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Chapter Nine
The Technology
Transfer Perspective
Modern Approaches
and Challenges

Maribel Rios

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

The Technology Transfer

Perspective
Modern Approaches and Challenges

Maribel Rios

T
echnology transfer can occur
during site-to-site transitions,
in-house scale-up, contractual
services, or any combination
thereof. The goal is to have new
processes produce results that are as
close as possible to the originals. The
tools, technologies, and methods used
to conduct technology transfer have
changed over the past couple of
decades. Many of those changes have
resulted from growing markets, an
increase in outsourcing, needs for
process knowledge, and a shift to
digital technologies. Today, both sides
of technology transfer leverage risk ADOBESTOCK (HTTP://STOCK.ADOBE.COM)

assessment/management, due diligence,

and new process analytical strategies to
address potential problems such as
regulatory noncompliance, shrinking
resources, and gaps in process
understanding. To gain some
perspective on the current state of
technology transfer, I spoke to some
professionals with many years of
expertise in the field.
An Evolving Process
Technology transfer itself always has
been part of the bioprocess industry,
but the way it is conducted has
undergone considerable changes. Holly
Prentice (HPrentice Consulting) points
out that technology transfer models
today are more efficient than they were
just 15 years ago: Approaches to
technology transfer were not as well
defined or laid out as they tend to be
today. Platform-based processes have
been a big contributor to those
efficiencies.
Ken Hughes (president of Roker
Biotechnologies and BPI editorial
advisor) agrees: The content of
technology transfer hasnt really
changed all that much; its rather the
nature of the technologies being
transferred. Systems to conduct
technology transfer activities have
become better. If you were doing
diligence for technology transfer in
the past, it would be in a document
room with paper binders that describe
process development and so on. But
with all the advances in electronic
formats, now you have virtual
documentation rooms that are
validated and secure. Fewer huge
teams are flying long distances and
sitting in rooms with hundreds of
binders full of material
One of the most dramatic shifts
over the past 15 years is the movement
away from a stepwise approach or a
one-time event to a lifecycle
approach, says Beth Haas (principal
consultant with Commissioning
Agents, Inc.). Although there are
clear stages that you need to go
through for every technical transfer,
we now overlap them, performing
more activities in parallel with the use
of cross-functional teams.
Evan Shave (Patheon) says that
development sites (usually the sending
site for a technology transfer)
increasingly are adopting operational
excellence (OE) principles (e.g.,
templates, streamlining, waste
reduction, standard work, and
identifying and measuring key
performance indicators). If not
adopting OE in practice, they are at
least familiar with the concepts,
making transfers to manufacturing
sites (already well-versed in OE) more
effective because both parties
understand the OE language and
mindset.

