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Formulation Development of Oligo-Based Sterile Injectables

Edition 2 / June 2021
Injectables Platform > Case Study: The Development Pathway for New Oligo-Based Injectable Drug Products

Edition 2 / June 2021

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Umberto Romeo, R&D Manager, CordenPharma Caponago, headshot

Author
Umberto Romeo,

R&D Manager
CordenPharma Caponago


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Case Study: The Development Pathway for New Oligo-Based Injectable Drug Products

R&D scientist working with lab equipment at CordenPharma Caponago in Italy

R&D Scientist in the lab at CordenPharma Caponago (IT).

The injectable Drug Product formulation & manufacturing site at CordenPharma Caponago (Italy) has demonstrated the ability to overcome challenges in small molecules, oligonucleotides, peptides, and biologics formulations. Combining over 30 years of accumulated expertise and customer knowledge sharing with CordenPharma’s strong network of integrated supply facilities across Europe & the US, and long-term peptide sourcing strategy designed for the integrated supply of both Drug Substance APIs and Injectable Drug Products, CordenPharma Caponago turns strategy into successful projects for ongoing Drug Product clinical trials in various therapeutic areas.

These milestones are supported by our newly completed large-scale aseptic fill & finish facility, which offers the capacity to manufacture large quantities of sterile injectable vials, Pre-Filled Syringes and cartridges from clinical-phase to commercial supply.

CordenPharma Caponago Case Study: The Challenges & Best Practices for New Oligo-Based Injectable
Drug Products

Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications in a myriad of indications, with several oligonucleotide-based drugs recently gaining approval. However, despite these recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation.

In fact, before oligonucleotides can become drugs, they must overcome a billion years of evolutionary defenses designed to keep invading nucleic acids on the outside of cells from getting to the inside of cells. Not surprisingly, significant effort has been placed in developing a wide array of delivery technologies.

The foremost of these is the development of N-acetylgalactosamine (GalNAc), which is especially effective for siRNA conjugates delivering to the liver. Tris-GalNAc binds to the Asialoglycoprotein receptor that is highly expressed on hepatocytes, resulting in rapid endocytosis. While the exact mechanism of escape across the endosomal lipid bilayer membrane remains unknown, sufficient amounts of siRNA enter the cytoplasm to induce robust, target-selective RNAi responses in vivo.

Multiple GalNAc-siRNA conjugate clinical trials, including two phase III trials, are currently underway by three biotech companies to treat a wide variety of diseases. GalNAc-siRNA conjugates are a simple solution to the siRNA delivery problem for liver hepatocytes, and have shown the RNAi (and antisense oligonucleotide) field the path forward for targeting other tissue types.

Diagram showing the delivery of oligonucleotides to the liver with GalNAc

‘Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug’

(Image © 2020 The American Society of Gene and Cell Therapy – ScienceDirect – June 16, 2020 –
by Alexandre J. Debacker, Jon Voutila, Matthew Catley, David Blakey, Nagy Habib)

The overall goal of oligonucleotides, and formulation development in general, is to transform a highly-purified Drug Substance into a stable, efficacious pharmaceutical Drug Product for administration to patients. The first step is often called pre-formulation characterization, which involves determining the oligo physicochemical properties and pathways of instability, allowing for the design of formulations containing various excipients to ensure formulation stability under defined storage conditions. At the same time, analytical methods to monitor the oligo physicochemical integrity and biological activity under formulation conditions (i.e., in the presence of excipients) need to be developed, along with specifications to define acceptable limits to any changes in these parameters.

Specific formulations at different oligo concentrations with targeted levels of various pharmaceutical excipients are then experimentally tested to ensure stability, solubility and tonicity over the shelf life. In addition, the primary container is selected (i.e., vial, cartridge or Pre-Filled Syringe) to store the oligo–excipient mixture and facilitate parenteral administration by the patient or a medical professional. The entire biopharmaceutical drug or vaccine dosage form (oligo, excipients, primary container, and delivery device) must be designed for both scalability, to allow for commercial manufacturing under sterile conditions, and the ability to meet all regulatory guidelines for the production and testing of biopharmaceutical dosage forms for human use.

The CordenPharma Caponago site has gained relevant experience with the successful formulation development and industrialization at clinical and commercial scale of several GalNac-siRNA conjugates. The whole formulation strategy revolves around the identification of solutions to maximize the possibilities of a viable and successful GMP scale-up to match the desired QTPP requested by our customers and ultimately, to reach the clinic following current regulations (ICH Q8, Q9, Q10).

In addition, CordenPharma Caponago’s experience in drawing upon its integrated network of internal drug substance plants and relevant R&D labs, as well as externally establishing reliable global laboratory services, has confirmed its capability to support the progression of many peptide-formulated drugs along their drug development pipeline.

About CordenPharma Caponago

CordenPharma Caponago is fully equipped to support Drug Product manufacturing starting from early CMC development through the commercial supply of a broad range of molecules. The small-scale aseptic fill & finish facility supports initial formulation development, as well as early clinical stages for a variety of peptides, small molecules, oligonucleotides, and in a few cases, biologics. With a flexible multi-role compounding area, including both traditional systems and fully-disposable technology, linked to a flexible filing line adapted for “ready-to-use” packaging, customers benefit from a successful peptide formulation outcome.

The experience gained in the flexible small-scale production environment helps us design and implement it into large-scale manufacturing to target a wide range of formulated peptide and mRNA injectable drug products.


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