mM 6.19 mM - Edetate disodium d_ihydrate ^{0.05 - - - - -} Glacial acetic acid - - 9.99 mM - - - adipic acid - - - 22.99 mM - - Sodium hydroxide for pH for pH for pH for pH for pH for pH Hydrochloric acid for pH for pH for pH for pH for pH for pH WFI qs to 1 ml Final/Target pH of C_omposition ^{pH 5.5 pH 5.5 pH 5.5 pH 5.5 pH 5.5 pH 5.5} 21 PD1 Compositions (7-15) Compositions Name of Ingredients 7 8 9 10 11 12 13 14 15 mg/ mg/ mg/ mg/ mg/m mg/ mg/m mg/ mg/ ml ml ml ml l ml l ml ml Pembrolizumab 25 25 25 25 25 25 25 25 25 Polysorbate 80 0.2 - - 0.2 0.2 0.2 0.2 0.2 0.2 Polysorbate 20 - 0.4 - - - - - - - Poloxamer 188 - - 0.5 - - - - - - Sucrose - 70 70 70 70 71 - - - α,α-trehalose dihydrate 79 - - - - - 76 76 76 1.93 1.93 1.93 L-Histidine mM mM _mM ^{- - - - - -} L-Histidine HCl 8.11 8.11 8.11 monohydrate mM mM _mM ^{- - - - - -} Dibasic sodium phosphate n_hydrous ^{- - -} 0.58 0.58 a - _mM - _mM ^{- -} Monobasic sodium ^{- - -} 10.15 10.15 p_{hosphate monohydrate} - _mM - _mM ^{- -} ^{- - - - -} 2.63 2.63 S_{uccinic acid mM} ^{- -} mM Sodium succinate 6.11 6.1 x_ahydrate ^{- - - -} 1 h_e - _mM ^{- -} mM c_{ial acetic acid} ^{- - -} 1.83 m_M - 1.83 G_la ^{- -} _mM - c_{etate trihydrate} ^{- - -} 8.82 m_M - 8.82 S_{odium a} ^{- -} _mM - WFI q.s. to 1 mL Final/Target pH of C_omposition ^{5.5 5.5 5.5 5.5 6.0 5.5 6.0 5.5 5.5} [00113] Proposed compositions (1-15) demonstrated lower change from Initial Value compared to the RLD composition thereby suggesting that the proposed compositions may be more stable than the RLD composition. Proposed compositions (1-15) demonstrated comparable or lower difference from initial values for all four CQAs for all three stress conditions in comparison to RLD as mentioned in the studies. [00114] All compositions (1-15) achieved pH 5.5 + 0.4 with target of 5.5 with exception of Composition 11 and 13 with Target pH of 6.0. [00115] Osmolality of all the compositions was in the range between 220 -330 mOsm/kg. [00116] All compositions 1-15 achieved Protein Concentration ~ 25.00 + 1.2 mg/ml. 22 * ^{C T S} ^{le 7} ^{a .} ^r ₃ ^7. ₂ ^7. ₁ ^{7 6.} ₃ ^6. ₂ ^6. ₁ ^{6 5.} ₃ ^5. ₂ ^5. ₁ ^{5 4 3 2 1} N o^S _{. 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B} _s ^C _{ts nt} ^a _{p an C ce m} ^te _{/ N} ^: _{ol ( s hy ge H ntr} O s _rs/ ^{IF S} _{u % (} ^P _a ^c _tio ⁾ _% ^L ^C _{ti m} _o ^{/ n} _o ^r _n ^{) e} _{, ( n} ^k %_{g .} _{) en} _{N i}A ⁾ _n- _g _N ^{o 1} ^{t 0 70 18 18 67 1 9 0 2 2 5 In} _of _A ^. ₆₈ ^. ₆₁ ^. ₇₂ ^. ₈₉ ^. ₅ ^3. ₂ ^{0 9.} ₈ ^{.1 4} 4 ^. ₈ ⁵ ₃ ^.5 ₇ ^{* it} _{ia c} ⁿ _{8 5 6 9 l} ^a _o ^l _m ^{ys 3 5 2 2 b Ph 1 p} ^{ed 6.2 8 5 6 5} 2 ^. ₇ ^{2 1 0. 98 1} N N N ^{i o c o} 5 ^. ₀₂ ^. _{33 .1} ^. ₅₈ ¹ _{6 .5} ^.3 ₃ A A A ^{* l} _ity ^t _os ^y t_c _{a l} ^s e ^{R iti} ⁶ _L ^o ^P _D ⁿ ^{4 2 6 2 4 3 9} _D .^{h 1 s} ^{4 9 5 3 4 1 0} 2 ^. ₈ ^{. 6 3.} N N N 5 ^. ₇₃ ^. ₅₂ ^. ₈₃ ^. ₆₄ ³ ₁ ^. ₃₇ ³ ₂ A A A ^{* 50 o cy} ° ^t _{o c} ⁴ C_{+ le to} P ^{1 4 9 h 3} ₆ .₂ ^{.9 3 3} 4 ^. ₈ ^{2 3} 5 ^. ₈ ^{4 3} 4 ^. ₉ ^{2 0 9} 4 ^. ₂ ^. 3 ^{3 4 5} 8 ^. ₂ ^. 4 ³ N N N ^b _i ₇ A A A ^{* ili o} t_y ^t _o ^c s ^y _n _{t c} _{a le co} 1^{0 70 1 1 6 1 9 0 2 3 5 I} _m n^p ^. ₆₈ ^. ₃ ⁸ 4 ^. ₉ ⁸ 8 ^. ₆ ⁷ 6 ^. ₅ ³ 5 ^. ₇₈ ^{0 9.} ₈ ^. 4 ^{1 5} 6 ^. ₁₁ ² ₆ ^.6 ₄ ^{* it} _ia ^a l ^ri ^{P s} ^{1 o} ^{5 2 6 2 4 2 9} ^{.0 7 7 5 9 4 0} 1 ^. ₆ ^{. 4 5.} N N N ^{b h} 6 ^. ₃₃ ^. ₈₅ ^. ₆₁ ^. ₅₆ ² ₂ ^. ₇₁ ⁰ ₆ A A A ^{* ili o c} t_y ^t _os ^y _n _t _{t c o} _{a le} P _R L ^{5 h} ^{0 ot 1 4} C^{o c} _D desylan ato N,detatipicer pelpma S ^° ₊ ^y _c _{6 l} _De P ^{1 9 8 3 3 3 0 8 9 h} N ^{o 3} ^.4 ₉ ^{.1 9 4 3 1} 6 ^. ₃ ^{. 