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New Process Analytical Technology (PAT) and Downstream Processing (DSP) for the manufacture of in vitro transcribed mRNA

  • Full or part time
  • Application Deadline
    Friday, January 31, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

A fully funded 4 year BBSRC/Astra Zeneca PhD studentship is available in the School of Chemical Engineering at the University of Birmingham, starting in October 2020.

In vitro transcribed messenger RNA (IVT mRNA) is being touted as the next big thing in the biopharmaceutical sector. [1] The idea is beautiful in its simplicity … construct an mRNA sequence, deliver it to the target cell, then sit back and allow the cell’s own machinery to crank out the encoded protein which elicits the desired therapeutic effect … but the implementation is infinitely more complex. While there is indeed much cause for optimism, at the present time there are no approved mRNA products, and compared with biopharmaceutical proteins, there is a definitive lack of enabling technology to support process development of IVT mRNA products.

IVT mRNAs are produced in cell-free systems by in vitro transcription from DNA templates (encoding all the structural elements of a functional mRNA including the poly-adenylated (A) tail) using cocktails containing a RNA polymerase, ribonucleotides and 5′ capping agents. [1,2] Following mRNA synthesis, the mRNA product must be recovered from a complex soup containing spent polymerase, unincorporated ribonucleotides, the DNA template, and an assortment of product-related impurities, principal among these uncapped, shortened and lengthened RNA species in single- and double-stranded forms. While biological solutions are expected to improve the yield and fidelity of in vitro transcription, reduce product related impurity load and diversity, and lessen purification demands, the tracking and removal of residual critical impurities from single-stranded poly(A)-tailed mRNA products requires technological/engineering answers – specifically new process analytical technology (PAT) and new downstream process (DSP) separation technology. In this project new PAT screening tools [3] and DSP solutions [4] conceived at the University of Birmingham will be applied in the processing of IVT mRNAs.

The project is funded for 4 years, starting in October 2020, with a full studentship supported by the BBSRC and Astra Zeneca that covers University fees and stipend. The successful candidate shall be based at the University of Birmingham (supervised by Professors Owen R.T. Thomas and Tim R. Dafforn), and will spend at least 1 month per year at Astra Zeneca’s labs in Cambridge. Candidates for the studentship should be a UK/EU citizen and will have (or expect to obtain) a first or strong upper second-class degree (or equivalent) in a relevant discipline such as biochemical engineering, chemical engineering, biochemistry or biotechnology. The ideal candidate will combine: a deep interest in process analytical and separation challenges facing the manufacture of IVT mRNA; willingness to learn all aspects of the project; possess good communication, numeracy/mathematics and team working skills, and ability to write clearly and succinctly.

References

[1] R. Cross (2018) Chem. Eng. News, Sept. 3, Vol. 96, issue 35
[2] L. Van Hoecke and K. Roose (2019) J. Transl. Med. 17(1): 54
[3] C. Moore-Kelly, J. Welsh, A. Rodger, T.R. Dafforn, O.R.T. Thomas (2019) Anal. Chem. published online 4th October 2019. DOI: 10.1021/acs.analchem.9b03259
[4] B. Ketterer, C. Moore-Kelly, O.R.T. Thomas, M. Franzreb (2019) J. Chromatogr. A, published online 17th August; DOI:10.1016/j.chroma.2019.460429.

How good is research at University of Birmingham in Aeronautical, Mechanical, Chemical and Manufacturing Engineering?
Chemical Engineering

FTE Category A staff submitted: 32.50

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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