Primary container with improved protein drug stability and reduced immune response

Abstract

A primary drug container is described having an injection-molded thermoplastic wall having an interior surface defining a lumen, a PECVD (plasma-enhanced chemical vapor deposition) drug contact coating, and a polypeptide composition contained in the lumen. The drug contact coating is on or adjacent to the interior surface and is positioned so as to contact fluid within the lumen, and is essentially composed of SiO x C y H z The primary drug container contains a lower limit of 1,000 to an upper limit of 100,000 particles per mL of solution having an effective spherical diameter of greater than 2 micrometers and less than or equal to 10 micrometers (μm).

Description

[Technical Field]

[0001] Priority and Citation by Reference This application claims priority to U.S. Provisional Patent Application No. 62 / 752,007, filed October 29, 2018; U.S. Provisional Patent Application No. 62 / 891,467, filed August 26, 2019; and U.S. Provisional Patent Application No. 62 / 893,829, filed August 30, 2019. To provide continuity of disclosure, the entirety of each application identified in this paragraph is incorporated herein by reference. [Background technology]

[0002] Biologics are a class of therapeutic drugs produced using biological processes involving recombinant DNA. Biologics contain therapeutic proteins. Traditionally, these drugs have been stored in primary containers constructed of Type 1 borosilicate glass. These primary containers include vials, prefilled syringes, and cartridges. These drugs are stored in the primary container throughout their shelf life.

[0003] It has been observed that protein-based drugs can denature. Proteins can denature by unfolding or partial unfolding. These conformationally perturbed species are prone to aggregation, which can lead to the presence of particles in the drug product. The primary container can denature proteins. The following factors have been identified: Air / liquid interface - the air headspace in the container. The air / liquid interface is a major source of protein aggregation. Typically, this interface is much larger in a vial than in a prefilled syringe. The interface between the drug and the container wall - solid / liquid interface Silicone oil lubricant - silicone oil droplets break off from the syringe wall and interact with the drug. These droplets cause proteins in the liquid to unfold and potentially aggregate.

[0004] A major concern with biologics is the possibility that they may induce a harmful immune response when administered to a patient. The immune response can be caused by aggregates (particles) in the drug that is infused into the patient. These aggregates cause the production of antibodies in the patient, which can either (1) render the drug ineffective or (2) cause a severe immune response. Even a small number of particles can cause an immune response. The percentage of proteins that aggregate in the drug may be very, very small, but they can still cause an immune response. For example, patients treated with biologics for multiple sclerosis and Crohn's disease can develop an immune response within two years. This can reduce the effectiveness of the drug and may require the patient to stop taking the drug and / or switch drugs.

[0005] The number of protein-based drugs has increased significantly over the past five years, and this trend will continue. Drug therapy is increasingly being used to treat more chronic indications. This means that patients are taking the drug for longer periods of time and are more susceptible to side effects caused by the drug. Previously, protein drugs were taken for acute indications and had limited side effects.

[0006] The amount of particulate contaminants in a drug can increase over its shelf life. Millions of particles per mL can be detected in formulations of protein therapeutics. This concentration typically corresponds to particles with very small masses, but can be sufficient to trigger an immune response.

[0007] A primary drug container is a container with which the drug comes into direct contact during storage. Some non-limiting examples of primary drug containers are pre-filled syringes, cartridges, and vials.

[0008] The problem of particle contamination in primary drug containers is particularly acute in glass containers. See, e.g., Pharmacopeia (USP), Chapter 1660, Evaluation of The Inner Surface Durability of Glass Containers (which identifies inhomogeneities on the glass surface caused by phase separation and other factors that can lead to glass degradation, resulting in small particles in the drug in contact with the glass). Summary of the Invention [Means for solving the problem]

[0009] One aspect of the invention is a primary drug container comprising an injection-molded thermoplastic wall having an interior surface defining a lumen, a PECVD (plasma-enhanced chemical vapor deposition) drug contact coating, and a polypeptide contained in the lumen. The drug contact coating is on or adjacent to the interior surface and is positioned so as to be in contact with fluid within the lumen, and consists essentially of SiO x C y H z It consists of SiO x C y H z wherein x is 0.5 to 2.4, optionally 1.3 to 1.9, as measured by X-ray photoelectron spectroscopy (XPS), y is 0.6 to 3, optionally 0.8 to 1.4, as measured by XPS, and z is 2 to 9, optionally 2 to 6, as measured by Rutherford backscattering. The primary drug container contains a lower limit of 1,000 to an upper limit of 100,000 particles per mL of solution having an effective spherical diameter greater than 2 micrometers and less than or equal to 10 micrometers (μm).

[0010] Another aspect of the invention is a primary drug container comprising a wall and a PECVD drug contact coating. The wall has an interior surface defining a lumen. The PECVD drug contact coating is supported on or adjacent to the interior surface and is positioned so as to contact the fluid within the lumen. The primary drug container contains fewer than 10,000 particles (as measured by light obscuration particle counting) having a diameter of 2 to 50 micrometers (μm) per mL of solution.

[0011] Other aspects of the invention will be apparent from the specification, drawings, and claims hereof. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a plot showing the number of particles less than 10 μm (micrometers) in diameter per mL in a lot of uncoated 6 mL vials using the particle counting protocol described in Example 1 later in this specification. [Figure 2] 1 is a plot showing the number of particles less than 25 μm (micrometers) in diameter per mL in a lot of uncoated 6 mL vials using the particle counting protocol described in Example 1 later in this specification. [Figure 3] 1 is a plot showing the number of particles less than 50 μm (micrometers) in diameter per mL in a lot of uncoated 6 mL vials using the particle counting protocol described in Example 1 later in this specification. [Figure 4] 1 is a plot showing the number of particles between 50 and 100 μm (micrometers) in diameter per 100 containers in a lot of uncoated 6 mL vials using the particle counting protocol described in Example 1 later in this specification. [Figure 5] 1 is a plot showing the number of particles greater than 100 μm (micrometers) in diameter per 100 containers in a lot of uncoated 6 mL vials using the particle counting protocol described in Example 1 later in this specification. [Figure 6] FIG. 1 is a schematic cross-sectional view with an enlarged portion of a fixed-needle cyclic olefin polymer syringe barrel or wall showing a three-layer coating (adhesive, barrier, and pH protective) (the pH protective coating is on the drug-contacting surface), and optionally a further coating of silicone oil-free lubricant (PECVD lubricant coating) that does not define the drug-contacting surface. [Figure 7] Using the particle counting protocol described in Example 1 later in this specification, a comparison of the number of particles per mL resulting from the three layers and optional additional coatings in Figure 6 (left) with the number of particles per mL in a glass syringe conventionally lubricated with a surface coating of silicone oil (right) shows over 10 times the number of particles between 2 and 50 μm in diameter. [Figure 8] FIG. 8 is a Beckman Coulter HIAC 9703+ Liquid Particle Counter output field using the corresponding particle counting protocol described later in this specification, identifying numerous free-flowing lubricant particles for the glass syringe of FIG. 7 conventionally lubricated with a surface coating of silicone oil (polydimethylsiloxane). [Figure 9] 21 (C3a data, lower plot) and 22 (C5a data, higher plot) data for particles with diameters between 2 and 10 microns for all particulate samples generated by various stresses / formulations / container types. [Figure 10] 10 is a plot similar to FIG. 9 showing corresponding data for particles having diameters greater than 10 microns. For particles greater than 10 microns in diameter, no correlation is shown between complement activation and particle concentration. [Figure 11] 10 is a plot similar to FIG. 9 showing that complement activation in response to IVIg particles in vials is particle-mediated for particles having diameters between 2 and 10 microns. [Figure 12]FIG. 12 is a plot similar to FIG. 11 showing that complement activation in response to IVIg particles in the syringe is particle-mediated for particles having diameters between 2 and 10 microns. [Figure 13] 1 is a collage obtained from flow imaging microscopy of a stressed IVIg sample processed as described in Example 4. The collage is a series of randomly selected images of particles present in an IVIg sample that was processed by shaking overnight in a glass syringe on an orbital shaker. [Figure 14] 14 is a collage similar to FIG. 13 obtained from flow imaging microscopy of a stressed IVIg sample. The collage is a series of randomly selected images of particles present in an IVIg sample processed by 10 days of end-over-end rotation in a SiOPlas™ syringe. [Figure 15] 14 is a collage similar to FIG. 13 obtained from flow imaging microscopy of a stressed IVIg sample. The collage is a series of randomly selected images of particles present in an IVIg sample that was processed by shaking overnight in a SiOPlas™ syringe on an orbital shaker. [Figure 16] A collage similar to Figure 13 obtained from flow imaging microscopy of a stressed IVIg sample. The collage is a series of randomly selected images of particles present in an IVIg sample that was processed by freezing and thawing six times in a glass vial. [Figure 17] A collage similar to Figure 13 obtained from flow imaging microscopy of a stressed IVIg sample. The collage is a series of randomly selected images of particles present in an IVIg sample processed by end-over-end rotation in a silicone oil-lubricated glass syringe for 10 days. [Figure 18]14 is a collage similar to FIG. 13 obtained from flow imaging microscopy of a stressed IVIg sample. The collage is a series of randomly selected images of particles present in an IVIg sample that was processed by freeze-thawing six times in a SiOPlas™ vial. [Figure 19] 1 is a plot of the data from Example 4, showing that protein particles within IVIg samples did not stimulate C4a release concentrations in human serum samples. Concentrations are reported as fold increase over C4a levels in saline control samples. Particle concentrations refer to the concentration in the IVIg formulation prior to 10-fold dilution with human serum. The line represents a least-squares linear fit with a correlation coefficient r2=0.005. [Figure 20] 1 is a plot of data from Example 4 showing the effect of sample particle level on Bb concentration in human serum samples. Concentrations are reported as fold increase over Bb levels in saline control samples. Particle concentration refers to the concentration in the IVIg formulation before 10-fold dilution with human serum. The line represents a least-squares linear fit with a correlation coefficient r2 = 0.94. [Figure 21] 1 is a plot of data from Example 4 showing the effect of sample particle level on C3a concentration in human serum samples. Concentrations are reported as fold increase over C3a levels in saline control samples. Particle concentration refers to the concentration in the IVIg formulation before 10-fold dilution with human serum. The line represents a least-squares linear fit with a correlation coefficient r2 = 0.85. [Figure 22] 1 is a plot of data from Example 4 showing the effect of sample particle level on C5a concentration in human serum samples. Concentrations are reported as fold increase over C5a levels in saline control samples. Particle concentration refers to the concentration in the IVIg formulation before 10-fold dilution with human serum. The line represents a least-squares linear fit with a correlation coefficient r2 = 0.99. DETAILED DESCRIPTION OF THE INVENTION

[0013] IA drugs Optionally in all embodiments, the primary drug container contains a polypeptide composition, eg, a biopharmaceutical composition, in its lumen in contact with the PECVD coating.

[0014] Optionally in all embodiments, the primary drug container contains a protein composition in its lumen in contact with the PECVD coating.

[0015] Optionally in all embodiments, the primary drug container contains a biopharmaceutical from the following list of drugs and their indications, or any combination of two or more of these, contained within the lumen in contact with the PECVD coating:

[0016] List of biologics: 1. Approved on 4 / 5 / 2016 to Janssen / Johnson & Johnson as a biosimilar to Remicade, a TNF mAb, rDNA (Inflectra - infliximab - dyyb), which includes all of Remicade's current approved indications; manufactured by Celltrion.

[0017] 2. Polydeoxyribonucleotide, porcine derived (Defitelio-defibrotide sodium; polydeoxyribonucleotide, sodium salt), approved on 3 / 30 / 2016 to Jazz Pharmaceuticals for the treatment of hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after receiving a stem cell transplant from blood or bone marrow, called hematopoietic stem cell transplant (HSCT).

[0018] 3. IL-17 Mab, rDNA (Taltz; ixekizumab), approved on 3 / 22 / 2016 to Eli Lilly & Co. for the treatment of adults with moderate to severe plaque psoriasis.

[0019] 4. Anthrax Mab, rDNA (Anthim; Bacillus anthracis (anthrax) protective antigen (PA) monoclonal antibody, recombinant; ETI-204), approved on 3 / 22 / 2016 to Elusys Therapeutics, Inc. for the prevention of inhalation anthrax infection (for the U.S. biodefense Strategic National Stockpile (SNS)).

[0020] 5. Factor VIII rDNA (Kovaltry; Antihemophilic Factor (Recombinant)), approved to Bayer AG on March 17, 2016, for the treatment of hemophilia (requiring less frequent injections).

[0021] 6. Insulin glargine.rDNA (Basaglar; Abasria; LY2963016), approved on 12 / 16 / 2015 to Boehringer Ingelheim for the treatment of diabetes; a 505(b)(2) drug approval, many of which would now be called biosimilars.

[0022] 7. Factor X, blood-derived (Coagadex; Coagulation Factor X (human)), approved on 12 / 16 / 2015 to Bio Products Laboratory Ltd. for the treatment of hereditary factor X deficiency.

[0023] 8. von Willebrand factor, rDNA (Vonvendi), approved for Baxalta US (formerly Baxter) on 12 / 9 / 2015 for the treatment of von Willebrand disease (VWD).

[0024] 9. Lysosomal acid lipase, expressed in chicken eggs (Kanuma; sebelipase alfa), (a secondary product from genetically engineered animals), approved on 12 / 8 / 2015 for Alexion (through its acquisition of Synageva) for the treatment of lysosomal acid lipase (LAL) deficiency.

[0025] 10. Influenza vaccine, quadrivalent (Fluad; influenza vaccine with MF59 / squalene adjuvant, inactivated, egg-cultured, quadrivalent), approved for Novartis on 12 / 3 / 2015 (the product and its approval will be transferred to Seqirus, a CSL Group company) for the prevention of influenza; the first non-aluminum-based adjuvanted influenza vaccine in the United States.

[0026] 11. SLAMF7 mAb, rDNA (Empliciti; elotuzumab; signaling lymphocyte-activation molecule family member 7 monoclonal antibody, recombinant), approved on November 30, 2015, to Bristol Myers Squibb (BMS; in collaboration with Abbvie) for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1 to 3 prior therapies.

[0027] 12. EGFr mAb, rDNA (Portrazza-necitumumab; epidermal growth factor receptor monoclonal antibody), approved on 11 / 24 / 2015 to Janssen Biotech for the treatment of metastatic squamous non-small cell lung cancer (VWD) in combination with gemcitabine and cisplatin.

[0028] 13. Darzalex (daratumumab), a CD38 mAb, approved on 11 / 16 / 2015 to Eli Lilly for the treatment of multiple myeloma.

[0029] 14. Factor VIII, rDNA, pegylated (Adynovate-BAX 111), approved for Baxalta (formerly Baxter) on 11 / 11 / 2015, for the treatment of hemophilia A.

[0030] 15. IL-5 mAb, rDNA (Nucala; mepolizumab), approved on 11 / 4 / 2015 to GlaxoSmithKline (GSK) for the treatment of asthma.

[0031] 16. Approved on 10 / 27 / 2015 to Alexion Pharmaceuticals, HSV-1 / GM-CSF, rDNA, rDNA (Imlygic - alimogene laherparepvec; a live herpes simplex virus type 1 (HSV-1) oncolytic virus that results in expression of GM-CSF) for the treatment of unresectable recurrent cutaneous melanoma.

[0032] 17. Alkaline phosphatase, rDNA (Strensiq; asfotase alfa; alkaline phosphatase catalytic domain fusion protein), approved on 10 / 23 / 2015 to Alexion Pharmaceuticals for the treatment of birth-, infantile-, and juvenile-onset hypophosphatasia (HPP).

[0033] 18. rDNA (Praxbind-idarucizumab), a dabigatran mAb, approved on 10 / 16 / 2015 to Boehringer Ingelheim to reverse the anticoagulant effects of Pradaxa (dabigatran).

[0034] 19. Insulin degludec, rDNA (Tresiba-insulin degludec), approved for Novo Nordisk on 10 / 16 / 2015, for the treatment of diabetes mellitus.

[0035] 20. Insulin degludec / aspart, rDNA (Ryzodeg 70 / 30 - a 70 / 30 mixture of insulin degludec (approved the same day) and insulin aspart), approved for Novo Nordisk on 10 / 16 / 2015, for the treatment of diabetes mellitus.

[0036] 21. Factor VIII, rDNA (Nuwiq), approved on 10 / 16 / 2015 to Octapharma USA for the treatment of hemophilia A.

[0037] 22. Approval was granted to Amgen Inc. on August 27, 2015 for the treatment of high low-density lipoprotein (LDL) cholesterol levels for the PCSK9 mAb, rDNA (Repatha-evolocumab; proprotein convertase subtilisin kexin type 9 monoclonal antibody).

[0038] 23. A PCSK9 mAb, rDNA (Praluent-alirocumab; proprotein convertase subtilisin kexin type 9), was approved on July 24, 2015, to Sanofi and Regeneron Pharmaceuticals for the treatment of high low-density lipoprotein (LDL) cholesterol levels.

[0039] 24. Crotalidae Immuno F(ab')2 (Horse) (Anavip), manufactured by Instituto Bioclon SA (Mexico), was approved on May 6, 2015, for ProFibrix, BV, for the treatment of North American rattlesnake bites.

[0040] 25. Approval granted to The Medicines Company on 4 / 30 / 2015 for fibrin sealant (RAPLIXA; Raplixa spray - human plasma-derived fibrinogen and thrombin) (originally developed by the merged ProFibrix, BV) for the treatment of mild to moderate bleeding when control of bleeding by standard surgical techniques is ineffective or impractical in adults undergoing surgery.

[0041] 26. Approval granted to Cangene / Emergent Biosolutions on 4 / 29 / 2015 for the treatment of hemophilia B, Factor IX, rDNA (Coagulation Factor IX (Recombinant) - Ixinity).

[0042] 27. DTaP-IPV vaccine (Quadracel-diphtheria-tetanus toxoid and sterile pertussis-adsorbed and inactivated poliovirus) licensed on 26 / 03 / 2015 to Sanofi Pasteur for active immunization against diphtheria, tetanus, pertussis, and poliomyelitis in children 4 to 6 years of age.

[0043] 28. Approval granted on 3 / 24 / 2015 to Emergent BioSolutions Inc. for the treatment of inhalational anthrax in combination with an appropriate antimicrobial, anthrax immune globulin (Anthracil Immune Globulin Intravenous (Human)-Anthracil; AIGIV).

[0044] 29. Approval granted on 3 / 10 / 2015 to United Therapeutics Corp. for the GD2 mAb, rDNA (dinutuximab-Unituxin; ch14.18), (in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis retinoic acid (RA)) for the treatment of pediatric patients with high-risk neuroblastoma.

[0045] 30. Approval granted to Sandoz / Novartis on 3 / 6 / 2015 for the treatment of neutropenia (same indication as Neupogen), G-CSF, rDNA / Sandoz (filgrastim-sndz-Zarxio; Zarzio; granulocyte colony-stimulating factor, recombinant); first biosimilar approval.

[0046] 31. Approval granted on March 4, 2015 to Bristol-Myers Squibb Co. (BMS; licensed from Ono Pharm.) for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression during or after platinum-based chemotherapy, rDNA / Sandoz (nivolumab-Opdivo; ONO-4538; BMS-936558; MDX1106; programmed cell death 1 monoclonal antibody, recombinant).

[0047] 32. Approval granted to Sanofi on 2 / 25 / 2015 for insulin glargine, rDNA (Toujeo-Gly(A21)-human insulin Arg(B31)-Arg(B32)-OH, recombinant) for once-daily long-acting basal insulin treatment in adults with type 1 and type 2 diabetes.

[0048] 33. Approval granted on 1 / 25 / 2015 to NPS Pharmaceuticals (merged by Shire) for the treatment of hypocalcemia (low blood calcium levels) in patients with hypoparathyroidism, Parathyroid Hormone (1-84), rDNA (Natpara; Preos; Preotact).

[0049] 34. Neisseria meningitidis vaccine (secukinumab-Bexsero; Cosentyx), approved by Novartis on January 23, 2015, for the prevention of invasive meningococcal disease.

[0050] 35. IL-17 mAb, rDNA (secukinumab-Cosentyx), approved on 1 / 21 / 2015 to Novartis for the treatment of adults with moderate to severe plaque psoriasis.

[0051] 36. Programmed death receptor-1 mAb, rDNA (nivolumab-Opdivo), approved on 12 / 22 / 2014 to Bristol-Myers Squibb for the treatment of advanced melanoma (for patients with unresectable or metastatic melanoma and disease progression after treatment with Yervoy in patients with BRAF V600 mutation-positive tumors).

[0052] Approval granted to Sanofi Pasteur on 12 / 12 / 2014 for prophylactic use in adults 37.8-64 years of age, influenza vaccine, quadrivalent, id (Fluzone intradermal quadrivalent).

[0053] 38. Approval granted to Merck & Co. on December 10, 2014 for preventive use in women aged 9 to 26 years, HPV vaccine, 9-valent, rDNA (Human Papillomavirus 9-valent Vaccine, Recombinant - Gardasil 9).

[0054] 39. Accelerated approval granted to Amgen on 12 / 03 / 2014 for the CD3-CD19 bispecific mAb, rDNA (blinatumomab-AMG103; CD19-CD3 bispecific monoclonal antibody; CD3-CD19 bispecific T-cell engager (BiTE)); breakthrough therapy designation, for the treatment of Philadelphia chromosome-negative relapsed / refractory precursor B-cell acute lymphoblastic leukemia (ALL).

[0055] 40. Meningococcal B vaccine (Trumemba), granted accelerated approval to Pfizer on October 29, 2014, for active immunization to prevent invasive Neisseria meningitidis serogroup B strains in people aged 10 to 25 years.

[0056] 41. Approval granted to Baxter on 10 / 24 / 2014 for factor VIII, porcine rDNA (antihemophilic factor (recombinant), porcine sequence - Obizur; OBI-1; factor VIII, porcine recombinant) for the treatment of adult patients with acquired (not hereditary) hemophilia A.

[0057] 42. Glucagon-like peptide-1, rDNA (Trulicity), approved on September 18, 2014, to Eli Lilly & Co. for the treatment of adult patients with type 2 diabetes.

[0058] 43. Approval granted to Baxter (and Halozyme Therapeutics) on 9 / 12 / 2014 for Immunoglobulin & Hyaluronidase rDNA (Immunoglobulin Injection 10% (Human) with Recombinant Human Hyaluronidase - HYQVIA; Gammagard combined with Hylenex) for the treatment of adult patients with primary immunodeficiencies (PI).

[0059] 44. PD-1 mAb, rDNA (Keytruda-pembrolizumab; MK-3475), approved on September 4, 2014, to Merck & Co. for the treatment of patients with advanced melanoma that has not responded to other therapies.

[0060] 45. Insulin glargine, rDNA / Lilly (Basaglar), was granted tentative approval on August 18, 2014, to Eli Lilly & Co. in partnership with Boehringer Ingelheim for the treatment of diabetes.

[0061] 46. ​​Interferon beta-1a, PEG-, rDNA (Plegridy), approved on 8 / 15 / 2014 for Biogen Idec, for the treatment of relapsing forms of multiple sclerosis (RMS).

[0062] 47. C1-esterase inhibitor, rDNA (Conestat alfa-Rhucin; Ruconest; C1INH; C1-INH; Human complement C1 esterase inhibitor, recombinant, transgenic rabbit), approved on 7 / 17 / 2014 to Salix Pharmaceuticals, Ltd. (and Pharming Group NV) for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE).

[0063] 48. Approved on 6 / 27 / 2014 for MannKind Corp., Insulin, rDNA, Inhalation / MannKind (Insulin Human (rDNA Origin)) Inhalation Powder - Afrezza; Afresa Inhalation Powder; Technosphere Insulin) for improving glycemic control in adults with diabetes mellitus.

[0064] 49. Factor VIII / Biogen-Idec, rDNA (Eloctate), approved on 6 / 6 / 2014 to Biogen Idec Inc., for the treatment of hemophilia A.

[0065] 50. rDNA (Entyvio-vedolizumab), an integrin mAb, approved on 5 / 20 / 2014 to Takeda Pharmaceuticals America, Inc. for the treatment of ulcerative colitis and Crohn's disease.

[0066] 51. IL-6 mAb, rDNA (Sylvant-siltuximab; CNTO 328), approved on 4 / 23 / 2014 to Janssen / J&J for the treatment of multicentric Castleman disease (MCD).

[0067] 52. VEGF-2 mAb, rDNA (VEGRFr mAb-Cyramza; Ramucirumab), approved on 4 / 21 / 2014 to Eli Lilly & Co. for the treatment of advanced gastric cancer.

[0068] 53. GLP-1 / Albumin Fusion Protein, rDNA (Tanzeum-Glucagon-Like Peptide-1 (GLP-1)-Albumin Fusion Protein), approved on 4 / 15 / 2014 for GlaxoSmithKline (GSK) for glycemic control in type 2 diabetes.

[0069] 54. Factor IX-Fc fusion protein, rDNA (Coagulation Factor IX (recombinant), Fc fusion protein - Alprolix; Factor IX-XTEN), approved on 3 / 28 / 2014 for Biogen Idec, for the treatment of hemophilia B.

[0070] 55. Hyaluronic acid, cross-linked (Monovisc), approved on 2 / 25 / 2014 to Anika Therapeutics for the treatment of osteoarthritis of the knee.

[0071] 56. Leptin, rDNA (metreleptin-methionyl human leptin, recombinant), approved on 2 / 24 / 2014 as replacement therapy to treat complications of leptin deficiency.

[0072] 57. Approved on 2 / 14 / 2014 for BioMarin (marketed by DePuy Synthes, a division of Johnson & Johnson), N-acetylgalactosamine-6-sulfatase, rDNA (elosulfase alfa-vimizim; N-acetylgalactosamine-6-sulfatase; rhGALNS; BMN-110, elosulfase alfa; chondroitin sulfatase), for the treatment of mucopolysaccharidosis type IVA (Morquio A syndrome).

[0073] 58. Factor XIII, rDNA (Coagulation Factor XIII A Subunit (Recombinant)-Tretten), approved on 12 / 23 / 2013 to Novo Nordisk A / S for the routine prophylaxis of bleeding in adults and children with congenital factor XIII A subunit deficiency (hemophilia).

[0074] 59. Influenza Vaccine, H5N1 (Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted), approved on 22 / 11 / 2013 to ID Biomedical / GSK for the prevention of H5N1 influenza, commonly known as avian influenza; a full BLA has been approved for this vaccine, adjuvanted with egg-cultured AS03, for pandemic / biofense stockpile use only.

[0075] 60. rDNA / Roche (obinutuzumab-Gazyva; GA101), a CD20 mAb, approved on 1 November 2013 to Genentech / Roche for use in combination with chlorambucil chemotherapy for the treatment of previously untreated chronic lymphocytic leukemia (CLL).

[0076] 61. Tetanus and diphtheria toxoid adsorbed (Tenivac), approved to Sanofi on 25 / 10 / 2013, for the prevention of tetanus and diphtheria.

[0077] 62. Factor VIII, rDNA / Novo (Antihemophilic Factor (Recombinant)-NovoEight; Factor VIII, Recombinant), approved on 10 / 15 / 2013 for Novo Nordisk, for the treatment of hemophilia A.

[0078] 63. Flu vaccine, quadrivalent / GSK (Flulaval quadrivalent), approved for GlaxoSmithKline (GSK) on August 16, 2013, for the prevention of influenza.

[0079] 64. Complete BLA approved on 7 / 18 / 2013 to Janssen Biotech, Johnson & Johnson, TNF Mab, rDNA, human / J&J (golimumab-Simponi Aria) for the treatment of moderately to severely active rheumatoid arthritis.

[0080] 65. Factor IX, rDNA / Baxter (Coagulation Factor IX (Recombinant)-Rixubis), approved on 6 / 27 / 2013 to Baxter Healthcare for the treatment of hemophilia B.

[0081] 66. Fluzone Quadrivalent Influenza Vaccine, Approved by Sanofi on June 10, 2013, for the Prevention of Influenza

[0082] 67. Prothrombin Complex / CSL (Prothrombin Complex Concentrate (Human) - Kcentra), approved on 4 / 29 / 2013 to CSL Behring GmbH for the urgent reversal of acquired coagulation factor deficiencies induced by vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with sudden massive bleeding.

[0083] 68. Botulinum Antitoxin / AG (Botulinum Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Horse); Clostridium botulinum Toxin Immune Globulin, Horse) approved on 3 / 23 / 2013 to Cangene Corp. for the treatment of botulism after proven or suspected exposure to botulinum neurotoxin.

[0084] 69. HER2 receptor Mab-DM1, rDNA (ado-trastuzumab emtansine-Kadcyla; trastuzumab emtansine; trastuzumab-DM1; T-DM1; trastuzumab-MCC-DM1; Herceptin-DM1 conjugate), approved on 2 / 22 / 2013 to Genentech / Roche for the treatment of HER2-positive metastatic breast cancer (mBC).

[0085] 70. Apolipoprotein B, antisense (mipomersen-Kynamro; ISIS 301012), approved on 1 / 17 / 2013 to Isis Pharmaceuticals and Genzyme / Sanofi for use as an adjunct to lipid-lowering medications and diet to lower low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC), and non-high-density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

[0086] 71. Plasma SD / Octapharma (Octaplus - Plasma, solvent-detergent inactivated), approved for Octapharma AG on 1 / 17 / 2013 for the required replacement of clotting proteins (clotting factors).

[0087] 72. Influenza vaccine, rHA, rDNA (influenza vaccine, purified recombinant influenza hemagglutinin-FluBlok; influenza hemagglutinin vaccine, insect cell culture, recombinant), approved on 1 / 17 / 2013 to Protein Sciences Corp. and distributed by Emergent Biosolutions, Inc., for the prevention of influenza in persons 18 to 49 years of age.

[0088] 73. Glucagon-like peptide 2, rDNA (teduglutide (rDNA origin)-GATTEX), approved on 12 / 21 / 2012 to NPS Pharmaceutical for the treatment of adults with short bowel syndrome (SBS) who require additional nutrition from intravenous nutritional support (parenteral nutrition).

[0089] 74. Immunoglobulin (IGIV) / Biotest (Immunoglobulin Intravenous (Human) - Bivigam), approved on 12 / 20 / 2012 to Biotest Pharmaceuticals Corp., for the treatment of primary immunodeficiency disorders (PIDD).

[0090] 75. Varicella Zoster Immune Globulin / Cangene (Varicella Zoster Immune Globulin (Human)-VariZIG; VZVIG), approved on 12 / 19 / 2012 for Cangene Corp. for post-exposure prophylaxis of chickenpox in high-risk individuals to reduce the severity of chickenpox.

[0091] 76. Fluarix 4-valent (Influenza Virus Vaccine - Fluarix 4-valent), approved for GlaxoSmithKline (GSK) on 17 / 12 / 2012 for the prevention of disease caused by the four seasonal influenza (flu) virus subtype A and B strains represented by the antigens in this vaccine.

[0092] 77. Anthrax Mab, rDNA / HGSI (raxibacumab-ABthrax; Bacillus anthracis protective antigen human monoclonal antibody, recombinant), approved on 12 / 14 / 2012 to Human Genome Sciences Inc., a subsidiary of GlaxoSmithKline (GSK), for the treatment of inhalational anthrax when alternative therapies are not available or appropriate and for the prophylaxis of inhalational anthrax.