9 .} N N 5 ^. ₇₈ ^. ₇₆ ^. ₄₄ ⁴ ₆ ^. ₇₅ ⁷ ₉ A A A ^{* li}t_y ^to _s ^c t ^y a_c _{b le} _i 1^{0 7 1 1 6 1 9 2 I} ^. ₆ ⁰ 8 ^. ₄ ⁸ 5 ^. ₈ ⁸ 8 ^. ₄ ⁷ 9 ^. ₈ ³ 8 ^. ₆₃ ^{0 9 0} ^. ₈ ^. 1 ^{1 5 3} 9 ^. ₅₂ ^{1 5} 5 ^.7 ₆ ^{* nit} _ial P ^{3 2 7 2 4 2} ^{8 0 9 ho 1} ^{. 2 3 7 6 6} 4 ^. ₇ ^{. 5 4.} N N N 8 ^. ₃₉ ^. ₄₂ ^. ₄₉ ^. ₀₉ ¹ ₈ ^. ₇₇ ⁰ ₄ A A A ^{* ili} _ty ^t _o ^c s ^y t_c _{a l} _{b e} ⁵ ^{2. 2 6} _D ^{P 1} ^{9 0 7} 6 ^. ₈ ^{6 2} 2 ^. ₂ ^{1 4} 3_.5 ^{2 3} . ^{5 0 9} 6 ^. ₉ ^. 1 ^{2 5} 4 ^. ₈ ³ 6 ^. 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N N 3^{* P} 5₆ A A A ^{bi h 3} ^l _i ^{o c} t_y ^t _os ^y _c _{t le} 8^{9 9} _a 3^{7 2. 5. 58 35 33 51 14 9 0. 26 25 5. *} .₂ ^. ₁ ⁸ 4_{6 4} ^. ₇₃ ^. ₈₇ ^. ₈₄ ^. ₇₁ ^. ₄₄ ^. ₈ ¹ 6₄ ^. _{1 2} ^{4 I} 1₈ ^nit _ial N ^{5 4 2 2 7 9} N N N A ^4. ₈ ^{5 .6 5 1 44 32 2} 2 ^. _{18 1} ^. ₇₂ ^. ₆₇ ^. _{8 .} _{2 9} ^2. ₂ ^{8 1.7} A A A ^{* Ph 1} 9 ^. _{22 0} ^{li o} t_y ^to _s ^c t ^y a_c _{b le} N ^{6 3 3 3 9} N N N _i ⁸ A ^6. ₀ ^{3 .1 3 63 34 33 31 5 4.2} A A A ^{* 6} _D ^{P 1} 5 ^. _{95 2} ^. ₆₆ ^. ₂₂ ^. ₃₆ ^. ₈₆ ^. ₇₉ ^. _{58 3} ^{5 h} ^{0 o cy} ° ^t _{o c} _{C + le} 9^. ₂ ^{13 8} N ^{2 9 5 2} N N N .₄ ⁶ A ^{.3 7 3 0 26 93 6 *} 7 ^. _{53 1} ^. ₆₇ ^. ₃₂ ^. ₆₁ ^. ₀₈ ^. ₆ A A A 7 ^{b P} ^{i h 3} ^{li o c} t_y ^t _os ^y t_c _{a le} 8^{9 9} 8 ^{7 2} 2 ^{. 5. 59 35 33 51 14 99 0. 24 2 5 *} . ^{. 7 1} 5_{5 6} ^. ₀₇ ^. ₇₇ ^. ₈₈ ^. ₃₅ ^. ₇₇ ^. ₈ ^{1 5} 6₃ ^. _{69 5} ^. ₅ ^Init _ial N A ^{65 3 3} ^. ₈ ^4. ₁ ^{.0 3} 5 ^{4 6} ^{. 2 4 3} ^{. 3.} ₈ ^{18 9 1} N N N ^{* P} ^{. 8.} ₇ ^. ₂ A A A ^{b h 1} 6_{4 68 25 03 98 5} ^ili ^{o c} t_y ^t _os ^y t_cle A ^{7 2 3 4 5} _a N ⁹ N N N ⁹ ^1. ₉ ^8. ₀ ^.9 ₀ ^0. ₁ ^{5 3} ^{. 7 3} ^{. 6 2 2 * 6} ^{. 6. 7.} ₁ ^.6 A A A _D ^{Ph 1} 2_{8 4 96 12 13 75 8 3} ^{50 o c} ° ^t _o ^y C_{+ cle} 2^{9 23 76} N ^{4. 95 51 25 23 94 4} N N N ^{* P} .₄ ^. ₇ ^. ₂ A ⁸ ₁ ^. ₂ ^. ₂ ^{. . . .7} A A A ^{i ho 3} 2_{8 1 1 07 72 98 5} ^li _ty ^t _o ^c s ^y t_c _{a l} _{b e} ^{* 9 8.} ₂ ^8. ₁ ^{8 7.} ₃ ^7. ₂ ^7. ₁ ^{7 6.} ₃ ^6. ₂ ^6. ₁ ^{6 5.} ₂ ^{5 S} ^. ₁ ^{5 4 3 2 1 .} _N ^{C o} ^{le B S} M ^{T (} _% ^{C P} M ^{P P B} M A ^{C C} M H ^{P ( .} m ^P O ^p _D ^T _B ^{ar in P a o o o a re u a a c h a o} M^{u ro s} _H ^e _. ^T ^{c d R i} _A ^o _i ^{n t} _al ^{) nt st in -p rit s} _ic ^{in id} _ro ^{tio n} W^{rit g} _/ ^te _m ^{esc st} _N o^B ^l _n ^o _g ^a _s ^r _s ^P _{e O} ^en _p t _ea ^p _{e ea} ^y -_V ^P _i _{e c m} _V ^{a n} _om ^y ^b _m L^{in ola ri} _P p _a ^./ ^L ^l _{) a} ^e _{y ak} ^xi _s ^{d -} _{( k a k k by} ^ari _ak ^{a to E e} ^g _{x y} _{c r S )} ^C ^{o li} _{ty ti r} _{o a N} _m ^I _E _{s %} ^iz _{Pr H} ^a _n ^{ria r} _s ⁽ _{ed ot} ^IC _{ts nt} ^a _h _{p a E} ⁿ _{c ( n} ^{e F} ⁿ h_{n C en m} ^t O ^er _{o. D} _{ol %} _{u im ei s} _{t n (% y ge H} _i ^{R P} _tra ^{s s/ : S} _on ^e _, ^{l p} ^{a u} _A ⁾ _(% ^L _t )^C _{i m} _o ^C ^{/k o} _n ^cr _{N ti} ^r v ⁱ _{t H} _i A _{e es} ^P _{( n} L _% g_{) di} ) _ti ^e o ^en ^{- C} _{N ) ns} ⁱ _n ^ot _A ^{11 96 3 1 2 2 5 1 9 2 I} _g ^{n 5 .} ₅ ^{.4 0. 6} 2 ⁹ _. ^0. ₀ ^6. ₂ ^7. ₈ ^5. ₉ ^{9. 0} 8 ^{.1 4.} ₁ ²⁴ ₉ ^5. ₅ ^{* nit} _o _{i f} ^a _. ^l _{7 5 5 2 7 8 2 4 3 3 7 1 a} ^y _{l co} _sed ^Ph _m N ⁵ A ^{8 4} ^. ₉ ^{1 5 3 62 38 37 23 9 2} N N N ^{l o 1} ^{c po} 9 ^. ₀ ^. 1 ⁶ ₉ ¹ _.8 ^. ₅₂ ^. ₆₃ ^. ₉₉ ^. ₃ ⁷ 8 ^. ₇ ^. 9 ¹ ₁ A A A ^{* i}t_y ^to _st ^y a_c _{b le} ^{R si} i_L ^tio ^{6 6} _D A ⁶ _D ^{P 1 n} N ³ ^. ₁ ^{3 5. 3 5 3 3} 8 ^. ₈₂ ^{7 8} 9 ^. ₉ ⁵ 7 ^. ₂ ¹ 3 ^. ₇ ⁶ 4 ^{. 3} 0 ^{2 95} 6_.2 ^{. 4} 5 ^. 