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Town Meeting 26th July 2012
EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies
Challenges in characterising biopharmaceuticals for ease of manufacture
Town Meeting 26th July 2012 2.00 pm-7.00 pm
University College London
Note of Meeting
This Town Meeting aimed to bring together key industrialists facing the challenges of biophysical
characterisation during bioprocess development and product formulation. It also brought in
academics with interests in these challenges, as well as those involved in developing biophysical
and associated computational or data handling techniques, that may have a relevant impact in
future. The meeting first introduced the challenges of the sector with three keynote presentations
from Industry representatives. This was then followed by an anonymous voting session using
handheld voting paddles, to assess the importance of various perceived challenges in the sector.
Based on these results, two key challenges were taken forward for further discussion in parallel
break-out sessions. The main points of these were discussions were fed back to all attendees for
final discussion and commenting on future directions, and these are also reported here.
Aims of the meeting
 Identify key analytical research challenges for the bioprocessing industry
 Identify emerging areas in UK academia that potentially address these challenges
 Facilitate collaborations to address key bioprocess research challenges
 Provide mechanisms to promote collaborations
Key points of presentations
Several key challenges to the bioprocess and formulation development sector were raised within
the three keynote presentations and following Q&A sessions. These were:

Identifying and understanding of product critical quality attributes (CQAs) used to define
testing requirements for process control, that relate to clinical outcomes and manufacturing
issues, and also relate to administration including choice of dosage device.

Testing throughout the process, and not just at the end, is required for optimal process
development and understanding. A defined controlled process equates to a defined
controlled product.

There are a very large number of potential product attributes to assess, and also a very
wide range of analytical techniques available. We need a very good understanding of the
limits of each of these techniques, and also on the role of low levels of impurities.

Novel biomolecules require novel processes, e.g.non-MAb based, antibody-drug and other
conjugated biomolecules, enzymes etc
 Less industry/regulatory experience and process understanding
 How we reduce the timescales and costs associated (already too high) to develop
novel processes ‘from scratch’?
 Can we take lessons learnt from Mab processes?
 What would be the associated analytical support?
 Increased requirement to support the de-novo development
Town Meeting 26th July 2012
 Defining potential product CQAs (critical quality attributes) with less historical
information of product type and associated process
 Understanding the effect of process change (from manufacture to formulation)

Relevant questions for industry in developing new products and process are:
 Can the product purity and freedom from contaminants be demonstrated
 Is all of this the same when I transfer the process in scale?
 Can the effect of process changes be demonstrated?
 Does the process make the correct product?
 Is the product potent, stable and safe? Can this be validated?

Challenges identified in formulation (Paul Matejtschuk)
 Excipient choice for maximising activity
 Rapid screening DoE/microplate methods
 Modelling impact of excipient choice and interaction on biophysical properties
 Scalability & relevance of effects seen at small scale

