Enhanced cell stability during manufacture and administration

Biotechnology is an industry that began several decades ago to address the issues surrounding the translation of new
discoveries into therapies that can be mass produced and delivered to patients whilst complying with regulations. Typically
this field has addressed and overcome issues associated with the mass production of therapeutic proteins, by utilising
recombinant DNA technology and cultured cells to produce the protein efficiently and at high yield. More recently however,
it is the cells themselves that have been the subject of biotechnology manufacturing for therapy, and cells are much more
fragile and complex than the proteins this industry is more used to working with. However, a more elegant approach is to
provide to patients human cells capable of producing such proteins within the patient. One good example would be
pancreatic cells able to produce insulin rather than have diabetic patients having to self administer insulin on a daily basis.

The use of whole cells for therapeutics is becoming increasingly important for regenerative medicine and other therapeutic
niches with early stage clinical trials currently underway and many more at early discovery stage. Preliminary whole cell
therapies have included vaccines against pre-existing melanoma and prostate cancer and more recently a regenerative
medicine whole cell therapy to help with the effects of stroke. The quality of manufacture of these cells will be critical if they
are to be effective when applied to the patient. It is generally accepted that the manufacture of these therapeutic cells
requires careful consideration and forward thinking from the outset. Initial cell sourcing to expansion phases to storage and
delivery to the patient all require a great deal research and development to ensure the quality and intended functionality of
the cells remains high and constant throughout these stages.
The term bioprocessing has become an umbrella term for the separation of cells from their culture medium and transfer to
a liquid vehicle that allows transfer to a patient. Bioprocessing therefore involves different steps many of which cause a
degree of stress to the cells. In addition, it has recently become evident that during the cell manufacturing process it is
essential to include holding stages prior to and post processing and prior to administration to the patient. This allows
flexibility within the process and is essential when dealing with vast numbers of cells in numerous cell culture vessels.
These holding stages may last up to several hours and we have found that they often lead to decreased quality and
specification of the cells prior to application to the patient. This project aims to address these issues by utilising clinically
relevant cell lines to investigate bioprocessing and storage problems associated with cellular stress and instability. This
project will create stabilisation formulations to investigate short, intermediate and long term storage of cells in both liquid
refrigerated and frozen states and combine this with ultra scale-down processing techniques developed by UCL which
mimic the stresses the cells undergo during large scale manufacture. A panel of biological tests will be applied to the cells
to investigate their quality following the physical insults. This will help establish a) the optimal stabilisation formulations and
b) the robustness of the cells during storage and bioprocessing holds. The objective is to create a robust toolkit that will be
of value to the biotechnology and regenerative medicine sector. The toolkit would be used in the early stages of product
R&D enabling cost effective use of precious cells whilst developing a robust manufacturing and administration protocols
that meet the current regulatory and economic challenges.

This project aims to create a toolkit of stabilisation media and bioprocessing parameters as an exemplar for preparation of
whole cell therapeutics whilst maintaining product efficacy. The aim is to use this toolkit to benefit a wide range of groups
from academics, biotech SMEs, cell banking facilities, regulatory bodies, charities and the wider public.

This project aims to create a toolkit of stabilisation media and bioprocessing parameters as an exemplar for preparation of
whole cell therapeutics whilst maintaining product efficacy. The aim is to use this toolkit to benefit a wide range of groups
from academics, biotech SMEs, cell banking facilities, regulatory bodies, charities and the wider public.

Beneficiaries and how they will benefit:

(i) Academic groups and biotech SMEs in the regenerative medicine field that aim to trial and commercialise whole cell
therapeutics: The toolkit and information provided will provide a defined starting point for preparation of their products at
scale required for manufacture and for storage. The outcome of our project will allow these groups to create at speed a
bespoke set of bioprocessing and storage parameters and enable the transition from bench to clinic in a more cost effective
manner by quicker negotiation of vital product development steps.

(ii) Cell banking facilities such as the UK stem cell bank (UKSCB) at NIBSC (HPA): The UKSCB has recently been set up
to provide stem cell banking, storage and research facilities within a GMP environment with a view to being a key part of
the supply chain for provision of clinical grade stem cells for therapeutic use. Organisations such as these would benefit
from outcomes of this project by utilising formulations and bioprocessing parameters to help develop their strategies for
stem cell production and storage.

(iii) Regulatory bodies such as the MHRA in the UK: Such government agencies are responsible for standards of safety,
quality and performance of medicines and healthcare products. The stabilisation media utilised within this project will
conform to the standards imposed by regulatory bodies. Also the ultra scale-down techniques employed will help provide
an increase in the quality of the data available and its understanding when making decisions on regulatory issues.

(iv) Charities within the regenerative medicine field: e.g. the Anthony Nolan Trust who utilise cells from cord blood for
therapeutic use and Cancer Research UK who fund much of the early discovery phase research of regenerative medicines.
This research will allow implementation of scale up development at an earlier point in product development by reducing
time taken for product development.

How the stem cell community will benefit:
An eventual project aim of producing the "stabilisation media and bioprocessing toolkit" is to enable a reduction of time
taken for cell therapies to progress through product development prior to and during clinical trials. With strict processing parameters established early on, any cell therapy may have a better chance of progressing successfully through lengthy
clinical trial phases and into the public domain without loss of efficacy due to bioprocessing and storage. Currently can take
10-15 years for medicines and therapies to enter the public domain. Any reduction in this time frame would be seen as
being beneficial to the public.

Research staff involved in this project would benefit by increasing their depth of knowledge in what is a rapidly growing
field. By broadening research and project management skills this would enable career progression in either an academic or
industry setting. The lead company on this programme would also benefit by progressing their products into the whole cell
market and by licensing out the formulations to cell therapy companies.