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Chapter Seven
The Process Development
Perspective
Implementing Tools
for Optimization

Maribel Rios

Series
2017
B i o P r o c e s s STATE OF THE INDUSTRY

The Process Development

Perspective
Implementing Tools for Optimization

Maribel Rios

P
rocess development can make
or break a companys
manufacturing performance
and ultimately the success of
its products. Process developers must
think about how their work will
translate into full manufacturing and
commercial scales. More than ever,
biomanufacturers are striving toward
efficient means of accelerating process
development timelines and reducing
development costs. Resources must be
dedicated to implementing systems
that will aid in process understanding, ADOBE STOCK (HTTP://STOCK.ADOBE.COM)

flexibility, and meeting production

demands. Tools such as design of
experiments (DoE) and risk-based
approaches such as quality by design
(QbD) and process analytical
technologies (PAT) were designed to
help manufacturers better understand
their processes. And equipment
innovations such as single-use systems
can ease development work. Industry
experts explain here the real-word
applications of these innovations,
including their difficulties and
challenges.
Survey Results
Out of the nearly 300 self-selected
respondents to BPIs State of the
Industry survey, the highest
percentage of respondents (26%)
indicate that they work in process
development. We asked four questions
of this group. Figure 1 shows the hits
and misses of the industry over the
past 15 years. Figure 2 focuses on how
digital technology has affected process
development work. Figure 3 shows the
impact of single-use technologies in
process development work. And
Figure 4 shows results of the final
question, which asked participants the
extent to which they agree or disagree
on statements regarding the influence
of QbD on their work.
Streamlining Development
Manufacturing cant occur until
process development work is done. So
developers are under pressure to meet
tight deadlines and streamline their
work. Balancing the scope of work
with expectations for effective and
robust process solutions can be a
challenge, says Yuval Shimoni (who
provides quality oversight to the
contamination control and product
stability programs at Bayer). One
powerful tool is design of experiments
(DoE), which narrows the number of
experimental runs needed using
factorial design. Leveraging a platform
process (unit operations and raw
materials, including host cells),
implementing well-thought upgrades
(not just to production process stream
but also to associated analytics and
assays as well), and applying a
knowledge-based DoE is a powerful
combination, he says. It allows for
continuous improvement and good
predictability while minimizing the
number of experimental runs (shorter
time to results). Chances for success
can be further increased (or risk
reduced) through leveraging qualified
scale-down systems because a higher
number of parallel runs can be
performed for increased confidence
levels following statistical analyses.
Shimoni discussed those concepts in an
article in BPI and elaborated on the
application of multivariate analysis
(MVA) tools in a BPI-West
presentation (San Francisco) in March
2017 (1).
Certainly, the application of DoE
and MVA have streamlined some of
my applications, says Hiten Gutka
(formulation scientist at