4 ² N N N ^h 3 A A A ^{* 50 o cy s} ^{° t 1} ^C _o _{+ cle} ⁰ ^P _t 1^{3 2 7} N ^{6 9 4 2 2 9 6 b h 3} _o ₁ _. ² 1 ^. ₄ ⁷ 3 ^. ₅₇ A ^{.6 3} 4 ^. ₃ ⁶ 5 ^. ₂ ⁵ 7 ^. ₁ ⁸ 4 ^. ₅ ³ 9 ^. ₂ ^. 4 ⁴ N N N 4 A A A ^{* ili o} t_y ^t _c _{o y} _{st c 2} _{a le in} 1^{1 9 5 5 3 3 5 1 9 2 I} _c 1⁷ .₉ ^{. 2} 1 ^{. .} 6 ⁸ ₄ ^{4 8} 9 ^. ₇ ^{5 4 1 3 9 0. 5 2} 9 ^. ₇₃ ^. ₆₃ ^. ₆₁ ^. ₇₆ ^. ₈₆ ¹ ₅ ^. ₇₂ ^{5 5} 2 ^.5 ₃ ^{* nit} _o _{ia m} _l ^p ^{P a} N ^{5 4 3 3 6 3 9 ho 1 ris} A ^5. ₇ ⁴ 5 ^. ₂ ^. 5 ^{3 2 4 4} 3 ^. ₁₅ ^. ₅ ⁹ 3_. ^{4 1} 2 ^. ₄ ⁶ 9_. ^{8 1} 3 ^. ₁ ^. 6 ⁷ N N N 8 A A A ^{* li}t_y ^to _s ^c t ^y a_c ^o _n _{b le} 6 _i ¹ _t P 0 _o N ⁷ A ^{0 2} ^. ₉ ^{9 3} _D ¹ ^{. 40 55 39 36 23 97 2} N N N ^{ho c} _R ₂ ^. ₀₈ ⁸ ₃ ^. ₄₄ ^. ₇₄ ^. _{77 .9} ^. _{34 .4} ^.4 ₄ A A A ^{* 50 L} ° ^t _o ^y _c _{C + le D} P ^{41 3 6 1 8 h 3} . ⁴ 8 ^. ₅ ⁵ 6 ^. ₄ ² 4 ^. ₃ ^5. ₆ ^{2 5} 3 ^. ₀ ^{4 2} 6 ^. ₅ ^{5 1} 2 ^. ₆ ^{9 9} 1 ^. ₈ ^{5 3} 5 ^. ₈ ^. 7 ⁹ N N N 2 A A A ^{* li o} ^t _y ^to _s ^c t ^y a_c _{b le} _i 8^{8 9} .₈ ⁷ _. ^{2 5 5 3 3 1 9 I} 2 ^. ₈ ^{.4 8 5 4 5} 7 ^. ₈ ^{1 3 9 0. 26 2} 9 ^. ₆₅ ^. _{54 .8} ^. ₆₇ ^. ₈₄ ¹ ₆ ^. ₂₅ ⁵ ₉ ^5. ₈ ^{* nit} _ial N ^{5 4 P} ^{2 3 6 4 3 2 9 4} N N ^{b h 1} A ^4. ₇ ⁵ 6 ^. ₂ ^. 4 ^{9 1} 7 ^. ₄ ⁵ 9 ^. ₅ ⁵ 3 ^. ₃ ³ 6 ^. ₀ ¹ 7 ^. ₅ ⁵ 7 ^. ₃ ^. 3 ⁵ N 3 A A A ^{* ili o} t_y ^t _o ^c s ^y _c _{ta le} ¹ ^{6 P} ₁ N ⁷ A ^{0 2 3 4 5 3 3 2 9 2} _D ^{h 1} ^. ₄ ⁹ 6 ^. ₅ ^. 4 ^{2 2} 2 ^. ₀ ⁴ 8 ^. ₇ ⁵ 1 ^. ₉ ⁵ 2 ^. ₃ ^{8 6 .} N N N 3 ^. ₇₅ ^. ₈₈ ⁸ ₉ A A A ^{* 50 o cy} ° ^t _{o c} _{C + le} 6^{3 6 2 1 7 5 2 2 9 P} ⁵ N N ^{b h 3} ⁹ _.3 ⁸ _.1 ¹ _.9 ^{.3 7} 4 ^. ₈ ⁹ 6 ^. ₇ ¹ 9 ^. ₄ ⁶ 6 ^. ₆ ¹ 9 ^. ₈ ⁴ 5 ^. ₃ ^. 2 ³ N 6 A A A ^{* il} _i ^o t_y ^t _o ^c s ^y t_c _{a le} 9^{2 9} . ⁷ 3 ^{. 2} 1 ^{. 5 5 3 3 5} 8 ⁸ ₂ ^{.4 8} 8 ^. ₄ ⁶ 6 ^. ₀ ⁴ 5 ^. ₆ ¹ 9 ^{. 1} 4 ^{3 99 0 2} 2_.9 ^. ₈ ^. 6 ^{1 5} 5 ^. ₃ ² 1 ^{5 5 I} 3 ^.4 ₆ ^{* nit} _ial N ^{5 4 3 3} A ⁸ _. ^{1 65 48 35 15 9 1} N N N ^{b Pho 1} ^c 8 ¹ _.2 ^.0 ₃ ^. ₆₇ ^. ₃₁ ^. ₃₃ ^. ₆₈ ^. ₉ ⁸ 9 ^. ₄ ^. 3 ⁵ ₁ A A A ^{* il} _ity ^t _os ^y t_c _{a le} 6¹ N A ^2. ₈ ^{7 3} 9 ^. ₁ ^. 1 ^{6 2} 2 ^. ₁ ⁴ 2 ^. ₂ ^{8 2} 6 ^. ₄ ⁵ 3 ^. ₃ ⁶ 2 ^. ₂ ⁷ 7 ^. ₅ ^. 9 ² N N N _D ^{Ph 1} 2 7^{2 4 5 3 3 2 9} 7 A A A ^{* 50 o} ° ^{t c} o ^y _c _{C + le} P ^{88 3 6 2 1 8 5 2 1 9 b h 3} . ^{5 5 2 7 6 5 5 3} N N N ^{o c} 2 ^. ₃ ⁴ 1 ^. ₆ ^. 9 ⁰ ₁ ^. ₅₃ ^. ₄₆ ^. ₄₄ ^. ₆₈ ^. ₈₈ ^. ₉ ^. 5 ⁸ ₃ A A A ^{* ili} _ty ^t _os ^y t_c _{a le} ^{9 8.} ₂ ^8. ₁ ^{8 7.} ₃ ^7. ₂ ^7. ₁ ^{7 6.} ₃ ^6. ₂ ^6. ₁ ^{6 5.} ₂ ^{5 S} ^. ₁ ^{5 4 3 2 1 .} _N o ^* ^{C B} ^{le i S} M M M A M ^{. T} ^{n P T (} ^{a o} _% ^C ^{o Po P P B C C} H ^{P (} ^{a re u a a c h a o} M^u _m ^Pr O ^p ^{o s} _{H D} ^T _B e^e ^{a d R i s} _{.N A} ^{r n t} _al ^{) nt st in -p rit s} _ic ^{in id} _ro ^{tio n} _o W^{rit g} _/m ^te _m o^{sc t o B} ^c _in ^o _g ^a _ss ^P ^l _{e O} ^en _p t _ea ^p _{e ea} ^y k_{- V} ^P _i _{e c m} _V ^{a n} ^E _m ^y ^{b L in la ri} _P p _ar ^. _{/ N} ^L ^o _{) ay ak} ^{xid -} _{( k a b} ^a _a ^t P_{k y} ^ria _k ^{ar og} _xc ^e _{r y} _{S )} ^C ^{o li} _t n _{ty io am} ^{IF E} ^rle _% ^iz _{s e r H n} ^ia _n ^ra _{ha EC c (m n} ^{et n E} _s ⁽ _{s % d ot} ^I _{C ts ts ph ng en} O ^er _o. ^: _olu ^R _{im ein} ⁽ _{% y} _{( e H} P _trat ^s _m ^{s/ C Sc} _t ^e _io ^{l p} _A a^ur _H ⁾ _% ^L ^{) C} _ion ^{/k o} _{n ti} ⁱt ^g _n ^re _{, ve ies} ^P ₍ L _{% ) di e} ) _{tio n} _NA _{C n}- _{) s ing} _N ^o _o ^t _A ^{11 9 1 2 2 5 1 9 2 I} _{f c} ^{n 5 6} ^a _. ^{. 3} 5 ^{.4 0. 6} 2 ⁹ _. ^0. ₀ ^6. ₂ ^7. ₈ ^5. ₉ ^{9. 0} 8 ^{.1 4.} ₁ ²⁴ ₉ ^5. ₅ ^{* nit} _{i o} ^l _{7 5 5 2 7 8 2 4 3 3 7 1 a m} ^y _l _se ^p _d ^P N ^{5 h 1 o} A ^{8 4} ^. ₉ ^{1 5 3 62 38 37 23 97 2} N N N ^{il o c si} 9 ^. ₀ ^. 