Exosomes are small membrane vesicles that are secreted by a multitude of cell types, which play a role in cell to cell communication. They can serve as clinically valuable tools for early diagnosis, prognosis and potentially targeted treatment.
From a manufacturing stand-point, the challenge resides not only in the production but also in the characterization. Exosomes have the potential to make cell and gene therapies commercially viable for large populations.
We are still at a very early stage and most developers of these innovative technologies are in pre-clinical or early clinical stages, working to demonstrate the efficacy and the potential of exosomes-based therapies.

News update – 02 November 2021:

Lonza expands its Exosomes manufacturing offering with two acquisitions; Codiak Bioscience’s exosome manufacturing site in Lexington, Massachusetts (US) alongside Exosomics’ service unit located in Siena (IT). These acquisitions build on Lonza’s exosomes development and manufacturing and bring leading licensed technologies, expertise and capabilities to Lonza and its customers.

The investment in this emerging area reflects Lonza’s strategy to differentiate through innovation. From the development of the exosome modality to the industrial production of mRNA vaccines and supporting the manufacture of live biotherapeutics, Lonza operates at the cutting edge of manufacturing technology to help customers deliver innovative new therapies to patients worldwide.

Read the full press releases here:

 

Exosomes are membrane-based extracellular vesicles naturally released by cells. They are manufactured by isolation from cell culture. Since the manufacturing conditions can strongly affect the quality attributes of the final exosome-based product, process control and characterization is crucial in both the upstream and downstream processing steps. Targeted delivery also uses the surface markers for delivering therapies to specific cells or tissues, thus potentially lowering side effects. Once released by the producer cell, exosomes can be selectively taken up by neighboring or distant cells without eliciting an immune response. This form of cell-to-cell communication is similar to sending and receiving package deliveries, with the surface markers of exosomes acting like a postal delivery code. The producer cell utilizes complex machinery to package and sort biologic and metabolic cargo into exosomes. Once released from producer cells, exosomes take part in various fundamental biological processes and pathologies. Exosomes can also be charged with therapeutic cargo. This approach to targeted delivery uses the surface markers on exosomes for delivering therapies to specific cells or tissues, thus reducing the potential for side effects. Large-scale exosome manufacturing relies on the characterization of the right particle populations. In general, isolation and purification have proven to be challenging due to issues with separating exosomes from other extracellular vesicles and particulate impurities. Pure populations can only be assessed by a combination of analytical techniques.

Prime biological cargo delivery


Exosomes are produced by all cells. They are a sub-group of extracellular vesicle with a size range typically between 30 and 150 nm, have a Phospholipid Bilayer shell with specific surface markers, and a genetic package containing of RNA, DNA and proteins.

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Some cells can use exosomes to transfer genetic material from one to another. Specifically, an exosome can transfer microRNAs to control the expression of a gene, and messenger RNAs to manufacture proteins. They also transfer proteins themselves, lipids, DNA and others.

Exosomes are acting as cargo delivery systems in our body to deliver specific packages with positive or negative messages from one cell to another in a targeted way at distance. Simply put, they are a fresh and well conserved source of biomarkers coming from live cells which reflect those of the parenteral cells.


So what stands in the way?


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Aside from decoding the biology and mechanism for therapeutic effect in this novel field, these are some key challenges faced by exosomes-based therapy developers. Those are linked to the very early and pre-clinical stage which most of the exosomes-based therapies are in. There are limited characterization methods available, a need for precise isolation and purification methods and few partners who can provide access to end-to-end GMP manufacturing expertise. Identifying optimal formulation, obtaining starting cell-lines, media, gene editing & cargo loading can be a challenge, as well as defining functional assays.


No mountain high enough


Choosing the right partner becomes critical in such a pioneering field. By leveraging our knowledge in 2D/3D cell culture and our viral manufacturing expertise, alongside the latest exosome characterization technologies, we can provide a complete path for exosome manufacturing.