[0093] 78. Fibrin Sealant Patch / J&J (Fibrin Sealant Patch - Human Fibrinogen and Human Thrombin - EVARREST Fibrin Sealant Patch), manufactured by Omrix Biopharmaceuticals Ltd. (Israel), approved on 12 / 7 / 2012 to Ethicon Biosurgery, Johnson & Johnson (J&J), for use as an aid in stopping problematic bleeding during surgery.

[0094] 79. Influenza vaccine, MDCK-cultured / Novartis (Flucelvax; Optaflu; influenza virus vaccine, inactivated), approved for Novartis on 11 / 20 / 2012 for the prevention of seasonal influenza in persons 18 years of age and older (first cell-culture influenza vaccine in the United States).

[0095] 80. Microplasmin, rDNA (ocriplasmin-Jetrea), approved for ThromboGenics on 10 / 18 / 2012 for the treatment of symptomatic vitreomacular adhesion.

[0096] 81. A full BLA was approved on 8 / 30 / 2012 for Sicor Biotech (Teva Pharmaceuticals) for G-CSF, rDNA / Teva (filgrastim; the same active agent as Neupogen and TevaGrastin, approved in the EU as a biosimilar of Neupogen) to reduce the duration of severe neutropenia in patients with certain types of cancer (non-myeloid malignancies) receiving chemotherapy that affects the bone marrow.

[0097] 82. VEGF Trap, rDNA (ziv-aflibercept-Zaltrap), approved on 8 / 3 / 2012 to Sanofi (in collaboration with Regeneron) for use in combination with 5-flourouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of metastatic colorectal cancer (mCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.

[0098] 83. MenC-Hib vaccine (Meningitis groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine - MenHibrix) (previously approved vaccine combination), approved on 14 / 06 / 2012 for GlaxoSmithKline for the prevention of invasive disease caused by Neisseria meningitidis serogroup C and Y strains and Haemophilus influenzae type b.

[0099] 84. rDNA / 2C4 (pertuzumab-Perjeta; Omnitarg; 2C4), a HER2 receptor Mab, approved on June 8, 2012 to Genentech / Roche for use in combination with Herceptin (trastuzumab) and docetaxel chemotherapy for the first-line treatment of HER2-positive metastatic breast cancer.

[0100] 85. Glucocerebrosidase, rDNA / Protalix (taliglucerase alpha-Elelyso; Uplyso; beta-glucocerebrosidase, recombinant (expressed in carrot); prGCD) approved on 5 / 1 / 2012 to Protalix BioTherapeutics Inc. and Pfizer (BLA holder) for the treatment of Gaucher disease (may be considered a biobetter version of Cerezyme by Genzyme / Sanofi).

[0101] 86. Human Cell, Autologous / Bovine Collagen Matrix (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen - GINTUIT) approved on 3 / 9 / 2012 to Organogenesis Inc. for topical application to surgically created vascular wound beds in the treatment of gingival alveolar (gingival; oral tissue) conditions (first cell-based product for oral tissue application).

[0102] 87. Pancreatic enzyme (pancrelipase - Ultresa; Viokase) approved on 3 / 1 / 2012 to Aptalis Pharma for the treatment of a rare pancreatic insufficiency indication (first full approval for a long-marketed, vested drug product).

[0103] 88. sBLA approved on 2 / 29 / 2012 for MedImmune (AstraZeneca), influenza vaccine, live, intranasal tetravalent (FluMist tetravalent; influenza vaccine, live, intranasal) for the prevention of seasonal influenza.

[0104] 89. Carboxypeptidase, rDNA-(glucarpidase-Voraxaze; CPG2; carboxypeptidase G2, recombinant), approved on 1 / 18 / 2012 to BTG plc (formerly Protherics) for the treatment of methotrexate toxicity.

[0105] 90. VEGF Trap, rDNA-(aflibercept-Eylea; VEGF Trap-Eye), approved on 11 / 18 / 2011 to Regeneron Pharmaceuticals (distributed globally by Bayer) for the treatment of wet (neovascular) age-related macular degeneration (AMD).

[0106] 91. Asparaginase / Erwinia (Erwinaze - asparaginase Erwinia chrysanthemi; Erwinase; L-asparagine aminohydrolase; L-asparaginase), approved on 11 / 18 / 2011 to EUSA Pharma Inc., for the treatment of acute lymphoblastic leukemia (ALL).

[0107] 92. Approval granted on 11 / 10 / 2011 to New York Blood Center, Inc. for use in hematopoietic stem cell transplant procedures in patients with disorders affecting the hematopoietic (blood-forming) system, Umbilical Cord Blood Stem Cells-(HEMACORD; Hematopoietic Progenitor Cell-Umbilical Cord (HPC-C) Cell Therapy).

[0108] 93. CD30 mAb-monomethyl auristatin E- (Adcetris; brentuximab vedotin; CD30 mAb-cytotoxin conjugate), granted accelerated approval under orphan drug status on 8 / 19 / 2011 to Seattle Genetics, Inc., for the treatment of Hodgkin lymphoma; currently the only immunotoxin on the U.S. market.

[0109] 94. Centruroides (Scorpion) Immune F(ab)2 (Horse) Injection (Anascorp), manufactured by Instituto Bioclon, SA (Mexico), approved on August 3, 2011, to Rare Disease Therapeutics Inc. for the treatment of scorpion stings.

[0110] 95. Fibroblast, autologous (azfibrocel-T-laViv; Isolagen Therapy), approved on 6 / 22 / 2011 to Fibrocell Science, Inc., for the treatment of the appearance of nasolabial folds (laugh lines).

[0111] 96. CTLA4-Ig, rDNA (belatacept-Nulojix; BMS-224818; CTLA4-Ig variant; cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-immunoglobulin G1 fragment fusion protein, recombinant), approved on 6 / 15 / 2011 for Bristol-Myers Squibb (BMS) for the prevention of acute rejection in adult kidney transplant recipients.

[0112] 97. Approved on 6 / 3 / 2011 for Kedrion, SpA, Albumin, Human (Kedbumin), for the treatment of hypovolemic shock, hypoalbuminemia, prevention of central volume depletion after paracentesis due to ascites in cirrhosis, ovarian hyperstimulation syndrome (OHSS), adult respiratory distress syndrome (ARDS), burns, hemodialysis patients undergoing long-term dialysis, for patients unable to tolerate significant volumes of saline solution, and as a priming solution for cardiopulmonary bypass surgery.

[0113] 98. CTLA-4 Mab, rDNA / Medarex (Yervoy; ipilimumab; MDX-010; cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody, recombinant), approved on 3 / 25 / 2011 for Bristol-Myers Squibb (BMS) for the treatment of late-stage melanoma.

[0114] 99. Adenovirus Types 4 and 7 Vaccine, Live, Oral (consisting of Adenovirus Vaccine Type 4 and Adenovirus Vaccine Type 7), approved on March 16, 2011, to Teva Pharmaceuticals for the purpose of immunization of U.S. military personnel only.

[0115] 100. B-cell activator Mab, rDNA: (belimumab-Benlysta; LymphoStat-B), approved on 3 / 9 / 2011 to Human Genome Sciences, Inc. (for distribution with GlaxoSmithKline / GSK) for the treatment of adults with active, autoantibody-positive systemic lupus erythematosus.

[0116] 101. Factor XIII, Human, Approved on 2 / 17 / 2011 to CSL Behring for the Treatment of Factor XIII Deficiency: (Cortifact)

[0117] 102. Urate oxidase, rDNA, PEG-:(Pegloticase-Krystexxa; Puricase; PEG-uricase; Pig-baboon urate oxidase, recombinant, PEGylated), approved on 9 / 14 / 2010 to Savient Pharmaceuticals for the treatment of chronic refractory gout.

[0118] 103. Botulinum toxin A / Merz: (Xeomin; Clostridium botulinum toxin type A; NT 201), approved on 7 / 30 / 2010 to Merz Pharmaceuticals for the treatment of adults with spasmodic torticollis or blepharospasm.

[0119] 104. Antitrypsin, alpha-1 / Kamada: (alpha-1-proteinase inhibitor (human) - Glassia; Respira; alpha-1 antitrypsin; AAT; A1P1), approved on 7 / 1 / 2010 to Kamada Ltd. for the treatment of alpha-1-antitrypsin deficiency.

[0120] 105. RANKL Mab, rDNA: (Denosumab-Prolia; AMG 531; AMG 162. Receptor activator of nuclear factor-κB ligand (RANKL) monoclonal antibody, recombinant), approved on 6 / 1 / 2010 to Amgen Inc. for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture.

[0121] 106. Glucosidase, rDNA / Lumizyme: (Alglucosidase alfa-Lumizyme; alpha glucosidase; glucosidase alfa; rhGAA)), approved on 05 / 25 / 2010 to Genzyme Corp. for the treatment of Pompe disease.

[0122] 107. Prostate cancer cellular vaccine (rDNA), approved on 4 / 29 / 2010 to Dendreon Corp., for the treatment of asymptomatic or minimally symptomatic metastatic prostate cancer that is refractory to standard hormone therapy: (autologous antigen-presenting cells (APCs) primed with sipuleucel-T-Provenge-prostatic acid phosphatase (PAP)-granulocyte-macrophage colony-stimulating factor (GM-CSF) recombinant fusion protein (PAP-GM-CSF; PA2024); PA2024-loaded APCs; APC8015).

[0123] 108. Pancreaze / J&J: (Pancreaze; pancreatic enzyme product), NDA approved for Johnson & Johnson (J&J) on 4 / 12 / 2010 for the treatment of pancreatic insufficiency.

[0124] 109. Fibrin sealant / TachoSil (absorbable fibrin sealant patch), approved on 4 / 2 / 2010 to Nycomed Austria GmbH, for use as an adjunct to hemostasis in cardiovascular surgery when control of bleeding by standard surgical techniques such as suturing, ligation, or cauterization is ineffective or impractical.

[0125] 110. SCIG (Subcutaneous Immunoglobulin (Human) - Hizentra; (Vivaglobin is an older, lower concentration product) approved on 3 / 4 / 2010 to CSL Behring for the treatment of primary immunodeficiencies.

[0126] 111. Glucocerebrosidase, rDNA / Shire (velaglucerase alfa; ceramidase, glucosyl- (human HT-1080 cells); human glucosylceramidase (EC 3.2.1.45 or β-glucocerebrosidase), glycoform alpha; β-glucocerebrosidase), approved on 2 / 26 / 2010 to Shire Pharmaceutical for the treatment of Gaucher disease.

[0127] 112. The pneumococcal vaccine (13)-CRM197 (Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein)-Prevnar 13; Prevenar 13; Pneumococcal capsular antigen-diphtheria CRM197 protein conjugate vaccine; PCV13) was approved for Pfizer (developed by Wyeth) on February 24, 2010, for the prevention of pneumococcal-associated disease.

[0128] 113. Meningococcal conjugate vaccine / Novartis (Meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine - Menveo; MenACWY-CRM) approved for the prevention of invasive meningococcal disease by Novartis on 2 / 19 / 2010.

[0129] 114. Collagenase (Clostridial Collagenase-Xiaflex for Injection), approved on 2 / 3 / 2010 to Auxilium Pharmaceuticals Inc., for the treatment of Dupuytren's disease.

[0130] 115. Glucagon-like peptide-1, rDNA (liraglutide-Victoza; Arg34-GLP-1(7-37); GLP-1 (recombinant); NN-2211), approved on 1 / 25 / 2010 to Novo Nordisk for the treatment of type 2 diabetes.

[0131] 116. Interleukin-6 receptor Mab, rDNA (tocilizumab; Actemra; RoActemra; interleukin-6 receptor monoclonal antibody, recombinant; IL-6r Mab), approved on 1 / 8 / 2010 for Amgen, for the treatment of rheumatoid arthritis (RA).

[0132] 117. Influenza Vaccine, High Dose (Fluzone High Dose), approved on 12 / 23 / 2009 for Sanofi Pasteur for the prevention of influenza in persons 65 years of age and older; full BLA approved; this is a higher dose (60 Aμg of each influenza strain HA antigen versus 15 Aμg) formulation of Fluzone, the most used influenza vaccine in the United States (US).

[0133] 118. VWF / factor VIII complex (Wilate), approved on 12 / 4 / 2009 to Octapharma USA, Inc., for the treatment of von Willebrand disease (VWD).

[0134] 119. Kallikrein inhibitor, rDNA (ecallantide-Kalbitor; DX-88; kallikrein inhibitor protein, recombinant), approved on 12 / 1 / 2009 to Dyax Corp. for the treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age and older.

[0135] 120. Influenza vaccine / Novartis Italy (Agriflu), approved for Novartis on 27 / 11 / 2009 for the prevention of H1N1 (swine flu) influenza; this (or a similar) conventional inactivated egg-cultured vaccine has been produced in Siena (Italy) for a long time, primarily for the European market.

[0136] 121. Influenza Vaccine, H1N1 / GSK Canada, approved on November 10, 2009 to ID Biomedical, a subsidiary of GlaxoSmithKline (GSK), for the prevention of H1N1 (swine flu) influenza; a new and separate product, approved as a supplemental Biologics License Application (BLA). (This is the H1N1 analog or biosimilar / biogeneric monovalent version of Influenza Vaccine / GSK Canada (FluLaval)).

[0137] 122. CD20 Mab, human, rDNA (ofatumumab-Arzerra; HuMax-CD20; CD20 monoclonal antibody, human, recombinant), approved on 10 / 26 / 2009 to GlaxoSmithKline (and Genmab) for the treatment of chronic lymphocytic leukemia in patients who have not responded to Campath (alemtuzumab) or fludarabine.

[0138] 123. Antitrypsin, alpha-1 / Talecris (alpha-1-proteinase inhibitor (human)-prolastin-C; alpha-1-antitrypsin), approved on 10 / 19 / 2009 to Talecris Biotherapeutics for the treatment of alpha-1-antitrypsin (AAT) deficiency.

[0139] 124. HPV vaccine, rDNA / GSK (Cervarix MEDI 501; human papillomavirus (HPV) vaccine types 16 and 18 L1 virus-like particle, recombinant), approved on 10 / 16 / 2009 to GlaxoSmithKline, Inc., for the prevention of cervical cancer in women.

[0140] 125. C1-esterase inhibitor / CSL (Berinert P; C1INH; C1-INH; complement C1 esterase inhibitor, plasma-derived), approved on 10 / 09 / 2009 to CSL Behring LLC for the acute treatment of hereditary angioedema (HAE).

[0141] 126. IL-12 / 23 p40 Mab, rDNA (ustekinumab-STELARA; CNTO 1275; interleukin-12 (IL-12) and interleukin-23 (IL-23) p40 subunit monoclonal antibody, human, recombinant), approved on 9 / 25 / 2009 to Centocor Ortho Biotech Inc. (Johnson & Johnson) for the treatment of moderate to severe plaque psoriasis.

[0142] 127. Immunoglobulin (IGIV) / Bio Products (Immunoglobulin Intravenous (Human)-Gammaplex), approved on 9 / 17 / 2009 to Bio Products Lab., for the treatment of primary humoral immune deficiencies.

[0143] 128. Influenza vaccine, H1N1 / Novartis, approved on September 15, 2009, to Novartis AG for the prevention of H1N1 (swine flu) influenza; a new and separate product, but approved as a supplemental Biologics License Application (BLA).

[0144] 129. Influenza vaccine, H1N1 / Sanofi, approved on 15 / 09 / 2009 to Sanofi-Pasteur for the prevention of H1N1 (swine flu) influenza; a new and separate product, but approved as a supplemental Biologics License Application (BLA).

[0145] 130. Influenza vaccine, H1N1 / CSL, approved on 15 / 9 / 2009 to CSL Ltd. for the prevention of H1N1 (swine flu) influenza; a new and separate product, approved as a supplemental Biologics License Application (BLA).

[0146] 131. Influenza Vaccine, Live rDNA, H1N1, approved on 9 / 15 / 2009 for MedImmune (AstraZeneca) for the prevention of H1N1 (swine flu) influenza; a novel and separate product, approved as a supplemental Biologics License Application (BLA).

[0147] 132. Haemophilus b vaccine / GSK (Hiberix; Haemophilus influenzae type b vaccine; Hib vaccine), approved for GlaxoSmithKline (GSK) on August 19, 2009, as a Hib vaccine booster dose for children 15 months to 4 years of age.

[0148] 133. Interferon betaser, rDNA / Novartis (interferon beta-1b-Extavia; 2-166-interferon beta1 (human fibroblast-derived (reduced)), 17-L-serine-; interferon betaser, recombinant; NVF233), approved on 8 / 15 / 2009 to Novartis Pharmaceuticals for the indication of multiple sclerosis.

[0149] 134. Interleukin-1 Mab, rDNA (canakinumab-Ilaris; interleukin-1 beta monoclonal antibody; ACZ885), approved on 6 / 17 / 2009 to Novartis Pharmaceuticals for the treatment of Cryopyrin Associated Periodic Syndrome (CAPS).

[0150] 135. Pancreatic Enzymes / Solvay (pancrelipase-Creon; pancreatic enzyme, porcine origin), approved for Solvay on 5 / 1 / 2009 for the treatment of exocrine pancreatic enzyme insufficiency.

[0151] 136. A BLA was approved on 4 / 29 / 2009 for Ipsen for the treatment of spasmodic torticollis, and simultaneously an sBLA was approved for Medicis for Reloxin (a renamed Dysport), botulinum toxin A / Ipsen (abobotulinum toxin A - Dysport; Reloxin; Clostridium botulinum toxin type A) for the treatment of glabellar (frown) wrinkles.

[0152] 137. TNF Mab, rDNA, human / J&J (Simponi; golimumab; CNTO 148; tumor necrosis factor-α human monoclonal antibody, recombinant), approved on April 24, 2009, to Centocor Ortho Biotech Inc. / Johnson&Johnson for the treatment of three types of immune dysfunction-associated arthritis.

[0153] 138. Japanese encephalitis vaccine / Intercell-(Ixiaro; Japanese encephalitis SA14-4-2 virus vaccine; IC51), approved on March 30, 2009 to Intercell Biomedical (marketed by Novartis), for the prevention of Japanese encephalitis.

[0154] 139. Antithrombin III, rDNA (antithrombin III (human)-ATryn; rhATIII; AT-III, recombinant transgenic goat), approved on 2 / 6 / 2009 to GTC Biotherapeutics, Inc. (Genzyme) for the prevention of blood clots in patients with antithrombin deficiency.

[0155] 140. Fibrinogen / CSL (Fibrinogen Concentrate (Human)-RiaSTAT; Haemocomplettan P; Factor I), approved on 1 / 16 / 2009 to CSL Behring, for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia).

[0156] 141. C1-esterase inhibitor / Sanquin (Cinryze; CetorA; C1INH; C1-INH; complement C1 esterase inhibitor, plasma-derived), approved on 10 / 10 / 2008 to Lev Pharmaceuticals for the routine prevention of angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE; C1 inhibitor deficiency).

[0157] 142. Insulin aspart, rDNA, 50 / 50 mixture, approved for Novo Nordisk on 8 / 26 / 2008 (Novolog mixture 50 / 50; biphasic insulin aspart 50 / 50), for the treatment of diabetes mellitus.

[0158] 143. Thrombopoietin peptibody, rDNA (romiplostim-NPLATE; AMG-531; Amgen megakaryopoietin-poietin-mimetic peptibody, recombinant), approved on 8 / 22 / 2008 for Amgen, for the treatment of adults with chronic thrombocytopenic purpura (ITP).

[0159] 144. DTaP-Hib-Polio Vaccine / Sanofi (Pentacel; ActHIB reconstituted with diphtheria-tetanus toxoid and sterile pertussis adsorbent combined with inactivated poliovirus vaccine; ActHIB+Quadracel; diphtheria & tetanus toxoid & sterile pertussis vaccine adsorbent + Haemophilus influenzae type b (Hib) vaccine + poliovirus vaccine (inactivated) (human diploid cells)) approved for Sanofi Pasteur on 6 / 20 / 2008 (as a combination of two previously approved combination vaccines, these two are mixed before administration and BIOPHARMA does not consider this to be a new, separate / exclusive product).

[0160] 145. Interferon alpha-2b, rDNA, PEG- + ribavirin (PEGPAK; PEG-Intron and ribavirin combination packaging), approved for Schering-Plough on 6 / 13 / 2008, for the treatment of chronic hepatitis C.

[0161] 146. Approved on 4 / 23 / 2008 for UCB (marketed in the US by Bayer Schering), TNF Mab Fab', rDNA, PEG-(certolizumab pegol-Cimzia; CDP 870; tumor necrosis factor monoclonal antibody Fab fragment, recombinant--polyethylene glycol (PEG) polymer conjugate) for the treatment of resistant Crohn's disease in adults.

[0162] 147. Rotavirus vaccine, live / GSK (Rotavirus vaccine, live, oral, monovalent - Rotarix; RIX-4414), approved on 4 / 4 / 2008 for GlaxoSmithKline (GSK) for the prevention of rotavirus gastroenteritis in infants.

[0163] 148. Approved on 3 / 24 / 2008 to GlaxoSmithKline, DTaP-IPV / GSK (Diphtheria & Tetanus Toxoid & Sterile Pertussis Vaccine Adsorbed + Poliovirus Vaccine (Inactivated) (Human Diploid Cells) – Kinrix) for childhood vaccination.

[0164] 149. Fibrin Sealant / Baxter (Fibrin Sealant, VH S / D 4-Artiss; Fibrin Sealant, Steam-Heated Solvent / Surfactant Treated) approved on 3 / 19 / 2008 to Baxter Healthcare for use in attaching skin grafts to burn patients. (This appears to be the next generation and replacement for Tisseel Kit VH.)

[0165] 150. Interleukin-1 trap, rDNA (Arcalyst; Rilonacept; IL-1 Trap, recombinant), approved on 2 / 27 / 2008 to Regeneron Pharmaceuticals Inc., for the long-term treatment of two Cryopyrin-Associated Periodic Syndrome (CAPS) disorders: Familial Cold Auto-Inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

[0166] 151. Antihemophilic Factor (Recombinant), Plasma / Albumin Free (Xyntha; Recombinant Coagulation Factor VIII; Updated Version of ReFacto, Now with Non-Human or Animal Products Used in Its Manufacturing or Formulation), for the Treatment of Hemophilia A; Full BLA Approved for Wyeth on 2 / 21 / 2008.

[0167] 152. Somatropin, rDNA / Cangene (Somatropin (rDNA origin) Injectable - Accretropin) - 505(b)(2) follow-on protein, NDA approved on 1 / 24 / 2008 to Cangene Corp. (marketed by Apotex) for the treatment of growth failure or short stature in children.

[0168] 153. Thrombin, rDNA (Recothrom; thrombin, recombinant; rhThrombin), approved on 08 / 1 / 17 to ZymoGenetics, Inc., to help stop bleeding from small blood vessels after surgery.

[0169] 154. EPO, rDNA, PEG-(long-acting erythropoietin receptor activator; Mircera; CERA; epoetin alfa (recombinant), pegylated; methoxypolyethylene glycol-epoetin beta)), approved on 07 / 11 / 14 to Hoffmann-La Roche Inc. for the treatment of anemia associated with chronic renal failure in adults.

[0170] 155. HDE approved on 07 / 10 / 29 to Genzyme Corp., Skin, Cultured / Epicel (Cultured Epidermal Autograft - Epicel; Cultured Autologous Keratinocyte Service; CEA) for the treatment of life-threatening wounds resulting from severe burns.

[0171] 156. Influenza vaccine / CSL (influenza virus vaccine, trivalent, types A and B - AFLURIA; Fluvax; Enzira), approved on 28 / 09 / 07 to CSL Ltd., for the prevention of influenza.

[0172] 157. Smallpox Vaccine / Vero, approved on 07 / 08 / 31 to Acambis plc for the prevention of smallpox (in the Biological Defense Stockpile).

[0173] 158. Thrombin / Omrix (Evithrom), approved on 8 / 27 / 2007 to Omrix Biopharmaceuticals for the control of hemorrhage (inaccessible / otherwise untreatable blood exudation and minor bleeding from capillaries and venules).

[0174] 159. Fibrin sealant / Thermogenesis (CryoSeal Fibrin Sealant System; CryoSeal FS System; cryoprecipitate + thrombin, autologous), approved on 7 / 26 / 2007 to Thermogenesis Corp., for control of bleeding during liver surgery.

[0175] 160. Immune Globulin (IGIV), liquid / CSL (Immune Globulin Intravenous (Human), 10% liquid - Privigen), approved on 7 / 26 / 2007 to CSL BioPlasma Inc., for the treatment of primary immunodeficiencies.

[0176] 161. Influenza vaccine, H5N1 / Sanofi (influenza virus vaccine, H5N1; pandemic influenza vaccine; avian influenza vaccine), approved on 4 / 17 / 2007 to Sanofi Pasteur Inc., for active immunization of adults at high risk of exposure to H5N1 influenza virus (for use in the event of an avian influenza-related influenza epidemic / pandemic).

[0177] 162. Parexel, somatropin, rDNA / BioPartners (Somatropin (rDNA origin for injection) - Valtropin; human growth hormone, recombinant), approved on 4 / 19 / 2008 to a CRO acting on behalf of LG Life Sciences, for the treatment of growth failure.

[0178] 163. Protein C, plasma-derived (Seprotin), approved on 3 / 27 / 2007 to Baxter Healthcare for the treatment of severe congenital protein C deficiency.

[0179] 164. Complement C5 Mab, rDNA (eculizumab-Soliris; complement C5 monoclonal antibody, recombinant), approved on 3 / 16 / 2007 to Alexion Pharmaceuticals, Inc., for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

[0180] 165. Poly-4-hydroxybutyrate, rDNA, approved on 2 / 12 / 2007 to Tepha, Inc. for use as a surgical suture (TephaFLEX absorbable suture; poly-4-hydroxybutyrate; P4HB; poly(4HB); PHA4400).

[0181] 166. Albumin (human) (one of many albumin products), approved on 06 / 10 / 17 to Octapharma Pharmazeutika Produktionsgesm.bH, for restoring and maintaining circulatory blood volume.

[0182] 167. Influenza Vaccine / ID Biomedical (Influenza Virus Vaccine, Trivalent - FluLaval; Fluviral), approved on 06 / 10 / 05 for GlaxoSmithKline (merged with ID Biomedical) for active immunization against influenza in adults 18 years of age and older.

[0183] 168. EGF receptor Mab, human, rDNA (panitumumab-Vectibix; ABX-EGF; epidermal growth factor receptor monoclonal antibody, human, recombinant; E7.6.3; rHuMAb-EGFr; transgenic XenoMouse-derived human EGF receptor Mab), approved on 9 / 27 / 2006 to Amgen Inc. "for the treatment of patients with metastatic colorectal cancer expressing epidermal growth factor receptor (EGFr) after disease progression, during or after a fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimen."

[0184] 169. Iduronate 2-sulfatase, rDNA (Idursulfase; Elaprase; L-iduronate 2-sulfate sulfatase precursor; recombinant; I2S; chondroitin sulfatase) approved on 7 / 24 / 2006 to Shire Pharmaceuticals Group plc (through its acquisition of Transkaryotic Therapies, Inc.) for the treatment of Hunter syndrome (mucopolysaccharidosis II; MPS II).

[0185] 170. VEGF Mab Fab, rDNA (Lucentis; vascular endothelial growth factor monoclonal antibody fragment, recombinant), approved on 6 / 30 / 2006 to Genentech, Inc., for the treatment of age-related macular degeneration.

[0186] 171. HPV Vaccine, rDNA / Merck (tetravalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine; Gardasil; human papillomavirus (HPV) types 6, 11, 16, and 18 L1 virus-like protein (VLP), recombinant), approved on June 8, 2006 for Merck & Co., Inc., for vaccination in females 9 to 26 years of age for the prevention of disease caused by human papillomavirus (HPV) types 6, 11, 16, and 18.

[0187] 172. Somatropin, rDNA / Sandoz (Somatropin (rDNA origin)-Omnitrope; human growth hormone, recombinant), approved on 5 / 30 / 2006 to Sandoz, Inc., a subsidiary of Novartis AG, for the treatment of growth hormone deficiency.

[0188] 173. Varicella Virus Vaccine / Adult (Varicella Zoster Vaccine (Live) (Oka / Merck); Zostavax; Varicella Virus Vaccine for Adults), approved on 5 / 25 / 2006 for Merck & Co., Inc., for the prevention of herpes zoster (shingles) in persons 60 years of age and older.

[0189] 174. Glucosidase, rDNA (alglucosidase alpha-Myozyme; Pompase; alpha glucosidase; glucosidase alpha (rhGAA) (recombinant)), approved on 4 / 28 / 2006 to Genzyme Corp., for the treatment of Pompe disease.

[0190] 175. Rotavirus Vaccine, rDNA / Merck (Rotavirus Vaccine, Quintavalent-RotaTeq; WC3 Pentavalent Vaccine), approved on February 3, 2006 to Merck & Co., Inc., for the prevention of rotavirus gastroenteritis in children.

[0191] 176. Hepatitis B immune globulin, im / Cangene (hepatitis B immune globulin (human); HepaGam B), approved on 1 / 27 / 2006 to Cangene Corp., for postexposure prophylaxis after acute exposure to hepatitis B virus.

[0192] 177. Insulin, rDNA, inhaled / Pfizer, approved on 1 / 27 / 2006 to Pfizer, Inc., for the treatment of adults with type 1 and type 2 diabetes (Exubera insulin, recombinant powder for inhalation).

[0193] 178. Immunoglobulin (SCIG) (Vivaglobin), approved on 1 / 9 / 2006 to ZLB Behring, for the treatment of primary immunodeficiencies.

[0194] 179. CTLA4-Ig, rDNA (Orencia; abatacept; cytotoxic T-lymphocyte-associated antigen 4--immunoglobulin G1 fragment fusion protein, recombinant; BMS-188667), approved on 12 / 26 / 2005 to Bristol-Myers Squibb Co. for the second-line treatment of rheumatoid arthritis in adult patients with moderate to severe disease.

[0195] 180. Insulin-like growth factor-1 / IGFBP-3, rDNA (Mecasermin rinfibate-IPLEX; SomatoKine; Insulin-like growth factor-I--insulin-like growth factor-binding-3 protein complex, recombinant; IGF-1 / IGFBP3 complex), approved on 12 / 12 / 2005 to Insmed Inc. for the treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.

[0196] 181. Approval for hyaluronidase, rDNA (Hylenex; Enhanze SC; Cumulase; Chemophase; rHuPH20; PH-20 hyaluronidase, recombinant human), Hyelex (formerly Enhanze SC), approved on 12 / 5 / 2005 to Halozyme Therapeutics Inc. for use as a "spreading agent" to enhance local anesthesia, delivery of contrast media, and for subcutaneous fluid replacement (subcutaneous infusion therapy), for sale by Baxter.

[0197] 182. Hyaluronidase, ovine / Primapharm (Hydase), approved on 10 / 25 / 2005 to PrimaPharm, Inc. for use as a "spreading agent" to enhance local anesthesia, contrast delivery, and for subcutaneous fluid replacement (subcutaneous infusion therapy).