2 BioProcess International 15(6)e C hapter 9 of 11 State of the I ndustry 2017

 Shave says that another shift in
technology transfer has been the
development and implementation of
scalable single-use technologies in
bioprocessing. For development sites,
the opportunity to use scaled down
single-use equipment that is
representative of manufacturing scale
single-use equipment significantly aids
the transfer and scale-up process. And
the availability and adoption of single-
use technologies at good
manufacturing practice (GMP) scale
has made it easier for facilities in
different locations to replicate
equipment and processes, making
transfers of established processes more
successful.
Evan Shave (Patheon) says that
development sites (usually the sending
site for a technology transfer)
increasingly are adopting operational
excellence (OE) principles (e.g.,
templates, streamlining, waste
reduction, standard work, and
identifying and measuring key
performance indiators). If not
adopting OE in practice, they are at
least familiar with the concepts,
making transfers to manufacturing
sites (already well-versed in OE) more
effective because both parties
understand the OE language and
mindset.
Shave says that another shift in
technology transfer has been the
development and implementation of
scalable single-use technologies in
bioprocessing. For development sites,
the opportunity to use scaled down
single-use equipment that is
representative of manufacturing scale
single-use equipment significantly aids
the transfer and scale-up process. And
the availability and adoption of single-
use technologies at good
manufacturing practice (GMP) scale
has made it easier for facilities in
different locations to replicate
equipment and processes, making
transfers of established processes more
successful.
Risk Management
Everyone I spoke with agreed that one
of the major changes in technology
transfer has been the adoption of risk
assessment and risk management and
3 BioProcess International
the associated tools. Such tools include
failure modes and effects analysis
(FMEA), gap analysis, hazard and
operability studies (HAZOP), and
hazard analysis and critical control
points (HACCP). They help
manufacturers evaluate all aspects of
a technology transfer (e.g., procedures,
equipment, facility, documentation)
and provide a clear framework for
making risk-based decisions, says
Shave.
Discussions about risk management
became a major part of technology
transfer around the turn of the
century, but it grew even faster once
the US FDA and other industry
stakeholders started talking about
risk-based processing and as the use of
contract manufacturing organizations
(CMO) increased. In the 1990s,
there was almost no discussion about
risk management. You just sent your
process to a CMO or other company
and hoped that it would work out
well, says Bryan Monroe (founder of
Primus Consulting and BPI editorial
advisor). When it didnt, there was an
opportunity internally to decide whose
fault it was. Now, often before you
even lock down a transfer deal with a
CMO, there is at least some
preliminary discussion of risk
management scenarios. Its been a
positive change for the industry on
both sides.
Hughes says technology transfer
always has been about risk
management, but it is now overtly
discussed and documented, and
objective metrics are more vigorously
applied than before. If you look at the
ISO series, risk management has
become a big focus of what people are
doing now as well as showing that an
a priori discussion of risk has been
appropriately expedited and managed.
This is the case in ISO 9001, ISO
13485, and ISO 15189. The whole
regulatory environment is moving
toward risk management,whether its
through regulatory oversite at the
FDA or control of operations of a
fully integrated QMS. Risk, a priori
risk development, and the involvement
of risk discussions through all levels of
management is more focused
generally. But really thats just
15(6)e C hapter 9 of 11 State of the I ndustry 2017
formalizing what already had to
happen.
When ICH Q9 came out it, there
were many opportunities to use risk
management and risk assessment tools
to prioritize activities and formalize
gap assessments typically done in
technology transfer to ensure
marketing of safe and effective drugs,
says Haas. Clear boundaries on what
is considered acceptable use of risk
assessment tools and where to
incorporate them specifically in
terms risk management lifecycles
are still evolving. People are now
adjusting to the need to do risk
management activities, learning what
the expectations are from regulatory
agencies, and making case-by-case
decisions rather than applying one risk
management tool across the board.
But risk management tools are only as
good as the inputs. You need to pick
the right tool for each case, use cross-
functional teams, and stay open
minded.
Due Diligence
Hand-in-hand with risk managment
activities is due diligence, which has
become increasingly important as the
use of CMOs continues to rise.
Manufacturers can perform due
diligence continuously to identify
gaps. By formalizing gap
identification and quality agreement
requirements, alignment between the
QMS of the market authorization
holders and the CMOs is now a key
element in setting up a technical
transfer, says Haas. Negotiation to
obtain agreement on QMS philosophy
and its implementation for the product
thats been transferred can streamline
a technical transfer and regulatory
approval.
About 25 years ago, all you had to
do was to was call a company and ask
whether they had a slot available, says
Monroe. If they did, then that was
the end of it. Nobody actually saw
anybody face to face. There werent a
lot of choices, and the demand wasnt
so huge that you had to worry about
calendar access. You could do just-in-
time manufacturing. Well you cant do
that anymore. Its much more
structured. Now when companies
oiutosurce, they ask for request for
proposals (RFPs) from different
CMOs for a particular project. The