2 BioProcess International 15(6)e C hapter 7 of 11 State of the I ndustry 2017

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Figure 1: BPI received nearly 300 responses to its state-of-the-industry survey in AprilMay 2017. Of
respondents who indicated that their work is in process development, here are the hits and misses
of some industry trends that have taken place over the past 15 years.
Ballroom Design
Enterprise Resource Planning
Quality Risk Management
Just-in-Time Manufacturing
Modular Manufacturing
Membrane Chromatography
Transgenics
Sensors for Continuous Processes
Process Analytical Technology
Perfusion Technologies
Quality By Design
High-Throughput Screening
Multivariate Analysis
Design of Experiments
0 10 20 30 40 50 60 70 80 90 100
Hit Miss
Figure 2: BPI received nearly 300 responses to its state-of-the-industry survey in AprilMay 2017. Of
respondents who indicated that their work is in process development (PD), here is how they said
digital technology has changed their work over the past 15 years.
Automation of clone selection enables
better monitoring of workflow steps.
Automated tracking and logistics tools
are increasing speed and confidence in
our managment of multiple product lines.
Autogenerated reports are
streamlining our BLA submissions.
E-filing regulatory documents
is becoming the norm.
Data mining assists with
prior-knowledge assessments.
Big-data analytics have improved
process monitoring, trend analysis, etc.
Serialization/tracking are helping with
raw-material control/product logistics.
DoE/multivariate analysis
are streamlining PD overall.
21 CFR Part 11 is still a challenge.
Other
OncoBiologics). Simple screening
studies that involve the
conformational and colloidal stability
evaluation of antibody therapeutics
can be easily streamlined with the
application of such tools. In addition,
they are easily applicable to high
throughput approaches and with lower
demands on material supply.
to use statistics to show anything they
want, especially if they dont
understand what theyre looking at. So
some users purchase off-the-shelf
programs and show diagrams of how
they narrowed down their DoE but,
when they run a process, it doesnt look
anything like they saw in their DoE.
Rosenblatt says process
understanding is key to understanding
appropriate DoE experiments. If you
have an idea of the general principles
or have an idea of the design space
and what the parameters are, you can
narrow down your DoE to something
more manageable to run fewer
experiments. That allows you to see
how different parameters interact,
giving you a better idea when you
actually run the process. You wont
have the exact design space (you dont
get to that until process validation),
Neutral Percentage of Respondents (%) but at least youll have an idea of the
parameters you should be looking for,
what you should try to control, and
what you dont have to worry about.
Tools to Accelerate Development
To speed up process development,
bioindustry experts leverage a design-
39.6%
space approach. The need to establish
32.1% a design space around a process has
had a big impact on process
17.0% development, says Susan Woodard
(downstream bioprocessing and
45.3%
purification process development at
47.2% Texas A&M University).
Considerable assay work is essential
37.7% to determine the impact of small
changes to process variables on
28.3%
products. Understanding which assays
75.5%
will provide the needed information
requires that assays be considered a
35.8% critical part of process development.
Shimoni agrees: Parallel, accurate
0 10 20 30 40 50 60 70 80 90 100
1.9% and well-documented execution and
Respondents Who Agree (%)
analysis of multiple inputs while
meeting regulatory expectations and
using industry-leading strategies are
Barry Rosenblatt (president of essentials to speed process development
SMEbiotech Consulting) agrees: Its by increasing efficiency and
almost unusual to see a group thats not effectiveness. For example, recent cell
using some form of DoE to conduct line selection and development
process development and look at technologies have significantly
multivariant parameters to narrow the accelerated timelines while introducing
range and define the design space of the capability to document clonality of
their downstream or upstream selected production-cell candidates.
processes. Sometimes users know how He says that other technological