[0198] 183. PDGF, rDNA / bone matrix (platelet-derived growth factor (PDGF)-BB, recombinant with inorganic bone matrix; rhPDGF-BB; GEM 21S), approved on 10 / 21 / 2005 to BioMimetic Therapeutics, Inc. for distribution by Osteohealth Co. (Luitpold Pharmaceuticals, Inc., Sankyo Co., Ltd.) for the treatment of alveolar bone defects and associated gingival recession.

[0199] 184. Measles-Mumps-Rubella & Chickenpox Vaccine (Measles, Mumps, Rubella, and Chickenpox (Oka / Merck) Virus Vaccine Live-ProQuad; MMR II+Varivax Vaccine), approved for Merck & Co., Inc. on September 6, 2005, for vaccination against measles, mumps, rubella (German measles), and varicella (chickenpox) in children 12 months to 12 years of age.

[0200] 185. Influenza vaccine / GSK Canada, approved on 8 / 31 / 2005 to GlaxoSmithKline Biologicals (Influenza virus vaccine, trivalent, types A and B - Fluarix) for the prevention of influenza.

[0201] 186. Influenza vaccine approved on 8 / 31 / 2005 to Sachsische Serumwerke AG / GSK Germany for distribution by GlaxoSmithKline for the prevention of influenza (influenza virus vaccine, trivalent - Fluarix; Influsplit SSW; Alpharix).

[0202] 187. Insulin-like growth factor-1, rDNA / Tercica (Insulin-like growth factor-1, recombinant - Increlex; IGF-1), approved on 8 / 31 / 2005 to Tercica, Inc. (in partnership with Genentech) for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone.

[0203] 188. Calcitonin, rDNA (Calcitonin (Salmon)-Fortical; Calcitonin, Recombinant), approved on 8 / 15 / 2005 to Unigene, Inc. (sold by Upsher-Smith Labs.) for the treatment of postmenopausal osteoporosis.

[0204] 189. Insulin detemir, rDNA- (Insulin detemir, recombinant-Levemir), approved on 6 / 17 / 2005 to Novo Nordisk Inc. for the treatment of diabetes mellitus (types 1 and 2; (long-acting recombinant insulin analog)

[0205] 190. dTpa Booster / Sanofi (tetanus toxoid, attenuated diphtheria toxoid, and sterile pertussis adsorbed - Adacel; dTpa; Tdap), approved on June 10, 2005, to Aventis Pasteur Ltd. for use as a tetanus, diphtheria, and pertussis (whooping cough) booster vaccine for persons 11 to 64 years of age.

[0206] 191. Arylsulfatase B, rDNA (N-acetylgalactosamine 4-sulfatase-Naglazyme; Aryplase; Galsulfase; Chondroitinase; rhASB (recombinant)), approved on 5 / 31 / 2005 to BioMarin Pharmaceutical Inc., for the treatment of mucopolysaccharidosis VI (MPS VI).

[0207] 192. dTpa Booster / GSK (tetanus toxoid, attenuated diphtheria toxoid, and sterile pertussis adsorbed-Boostrix; dTpa; Tdap), approved on 5 / 3 / 2005 to GlaxoSmithKline Biologicals SA for use as a tetanus, diphtheria, and pertussis (whooping cough) booster vaccine for persons 10 to 18 years of age.

[0208] 193. Tetanus toxoid / Chiron (tetanus toxoid concentrate (for further manufacturing uses)), approved on 3 May 2005 to Chiron Behring GmbH & Co. (Chiron Corp.; merged with Novartis AG) for use as a component of the Boostrix combination vaccine (see above).

[0209] 194. Vaccinia immune globulin, iv / Cangene (VIG; VIVIG), approved on 5 / 3 / 2005 to Cangene Corp. for the treatment of a rare complication of smallpox vaccination (a severe systemic skin or other serious infection caused by the live vaccinia virus in the current smallpox vaccine).

[0210] 195. Hyaluronidase, rDNA (Cumulase; Enhanze SC; Chemophase; rHuPH20; PH-20 Hyaluronidase, Recombinant Human) approved for Halozyme Therapeutics, Inc., for use in in vitro fertilization (IVF) procedures (oocyte preparation prior to IVF) - Medical device approval for Cumulase on 4 / 19 / 2005.

[0211] 196. Vaccinia immune globulin, iv / DVC (VIG; VIGIV), approved on 2 / 18 / 2005 to DynPort Vaccine Co. LLC for the treatment of a rare complication of smallpox vaccination (a severe systemic skin or other serious infection caused by the live vaccinia virus in the current smallpox vaccine).

[0212] 197. Thrombin, Concentrate (Thrombin (Human) (For Further Manufacturing Use)) approved on 2 / 18 / 2005 to Baxter Healthcare Corp. for the further manufacture of FloSeal Matrix Hemostatic Sealant, used to control bleeding.

[0213] 198. Meningococcal conjugate vaccine (Menactra; meningococcal (Groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine; MCV-4), approved on January 14, 2005, for Sanofi Pasteur Inc., for the prevention of meningococcal disease in adolescents and adults aged 11 to 55 years.

[0214] 199. Approved on 12 / 17 / 2004 to Eyetech Pharmaceuticals, Inc., VEGF aptamer, PEG-(pegaptanib sodium-Macugen; vascular endothelial growth factor / vascular permeability factor (VEGF) aptamer, synthetic oligonucleotide, PEGylated) for the treatment of neovascular (wet) age-related macular degeneration.

[0215] 200. Keratinocyte growth factor, rDNA* (Palifermin-Kepivance; des1-23 KGF; 24-163 fibroblast growth factor 7 (human)), approved on 12 / 15 / 2004 to Amgen Inc., for the treatment of severe oral mucositis (stomatitis) in patients with blood cancers receiving high-dose chemotherapy followed by bone marrow transplantation.

[0216] 201. Integrin Mab, rDNA (Tysabri-natalizumab; Antegren; integrin alpha(4) humanized monoclonal antibody), approved on 11 / 24 / 2004 to Biogen Idec for the treatment of multiple sclerosis (formerly Antegren (trade name), now Tysabri; change at FDA request).

[0217] 202. Hyaluronidase, bovine / Amphastar-(Hyaluronidase, bovine-Amphadase), approved on 10 / 24 / 2004 to Amphastar Pharmaceuticals, Inc., for use as a "diffusing agent," e.g., as an adjuvant to improve absorption and dispersion of other injected drugs; for subcutaneous infusion therapy; and as an adjuvant in subcutaneous urography to improve absorption of radiopaque agents.

[0218] 203. Enfuvirtide, synthetic (T-20; Fuzeon; pentafuside; DP-178), full approval (upgraded from accelerated approval granted in March 2003), approved on 10 / 15 / 2004 to Hoffmann-La Roche Inc., for the treatment of HIV-1 infection in combination with other antiretrovirals in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy (synthetic peptide, not a biologic).

[0219] CD15 Mab-Tc 99m radioconjugate (technetium (99mTc) fanolesomab; Neutrospec; Leutech; TC99M-labeled CD15 monoclonal antibody) approved on 7 / 2 / 2004 to Palatin Technologies, Inc. for diagnostic imaging of appendicitis in patients aged 204.5 years or older with equivocal signs of appendicitis.

[0220] 205. Luteinizing hormone, rDNA (Lutropin alfa-Luveris; human luteinizing hormone, recombinant), approved on 5 / 24 / 2004 to Serono, Inc., for the treatment of infertility (stimulation of ovarian follicle development in infertile hypogonadotropic hypogonadal women with severe LH deficiency, in combination with FSH (Gonal-f)).

[0221] 206. Immunoglobulin (IGIV) / Octapharma (Octagam; immunoglobulin intravenous (human)), approved on 5 / 21 / 2004 for Octapharma AG, for the treatment of primary immunodeficiencies.

[0222] 207. Hyaluronidase, ovine (Vitrase; hyaluronic acid 4-glycanohydrolase), approved on 5 / 4 / 2004 to ISTA Pharmaceuticals Inc., for use as a diffusing agent to promote dispersion and absorption of drugs, particularly as a local anesthetic during ophthalmic surgery; for subcutaneous infusion therapy; and as an adjuvant in subcutaneous urography to improve absorption of radiopaque agents.

[0223] 208. Insulin glulisine, rDNA (Apidra; (LysB3, GluB29) insulin; insulin (human), 3B-l-lysine, 29B-l-glutamic acid, recombinant), approved on 4 / 16 / 2004 to Aventis Pharma for use as a rapid-acting insulin for the treatment of diabetes mellitus.

[0224] 209. VEGF Mab, rDNA (Avastin; bevacizumab; vascular endothelial growth factor monoclonal antibody, recombinant), approved on 2 / 26 / 2004 to Genentech, Inc., for use in combination with 5-fluorouracil for the treatment of metastatic carcinoma of the colon or rectum.

[0225] 210. Approved on 2 / 12 / 2004 to ImClone Systems Inc. (EGF receptor Mab, rDNA (cetuximab-Erbitux; IMC-C225; epidermal growth factor receptor monoclonal antibody, recombinant), for sale by Bristol-Myers Squibb Co., for use in combination with irinotecan in the treatment of patients with EGFR-expressing metastatic colorectal cancer that is resistant to irinotecan-based chemotherapy, and for the monotherapy treatment of patients with EGFR-expressing metastatic colorectal cancer that is intolerant to irinotecan-based chemotherapy.

[0226] 211. Rho(D) immunoglobulin / ZLB (Rho(D) immunoglobulin intravenous (human) - Rhophylac), approved on 2 / 12 / 2004 to ZLB Bioplasma AG for pre- and post-partum prophylaxis of Rho(D) immunization in Rho(D)-negative women.

[0227] 212. Hyaluronic acid / Anika (ORTHOVISC high molecular weight hyaluronan), approved on 2 / 5 / 2004 to Anika Therapeutics, Inc. for distribution in the U.S. by Ortho Biotech Products, LP (Johnson & Johnson) for the treatment of pain associated with osteoarthritis of the knee.

[0228] 213. Immunoglobulin intravenous (human) (Flebogamma), approved on 12 / 18 / 2003 to Instituto Grifols (Probitas Pharma) for the treatment of primary immunodeficiencies.

[0229] 214. Hyaluronic acid / Medicis (Restylane), approved 12 / 12 / 2003 to Medicis Pharmaceutical Corp. for the correction of moderate to severe facial wrinkles and grooves, e.g., nasolabial folds (lines / grooves near the nose and mouth).

[0230] 215. CD11a Mab, rDNA (efalizumab-Raptiva; CD11a monoclonal antibody, recombinant), approved on 10 / 27 / 2003 to Genentech, Inc. and Xoma Ltd. for the treatment of moderate to severe psoriasis in adults who are candidates for systemic therapy or phototherapy.

[0231] 216. Botulism Immune Globulin Intravenous (Human) (BabyBIG), approved on 10 / 23 / 2003 to the California Department of Health Services for the treatment of infant botulism caused by Clostridium botulinum types A or B.

[0232] 217. Full approval was granted on 8 / 29 / 2003 to Serono Inc. for the treatment of HIV patients with wasting or cachexia, Somatropin, rDNA / Serono (Somatropin (rDNA origin)-Serostim; Human Growth Hormone, Recombinant).

[0233] 218. Factor VIII, rDNA, PFM (Antihemophilic Factor (recombinant), Plasma / Albumin-Free Method - Advate; Factor VIII, recombinant; rAHF-PFM), approved on 7 / 25 / 2003 to Baxter Hyland Immuno for the treatment of hemophilia A.

[0234] 219. Supplemental Biologics License Application (BLA) approved on 7 / 24 / 2003 to Amgen Inc., TNF receptor-IgG Fc, rDNA (etanercept-Enbrel; tumor necrosis factor receptor 2-immunoglobulin G1 Fc fusion protein, recombinant) for the treatment of active ankylosing spondylitis.

[0235] 220. Antitrypsin, alpha-1 / Aventis (alpha-1-proteinase inhibitor (human) - Zemaira), approved on 7 / 8 / 2003 to Aventis Behring LLC for long-term breast augmentation and maintenance therapy in individuals with evidence of alpha-1-proteinase inhibitor deficiency and emphysema.

[0236] 221. Approved on 6 / 27 / 2003 to Corixa Corp. (formerly Coulter Pharmaceutical) (marketed by GlaxoSmithKline (GSK)), CD20 Mab, rDNA-I 131 radioconjugate (iodine I 131 tositumomab-Bexxar; CD20 monoclonal antibody-iodine I 131 radioimmunoconjugate) for the treatment of patients with CD20-positive follicular non-Hodgkin's lymphoma (NHL) (with or without transformation) whose disease is resistant to rituximab and has relapsed after chemotherapy.

[0237] 222. Approved on 6 / 20 / 2003 to Genentech, Inc. (manufactured by Tanox, Inc. and parallel marketed by Novartis Pharmaceutical Corp.), immunoglobulin E Mab, rDNA (omalizumab-Xolair; rhuMab-E25; immunoglobulin E25 monoclonal antibody, recombinant; IgE Mab, rDNA) for the treatment of moderate to severe allergic asthma.

[0238] 223. Hirudin, desulfato-rDNA / Aventis (Iprivask; Desirudin; Revasc; desulfatohirudin; Hirudin, desulfato-recombinant), approved 4 / 3 / 2003 to Aventis Pharma for the prevention of deep vein thrombosis, which may result in pulmonary embolism, in patients undergoing elective total hip replacement surgery.

[0239] 224. Influenza vaccine, live rDNA, frozen (FluMist), approved on 6 / 17 / 2003 to MediImmune Vaccines, Inc. (a subsidiary of MediImmune, Inc.) for the prevention of influenza in healthy persons 5 to 50 years of age.

[0240] 225. Iduronidase, rDNA (Laronidase; Aldurazyme; α-L-iduronidase), approved on 4 / 30 / 2003 to Biomarin Pharmaceutical Inc. (and Genyzme Corp.) for the treatment of mucopolysaccharidosis I (MPS I).

[0241] 226. Galactosidase beta, rDNA (agalsidase beta-Fabrazyme; alpha-galactosidase A), approved on 4 / 24 / 2003 to Genzyme Corp., for the treatment of Fabry disease.

[0242] 227. Somatropin antagonist, PEG-, rDNA (Pegvisomant-Somavert; somatropin antagonist, PEGylated, recombinant), approved on 3 / 25 / 2003 to Pharmacia Corp. for the treatment of acromegaly.

[0243] 228. Enfuvirtide, synthetic (T-20; Fuzeon; pentafuside; DP-178), approved on 3 / 15 / 2003 to Hoffmann-La Roche Inc., for the treatment of HIV infection.

[0244] 229. LFA-3 / IgG1, rDNA (Alefacept; Amevive; leukocyte function-associated antigen-3 / immunoglobulin G (IgG) fusion protein, recombinant), approved on 1 / 30 / 2003 to Biogen Corp. for the treatment of moderate to severe chronic plaque psoriasis.

[0245] 230. Antitrypsin, alpha-1 / Baxter (alpha-1 proteinase inhibitor (human); Aralast; alpha-1 antitrypsin; AAT; A1P1), approved on 1 / 9 / 2003 to Alpha Therapeutic Corp. (marketed by Baxter) for enzyme replacement therapy in patients with heredity emphysema (AAT deficiency).

[0246] 231. TNF Mab, rDNA, human (adalimumab; Humira; D2E7; tumor necrosis factor-alpha human monoclonal antibody), approved on 12 / 30 / 2002 to Abbott Laboratories for the treatment of rheumatoid arthritis.

[0247] 232. DTaP & Hepatitis B & Polio Vaccine (Diphtheria-Tetanus Toxoid and Sterile Pertussis (Adsorbed Purified), Hepatitis B (Recombinant), and Inactivated Poliovirus Vaccine (Combined); Pediarix; Infanrix+Engerix-B+IPOL) approved on 12 / 13 / 2002 to GlaxoSmithKline Inc. for the prevention of diphtheria, tetanus, pertussis (whooping cough), hepatitis B, and polio - combined vaccine; poliovirus vaccine (mixture of three inactivated strains) is the only component not previously approved.

[0248] 233. Parathyroid hormone (1-34), rDNA (Teriparatide (rDNA origin); Forteo; LY333334; Parathyroid hormone (1-34), recombinant), approved on 11 / 26 / 2002 to Eli Lilly & Co., for the treatment of osteoporosis.

[0249] 234. Interferon alfa-2a, rDNA, PEG- (peginterferon alfa-2a; Pegasys; interferon alfa-2a, recombinant, pegylated), approved on 10 / 16 / 2002 to Hoffmann-La Roche Inc., for the first-line treatment of chronic hepatitis C.

[0250] 235. Urate oxidase, rDNA (urate oxidase, recombinant; rasburicase; re-Uox; Elitek; Fasturtec), approved on 7 / 16 / 2002 to Sanofi-Synthelabo for the control of plasma uric acid levels (hyperuricemia) in pediatric patients receiving tumor lysis and cancer chemotherapy that results in elevated uric acid.

[0251] 236. Bone morphogenetic protein-2, rDNA (bone morphogenetic protein-2, recombinant; BMP-2; INFUSE Bone Graft)-PMA, approved 7 / 2 / 2002 to Medtronic Sofamor Danek, which uses recombinant bmp-2 (from Genetics Institute / Wyeth) as part of the INFUSE Bone Graft / LT-CAGE Lumbar Tapered Fusion Device for the treatment of certain types of spinal degenerative disc disease (lumbar spinal fusion).

[0252] 237. DTaP Vaccine / Aventis Canada Diphtheria-Tetanus Toxoid and Sterile Pertussis Adsorbed (DTaP) (DAPTACEL)-BLA, approved on 5 / 14 / 2002 to Aventis Pasteur, Ltd., for the first four doses of a diphtheria-tetanus toxoid and pertussis vaccination series administered to infants and children 6 weeks to 7 years of age.

[0253] 238. Botulinum toxin type A purified neurotoxin complex (BOTOX COSMETIC), approved as a supplemental BLA on 4 / 12 / 2002 to Allergan, Inc., for the temporary improvement of the appearance of moderate to severe glabellar wrinkles ("frown lines") secondary to corrugator supercilii and / or procerus muscle activity in adult patients <65 years of age.

[0254] 239. Secretin, synthetic (SecreFlo; porcine secretin), approved on 4 / 5 / 2002 to Repligen Corp. for the diagnosis of gastrinomas (tumors that secrete gastrin) and pancreatic disorders.

[0255] 240. Interferon beta-1a, rDNA / Serono (Rebif), approved on 3 / 7 / 2002 to Serono, Inc., for the treatment of relapsing forms of multiple sclerosis.

[0256] 241. Approved on 2 / 29 / 2002 to IDEC Pharmaceuticals Corp., CD20 Mab / Y-90 radioconjugate (ibritumomab tiuxetan; Zevalin; CD20 monoclonal antibody-chelating group conjugate); regimen includes rituximab, indium-111 ibritumomab tiuxetan, and yttrium-90 ibritumomab tiuxetan, for the treatment of B-cell non-Hodgkin's lymphoma.

[0257] 242. G-CSF, rDNA, PEG-(pegfilgrastim; Neulasta; pegylated granulocyte colony-stimulating factor), approved on 1 / 31 / 2002 to Amgen, Inc., for the treatment of febrile neutropenia in patients receiving chemotherapy for nonmyeloid malignancies.

[0258] IB container Optionally in all embodiments, the primary drug container has a F of less than 15N. i The plunger breakloose force is expressed by F less than 5N. m and the number of particles greater than 2 microns during a two-year shelf life is less than 2000; optionally, the syringe containing the monoclonal antibody is stored at a temperature ranging from 4° C. to 25° C.

[0259] In any embodiment, optionally, the primary drug container can be a syringe, cartridge, or vial, optionally a delivery device, optionally a pre-filled syringe or a pre-filled cartridge.

[0260] Optionally in any embodiment, the primary drug container may be made of glass or a thermoplastic, preferably an injection-moldable thermoplastic, optionally selected from COC (cyclic olefin copolymer), COP (cyclic olefin polymer), polypropylene, PET (polyethylene terephthalate), polycarbonate, polystyrene, or a combination of any two or more thereof. COP containers are specifically contemplated.

[0261] Containers should be manufactured to have a low particle count. For example, the following measures may be useful:

[0262] Supervised and controlled ISO Class 7 Manufacturing Room.

[0263] To ensure low particle load and avoid bioburden contamination, open container products are processed under additional HEPA airflow for part handling to achieve ISO Class 5 for particles.

[0264] Automation of the molding and coating cells is used to minimize manual part handling.

[0265] Process control in molding and coating to reduce particle generation and cosmetic defects.

[0266] Empty Container Inspection - Automated online particle inspection for empty containers. Detects 50 μm particles with <5% false positives.

[0267] Optionally in all embodiments, the secondary packaging for the container does not include Tyvek.

[0268] IC drug contact coating Optionally in any embodiment, the drug contact coating is essentially SiO x C y H z wherein x is from 0.5 to 2.4, optionally from 1.3 to 1.9, as measured by X-ray photoelectron spectroscopy (XPS); y is from 0.6 to 3, optionally from 0.8 to 1.4, as measured by XPS; · z is 2 to 9, optionally 2 to 6, as measured by Rutherford backscattering.

[0269] Optionally in all embodiments, the thickness of the drug contact coating is from 5 nm to 1000 nm, optionally from 10 nm to 500 nm, optionally from 10 nm to 300 nm.

[0270] Optionally in all embodiments, the drug contact coating is lubricious.

[0271] Optionally in all embodiments, the drug contact coating is a solid lubricious coating.

[0272] Optionally in all embodiments, the drug contact coating is a pH protective coating.

[0273] Optionally in all embodiments, the drug contact coating is SiO , applied by plasma enhanced chemical vapor deposition (PECVD). x C y H z where x is 0.5 to 2.4, y is 0.6 to 3 (x and y are measured by X-ray photoelectron spectroscopy (XPS)), and z is 2 to 9 (z is measured by Rutherford backscattering analysis). A "lubricious coating" is defined as a coating that reduces the breakloose-force or maintenance force required to advance a plunger within a syringe barrel compared to the breakloose-force or maintenance force required for a syringe that would occur under otherwise identical conditions without the lubricious coating. This is the fourth of the four-layer coatings described herein. The properties and applications of lubricious coatings are described in WO 2013 / 071138, which is incorporated herein by reference. One contemplated lubricious coating, sometimes referred to as l-OMCTS, has the molecular formula SiO , prepared using octamethylcyclotetrasiloxane (OMCTS) as the organosilicon precursor. x C y H z wherein x is 0.5 to 2.4, y is 0.6 to 3 (x and y are measured by X-ray photoelectron spectroscopy (XPS)), and z is 2 to 9 (z is measured by Rutherford backscattering analysis).

[0274] Optionally in all embodiments, the drug contact coating is a gas barrier coating, an elutable barrier coating, or both.

[0275] Optionally in all embodiments, the drug contact coating is plasma treated to provide reduced protein adhesion.

[0276] Optionally in any embodiment, the drug contact coating or treatment increases protein adhesion without returning these adhesive proteins to solution, thus not increasing the number of particles in the container, but rather reducing the number of particles in the container over a long shelf life.

[0277] Optionally in any embodiment, a drug container is provided having a multi-layer PECVD coating, the final coating of which is a drug contact coating. Optionally in any embodiment, the multi-layer coatings contemplated herein are each a SiO 2 coating as described herein, applied by plasma-enhanced chemical vapor deposition (PECVD). x C y H z an adhesive or bonding coating or layer of SiO as described herein x and a barrier coating or layer of SiO as described herein. x C y H z Optionally in any embodiment, the multi-layer coatings contemplated herein may be a three-layer coating, including a pH protective coating or layer (in this case, a drug contact layer) of SiO , optionally applied by plasma-enhanced chemical vapor deposition (PECVD) in the manner described elsewhere herein. x C y H z Adhesive or bonding coatings or layers of SiO x a barrier coating or layer of SiO x C y H zand a lubricious coating or layer (in this case the drug contact layer) of 1-OMCTS.

[0278] Optionally in all embodiments, the drug contact coating is chemically homogeneous. "Homogeneous" refers to the PECVD drug contact coating, which is characterized by the difference in the SiO 2 content at different locations in a given container. x C y H z is defined as having an atomic standard deviation (%) of less than 5%, alternatively less than 4%, alternatively less than 3%, alternatively less than 2%, alternatively less than 1% for each element (Si, C, and O) as determined by X-ray photoelectron spectroscopy (XPS) analysis.

[0279] Optionally in all embodiments, the drug contact coating does not include a fluid lubricant.

[0280] Optionally in all embodiments, the drug contact coating is free of silicone oil.

[0281] ID additional PECVD coating In all embodiments, optionally, the primary drug container also has a barrier coating or layer that provides a barrier improvement factor of at least 3, optionally at least 5, optionally at least 10, optionally at least 20, optionally at least 50.

[0282] Optionally, in all embodiments, the primary drug container also has an adhesive coating or layer disposed between the interior surface and the PECVD drug contact coating.

[0283] Optionally in any embodiment, the primary drug container also has a pH protective coating or layer for a pH of 5 to 9. Optionally in any embodiment, the pH protective coating has a silicon decomposition rate of less than 1 μg / day (micrograms per day), alternatively less than 0.5 μg / day, alternatively less than 0.4 μg / day, alternatively less than 0.3 μg / day, alternatively less than 0.2 μg / day when the lumen contains water for injection, alternatively the drug, or an aqueous phosphate buffered test solution having a pH of 5 to 8.

[0284] Optionally in any embodiment, the drug contact coating is essentially PECVD SiO x C y H z a coating or layer, wherein x is from 0.5 to 2.4, optionally from 1.3 to 1.9, as measured by X-ray photoelectron spectroscopy (XPS); y is from 0.6 to 3, optionally from 0.8 to 1.4, as measured by XPS; · z is 2 to 9, optionally 2 to 6, as measured by Rutherford backscattering.

[0285] Optionally, in any embodiment, the primary drug container may have a PECVD SiO 2 layer between the drug contact coating and the interior surface. x A barrier coating or layer, and PECVD SiO between the barrier coating or layer and the interior surface x C y H z It may further comprise an adhesive coating or layer.

[0286] Suitable coatings, coating sets, and surface treatments are shown in FIG. 6 and further discussed herein.

[0287] Bonding Coating or Layer 6, a bonding coating or layer, sometimes referred to as an adhesive coating or layer, is provided. The bonding coating or layer optionally functions to improve adhesion of the barrier coating or layer to a substrate, particularly a thermoplastic substrate, while the bonding layer can be used to improve adhesion to a glass substrate or to another coating or layer.

[0288] Optionally, the tie coating or layer improves adhesion of the barrier coating or layer to the substrate or wall. For example, to improve adhesion of the barrier layer or coating to the substrate, a tie coating or layer, also referred to as an adhesive layer or coating, can be applied to the substrate and the barrier layer can be applied to the adhesive layer. Optionally, the adhesive or tie coating or layer is also believed to reduce stress on the barrier coating or layer, making the barrier layer less susceptible to damage from thermal expansion or contraction or mechanical shock.

[0289] Optionally, a tie coating or layer applied underneath the barrier coating or layer can improve the function of a pH protective coating or layer applied over the barrier coating or layer.

[0290] Optionally, the adhesive or bonding coating or layer is also believed to decouple defects between the barrier coating or layer and the COP substrate. This is believed to result from the fact that any pinholes or other defects that may form when the adhesive or bonding coating or layer is applied tend not to persist when the barrier coating or layer is applied, such that pinholes or other defects in one coating do not match defects in the other coating. Optionally, the adhesive or bonding coating or layer has some effectiveness as a barrier layer, such that even defects that would provide a leak path through the barrier coating or layer are blocked by the adhesive or bonding coating or layer.

[0291] Optionally, the bond coating or layer is SiO x C y Hz or SiN x C y H z Preferably, SiO x C y H z SiO x C y H z may comprise, or essentially comprise, SiO x C y H z where x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from 2 to 9, optionally from 2 to 6, as measured by Rutherford backscattering. The atomic ratios of Si, O, and C in the bond coating or layer 289 can optionally be: Si 100:O 50-150:C 90-200 (i.e., x = 0.5 to 1.5, y = 0.9 to 2); Si 100:O 70-130:C 90-200 (i.e., x = 0.7 to 1.3, y = 0.9 to 2) Si 100:O 80-120:C 90-150 (i.e., x = 0.8 to 1.2, y = 0.9 to 1.5) Si 100:O 90-120:C 90-140 (i.e., x=0.9 to 1.2, y=0.9 to 1.4), or Si 100:O 92-107:C 116-133 (i.e., x = 0.92 to 1.07, y = 1.16 to 1.33). It could be.

[0292] The atomic ratio can be determined by XPS. Taking into account H atoms that are not measured by XPS, therefore, the bond coating or layer 289 may, in one embodiment, be of the formula Si w O x C y H z (or its equivalent SiO x C y), for example, where w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9. Thus, typically, bond coating or layer 289 will contain 36% to 41% carbon, normalized to 100% carbon + oxygen + silicon.

[0293] Optionally, the tie coating or layer can be similar or identical in composition to the pH protective coating or layer 286 described elsewhere herein, although this is not required.

[0294] Optionally, the bond coating or layer 289 is, on average, 5 to 200 nm (nanometers), optionally 5 to 100 nm, optionally 5 to 20 nm thick. These thicknesses are not critical. Generally, although not necessarily, the bond coating or layer 289 will be relatively thin because its function is to modify the surface properties of the substrate.

[0295] Tie coating or layer 289 has an inner surface facing lumen 212 and an outer surface facing the inner surface of wall 214. Optionally, tie coating or layer 286 is at least coextensive with the barrier coating or layer. Optionally, the tie coating or layer is applied by PECVD from a precursor feed material including, for example, octamethylcyclotetrasiloxane (OMCTS), tetramethyldisiloxane (TMDSO), or hexamethyldisiloxane (HMDSO).

[0296] Barrier Coating or Layer With reference to FIG. 6, a barrier coating or layer can optionally be applied to the container of a pharmaceutical package, e.g., a thermoplastic package, by plasma-enhanced chemical vapor deposition (PECVD) or other chemical vapor deposition process to prevent oxygen, carbon dioxide, or other gases from entering the container, the barrier coating optionally being effective to reduce the ingress of atmospheric gases into the lumen compared to an uncoated container and / or to prevent leaching of medicinal material into or through the package wall.

[0297] A barrier coating or layer may optionally be applied directly or indirectly to the thermoplastic wall to reduce the oxygen and / or moisture transmission rate.

[0298] The barrier coating or layer may optionally be silicon oxide, titanium oxide, or zinc oxide applied directly or indirectly to the COP thermoplastic wall to reduce the oxygen and / or moisture transmission rate.

[0299] A barrier coating or layer can optionally be applied directly or indirectly to the thermoplastic wall of a plastic container (e.g., an adhesive or bond coating or layer can be interposed therebetween) so that in the filled pharmaceutical packaging or other container, the barrier coating or layer is located between the interior or inner surface of the wall and the lumen adapted to contain the fluid to be stored. x is carried by the thermoplastic wall of the plastic container. Barrier coatings or layers described elsewhere herein or in U.S. Pat. No. 7,985,188 can be used in any embodiment.

