- Cancer Biology & Biomarkers
- Chromatography & Mass Spectrometry
- Contract Research, Clinical Trials and Outsourcing
- Drug Discovery
- Drug Targets
- Flow Cytometry
- Informatics & Lab Automation
- Ingredients, Excipients and Dosages
- Microbiology & RMMs
- NIR, PAT & QbD
- Raman Spectroscopy
- Screening, Assays & High-Content Analysis
- Thermal Processing
Approaches in subcutaneous delivery of monoclonal antibodies
24 August 2016 • Author(s): Claus Geiger, Till Bussemer, Tanya Mezhebovsky and Bernardo Perez-Ramirez, Sanofi
Currently, subcutaneous delivery of therapeutic proteins is a fast-growing field, especially for such established modalities as monoclonal antibodies, which require large quantities of drug to be administrated. Different approaches, including high protein concentration, speciality formulations and drug delivery matrices, as well as devices enabling a more rapid administration of larger liquid volumes, are being developed. The fastest growing field is the development of drug-device-combination products, requiring optimisation of highly complex and dynamic systems. The early identification of patients’ needs translated into target product profile for drugs and devices, as well as their integration during the development process, are key success factors. The state of this field will be discussed in this article.
Biopharmaceutical products emerged as a direct consequence of the explosive development of life sciences and, in particular, cell and molecular biology during the past few decades. Biotherapeutics represent a broad range of molecules: hormones, growth factors, peptides, small proteins, cytokines, therapeutic replacement enzymes, blood factors, anticoagulants, monoclonal antibodies, their fragments and fusion proteins, and there are now over 170 launched products1. The first approved biopharmaceutical drug product was the hormone recombinant human insulin, marketed by Eli Lilly as Humulin in 1982 and produced by the process developed at Genentech as secreted from the correspondingly started cell culture1.
In 1995 Genzyme pioneered the concept of enzyme replacement therapy by introducing to the market the recombinant product imiglucerase (Cerezyme), obtained from genetically engineered Chinese hamster ovary cells. In 1997 the first full length chimeric monoclonal antibody, rituximab, and the first full length humanised monoclonal antibody, daclizumab, were approved for commercialisation2,3. This started the era of monoclonal antibody biotherapeutics, currently the fastest growing field of pharmaceuticals with projected annual sales of 125 billion US dollars by 20204 . Presently, the annual sales of Humira (a monoclonal antibody which inhibits TNF to generate antiinflammatory effect) are above 12 billion US dollars4 . Humira (the biggest blockbuster biotherapeutic of today) is a monoclonal antibody drug product that is administered at high concentration in liquid formulation in a prefilled syringe (PFS) for subcutaneous administration. It has set the bar high and paved the way for increasing convenience to patients.
The emergence of biotherapeutic drug products required innovative approaches in process development, including novel approaches in formulation; this is very different from those applied to small-molecule drugs. Biotherapeutics are complex molecules with marginally stable conformational and colloidal stability, so that physical stability (to avoid any fold compromise, potentially leading to particulate matter formation in the size range from aggregates to visible flocculants) and chemical stability (to avoid any hydrolysis, deamidation, oxidation racemisation or isomerisation) are to be optimised during formulation development2. Originally, the main approach to biotherapeutic drug formulation development was lyophilisation, as removal of water significantly slowed chemical degradation processes and improved longterm stability. Lyo formulation development requires optimisation of the vehicle composition followed by lyo cycle optimisation for time-efficient water removal (economic considerations) without compromising potency of the biotherapeutic drug.
ABB Analytical Measurement ACD/Labs ADInstruments Ltd Advanced Analytical Technologies GmbH Analytik Jena AG Astell Scientific Ltd B&W Tek Bachem AG Bibby Scientific Limited Bio-Rad Laboratories BioNavis Ltd Biopharma Group Black Swan Analysis Limited Butterworth Laboratories Ltd CAPSUGEL NV Charles Ischi AG | Kraemer Elektronik Cherwell Laboratories CI Precision Cobalt Light Systems Coulter Partners CPC Biotech srl Dassault Systèmes BIOVIA DiscoverX Edinburgh Instruments Enterprise System Partners (ESP) Eurofins BioPharma Product Testing EUROGENTEC F.P.S. Food and Pharma Systems Srl GE Analytical Instruments IDBS JEOL Europe Kaiser Optical Systems Inc. L.B. Bohle Maschinen + Verfahren GmbH Lab M Ltd. LabWare Linkam Scientific Instruments Limited Lonza MA Business Metrohm Molins Technologies Multicore Dynamics Ltd Nanosurf New England Biolabs, Inc. Ocean Optics Panasonic Biomedical Sales Europe B.V. Peak Scientific ReAgent Russell Finex Limited Sentronic GmbH Source BioScience Takara Clontech Tornado Spectral Systems Tuttnauer Viavi Solutions, Inc Watson-Marlow Fluid Technology Group Wickham Laboratories Limited WITec GmbH Xylem Analytics YMC Europe GmbH Yusen Logistics