amount of outsourcing that we do now
has helped in terms of preparing both
sides for what they are looking for. Do
you want to be in our Berkeley or
Copenhagen site? Do you want to be
in Seattle? If location is important,
then it is discussed right away. That
has been a big change, because 2025
years ago that conversation didnt
occur at all or occurred after the fact.
Nobody was thinking that far ahead.
Keeping Pace with Regulations
During the past 1520 years, both
The International Council on
Harmonisation of Technical
Requirements for Pharmaceuticals for
Human Use (ICH) and the US FDA
have made revisions to several
regulations and guidance documents
(see Regulatory Affairs article in this
issue). Such revisions were made to
incorporate knowledge gained and to
align with quality by design (QbD)
and process analytical technology
(PAT) principles. In 2011, the FDA
updated its process validation
guideline that referenced changes in
ICH Q8, Q9, and Q10 as well as the
risk-based approach brought about by
the agencys initiative for current good
manufacturing practices for the 21st
century. But the overall effect these
revisions will have on technology
transfer is still evolving. Industry is
still adjusting to the revisions in ICH
Q8, Q9, Q10, and Q11 and their
effect on the industry overall,
especially the shift in process
validation approaches in which the
three-batch rule is no longer the
standard, says Haas.
Information is invaluable, and the
faster you can realize what data
means, the more advantageous it can
be, says Monroe. He worked at a
company that leveraged a patent
application simply because an assay
that the company conducted was
completed one day before another
company had done it. Its never been
easy to handle a lot of information and
a lot of different kinds of information.
One challenges we have right now is
that small companies may not know
4 BioProcess International
what they should or should not record
in a way that makes a project viable
somewhere down the road. I worked
with a virtual company in the Bay
Area that had some great ideas and
equally solid data but often poorly
captured. When a company was
interested in licensing a particular
program, they often were interested in
data that the inventor company didnt
realize should have been recorded, or
they did an incomplete job of doing
so. Thats where big data is still
struggling. There is no list that says
what you should absolutely capture
without exception and what data are
just nice to have. For every project,
those lists can vary, and the amount of
data can be overwhelming if you cant
manage it.
Process analytical technology
(PAT) was introduced to encourage an
increase in process understanding
through real-time or near-real-time
process analysis, monitoring, and
control. Implementing a PAT strategy
can help minimize variability and
boost product quality. Introducing
PAT into an early stage process can
result in critical quality attributes
(CQAs) being identified and tested
significantly earlier compared with the
traditional approach, says Shave. In
addition, PAT can provide invaluable
data for assessing the impact of
deviations. If QbD strategies have
been used during process
development, then a wealth of data
can be used earlier in the products
lifecycle to set parameter ranges and
criticality rankings.
QbD has a huge potential not only
to formalize process knowledge, but
also to use that knowledge to greater
success in the overall technical transfer
program says Haas. Improved
process understanding can prevent
drug shortages, improve
troubleshooting, and enable a more
consistent process and drug product.
But implementing PAT can be
expensive, especially for small
companies. Moreover, the
biomanufacturing industry is still
struggling with incorporating it at the
full commercial scale. We are still
wrestling with PAT, but that will
pass, says Monroe. We still have a lot
15(6)e C hapter 9 of 11 State of the I ndustry 2017
happening at the process development
level that doesnt have the same degree
of scrutiny. For example, if Im a small
company, Im going to do as little as I
can get away with and still get the
answers Im looking for regarding how
my process is doing. I dont have a lot
money or resources. What often
happens is that youll get processes
that are transferred with very little
depth of analytical information in
certain places in the process that
might be very easy to fill in at the
clinical or commercial scale, but that
takes time and effort. And yet, the
work was never initiated before that
stage, either because of equipment,
personnel or time simply not being
available. Or, more likely, awareness
that it should have been.
However, Monroe is optimistic
that as the industry continues to
mature, fewer of those gaps will cause
difficulties, and manufacturers will be
comfortable incorporating PAT-
inspired capabilities earlier in the
process. Were outsourcing a lot
more, but were also aggressive about
certain cost-cutting strategies. PAT
and process understanding fall into
that kind of learning. As weve
become familiar with what were
trying to do, how were trying to do it
is changing every day.
Elements of Success
Those who have conducted technology
transfers for many years have some
advice about the key points for success.
I see some differences between the
technical transfer of small-molecule
and large-molecule processes, says
Haas. For the latter, technical transfer
is not nearly as well defined in terms of
a formal system for knowledge transfer
and risk assessment involving project
management and project engineering
as key elements of the overall planning.
People are looking for guidance in that
area, particularly small companies. A
formal system allows critical risks to be
continually reassessed throughout a
tech transfer ensuring the assumptions
are still valid and the timeline has not
been affected.
Establishing business and
regulatory strategies and continually
assessing those against the goal for a