[0300] The barrier layer may optionally be a layer of SiO x " coatings, containing silicon, oxygen, and optionally other elements, where x, the ratio of oxygen atoms to silicon atoms, is from about 1.5 to about 2.9, or from 1.5 to about 2.6, or about 2. Some suitable barrier compositions are, for example, those where x is 2.3.

[0301] Optionally, the barrier coating or layer 288 is 2 to 1000 nm thick, optionally 4 nm to 500 nm thick, optionally 10 to 200 nm thick, optionally 20 to 200 nm thick, optionally 20 to 30 nm thick, and is SiO x where x is from 1.5 to 2.9. xThe barrier coating or layer 288 has an inner surface 220 facing the lumen 212 and an outer surface 222 facing the inner surface of the bonding coating or layer 289. For example, a barrier coating or layer such as 288 of any embodiment can be applied to a thickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150 nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm, or at least 800 nm, or at least 900 nm. The barrier coating or layer may be at most 1000 nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick.

[0302] Ranges of 4 nm to 500 nm thick, optionally 7 nm to 400 nm thick, optionally 10 nm to 300 nm thick, optionally 20 nm to 200 nm thick, optionally 20 to 30 nm thick, and optionally 30 nm to 100 nm thick are contemplated. Specific thickness ranges consisting of any one of the minimum thicknesses recited above plus any one thickness greater than or equal to the maximum thickness recited above are expressly contemplated.

[0303] SiO x or other barrier coatings or layers, the thickness can be measured by, for example, transmission electron microscopy (TEM) and the composition can be measured by X-ray photoelectron spectroscopy (XPS).

[0304] Optionally, the barrier coating or layer is effective to reduce the ingress of atmospheric gases into the lumen compared to a container not including the barrier coating or layer. Optionally, the barrier coating or layer provides a barrier to oxygen permeating the wall. Optionally, the barrier coating or layer is a barrier to leaching of the wall composition by the contents of the lumen.

[0305] pH protective coating or layer SiO as defined herein x It has been found that certain barrier coatings or layers, such as SiO , possess the property of being entities that measurably diminish in barrier improvement in less than six months as a result of attack by certain relatively high pH contents of the coated containers described elsewhere herein, particularly when the barrier coating or layer is in direct contact with the contents. x have found that the barrier layer or coating of SiO is eroded or dissolved by some fluids, for example, aqueous compositions having a pH above about 5. Because coatings applied by chemical vapor deposition can be very thin—tens to hundreds of nanometers thick—even a relatively slow rate of erosion can remove or reduce the effectiveness of the barrier layer in less time than the desired shelf life of the product packaging. This is particularly problematic for aqueous fluid pharmaceutical compositions, many of which have a pH similar to that of blood and other human or animal bodily fluids, near 7, or more broadly in the range of 4 to 8, or even 5 to 9. The higher the pH of a pharmaceutical preparation, the more likely it is that SiO will be dissolved. x Optionally, this problem can be addressed by protecting the barrier coating or layer 288, or other pH-sensitive material, with a pH-protective coating or layer 286.

[0306] The pH protective coating or layer optionally provides protection of the underlying barrier coating or layer, including surfactants, from the contents of the container having a pH of 4 to 8. For prefilled pharmaceutical packages that contact the contents of the lumen, from the time it is manufactured to the time it is used, the pH protective coating or layer optionally prevents or inhibits attack of the barrier coating or layer sufficiently to maintain an effective oxygen barrier throughout the intended shelf life of the prefilled syringe. The rate of erosion, dissolution, or leaching (other names for related concepts) of the pH protective coating or layer, if directly contacted by the fluid, is lower than the rate of erosion of the barrier coating or layer when directly contacted by a fluid having a pH of 5 to 9. The pH protective coating or layer is effective to separate fluids having a pH of 5 to 9 from the barrier coating or layer for at least a period of time sufficient to allow the barrier coating to function as a barrier throughout the shelf life of the pharmaceutical package or other container.

[0307] We have developed a SiO 2 film formed from a polysiloxane precursor as the top layer shown in FIG. x C y H z or SiN x C y H z It has further been discovered that certain pH protective coatings or layers of SiO 2 , which have a substantial organic component, do not erode rapidly when exposed to fluids, and in fact erode or dissolve more slowly than Type 1 borosilicate glass when the fluid has a pH within the range of 4 to 8 or 5 to 9. For example, at pH 8, the rate of decomposition of a pH protective coating or layer made from the precursor octamethylcyclotetrasiloxane, or OMCTS, is significantly slower. Thus, SiO 2 x C y H z or SiN x C y H z These pH protective coatings or layers of SiO xThe protective layer can be used to cover the barrier layer of SiO , thereby preserving the benefits of the barrier layer by protecting it from fluids in pharmaceutical packaging. x The layer is then coated with the contents stored in the container (wherein the contents are otherwise SiO x SiO x is applied over at least a portion of the layer.

[0308] Although the present invention does not rely on the accuracy of the following theory, it is further believed that pH protective coatings or layers effective in preventing corrosion can be made from siloxanes and silazanes as described in this disclosure: SiO 2 coated from cyclic siloxane or linear silazane precursors, such as octamethylcyclotetrasiloxane (OMCTS). x C y H z or SiN x C y H z The coatings are believed to contain complete cyclic siloxane rings and longer runs of repeating units of the precursor structure. These coatings are believed to be nanoporous yet structured and hydrophobic, and these properties are believed to contribute to their success as pH protective coatings or layers. This is shown, for example, in U.S. Patent No. 7,901,783. SiO x C y H z or SiN x C y H z The coating can also be applied from a linear siloxane or linear silazane precursor, such as hexamethyldisiloxane (HMDSO) or tetramethyldisiloxane (TMDSO).

[0309] The inventors offer the following theory for the application of the pH protective coatings or layers described herein: The present invention is not limited by the correctness of this theory or to the embodiments that can be foreseen by use of this theory.

[0310] SiO x The decomposition rate of the barrier layer is believed to depend on the SiO bonds within the layer. Oxygen bonding sites (silanols) are believed to increase the decomposition rate.

[0311] OMCTS-based pH protective coatings or layers are typically made of SiO x It bonds with silanol sites on the barrier layer to form SiO x It is believed that this "heals" or passivates the surface, thus dramatically slowing the rate of degradation. In this hypothesis, the thickness of the OMCTS layer is not the direct means of protection - the direct means is the thickness of the SiO x Surface passivation. It is contemplated that the pH protective coating or layer as described herein can be improved by increasing the crosslink density of the pH protective coating or layer.

[0312] The pH protective coating or layer is optionally effective to cause the barrier coating or layer to remain at least substantially undegraded as a result of attack by the fluid 218 for a period of at least six months.

[0313] The pH protective coating or layer may optionally prevent or reduce precipitation of compounds or components of the composition in contact with the pH protective coating or layer, and in particular may prevent or reduce insulin precipitation or blood clotting compared to uncoated surfaces and / or surfaces coated with a barrier using HMDSO as a precursor.

[0314] 1 and 2, the pH protective coating or layer 286 may be Si, as defined above. w O x C y H z (or its equivalent SiO x C y ) or Si w N x C y H z or its SiN equivalent x C y ), preferably SiOx C y H z wherein x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from 2 to 9, optionally from 2 to 6, as measured by Rutherford backscattering. The atomic ratios of Si, O, and C in the pH protective coating or layer 286 are optionally: Si 100:O 50-150:C 90-200 (i.e., x = 0.5 to 1.5, y = 0.9 to 2); Si 100:O 70-130:C 90-200 (i.e., x = 0.7 to 1.3, y = 0.9 to 2) Si 100:O 80-120:C 90-150 (i.e., x = 0.8 to 1.2, y = 0.9 to 1.5) Si 100:O 90-120:C 90-140 (i.e., x = 0.9 to 1.2, y = 0.9 to 1.4) Si 100:O 92-107:C 116-133 (i.e., x=0.92 to 1.07, y=1.16 to 1.33), or Si 100:O 80-130:C 90-150 It could be.

[0315] Alternatively, the pH protective coating or layer can have an atomic concentration of less than 50% carbon and greater than 25% silicon, as determined by X-ray photoelectron spectroscopy (XPS), normalized to 100% carbon, oxygen, and silicon. Alternatively, the atomic concentrations are 25 to 45% carbon, 25 to 65% silicon, and 10 to 35% oxygen. Alternatively, the atomic concentrations are 30 to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, the atomic concentrations are 33 to 37% carbon, 37 to 47% silicon, and 22 to 26% oxygen.

[0316] Optionally, the atomic concentration of carbon in the pH protective coating or layer, as determined by X-ray photoelectron spectroscopy (XPS), normalized to 100% carbon, oxygen, and silicon, can exceed the atomic concentration of carbon in the atomic formula for the organosilicon precursor. For example, embodiments are contemplated in which the atomic concentration of carbon is increased by 1 to 80 atomic percent, alternatively 10 to 70 atomic percent, alternatively 20 to 60 atomic percent, alternatively 30 to 50 atomic percent, alternatively 35 to 45 atomic percent, or alternatively 37 to 41 atomic percent.

[0317] Optionally, the atomic ratio of carbon to oxygen in the pH protective coating or layer can be increased compared to the organosilicon precursor, and / or the atomic ratio of oxygen to silicon can be decreased compared to the organosilicon precursor.

[0318] Optionally, the pH protective coating or layer can have an atomic concentration of silicon that is less than the atomic concentration of silicon in the atomic formula for the feed gas, normalized to 100% carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS). For example, embodiments are contemplated in which the atomic concentration of silicon is reduced by 1 to 80 atomic percent, alternatively 10 to 70 atomic percent, alternatively 20 to 60 atomic percent, alternatively 30 to 55 atomic percent, alternatively 40 to 50 atomic percent, or alternatively 42 to 46 atomic percent.

[0319] Alternatively, any embodiment contemplates a pH protective coating or layer that can be characterized by a sum formula, where the atomic ratio C:O can be increased and / or the atomic ratio Si:O can be decreased compared to the sum formula of the organosilicon precursor.

[0320] The atomic ratio of Si:O:C or Si:N:C can be determined by XPS (X-ray photoelectron spectroscopy). Thus, taking into account H atoms, the pH protective coating or layer may in one aspect be of the formula Siw O x C y H z , or its equivalent SiO x C y For example, when w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9, optionally from about 2 to about 6.

[0321] The thickness of the applied pH protective coating or layer is optionally 10 to 1000 nm; alternatively 10 nm to 900 nm; alternatively 10 nm to 800 nm; alternatively 10 nm to 700 nm; alternatively 10 nm to 600 nm; alternatively 10 nm to 500 nm; alternatively 10 nm to 400 nm; alternatively 10 nm to 300 nm; alternatively 10 nm to 200 nm; alternatively 10 nm to 100 nm; alternatively 10 nm to 50 nm; alternatively 20 nm to 1000 nm; alternatively 50 nm to 1000 nm; alternatively 50 nm to 800 nm; optionally 50 to 500 nm; optionally 100 to 200 nm; alternatively 100 nm to 700 nm; alternatively 100 nm to 200 nm; alternatively 300 to 600 nm. The thickness need not be uniform throughout the container, and preferred values ​​will typically vary in different parts of the container.

[0322] The pH protective coating or layer has a pH of 1.25 to 1.65 g / cm as determined by X-ray reflectivity (XRR). 3 , or 1.35 to 1.55 g / cm 3 , or 1.4 to 1.5 g / cm 3 , or 1.4 to 1.5 g / cm 3 , or 1.44 to 1.48 g / cm 3 Optionally, the organosilicon compound can be octamethylcyclotetrasiloxane, and the pH protective coating or layer can have a density that may be higher than the density of a pH protective coating or layer made from HMDSO as the organosilicon compound under the same PECVD reaction conditions.

[0323] The pH protective coating or layer may optionally have an RMS surface roughness value (as measured by AFM) of from about 5 to about 9, optionally from about 6 to about 8, and optionally from about 6.4 to about 7.8. a The surface roughness value can be from about 4 to about 6, optionally from about 4.6 to about 5.8. The R max The surface roughness value can be from about 70 to about 160, optionally from about 84 to about 142, and optionally from about 90 to about 130.

[0324] The pH protected inner surface may optionally have a contact angle (using distilled water) of from 90° to 110°, optionally from 80° to 120°, optionally from 70° to 130°, as measured by Goniometer Angle measurement of a water droplet on the pH protected surface in accordance with ASTM D7334-08, "Standard Practice for Surface Wettability of Coatings, Substrates and Pigments by Advancing Contact Angle Measurement."

[0325] Optionally, the FTIR absorbance spectrum of the pH protective coating or layer 286 of any embodiment has a ratio of the maximum amplitude of the normally positioned Si-O-Si symmetric stretching peak between about 1000 and 1040 cm to the maximum amplitude of the normally positioned Si-O-Si asymmetric stretching peak between about 1060 and about 1100 cm greater than 0.75. Alternatively, in any embodiment, this ratio can be at least 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or at least 1.2. Alternatively, in any embodiment, this ratio can be at most 1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at most 1.3. Any minimum ratio described herein can be combined with any maximum ratio described herein as an alternative embodiment of the invention of Figures 1-5.

[0326] Optionally, in all embodiments, the pH protective coating or layer 286 has a non-oily appearance in the absence of a pharmaceutical agent, which has been observed in some cases to distinguish an effective pH protective coating or layer from a lubricious layer, which has been observed in some cases to have an oily (i.e., shiny) appearance.

[0327] Optionally, for pH protective coating or layer 286 in any embodiment, the silicon degradation rate (measured in the absence of pharmaceutical agent to avoid altering the dissolution reagent) at 40° C. in 50 mM potassium phosphate buffer diluted with water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt % polysorbate 80 surfactant is less than 170 ppb / day. (Polysorbate 80 is a common component of pharmaceutical preparations, available, for example, as Tween®-80 from Uniqema Americas LLC, Wilmington Delaware.)

[0328] Optionally, for containers up to 10 mL, the pH protective coating or layer in any embodiment, the silicon decomposition rate is less than 160 ppb / day, or less than 140 ppb / day, or less than 120 ppb / day, or less than 100 ppb / day, or less than 90 ppb / day, or less than 80 ppb / day. Optionally, the silicon decomposition rate is greater than 10 ppb / day, or greater than 20 ppb / day, or greater than 30 ppb / day, or greater than 40 ppb / day, or greater than 50 ppb / day, or greater than 60 ppb / day. For the pH protective coating or layer 286 in any embodiment, any minimum ratio described herein can be combined with any maximum ratio described herein.

[0329] Optionally, for the pH protective coating or layer in any embodiment, upon dissolution from the container in a test composition having a pH of 8, the total silicon content of the pH protective coating or layer and the barrier coating is less than 66 ppm, or less than 60 ppm, or less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.

[0330] The pH protective coating or layer has an inner surface facing the lumen 212 and an outer surface facing the inner surface of the barrier coating or layer 288. Optionally, the pH protective coating or layer is at least coextensive with the barrier coating or layer 288. Alternatively, the pH protective coating or layer may be narrower in extent than the barrier coating, such as when fluids do not or rarely come into contact with certain portions of the barrier coating that lack the pH protective coating or layer. Alternatively, the pH protective coating or layer 286 may be broader in extent than the barrier coating, as it may cover areas where no barrier coating is provided.

[0331] The pH protective coating or layer 286 can optionally be applied by plasma-enhanced chemical vapor deposition (PECVD) of a precursor feedstock comprising an acyclic siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazanes, a polycyclic silazanes, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors. Some specific, non-limiting precursors contemplated for such use include octamethylcyclotetrasiloxane (OMCTS).

[0332] Optionally, the FTIR absorbance spectrum of the pH protective coating or layer 286 ranges from about 1000 to 1040 cm -1 The maximum amplitude of the Si-O-Si symmetric stretching peak is from about 1060 to about 1100 cm -1 The ratio of the maximum amplitude of the Si-O-Si asymmetric stretching peak to the maximum amplitude of the Si-O-Si asymmetric stretching peak is greater than 0.75.

[0333] In the presence of a fluid composition having a pH of 5 to 9 contained in the lumen, the calculated shelf life of the container is up to 36 months at a storage temperature of 4° C. Optionally, the rate of erosion of the pH protective coating or layer 286, if directly contacted by a fluid composition having a pH of 8, is less than 20%, optionally less than 15%, optionally less than 10%, optionally less than 7%, optionally 5% to 20%, optionally 5% to 15%, optionally 5% to 10%, optionally 5% to 7%, of the rate of erosion of the barrier coating or layer when directly contacted by the same fluid composition under the same conditions. Optionally, the fluid composition removes the pH protective coating or layer 286 at a rate of 1 nm or less of pH protective coating or layer thickness per 44 hours of contact with the fluid composition.

[0334] The rate of silicon degradation of the pH protective coating or layer and the barrier coating or layer from the container by 50 mM potassium phosphate buffer, optionally diluted with water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt% polysorbate 80 surfactant, is less than 170 parts per billion (ppb) per day for containers up to 10 mL.

[0335] Optionally, the total silicon content of pH protective coating or layer 286 and barrier coating or layer 288 upon dissolution from the container in 0.1 N aqueous potassium hydroxide at 40° C. is less than 66 ppm for containers up to 10 mL.

[0336] Optionally, the calculated shelf life (total Si / Si decomposition rate) of the container 210 is greater than 2 years.

[0337] Optionally, the pH protective coating or layer 286 exhibits an O-parameter of less than 0.4, measured using attenuated total reflection (ATR), as measured as follows:

number

[0338] The O-parameter is defined in U.S. Patent No. 8,067,070, where O-parameter values ​​of 0.4 to 0.9 are most commonly claimed. The O-parameter can be measured from physical analysis of an FTIR amplitude plot versus wavenumber to find the numerator and denominator of the above equation, as shown in Figure 5 of U.S. Patent No. 8,067,070, except annotated to show the interpolation of wavenumber and absorbance scales, at 1253 cm -1 and an absorbance of 0.0424 at 1000 to 1100 cm -1 A maximum absorbance of 0.08 at 0.08 is derived, resulting in a calculated O-parameter of 0.53. The O-parameter can also be determined from the number of absorbance versus wavenumber data.

[0339] U.S. Patent No. 8,067,070 asserts that the claimed O-parameter range provides an excellent pH protective coating or layer, relying solely on experiments using HMDSO and HMDSN, both of which are acyclic siloxanes. Surprisingly, the inventors have discovered that O-parameters outside the range claimed in U.S. Patent No. 8,067,070 provide even better results than those obtained with U.S. Patent No. 8,067,070. Alternatively, in the embodiments of Figures 1-5, the O-parameter has a value of 0.1 to 0.39, or 0.15 to 0.37, or 0.17 to 0.35.

[0340] Optionally, the pH protective coating or layer exhibits an N-parameter of less than 0.7, measured using attenuated total reflection (ATR), as measured as follows:

number

[0341] The N-parameter is also described in U.S. Pat. No. 8,067,070 and is measured similarly to the O-parameter, except that the intensity at two specific wavenumbers (neither of these wavenumbers is a range) is used. U.S. Pat. No. 8,067,070 claims a passivation layer having an N-parameter of 0.7 to 1.6. Again, the inventors have produced better coatings using a pH protective coating or layer 286 having an N-parameter of less than 0.7, as described above. Alternatively, the N-parameter has a value of at least 0.3, or 0.4 to 0.6, or at least 0.53.

[0342] Si w O x C y H z or its equivalent SiO x C y The protective coating or layer may also have utility as a hydrophobic layer, regardless of whether it also functions as a pH protective coating or layer. Suitable hydrophobic coatings or layers and their applications, properties, and uses are described in U.S. Patent No. 7,985,188. Dual-functional protective / hydrophobic coatings or layers having properties of both types of coatings or layers may be provided for any embodiment of the present invention.

[0343] Layered composite layers SiO x Another means contemplated herein for adjacent layers of a barrier coating or layer is a layered composite of any two or more adjacent PECVD layers, such as barrier coating or layer 288 and pH protective coating or layer 286 and / or lubricious coating or layer 281. A layered composite may be composed of separate layers of protective and / or barrier layers or coatings (with intermediate composition transitions or interfaces between them), or a protective and / or hydrophobic layer and SiO x (with another pH protective coating or layer of intermediate composition between them), or from the protective and / or hydrophobic layer composition, more SiO xIt may be a single coating or layer with a continuous or stepped change through the primer coating or layer in the normal direction to a composition approaching 100%.

[0344] The layers in a layered composite can go in either direction. For example, SiO x The composition can be applied directly to the substrate and can progress from the surface of a primer coating or layer to a further composition, and optionally to another type of coating or layer, such as a hydrophobic coating or layer, or a lubricious coating or layer. Additionally, in any embodiment, an adhesive coating or layer, such as a Si w O x C y or its equivalent SiO x C y H z Optionally, a primer coating or layer may be applied directly to the substrate prior to applying the barrier layer. Progressive primer coatings or layers are particularly contemplated when one composition layer adheres better to one substrate than to another. In this case, the better-adhering composition may be applied directly to the substrate, for example. Because the primer coating or layer has gradual changes in properties, it is contemplated that more distant portions of a layered primer coating or layer may be less compatible with the substrate than closer portions of the layered primer coating or layer; thus, adjacent portions of a primer coating or layer at approximately the same depth may have approximately the same composition, while more widely separated portions at substantially different depths may have more dissimilar properties. It is also contemplated that portions of a primer coating or layer that form a better barrier to material migration or that form a substrate may be applied directly to the substrate to prevent more distant primer coating or layer portions that form an insufficient barrier from becoming contaminated with the material that the barrier is intended to prevent.

[0345] Instead of being layered, the applied coating or layer can optionally have an abrupt transition between one layer and the next without a substantial gradient in composition. Such a primer coating or layer can be produced, for example, by providing the gas for producing the layer as a non-plasma steady-state flow, and then energizing the system using a brief plasma discharge to form the coating or layer on the substrate. If a next primer coating or layer is to be applied, the gas for the previous primer coating or layer is removed, the gas for the next primer coating or layer is applied in a steady-state manner, and then the plasma is energized to again form another layer (with little, if any, gradual transition at the interface) on the substrate or the surface of the previous outermost primer coating or layer.

[0346] Some embodiments can be carried out under conditions effective to form a hydrophobic pH protective coating or layer on the substrate. Optionally, the hydrophobic properties of the pH protective coating or layer can be determined by setting the ratio of O to organosilicon precursor in the gaseous reactant and / or by setting the power used to generate the plasma. Optionally, the pH protective coating or layer can have a lower wetting tension than the uncoated surface, optionally 20 to 72 dyne / cm, optionally 30 to 60 dynes / cm, optionally 30 to 40 dynes / cm, or optionally 34 dyne / cm. Optionally, the pH protective coating or layer can be more hydrophobic than the uncoated surface.

[0347] equipment PECVD equipment for forming a PECVD coating or layer PECVD tools, i.e., systems and precursor materials suitable for applying any of the PECVD coatings or layers described herein (specifically including the bond coating or layer 289, the barrier coating or layer 288, or the pH protective coating or layer 286), are described in U.S. Pat. No. 7,985,188, which is incorporated by reference.

[0348] The container having the wall 214 can be conveyed to a tie coater 302, which is an apparatus suitable for applying a bond coating or layer to the interior surface of the wall, such as the PECVD apparatus described in U.S. Pat. No. 7,985,188.

[0349] The container can then be conveyed to a barrier coater 304, which is an apparatus suitable for applying a barrier coating or layer to the interior surface of a wall, such as the PECVD apparatus described in U.S. Pat. No. 7,985,188.

[0350] The container can then be transported to a pH protective coater 306, an apparatus suitable for applying a pH protective coating or layer to the interior surface of a wall, such as the PECVD apparatus described in U.S. Patent No. 7,985,188, which completes the coating set-up.

[0351] Optionally, further steps can be performed by the system, for example, the coated container can be conveyed to a fluid filling machine 308, which transfers fluid from a fluid supply 310 to the lumen of the coated container.

[0352] For another example, the filled containers can be transported to a stopper installer 312, which takes a stopper, such as a plunger or plug, from a stopper supply 314 and installs it into the lumen of the coated container.

[0353] In any embodiment of the present invention, the bond coating or layer may optionally be applied by plasma-enhanced chemical vapor deposition (PECVD).

[0354] In any embodiment of the present invention, a barrier coating or layer may optionally be applied by PECVD.

[0355] In any embodiment of the present invention, a pH protective coating or layer may optionally be applied by PECVD.

[0356] In any embodiment of the invention, the container may comprise or consist of a syringe barrel, a vial, a cartridge, or a blister pack.

[0357] SiO x The reaction conditions for forming the barrier layer are described in US Pat. No. 7,985,188, which is incorporated by reference.

[0358] Bonding or adhesive coatings or layers can be produced using, for example, tetramethyldisiloxane (TMDSO) or hexamethyldisiloxane (HMDSO) at a flow rate of 0.5 to 10 sccm, preferably 1 to 5 sccm; an oxygen flow of 0.25 to 5 sccm, preferably 0.5 to 2.5 sccm; and an argon flow of 1 to 120 sccm as precursors, preferably in the upper range for 1 mL syringes and in the lower range for 5 mL vials. The total pressure in the chamber during PECVD can be 0.01 to 10 Torr, preferably 0.1 to 1.5 Torr. The applied power level can be 5 to 100 watts (preferably in the upper range for 1 mL syringes and in the lower range for 5 mL vials). The coating time (i.e., the "on" time of the RF power source) is 0.1 to 10 seconds, preferably 1 to 3 seconds. The power cycle can optionally be slow ramped or gradually increased from 0 watts to full power over a short period of time, such as 2 seconds, to improve plasma uniformity when powered on, but ramping up over a period of time is optional.

[0359] The pH protective coating or layer 286 described herein can be applied in many different ways. In one example, the reduced pressure PECVD process described in U.S. Patent No. 7,985,188 can be used. In another example, instead of using reduced pressure PECVD, atmospheric pressure PECVD can be used to apply the pH protective coating or layer. In another example, the coating can simply be evaporated and the SiO 2 to be protected can be applied. x In another example, the coating can be applied to the SiO layer to be protected. x In yet another example, a SiO x A pH protective coating or layer 286 can be applied from a liquid medium for use in rinsing or cleaning the layer.

[0360] Other precursors and methods can be used to apply pH protective coatings or layers or passivation treatments. For example, hexamethylenedisilazane (HMDZ) can be used as a precursor. HMDZ has the advantage of not containing oxygen in its molecular structure. This passivation treatment is carried out on SiO x It is assumed that the barrier layer is surface-treated with HMDZ. To slow down and / or eliminate decomposition of the silicon dioxide coating at the silanol bonding sites, the coating must be passivated. It is assumed that passivating the surface with HMDZ (and optionally applying a small monolayer of a coating derived from HMDZ) will toughen the surface against dissolution, resulting in reduced decomposition. It is assumed that HMDZ will react with -OH sites present in the silicon dioxide coating, resulting in the generation of NH3 and the bonding of S-(CH3)3 to the silicon (it is assumed that a hydrogen atom will be generated and combine with the nitrogen from the HMDZ to produce NH3).

[0361] It is envisioned that this HMDZ passivation can be achieved through several possible routes.

[0362] A possible route is the dehydration / vaporization of HMDZ at ambient temperature. First, SiO2 is prepared using, for example, hexamethylenedisiloxane (HMDSO). x The surface is coated with silicon dioxide. The coated silicon dioxide surface is then reacted with HMDZ vapor. In some embodiments, the object is coated with SiO x Once the surface is coated, the vacuum is maintained. The HMDSO and oxygen are pumped out to obtain a base vacuum. Once the base vacuum is obtained, HMDZ vapor is flowed across the silicon dioxide surface (coated on the target part) at pressures ranging from the mTorr range to many Torr. The HMDZ is then pumped out (resulting in the reaction by-product NH3). The amount of NH3 in the gas stream can be monitored (using a residual gas analyzer—RGA, for example), and the reaction is complete when no more NH3 is detected. The components are then vented to the atmosphere (using clean dry gas or nitrogen). The resulting surface is then found to be passivated. It is envisioned that this method can optionally be achieved without forming a plasma.

[0363] Or, SiO x After the formation of the barrier coating or layer, the vacuum can be released prior to dehydration / evaporation of the HMDZ. x The dehydration / vaporization of the HMDZ can be carried out in the same equipment used to form the barrier coating or layer or in a separate equipment.

[0364] Dehydration / vaporization of HMDZ at elevated temperatures is also contemplated. The process can alternatively be carried out at elevated temperatures above room temperature, up to about 150°C. The maximum temperature is determined by the material from which the coated part is constructed. A high temperature should be selected that will not deform or otherwise damage the coated part.

[0365] Plasma-assisted dehydration / vaporization of HMDZ is also envisioned. After performing any of the above dehydration / vaporization embodiments, once HMDZ vapor is introduced into the part, a plasma is ignited. The power of the plasma can range from a few watts to 100+ watts (SiO x The power may range from 0.1 W to 0.5 W (similar to that used to coat a substrate with HMDZ). The above is not limited to HMDZ, but would be applicable to any molecule that will react with hydrogen, such as any of the nitrogen-containing precursors described herein.

[0366] Another way to apply a pH protective coating or layer is to apply an amorphous carbon or fluorocarbon coating, or a combination of the two, as the pH protective coating or layer.

[0367] Amorphous carbon coatings can be formed by PECVD using saturated hydrocarbons (e.g., methane or propane) or unsaturated hydrocarbons (e.g., ethylene, acetylene) as precursors for plasma polymerization. Fluorocarbon coatings can be derived from fluorocarbons (e.g., hexafluoroethylene or tetrafluoroethylene). Either type of coating, or a combination of both, can be applied by vacuum PECVD or atmospheric pressure PECVD. Because amorphous carbon and / or fluorocarbon coatings do not contain silanol bonds, amorphous carbon and / or fluorocarbon coatings offer superior SiO 2 deposition properties to siloxane coatings. x It is envisioned that this will provide passivation of the barrier layer.

[0368] SiO using a fluorosilicon precursor x It is further envisioned that a pH-protective coating or layer can be provided that overcomes the barrier layer. This can be achieved by using a fluorinated silane precursor, such as hexafluorosilane, as a precursor and a PECVD process. The resulting coating would also be expected to be a non-wetting coating.

[0369] It is further contemplated that any embodiment of the pH protective coating or layer process described herein can also be practiced without the use of the object to be coated to contain plasma. For example, the exterior surfaces of medical articles, such as catheters, surgical instruments, plugs, and others, can be protected or passivated by sputtering a coating using a radio frequency target.

[0370] SiO x Yet another coating modality contemplated for protecting or passivating a barrier layer is to coat the barrier layer with a polyamidoamine-epichlorohydrin resin. For example, the part to be coated with the barrier can be dip-coated in a fluid polyamidoamine-epichlorohydrin resin melt, solution, or dispersion and cured by autoclaving or other heating at temperatures between 60°C and 100°C. It is envisioned that polyamidoamine-epichlorohydrin resin coatings can be used preferentially in aqueous environments with a pH of 5-8, since such resins are known to provide high wet strength in paper in that pH range. Since wet strength is the ability of paper to maintain its mechanical strength over time when fully submerged in water, SiO x It is anticipated that a coating of polyamidoamine-epichlorohydrin resin on a barrier layer will have similar resistance to dissolution in aqueous media. Because polyamidoamine-epichlorohydrin resin provides improved lubricity to paper, it is also anticipated that it will provide lubricity in the form of a coating on a thermoplastic surface made from COC or COP.

