Robotic arms. Gloveless isolators. Manufacturing pods.
Process modeling. Big data. Automation.
Welcome to the future—or “next generation”—of pharmaceutical manufacturing,
“Industry 4.0.” Pharmaceutical manufacturing is on the precipice
of a paradigm change, particularly when it comes to biologic
products. As biologic lots become more and more specific,
some even personalized for individual patients, the need
for flexible, high-tech manufacturing equipment and
solutions becomes critical.
Yet when a biologics manufacturer decides to employ
these next generation technologies, serious
practical considerations emerge around finances,
training, and implementation. Barry Starkman,
Principal Consultant, Parenteral Manufacturing,
DPS Engineering, and Mike Vandiver, Vice
President, Manufacturing and Plant Design, Just
Biotherapeutics, are both well aware of the heavy
decisions involved in putting these new technologies to
work. They will share their experiences at the 2017 PDA
Annual Meeting (Plenary 3: “Next Generation Manufacturing
& Facilities,” April 4, 8:30 a.m.).
In theory, next generation manufacturing should require
less capital investment than conventional facilities. Still,
cost does factor in when installing and implementing
new technologies. Yet some companies have found
ways to successfully manage these expenses.
“I think that the big issue is around investment,”
explained Starkman. “The cost for putting in a filling
line, once you’ve made the decision to do that, is pretty
steep.” For this reason, he explained, some biologics
manufacturers are using their clinical manufacturing
facilities to launch. This enables the company to
gauge how well the product performs on the market
before committing to invest in flexible manufacturing
Vandiver believes that the production of innovative biologics
necessitates flexible manufacturing.
“In the past, to very successfully supply the world with biotherapeutics
required a huge investment and substantial fixed assets,”
he said, adding, “in the future, the primary characteristic of next
generation biologics manufacturing is flexibility. The key tenets supporting
flexibility are speed and cost-effectiveness.”
Starkman, who handles the conceptual design of facilities for DPS
Engineering’s clients, also pointed out that companies that have
invested significantly in the research and development of a new
biologic product may be gun-shy about taking the risk when there are
major obstacles to overcome in getting the product on the market in
a timely manner. Particularly when one of those hurdles is fitting next
generation manufacturing technologies in with existing regulations.
“At some level, as you’re moving technology [ahead], somebody
has to be first, and then you run the risk of a regulator either not
understanding or not agreeing,” he said. “And when you have large
sums of money on the line, both in terms of investment and in
research and development as well as the capital equipment…it becomes
quite easy to say ‘you know, let’s just go with what we know.’
“That’s a very difficult decision for the owner to make, to go forward
with something totally new. I’m not sure how to overcome
that in total. Other than the fact that more work may need to be
done with prototypical process design.”
In addition, Vandiver noted that certain products may be
produced using legacy systems for a variety of reasons. Moving
existing products to new production technologies would require
a large investment in clinical trials to establish comparability,
something many companies may not be able to do.
“When you look at these [legacy] systems, people have invested
hundreds of millions of dollars in a facility such as this. And for
them, it may not necessarily make sense to invest in one of these
other types of facilities,” he said. “They made such a large investment;
they want to make sure it’s fully depreciated. And, if I were
in their shoes, I would believe the same thing.”
Maik Jornitz, CEO, G-Con Manufacturing, and moderator of
the Annual Meeting session featuring Starkman and Vandiver,
sees the key performance factors behind next generation manufacturing
as flexibility, speed and cost.
“Flexibility is required to be able to act rapidly on changing environments,
but also to be able to manufacture multiple products
within the same facility. Speed, another key aspect, means the
time-to-run frame needs to be lowered to less than a year instead
of the [current] three to four years,” he said. “Cost, the third element,
should be [seen] as total cost of ownership and not in the
legacy approach of cost per square foot.”
Just Biotherapeutics is designing and building a small, efficient biologics
manufacturing facility, named “J.Pod,” that Vandiver believes will
drive down capital investment and the cost of goods. He sees J.Pod as
complementary to existing conventional production facilities.
“I want to be very clear. I am not actually advocating that these
new types of flexible facilities actually replace conventional
facilities,” he emphasized. “I believe they complement existing
conventional production facilities,” explaining that, if you need
multimetric tons of product, it would not make sense to invest
in a J.Pod facility. But it would be suitable for moderate-scale
production, up to a metric ton.
Just Biotherapeutics starts by using modeling of the process technologies
under consideration in order to identify bottlenecks and
prioritize technologies on which to focus attention.
“We actually use modeling first,” Vandiver explained. “We start
by modeling mass throughput and investigating options. We then
model the economics around these options, in terms of cost of
goods.” This allows his company to determine the impact of volumetric
productivity and its role in reducing the cost of goods.