4 BioProcess International 15(6)e C hapter 7 of 11 State of the I ndustry 2017

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Outsourcing Process Development
The biopharmaceutical service industry is
steadily increasing in China. Contract
manufacturing organizations (CMOs) and
proprietary development companies
have expanded their collaborations with
US biotech companies to provide
biopharmaceutical drug substance and
process development support. Several
Chinese drug developers have partnered
products with US companies to provide
access to US and other first-world
markets. In multiple cases, Chinese
companies continue to provide bulk
drug substances for clinical trials and,
perhaps, for commercial production once
products are licensed.
CMOs in China also have expanded their
reach with production of clinical testing
Figure 3: BPI received nearly 300 responses to its state-of-the-industry survey in AprilMay 2017. Of
respondents who indicated that their work is in process development, here is how they said that
single-use technology (SUT) has changed their work in the past 15 years.
Scalable SUT enable us to develop
continuous prodcution platforms.
My company cant progress without SUT.
SUT enables cost effective
multiproduct development.
We scale-up into stainless steel
for manufacturing.
We see significant cost savings with SUT.
SUT bags still leak at process scales.
Implementation challenges remain.
SUT materials are more interchangeable
SUT is now more robust at large scales.
0 20
Percentage of Respondents (%)
Agree/Strongly Agree
advancements, including the use of
semisolid media, also increase fidelity
with performance at commercial scale.
Implementing process analytical
technology (PAT) has its hurdles,
however. Some people are still trying
to implement PAT strategies to process
development, but theyre not quite
there yet, says Rosenblatt. The
biggest issue is figuring out the
appropriate sampling scheme to achieve
real-time evaluations, whether its using
a sampling port that must feed into the
PAT instrument or using electrodes in
a feed stream to measure certain inputs,
or something else entirely. There are
still some unresolved issues.
6 BioProcess International
by Scott Wheelwright
materials for drugs developed by US and
European companies. In many cases, the
entire development process, from cell
line development through product
manufacturing, has been performed by
the CMO. WuXi Apptec and Boehringer
Ingelheim continue to expand their GMP
manufacturing capabilities in China.
While BI continues to provide
development services through their
European sites, WuXi has expanded its
development capabilities in China and
has grown its staff for process
development, analytical method
development, and manufacturing. JHL
and MabPlex also offer process
development support on a contract
basis.
40 60 80
Disagree/Strongly Disagree Neutral
One problem is the lack of
confidence some operators have in their
equipment. For disposable bioreactors,
you need the appropriate probes to
monitor the process, says Rosenblatt.
But one significant problem has been
that users arent as comfortable with
the accuracy and the reproducibility of
the probes as they should be. It is not
unusual to find people using
nondisposable probes (because they
came with the instrument) and are
then throwing them away after just one
use because the probes are so unreliable
that they cant be used for a second run.
In effect, operators are using a
nondisposable probe as a disposable
15(6)e C hapter 7 of 11 State of the I ndustry 2017
probe. A good number of users are
doing offline measurements to support
probe use. For a probe that measures
pH, for example, some users will pull a
sample periodically, conduct a pH test
in the laboratory, and then adjust the
reading on the probe to match the
offline pH. Operators are using an
in-line gross measurement, but not
relying on it. They do offline checks
just to make sure that the pH
environment in the bioreactors isnt
completely out of specification. Its a bit
problematic.
Rosenblatt says problems can occur
at downstream processes because of
in-process controls. The problem that
users are running into is that the ability
to check product quality attributes isnt
quite there yet. For example, when
monitoring host-cell proteins [HCPs],
currently there are no real online
measurements that users find
trustworthy to allow them to monitor
HCPs throughout a process. So people
have to take a sample out and run it
through instruments. Those
instruments have become faster and
more efficient, but they still do not
allow for real-time online
measurement. Its not quite PAT yet.
Areas of Improvement
For process development experts to add
the greatest value to process
100 understanding and product quality,
difficulties in implementing analytical
and design tools will need to be
addressed. Most respondents to the
BPI survey agreed that QbD and high-
throughput analytics have been a major
factor in accelerating process and
product development. However, the
expense associated with incorporating
QbD, PAT, and other risk-based tools
in bioprocess can be too much for some
companies. The problem is that QbD
is expensive, especially for small
companies, says Nanda Subbarao
(senior consultant at Biologics
Consulting Group and member of
BPIs editorial board). There are
always at least two groups for every
change in the industry. Large
companies readily embrace new
changes because they have the
resources, the deep pockets, and the
in-house expertise. They want to be
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Figure 4: BPI received nearly 300 responses to its state-of-the-industry survey in AprilMay 2017. Of
respondents who indicated that their work is in process development, here is how they said quality
by design (QbD) has influenced their work.
Percentage of Respondents (%)
70
Agree/Strongly Agree
60
50
40
30
20
10
0 unit operations instead of five or six
Our products are
based on proprietary
platforms, preliminary
characterization is
streamlined.
considered as thought leaders, and
when they develop a product, they fully
well know that they are going to take
that product to market. But there is
another group of companies (small and
medium sized) that are essentially just
trying to get by. They use QbD but
only the principle of it.
We have seen an increasing trend
followed by multiple biopharmaceutical
companies producing a diverse range of
protein products, says Shimoni. They
are tending toward end-to-end
continuous integrated bioproduction,
including downstream processes and
at/online PAT. The inherently smaller
scale of unit operations in some process
phases (notably, in cell culture) also
facilitates recent advancements in single
use and disposable technologies. He
says that improvements are likely to
occur in process development areas
serving both traditional batch (or fed
batch) and continuous processes. One
example is the need for better
understanding of the risk presented by
leachables from the increased use of
single-use systems over prolonged
periods. Downstream processing
technologies also need further
development to allow commercial-scale
use of integrated continuous processes.
Such technologies include capture and
purification systems of products made