Freeze drying process challenges (Paul Matejtschuk)
 scalability
 Heterogeneous ice nucleation
 Impact of formulation
 Moisture and appearance
Key issues identified in voting, discussion and breakout group
1. Voting session
In questions 1-9 delegates were asked to rate the priority of the topic in question
Q1. Characterisation of protein degradation during bioprocess manufacturing
Town Meeting 26th July 2012
Q2. Characterisation of protein degradation of final dosage form
Q3. Characterisation of <2% contaminants
Q4. High-throughput screens vs accuracy
Q5. Low volume screens/assays
Q6. Predictive tools for formulation excipient selection
Town Meeting 26th July 2012
Q7. Characterisation of interactions between excipients and proteins
Q8. Characterisation of heterogeneity and phase states in freeze-dried formulations
Q9. Analytical methods to complement thermal forced degradation studies
Town Meeting 26th July 2012
In questions 9-13 delegates were asked to indicate their agreement (or disagreement) to the
proposed topic being a priority for research
Q10. Unknown Unknowns (Identifying unidentified impurities)
Q11. Fit for purpose early stage (Tools to show that a candidate product is Fit for purpose (i.e.
readily manufactured) , at an early development stage?)
Q12. Protein stability
Town Meeting 26th July 2012
Q13. Predictive vs Quantitative (Analysis measurements early in development should be predictive
with regard to manufacturing rather than aim to be quantitatively precise)
2. Breakout Group 1 Protein degradation of final dosage form.
Need assay(s) that work with very low amounts of material, combine assays to get more
information, develop platform assays.
Assays need to provide information on site specificity
Assays need to be able to predict final performance of dosage form (account for all the
production steps and the rate issues)
Rather than focus on developing a small no of high fidelity (sensitivity, precision and accuracy)
assays, consider a high throughput assay approach to collect a large amount of information
(probably lower fidelity) based on measuring a large(r) number of parameters but still using small
amounts of materials.
Ultimately the sector needs screens that are high-throughput AND high accuracy, AND low
volume, yet able to cope with high protein concentrations. Want to get high throughput
predictive assays using platform technologies.
3. Breakout Group 2: Protein stability during bioprocessing.
There was a perceived need to understand the interaction between molecule and environment in
bioprocessing. The environmental context includes:
hydrodynamics (flow)
crude lysates/homogenates (eg proteolysis)
There is a need for low volume, low concentration analytical tools for aggregation, shelf-life, safety
(immunogenicity), potency and specific bioactivity in particular for scale up prediction. The
analytics also need to cope with products within crude/complex mixtures.
There is a need for prediction from early measurements or indicators. Such analytical tools will be
essential for this. However, there is also a need for molecular modelling and statistical methods to
enable predictability in terms of linking molecular information to manufacturing performance.
Both formulation and bioprocessing has a need for more capability in high throughput process
screening, as well as to determine any intrinsic (molecular) indicators for process performance.
Follow-up actions and next steps
Town Meeting 26th July 2012
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Form a Linked In group to facilitate further discussion and collaboration.
Shared materials and databasing of results would be extrememly useful for
academics and SMEs alike. How do we to take forward the idea of materials
sharing, and data sharing on biophysical characterisation? Systems to study include
Mabs, Fabs, bispecifics.
Gap analysis and review of day to scope out potential feasibility topics.
Submit proposals for follow on projects using the mechanism of the EPSRC CDT
and EPSRC Centre Feasibility Studies.
Attendees
Over 130 invites were sent out to both academics and industrialists with potential interest
in the Town Meeting, using our existing network database, and also to those suggested
after preliminary discussions with key contacts. The meeting was also publicised via the
KTN and ABPI. Travel bursaries were also made available to academics attending this
town meeting, using EPSRC Centre funds to maximise the potential outreach.
Town Meeting Thursday 26 July 2012, Delegate List
Executive Suite, Roberts Building, UCL
Organisation
Name
GlaxoSmithKline
MedImmune
University of Reading
Ahmed Yasin
Alastair Kippen
Andre Cobb
University College London
Syntaxin
Aston University
University Strathclyde
Imperial College
Andrew Davidson
Andrew Splevins
Anne V Hine
Brian McNeil
Daryl Williams
BioMoti Limited
University of Manchester
Davidson Day Ateh
Ewan Blanch
GlaxoSmithKline
LGC
Gary Finka
Gavin O'Connor
Town Meeting 26th July 2012
LGC
Arecor
Helen Parkes
Jan Jezek
University College London
University College London
Lonza Biologics
University of Manchester
University College London
Joseph Ndieyria
Keying Li
Larcombe Lee
Malcolm Rhodes
Mike Hoare
University College London
University Greenwich
University College London
NIBSC
PALL Europe
Medimmune
Malvern Instruments
University of Manchester
Nesrine Chakroun
University Greenwich
University of Nottingham
Simon C. W. Richardson
Stephanie Allen
University College London
Kings College London
University College London
University College London
University of Reading
University of Manchester
Aston University
Steve Brocchini
PAUL D DYER
Paul Dalby
Paul Matejtschuk
Peter Ball
Richard Turner
Robert Jack
Robin Curtis
Sukhi Bansal
Suzy Farid
Teresa Barata
Vatility Khutoryanskiy
Xue-Feng Yuan
Yvonne Perrie
Town Meeting 26th July 2012
TOWN MEETING INVITATION
Challenges in characterising biopharmaceuticals
for ease of manufacture
July 26th 2012 2.00-7.00 pm
Venue: UCL, Executive Suite, Roberts Building