[0371] SiO xYet another approach to protecting a layer is to apply a liquid-applied coating of a polyfluoroalkyl ether as a pH-protective coating or layer, followed by atmospheric plasma curing of the pH-protective coating or layer. For example, it is contemplated that the process implemented under TriboGlide® described herein can be used to provide a pH-protective coating or layer that is also a lubricious layer (since TriboGlide® is traditionally used to provide lubricity).

[0372] Exemplary PECVD reaction conditions for preparing a pH protective coating or layer 286 in a 3 ml sample size syringe (open ended) with a 1 / 8 inch tube diameter are as follows:

[0373] To deposit a pH protective coating or layer, for example, precursor feed or process gases having the following base volume ratios can be used: a precursor, e.g., OMCTS, or one of the other precursors of any embodiment, having from 0.5 to 10 basis volumes, optionally from 1 to 6 basis volumes, optionally from 2 to 4 basis volumes, optionally no more than 6 basis volumes, optionally no more than 2.5 basis volumes, optionally no more than 1.5 basis volumes, optionally no more than 1.25 basis volumes; 0 to 100 base volumes, optionally 1 to 200 base volumes, optionally 1 to 80 base volumes, optionally 5 to 100 base volumes, optionally 10 to 70 base volumes of a carrier gas of any embodiment, for example argon. 0.1 to 10 basis volumes, optionally 0.1 to 2 basis volumes, optionally 0.2 to 1.5 basis volumes, optionally 0.2 to 1 basis volume, optionally 0.5 to 1.5 basis volumes, optionally 0.8 to 1.2 basis volumes of oxidizer. Power levels can be, for example, 0.1 to 500 watts. Specific flow rates and power levels contemplated include: OMCTS: 2.0sccm Oxygen: 0.7sccm Argon: 7.0sccm Power: 3.5 watts

[0374] Surface Treatment "Plasma," as referred to in any embodiment, has its usual meaning in physics of one of four fundamental states of matter characterized by extensive ionization of its constituent particles, generally gaseous form, and incandescence (i.e., it produces a glow discharge, meaning that it emits light).

[0375] "Converting plasma treatment" refers to any plasma treatment that reduces the adhesion of one or more biomolecules to the treated surface.

[0376] "Conditioning plasma treatment" refers to any plasma treatment of a surface to prepare the surface for a further conversion plasma treatment. "Conditioning plasma treatment" includes a plasma treatment that, by itself, reduces adhesion of one or more biomolecules to the treated surface, but is followed by a conversion plasma treatment (which further reduces adhesion of one or more biomolecules to the treated surface). "Conditioning plasma treatment" also includes a plasma treatment that, by itself, does not reduce adhesion of one or more biomolecules to the treated surface.

[0377] "Remote" conversion plasma treatment, generally speaking, is a conversion plasma treatment of a surface located at a "remote" point where the radiant energy density (e.g., joules per cm) of the plasma is substantially less than the maximum radiant energy density of any point of the plasma glow discharge (hereinafter referred to as the "brightest point"), but the remote surface is close enough to some portion of the glow discharge to reduce adhesion of one or more biomolecules to the treated remote surface. "Remote" is similarly defined with respect to remote conditioning plasma treatment, except that the remote surface must be close enough to some portion of the glow discharge to condition the surface.

[0378] The radiant energy density at the brightest point of the plasma is determined spectrophotometrically by measuring the radiant intensity of the strongest emission line of light in the visible spectrum (380 nanometers (nm) to 750 nm wavelength) at the brightest point. The radiant energy density at a remote point is determined spectrophotometrically by measuring the radiant energy density of the same emission line of light at the remote point. The "remoteness" of a point is quantified by measuring the ratio of the radiant energy density at the remote point to the radiant energy density at the brightest point. This specification and claims quantitatively define "remote" as a specific range of this ratio. Generally, this ratio is 0 to 0.5, optionally 0 to 0.25, optionally about 0, and optionally exactly 0. Remote conversion plasma processing can be performed when this ratio is zero (even though this indicates no measurable visible light at the remote point). This is because the dark discharge or afterglow regions of the plasma contain energetic species that are not energetic enough to emit light, but are energetic enough to modify the treated surface to reduce the adhesion of one or more biomolecules.

[0379] A "non-polymerizing compound" is operationally defined for all embodiments as a compound that does not polymerize or otherwise form an additional coating on the treated surface under the conditions used for a particular plasma treatment of the surface. Numerous non-limiting examples of compounds that can be used under non-polymerizing conditions are: O 2 , N 2 , air, O 3 , N 2 O, H 2 , H 2 O 2 , NH 3 , Ar, He, Ne, and any combination of two or more of the foregoing. These may also include alcohols, organic acids, and polar organic solvents, as well as materials that may polymerize under plasma conditions different from those used. "Non-polymerizing" includes compounds that react and bond with existing polymerized surfaces and locally modify their composition at the surface. The essential distinguishing feature of a non-polymerizing coating is that it does not accumulate thickness (i.e., does not accumulate an additional coating) as treatment time increases.

[0380] A "substrate" is a substance or other solid form (such as granules, beads, or particles).

[0381] A "surface" is broadly defined as either the original surface of a substrate ("surface," as used herein, includes any portion of a surface) or a coated or treated surface that has been prepared by any suitable coating or treatment method, such as liquid application, condensation from a gas, or chemical vapor deposition (including plasma-assisted chemical vapor deposition carried out under conditions effective to form a coating on the substrate).

[0382] A treated surface is defined for all embodiments as a surface that has been plasma treated as described herein.

[0383] The terms "optionally" and "or" are considered to have the same meaning and can be used interchangeably in this specification and claims.

[0384] The "material" in any embodiment can be any material from which a substrate can be formed, including, but not limited to, a thermoplastic material, optionally a thermoplastic injection-moldable material. The substrate according to any embodiment can be made from, for example, but not limited to, olefin polymers; polypropylene (PP); polyethylene (PE); cyclic olefin copolymers (COC); cyclic olefin polymers (COP); polymethylpentene; polyesters; polyethylene terephthalate; polyethylene naphthalate; polybutylene terephthalate (PBT); PVdC (polyvinylidene chloride); polyvinyl chloride (PVC); polycarbonate; polymethyl methacrylate; polylactic acid; polystyrene; hydrogenated polystyrene; poly(cyclohexylethylene) (PCHE); epoxy resins; nylon; polyurethane-polyacrylonitrile; polyacrylonitrile (PAN); ionomer resins; or Surlyn® ionomer resins.

[0385] The term "container" as used throughout this specification can be any type adapted to contain or transport a liquid, gas, solid, or any two or more of these. An example of a container is one having at least one opening (e.g., one, two, or more) depending on the intended use, and a wall defining an interior contact surface.

[0386] The term "stress conditions" can be in any form, such as acidic or basic conditions, agitation, movement, freeze-thaw cycles, storage for extended periods, etc.

[0387] The method of the present invention for treating a surface, optionally a substrate surface, includes treating the surface with a conversion plasma of one or more non-polymeric compounds in a chamber to form a treated surface.

[0388] According to various embodiments, a wide variety of surfaces can be treated. One example of a surface is the luminal surface of a container, where the container is, for example, a vial, bottle, jar, syringe, cartridge, blister pack, or ampoule. For further example, the surface of the material can be the fluid surface of an article of labware, such as a microplate, centrifuge tube, pipette tip, well plate, microwell plate, ELISA plate, microtiter plate, 96-well plate, 384-well, centrifuge tube, chromatography vial, evacuated blood collection tube, or sample tube.

[0389] The treated surface of all embodiments may be a PECVD coated SiO x C y H z or a coating or layer of SiNxCyHz, where x is from about 0.5 to about 2.4 as measured by X-ray photoelectron spectroscopy (XPS), y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9, optionally from about 2 to about 6 as measured by Rutherford backscattering spectroscopy (RBS). Another example of a surface to be treated is SiO xwhere x is from about 1.5 to about 2.9 as measured by XPS, optionally an oxide or nitride of an organometallic precursor which is a compound of a metal element from Group III and / or Group IV of the periodic table, for example, in Group III: boron, aluminum, gallium, indium, thallium, scandium, yttrium, or lanthanum (aluminum and boron are preferred), and in Group IV: silicon, germanium, tin, lead, titanium, zirconium, hafnium, or thorium (silicon and tin are preferred).

[0390] The gas used to treat the surface in any embodiment can be an inert or reactive gas and can be any of the following: O2, N2, air, O3, N2O, NO2, N2O4, H2, H2O2, H2O, NH3, Ar, He, Ne, Xe, Kr, nitrogen-containing gases, other non-polymerizable gases, combinations of gases (Ar / O2 mixtures, N2 / O2 mixtures (after a pre-treatment conditioning step with Ar), volatile polar organic compounds, C1-C 12 Combinations of hydrocarbons and oxygen; C1-C 12 a silicon-containing gas; or a combination of two or more of these. The process employs a non-polymerizing gas as defined herein.

[0391] Volatile polar organic compounds of any embodiment include, for example, water, such as tap water, distilled water, or deionized water; alcohols, such as C1-C 12 Alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, and t-butanol; glycols, such as ethylene glycol, propylene glycol, butylene glycol, polyethylene glycol, and others; glycerin, C1-C 12 Linear or cyclic ethers, such as dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, glyme (CH3OCH2CH2OCH3); n- cyclic ethers, such as diethylene oxide, triethylene oxide, and tetraethylene oxide; cyclic amines; cyclic esters (lactones), such as acetolactone, propiolactone, butyrolactone, valerolactone, and caprolactone; C1-C 12 Aldehydes, such as formaldehyde, acetaldehyde, propionaldehyde, or butyraldehyde; C1-C 12 Ketones, such as acetone, diethyl ketone, dipropyl ketone, or dibutyl ketone; C1-C 12 Carboxylic acids, such as formic acid, acetic acid, propionic acid, or butyric acid; ammonia, C1-C 12 Amines, such as methylamine, dimethylamine, ethylamine, diethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, or dodecylamine; hydrogen fluoride, hydrogen chloride, C1-C 12 It may be an epoxide, such as ethylene oxide or propylene oxide; or a combination of any two or more of these.

[0392] C1 to C in all embodiments 12 The hydrocarbon may optionally be methane, ethane, ethylene, acetylene, n-propane, i-propane, propene, propyne; n-butane, i-butane, t-butane, butane, 1-butyne, 2-butyne, or a combination of any two or more thereof.

[0393] The silicon-containing gas in any embodiment can be silane, an organosilicon precursor, or a combination of any two or more thereof.The silicon-containing gas can optionally be acyclic or cyclic, substituted or unsubstituted silane, such as a silane substituted or unsubstituted with Si1-Si4, comprising, essentially consisting of, or consisting of any one or more of silane, disilane, trisilane, or tetrasilane; acyclic silane substituted with hydrocarbon or halogen, such as tetramethylsilane (TetraMS), tetraethylsilane, tetrapropylsilane, tetrabutylsilane, trimethylsilane (TriMS), triethylsilane, tripropylsilane, tributylsilane, trimethoxysilane, fluorinated silane such as hexafluorodisilane, octamethylcyclotetrasilane, tetramethylcyclotetrasilane, or a combination of any two or more thereof. The silicon-containing gas can be a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, an alkyltrimethoxysilane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, or a combination of any two or more thereof, such as hexamethyldisiloxane (HMDSO), tetramethyldisiloxane (TMDSO), octamethylcyclotetrasiloxane (OMCTS), tetramethyldisilazane, hexamethyldisilazane, octamethyltrisilazane, octamethylcyclotetrasilazane, tetramethylcyclotetrasilazane, or a combination of any two or more thereof.

[0394] The power used to excite the plasma used in the plasma treatment in any embodiment can be, for example, 1 to 1000 watts, optionally 100 to 900 watts, optionally 50 to 600 watts, optionally 100 to 500 watts, optionally 500 to 700 watts, optionally 1 to 100 watts, optionally 1 to 30 watts, optionally 1 to 10 watts, and optionally 1 to 5 watts.

[0395] The frequency of the power used to excite the plasma used in plasma processing can be any type of energy that will ignite the plasma in the plasma region in all embodiments, for example, it can be direct current (DC) or alternating current (electromagnetic energy) with a frequency between 3 Hz and 300 GHz. Electromagnetic energy in this range generally includes radio frequency (RF) energy and microwave energy, more specifically characterized as extremely low frequency (ELF) from 3 to 30 Hz, super low frequency (SLF) from 30 to 300 Hz, voice frequency or extremely low frequency (VF or ULF) from 300 Hz to 3 kHz, very low frequency (VLF) from 3 to 30 kHz, low frequency (LF) from 30 to 300 kHz, medium frequency (MF) from 300 kHz to 3 MHz, high frequency (HF) from 3 to 30 MHz, very high frequency (VHF) from 30 to 300 MHz, extremely high frequency (UHF) from 300 MHz to 3 GHz, microwave (SHF) from 3 to 30 GHz, extremely high frequency (EHF) from 30 to 300 GHz, or a combination of any two or more of these. For example, radio frequency energy, typically 13.56 MHz, is useful RF energy, and ultra-high frequency energy, typically 2.54 GHz, is useful microwave energy, as two non-limiting examples of commonly used frequencies.

[0396] In any embodiment, the plasma excitation energy may be continuous during the processing step, or may be pulsed multiple times during the processing step. If pulsed, it may be applied on for a time ranging from 1 millisecond to 1 second, and then off for a time ranging from 1 millisecond to 1 second, alternating in a regular or variable sequence during the plasma processing. A total duty cycle (one "on" period plus one "off" period) may be from 1 to 2000 milliseconds (ms), optionally from 1 to 1000 milliseconds (ms), optionally from 2 to 500 ms, optionally from 5 to 100 ms, and optionally from 10 to 100 ms.

[0397] Optionally in any embodiment, the relationship between the power on and power off portions of the duty cycle can be, for example, power on for 1 to 90 percent of the time, optionally 1 to 80 percent of the time, optionally 1 to 70 percent of the time, optionally 1 to 60 percent of the time, optionally 1 to 50 percent of the time, optionally 1 to 45 percent of the time, optionally 1 to 40 percent of the time, optionally 1 to 35 percent of the time, optionally 1 to 30 percent of the time, optionally 1 to 25 percent of the time, optionally 1 to 20 percent of the time, optionally 1 to 15 percent of the time, optionally 1 to 10 percent of the time, or optionally 1 to 5 percent of the time, and power off for the remaining time of each duty cycle.

[0398] Plasma pulsing, as described by Mark J. Kushner in Pulsed Plasma-Pulsed Injection Sources For Remote Plasma Activated Chemical Vapor Deposition, J. APPL. PHYS. 73, 4098 (1993), can optionally be used.

[0399] The flow rate of the process gas during plasma treatment according to all embodiments can be from 1 to 300 sccm (standard cubic centimeters per minute), optionally from 1 to 200 sccm, optionally from 1 to 100 sccm, optionally from 1 to 50 sccm, optionally from 5 to 50 sccm, optionally from 1 to 10 sccm.

[0400] Optionally in any embodiment, the plasma chamber is pumped down to a base pressure of 0.001 milliTorr (mTorr, 0.00013 Pascals) to 100 Torr (13,000 Pascals) before supplying gas. Optionally, the supply gas pressure in any embodiment can range from 0.001 to 10,000 mTorr (0.00013 to 1300 Pascals), optionally from 1 mTorr to 10 Torr (0.13 to 1300 Pascals), optionally from 0.001 to 5000 mTorr (0.00013 to 670 Pascals), optionally from 1 to 1000 milliTorr (0.13 to 130 Pascals).

[0401] In all embodiments, the treatment volume in which the plasma is generated may be, for example, 100 mL to 50 liters, preferably 8 liters to 20 liters, if a treatment vessel separate from the surface to be treated is used, or, for example, 0.1 to 20 mL, optionally 0.5 to 10 mL, if the surface to be treated is part of the inner surface of the vessel, which also serves as a vessel in which the plasma is contained, for example, if the treatment vessel is a syringe barrel, vial, or cartridge intended to serve as primary packaging for a drug.

[0402] The plasma treatment time in any embodiment can be, for example, 1 to 300 seconds, optionally 3 to 300 seconds, optionally 30 to 300 seconds, optionally 150 to 250 seconds, optionally 150 to 200 seconds, optionally 90 to 180 seconds.

[0403] The number of plasma treatment steps can vary in any embodiment. For example, one plasma treatment can be used; optionally, two or more plasma treatments can be used, using the same or different conditions.

[0404] In all embodiments, the plasma processing tool used can be any suitable tool, for example, a plasma processing tool of the type shown in U.S. Patent No. 7,985,188, Figure 2, which uses the inner cavity of the container to be processed as a vacuum chamber, can be used in all embodiments.

[0405] The plasma treatment process of any embodiment can optionally be combined with a treatment using an ionized gas. The ionized gas can be, for example, any of the gases identified as suitable for plasma treatment. The ionized gas can be delivered in any suitable manner. For example, the ionized gas can be delivered from an ionized blow-off gun or other ionized gas source. A convenient gas delivery pressure is 1 to 120 psi (pounds per square inch) (6 to 830 kPa, kilopascals) (gauge pressure, or optionally absolute pressure), optionally 50 psi (350 kPa). The water content of the ionized gas can be 0 to 100%. The polar treatment surface finish with ionized gas can be carried out for any suitable treatment time, for example, 1 to 300 seconds, optionally 10 seconds.

[0406] IE plugging Optionally in all embodiments, the interior surface of the primary drug container is generally cylindrical and further comprises a plunger or bung located on and slidable within the interior surface. Optionally in all embodiments, the plunger is an O-ring plunger.

[0407] Optionally in any embodiment, the plunger is a two-position plunger having a first position for use while storing the primary drug container and a second position for use while dispensing drug from the primary drug container.

[0408] Optionally in any embodiment, the plunger is a two-position plunger having a first position for use during storage of the primary drug container and a second position for use during dispensing of drug from the primary drug container with lubricant.

[0409] Optionally in any embodiment, the plunger is a two-position plunger having a first position for use during storage of the primary drug container and a second position for use during dispensing of drug from the primary drug container without applying a lubricant to reduce particle count.

[0410] Suitable plungers are described, for example, in U.S. Patent Application Publication No. 2014 / 059531, filed October 7, 2014; U.S. Patent Application No. 62 / 192,192, filed July 14, 2015; and U.S. Patent Application No. 62 / 269,600, filed December 18, 2015, the entire text and drawings of which are incorporated herein by reference.

[0411] Optionally, in any embodiment, the plunger can have a resilient core covered with an outer layer of a fluorinated polymer such as polytetrafluoroethylene. Such plungers are commercially available, for example, the Datwyler Omniflex plunger, which consists of a bromobutyl rubber core and a fluoropolymer conformal coating applied to the outer surface of the plunger to block potential leaching into the drug.

[0412] Optionally in all embodiments, the primary drug container comprises a hypodermic needle having an internal lumen and an internal delivery tube in communication with the distal end. Optionally in all embodiments, the primary drug container comprises a needle shield. Optionally in all embodiments, the tip of the needle is covered by the needle shield.

[0413] Number of particles during the validity period In all embodiments, optionally, the particle count in the primary drug container is measured immediately, optionally after 1 day, optionally after 1 month, optionally after 3 months, and optionally after 1 year after water for injection is placed in the lumen.

[0414] In any embodiment, optionally, the primary drug container can contain the polypeptide composition in the lumen in contact with the PECVD coating, where the particle count is measured after the polypeptide composition is placed in the lumen, optionally after 1 day, optionally after 1 month, optionally after 3 months, optionally after 1 year, optionally at the end of the therapeutic useful life.

[0415] Microflow imaging (MFI) is a particle analysis technique that uses flow microscopy to quantify particles contained in a solution based on size. Optionally in any embodiment, this technique can be used to characterize subvisible particles from approximately 1 μm to >50 μm.

[0416] Optionally, in all embodiments, a dynamic image analysis (DIA) FlowCam® can be used for some measurements. A dynamic image particle analyzer performs all three functions in one instrument. It examines the fluid under a microscope, takes magnified images of particles within the fluid, and characterizes the particles using various measurements. Dynamic image particle analysis combines the benefits of manual microscopy with those of volumetric measurement techniques. Microscopic particle measurements are made quickly from enough images to produce statistically significant results. Furthermore, many different measurements are made for each particle, providing the detailed information often needed for thorough particle analysis. The addition of specialized software allows for advanced post-processing of the data, allowing for more thorough sample analysis and better data understanding. The ability of an image processing system to resolve particle details is essential for accurate measurements. The instrument's optical system and sensors affect its ability to size and characterize particles that are not detectable by the naked eye. For this reason, counting in dynamic imaging particle analysis systems should be limited to particles with an equivalent spherical diameter (ESD) of 1 μm or greater, and particle characterization (i.e., shape) should be limited to particles with an ESD of 2 μm or greater. (The ESD of an irregularly shaped object is defined, for purposes of this application, as the diameter of a sphere of equivalent volume.) It is important to optimize the settings of this type of instrument specifically for the sample being analyzed to ensure accurate results. Multiple filters can be created, stored, and reused, allowing the analyst to separate a sample into its component parts based on particle characteristics. When analyzing protein therapeutics, this is particularly useful when separating silicone oil from the protein.

[0417] -Source: Fluid Imaging Technologies a. Performance: number, size, limited form b. Range: 2 to 10,000 μm c.Concentration: 10 6 particles / mL

[0418] Note: The presence of air, immiscible oils, semi-solids, refractive index fluctuations, and density extremes will result in different results between the three techniques: LO, MM, and DIA (Flow Cam). [Example]

[0419] Actual example Light Obscuration Particle Counting Protocol for Example 1 The injection-molded COP specimens used for this study were 2 mL, 5 mL, 6 mL, 10 mL, or 25 mL vials with a three-layer coating made as described below in Example 3. For example, 6 mL COP vials with a three-layer coating were provided under the following conditions:

[0420] [Table 1]

[0421] The number of visually undetectable particles, as determined in Example 1 below, was generally measured in accordance with the United States Pharmacopeia (USP), Chapter 788 (Particulate Matter in Injections), Method 1 (Light Obscuration Particle Count).

[0422] The medium for collecting particles was Particle Free Water (PFW), which is Type I water (ultrapure water, with a resistivity of 18.2 MΩ) that has been filtered through a 0.22 μm pore size filter, such as can be obtained from a Millipore MilliQ or equivalent water filtration system.

[0423] Particle counts were performed using a BeckmanCoulter HIAC 9703+ Liquid Particle Counter, but can be substituted with any equivalent instrument capable of performing USP 788.

[0424] Example 1 - Light Obscuration Analysis A 50 mL polypropylene (PP) sample tube was cleaned by rinsing the outside of the tube with PFW and placing it in a laminar flow hood to dry. The inside of the 50 mL tube was rinsed by adding approximately 5 mL of PFW, replacing the cap, shaking vigorously, discarding the PFW, and shaking all droplets dry. This PFW rinse was repeated two more times. A clean PP tube was filled with enough PFW to fill all test articles together, and the required validation tests were performed.

[0425] The stoppers for the test articles were prepared by scrubbing with soap and water, then rinsing thoroughly with PFW, followed by isopropyl alcohol (IPA). The stoppers were allowed to air dry in a laminar flow hood.

[0426] A 5 mL pipette tip was cleaned by rinsing the outside with PFW, then rinsed inside by aspirating the PFW to the end and discarding the rinse PFW. The internal rinse was repeated two more times.

[0427] A blank sample was selected from the PFW placed in a PP sample tube and tested for particle count to confirm that the blank particle count in the cumulative count column of the 10 μm channel was approximately 1 particle / mL.

[0428] Each test article was filled with PFW using a pipette tip according to the fill volumes suggested in the table below for various sized parenteral drug products.

[0429] [Table 2]

[0430] The test articles were sealed with the provided stoppers, which were rinsed with PFW at least three times before attachment.

[0431] Particle samples were collected by slowly inverting the test article 20 times to suspend the particles. The stopper was removed from the test article, and its contents and those of the other samples were then combined into a new PP sample tube. The sample tube was allowed to sit for 2 minutes to degas before testing. The sample suction probe was placed into the sample tube so that its end was very close to, but not touching, the bottom of the sample tube. The sample was then drawn and tested on a particle counter using the appropriate USP 788 method in the system software.

[0432] Figures 1-3 and 7-8 show the results of tests using the above protocol.

[0433] The number of particles of the specified size measured using the above protocol for the syringe is as described in Figure 6 (with a three-layer coating further including an optional silicone oil-free lubricant ("L-OMCTS")) and shows similar results to the left plot in Figure 7.

[0434] Example 2—FlowCam® Dynamic Image Analysis (DIA) FlowCam® is a registered trademark of Fluid Imaging Technologies, Inc., Scarborough, Maine, for dynamic imaging particle analyzer, also known as dynamic image analyzer. The FlowCam® dynamic imaging particle analyzer performs all three functions in one instrument. It examines fluids under a microscope, takes magnified images of particles within the fluid, and characterizes the particles using various measurements. Dynamic imaging particle analysis combines the benefits of manual microscopy with those of volumetric measurement techniques. Microscopic particle measurements are made quickly from enough images to produce statistically significant results. Furthermore, many different measurements are made for each particle, providing the detailed information often needed for thorough particle analysis. The addition of specialized software enables advanced post-processing of the data, allowing for more thorough sample analysis and better data understanding. The ability of an imaging system to resolve particle details is essential for accurate measurements. The instrument's optical system and sensors affect its ability to size and characterize particles that are not detectable by the naked eye. For this reason, counting in dynamic imaging particle analysis systems should be limited to particles with an equivalent spherical diameter (ESD) of 1 μm or greater, and particle characterization (i.e., shape) should be limited to particles with an ESD of 2 μm or greater. (The ESD of a particle is the diameter of a sphere with the same volume as the actual particle, making it particularly useful for characterizing and sizing non-spherical particles.) It is important to optimize the settings of this type of instrument specifically for the sample being analyzed to ensure accurate results. Multiple filters can be made, stored, and reused, allowing the analyst to separate a sample into its component parts based on particle characteristics. When analyzing protein therapeutics, this is particularly useful for separating silicone oil from the protein. -Source: Fluid Imaging Technologies a. Performance: number, size, limited form b. Range: 2 to 10,000 μm c.Concentration: 10 6 particles / mL

[0435] This example evaluates the particle count and size distribution of three-layer coated and four-layer coated syringes of the present invention when eluted with PFW. Typically, filled, sealed syringes are subjected to one of the following two treatments: 1) 20 slow inversions {USP 788} or 2) An adapted shake table method used to ensure consistency: The syringe is placed horizontally on a shake table and shaken at 1000 rpm for 10 minutes. This allows sufficient time for free linear movement of the headspace bubbles from edge to center and for slight variations in lubricant shedding.

[0436] The selection of aspirated volume, flow rate, objective lens, and flow cell diameter is study specific and based on either syringe lubricant evaluation or exogenous particle contamination characteristics (number, morphology, and species).

[0437] After cleaning, setup, focusing, and system suitability checks, samples are dispensed and pooled (for pooled samples) into pre-cleaned containers via pre-cleaned extraction funnels and syringe pumps, or aspirated (individually) as appropriate, and allowed approximately 10 minutes for floating air bubbles to dissipate (as confirmed by time series plots).

[0438] The instrument flow cell and sample funnel are cleaned between injections (aspirations).

[0439] Post-analysis data sorting including longest dimension, size as Estimated Spherical Diameter (ESD) or Average Basal Diameter (ABD), aspect ratio, edge gradient, frequency, and transparency will be applied based on study requirements.

[0440] The syringes are tested using the following parameters: Procedure for using the FlowCam® 10X in Example 2:

[0441] [Table 3]

[0442] System Calibration in Example 2 - Particle Size and Count Verification Calibrations are performed at the start of each test day to verify the status of system calibration / system performance and prior to any formal testing of samples. Compliance is checked against two different reference standards:

[0443] Reference Standard A - 4X bead mix (20, 50, 100 microns) to demonstrate the system's ability to detect particles across the reference range.

[0444] Reference Standard B - A concentration reference standard (e.g., 10 micron and 50 micron beads at approximately 300 particles / mL) to demonstrate that the system can accurately count the number of particles present in a sample of "known concentration" of particles.

[0445] Click once on the "visual spreadsheet" icon. Prime the system with filtered water by selecting the "set-up and focus" tab; connect the beaker containing the filtered water to the inlet line and the empty waste beaker to the outlet line. Click "start pump" on the "pump" window with a flow rate of approximately 1 mL / min. Let the system run for at least 5 minutes.

[0446] After 5 minutes, click "stop pump" and attach the appropriate pre-prepared Reference Standard A sample beaker to the inlet line. Run the reference standard solution in "set-up and focus" mode to flow the reference solution through the line for approximately 1 minute to prime the inlet line and flow cell with test solution for future analysis. Prime the flow cell before the start of every run for any test solution (standard or sample).

[0447] Select "analyze" then "auto image* mode." Select "stop after 1 mL."

[0448] Click "OK" once and enter the name of the test as "Calibration Test" and the test date in the "reason for change" field.

[0449] Select "accept."

[0450] Enter a file name (Test Reference - Calibration Test Reference Standard "A-Bead Size" and the date of analysis).

[0451] Select "OK"; confirm "OK".

[0452] Repeat steps 6.1 through 6.4.3 for a previously prepared solution identified as Reference Standard B (e.g., 10 micron and 50 micron beads at approximately 300 particles / mL), but enter the file name as Reference Standard B.

[0453] Acceptance Criteria for Calibration Tests in Example 2 Reference Standard "A-Bead Size". Click on each appropriate particle (bead) size to be measured (20, 50, and 100 micron sizes, respectively) and view the highlighted peaks on the diameter vs. frequency graph. If the largest peak for each measurement is highlighted, the instrument measured the beads correctly.

[0454] Reference standard "B - Particle concentration". The particles / mL value will be shown in the main window and via the "statistics" menu item in the view window. The particle measurement should be within ±10% of C of the listed particle concentration in A (as stated by the manufacturer / supplier).

[0455] If the instrument fails calibration, notify the lab director. If adjustments are needed, refer to the FlowCam® system manual for optimization of the optical path and camera focal length.

[0456] Analysis in Example 2: Prime the system with filtered water by selecting the "set-up and focus" tab in the "Setup" menu; connect the beaker containing the filtered water to the inlet line and the empty waste beaker to the outlet line. Click "start pump" on the "pump" window with a flow rate of approximately 1 mL / min. Let the system run for at least 5 minutes.

[0457] Individual containers are tested by inverting 20 times to suspend the particles. Pooled samples with residual volume should be spun by hand or machine before testing.

[0458] After 5 minutes of priming, click "pause pump" to switch the infusion line from filtered water to test solution. Run the test solution through the infusion line in "set-up and focus" mode by clicking "resume pump" to flow the test solution through the infusion line and flow cell for approximately 1 minute. This primes the infusion line and flow cell with test solution for future analysis and should be done immediately before any analysis, before the start of a run, and between runs. After 1 minute, click "pause pump" to exit the "set-up and focus" screen.

[0459] A context file establishes the appropriate operational execution conditions within the Visual Spreadsheet. To open an existing context file or create a new context file for sample analysis, do the following:

[0460] To load an existing context file in Visual Spreadsheet, click the "context" tab in the "setup" pull-down menu, then click the "Load" tab. In this window, click "Load a Context File."