technology transfer are also key, says
Haas. Other key requirements include
risk management, early project
management and process involvement,
QMS alignment, and supply chain
mapping. A solid program for your
knowledge transfer is required to
ensure successful plant readiness,
process qualification, and the transfer
to commercial production.
Effective communication and
planning are key, including a review of
all information by both sides of a
transfer and not owned primarily by
one side, says Prentice. Lack of
alignment can arise between both
sides, creating conflicts in objectives.
Thats a common source of problems.
Shave agrees that communication
and understanding key drivers and risk
appetite are essential to a successful
technology transfer. When a CMO
transfers in a process from an external
client, it is imperative that the key
drivers and risk appetite of that client
are understood. The receiving site
must be adaptable and able to adjust
its service level to the clients changing
requirements.
He adds that flexibility through
process knowledge also is important.
It is essential that technology transfer
teams have sufficient process
knowledge to allow them to know
where in the process they can be
flexible in regard to equipment
configurations or process parameters
without compromising the product or
overall process. For example, such
knowledge may allow a receiving site
to justify fitting a new process into
existing equipment (which may be
slightly different compared with the
equipment at the sending site), thereby
reducing the need for expensive capital
equipment purchases.
Shave also says technology transfer
should include accurate and detailed
scheduling of project team resources
and key project milestones. Scheduling
using visual tools such as Gantt charts
are key for technology transfer project
managers. When effective schedules
are generated, timeline delays and the
ensuing fire-fighting can be
minimized.
Hughes says its important to have
skilled people at both ends of a
5 BioProcess International
technology transfer, especially those
who understand the nuances of
technology involved and experience.
That hasnt changed. Have as much
disclosure and open dialogue as you
possibly can. The best technology
transfers Ive been involved with are
with people who discuss openly and
freely what were trying to achieve.
Other than that, a focus on the quality
system is key. Im a hardcore believer
that quality assurance and R&D
should be closely aligned. And that
speaks to the cost of nonconformance
that we all know about. If quality
assurance (QA), process development,
and R&D are closely aligned, then
you will have a good experience on
both ends of the transfer. People are
going to understand not only what
youre doing and why youre doing it,
but also the difficulties associated
with implementing it.
Monroe believes that the capture of
information, regardless of how
infinitesimally small it may seem at the
time, is key to a successful technology
transfer. You need good data
management systems, such as excellent
laboratory notebook record-keeping or
whatever the system may be. I dont
think the value of that can be
underestimated because you dont know
what might be important in 10 years.
Opportunities Ahead
Although technology transfer always
has been part of the bioprocess
industry, some essentials still can be
forgotten. One element that often is
overlooked is the willingness to
incorporate new technology into a
process when it is transferred to a
different facility or when the scale
changes, says Shave. Manufacturers
should evaluate the significance of a
change and its effect on critical quality
attributes (CQAs). Doing so can be a
good opportunity to make a process
more efficient or lower the cost of
goods.
Shave also emphasizes the
importance of understanding cultural
and language differences between
sending and receiving sites.
Technology transfer can take place
between companies located thousands
of miles apart. Even within a
15(6)e C hapter 9 of 11 State of the I ndustry 2017
companys own network, it is
important to understand and
acknowledge cultural differences
before the initiation of technology
transfer activities to prevent
misunderstanding and frustration
between sending and receiving sites.
Finally, Haas believes that
technology transfer faces some unique
challenges moving forward, especially
as the number of emerging therapies
continue to move along the
development pipeline. Tech transfer
requirements for combination drug
products, cell and gene therapies, and
online patient monitoring are clear cut.
We will have to see how they fit with
existing regulations and what kinds of
changes theyre going to make in the
regulations. New technologies such as
spray drying and 3D printing and the
shift to specialty drugs and
individualized medicine will require
flexible manufacturing and increased
automation and process control.
The continuing evolution in how
technology transfer is conducted along
with increased process analytics and
regulatory revisions undoubtedly will
change the landscape of how processes
are transferred. It will be interesting to
see how technology transfer will be
defined and conducted in the future for
these emerging therapies, says Haas.
But I feel encouraged by recent
regulatory harmonization activities,
and I hope those will continue. Product
globalization and the increase in the
number of virtual companies also will
present challenges. For such
companies, supply chain and
distribution are much bigger parts of
technology transfer project
management, making transportation,
serialization, and the complexity of
data management to play much larger
roles in tech transfer than in the past.
Maribel Rios is managing editor of
BioProcess International; mrios@
bioprocessintl.com.
This is an extended version of the article
published in BPIs June 2017 print issue.
To share this article in a PDF or professionally
printed format, contact Rhonda Brown,
rhondab@fosterprinting.com, 1-866-879-9144
x194.