Background: The EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular
Therapies was launched in November 2011. Our mission is to build on our position as the
leading resource for research in the innovative manufacture of biopharmaceuticals. A key
research objective is to develop methods for assessing, at a very early stage in the development
process, the ease of manufacture (the manufacturability) of new biopharmaceuticals.
The Centre invites you to take part in a Town Meeting to discuss and develop the research
challenges set out in the attached brief and to identify new directions to solve these. The meeting
is open to researchers of any discipline that feel they have expertise that may contribute to a
solution. We welcome participation from beyond the bioprocessing community.
Objective: The objective of the meeting is to identify projects with new, and potentially radically
different, research directions to address these challenges and to facilitate the initiation of research
activity in this area.
The Centre has resources for feasibility studies with PDRAs at the Centre or collaborating
institutions. These studies should provide preliminary data for grants, or for a short communication
type paper, and there are up to six of these available for immediate use. Additionally there is
funding for PhD projects at the Centre and collaborating institutions starting in 2013 and 2014
through the EPSRC Centre for Doctoral Training. The Centre is ready to partner with other
institutions in bids for responsive mode funding for projects that promise to deliver step changes in
assessing manufacturability.
Registration
Attendance is free and will be limited to 40 delegates and preregistration is required. Up to ten
travel bursaries are available, on application, to academic attendees at this meeting
To register please send an email to [email protected] with contact details and a paragraph
description of your research expertise including relevant links to web pages
Preliminary Agenda:
See Page 2
Context for the Town Meeting
See Page 3
Availability of travel bursaries
See Page 4
Town Meeting 26th July 2012
Provisional Agenda
July 26th 2012, 2.00 - 7.00 pm
Venue: UCL, Executive Suite, Roberts Building
Time
Event
13.30-14.00
Registration
14.00-14.15
Chairman’s welcome and introduction - Dr Paul Dalby, UCL
Scene setting presentations on the principal analytical challenges in
biopharmaceutical process development
14.15-14.35
Dr Ahmed Yasin, GlaxoSmithKline
14.35-14.55
Dr Alistair Kippen, MedImmune Ltd
14.55-15.15
Dr Paul Matejtschuk, NIBSC
15.15-15.35
Discussion on challenges identified, chaired by Paul Dalby
15.35-16.05
Tea and networking
16.05-16.35
Delegate rating of the research challenges identified in session 1
16.35-17.10
Parallel breakout sessions: research priorities to address the challenges outlined
17.10-17.50
Feedback sessions reporting on priority research areas identified
17.50-18.00
Q&A and Chairman’s closing comments
18.00-19.00
Drinks and canapés and informal discussions to develop research ideas
17.50-18.00
Chairman’s closing comments
18.00-19.00
Drinks and canapés and informal discussions to develop research ideas
Town Meeting 26th July 2012
Background and context for the meeting
Purpose of the Town Meeting
To identify new avenues of research that will significantly improve the understanding and prediction
of manufacturability of protein based therapeutics
Overall aim of the Centre’s research programme on manufacturability
To create rapid analytical tools and modelling methods for characterising the properties of proteins
and their behaviour in bioprocesses and final drug product dosage forms, that allow lead
biopharmaceutical candidates to be ranked in terms of their ease of manufacture.
Context
Ranking of lead protein candidates would allow decision makers to weigh up manufacturability and
product dosage form options along with their knowledge of potential clinical efficacy, to select the
most promising proteins from panels of candidates, and eliminate those most likely to fail due to
difficulties in bulk product manufacture and final formulation.
There are significant technical challenges to obtaining rapidly measured protein properties, and
also to linking them to their manufacturability. The challenges of measurement include scarcity of
materials at early stages of development, the need to measure a wide range of representative
protein concentrations (e.g. from 0.1 to 100 mg/ml), and the complexity of the solutions containing
the protein, particularly at the early stages of manufacture (e.g. fermentation). A second challenge
is in identifying the appropriate measureable protein properties that can be used as indicators of
their manufacturability. Manufacturability of the bulk product depends upon the tolerance of the
protein to stresses that occur during typical operations e.g. chromatography, filtration, viral
inactivation, and chemical modification (e.g. PEGylation). Stresses include altered salt
concentration, extreme pH, high protein concentration, shear, agitation and interaction with
hydrophobic surfaces. Manufacturability of the final dosage form depends on the product’s
stability during formulation operations where the following factors need to be considered: available
delivery modes (typically intra-venous, sub-cutaneous, or intra-muscular injections, infusion, nasal
spray), product forms (liquid, spray- or freeze-dried formulation), and also acceptable additives or
chemical modifications that improve product stability, solubility, viscosity, half-life and partitioning in
the body, and that minimise immunogenicity.
The Centre is seeking to find collaborative partners in a broad range of disciplines that can
contribute to this complex research problem. These may include (but not limited to) molecular
biology, biophysics, computational modelling of protein structure or complex biological solutions,
multi-parameter statistical analysis, predictive tools, novel physics, automation, microfluidics, and
instrument development.
Town Meeting 26th July 2012