[0461] In the context file menu, select with the mouse the appropriate context file from those available (sorted by sample size) and click "OK". Confirm by clicking "OK". Review the preset parameters in the context file under the individual tabs, such as "Sample volume"* under the "fluidics" tab and minimum-maximum particle diameter under the "filter" tab, to ensure that the settings are appropriate for the sample analysis.

[0462] Once all settings are established, if changes are required, make the necessary changes (refer to the FlowCam® system manual for optimal operating conditions) and exit the context window by pressing "OK". You will be prompted to enter a "reason for change", then press "accept".

[0463] To create a new context file (this should only be done by a system administrator; see the FlowCam® system manual for optimal operating conditions), click on "Visual Spreadsheet," then "Setup," then "Context." Enter the appropriate execution settings under each tab in the context window.

[0464] After making all changes, click "Save Context File As" under the "Load" tab, enter a "File Name", and click OK. Include the file name, sample size, creation date, and the initials of the person who created the file. Proceed to the sample analysis steps below.

[0465] Adjustment of the optical path and focal length of the camera in Example 2. Instrument accuracy is based on proper alignment of the camera with the flow cell (optical path) and proper focal length (depth of focus of the objective lens within the flow cell). The instrument will maintain proper alignment between sample runs and between calibrations. Calibration and system suitability will confirm proper instrument alignment.

[0466] If the instrument fails calibration, notify the lab director. If adjustments are needed, refer to the FlowCam® system manual for optimization of the optical path and objective focal length.

[0467] Sample analysis in Example 2. Left click twice on the "visual spreadsheet" icon to open it. Under "auto image mode", select "analyze". If you made changes to the "context" file, click "yes" when the instrument asks "Do you want to use context setting changes for analysis?" Under "Notes", enter sample information, study reference, analyst and date.

[0468] Under the example file title "4X List", enter a file name (data entry in this field should include study reference). The file name must include sample information and study date; click "OK" and confirm by clicking "OK" twice.

[0469] This analysis will proceed according to the execution conditions described in the context file.

[0470] Instruments are very sensitive to vibrations during analysis. Bench vibrations can fool the instrument into falsely identifying routine flow cell contamination as particles. These false signals result in confusing analyses and bad data, requiring the analyst to repeat runs. Bench vibrations must be minimized while an analysis is being performed. If the instrument detects a false signal (recognized by repeated images of a long band in the view window or repeated images of the same particle), the instrument requires an immediate "recalibration." To recalibrate, click the pull-down menu on the Tools menu and click Recalibrate. This resets the background and retrains the instrument. Runs with these false signals can be further processed with correction filters.

[0471] Post-run analysis in Example 2: Data Sorting The FlowCam® system is currently utilized as a laboratory tool to collect data on particle counts and to record images of these particles to help characterize particle morphology.

[0472] Load individual sample runs for processing by opening the data file from the File menu. The data file will be displayed in a visual spreadsheet window.

[0473] Data review Within the visual spreadsheet, data is presented and sorted into each of four windows. The display of data within these four windows can be altered to show particles identified in the sample analysis by size, shape, and frequency (see the operating manual for instructions on data sorting).

[0474] By right-clicking in each window, a drop-down menu allows changes to the data display. For example, by right-clicking in a window, then clicking the "Histogram" menu and selecting the "Circle Fit Frequency" tab, a bar graph will appear in the window showing the distribution of particles based on their comparison to a perfect sphere (1.0 being a perfect sphere). This comparison is used to isolate and identify particles such as air bubbles and silicone oil, which appear as nearly perfect spheres in aqueous solutions.

[0475] By right-clicking on the same window, selecting the "Scatter Plot" menu, and clicking "diameter vs. circle fit," the same data is shown as a scatter plot, where each red dot represents a particle counted by the instrument. These are sorted by diameter on the X axis and by circle fit on the Y axis (1.0 being a perfect sphere).

[0476] By left-clicking and dragging the mouse to highlight a selection of red dots on the scatter plot, two new windows will open: the first is a summary window showing the total number of highlighted particles and details regarding statistical analysis, and the second is an image of the selected particles themselves.

[0477] This technique can be used, for example, to identify all particles of a certain size and shape in a particular sample (e.g., silicone oil droplets are typically 2-30 µm and have a circular fit of >0.8).

[0478] MFI is used to measure particle counts in the container and the drug-containing container at t=0. Particle counts are then taken at different time intervals to assess the increase in particle count. Furthermore, MFI allows for the assessment of particle morphology. MFI can be used to determine whether particles are container-associated or drug-associated. In the case of biologics, MFI can identify aggregated proteins with unique morphologies that container particles do not have.

[0479] Example 3 - Hypothetical Example: SiO2 Medical Products, Inc. containers reduce immune responses to OVA This example demonstrates that a container of the present invention (a syringe in this example) is expected to reduce unwanted immune responses to certain drugs or proteins (e.g., ovalbumin (OVA)) when compared to a borosilicate glass container (a syringe in this example) that uses silicone oil as a lubricant.

[0480] The syringe of the present invention is a fixed-needle, 1 mL-long syringe barrel made of cyclic olefin polymer (COP) having a three- or four-layer barrier coating system on its inner surface defining a lumen. The three-layer barrier coating system is applied as a sequence of three separate coatings—an adhesive or bonding coating or layer, a barrier coating or layer, and a pH-protective coating or layer—under the conditions and using the materials specified below.

[0481] [Table 4]

[0482] Here, a four-layer barrier coating system is used, with the three-layer coating specified above, followed by a fourth lubricious layer formed by introducing octamethylcyclotetrasiloxane -OMCTS- as a precursor, which is reacted with a co-flow of oxygen to form a cross-linked lubricious coating that tightly adheres to the three-layer barrier coating system.

[0483] The plunger used is a commercially available Datwyler Omniflex plunger, which consists of a bromobutyl rubber core and a fluoropolymer conformal coating applied to the exterior surface of the plunger to block potential leaching into the drug.

[0484] The borosilicate glass syringe used as a comparative example is a pre-fillable BD Hypak™ glass syringe with a fixed needle, a 1 ml long fixed needle syringe with a 27 gauge thin wall needle, used with a Datwyler Omniflex plunger, and siliconized with silicone oil according to standard commercial pharmaceutical practice.

[0485] OVA samples for injection are prepared at 0.25 mg / mL in 20 mM sodium phosphate buffer (pH 7.4) containing 9% (w / v) sucrose.

[0486] Materials used to prepare samples for injection are of United States Pharmacopeia grade or higher. OVA is purchased from Fisher Scientific (Waltham, Massachusetts) and / or OVA Laboratories, Inc. (Wilmington, Massachusetts).

[0487] Clinical Protocol: Adult female CB6F1 (BALB / cx C57 BL / 6) mice over 6 weeks of age (available from Charles River Laboratories, Inc., Wilmington, Massachusetts) were used. Four or five mice were housed in sterile, air-filtered cages with unlimited access to food and water. Mice were allowed to acclimate for a minimum of one week before the start of the study. On days 1 and 15, mice were injected subcutaneously in the scruff of the neck. Samples were administered using a non-siliconized syringe; each 200 μL injection contained 50 μg of OVA. Groups of 5 to 8 mice were treated with OVA, OVA containing emulsified silicone oil microdroplets, OVA containing silicone oil microdroplets eluted from a syringe, and OVA containing aluminum microparticles. Control groups of mice were injected with buffer or protein-free buffer containing emulsified silicone oil microdroplets. Group 1 of mice is treated with OVA in a glass syringe with silicone oil as a lubricant, and group 2 of mice is treated with OVA in a syringe of the present invention without silicone oil.

[0488] Antibody Testing Protocol in Example 3: Submandibular blood draws are performed before the start of the study to serve as a baseline for each mouse, and on days 11 and 29 to capture primary and secondary immune responses. Blood samples are collected in sterile microcentrifuge tubes and placed on ice. Samples are then centrifuged at 15,000 rpm for 10 minutes at 4°C. Serum is then obtained and stored in aliquots at -80°C until further analysis.

[0489] OVA-specific antibodies are measured using an indirect ELISA. Immulon® 4HBX plates are coated with 10 μg / mL OVA (in 20 mM Tris, pH 8.5) (100 μL / well) and incubated overnight at room temperature with gentle agitation. Plate wells are drained and then treated with 300 μL of blocking solution (PBS (pH 7.4), 2% BSA, 0.05% Tween 20®) for 1.5 hours. Plates are washed three times with wash buffer (PBS, 0.05% Tween 20®) using an EL x50 plate washer (BioTek, Winooski, Vermont). Dilution buffer (PBS (pH 7.4), 2% BSA, 0.05% Tween 20®) is then added to the plate (50 μL / well). Serum samples are pretreated in 300 mM acetic acid for 1 hour. 41After adjusting the pH to 7.4 with 1 M Tris buffer (pH 9.5), 50 μL of the diluted serum sample was immediately transferred to the first row of the plate. The sample was serially diluted down the plate with dilution buffer and incubated for 1 hour. The plate was washed five times with wash buffer. Next, horseradish peroxidase-conjugated goat anti-mouse antibodies of subclasses IgG1, IgG2a, IgG2b, IgG2c, IgG3, or IgM were diluted in blocking solution and added to the wells (50 μL / well). The CB6F1 (F1 generation of a BALB / c x C57BL / 6 cross) mouse strain is capable of producing both the IgG2a and IgG2c immunoglobulin isotypes, since the IgG2a immunoglobulin isotype is encoded by the parental BALB / c mouse strain and the IgG2c isotype is obtained from the C57BL / 6 strain. After a second incubation for 1 hour, the plate was washed five times. Substrate solution 1-Step™ Ultra TMB is added (50 μL / well). After 25 minutes, the reaction is stopped by adding 30 μL of 0.5 M sulfuric acid. Absorbance is measured at 450 nm using a Vmax® microplate reader (Molecular Devices Corporation, Sunnyvale, California). The absorbance value is used to determine the endpoint titer for each mouse. We define the endpoint titer in this example as the reciprocal of the highest dilution that gives a signal above the cutoff. The cutoff value is calculated for each mouse using pre-treatment blood drawn on day 0 and a statistically defined endpoint titer determination method.

[0490] The unwanted immune response was characterized by the number of mice in each group exhibiting anti-OVA antibodies after the final injection on day 29.

[0491] The results show that more mice injected with OVA in a glass syringe containing silicone oil developed one or more of anti-OVA IgG1, IgG2a, and IgG3 antibodies compared to mice injected with OVA in a syringe of the present invention without silicone oil.

[0492] Example 4 - Working Example: SiO2 Medical Products, Inc. containers reduce particle counts due to particle activation compared to borosilicate glass containers Example 4 summarizes experimental work conducted by Carly F. Chisholm, William Behnkel, Yekaterina Matskiv, and Theodore W. Randolph (each from the Center for Pharmaceutical Biotechnology, Dept. Chemical and Biological Engineering, University of Colorado, Boulder, Colorado 80309) and Ashley A. Frazer-Abel (from Exsera Biolabs, Anschutz Medical Campus, Aurora, Colorado 80045). They have written a paper entitled "Subvisible Particles in IVIg Formulations Activate Complement in Human Serum." Funding for this research was provided by the NIH under RO1 EB006006 and by SiO2 Medical Products, Inc., which provided the testing protocols used in this work.

[0493] Materials used for Example 4 were USP grade or higher. Intravenous immunoglobulin (IVIG; GAMMAGARD LIQUID®, Shire US Inc., Lexington, MA) was purchased from the Wardenburg Pharmacy at the University of Colorado at Boulder. Chemicals purchased from Sigma Aldrich (St. Louis, Missouri) included monobasic sodium phosphate, dibasic sodium phosphate, and glycine. Chemicals purchased from Fisher Scientific (Waltham, Massachusetts) included polysorbate 20 (Tween 20™, NF, Multi-Compendial, JT Baker), 10X phosphate-buffered saline, and HyClone™ water for injection (WFI). Siliconized glass syringes were BD Hypak SCF 1 mL long 27G½ (BD Medical-Pharmaceutical Systems, Franklin Lakes, NJ). SiOPlas™ syringes (1 ml), (SiO2 Medical Products, Inc., Auburn, AL) consisted of cyclic olefin polymer (COP) syringe barrels whose interior surfaces were coated with a silica-based barrier coating system and a crosslinked organosiloxane lubricant (both applied by plasma-assisted chemical vapor deposition) as described in Example 3. SiOPlas™ vials (6 ml) consisted of COP coated on the inside of the vial with a barrier coating system. 6 mL Ompi EZ-fill® borosilicate glass vials (Schott, AG) were provided by SiO2 Medical Products, Inc. (Auburn, AL).

[0494] Protein formulations Prior to use, IVIg was formulated at a protein concentration of 1 mg / mL in phosphate-buffered saline (PBS) at pH 7.4 or in 250 mM glycine (pH 4.25) containing 0.02% (v / v) polysorbate 20 (PS20). To remove any pre-existing particulate matter, a GAMMAGARD LIQUID® sample (in 250 mM glycine) containing 100 mg / mL immunoglobulin G was centrifuged at 20,000 × g for 20 minutes at 4°C, and the supernatant was used as the stock solution. This IVIg stock solution was diluted 1:100 with 0.22 micron-filtered PBS (pH 7.4) or 250 mM glycine (pH 4.25) containing 0.02% (v / v) polysorbate 20 to yield a final concentration of 1 mg / mL IVIg.

[0495] Accelerated stress testing of IVIg formulations using agitation Siliconized glass and SiOPlas™ syringes (the latter 1 mL long syringes prepared as described in Example 3) were filled with 1 mg / mL IVIg (in 250 mM glycine, pH 4.25, containing 0.02% (v / v) PS20). The syringes were filled so that there was a uniform 4 mm headspace gap between the liquid and the stopper (Datwyler Pharma Packaging, Pennsauken, NJ). The syringes were rotated end-over-end at room temperature for 10 days, so that air bubbles in the headspace gap migrated from one end of the syringe to the other with each rotation. In some of the syringes tested, the air bubbles became trapped at one end of the syringe and could not be displaced when the syringe was rotated. These syringes were excluded from further analysis. After 10 days of end-over-end rotation, each formulation was expelled from the syringe through the needle using an automated syringe pump at 150 mm / min, and samples were collected into pre-rinsed polypropylene tubes and tested for visually undetectable particle concentrations and for complement activation capacity.

[0496] Another set of identical siliconized glass and SiOPlas™ syringes was filled with 1 mg / mL IVIg (in PBS). The syringes were placed horizontally on an orbital shaker and shaken overnight at room temperature. After shaking, the formulation was expelled from the syringe through the needle using an automated syringe pump at 150 mm / min, collected in pre-rinsed polypropylene tubes, and tested for subvisible particle concentration and complement activation capacity.

[0497] Accelerated stress testing of IVIg preparations using freeze-thawing Borosilicate vials (6 mL) and SiOPlas™ vials (6 mL) prepared as described in Example 1 were filled with 4 mL of formulation containing 1 mg / mL IVIg (in PBS pH 7.4). The contents of the vials were subjected to one or six freeze-thaw cycles. In each freeze-thaw cycle, the vial was first immersed in liquid nitrogen for 2 minutes and then thawed in a 30°C water bath for 14.5 minutes. Each vial was gently swirled to mix before being subjected to the next freeze-thaw cycle.

[0498] Analysis of particle concentrations that cannot be detected visually Flow imaging microscopy (FlowCAM®, Fluid Imaging Technologies, Scarborough, Maine) was used to obtain particle concentrations and images of particles in the various stressed formulations, as previously described. Because 15 samples subjected to six freeze-thaw cycles contained particle concentrations approaching or exceeding the upper limit of the flow imaging microscopy instrument, these formulations were diluted 100-fold with phosphate-buffered saline (pH 7.4) prior to analysis. Particle counts were measured for formulations expelled from each syringe and vial tested for complement activation.

[0499] Analysis of soluble protein fractions by size exclusion chromatography Size-exclusion chromatography was used to monitor the retention of monomeric protein and the appearance of any soluble aggregates in IVIG samples after agitation or freeze-thaw stress. A TSKgel G3000SWXL column (TOSOH Biosciences, Montgomeryville, Pennsylvania) was used with an Agilent 1100 Series system (Santa Clara, CA). The eluent was monitored by absorbance at 280 nm using Agilent ChemStation software. A mobile phase of 100 mM sodium sulfate, 100 mM sodium phosphate, and 0.05% (w / v) sodium azide, pH 6.7, was passed through the system at 0.6 mL / min. Peak areas in the chromatograms were quantified using GRAMS / AI software version 9.1 (Thermo Fisher Scientific Inc., Waltham, Massachusetts).

[0500] Complement activation in human serum samples Pooled samples from three vials or syringes of various stressed IVIg formulations and unstressed control samples of each formulation were sent to Exsera Biolabs (Denver, CO) for analysis of their ability to activate complement. Complement activation was measured in pooled normal human serum from three individual donors previously screened for normal complement function. Test samples of stressed IVIg formulations were diluted 10-fold with pooled human serum, mixed, and incubated at 37°C for 30 minutes. After incubation, samples were stored at -80°C until further testing. For analysis of complement activation, concentrations of four complement cascade proteins, C3a, Bb, C4a, and C5a, were measured by ELISA using kits purchased from Quidel Corporation (San Diego, CA). C4a was chosen because it is a marker of classical or lectin pathway activation, Bb as a characteristic marker of the alternative pathway for complement activation, C3a as a central component of complement activation, and C5a as a marker of terminal complement pathway activation. Forty triplicate ELISA measurements were performed for each complement cascade protein. In addition to testing the stressed IVIG samples, several controls were analyzed. These control samples included pooled serum alone or serum samples to which saline solution, phosphate-buffered saline containing zymosan, or heat-aggregated gamma globulin in phosphate-buffered saline was added in a 1:9 ratio. The mean of the measurements was plotted against the number of particle samples as a fold increase compared to the concentration measured in the saline control.

[0501] As expected, each accelerated stress test method resulted in small particles in the formulations tested (Table 1). Freeze-thawing of IVIg (in PBS pH 7.4) resulted in the highest number of visually undetectable particles. A single freeze-thaw cycle resulted in 3.2 x 10 particles in borosilicate and SiOPlas™ vials, respectively. 5 and 7.1 x 10 5Particles larger than 10 microns were also produced, with 8 x 10 particles in the borosilicate vial. 3 particles were detected, with 5.1 x 10 particles in the SiOPlas™ vial. 4 particles were observed.

[0502] The application of multiple freeze-thaw cycles further increased the particle number by approximately an order of magnitude. After six cycles, the particle concentrations in the borosilicate and SiOPlas™ vials, respectively, that were greater than 2 microns in size were 4.8 x 10 6 and 2.1 × 10 6 Particles larger than 10 microns also occurred, with 2.3 x 10 particles / mL in the borosilicate and SiOPlas™ vials, respectively. 5 and 3.6 x 10 5 It was.

[0503] The number of particles generated as a result of agitation stress depends on the type of vessel and also on the type of agitation applied. 41 Overnight agitation of the IVIg formulation (in PBS pH 7.4) using an orbital shaker resulted in the production of 2.4 x 10 particles of size greater than 2 microns in a siliconized glass syringe. 6 particles, and in the corresponding SiOPlas™ syringe, 6.0 x 10 5 As was the case with the freeze-thaw study, nearly an order of magnitude fewer large (>10 micron) particles were formed in both syringe types.

[0504] Ten days of end-over-end rotation was the mildest accelerated stability test applied. The IVIg formulation (in glycine pH 4.25) showed 3 x 10 particles in the >2 micron particle size range in SiOPlas™ and siliconized glass syringes, respectively, after 10 days of end-over-end rotation. 3 and 1.03 × 10 5Only 1.0 x 10 particles / mL were detected. Correspondingly, few particles larger than 10 microns occurred, with 2.0 x 10 particles / mL in the siliconized glass and SiOPlas™ syringes, respectively. 3 and 90 particles / mL were detected.

[0505] A collection of typical flow imaging microscopy images of particles generated by various accelerated stress methods is shown in Figure 1. Samples in vials stressed by freeze-thawing contained primarily non-spherical microparticles typical of proteinaceous aggregates (Figure 1a), whereas samples in siliconized glass syringes stressed by agitation (Figure 1b) contained numerous spherical particles typical of lubricant droplets. Agitation in SiOPlas™ syringes (Figure 1c) produced particles with various morphologies that could be included in both irregularly shaped protein aggregates and silicone oil spherical droplets.

[0506] For all of the accelerated stress conditions tested, size exclusion chromatography analysis showed that only minimal (<5%) amounts of insoluble protein were formed. No soluble aggregates were detected under any of the conditions. Application of six freeze-thaw cycles to IVIg in borosilicate glass vials produced the highest number of particles greater than 2 microns per mL—nearly 5 million particles—which represented a loss of only 3.7% of the original monomeric protein.

[0507] Complement activation in human serum in response to particles generated under accelerated stress conditions. Particles greater than 2 microns in size within IVIg formulations subjected to accelerated stress conditions activated complement in a linear dose-dependent manner when the IVIg formulation was diluted 10-fold in human serum. Particles greater than 10 microns in IVIg formulations did not correlate with activated complement.

[0508] The observed complement activation was consistent with activation via the alternative pathway. No increase was seen for C4a, a marker of the classical or lectin pathways, compared to saline control levels (Figure 2). In contrast, Bb, a marker of the alternative pathway for complement activation, increased linearly (r 2 =0.94) (Figure 3).

[0509] Increased concentrations of the anaphylatoxins C3a and C5a were also observed when the particles were diluted in serum (Figures 4 and 5). Similar to the Bb response, the fold increase over saline control was linearly dependent on particle dose, with correlation coefficients r for C3a and C5a. 2 were 0.85 and 0.99, respectively. Responses to IVIg formulations in borosilicate glass vials subjected to six freeze-thaw cycles resulted in increases in C3a and C5a concentrations that were 2.4- and 8.9-fold higher than those observed in saline controls.

[0510] For comparison, a positive control containing 1 mg / mL zymosan or 1 mg / L heat-aggregated gamma globulin stimulated an approximately 11-fold increase (relative to saline) in C3a, Bb, and C4a, and an approximately 32-fold increase (relative to saline) in C5a levels.

[0511] The experimental results are tabulated in Tables 1-2 and Figures 9-22. Note that the data in the first row of Table 2 does not match any of the data in Table 1, but otherwise each table is a different representation of the same experimental data. Table 1 shows the concentration of visually undetectable particles in stressed samples submitted for complement activation testing. Samples were pooled from triplicate samples from each stress / container combination. Container-to-container variation in particle concentration in samples prior to pooling was <15%.

[0512] [Table 5]

[0513] [Table 6]

[0514] Looking more closely at the results for vials after a single freeze-thaw, complement activation in IVIg samples in borosilicate and SiO2 vials was not significantly different from that elicited by the initial IVIg solution, and the difference between borosilicate and SiO2 vials was not statistically significant. A large, statistically significant increase in complement activation was observed after six freeze-thaw cycles. Complement activation, determined by measuring both C3a and C5a levels, was significantly higher in borosilicate vials compared with SiO2 vials in terms of the frozen-thawed IVIg. Responses to IVIg samples in borosilicate vials treated with six freeze-thaw cycles (3.3 + / - 0.1 and 9.9 + / - 0.3-fold greater than the C3a and C5a responses to saline controls) were in the range typically associated with adverse infusion reactions, such as flushing and possible anaphylaxis. Initial particle levels in the IVIg preparation were 3000 / mL (>2 microns) and 300 / mL (>10 microns). After a single freeze-thaw, particle levels in the SiO2 vials were 7.1 x 10 5 particles / mL (greater than 2 microns), and 5.1 x 10 4 in the borosilicate vials, the numbers were lower, 3.2 x 10 for particles greater than 2 microns and greater than 10 microns in size, respectively. 5 pcs and 8 x 10 3 After six freeze-thaw cycles, the particle level in the SiO2 vial was 2.1x10 6 particles / mL (greater than 2 microns), and 3.6 x 10 5 in the borosilicate vials, the numbers were now higher, 4.8 x 10 for particles greater than 2 microns and greater than 10 microns in size, respectively. 6 and 2.3 x 10 5 There were 100 pieces.

[0515] Looking more closely at the syringe results, complement activation was highly linear in particle content for both C3a and C5a (r 2 >0.99). In each condition, complement activation, as determined by measured levels of both C3a and C5a, was significantly higher in the siliconized glass syringes compared with the SiO2 four-layer syringes. Responses to IVIg samples in borosilicate vials treated with six freeze-thaw cycles (3.3 + / - 0.1 and 9.9 + / - 0.3 times greater than the C3a and C5a responses to saline controls) were in the range typically associated with adverse infusion reactions, including flushing and possible anaphylaxis. After overnight agitation on a shaking table, particle levels in the SiO2 syringes were 6 x 10 5 cells / mL (>2 microns) whereas in the siliconized glass syringe the number was 2.4 × 10 6 After 10 days of end-over-end rotation, the particle level in the SiO2 syringe was 3 x 10 3 cells / mL (>2 microns) in the siliconized glass syringe, whereas the number was 1.0 × 10 5 There were 100 pieces.

[0516] The following conclusions were reached from the experiments in Example 4. First, complement activation (C5a and C3a) was directly proportional to the concentration of particles in the 2-10 micron size range. Second, complement activation was independent of how the particles were generated, including formulation pH, applied stress, and the presence of surfactant. Third, for identical formulations and applied stresses, SiO2 medical vials and syringes generally had lower particle levels than borosilicate vials and siliconized glass syringes.

Claims

1. a thermoplastic wall having an interior surface defining a lumen; a drug contact coating on or adjacent to the interior surface and positioned to contact a polypeptide composition within the lumen, wherein the drug contact coating is a SiO x C y H z It consists of, where: x is between 0.5 and 2.4, as measured by X-ray photoelectron spectroscopy (XPS); y is between 0.6 and 3, as determined by XPS; z is 2 to 9, as measured by Rutherford backscattering; 1. A drug container that is a syringe, comprising: the drug contact coating is free of silicone oil; a drug container containing particles having an effective spherical diameter of more than 2 micrometers and less than or equal to 10 micrometers (μm), with a lower limit of 1,000 and an upper limit of 50,000 particles per mL of the polypeptide composition (wherein the particle count is determined by filling the drug container with the polypeptide composition comprising 1 mg / mL IVIg (in 250 mM glycine, pH 4.25, containing 0.02% (v / v) PS20), rotating the drug container end-over-end at room temperature for 10 days so that air bubbles in the headspace void move from one end of the syringe to the other with each rotation, and testing the polypeptide composition in the treated drug container for particle concentration using flow imaging microscopy).

2. 10. The drug container of claim 1, wherein the drug contact coating in the drug container is a lubricious coating.

3. 3. The drug container of claim 1, wherein the drug contact coating in the drug container is a pH protective coating.

4. 4. The drug container of claim 3, wherein the pH protective coating within the drug container has a silicon decomposition rate of less than 1 μg (microgram) per day.

5. The drug container according to any one of claims 1 to 4, wherein the drug contact coating in the drug container is a gas barrier coating.

6. The drug contact coating within the drug container is chemically homogeneous, and homogeneity is achieved by varying the SiO x C y H z The drug container of any one of claims 1 to 5, wherein the drug container has an atomic standard deviation (%) of less than 5% for Si, C, and O as determined by X-ray photoelectron spectroscopy (XPS) analysis.

7. the drug contact coating in the drug container a bond coating or layer comprising or consisting of SiOxCyHz or SiNxCyHz, wherein x is from 0.5 to 2.4 as measured by X-ray photoelectron spectroscopy (XPS), y is from 0.6 to 3 as measured by XPS, and z is from 2 to 9 as measured by at least one of Rutherford backscattering spectroscopy (RBS) and hydrogen forward scattering spectroscopy (HFS), a bonding coating or layer having an outer surface facing the wall surface and having an inner surface; a barrier coating or layer of SiOx, where x is 1.5 to 2.9 as measured by XPS, located between the inner surface of the bond coating or layer and the lumen; and a pH protective coating or layer of SiOxCyHz located between the barrier coating or layer and the lumen, wherein x is from 0.5 to 2.4 as measured by XPS, y is from 0.6 to 3 as measured by XPS, and z is from 2 to 9 as measured by at least one of RBS or HFS; The drug container according to any one of claims 1 to 6, comprising:

8. 8. The drug container of claim 7, wherein the drug contact coating in the drug container further comprises a lubricious coating or layer of SiOxCyHz, on top of the pH protective coating, where x is 0.5-2.4, y is 0.6-3, and x and y are determined by X-ray photoelectron spectroscopy (XPS), and z is 2-9, and z is determined by Rutherford backscattering spectroscopy.