1 ⁶ ₉ ¹ _.8 ^. ₅₂ ^. ₆₃ ^. ₉₉ ^. ₃₈ ^. ₇ ^. 9 ¹ ₁ A A A ^{* i} _ty ^to _s ^y t ^t a_cl _{b e} ⁱ ^{R on} ⁶ L P _D ^s N ^{6 3 5 3 5 3 3 3 9 4} N N N _D ^{h 1} A ^6. ₁ ³ 8 ^. ₈ ^. 2 ^{7 8} 9 ^. ₉ ⁵ 7 ^. ₂ ¹ 3 ^. ₇ ⁶ 4 ^. ₀ ^{2 5} 6_.2 ^. ₅ ^. 4 ² ₃ A A A ^{* 50 o c 1} ° ^t _o ^y _c ³ C_{+ le to} P ₁ 1^{3 2 7} N ^{6 9 4 2 2 9 6} N N N ^{i ho 3} ₅ _i _. ² 1 ^. ₄ ^{7 .} 3 ^. ₅₇ A ^{6 3} 4 ^. ₃ ⁶ 5 ^. ₂ ⁵ 7 ^. ₁ ⁸ 4 ^. ₅ ³ 9 ^. ₂ ^. 4 ⁴ ₄ A A A ^{* li} _ty ^t _o ^c s ^y t_{c n} _{a l} _{b e com} 8^{9 9} . ⁷ 5 ^{. 2} 1 ^{. 5. 5 3 3 5 1 9} 6 ⁸ ₄ ^{3 9} 7 ^. ₁ ⁵ 5 ^. ₄ ⁴ 8 ^. ₄ ¹ 3 ^. ₄ ⁴ 4 ^. ₁ ⁹ 3 ^{. 0 2} 8 ^. 4 ^{1 5 2} 6 ^. ₁₆ ^{5 5 I} 3 ^.7 ₂ ^{* ni p} ^t _ia ^a l ^ris ^{P o} ^{6 h 1} _n N ^{3 4 3 5 4 3 1 9} N ^{i o} A ^5. ₇ ⁴ _t ₄ ^. ₂ ^. 6 ^{0 8} 9 ^. ₁ ⁷ 4 ^. ₇ ⁴ 7_. ^{8 7 7 2} N N 6 ^. ₀₄ ^. ₃₅ ^. ₆₅ ^. ₃ A A A ^{* li} _ty ^{to c} s ^y t_{c o} _{a l} _{b e} ¹ _R 3 ^L N ⁷ A ^{8 2 4 4 4 3 3 2 9 6} _D ^{P 1} _D .₄ ¹ 7 ^. ₅ ^. 3 ^{0 8} 4 ^. ₀ ^{7 5 8 5 8 1.} N N N ^h 7 ^. ₈₈ ^. ₈₅ ^. ₈₁ ^. ₃₄ ^. ₁₃ ⁷ ₇ A A A ^{* 50 o cy} ° ^t _{o c} _{C + le} P ^{1 4 5 2 2 7 5 2 1 9 4 ho 3} ^{10 4} .₅ ^. ₇ ⁵ 3 ^. ₂ ^. 7 ^{7 2 4} 1 ^. ₂₉ ^. ₉ ¹ 9_.1 ⁹ _.5 ⁹ _. ⁵ 4 ^. ₂ ^. 9 ⁵ N N N 5 A A A ^{* ili} _ty ^{to c} s ^y t_c _{a l} _{b e} 1^{0 2} 1 ^{. 9} ^{5 7 6} 9 ^. ₄ ^{. 7 2 2 6 1 9} 2 ^{3 2} 3 ^. ₇ ⁰ 0 ^. ₉ ³ 7 ^. ₁ ⁴ 6 ^. ₀ ² 4 ^. ₈ ⁹ 2 ^{. 0} 6 ^{. 2} 4 ^{3 4} 6 ^. ₇ ² 7 ^{6 5 I} 0 ^.5 ₀ ^{* nit} _ial P N ² A ^{6 7} ^. ₁ ^{3 4 53 41 3 5 1 9 1} N N ^{5 i ho 1} ^c 7 ^. ₈ ^. 3 ⁹ ₄ ^. ₉₈ ^. ₀ ³ 8 ^. ₇ ⁰ 4 ^. ₇ ⁵ 5 ^. ₄ ⁸ 9 ^. ₆ ^. 7 ³ ₃ A A ^.5 ₁ ^{* li} _ty ^to_s ^y t_c _{a l} _{b e} 1⁶ 4 N ² A ^{0 7 5 5 3 2 4 2 9} ^. ₉ ⁹ 5 ^. ₀ ^. 5 ^{5 5} 3 ^. ₇ ⁸ 7 ^. ₇ ⁹ 0 ^. ₀ ⁷ 7 ^. ₇ ³ 9 ^. ₁ ⁷ 6 ^{. 2} 7 ^. 6 ² N N ⁵ _D ^P 4 A A ^{. h 1} ⁵ ₂ ^{* 50 o cy} ° ^t _{o c} _{C + le} P ^{7 4 5 3 6 4 h 3} 7 ^6. ₀ ^{3 3. 3 1 9 3} N N ^{5 i o c} 9 ^. ₉₁ ^{9 5} 3 ^. ₁ ⁰ 6 ^. ₉ ⁴ 0 ^. ₂ ⁹ 0 ^. ₉ ⁵ 5 ^. ₈ ⁶ 4 ^. ₉ ^. 5 ⁰ ₆ A A ^.5 ₀ ^{* li} _ty ^t _os ^y t_c _{a l} _{b e} 8^{2 9} ^{7 .5 7 6 7} 9 ^. ₄ ^. 0 ^{2 2 2} 2 ^. ₇ ^{1 2} 3 ^. ₀ ^{3 6} 5 ^. ₆ ^{2 1 9 0 2} 5 ^. ₁ ⁴ 6 ^. ₁ ⁹ 7 ^. ₆ ^. 7 ^{3 4} 3 ^. ₆ ² 6 ^{5 5 I} 9 ^.4 ₂ ^{* nit} _ial P N ^{3 h 1} A ^{4 6} ^. ₉ ^{5 4 45 49 37 45 17 97 2} N N ^{5 il o c} 7 ^. ₀ ^. 3 ⁷ ₁ ^. ₃₉ ^. ₉₂ ^. ₆₄ ^. ₀₈ ^. ₂₈ ^. ₆ ^. 5 ³ ₅ A A ^.4 ₂ ^{* i} _ty ^to _s ^y t_c _{a l} _{b e} ¹5 N ² A ^{3 7} ^. ₀ ^{6 5 5} 6 ^. ₉ ^. 3 ^{2 5 3} 9 ^. ₄ ^{9 3} 1 ^. ₃ ^{0 4} 0 ^. ₀ ^{3 2 9 6} ² 8 ^. ₄ ⁶ 8 ^. ₄ ⁷ 5 ^. ₈ ^. 3 ¹ N N ⁵ _D ^{Ph 1} 8 A A ^.4 ₁ ^{* 50 o} ° ^{t c} o ^y _c _{C + le} 8^{4 5 P} ^{3 3 6 4 3 1 9 2 b h 3} 9 ^7. ₄ ^{2 5 1 5 9 5 7} N N ^{5 o c} 6 ^. ₅ ^. 3 ⁴ ₃ ^. ₁₈ ^. ₃₉ ^. ₁₁ ^. ₆₄ ^. ₂₆ ^. ₂ ^. 8 ⁷ ₃ A A ^.4 ₄ ^{* il}i_ty ^t _os ^y t_c _{a le} ^{9 8.} ₂ ^8. ₁ ^{8 7.} ₃ ^7. ₂ ^7. ₁ ^{7 6.} ₃ ^6. ₂ ^6. ₁ ^{6 5.} ₂ ^5. ₁ ^{5 4 3 2 1 o} _. ^S. _N ^{* R} ^{C e S} M ^{i T} M M A M H O ^{l l PR a} _m ^{C P} ^{p o o o P} ^{s a r P} ^{e u B C P} ^{r a a c a o} M^{u (} ^r _m ^{Pr (} ^o _m ^p O^s _{mH D} ^{C T B} ^{e o es} _.N ^T ^{e a} ^{a ti a in u t} _al ^{nte t} _p ^{in -p it s} ^y _ic ^{in id} _i ^{tio n} _o W^{it g} ^y _/m ^{te s o sc nd t} _P ^o _A ^{r ve} _ss ^P _e ^rit_{i O} x^nt _ea ^p _{e eak - V} ^P _{e c} _V ⁿ ^E _m ^{b L in} _m /^{la r i} ^{l ip} _{tio ar} ^. _{/ N} ^B ^{co B} _{a a e} ^lo _{i y k s} ^{id -} _{( k a b} ^a P_{k y} ^ri _a a _k ^{ar x e} ^c r _y _{S )} ^C ^{o k} _{i t} n g_{) ty io ns am} ^{IF L} ^E ^r _n ^le _{d %} ⁱ _z _i ( _{ed ro H} I _nt ^ia _n ^h _{a EC c n} _e ^{et n} _{s n} _{s g % te} ^C _{s ts ng H n} ^e t_{rs o.