Injectables 2 Past Paper PDF

PR5217: Injectables 2 Associate Professor Matthias G. Wacker, PhD Department of Pharmacy | Faculty of Science [email protected] © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Righ...

PR5217: Injectables 2 Associate Professor Matthias G. Wacker, PhD Department of Pharmacy | Faculty of Science [email protected] © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Learning outcomes To learn about formulation aspects relevant to biologics and biosimilars To understand the biopharmaceutics and production of long- acting injectables. © Copyright National University of Singapore. All Rights Reserved.  Written Questions in PR5217 © Copyright National University of Singapore. All Rights Reserved.  Aseptic Production © Copyright National University of Singapore. All Rights Reserved.  Aseptic Production A clean environment with different cleanroom grades, depending on the risk associated with operations. Typically, process steps that involve working with an open product for parenteral administration require cleanroom grade A standard. Sterile materials are being used. Operators are not allowed to contaminate the product. Stringent cleaning and disinfection protocols are being conducted. © Copyright National University of Singapore. All Rights Reserved.  Aseptic Filtration Terminal sterilization is the safest method, but aseptic filtration (often referred to as “sterile filtration”) is also applicable to: Thermolabile liquids Conditions according to Ph. Eur. To remove pyrogens 0.22 µm pore size © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Aseptic Manufacture © Copyright National University of Singapore. All Rights Reserved.  Cleanroom Sinovac © Copyright National University of Singapore. All Rights Reserved. Source: https://www.youtube.com/watch?v=cZRMTF3yQeA  Biologics © Copyright National University of Singapore. All Rights Reserved.  Biologics and Biosimilars Biologics are at least partially manufactured by living organisms. Their synthesis does not follow conventional chemical processes and their composition is usually more complex. Biosimilars are biologics that show very similar clinical performance as compared to a an already approved reference product. © Copyright National University of Singapore. All Rights Reserved.  Formulation Science Biosimilars Biosimilars should use the same dosage form and the excipients are widely identical. Small differences in certain excipients (e.g., human serum albumin) may not preclude a finding of biosimilarity if data and information provided show that the proposed product is highly similar to the reference product. © Copyright National University of Singapore. All Rights Reserved.  Injection Sites Injection sites for subcutnaoeus tissue can be arm, abdomen, or thigh. Injection site differences matter more for large molecules. © Copyright National University of Singapore. All Rights Reserved. Source: Zuo et al. 2021, J Control Rel (https://doi.org/10.1016/j.jconrel.2021.06.038) © Copyright National University of Singapore. All Rights Reserved. Source: Li et al. 2021, J Pharm Sci (https://doi.org/10.1016/j.xphs.2021.10.031) © Copyright National University of Singapore. All Rights Reserved.  Protein Formulation Biologics commonly require formulations improving their chemical stability (shelf life). Common stabilizers are surfactants and buffers that keep the pH at a constant level and lower interactions in highly concentrated protein solutions (IgG antibodies ~2-150 mg/mL). Lyophilization requires specific ingredients such as lyoprotectants and cryoprotectants. © Copyright National University of Singapore. All Rights Reserved.  Case studies: Antibodies © Copyright National University of Singapore. All Rights Reserved.  Pharmaceutical Development Route of administration Physical form Functional requirements Oral Sterility Solid Topical Viscosity Semisolid Parenteral Particle size Rectal Liquid Release behavior Inhalation Gas Stability Ophthalmic © Copyright National University of Singapore. All Rights Reserved. 18  Erbitux® Erbitux (Cetuximab) is an antibody indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. © Copyright National University of Singapore. All Rights Reserved.  Regulatory Requirements European Pharmacopeia Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation […]. Containers for parenteral preparations […] are sufficiently transparent to permit the visual inspection […]. Injections are sterile solutions, emulsions or suspensions. They are prepared by dissolving, emulsifying or suspending the active substance(s) […] in water for injections […]. © Copyright National University of Singapore. All Rights Reserved. 20  Excipients Erbitux® Formulation type: Solution for injection Inactive ingredients: Glycine Polysorbate 80 Sodium chloride Citric acid monohydrate Sodium hydroxide Water for injections © Copyright National University of Singapore. All Rights Reserved.  