9. The drug container of any one of claims 1 to 8, wherein the polypeptide composition comprises a drug from the following list of biopharmaceuticals, or any combination of two or more thereof: TNF mAb, rDNA (Inflectra-infliximab-dyyb); Polydeoxyribonucleotide, porcine origin (Defitelio-Defibrotide sodium; Polydeoxyribonucleotide, sodium salt); IL-17 Mab, rDNA (Taltz; ixekizumab); Anthrax Mab, rDNA (Anthim; Bacillus anthracis (anthrax) protective antigen (PA) monoclonal antibody, recombinant; ETI-204); Factor VIII rDNA (Kovaltry); Antihemophilic Factor (recombinant); Insulin glargine. rDNA (Basaglar; Abasria; LY2963016); Factor X, blood-derived (Coagadex; coagulation factor X (human)); von Willebrand factor, rDNA (Vonvendi); Lysosomal acid lipase, expressed in chicken eggs (Kanuma; sebelipase alfa) (a secondary product from genetically engineered animals), approved on 12 / 8 / 2015 for Alexion (through its acquisition of Synageva) for the treatment of lysosomal acid lipase (LAL) deficiency; Influenza vaccine, quadrivalent (Fluad; influenza vaccine with MF59 / squalene adjuvant, inactivated, egg-cultured, quadrivalent), approved for Novartis on 12 / 3 / 2015 (the product and its approval will be transferred to Sequrus, a CSL Group company) for the prevention of influenza; the first non-aluminum-based adjuvanted influenza vaccine in the United States; SLAMF7 mAb, rDNA (Empliciti; elotuzumab; signaling lymphocyte activation molecule family member 7 monoclonal antibody, recombinant), approved on 11 / 30 / 2015 to Bristol Myers Squibb (BMS; in collaboration with Abbvie) for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1 to 3 prior therapies; EGFr mAb, rDNA (Portrazza-necitumumab; epidermal growth factor receptor monoclonal antibody), approved on 2015 / 11 / 24 to Janssen Biotech for the treatment of metastatic squamous non-small cell lung cancer (VWD) in combination with gemcitabine and cisplatin; rDNA Darzalex (daratumumab), a CD38 mAb approved for Eli Lilly on 11 / 16 / 2015, for the treatment of multiple myeloma; Factor VIII, rDNA, pegylated (Adynovate-BAX 111), approved on 11 / 11 / 2015 for Baxalta (formerly Baxter) for the treatment of hemophilia A; IL-5 mAb, rDNA (Nucala; mepolizumab), approved on 11 / 4 / 2015 for GlaxoSmithKline (GSK) for the treatment of asthma; HSV-1 / GM-CSF, rDNA, rDNA (Imlygic - alimogen laherparepvec; a live herpes simplex virus type 1 (HSV-1) oncolytic virus that results in expression of GM-CSF), approved on 10 / 27 / 2015 to Alexion Pharmaceuticals for the treatment of unresectable recurrent cutaneous melanoma; Alkaline phosphatase, rDNA (Strensiq; asfotase alfa; alkaline phosphatase catalytic domain fusion protein), approved on 10 / 23 / 2015 to Alexion Pharmaceuticals for the treatment of birth-, infantile-, and juvenile-onset hypophosphatasia (HPP); rDNA (Praxbind-idarucizumab), a dabigatran mAb, approved on 10 / 16 / 2015 to Boehringer Ingelheim for reversing the anticoagulant effects of Pradaxa (dabigatran); Insulin degludec, rDNA (Tresiba-insulin degludec), approved on 10 / 16 / 2015 to Novo Nordisk for the treatment of diabetes mellitus; Insulin degludec / aspart, rDNA (Lyzodeg 70 / 30 - a 70 / 30 mixture of insulin degludec (approved the same day) and insulin aspart), approved for Novo Nordisk on 10 / 16 / 2015, for the treatment of diabetes mellitus; Factor VIII, rDNA (Nuwiq), approved on 10 / 16 / 2015 to Octapharma USA for the treatment of hemophilia A; A PCSK9 mAb, rDNA (Repatha-evolocumab; proprotein convertase subtilisin kexin type 9 monoclonal antibody), granted approval to Amgen Inc. on August 27, 2015, for the treatment of high low-density lipoprotein (LDL) cholesterol levels; A PCSK9 mAb, rDNA (Praluent - alirocumab; proprotein convertase subtilisin kexin type 9), granted approval on 7 / 24 / 2015 to Sanofi and Regeneron Pharmaceuticals for the treatment of high low-density lipoprotein (LDL) cholesterol levels; Crotalidae Immune F(ab')2 (Equine) (Anavip), manufactured by Instituto Bioclone S.A. (Mexico), approved on May 6, 2015 for ProFibrix, BV, for the treatment of North American rattlesnake bites; Fibrin sealant (RAPLIXA; Raplixa spray - human plasma-derived fibrinogen and thrombin) (originally developed by the merged ProFibrix, BV), approved on 4 / 30 / 2015 to The Medicines Company for the treatment of mild to moderate bleeding when control of bleeding by standard surgical techniques is ineffective or impractical in adults undergoing surgery; Factor IX, rDNA (Coagulation Factor IX (Recombinant) - Ixinity), approved on 4 / 29 / 2015 to Cangene / Emergent Biosolutions for the treatment of hemophilia B; DTaP-IPV vaccine (Quadracel-diphtheria-tetanus toxoid and sterile pertussis-adsorbed and inactivated poliovirus), licensed for Sanofi Pasteur on 26 / 03 / 2015, for active immunization against diphtheria, tetanus, pertussis, and poliomyelitis in children aged 4 to 6 years; Anthrax immune globulin (Anthrax immune globulin intravenous (human) - Anthracil; AIGIV), approved on March 24, 2015, to Emergent BioSolutions Inc. for the treatment of inhalational anthrax in combination with an appropriate antimicrobial; Approval was granted to United Therapeutics Corp. on March 10, 2015 for the treatment of pediatric patients with high-risk neuroblastoma (in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis retinoic acid (RA)), a GD2 mAb, rDNA (dinutuximab-Unituxin; ch14.18); Approval granted to Sandoz / Novartis on 3 / 6 / 2015 for G-CSF, rDNA / Sandoz (filgrastim-sndz-Zarxio; Zarxio; granulocyte colony-stimulating factor, recombinant) for the treatment of neutropenia (same indication as Neupogen); first biosimilar approved; Approval was granted on March 4, 2015 to Bristol-Myers Squibb Co. (BMS; licensed from Ono Pharm.) for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression during or after platinum-based chemotherapy, including the PD-1 mAb, rDNA / Sandoz (nivolumab-Opdivo; ONO-4538; BMS-936558; MDX1106; programmed cell death 1 monoclonal antibody, recombinant); Insulin glargine, rDNA (Toujeo-Gly(A21)-human insulin Arg(B31)-Arg(B32)-OH, recombinant), approved on 2 / 25 / 2015 to Sanofi for once-daily long-acting basal insulin treatment in adults with type 1 and type 2 diabetes; Parathyroid hormone (1-84), rDNA (Natpara; Preos; Preotact), approved on 1 / 25 / 2015 to NPS Pharmaceuticals (merged by Shire) for the treatment of hypocalcemia (low blood calcium levels) in patients with hypoparathyroidism; A Neisseria meningitidis vaccine (secukinumab-Bexsero; Cosentyx), approved on January 23, 2015, to Novartis for the prevention of invasive meningococcal disease; IL-17 mAb, rDNA (secukinumab-Cosentyx), approved on January 21, 2015, to Novartis for the treatment of adults with moderate to severe plaque psoriasis; The programmed death receptor-1 mAb, rDNA (nivolumab-Opdivo), granted approval on 12 / 22 / 2014 to Bristol-Myers Squibb for the treatment of advanced melanoma (for patients with unresectable or metastatic melanoma and disease progression after treatment with Yervoy in patients with BRAF V600 mutation-positive tumors); Influenza vaccine, quadrivalent, i.d. (Fluzone intradermal quadrivalent), granted approval to Sanofi Pasteur on 12 / 12 / 2014 for prophylactic use in adults 8 to 64 years of age; HPV vaccine, 9-valent, rDNA (Human papillomavirus 9-valent vaccine, recombinant—Gardasil 9), granted approval to Merck & Co. on 12 / 10 / 2014 for prophylactic use in females aged 9-26 years; A CD3-CD19 bispecific mAb, rDNA (blinatumomab-AMG103; CD19-CD3 bispecific monoclonal antibody; CD3-CD19 bispecific T-cell engager (BiTE)), granted accelerated approval to Amgen on 12 / 03 / 2014 for the treatment of Philadelphia chromosome-negative relapsed / refractory precursor B-cell acute lymphoblastic leukemia (ALL); breakthrough therapy designation; Meningococcal B vaccine (Meningococcal Group B Vaccine - Trumemba), granted accelerated approval to Pfizer on 10 / 29 / 2014 for active immunization to prevent invasive Neisseria meningitidis serogroup B strains in 10-25 year olds; Approval was granted to Baxter on 10 / 24 / 2014 for the treatment of adult patients with acquired (not hereditary) hemophilia A, Factor VIII, porcine rDNA (Antihemophilic Factor (recombinant), porcine sequence - Obizur; OBI-1; Factor VIII, porcine recombinant); Glucagon-like peptide-1, rDNA (Trulicity), approved on September 18, 2014, to Eli Lilly & Co. for the treatment of adult patients with type 2 diabetes; Approval was granted to Baxter (and Halozyme Therapeutics) on 9 / 12 / 2014 for the treatment of adult patients with primary immunodeficiency (PI), Immunoglobulin & Hyaluronidase rDNA (Immunoglobulin Injection 10% (Human) with Recombinant Human Hyaluronidase - HYQVIA; Gammagard combined with Hylenex); A PD-1 mAb, rDNA (Keytruda-pembrolizumab; MK-3475), granted approval to Merck & Co. on September 4, 2014, for the treatment of patients with advanced melanoma that has not responded to other therapies; insulin glargine, rDNA / Lilly (Basaglar), which was granted tentative approval to Eli Lilly & Co., a partner with Boehringer Ingelheim, on August 18, 2014, for the treatment of diabetes; Interferon beta-1a, PEG-, rDNA (Plegridy), approved on 8 / 15 / 2014 for Biogen Idec, for the treatment of relapsing forms of multiple sclerosis (RMS); A C1-esterase inhibitor, rDNA (Conestat alfa-Rhucin; Ruconest; C1INH; C1-INH; human complement C1 esterase inhibitor, recombinant, transgenic rabbit), approved on 7 / 17 / 2014 to Salix Pharmaceuticals, Ltd. (and Pharming Group NV) for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE); Insulin, rDNA, Inhalation / MannKind (Insulin Human (rDNA Origin)) Inhalation Powder - Afrezza; Afreza Inhalation Powder; Technosphere Insulin), approved on 6 / 27 / 2014 to MannKind Corp., for improving glycemic control in adults with diabetes mellitus; Factor VIII / Biogen-Idec, rDNA (Eloctate), approved on June 6, 2014, to Biogen Idec Inc., for the treatment of hemophilia A; An integrin mAb, rDNA (Entyvio-vedolizumab), approved on 5 / 20 / 2014 to Takeda Pharmaceuticals America, Inc. for the treatment of ulcerative colitis and Crohn's disease; IL-6 mAb, rDNA (Sylvant-siltuximab; CNTO 328), approved on 4 / 23 / 2014 to Janssen / J&J for the treatment of multicentric Castleman disease (MCD); VEGF-2 mAb, rDNA (VEGRFr mAb-Cyramza; ramucirumab), approved on 4 / 21 / 2014 to Eli Lilly & Co. for the treatment of advanced gastric cancer; GLP-1 / Albumin Fusion Protein, rDNA (Tanzeum-Glucagon-Like Peptide-1 (GLP-1)-Albumin Fusion Protein), approved on 4 / 15 / 2014 for GlaxoSmithKline (GSK) for glycemic control in type 2 diabetes; Factor IX-Fc fusion protein, rDNA (Coagulation Factor IX (recombinant), Fc fusion protein - Alprolix; Factor IX-XTEN), approved on 3 / 28 / 2014 to Biogen Idec, for the treatment of hemophilia B; hyaluronic acid, cross-linked (Monovisc), approved on 2 / 25 / 2014 to Anika Therapeutics for the treatment of osteoarthritis of the knee; Leptin, rDNA (metreleptin-methionyl human leptin, recombinant), approved on 2 / 24 / 2014 as replacement therapy to treat complications of leptin deficiency; Approved for BioMarin on 2 / 14 / 2014 (marketed by DePuy Synthes, a division of Johnson & Johnson), N-acetylgalactosamine-6-sulfatase, rDNA (elosulfase alfa-vimizim; N-acetylgalactosamine-6-sulfatase; rhGALNS; BMN-110, elosulfase alfa; chondroitin sulfatase), for the treatment of mucopolysaccharidosis type IVA (Morquio A syndrome); Factor XIII, rDNA (Coagulation Factor XIII A Subunit (Recombinant) - Tretten), approved on 12 / 23 / 2013 to Novo Nordisk A / S for the routine prophylaxis of bleeding in adults and children with congenital factor XIII A subunit deficiency (hemophilia); Influenza Vaccine, H5N1 (Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted), approved on 11 / 22 / 2013 to ID Biomedical / GSK for the prevention of H5N1 influenza, commonly known as avian influenza; a complete BLA has been approved for this vaccine, adjuvanted with egg-cultured AS03, for pandemic / biofense stockpile use only; CD20 mAb, rDNA / Roche (obinutuzumab-Gazyva; GA101), approved on 11 / 1 / 2013 to Genentech / Roche for use in combination with chlorambucil chemotherapy for the treatment of previously untreated chronic lymphocytic leukemia (CLL); Tetanus and diphtheria toxoid precipitated purified (Adsorbed) (Tenivac), approved to Sanofi on 10 / 25 / 2013 for the prevention of tetanus and diphtheria; Factor VIII, rDNA / Novo (Antihemophilic Factor (Recombinant)-NovoEight; Factor VIII, Recombinant), approved on 10 / 15 / 2013 to Novo Nordisk for the treatment of hemophilia A; Influenza vaccine, quadrivalent / GSK (Flulaval quadrivalent), approved for GlaxoSmithKline (GSK) on 8 / 16 / 2013 for influenza prevention; Complete BLA approved on 7 / 18 / 2013 to Janssen Biotech, Johnson & Johnson, TNF Mab, rDNA, human / J&J (golimumab-Simponi Aria) for the treatment of moderately to severely active rheumatoid arthritis; Factor IX, rDNA / Baxter (Coagulation Factor IX (Recombinant) - Rixubis), approved on 6 / 27 / 2013 to Baxter Healthcare for the treatment of hemophilia B; Influenza vaccine, quadrivalent / Sanofi (Fluzone quadrivalent), approved for Sanofi on June 10, 2013, for influenza prevention; Prothrombin complex / CSL (Prothrombin Complex Concentrate (Human) - Kcentra), approved on 4 / 29 / 2013 to CSL Behring GmbH for the urgent reversal of acquired coagulation factor deficiencies induced by vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute massive bleeding; Botulinum Antitoxin / A-G (Botulinum Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Horse); Clostridium botulinum Toxin Immune Globulin, Horse), approved on 3 / 23 / 2013 to Cangene Corp., for the treatment of botulism after documented or suspected exposure to botulinum neurotoxin; HER2 receptor Mab-DM1, rDNA (ado-trastuzumab emtansine-Kadcyla; trastuzumab emtansine; trastuzumab-DM1; T-DM1; trastuzumab-MCC-DM1; Herceptin-DM1 conjugate), approved on 2 / 22 / 2013 to Genentech / Roche for the treatment of HER2-positive metastatic breast cancer (mBC); Apolipoprotein B, antisense (mipomersen-Kynamro; ISIS 301012), approved on 1 / 17 / 2013 to Isis Pharmaceuticals and Genzyme / Sanofi for use as an adjunct to lipid-lowering medications and diets to lower low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC), and non-high-density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH); Plasma SD / Octapharma (Octaplus - plasma, solvent-detergent inactivated), approved on 1 / 17 / 2013 to Octapharma AG for the required replacement of coagulation proteins (clotting factors); Influenza vaccine, rHA, rDNA, approved on 1 / 17 / 2013 to Protein Sciences Corp. and marketed by Emergent Biosolutions, Inc. for the prevention of influenza in persons 18-49 years of age (Influenza vaccine, purified recombinant influenza hemagglutinin - FluBlok; Influenza hemagglutinin vaccine, insect cell culture, recombinant); Glucagon-like peptide 2, rDNA (teduglutide (rDNA origin) - GATTEX), approved on 12 / 21 / 2012 to NPS Pharmaceuticals for the treatment of adults with short bowel syndrome (SBS) who require additional nutrition from intravenous nutritional support (parenteral nutrition); Immunoglobulin (IGIV) / Biotest (Immunoglobulin Intravenous (Human) - Bivigam), approved on 12 / 20 / 2012 to Biotest Pharmaceuticals Corp., for the treatment of primary immunodeficiency disorders (PIDD); Varicella Zoster Immune Globulin / Cangene (Varicella Zoster Immune Globulin (Human) - VariZIG; VZVIG), approved on 12 / 19 / 2012 to Cangene Corp. for post-exposure prophylaxis of chickenpox in high-risk individuals to reduce the severity of chickenpox; Fluarix 4-valent (Influenza Virus Vaccine - Fluarix 4-valent), approved on 17 / 12 / 2012 for GlaxoSmithKline (GSK) for the prevention of disease caused by the four seasonal influenza (flu) virus subtypes A and B strains represented by the antigens in this vaccine; Anthrax Mab, rDNA / HGSI (raxibacumab-ABthrax; Bacillus anthracis protective antigen human monoclonal antibody, recombinant), approved on 12 / 14 / 2012 to Human Genome Sciences Inc., a subsidiary of GlaxoSmithKline (GSK), for the treatment of inhalational anthrax when alternative therapies are not available or appropriate and for the prophylaxis of inhalational anthrax; Fibrin Sealant Patch / J&J (Fibrin Sealant Patch - Human Fibrinogen and Human Thrombin - EVARREST Fibrin Sealant Patch), manufactured by Omrix Biopharmaceuticals Ltd. (Israel), approved on 12 / 7 / 2012 to Ethicon Biosurgery, Johnson & Johnson (J&J), for use as an aid in stopping problematic bleeding during surgery; Influenza vaccine, MDCK culture / Novartis (Flucelvax; Optaflu; influenza virus vaccine, inactivated), approved for Novartis on 11 / 20 / 2012 for the prevention of seasonal influenza in persons 18 years of age and older (first cell-culture influenza vaccine in the United States); microplasmin, rDNA (ocriplasmin-Jetrea), approved on 10 / 18 / 2012 to ThromboGenics for the treatment of symptomatic vitreomacular adhesion; G-CSF, rDNA / Teva (filgrastim; the same active agent as Neupogen and TevaGrastin, approved in the EU as a biosimilar of Neupogen), for which a complete BLA was approved on 8 / 30 / 2012 for Sicor Biotech (Teva Pharmaceuticals) to reduce the duration of severe neutropenia in patients with certain types of cancer (non-myeloid malignancies) receiving chemotherapy that affects the bone marrow; VEGF Trap, rDNA (ziv-aflibercept-Zaltrap), approved on 8 / 3 / 2012 to Sanofi (in collaboration with Regeneron) for use in combination with 5-flourouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of metastatic colorectal cancer (mCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen; MenC-Hib vaccine (Meningitis groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine - MenHibrix), approved for GlaxoSmithKline on 6 / 14 / 2012 for the prevention of invasive disease caused by Neisseria meningitidis serogroup C and Y strains and Haemophilus influenzae type b (previously approved vaccine combination); rDNA / 2C4 (pertuzumab-Perjeta; Omnitarg; 2C4), a HER2 receptor Mab, approved on June 8, 2012 to Genentech / Roche for use in combination with Herceptin (trastuzumab) and docetaxel chemotherapy for the first-line treatment of HER2-positive metastatic breast cancer; Glucocerebrosidase, rDNA / Protalix (taliglucerase alfa-Elelyso; Uplyso; beta-glucocerebrosidase, recombinant (expressed in carrot); prGCD) (may be considered a biobetter version of Cerezyme by Genzyme / Sanofi), approved on 5 / 1 / 2012 to Protalix BioTherapeutics Inc. and Pfizer (BLA holders) for the treatment of Gaucher disease; Human Cell, Autologous / Bovine Collagen Matrix (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen - GINTUIT), approved on March 9, 2012 to Organogenesis Inc. for topical application to surgically created vascular wound beds in the treatment of gingival-alveolar (gums; oral tissue) conditions (first cell-based product for oral tissue application); Pancreatic enzyme (pancrelipase - Ultresa; Viokase), approved on 3 / 1 / 2012 to Aptalis Pharma for the treatment of a rare pancreatic insufficiency indication (first full approval for a long-marketed, proprietary drug product); Influenza vaccine, live, intranasal tetravalent (FluMist tetravalent; influenza vaccine, live, intranasal), for which an sBLA was approved on 2 / 29 / 2012 for MedImmune (AstraZeneca), for the prevention of seasonal influenza; Carboxypeptidase, rDNA-(Glucarpidase-Voraxaze; CPG2; Carboxypeptidase G2, recombinant), approved on 1 / 18 / 2012 to BTG plc (formerly Protherics) for the treatment of methotrexate toxicity; VEGF Trap, rDNA-(aflibercept-Eylea; VEGF Trap-Eye), approved on 11 / 18 / 2011 to Regeneron Pharmaceuticals (marketed globally by Bayer) for the treatment of wet (neovascular) age-related macular degeneration (AMD); Asparaginase / Erwinia - (Erwinaze - asparaginase Erwinia chrysanthemi; Erwinase; L-asparagine aminohydrolase; L-asparaginase), approved on 11 / 18 / 2011 to EUSA Pharma Inc. for the treatment of acute lymphoblastic leukemia (ALL); Approval was granted to New York Blood Center, Inc. on 11 / 10 / 2011 for use in hematopoietic stem cell transplant procedures in patients with disorders affecting the hematopoietic (blood-forming) system, Umbilical Cord Blood Stem Cells-(HEMACORD; Hematopoietic Progenitor Cell-Umbilical Cord (HPC-C) Cell Therapy); CD30 mAb-monomethyl auristatin E- (Adcetris; brentuximab vedotin; CD30 mAb-cytotoxin conjugate), granted accelerated approval under orphan drug status on 8 / 19 / 2011 to Seattle Genetics, Inc., for the treatment of Hodgkin lymphoma; currently the only immunotoxin on the U.S. market; Centruroides (Scorpion) Immune F(ab)2 (Horse) Injection (Anascorp), manufactured by Instituto Bioclone, S.A. (Mexico), approved on August 3, 2011, to Rare Disease Therapeutics Inc. for the treatment of scorpion stings; Fibroblast, autologous (azfibrocel-T-laViv; Isolagen therapy), approved on June 22, 2011, to Fibrocell Science, Inc., for the treatment of the appearance of nasolabial folds (laugh lines); CTLA4-Ig, rDNA (belatacept-Nulojix; BMS-224818; CTLA4-Ig variant; cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-immunoglobulin G1 fragment fusion protein, recombinant), approved for Bristol-Myers Squibb (BMS) on 6 / 15 / 2011 for the prevention of acute rejection in adult kidney transplant recipients; Albumin, human (Kedbumin), approved on 6 / 3 / 2011 to Kedrion, S.p.A. for the treatment of hypovolemic shock, hypoalbuminemia, prevention of central volume depletion after paracentesis due to ascites in cirrhosis, ovarian hyperstimulation syndrome (OHSS), adult respiratory distress syndrome (ARDS), burns, hemodialysis patients undergoing long-term dialysis, for patients unable to tolerate significant volumes of saline solution, and as a priming solution for cardiopulmonary bypass surgery; CTLA-4 Mab, rDNA / Medarex (Yervoy; ipilimumab; MDX-010; cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody, recombinant), approved on 3 / 25 / 2011 to Bristol-Myers Squibb (BMS) for the treatment of late-stage melanoma; Adenovirus Types 4 and 7 Vaccine, Live, Oral (consisting of Adenovirus Vaccine, Type 4 and Adenovirus Vaccine, Type 7), approved on March 16, 2011 to Teva Pharmaceuticals for the immunization of U.S. military personnel only; B-cell activator Mab, rDNA, approved on 3 / 9 / 2011 to Human Genome Sciences, Inc. (for distribution with GlaxoSmithKline / GSK) for the treatment of adults with active, autoantibody-positive systemic lupus erythematosus: (belimumab-Benlysta; LymphoStat-B); Factor XIII, human: (Cortifact), approved on 2 / 17 / 2011 to CSL Behring for the treatment of factor XIII deficiency; Approved on 9 / 14 / 2010 to Savient Pharmaceuticals for the treatment of chronic refractory gout, urate oxidase, rDNA, PEG-: (pegloticase-Krystexxa; Puricase; PEG-uricase; porcine-baboon urate oxidase, recombinant, PEGylated); Botulinum toxin A / Merz: (Xeomin; Clostridium botulinum toxin type A; NT 201), approved on 7 / 30 / 2010 to Merz Pharmaceuticals for the treatment of adults with spasmodic torticollis or blepharospasm; Antitrypsin, alpha-1 / Kamada, approved on 7 / 1 / 2010 to Kamada Ltd. for the treatment of alpha-1-antitrypsin deficiency: (alpha-1-proteinase inhibitor (human) - Glassia; Respira; alpha-1 antitrypsin; AAT; A1P1); RANKL Mab, rDNA, approved on 6 / 1 / 2010 to Amgen Inc. for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture: (Denosumab-Prolia; AMG 531; AMG 162. Receptor activator of nuclear factor-κB ligand (RANKL) monoclonal antibody, recombinant); Glucosidase, rDNA / Lumizyme: (Alglucosidase alfa-Lumizyme; α-glucosidase; glucosidase alpha; rhGAA)), approved on 05 / 25 / 2010 to Genzyme Corp. for the treatment of Pompe disease; Prostate cancer cell vaccine (rDNA), approved on 4 / 29 / 2010 to Dendreon Corp., for the treatment of asymptomatic or minimally symptomatic metastatic prostate cancer that is refractory to standard hormone therapy: (autologous antigen-presenting cells (APCs) primed with sipuleucel-T-Provenge-prostatic acid phosphatase (PAP)-granulocyte-macrophage colony-stimulating factor (GM-CSF) recombinant fusion protein (PAP-GM-CSF; PA2024); PA2024-loaded APCs; APC8015); Pancreatic Enzymes / J&J: (Pancreaze; pancreatic enzyme product), NDA approved on 4 / 12 / 2010 to Johnson & Johnson (J&J) for the treatment of pancreatic insufficiency; Fibrin sealant / TachoSil (absorbable fibrin sealant patch), approved on 4 / 2 / 2010 to Nycomed Austria GmbH for use as an adjunct to hemostasis in cardiovascular surgery when control of bleeding by standard surgical techniques such as suturing, ligation, or cauterization is ineffective or impractical; Immune Globulin (SCIG) (Subcutaneous Immunoglobulin (Human) - Hizentra; (Vivaglobin is an older, lower concentration product)), approved on 3 / 4 / 2010 to CSL Behring for the treatment of primary immunodeficiencies; Glucocerebrosidase, rDNA / Shire (velaglucerase alfa; ceramidase, glucosyl- (human HT-1080 cells); human glucosylceramidase (EC 3.2.1.45 or β-glucocerebrosidase), glycoform alpha; β-glucocerebrosidase), approved on 2 / 26 / 2010 to Shire Pharmaceuticals for the treatment of Gaucher disease; Pneumococcal vaccine (13) - CRM197 (Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein) - Prevnar 13; Prevenar 13; Pneumococcal capsular antigen - diphtheria CRM197 protein conjugate vaccine; PCV13), approved for Pfizer (developed by Wyeth) on 2 / 24 / 2010 for the prevention of pneumococcal-associated disease; Approved on 2 / 19 / 2010 for the prevention of invasive meningococcal disease by Novartis, meningococcal conjugate vaccine / Novartis (meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine - Menveo; MenACWY-CRM); Collagenase (Clostridial Collagenase for Injection-Xiaflex), approved on February 3, 2010, to Auxilium Pharmaceuticals Inc. for the treatment of Dupuytren's disease; Glucagon-like peptide-1, rDNA (liraglutide-Victoza; Arg34-GLP-1(7-37); GLP-1 (recombinant); NN-2211), approved on 1 / 25 / 2010 to Novo Nordisk for the treatment of type 2 diabetes; Interleukin-6 receptor Mab, rDNA (tocilizumab; Actemra; RoActemra; interleukin-6 receptor monoclonal antibody, recombinant; IL-6r Mab), approved for Amgen on 1 / 8 / 2010 for the treatment of rheumatoid arthritis (RA); Influenza Vaccine, High Dose (Fluzone High Dose), approved for Sanofi Pasteur on 12 / 23 / 2009 for the prevention of influenza in persons 65 years of age and older; the complete BLA was approved; this is a higher dose (60 μg of each influenza strain HA antigen vs. 15 μg) formulation of Fluzone, the most used influenza vaccine in the United States (U.S.); VWF / Factor VIII complex (Wilate), approved on 12 / 4 / 2009 to Octapharma USA, Inc. for the treatment of von Willebrand disease (VWD); Kallikrein inhibitor, rDNA (ecallantide-Kalbitor; DX-88; kallikrein inhibitor protein, recombinant), approved on 12 / 1 / 2009 to Dyax Corp. for the treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age and older; Influenza vaccine / Novartis Italy (Agriflu), approved on 27 / 11 / 2009 for Novartis for the prevention of H1N1 (swine flu) influenza; this (or a similar) conventional inactivated egg-cultured vaccine has long been produced in Siena (Italy), mainly for the European market; Influenza Vaccine, H1N1 / GSK Canada, approved on 11 / 10 / 2009 to ID Biomedical, a subsidiary of GlaxoSmithKline (GSK), for the prevention of H1N1 (swine flu) influenza; another new product, approved as a supplemental Biologics License Application (BLA), is Influenza Vaccine / GSK Canada (FluLaval), an H1N1 analog or biosimilar / biogeneric monovalent version; CD20 Mab, human, rDNA (ofatumumab-Arzerra; HuMax-CD20; CD20 monoclonal antibody, human, recombinant), approved for GlaxoSmithKline (and Genmab) on 10 / 26 / 2009 for the treatment of chronic lymphocytic leukemia in patients who have not responded to Campath (alemtuzumab) or fludarabine; Antitrypsin, alpha-1 / Talecris (alpha-1-proteinase inhibitor (human)-Prolastin-C; alpha-1-antitrypsin), approved on 10 / 19 / 2009 to Talecris Biotherapeutics for the treatment of alpha-1-antitrypsin (AAT) deficiency; HPV vaccine, rDNA / GSK (Cervarix MEDI 501; Human Papillomavirus (HPV) Vaccine Types 16 and 18 L1 Virus-Like Particle, Recombinant), approved on 10 / 16 / 2009 to GlaxoSmithKline, Inc. for the prevention of cervical cancer in women; C1-esterase inhibitor / CSL (Berinert P; C1INH; C1-INH; complement C1 esterase inhibitor, plasma-derived), approved on 10 / 09 / 2009 to CSL Behring LLC for the acute treatment of hereditary angioedema (HAE); IL-12 / 23 p40 Mab, rDNA (ustekinumab-STELARA; CNTO 1275; interleukin-12 (IL-12) and interleukin-23 (IL-23) p40 subunit monoclonal antibody, human, recombinant), approved on 9 / 25 / 2009 to Centocor Ortho Biotech Inc. (Johnson & Johnson) for the treatment of moderate to severe plaque psoriasis; Immunoglobulin (IGIV) / Bio Products (Immunoglobulin Intravenous (Human) - Gammaplex), approved on 9 / 17 / 2009 to Bio Products Lab., for the treatment of primary humoral immune deficiency; An influenza vaccine, H1N1 / Novartis, approved on September 15, 2009, to Novartis AG for the prevention of H1N1 (swine flu) influenza; a new and separate product, approved as a supplemental Biologics License Application (BLA); The influenza vaccine, H1N1 / Sanofi, approved for Sanofi-Pasteur on September 15, 2009, for the prevention of H1N1 (swine flu) influenza; a new and separate product, approved