} ^F ^. _{s ) in (% e} _{o A C} ^P _{ra /} ^S _lu ⁾ _h L _t _{r C io} ^t _{t H} ^a _{i o} ( _n _o ^{P b} _n, ^{1 9 L} _m 1^{2 2 5 1 a 9} _% )^{2 I il} _N ^{15 6. 3} A _{. 5} ^{.4 C} ) ^{0. 6} 2 ⁹ _. ^0. ₀ ^6. ₂ ^7. ₈ ^{5. t} 9 ^{og 9. 0} 8 ^{.1 4.} ₁ ^{24 5} 9 ^{.5 * l ni} _t ⁱ _ty- _{7 5 5 (% 2 7 8 2 4 3} ^ra _{3 7 1 5 ia} _N ⁾ _{ph da} ^ot _A N ⁵ ⁿ A ^{8 4} ^. ₉ ^{1 5 3 6 3 3 2} _y ₍ ^{9 2} N N N ^{tab Ph c} _ta ^a ₉ ^. ₀ ^. 1 ⁶ ₉ ¹ _. ² 8 ^. ₅ ⁸ 2 ^. ₆ ⁷ 3 ^. ₉ ³ 9 ^. _{3 %} ⁷ 8 ^{) .} ₇ ^. 9 ¹ ₁ A A A ^{* i} _li ^o t_t ^y o ^c _le ¹ _o ^l _{y s} K _f ^y _s ^e _c _ed N ⁶ A ^{6 3} ^. ₁ ^{3 5. 38 55 31 36 3 9 P} ^{2 5 4.} N N N ^{5 + c yt} _om ₈ ^. ₈₂ ⁷ ₉ ^. ₉₇ ^. ₂₃ ^. ₇₄ ^. _{06 .2} ^. ₅₄ ² ₃ A A A ^{* 0° h y} C_6D ^o _to ^c _le ^{1 rud} _a ^p R ^o L ^si ^{13 2 7 t P} _D ^tio . ² 1 ^. ₄ ⁷ 3 ^. N ^{6 9} 5₇ A ^{.6 3 4} 4 ^. ₃ ^{6 2} 5 ^. ₂ ^{5 2} 7 ^. ₁ ^{8 9} 4 ^. ₅ ^{3 6} 9 ^. ₂ ^. 4 ⁴ N N N ^a 4 A A A ^{* y b} _i ^h l_i ^{o cyc 3 _} _U ⁿ t_{tos le} ^{029 7} ⁰ _to 1⁹ ⁰ ₆ ^{6. 3 1} 0 ^{. 0 67 21 24 59 16 99 0} N ^{2 5 8 6} ₃ _{M 9 8} ₄ ⁹ ₆ ^. ₄₁ ^. ₈₃ ^. ₇₅ ^. ₅₇ ^. ₄₂ ^. ₀₂ ^. ₈ ^. 5 ¹ ₅ A ⁵ ₅ ^.4 ₁ ^{* °C ,} _{2 i} _{- n} _c N ^{9 6 2 2 6 2} _om A ^{3 6} ^. ₉ ^. 4 ^{0 9 5 2 9} 6 ^{.5 3 6 1 1 7 9 0} 7 ^. ₇₆ ^. ₆₆ ^. ₄₂ ^. ₅₃ ^. ₀₄ ^. ₄ ^. 8 ⁵ N ² 2 A ^{5 5} 9 ^.5 ₆ ^* H0_% ⁵ _° ⁶ R_CM _/ ^{, pari} ^{87 9} .₇ ⁷ _. ² 2 ^{. 5} 8 ^{. 5 3 3 5 1 9 2 I so} ^{4 8} 6 ^. ₆ ⁵ 9 ^. ₈ ⁴ 5 ^. ₉ ¹ 8 ^. ₈ ³ 5 ^. ₁ ⁹ 8 ^{. 0} 8 ^{. 4 2} 6 ¹ ₄ ^. ₂₂ ⁶ ₅ ^5. ₅ ^{* nit} _{i n} _{al to} N ^{6 3 3 34 61 4 3 1 9 1} N N N ^{ta P} _R h^{c L} A ⁷ _.2 ² _.8 ^.3 ₄ ^. ₈₅ ^. ₈ ² 2 ^. ₇ ⁸ 2 ^. ₅ ⁸ 5 ^. ₇ ⁸ 4 ^. ₃ ^. 7 ⁵ ₆ A A A ^{* y b} _ili ^{o yc 1} _D _{t tos le} N ⁷ A ^{1 2} ^. ₀ ⁸ 5 ^{. 3 3} 9 ^. 5 ^{0 5 6} 4 ^. ₅ ^{1 3} 4 ^. ₄ ^{7 3} 4 ^. ₀ ^{5 2} 2 ^. ₉ ⁷ 7 ^{. 9} 0 ^{6 3.} 2_.8 ⁰ N N N ⁵ 5 A A A ^{* 0 + P} °_C6D ^{h c} ^{o y} t_o ^c _le ¹ ⁷ ^{2 2 7 9 5 2 2 t P} ² _. ⁷ 2 ^. ₂ ² N ^{6. 3 0 6 2 94 5.} N N N 9 ^. ₇₁ A ⁵ ₆ ^. ₄₆ ^. ₃₃ ^. ₆₇ ^. ₉₉ ^. ₃₅ ³ ₆ A A A ^{* y ab} _i ^h l_i ^{o cy 3} t_to ^c s_le 1⁹ ^{1 2 5 5 3 3 5 1 9 0} N ^{5 8 6} 2 ^7. ₀ ^. 2 ⁹ ₈ ^{.4 7} 3 ^. ₆ ⁶ 1 ^. ₉ ² 5 ^. ₁ ³ 6 ^. ₇ ⁴ 8 ^. ₀ ⁹ 7 ^. ₈ ^{. 2} 8 ¹ ₂ A ⁷ ₆ ^.4 ₉ ^{* °C 2} _{- M} , N ^{9 0 2} ^{5 4 5 5 3 2 4 2 9} ^{. 5 9 8 7 3 9 0.} N ^{2 5.} _% ^{5° 6} A _.7 ^. ₃ ² ₈ ^. ₇ ^. ₀ ^. ₆ ^. ₅ ^. ₇ ^. ₆ ³ A ⁸ ₈ ^{7 * R} _CM _{0 1 9 1 9 7 3 9 H/6} ^, ^{83 9} . ^{7 2 5 3 3 5 1 9 0 2} 2 ^. ₁ ^. 4 ^{8 5} 6 ^. ₄ ^8. ₇ ⁵ 3 ^. ₈ ³ 7 ^. ₈ ¹ 4 ^. ₇ ⁴ 1 ^. ₄ ⁹ 4 ^. ₈ ^. 6 ^{1 6} 4 ^. ₁ ² 1 ^{5 5 I} 2 ^.4 ₈ ^{* nit} _ial N ⁵ A ^{4 4} ^. ₈ ^{5 2 25 71 44 3 22 98 1} N N N ^{sta Ph cy} 2 ^. ₁ ^. 8 ⁶ ₁ ^. ₇₂ ^. ₆₇ ^. ₈ ² 2_.9 ^. ₂₉ ^. ₂ ^. 2 ⁷ ₀ A A A ^{* ty} b_{i o} _l ^{c 1} i_{to le} N ^{6 3 3 6 3 3 P} A ^6. ₀ ^{3 3} 5₉₅ ^{1 3 3 9 4} N N N ^{5 + c} ^{. . 3 4 3 1 5} 2 ^. ₆₆ ^. ₂₂ ^. ₃₆ ^. ₈₆ ^. ₇₉ ^. ₅ ^. 8 ² ₃ A A A ^{* 0°} _C6D ^{ho y} t_o ^c _le ¹ ^{9 1} ^{2 3 8 8} ^. ₄ ⁶ 7 ^. N ² 5 ^{. 9 5 2 2 9} 3 A ^{3 7} 1 ^. ₆ ³ 7 ^. ₃ ⁰ 2 ^. ₆ ⁶ 1 ^. ₀ ³ 8 ^. ₆₇ ⁶ N N N ^s A A A ^{* ty ta P} ^{b h c} i o ^{y 3} l_{i to} ^c _le 9^{96 3. 5 5 3 3 5 1 9} ^{. 7 6 2 3 4 9 0} N ^{2 5 2- 6} 2 ^. ₈ ^{1 4 .} ₇ ^. ₇ ^. ₁ ^. ₇ ^. ₁ ^. ₈ ^.1 A ^{5 .} ₅ ^{* 8°} _M _{4 6 9 5 6 5 3 3 8 2 9 C} ^, N ^{9 4 5 5 3 2 4 2 9 0 5 0} _% ²⁵ A ^5. ₈ ^. 6 ¹ ₄ ^{.3 7} 8 ^. ₀ ⁷ 8 ^. ₅ ⁹ 4 ^. ₀ ^{7 3} 1_.8 ^. ₁ ⁹ 8 ^. ₆ ^. 6 ³ N ² 4 A ⁶ ₂ ^.5 ₅ ^{* R° 6} _M _HC _/6 ^, ^{* 9 8. 8. 8 7. 7. 7. 7 6. 6 6 6 5 5 5 4 3 2 1} N ^S ^C _{2 1 3 2 1 3} ^. ₂ ^. ₁ ^. ₂ ^. ₁ ^o _{. .