Antibody solutions are typically highly concentrated Excipients in parenterals. Antibody Sodium chloride and aminoacids are typically used. Solutions Buffers adjust the pH and differ between lyophilized and non-lyophilized products. Viscosity reduction Buffers Tonicity © Copyright National University of Singapore. All Rights Reserved. Source: Strickley and Lambert 2011, J Pharm Sci (https://doi.org/10.1016/j.xphs.2021.03.017)  Excipients Erbitux® Adsorption to various materials reduces due to the presence of polysorbate. Steric stabilization decreases the occurrence of larger agglomerates in antibody solutions. © Copyright National University of Singapore. All Rights Reserved. Source: Mahler et al. 2010, J Pharm Sci (https://www.doi.org/10.1002/jps.22045); Kiese et al. 2008, J Pharm Sci (https://doi.org/10.1002/jps.21328)  Excipients Erbitux® Glycin weakly interacts with proteins, leading to a certain steric stabilization. Competition for water between the unfolding protein and glycine increases stability. All amino acids have a certain buffer capacity. © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved. Source: Li et al. 2021, J Pharm Sci (https://doi.org/10.1016/j.xphs.2021.10.031)  Injection Site Absorption of larger molecules (antibodies) depends on injection site. Bioavailibility differences Abdomen 64% Arm 75% Thigh 71% Muscle 81% IV 100% © Copyright National University of Singapore. All Rights Reserved. Source: Li et al. 2014, Clin. Pharmacol. Drug. Dev. (https://doi.org/10.1002/cpdd.60)  Case study: Long-acting injectable © Copyright National University of Singapore. All Rights Reserved.  Pharmaceutical Development Route of administration Physical form Functional requirements Oral Sterility Solid Topical Viscosity Semisolid Parenteral Particle size Rectal Liquid Release behavior Inhalation Gas Stability Ophthalmic © Copyright National University of Singapore. All Rights Reserved. 28  European Pharmacopeia Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation […]. Containers for parenteral preparations […] are sufficiently transparent to permit the visual inspection […]. Injections are sterile solutions, emulsions or suspensions. They are prepared by dissolving, emulsifying or suspending the active substance(s) […] in Water for injections […]. © Copyright National University of Singapore. All Rights Reserved. 29  Medroxyprogesterone acetate Medroxyprogesterone acetate (MPA) is a drug substance used as birth control. Molecular weight 386.52 g/mol Peroral bioavailability 99% © Copyright National University of Singapore. All Rights Reserved.  Dosage Form MPA has an aqueous solubility of approx. 1.54 ± 0.60 μg/mL and is formulated at 160 mg/mL. Micronized suspension for subcutaneous injection into abdomen or thigh (no clear instruction). © Copyright National University of Singapore. All Rights Reserved. Source: Gao et al. 2020, Int. J. Pharm. (https://dx.doi.org/10.2165/00044011-199714010-00005)  Biopharmaceutics Low blood levels of MPA are required for the pharmacological effect. Intramuscular administration guarantees a long duration of action after a single injection. © Copyright National University of Singapore. All Rights Reserved. Source: Gao et al. 2020, Int. J. Pharm. (https://dx.doi.org/10.2165/00044011-199714010-00005)  Selected Target Requirements Safety Sterile Non-pyrogenic preparations Efficacy Stable with controlled particle size Optimized dissolution rate for long-term absorption Syringable © Copyright National University of Singapore. All Rights Reserved. 33  Injection Site Small molecules are typically less affected by differences in the injection site. Long-acting injectables are more susceptible as they have a longer absorption process. © Copyright National University of Singapore. All Rights Reserved. Source: Gao et al. 2020, Int. J. Pharm. (https://dx.doi.org/10.2165/00044011-199714010-00005)  Depo-SubQ Provera® Formulation type: Suspension for injection Inactive ingredients: Medroxyprogesterone acetate Methylparaben Propylparaben Sodium Chloride Polyethylene Glycol Polysorbate 80 Monobasic Sodium Phosphate © Copyright National University of Singapore. All Rights Reserved. 35  Process Technologies © Copyright National University of Singapore. All Rights Reserved. 36  Formulation Technologies Sterilization Technologies (Injectables 1 lecture) Hot Melt Extrusion (Injectables 1 lecture) Homogenization Technologies Lyophilization (Lyophilization lecture) © Copyright National University of Singapore. All Rights Reserved. 37  High Pressure Homogenization High pressure homogenization uses high shear forces to mill particles down to the lower micrometer scale. Milling process occurs in a closed batch production process that makes it easy to keep the product sterile. Stability of the product can be a critical issue (e.g., hardly suitable for proteins). © Copyright National University of Singapore. All Rights Reserved. 38  High pressure homogenization © Copyright National University of Singapore. All Rights Reserved. Source: https://www.youtube.com/watch?v=E-C7DXzAKZM  Wet Bead Milling Wet bead milling produces particles by grinding and shearing the product. Friction is achieved by using the milling medium composed of ultra-crosslinked milling beads. © Copyright National University of Singapore. All Rights Reserved. 40  Wet bead milling © Copyright National University of Singapore. All Rights Reserved. Source: https://www.youtube.com/watch?v=jxmujqREj50  Summary Type of injection is often selected based on the desired pharmacokinetics. Parenterals come with specific requirements with regards to chemical, physical and microbiological contamination. Protein formulations are challenging because of the stability issues arising from the structure. Long-acting injectables are developed when there is medical need; the release behavior plays an important role. © Copyright National University of Singapore. All Rights Reserved. 42  Questions in PR5217 Answers provided twice a week © Copyright National University of Singapore. All Rights Reserved.  Thank you! © Copyright National University of Singapore. All Rights Reserved. 44