using perfusion bioreactors and systems
run by high-capacity yet small-
footprint equipment (2).
Continuous Processing
To implement continuous bioprocessing
successfully, a manufacturer must have
Disagree/Strongly Disagree Neutral
My company My company has QbD has radically
supports training not changed its changed my
in statistics for approach to QbD, departments
evaluating but benefits from approach to
risk assessment. PAT tools. process development.
good process understanding. With that
comes the potential to improve product
quality and reduce variability. It also
allows greater process flexibility to
adjust process parameters according to
need and increases productivity and
efficiency. However, the bioindustry
has been slow to adopt continuous
processing, and manufacturers have
stated concerns such as the lack of
robust analytical technologies and a
lack of easy fit into existing
infrastructure (3).
The key to continuous processing
is that you need to have the
appropriate online measurements
without having to rely on offline
measurements, says Rosenblatt. Ive
seen process development laboratories
achieve continuous processes, but they
still havent figured out how to get it
into the manufacturing plant, and
theyre still working on that. He says
another concept is semicontinuous
processing. Thats what my friend
Mike Ultee would call contiguous
processing. Its where you join discrete
steps together so you have a continuous
flow. The use of perfusion in a
bioreactor process is a great example of
this. The capture step is often linked
to the upstream bioreactor. As the
harvest fluid comes out of the
bioreactor, its being captured and then
pooled for processing further down
that line. Another example is
introduction of pH reduction for viral
inactivation as opposed to using
discrete detergents. Thats very easy to
group with the capture step, which
tends to use low pH for elution. You
8 BioProcess International 15(6)e C hapter 7 of 11 State of the I ndustry 2017
can group upstream, capture, and viral
inactivation using pH as one unit
operation. And you can do similar
groupings with polishing steps by
matching buffer systems without a
diafiltration step or desalting step in
between. Then you can group your
final ultrafiltration system to your
nanofiltration step so your final viral
removal step and your formulation step
are grouped. So now you have three
because you grouped them together.
Those baby steps allow you to move
closer to the idea of a continuous
process from start to finish.
Single-Use Systems
in Process Development
Clearly the adoption of single-use
technologies has had a huge impact on
bioprocessing (Figure 3). Outsourcing
providers that conduct process
development work (see Outsourcing
box) achieve the benefits of using
disposables to meet deadlines and
reduce risk. From a development
standpoint, lets say you are a CMO
[contract manufacturing organization]
or CDMO [contract development and
manufacturing organization] and you
have five different clients with five
early stage products, says Rosenblatt.
If you are using single-use
technology, it accelerates your ability
to turnover from one client to the
other, because now you dont have as
much cleaning to do, and you dont
have as much validation to do right up
front. And the possibility of crossover
between the two products is small. So
for CMOs, single-use systems are
more cost advantageous.
For sponsor companies, the benefits
of using single-use systems depends on
the product. For example, Rosenblatt
says that for a cell line producing
510g/L, a single-use 1,0002,000 L
bioreactor can be used to achieve the
product you need in one or two runs.
But if a cell line produces 12 g/L, it
translates from a capital cost change to
basically a cost-of-goods increase
because now every time you run a
batch, you have to buy a new
bioreactor. But if a company is
processing multiple products to get to
first-in-human studies and preclinical
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as quickly as it can, using single-use
bioreactors works out to your favor
because it can do multiple products in a
much shorter period and have multiple
lines going instead of one.
The use of disposables in
downstream processing depends on
capacity and size. If you need a
15,000-L bioreactor to get enough
materials, then a 2,000-L single-use
bioreactor isnt going to cut it, says
Rosenblatt. The same is true for
downstream columns. Single-use
columns are smaller than reusable
columns, but for early stage
development, you have smaller feed
streams. But when you get into
commercial manufacturing, it starts to
strain the economics a little bit. He
says some CMOs have found one
solution to that by using multiple
bioreactors. There are a couple of
companies putting in what they call six
packs or six 2,000-L bioreactors
running simultaneously. For process
development, you have to think about
all that. Its not like in the past when
the laboratory did benchtop
purification and then threw it over the
wall to the pilot plant to figure out.
The process thats developed up front
10 BioProcess International
right now in most companies has to be
almost good manufacturing practice
(GMP) or nearly clinical-scale ready so
that it can be easily placed in a pilot
plant or GMP facility without a lot of
modification. You design your process
right from the get-go to look like the
final process that youre coming out
with. It never works quite that way, but
process development people have to ask
themselves, How can I create and pass
along a process that has enough of
those questions answered so that the
manufacturing operators dont have to
do experiments at a 2,000-L or a
10,000-L scale? They have to answer
scale-up questions very early.
Process Development Never Ends
Regulatory agencies are encouraging
biomanufacturers to adopt the mindset
of continuous process improvement.
That means theres process
development going on all the time,
says Rosenblatt. Process validation
done only by testing three or four
batches is no longer acceptable thanks
to revised process validation guidelines
from the FDA and European
Medicines Agency (EMA). You do
have to show consistency, but youre
15(6)e C hapter 7 of 11 State of the I ndustry 2017
constantly reassessing your process
through commercial scale. Theres
continuous improvement and
continuous validation going on.
References
1 Shimoni Y. Qualification of Scale-
Down Bioreactors: Validation of Process
Changes in Commercial Production of
Animal-Cell-Derived Products, Part 1
Concept. BioProcess Int. 13(5) 2014: 3845.
2 Zydney AL. Continuous Downstream
Processing for High-Value Biological Products: A
Review. Biotechnol. Bioeng. 113(3) 2016: 465475.
3 Munk M. The Industrys Hesitation to
Adopt Continuous Bioprocessing:
Recommendations for Deciding What, Where,
2017: 1419. c
and When to Implement. BioProcess Int. 25(4)
Disclaimer: Shimoni says his views reflect his
own personal opinion and do not necessarily
reflect the views of Bayer.
Maribel Rios is managing editor of
BioProcess International; mrios@
bioprocessintl.com.
T
To share this article in a PDF or professionally
printed format, contact Rhonda Brown,
rhondab@fosterprinting.com, 1-866-879-9144
x194.
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