} ^T ^le M M M A M _A ^{a R S} ^{r c e P i} ^a _m ^{T C P} ^{p o o o P P B C} H ^{P (} ^{s a re ur a a c a o} M ^ur _m ^C ^{o Pr (} ^o _m O s^p _H D e^{Te B B} ^L ^{o la} ^{l t R in u t} _a ^{o iv a} _l ^{nt t in -p it s} _ic ^{in id tio n} _o W ^{it g} _/m ^{nc t} _e O s _m o^{sc Cst} _{.N E} ^{rl e} _ss ^P ^e _e ^ri _{ti O} ^en _p t _ea ^p _{e ea} ^y -_V ^P _i _{e c} _V ⁿ ^E _m ^y ^{b L en} _{in m} ^{la rip on} _Pa ^o. _G _s ^B _{ay ak es} ^xi _{s i} ^{d -} _{( k ak k by} ^ari _ak ^{a x e} _{r y} _{S ) tra} ^/kg ^l _{it t} _{y io} ^di _{t ra} / m_N ^. _{s n %} ⁱ _{z P H} ^a _n ^ri _{o d} _{l i} ^{a ch} _{E tio ) n io} ^{e IF S} _{u n} ⁽ _{ed rot} ^IC _{ts nt an C n ns} ^{te n ta} _{t g % e s g H rs o.} ^b _{io ) in (% e} _C ^P _{n A} ^L _/ ^il _{, N} ^{1 9 3} _H ^{1 6 2 )} ^{2 5 1} _hro ^{9 0 C i} ^{2 t} ^{2 5 I y}A ^{15 6} - _.7 ^. ₅ ^. 5 ⁴ ₅ ^{P 0} ^{L .} ₂ ⁹ 2_. ^{0 6 7 5} _m ⁹ 7 ^. ₀₈ ^. ₂₂ ^. ₈₄ ^. ₉₃ ^{a .} ₈ ^. 3 ¹ ₍ _{7 %} ⁴ ^{) .} ₁₁ ⁴ ₉ ^.5 ₅ ^{* l ni} _{ti d} _{a a} _N ^C _t ^o ₎ ^to _a ^t _A N ^{58 41} _(% ^g ^{5 3 6 r} ^{2 38 37 23 a} _p ^{97 2} N N N ^{i o P c} _of ⁿ A ^. ^a ₉ ^l ₉ ^. ₀₁ ^{) .6} ₉ ¹ _.8 ^. ₅₂ ^. ₆₃ ^. ₉₉ ^. _{3 h} _{8 y} ^. ₇ ^. 9 ¹ ₁ A A A ^{* li} _ty ^s _tab ^h _o ^yc _le ¹ K _co ^y _{( t} _{s %} ^ey _ed N ⁶ A ^{6 3} ^. ₁ ^{3 5 3 5} ^{. 8 5 31 36 3 ) 9} ^{2 5 4.} N N N ⁵ 8 ^. ₈₂ ⁷ ₉ ^. ₉₇ ^. ₂₃ ^. ₇₄ ^. _{06 .2} ^. ₅₄ ² ₃ A A A ^{* 0} _° ^{6 o P} C_{D +} ^{h c t} _m _o ^{y r p} t ^c _le ^{1 ud} _a ^o R ^si ^{13 2 7 9 4 2 9} _L ^t D ^ion . ² 1 ^. ₄ ⁷ 3 ^. N ⁶ 5₇ A ^{.6 3} 4 ^. ₃ ⁶ 5 ^. ₂ ^{5 2} 7 ^. ₁ ⁸ 4 ^. ₅ ³ 9 ^{. 6} 2 ^. 4 ⁴ N N N ⁱ 4 A A A ^{* l o} ⁱ _ty ^s _t ^{P c} a_b ^h _o ^y t ^c _le ^{3 _} _U ⁹ ^{02 t} ⁹ _o 1⁹ ⁰ ₆ ^{6 3 6 2 0} ₁ .₀ ^{. 10 7 1 24 59 16 99 0.} N ^{2 5. 8 2 6} _{39 0} ₄ ⁹ ₆ ^. ₄₁ ^. ₈₃ ^. ₇₅ ^. ₅₇ ^. ₄₂ ^. ₀₂ ^. ₈₅ ¹ ₅ A ⁵ ₅ ⁴ ₁ ^{* °C} _{- M} , _in _c N ^{9 6 2 2 5 2 9 5 6 2} _om A ^{3. 6} 9 ^. 4 ^{0 9} 6 ^{.5 3 6 1 1 7 9 0} 7 ^. ₇₆ ^. ₆₆ ^. ₄₂ ^. ₅₃ ^. ₀₄ ^. ₄ ^. N ² 8 ⁵ ₂ A ⁵ ₉ ^.5 ₆ ^* H0_% ⁵ R_° ⁶ C_M ^p / ^{, ariso} ^{8 9} ⁹ _. ^{7 2} 8 ^. ₂ ^. 5 ^{7 5 5 3} 5 ^{. 3 5 1 9 0 2 I} ^{1 9} 6 ^. ₀ ⁵ 7 ^. ₇ ³ 7 ^. ₈ ¹ 8 ^. ₃ ^{4 9} 5 ^. ₇₇ ^. ₈ ^. 6 ^{1 4 2} 3 ^. ₆₉ ⁵ ₅ ^5. ₅ ^{* ni} _n t_{ia t} _{l o} _R 6^{3 3 6 4 1 9 s P c L} N ^{5 4 3 4 2 3 8 8} N N N ^t _D A ^. ₈₆ ^. ₁ ^. 4 ⁰ ₅ ^. ₆₈ ^. ₂₅ ^. ₀ ³ 3 8 ^. ₉₈ ^. ₇ ¹ 5 ^. ₂ A A A ^{* it} _y ^a _b ^h i_o ^y l_to ^c _le ¹ N ^{7 2 4 5 P} A ^1. ₉ ⁸ 2 ^{. 3} 0 ^. 8 ^{9 0} 0 ^. ₁ ^{5 3} 4 ^. ₉ ^{7 3} 6 ^. ₁ ^{6 2} 2 ^. ₁ ^{6 9} 3 ^. ₇ ^{7 2} 5 ^. ₁ ^. 8 ⁶ N N N ^{5 + c} 3 A A A ^{* 0} _°C6D ^{ho y} t_o ^c _le ¹ ⁹ ^{29 2} . ^{3 7 9 5 2 2 9 4 o P c} 4 ^. ₇ ⁶ 2 ^. N ⁴ 2 ^. 8 A ^{8 5} 1 ^. ₂ ^{1 5 3 4 .} N N N 1 ^. ₂₁ ^. ₀₇ ^. ₇₂ ^. ₉₈ ⁷ ₅ A A A ^{* ili} _ty ^s _ta ^{h y} b_ot ^c _le ³ ^{1 9} ⁰ ₄ ^{6. 3 5 5} 9 ^{. 7 36 31 5 1 9 0} N ^{2 5 8 6} 6 ⁰ ₃ ^.4 ₈ ^. ₈₂ ^. ₆₉ ^. ₉ ¹ 7 ^. ₉ ⁶ 1 ^. ₁ ⁹ 2 ^. ₈ ^. 9 ¹ ₁ A ⁶ ₂ ^.5 ₁ ^{* °C 2} _{- M} , N ^{9 5 3 2 4 2 9 /} A ^{6. 3} 0 ^{.9 5} 3 ^{.4 7 6 8 8 2 9 0} 1 ^. ₆ ^. ₈ ^. ₈ ^. ₃ ^. ₈ ^. ₆ ^.3 N ² 5 A ^{6 5} 9 ^.5 ₂ ^{* R} H⁶ ₀ ² %⁵ _° ⁶ C_M _{8 9 9 9 3 1 5} ^, ^{11 9} ^{1 7 2 5 5} .₉ ^. ₁ ^. 6 ⁸ ₄ ^{.4 8 3 3 5 1 9 0 2} 9 ^. ₇ ⁵ 9 ^. ₇ ⁴ 3 ^. ₆ ¹ 3 ^. ₆ ³ 1 ^. ₇ ⁹ 6 ^. ₈ ^. 6 ^{1 5} 5 ^. ₇ ² 2 ^{5 5} 2 ^{. I} ⁵ ₃ ^{* l ni} _tia N ⁵ A ^{5 4} ^. ₇ ^{4 3. 32 64 4 3} ^{9 4 1 9} ^{6 8 1.} N N N ^{il os P cy} 5 ^. ₂₅ ³ ₃ ^. ₁₅ ^. _{53 .2} ^. _{49 .3} ^. ₁₆ ⁷ ₈ A A A ^{* i} _ty t_ab ^h _ot ^c _le ¹ N ^{7 2 3 4 5 3 2 5 + P c} A ^0. ₉ ⁹ 2 ^. ₀ ^. 8 ^{8 0} 3 ^. ₄ ⁵ 4 ^. ₇ ^{9 3} 4 ^. ₇ ⁶ 7_. ^{3 9} 9 ^. ₃ ^{7 2} 4_.4 ^.4 N N N 4 A A A ^{* 0°} _C6D ^{ho y} t_o ^c _le ¹ ¹ ^{3 6 1 8 2 0} ⁴¹ _. ⁴ 8 ^. ₅ ^{5 5 1 9 3} 6 ^. ₄ ² 4 ^. ₃ ^5. ₆ ² 3 ^. ₀ ⁴ 6 ^. ₅ ⁵ 2 ^. ₆ ⁹ 1 ^. ₈ ⁵ 5 ^. ₈ ^. 7 ⁹ N N N 2 A A A ^{* il o} ⁱ _ty ^s _t ^P a_b ^{h c} o ^y t ^c _le ³ ^{9 96 3. 