“Let’s just say that my initial market only requires two bioreactors.
Based on the volumetric productivities, our cost per gram is
potentially going to be something around $100–$150 a gram. As
we then require more capacity, our markets increase, our demands
increase. We can increase to four to six bioreactors very quickly and very cost-effectively. And we actually
see the potential to lower the cost per
gram to the $40–$60 range, so what we’re
seeing, then, is about a three-fold reduction
in the cost of goods.”
Yet, while the regulatory concerns of
migrating to new technologies remain,
both Starkman and Vandiver stressed that
regulatory agencies, such as the US FDA,
understand the need for innovative manufacturing
“I think there’s been a step change,” Starkman
said. “There is more of an openness.”
From what he’s seen with his clients, the
key to receiving regulatory approval when
implementing new technologies lies in
truly understanding the manufacturing
processes of the new equipment and effectively
communicating this to regulators.
Risk assessments, in particular, have
proven to be an effective tool.
“Certainly, FDA has moved toward new
technologies as an organization because
they see the value in it. It’s still in its early
stages but I think it’s in the right direction,
for sure,” Starkman said.
Vandiver agrees that the Agency is supporting
new technologies, especially
disposable technologies, which are becoming
the standard in the industry over
In fact, he pointed to a recent survey from
BioPharma-Reporter showing that “70% of
the respondents actually agree that disposable
technologies are becoming standard,
and it shows that the regulatory agencies
are supporting this as well.”
New Training for New Tech
When a biologics manufacturer makes the
decision to implement next generation
technologies, training is just as critical, if not more so, as it is when implementing
Starkman explained that training becomes
particularly pertinent when working with
automation, which requires a different
level of understanding. A worker on the
production line must understand “how
it feels to control the equipment, [as] the
days of just being able to turn a wrench
and being able to set up a machine like
that are somewhat diminished.”
With these new technologies, operators
are responsible not just for running it,
but for setup, preventative maintenance
and understanding how it operates.
Vendors do a “great job” of designing the
equipment and developing innovative
improvements. Yet at the end of the day,
“they don’t stay and run the machine; they
disappear after the machine is on the floor
producing every day.”
When building a line, DPS Engineering
brings the workers who will be responsible
for the line into the design process, including
taking operators to specialized training
at a site in Germany. This ensures the workers
understand upfront how the machine
works, moving up the learning curve, and
fostering commitment on both sides.
“You need to have that kind of commitment
in the parenteral drug business
because the criticality of what we’re doing
is so important,” Starkman explained.
“Building that relationship among all the
parties involved is very important, and it
starts at the very beginning.”
Just Biotherapeutics will also develop
internal training programs to prepare the
staff, mitigating risk.
“We are creating internal training programs
that bring people up to speed and prepare
them for these new types of operations,” he said. His company approaches it more as
expanding skill sets rather than replacing
old ones. This makes the employees more
flexible, enabling them to work in different
types of facilities—a highly desirable trait.
And Vandiver has found that Just’s staff
is receptive to learning to work with new
types of equipment. “For them, it’s exciting;
it’s new. They’re not doing the same
thing that they’ve done for the past 10 or
15 years,” he said. “They’re being exposed
to new ways of doing things. They have
actually embraced the change.”
Starkman agrees that workers have generally
been receptive to learning new skills.
“I think that people love the technology.
They love the sophistication of it. They
love the ability to learn new things.”
And while operator skill sets are changing,
one thing is staying the same: the human
element. At least for the time being.
In his personal time, Starkman is a pilot
and enjoys flying. He finds aerospace automation
analogous to biotech automation.
“Flying airplanes years ago was a very
‘seat-of-the-pants’ type of operation. You
flew an airplane by feel...today’s airplanes
are very automated. Everything is digital,”
he said. “There is a tendency for pilots to
get overly reliant on the automation of the
airplane—to just let it go—and they’re
not paying attention. There have been a
number of serious situations that have
occurred as a result.”
To prevent overreliance on automation,
Starkman recommends better understanding
of the manufacturing process itself. This
builds an “envelope” of understanding.
“We can build in controls with the right
sensors,” he said, and by “understanding
the process, understanding the risks of
the process very well, the machine can, in
effect, monitor itself at some levels better
than a human can. But I don’t think you
will ever get away from [a human presence]
in such a critical scenario like making
parenteral drugs. I think the human
factor is always going to be there.”
In the end, no matter what types of next-generation manufacturing technologies are implemented, multiple
factors need be taken into consideration. Such firms might
consider taking into account the specific needs of the product and
the market demands.
Jornitz urges companies to look into next generation manufacturing
to avoid being left behind.
“The early adopters are already out front,” he said. “The most
radical change that has to happen is in the attitude and thought
process within the industry.”