as a supplemental Biologics License Application (BLA); An influenza vaccine, H1N1 / CSL, approved on September 15, 2009 to CSL Ltd. for the prevention of H1N1 (swine flu) influenza; a new and separate product, approved as a supplemental Biologics License Application (BLA); Influenza vaccine, live rDNA, H1N1, approved on 9 / 15 / 2009 for MedImmune (AstraZeneca) for the prevention of H1N1 (swine flu) influenza; a new and separate product, approved as a supplemental Biologics License Application (BLA); Haemophilus b vaccine / GSK (Hiberix; Haemophilus influenzae type b vaccine; Hib vaccine), approved for GlaxoSmithKline (GSK) on 8 / 19 / 2009 as a Hib vaccine booster dose for children 15 months to 4 years of age; Approved on 8 / 15 / 2009 to Novartis Pharmaceuticals for the indication of multiple sclerosis, interferon betaser, rDNA / Novartis (interferon beta-1b-Extavia; 2-166-interferon beta1 (human fibroblast-derived (reduced)), 17-L-serine-; interferon betaser, recombinant; NVF233); Interleukin-1 Mab, rDNA (canakinumab-Ilaris; interleukin-1β monoclonal antibody; ACZ885), approved on 6 / 17 / 2009 to Novartis Pharmaceuticals for the treatment of Cryopyrin Associated Periodic Syndrome (CAPS); Pancreatic enzymes / Solvay (pancrelipase-Creon; pancreatic enzyme, porcine origin), approved for Solvay on 5 / 1 / 2009 for the treatment of exocrine pancreatic enzyme insufficiency; Botulinum toxin A / Ipsen (abobotulinumtoxin A - Dysport; Relaxin; Clostridium botulinum toxin type A), which had a BLA approved for Ipsen on 4 / 29 / 2009 for the treatment of spasmodic torticollis, and simultaneously had an sBLA approved for Medicis for Reloxin (a renamed Dysport) for the treatment of glabellar (frown) wrinkles; TNF Mab, rDNA, human / J&J (Simponi; golimumab; CNTO 148; tumor necrosis factor-α human monoclonal antibody, recombinant), approved on April 24, 2009, to Centocor Ortho Biotech Inc. / Johnson & Johnson for the treatment of three types of immune dysfunction-associated arthritis; Japanese encephalitis vaccine / Intercell-(Ixiaro; Japanese encephalitis SA14-4-2 virus vaccine; IC51), approved on 3 / 30 / 2009 for Intercell Biomedical (marketed by Novartis) for the prevention of Japanese encephalitis; Antithrombin III, rDNA (antithrombin III (human)-ATryn; rhATIII; AT-III, recombinant transgenic goat), approved on 2 / 6 / 2009 to GTC Biotherapeutics, Inc. (Genzyme) for the prevention of blood clots in patients with antithrombin deficiency; Fibrinogen / CSL (Fibrinogen Concentrate (Human) - RiaSTAT; Haemocomplete P; Factor I), approved on 1 / 16 / 2009 to CSL Behring for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia); C1-esterase inhibitor / Sanquin (Cinryze; CetorA; C1INH; C1-INH; complement C1 esterase inhibitor, plasma-derived), approved on 10 / 10 / 2008 to Lev Pharmaceuticals for the routine prevention of angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE; C1 inhibitor deficiency); Insulin aspart, rDNA, 50 / 50 mixture (Novolog mixture 50 / 50; biphasic insulin aspart 50 / 50), approved on 8 / 26 / 2008 to Novo Nordisk for the treatment of diabetes; Thrombopoietin peptibody, rDNA (romiplostim-NPLATE; AMG-531; Amgen megakaryocytopoietic protein 531; thrombopoietin mimetic peptibody, recombinant), approved for Amgen on 8 / 22 / 2008 for the treatment of adults with chronic thrombocytopenic purpura (ITP); DTaP-Hib-Polio Vaccine / Sanofi (Pentacel; ActHIB reconstituted with diphtheria-tetanus toxoid and sterile pertussis adsorbent combined with inactivated poliovirus vaccine; ActHIB + Quadracel; diphtheria & tetanus toxoid & sterile pertussis vaccine adsorbent + Haemophilus influenzae type b (Hib) vaccine + poliovirus vaccine (inactivated) (human diploid cells)) approved for Sanofi Pasteur on 6 / 20 / 2008 (as a combination of two previously approved combination vaccines, the two are mixed before administration and BIOPHARMA does not consider this to be a new, separate / exclusive product); Interferon α-2b, rDNA, PEG- + ribavirin (PEGPAK; combined packaging of PEG-intron and ribavirin), approved for Schering-Plough on 6 / 13 / 2008, for the treatment of chronic hepatitis C; Approved on 4 / 23 / 2008 to UCB (marketed in the US by Bayer Schering), TNF Mab Fab', rDNA, PEG-(certolizumab pegol-Cimzia; CDP 870; tumor necrosis factor monoclonal antibody Fab fragment, recombinant--polyethylene glycol (PEG) polymer conjugate) for the treatment of resistant Crohn's disease in adults; Rotavirus vaccine, live / GSK (Rotavirus vaccine, live, oral, monovalent—Rotarix; RIX-4414), approved for GlaxoSmithKline (GSK) on 4 / 4 / 2008 for the prevention of rotavirus gastroenteritis in infants; DTaP-IPV / GSK (Diphtheria & Tetanus Toxoid & Sterile Pertussis Vaccine Adsorbed + Poliovirus Vaccine (Inactivated) (Human Diploid Cells) - Kinrix), approved for GlaxoSmithKline on 24 / 3 / 2008 for pediatric vaccination; Fibrin Sealant / Baxter (Fibrin Sealant, VH S / D 4-Artiss; Fibrin Sealant, Steam-Heated Solvent / Surfactant Treated), approved on 3 / 19 / 2008 to Baxter Healthcare for use in attaching skin grafts to burn patients (this appears to be the next generation and replacement for Tisseel Kit VH); Interleukin-1 trap, rDNA (Arcalyst; Rilonacept; IL-1 Trap, recombinant), approved on 2 / 27 / 2008 to Regeneron Pharmaceuticals Inc. for the long-term treatment of two Cryopyrin-Associated Periodic Syndrome (CAPS) disorders: Familial Cold Auto-Inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS); Antihemophilic Factor (Recombinant), Plasma / Albumin Free (Xyntha; Recombinant Coagulation Factor VIII; Updated version of ReFacto, now with non-human or animal products used in its manufacture or formulation) for the treatment of hemophilia A; Full BLA approved for Wyeth on 2 / 21 / 2008; NDA approved on 1 / 24 / 2008 to Cangene Corp. (marketed by Apotex), somatropin, rDNA / Cangene (Somatropin (rDNA origin) Injectable - Accretropin) - 505(b)(2) successor protein, for the treatment of growth failure or short stature in children; Thrombin, rDNA (Recothrom; thrombin, recombinant; rhThrombin), approved on 08 / 1 / 17 to ZymoGenetics, Inc., to help stop bleeding from small blood vessels after surgery; EPO, rDNA, PEG-(long-acting erythropoietin receptor activator; Mircera; CERA; epoetin alfa (recombinant), pegylated; methoxypolyethylene glycol-epoetin beta)), approved on 07 / 11 / 14 to Hoffmann-La Roche Inc., for the treatment of anemia associated with chronic renal failure in adults; Skin, Cultured / Epicel (Cultured Epidermal Autograft - Epicel; Cultured Autologous Keratinocytes Service; CEA), HDE approved to Genzyme Corp. on 10 / 29 / 07 for the treatment of life-threatening wounds resulting from severe burns; Influenza Vaccine / CSL (Influenza Virus Vaccine, Trivalent, Types A and B - AFLURIA; Fluvax; Enzira), approved on 07 / 09 / 28 to CSL Ltd., for the prevention of influenza; Smallpox Vaccine / Vero, approved on 8 / 31 / 07 to Acambis plc for the prevention of smallpox (in the biodefense stockpile); Thrombin / Omrix (Evithrom), approved on 8 / 27 / 2007 to Omrix Biopharmaceuticals for the control of bleeding (inaccessible / otherwise untreatable blood oozing and minor bleeding from capillaries and venules); Fibrin sealant / Thermogenesis (CryoSeal Fibrin Sealant System; CryoSeal FS System; cryoprecipitate + thrombin, autologous), approved on 7 / 26 / 2007 to Thermogenesis Corp., for control of bleeding during liver surgery; Immune Globulin (IGIV), liquid / CSL (Immune Globulin Intravenous (Human), 10% liquid - Privigen), approved on 7 / 26 / 2007 to CSL BioPlasma Inc., for the treatment of primary immunodeficiencies; Influenza Vaccine, H5N1 / Sanofi (Influenza Virus Vaccine, H5N1; Pandemic Influenza Vaccine; Avian Influenza Vaccine), approved on April 17, 2007 to Sanofi Pasteur Inc. for the active immunization of adults at high risk of exposure to H5N1 influenza virus (for use in the event of an avian influenza-related influenza epidemic / pandemic); Parexel, approved on 4 / 19 / 2008 to CRO on behalf of LG Life Sciences, somatropin, rDNA / BioPartners (Somatropin (rDNA origin for injection) - Valtropin; human growth hormone, recombinant), for the treatment of growth failure; Protein C, plasma-derived (Seprotin), approved on 3 / 27 / 2007 to Baxter Healthcare for the treatment of severe congenital protein C deficiency; Complement C5 Mab, rDNA (eculizumab-Soliris; complement C5 monoclonal antibody, recombinant), approved on 3 / 16 / 2007 to Alexion Pharmaceuticals, Inc., for the treatment of paroxysmal nocturnal hemoglobinuria (PNH); Poly-4-hydroxybutyrate, rDNA (TephaFLEX absorbable suture; poly-4-hydroxybutyrate; P4HB; poly(4HB); PHA4400), approved on 2 / 12 / 2007 to Tepha, Inc., for use as a surgical suture; Albumin (human) (one of many albumin products), approved on 06 / 10 / 17 to Octapharma Pharmazeutika Produktionsgesm. b. H, for restoring and maintaining circulatory blood volume; Influenza Vaccine / ID Biomedical (Influenza Virus Vaccine, Trivalent - FluLaval; Fluviral), approved for GlaxoSmithKline (merged ID Biomedical) on 06 / 10 / 05 for active immunization against influenza in adults 18 years of age and older; EGF receptor Mab, human, rDNA (panitumumab-Vectibix; ABX-EGF; epidermal growth factor receptor monoclonal antibody, human, recombinant; E7.6.3; rHuMAb-EGFr; human EGF receptor Mab derived from transgenic XenoMouse), approved on 9 / 27 / 2006 to Amgen Inc. "for the treatment of patients with metastatic colorectal cancer expressing epidermal growth factor receptor (EGFr) after disease progression during or following a fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimen"; Iduronate-2-sulfatase, rDNA (Idursulfase; Elaprase; L-iduronate 2-sulfate sulfatase precursor; recombinant; I2S; chondroitin sulfatase), approved on 7 / 24 / 2006 to Shire Pharmaceuticals Group plc (through the acquisition of Transkaryotic Therapies, Inc.) for the treatment of Hunter syndrome (mucopolysaccharidosis II; MPS II); VEGF Mab Fab, rDNA (Lucentis; vascular endothelial growth factor monoclonal antibody fragment, recombinant), approved on 6 / 30 / 2006 to Genentech, Inc., for the treatment of age-related macular degeneration; HPV Vaccine, rDNA / Merck (tetravalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine; Gardasil; human papillomavirus (HPV) types 6, 11, 16, and 18 L1 virus-like protein (VLP), recombinant), approved on June 8, 2006 to Merck & Co., Inc. for vaccination in females 9 to 26 years of age for the prevention of disease caused by human papillomavirus (HPV) types 6, 11, 16, and 18; Somatropin, rDNA / Sandoz (Somatropin (rDNA origin) - Omnitrope; human growth hormone, recombinant), approved on May 30, 2006 to Sandoz, Inc., a subsidiary of Novartis AG, for the treatment of growth hormone deficiency; Varicella Virus Vaccine / Adult (Shivers Zoster Vaccine (Live) (Oka / Merck); Zostavax; Varicella Virus Vaccine for Adults), approved on May 25, 2006 to Merck & Co., Inc., for the prevention of herpes zoster (shingles) in persons 60 years of age and older; Glucosidase, rDNA (alglucosidase alpha-Myozyme; Pompase; alpha glucosidase; glucosidase alpha (rhGAA) (recombinant)), approved on 4 / 28 / 2006 to Genzyme Corp., for the treatment of Pompe disease; Rotavirus vaccine, rDNA / Merck (Rotavirus vaccine, pentavalent (Quintavalent)-RotaTeq; WC3 pentavalent vaccine), approved on February 3, 2006 to Merck & Co., Inc., for the prevention of rotavirus gastroenteritis in children; Hepatitis B immune globulin, i.m. / Cangene (hepatitis B immune globulin (human); HepaGam B), approved on 1 / 27 / 2006 to Cangene Corp. for post-exposure prophylaxis after acute exposure to hepatitis B virus; Insulin, rDNA, inhaled / Pfizer (Exubera insulin, recombinant powder for inhalation), approved on January 27, 2006 to Pfizer, Inc., for the treatment of adults with type 1 and type 2 diabetes; immunoglobulin (SCIG) (Vivaglobin), approved on 1 / 9 / 2006 to ZLB Behring for the treatment of primary immunodeficiencies; CTLA4-Ig, rDNA (Orencia; abatacept; cytotoxic T-lymphocyte-associated antigen 4--immunoglobulin G1 fragment fusion protein, recombinant; BMS-188667), approved on 12 / 26 / 2005 to Bristol-Myers Squibb Co. for the second-line treatment of rheumatoid arthritis in adult patients with moderate to severe disease; Insulin-like growth factor-1 / IGFBP-3, rDNA (Mecasermin rinfibate-IPLEX; SomatoKine; Insulin-like growth factor-I--insulin-like growth factor-binding-3 protein complex, recombinant; IGF-1 / IGFBP3 complex), approved on 12 / 12 / 2005 to Insmed Inc. for the treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) who have developed neutralizing antibodies to GH or who have a growth hormone (GH) gene deletion; Approval for hyaluronidase, rDNA (Hylenex; Enhanze SC; Cumulase; Chemophase; rHuPH20; PH-20 hyaluronidase, recombinant human), Hylex (formerly Enhanze SC), approved on 12 / 5 / 2005 to Halozyme Therapeutics Inc. for use as a "spreading agent" to enhance local anesthesia, contrast delivery, and for subcutaneous fluid replacement (subcutaneous infusion therapy), for sale by Baxter; Hyaluronidase, ovine / Primapharm (Hydase), approved on 10 / 25 / 2005 to PrimaPharm, Inc. for use as a "spreading agent" to enhance local anesthesia, contrast delivery, and for subcutaneous fluid replacement (subcutaneous infusion therapy); PDGF, rDNA / bone matrix (platelet-derived growth factor (PDGF)-BB, recombinant with inorganic bone matrix; rhPDGF-BB; GEM 21S), approved on 10 / 21 / 2005 to BioMimetic Therapeutics, Inc. for sale by Osteohealth Co. (Luitpold Pharmaceuticals, Inc., Sankyo Co., Ltd.) for the treatment of alveolar bone defects and associated gingival recession; Measles, Mumps, Rubella & Chickenpox Vaccine (Measles, Mumps, Rubella, and Chickenpox (Oka / Merck) Virus Vaccine Live-ProQuad; M-M-R II+Varivax Vaccine), approved on September 6, 2005 to Merck & Co., Inc., for vaccination against measles, mumps, rubella (German measles), and varicella (chickenpox) in children 12 months to 12 years of age; Influenza Vaccine / GSK Canada (Influenza Virus Vaccine, Trivalent, Types A and B - Fluarix), approved on 8 / 31 / 2005 to GlaxoSmithKline Biologicals for the prevention of influenza; Influenza vaccine / GSK Germany (influenza virus vaccine, trivalent - Fluarix; Influsplit SSW; Alpharix), approved on 8 / 31 / 2005 to Sachsische Serumwerke AG for distribution by GlaxoSmithKline for the prevention of influenza; Insulin-like growth factor-1, rDNA / Tercica (Insulin-like growth factor-1, recombinant - Increlex; IGF-1), approved on 8 / 31 / 2005 to Tercica, Inc. (in partnership with Genentech) for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone; Calcitonin, rDNA (Calcitonin (Salmon)-Fortical; Calcitonin, Recombinant), approved on 8 / 15 / 2005 to Unigene, Inc. (sold by Upsher-Smith Labs.) for the treatment of postmenopausal osteoporosis; Insulin detemir, rDNA - (Insulin detemir, recombinant - Levemir), approved on June 17, 2005 to Novo Nordisk Inc. for the treatment of diabetes mellitus (types 1 and 2); (long-acting recombinant insulin analog); dTpa Booster / Sanofi (tetanus toxoid, attenuated diphtheria toxoid, and sterile pertussis adsorbed - Adacel; dTpa; Tdap), approved on 6 / 10 / 2005 to Aventis Pasteur Ltd. for use as a tetanus, diphtheria, and pertussis (whooping cough) booster vaccine for persons 11 to 64 years of age; Arylsulfatase B, rDNA (N-acetylgalactosamine 4-sulfatase-Naglazyme; Aryplase; galsulfase; chondroitinase; rhASB (recombinant)), approved on 5 / 31 / 2005 to BioMarin Pharmaceutical Inc. for the treatment of mucopolysaccharidosis VI (MPS VI); dTpa Booster / GSK (tetanus toxoid, attenuated diphtheria toxoid, and sterile pertussis adsorbed-Boostrix; dTpa; Tdap), approved on 5 / 3 / 2005 to GlaxoSmithKline Biologicals S.A. for use as a tetanus, diphtheria, and pertussis (whooping cough) booster vaccine for persons 10-18 years of age; Tetanus Toxoid / Chiron (Tetanus Toxoid Concentrate (for further manufacturing uses) (see above)), approved on May 3, 2005 to Chiron Behring GmbH & Co. (Chiron Corp.; merged with Novartis AG) for use as a component of the Boostrix combination vaccine; Vaccinia immune globulin, i.v. / Cangene (VIG; VIVIG), approved on May 3, 2005 to Cangene Corp. for the treatment of rare complications of smallpox vaccination (severe systemic skin or other serious infections caused by the live vaccinia virus in the current smallpox vaccine); Hyaluronidase, rDNA (Cumulase; Enhanze SC; Chemophase; rHuPH20; PH-20 Hyaluronidase, Recombinant Human) approved to Halozyme Therapeutics, Inc. for use in in vitro fertilization (IVF) procedures (preparation of oocytes prior to in vitro fertilization) - Medical device approval for Cumulase on 4 / 19 / 2005; Vaccinia immune globulin, i.v. / DVC (VIG; VIGIV), approved on 2 / 18 / 2005 to DynPort Vaccine Co. LLC for the treatment of rare complications of smallpox vaccination (severe systemic skin or other serious infections caused by the live vaccinia virus in the current smallpox vaccine); Thrombin, Concentrate (Thrombin (Human) (For Further Manufacturing Use)), approved on 2 / 18 / 2005 to Baxter Healthcare Corp. for the further manufacture of FloSeal Matrix Hemostatic Sealant, used to control bleeding; A meningococcal conjugate vaccine (Menactra; meningococcal (Groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine; MCV-4), approved on January 14, 2005, to Sanofi Pasteur Inc. for the prevention of meningococcal disease in adolescents and adults aged 11 to 55 years; VEGF aptamer, PEG-(pegaptanib sodium-Macugen; vascular endothelial growth factor / vascular permeability factor (VEGF) aptamer, synthetic oligonucleotide, PEGylated), approved on 12 / 17 / 2004 to Eyetech Pharmaceuticals, Inc. for the treatment of neovascular (wet) age-related macular degeneration; Keratinocyte growth factor, rDNA* (Palifermin-Kepivance; des1-23 KGF; 24-163 fibroblast growth factor 7 (human)), approved on 12 / 15 / 2004 to Amgen Inc. for the treatment of severe oral mucositis (stomatitis) in patients with hematologic cancers receiving high-dose chemotherapy followed by bone marrow transplantation; An integrin Mab, rDNA (Tysabri - natalizumab; Antegren; integrin alpha(4) humanized monoclonal antibody) (formerly Antegren, now Tysabri; change at FDA request), approved on 11 / 24 / 2004 to Biogen Idec for the treatment of multiple sclerosis; Hyaluronidase, bovine / Amphaster-(Hyaluronidase, bovine-Amphadase), approved on 10 / 24 / 2004 to Amphastar Pharmaceuticals, Inc., for use as a "diffusion agent," e.g., as an adjuvant to improve absorption and dispersion of other injected drugs; for subcutaneous infusion therapy; and as an adjuvant in subcutaneous urography to improve absorption of radiopaque agents; Enfuvirtide, synthetic (T-20; Fuzeon; pentafuside; DP-178), full approval (upgraded from accelerated approval granted in March 2003), approved on 10 / 15 / 2004 to Hoffmann-La Roche Inc., for the treatment of HIV-1 infection in combination with other antiretrovirals in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy (synthetic peptide, not a biologic); CD15 Mab-Tc 99m radioconjugate (Technetium (99mTc) fanolesomab; Neutrospec; Leutech; TC99M-labeled CD15 monoclonal antibody), approved on 7 / 2 / 2004 to Palatin Technologies, Inc., for diagnostic imaging of appendicitis in patients 5 years of age and older with equivocal signs of appendicitis; Luteinizing hormone, rDNA (Lutropin alfa-Luveris; human luteinizing hormone, recombinant), approved on 5 / 24 / 2004 to Serono, Inc. for the treatment of infertility (stimulation of follicular development in infertile hypogonadotropic hypogonadal women with severe LH deficiency in combination with FSH (Gonal-f)); Immune Globulin (IGIV) / Octapharma (Octagam; Immune Globulin Intravenous (Human)), approved on 21 / 05 / 2004 to Octapharma AG, for the treatment of primary immunodeficiencies; Hyaluronidase, ovine (Vitrase; hyaluronate 4-glycanohydrolase), approved on 5 / 4 / 2004 to ISTA Pharmaceuticals Inc. for use as a diffusing agent to promote drug dispersion and absorption, particularly as a local anesthetic during ophthalmic surgery; for subcutaneous infusion therapy; and as an adjunct in subcutaneous urography to improve absorption of radiopaque agents; Insulin glulisine, rDNA (Apidra; (LysB3, GluB29) insulin; insulin (human), 3B-l-lysine, 29B-l-glutamic acid-, recombinant), approved on 4 / 16 / 2004 to Aventis Pharma for use as a rapid-acting insulin for the treatment of diabetes; VEGF Mab, rDNA (Avastin; bevacizumab; vascular endothelial growth factor monoclonal antibody, recombinant), approved on 2 / 26 / 2004 to Genentech, Inc. for use in combination with 5-fluorouracil for the treatment of metastatic cancer of the colon or rectum; Approved on 2 / 12 / 2004 to ImClone Systems Inc. (EGF receptor Mab, rDNA (cetuximab-Erbitux; IMC-C225; epidermal growth factor receptor monoclonal antibody, recombinant), for sale by Bristol-Myers Squibb Co., for use in combination with irinotecan in the treatment of patients with EGFR-expressing metastatic colorectal cancer that is resistant to irinotecan-based chemotherapy, and for the monotherapy treatment of patients with EGFR-expressing metastatic colorectal cancer that is intolerant to irinotecan-based chemotherapy; Rho(D) immunoglobulin / ZLB (Rho(D) immunoglobulin intravenous (human)-Rhophylac), approved on 2 / 12 / 2004 for ZLB Bioplasma AG, for pre- and post-partum prophylaxis of Rho(D) immunization in Rho(D)-negative women; hyaluronic acid / Anika (ORTHOVISC high molecular weight hyaluronan), approved on 2 / 5 / 2004 to Anika Therapeutics, Inc. for distribution in the U.S. by Ortho Biotech Products, L.P. (Johnson & Johnson) for the treatment of pain associated with osteoarthritis of the knee; Immune Globulin Intravenous (Human) (Flebogamma), approved on 12 / 18 / 2003 to Instituto Grifols (Probitas Pharma) for the treatment of primary immunodeficiencies; hyaluronic acid / Medicis (Restylane), approved on 12 / 12 / 2003 to Medicis Pharmaceutical Corp. for the correction of moderate to severe facial wrinkles and grooves, e.g., nasolabial folds (lines / grooves near the nose and mouth); CD11a Mab, rDNA (efalizumab-Raptiva; CD11a monoclonal antibody, recombinant), approved on 10 / 27 / 2003 to Genentech, Inc. and Xoma Ltd. for the treatment of moderate to severe psoriasis in adults who are candidates for systemic therapy or phototherapy; Botulism Immune Globulin Intravenous (Human) (BabyBIG), approved on 10 / 23 / 2003 to the California Department of Health Services for the treatment of infant botulism caused by Clostridium botulinum types A or B; Somatropin, rDNA / Serono (Somatropin (rDNA origin) - Serostim; Human Growth Hormone, Recombinant), full approval was granted to Serono Inc. on 8 / 29 / 2003 for the treatment of HIV patients with wasting or cachexia; Factor VIII, rDNA, PFM (Antihemophilic Factor (Recombinant), Plasma / Albumin-Free Method - Advate; Factor VIII, Recombinant; rAHF-PFM), approved on 7 / 25 / 2003 to Baxter Hyland Immuno for the treatment of hemophilia A; TNF receptor-IgG Fc, rDNA (etanercept-Enbrel; tumor necrosis factor receptor 2-immunoglobulin G1 Fc fusion protein, recombinant), for which a supplemental Biologics License Application (BLA) was approved on 7 / 24 / 2003 to Amgen Inc., for the treatment of active ankylosing spondylitis; Antitrypsin, alpha-1 / Aventis (alpha-1-proteinase inhibitor (human) - Zemaira), approved on 7 / 8 / 2003 to Aventis Behring LLC for long-term breast augmentation and maintenance therapy in individuals with evidence of alpha-1-proteinase inhibitor deficiency and emphysema; Approved on 6 / 27 / 2003 to Corixa Corp. (formerly Coulter Pharmaceuticals) for the treatment of patients with CD20-positive follicular non-Hodgkin's lymphoma (NHL) (with or without transformation) whose disease is resistant to rituximab and has relapsed after chemotherapy (marketed by GlaxoSmithKline (GSK)), CD20 Mab, rDNA--I 131 radioconjugate (iodine I 131 tositumomab-Bexxar; CD20 monoclonal antibody--iodine I 131 radioimmunoconjugate); Approved on 6 / 20 / 2003 to Genentech, Inc. (manufactured by Tanox, Inc. and parallel marketed by Novartis Pharmaceutical Corp.), immunoglobulin E Mab, rDNA (omalizumab-Xolair; rhuMab-E25; immunoglobulin E25 monoclonal antibody, recombinant; IgE Mab, rDNA) for the treatment of moderate to severe allergic asthma; Hirudin, desulfato-rDNA / Aventis (Iprivask; Desirudin; Revasc; desulfatohirudin; hirudin, desulfato-recombinant), approved on 4 / 3 / 2003 to Aventis Pharma for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing elective total hip replacement surgery; Influenza Vaccine, Live rDNA, Frozen (FluMist), approved on 6 / 17 / 2003 to MedImmune Vaccines, Inc. (a subsidiary of MedImmune, Inc.) for the prevention of influenza in healthy persons 5 to 50 years of age; Iduronidase, rDNA (Laronidase; Aldurazyme; α-L-iduronidase), approved on 4 / 30 / 2003 to Biomarin Pharmaceutical Inc. (and Genyzme Corp.) for the treatment of Mucopolysaccharidosis I (MPS I); Galactosidase beta, rDNA (agalsidase beta-Fabrazyme; α-galactosidase A), approved on 4 / 24 / 2003 to Genzyme Corp. for the treatment of Fabry disease; Somatropin antagonist, PEG-, rDNA (Pegvisomant-Somavert; somatropin antagonist, PEGylated, recombinant), approved on 3 / 25 / 2003 to Pharmacia Corp. for the treatment of acromegaly; Enfuvirtide, synthetic (T-20; Fuzeon; pentafuside; DP-178), approved on March 15, 2003, to Hoffmann-La Roche Inc. for the treatment of HIV infection; LFA-3 / IgG1, rDNA (Alefacept; Amevive; leukocyte function-associated antigen-3 / immunoglobulin G (IgG) fusion protein, recombinant), approved on January 30, 2003, to Biogen Corp. for the treatment of moderate to severe chronic plaque psoriasis; Antitrypsin, alpha-1 / Baxter (alpha-1 proteinase inhibitor (human); Aralast; alpha-1 antitrypsin; AAT; A1P1), approved on January 9, 2003 to Alpha Therapeutic Corp. (marketed by Baxter) for enzyme replacement therapy in patients with hereditary emphysema (AAT deficiency); TNF Mab, rDNA, human (adalimumab; Humira; D2E7; tumor necrosis factor-α human monoclonal antibody), approved on 12 / 30 / 2002 to Abbott Laboratories for the treatment of rheumatoid arthritis; DTaP & Hepatitis B & Polio Vaccine (Diphtheria-Tetanus Toxoid and Sterile Pertussis (Precipitated Purified), Hepatitis B (Recombinant), and Inactivated Poliovirus Vaccine (Combined); Pediarix; Infanrix + Engerix-B + IPOL) approved on 12 / 13 / 2002 to GlaxoSmithKline Inc. for the prevention of diphtheria, tetanus, pertussis (whooping cough), hepatitis B, and polio - a combined vaccine; poliovirus vaccine (combined mixture of three inactivated strains) is the only component not previously approved; Parathyroid hormone (1-34), rDNA (teriparatide (rDNA origin); Forteo; LY333334; parathyroid hormone (1-34), recombinant), approved on 11 / 26 / 2002 to Eli Lilly & Co., for the treatment of osteoporosis; Interferon alfa-2a, rDNA, PEG- (peginterferon alfa-2a; Pegasys; interferon alfa-2a, recombinant, pegylated), approved on 10 / 16 / 2002 to Hoffmann-La Roche Inc., for the first-line treatment of chronic hepatitis C; Urate oxidase, rDNA (urate oxidase, recombinant; rasburicase; re-Uox; Elitek; Fasturtec), approved on 7 / 16 / 2002 for Sanofi-Synthelabo for the control of plasma uric acid levels (hyperuricemia) in pediatric patients receiving tumor lysis and cancer chemotherapy that results in elevated uric acid; Bone morphogenetic protein-2, rDNA (bone morphogenetic protein-2, recombinant; BMP-2; INFUSE Bone Graft)-PMA, approved on 7 / 2 / 2002 to Medtronic Sofamor Danek, using recombinant bmp-2 (from Genetics Institute / Wyeth) as part of the INFUSE Bone Graft / LT-CAGE Lumbar Tapered Fusion Device for the treatment of certain forms of spinal degenerative disc disease (lumbar spinal fusion); DTaP Vaccine / Aventis Canada Diphtheria-Tetanus Toxoid and Sterile Pertussis Adsorbed (DTaP) (DAPTACEL)-BLA, approved on 5 / 14 / 2002 to Aventis Pasteur, Ltd., for the first four doses of a diphtheria-tetanus toxoid and pertussis vaccination series administered to infants and children 6 weeks to 7 years of age; Botulinum toxin type A purified neurotoxin complex (BOTOX COSMETIC), approved as a supplemental Biologics License Application (BLA) to Allergan, Inc. on 4 / 12 / 2002 for the temporary improvement of the appearance of moderate to severe glabellar wrinkles ("frown lines") associated with corrugator supercilii and / or procerus muscle activity in adult patients <65 years of age; Secretin, synthetic (SecreFlo; porcine secretin), approved on 4 / 5 / 2002 to Repligen Corp. for the diagnosis of gastrinomas (tumors that secrete gastrin) and pancreatic disorders; Interferon beta-1a, rDNA / Serono (Rebif), approved on March 7, 2002 to Serono, Inc., for the treatment of relapsing forms of multiple sclerosis; A CD20 Mab / Y-90 radioconjugate (ibritumomab tiuxetan; Zevalin; CD20 monoclonal antibody-chelating group conjugate) approved on 2 / 29 / 2002 to IDEC Pharmaceuticals Corp. for the treatment of B-cell non-Hodgkin's lymphoma; the regimen for the treatment of said B-cell non-Hodgkin's lymphoma includes rituximab, indium-111 ibritumomab tiuxetan, and yttrium-90 ibritumomab tiuxetan; G-CSF, rDNA, PEG-(pegfilgrastim; Neulasta; pegylated granulocyte colony-stimulating factor), approved on 1 / 31 / 2002 to Amgen, Inc., for the treatment of febrile neutropenia in patients receiving chemotherapy for nonmyeloid malignancies.

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