5 57 3 3 53 14 99 0.} N ^{2 5. 8 2 6} 8 ^. ₈ ^{1 .4 .} ₈ ⁶ _. ² _. ^. ₀ ^. ₇ ^. ₈ ¹ A ⁶ ₀ ^{5 * °C} _{- M} _{8 2 5 5 7 2 9 2 8 2 1} ^, N ^{9 4 5 5 3 2 4 2 9 0 2 5 6 2 6} A ^5. ₈ ^. 2 ¹ ₈ ^{.7 6} 5 ^. ₃ ⁷ 7 ^. ₈ ⁸ 8 ^. ₄ ^{7 3 9 .} 8 ^. ₉₈ ^. ₅₅ ^. ₅₁ ⁴ N 9 A ⁶ ₅ ^.5 ₃ ^* H⁰ _% ⁵ R^° _CM _/ ^, ^* ^C ^{le 9 8. 8 8 7 7 7 7 6 6 6 6 5 5 5 4 3 2 1 o S T} ^. _A ^a ₂ ^. ₁ ^. ₃ ^. ₂ ^. ₁ ^. ₃ ^. ₂ ^. ₁ ^. ₂ ^. _{1 . 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N ² 2 ⁸ ₈ A ⁶ ₁ ^.5 ₁ ^{* R°} H^{C 6} /_M ₆₀ ^, Shelf Life Determination [00117] The shelf-life of any of the described compositions 7-15 of the invention was measured by the stability of active protein in the pharmaceutical composition that is stored under specified storage conditions, for example, 2-8° C. [00118] Each batch was stored at temperatures, for example, 2° to 8° C. (refrigerator), and also subjected to an accelerated condition of 25+2) °C 60% RH (room temperature) to understand any impact on stability. The shelf life of protein in the formulation was determined by the storage period during which the active protein undergoes minimal degradation when stored at 2-8° C. Degradation of protein in a pharmaceutical composition can be detected using accelerated testing (also called stress testing) under exaggerated storage conditions designed to increase the rate of chemical or physical degradation of the drug substance. [00119] Samples of each batch of compositions 7-15 were then analyzed at different time points (e.g., time zero, 6 months) for the amount of therapeutic protein still present in the formulation compared to aggregates, fragments or unfolded or improperly folded protein. Samples stored under accelerated conditions such as higher temperatures (25 + 2 ° C.) were usually tested for degradation at time up to 6 months. For comparison, the same protein in compositions 7-15 either containing osmolyte and stabilizer were monitored to determine the stability impact of such excipients on shelf-life. [00120] All compositions (7-15) achieved pH 5.5 + 0.4 with target of 5.5 with exception of compositions 11 and 13 with a target pH of 6.0. Osmolality of all the compositions from 7-15 was in the range between 220 -330 mOsm/kg. 6 months stability data suggests that HMW for all the compositions were comparable to the reference product. Analysis of the therapeutic protein in the formulation was carried out by a variety of detection methods: SEC-HPLC to understand HMM, Monomer & LMW proteins; Cation exchange- Chromatography to understand impact on Acidic & Basic Impurities; Hydrophobic Interaction Chromatography to understand any impact on Pre & Post Peak to Main peak; SPR assay in a few cases; Protein A HPLC to understand oxidized impurities in few cases or a combination of any of these methods as mentioned in tables F- J. [00121] Cation Exchange Chromatography (%) & Purity - by HIC (%) data suggests that compositions 7-15 do not show significantly different impurity trends. Total Oxidized 33 impurities were evaluated for NIF 7 to NIF 13, the data were comparable to that of the reference product. SPR assay % (i.e. % Relative Binding assay) was comparable to that of the reference product for all the compositions. Overall, similar results were observed for all the present invention compositions (1-15) during different screening studies and stability studies. Generally, compositions 7-15 were comparable with the reference product data except compositions 4 and 6, wherein the sample precipitated during 1 cycle Photo + 6D 50°C exposure.