Upstream

Fully controlled and scalable (up/out) exosome generation technologies

Downstream and fill & finish

Selective exosome isolation technologies

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Characterization

A complete set of measurement tools to enable both upstream and downstream process development as well as quality control and product characterization

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Characterization


ZetaView® (NTA) for particle sizing and concetration determination FACS, qPCR and ELISA for analyzing exosomes and extracted exosome cargo Further characterization techniques currently on trial in R&D, targeted mid-2020 for GMP use
  • NTA - nanoparticle tracking analysis
  • FACS - FLourescence-activated cell sorting
  • qPCR - Real-time quantitative polymerase-chain-reaction
  • ELISA - enzyme-linked immunosorbent assay

 

Upstream


Source material Cell line engineering Expansion
Tissue acquisition and cell isolation (or exising cell line) Nucleofection / electroporation: Lonza Nucleofector™ and other electroporation methods
Lentiviral and AAV transduction methods
Large-scale 2D systems: CellSTACK®s and cell factories
Large-scale 3D systems: stir tank bioreactor (adherent and aggregate based cultures), Wave Bioreactor™ (suspension based cultures), hollow fiber (Quantum®)

Downstream


Isolation / purification Formulation implementation at DS Delivery
Tangential flow filtration (TFF) for clarification and volume reduction
Size-exclusion (SEC) / Ion-exchange for selection of exosomes
Ultracentrifugation
Compounding of buffer and target excipient composition
Process parameters to achieve final composition of exosome in bulk DS
Shipping and storage
End-to-end traceability, identification and injection

Formulation and Fill & Finish Drug Product


Formulation development DP process development and design GMP DP manufacturing and QC testing
Selection of appropriate buffer and excipients to have optimal formulatuon for improved stability
Development services for lyophilization of exosome for 5°C storage
Freeze / thaw and agitation study to support handling and transportation
Stability studies, manufacturing compatibility, particle assessment & ID testing*, light stability
Overfills, container closure system selection & qualification, container closure integrity in frozen state*
Extractables / leachables testing, in-use clinical administration design (pharmacy manual) and testing
GMP DP manufacturing
QC release and stability studies (including project specific development) and implementation of Pharmacopeia methods
Implementation of purity methods from customer for QC release and stability
*Lonza proprietary. Patent pending.

Our experts webinar on exosomes manufacturing


Why partner with us?

  • Leveraging 20+ years experience of cell therapy upstream and viral vector downstream, alongside 100+ iPSC, HEK and MSC customer projects
  • 2+ years of exosome manufacturing expertise, including research and development
  • Exosomes are strategic to our business and we are investing in expanding our capabilities in this area
  • Partnership with Exosomics S.p.A. to enable enhanced characterization technologies
  • Extensive bioprocessing and bioreactor experience for a wide range of applications
  • Development of manufacturing processes using various starting cell types including somatic cells, pluripotent and tissue-specific stem cells
  • End-to-end service offering:
    • Phase appropriate assay and process qualification
    • Full characterization
    • Tissue acquisition and cell line development
    • Upstream, downstream, formulation and fill & finish
    • Supply chain orchestration system through partnerships
    • Lifecycle regulatory support
  • Thought leadership through global, dedicated exosomes projects and collaborations
  • Open to a variety of collaboration options with exosomes developers

Technologies & Products


our global map of exosomes-related activities

Basel Stücki, Switzerland

Business Management & Support Services

Hochbergerstrasse 60A
Basel 4057
Switzerland

Houston, TX, USA

Clinical Manufacturing, Commercial Manufacturing, Cell and Gene Manufacturing, Viral Vector Manufacturing

14905 Kirby Dr
Houston, TX 77047
United States of America

Lexington, MA, USA

Research & Development

4 Hartwell Place
Lexington, MA 02421
United States of America

Rockville, MD, USA

Research & Development

9900 Medical Center Drive
Rockville, MD 20850
United States of America

Slough, UK

Production, Research & Development, Sales & Support

228 Bath Road
Berkshire SL1 4DX
United Kingdom

Geleen, The Netherlands

Clinical Manufacturing, Commercial Manufacturing, Cell and Gene Manufacturing, Process Development, Analytical Development

Urmonderbaan 20B
Geleen
Netherlands

Siena, Italy

Research & Development, Process Development

Strada Del Petriccio e Belriguardo 35
Siena 53100
Italy

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