Claims

CLAIMS: 1. A stable liquid pharmaceutical composition comprising: (a) an anti-human PD1 antibody; (b) a sugar; (c) a buffer; and (d) a non-ionic surfactant.

2. The stable liquid pharmaceutical composition of claim 1, wherein the anti PD1 antibody of the composition is at a concentration in the range of about 5 mg/mL to about 30 mg/mL

3. The stable liquid pharmaceutical composition of claim 1, wherein the sugar in the composition is a non-reducing sugar selected from the group comprises of sucrose, trehalose, α, α-trehalose dihydrate or mannitol.

4. The stable liquid pharmaceutical composition of claim 1, wherein the buffer in the composition is selected from the group comprising: citrate, L-Histidine, DiSodium Succinate Hexahydrate, Succinic Acid, Sodium citrate, Glacial acetic acid, Citric acid monohydrate, Citric adipic acid, L-Histidine, L-Histidine HCl monohydrate, and/or Succinic Acid.

5. The stable liquid pharmaceutical composition of claim 1, wherein the anti-PD-1 antibody is Nivolumab or Pembrolizumab.

6. The stable liquid pharmaceutical composition of claim 1, wherein the anti-PD-1 antibody is Pembrolizumab.

7. The stable liquid pharmaceutical composition of claim 1, wherein the non-ionic surfactant in the composition is selected from the group comprising: Sodium Chloride, Edetate disodium dehydrate, Polysorbate 20, Polysorbate 80, Poloxamer 188, Edetate disodium dihydrate or Polysorbate 80.

8. The stable liquid pharmaceutical composition of claim 1, wherein the sugar in the composition is present at a concentration of about 50 mg/ml to about 150 mg/ml.

9. The stable liquid pharmaceutical composition of claim 1, wherein the buffer in the composition is present at a concentration of about 0.05 mM to about 50 mM. 35

10. The stable liquid pharmaceutical composition of claim 1, wherein the buffer in the composition is present at a concentration of about 0.05mM to 25 mM.

11. The stable liquid pharmaceutical composition of claim 1, wherein the one non-ionic surfactant in the composition is present at a concentration in the range of about 0.01 mg/ml to about 2.0 mg/ml.

12. The stable liquid pharmaceutical composition of claim 1, wherein the composition has a pH of about 5.2 to about 6.5.

13. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml; L-histidine at a concentration of about 0.5 mM to about 5 mM; L-Histidine HCl monohydrate at a concentration of about 5 mM to about 15 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

14. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30mg/mL; sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; succinic acid at a concentration of about 5 mM to about 25 mM; edetate disodium dihydrate at a concentration of about 0.01 mg/ml to about 1.0 mg/ml; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

15. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30mg/mL; sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; succinic acid at a concentration of about 0.05 mM to about 2 mM; disodium Succinate Hexahydrate at a concentration of about 0.5 mM to about 10 mM; and 36 polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

16. A stable liquid pharmaceutical composition comprising: Pembrolizumab a concentration in the range of about 5 mg/mL to about 30mg/mL; sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; Glacial acetic acid at a concentration of about 5 mM to about 20 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

17. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30mg/mL; Mannitol at a concentration of about 5 mg/ml to about 15mg/ml; Sodium Chloride at a concentration of about 5 mg/ml to about 10 mg/ml; Citric acid monohydrate at a concentration of about 0.5 mM to about 5 mM; adipic acid at a concentration of about 5 mM to about 50 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

18. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30mg/mL; mannitol at a concentration of about 5 mg/ml to about 15 mg/ml, sodium chloride at a concentration of about 5 mg/ml to about 10 mg/ml; sodium citrate at a concentration of about 0.1 mM to about 5 mM; citric acid monohydrate at a concentration of about 3 mM to about 15 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

19. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; 37 L-Histidine at a concentration of about 5 mM to about 15 mM; sodium chloride at a concentration of about 5 mg/ml to about 10 mg/ml; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml: wherein said composition has a pH of about 5.2 to about 6.5.

20. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; L-Histidine at a concentration of about 0.5 mM to about 5 mM; L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM; and polysorbate 20 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

21. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; L-Histidine at a concentration of about 0.5 mM to about 5 mM; L-Histidine HCl monohydrate at a concentration of about 5 mM to about 20 mM; and Poloxamer 188 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

22. A stable liquid pharmaceutical composition comprising: Pembrolizumab a concentration in the range of about 5 mg/mL to about 30 mg/mL; Sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM; Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, wherein said composition has a pH of about 5.2 to about 6.5. 38

23. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; sucrose at a concentration of about 50 mg/ml to about 100 mg/ml; dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to 5 mM; monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

24. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; Sucrose at a concentration of about 50mg/ml to about 100 mg/ml; Succinic Acid at a concentration of about 1 mM to about 10 mM; Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

25. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml; Dibasic sodium phosphate anhydrous at a concentration of about 0.05 mM to about 5 mM; Monobasic sodium phosphate monohydrate at a concentration of about 5 mM to about 20 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

26. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml; 39 Sodium acetate trihydrate at a concentration of about 2 mM to about 20 mM; Glacial acetic acid at a concentration of about 0.5 mM to about 10 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml, wherein said composition has a pH of about 5.2 to about 6.5.

27. A stable liquid pharmaceutical composition comprising: Pembrolizumab at a concentration in the range of about 5 mg/mL to about 30 mg/mL; α,α-trehalose dihydrate at a concentration of about 50 mg/ml to about 100 mg/ml; Succinic Acid at a concentration of about 1 mM to about 10 mM; Sodium succinate hexahydrate at a concentration of about 2 mM to about 20 mM; and polysorbate 80 at a concentration in the range of about 0.05 mg/ml to about 2.0 mg/ml; wherein said composition has a pH of about 5.2 to about 6.5.

28. The stable liquid pharmaceutical composition of claim 1, wherein the composition is administered by an intravenous administration, by a subcutaneous administration, or a combination thereof.

29. The stable liquid pharmaceutical composition of claim 1, wherein the composition includes high concentrations of the anti-PD1 antibody, or antigen binding portions thereof, and (a) a sugar (b) a buffer; and (c) a non-ionic surfactant.

30. The stable liquid pharmaceutical composition of claim 1, wherein the composition is used for the prophylaxis or treatment of a PD-1 mediated disease or disorder.

31. The stable liquid pharmaceutical composition of claim 1, wherein the composition is used for the prophylaxis or treatment of cancer.

32. The stable liquid pharmaceutical composition of claim 1, wherein the composition is used for the prophylaxis or treatment of a PD-L1 expressing cancer. 40

33. The stable liquid pharmaceutical composition of claim 1, wherein the composition is used for the prophylaxis or treatment of breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, and melanoma.

34. The stable liquid pharmaceutical composition of claim 1, wherein the composition is used for the prophylaxis or treatment of non-small cell lung cancer, melanoma and kidney cancer. 41