November 2009
Cover Story
Biotech breathes new life
Cleaner, longer processes instill new meaning to technical, scientific
relationships
Fast Forward
- Biotech builds new set of challenges, opportunities into
pharmaceutical manufacturing.
- Concepts revolve around cleanliness, unknowns, high stakes.
- Intricate processes key to automation success.
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By Ellen Fussell Policastro
Manufacturing takes on a whole new meaning when speaking of biotechnology; it
is a different game with a new book of rules than traditional pharmaceutical
manufacturing. The key words, such as clean in place, contamination, and
molecules, are entering the family of process analytical technologies and supply
chain strategies—with different challenges and stakes in biotech.
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For biotech contract manufacturing organizations (CMOs), one of the main
challenges is transferring or developing processes for molecules with unknown
quality attributes, said Phillip P. Ropp, section leader in biotech development
at Diosynth Biotechnology, a contract pharmaceutical biotechnology manufacturer
in Research Triangle Park, N.C. “Without knowledge of the molecule’s quality
attributes, the CMO has the unenviable task of attempting to develop a
manufacturing process for a molecule without knowing what the final product
needs to be. Depending on the type or class of molecule and the mode of action,
this may not be a problem, but on other occasions, it can result failure of the
program.”
In a contract manufacturer setting, engineering sees use in disposable
technologies especially in purification, Ropp said. “Upstream cell culture
processes have seen the development of single use/disposable reactors and cell
removal technologies up to the thousand liter scale. Downstream single
use/disposable technologies at a similar scale have thus far been limited to
mixing tanks and tangential flow filtrations,” he said. “Single use/disposable
technologies for chromatography are just beginning to be developed, and the
scale is very limited at this time. In conjunction with the single
use/disposable chromatography systems, higher capacity and higher throughput
chromatography resins are required.”
Process analytical technologies
Process analytical technologies (PAT) are an active concept in the biotech
world as well as the pharmaceutical one, Ropp said. “Upstream fermentation and
cell culture operations have many PAT applications including DO, pH, off gas,
biomass probes, MeOH probes,” and the like. Downstream purification processes
also make use of PAT initiatives such as on-line pH, UV, and conductivity
measurements for chromatography and tangential flow filtrations operations.
“What are lagging are the more product-specific analytical techniques,” he said,
“although some techniques, such as UPLC, are being developed for at-line use as
opposed to in-line applications.”
In the near future, biotech and pharmaceutical manufacturing could be even
more related. “There may be a big drive for the production of bio-betters or
bio-superior type molecules,” Ropp said. These are molecules that have improved
properties over their proven marketed counter parts. Some examples are: Abs
against known targets that have superior binding properties or proven molecules
with improved half lives; engineered animal cell lines that produce more
consistent glycosylation or other post translational modifications of proteins;
glycosylation competent bacterial strains for expression of glycoproteins; and
improved half life of proteins through genetic engineering.
Supply chain strategy differs
In pharmaceutical manufacturing, particularly when you get to high-value
manufacturing, such as biotech drugs, there is a wide range of values per batch.
“It can range from $30,000 to $30 million per batch,” said Justin Neway, chief
science officer at Aegis Analytical Corporation, a provider of products and
services that address quality, compliance, supply chain predictability, and cost
of goods issues confronting life science manufacturers, in Lafayette, Colo. “We
have installations all over that spectrum from low to high. When you’re looking
at a batch worth $30,000, how many batches need to be at risk in order to
justify the expenditure to reduce that risk? You might spend a couple thousand
dollars on a statistics package and scratch your head on whether to hire someone
to do that, depending on the cost of quality. If you’re in a business where
you’re making $30 million batches, you can’t afford to lose one. That batch will
take you several months to make, and you can hire a bunch of people and spend a
lot on technology to avoid that.”
Life science manufacturers rarely know the cost of the batch, Neway said.
“They don’t have ongoing measures of batch cost. The reason is because to them
penetrating a market with a new drug and maintaining a market by excluding
competitors using sales or marketing methods is what they’re used to thinking
about. More and more, they’re having to compete with generics or making the
plant more efficient in order to avoid losing it in a merger.”
Long changeovers in biotech
The reason changing processes in biotech is a long, costly process is the
threat of cross contamination, Neway said. “You run one process in your
facility, and you have to clean out the old product before you can put the new
product in. Testing takes time. There are turnaround times, process
manufacturing, chemistry, physics, and biology on materials,” he said.
In life sciences, because these are life-threatening processes, there is a
high level of rigor, whereas in manufacturing plants, you are doing chemistry
and physics. “Nobody dies when the shade of pink is a little off. You don’t have
to worry about cross contamination,” Neway said. “If you’re making insulin one
day and EPO the next day, your risk of cross contamination or adverse affect of
an outcome has a large consequence. From a supply chain perspective, you need
more agility in changing from one to the other; but if you’re predicting how
many people will have certain disease and will require this drug, if your
numbers are wrong and you suddenly need something else, you need a changeover in
the plant, which is very costly.”
ABOUT THE AUTHOR
Ellen Fussell Policastro is a freelance writer /editor based
in Raleigh, N.C. Her e-mail is elizapolicastro@hotmail.com.
Intricate processes in bio-pharmaceuticals
The intricate and detailed process in biopharmaceutical automation
requires engineers to build a solid understanding of process requirements
as well as the levels of automation before designing a solution. Levels
include:
- Fully manual operation: Manual gauges, and manual valves
- Monitored manual operation: Manual valves, but some recording of
events and data
- Manual operation through a centralized control system: Data
historization
- Small sequence operation: Individual sequences under control
- Batch sequence operation
- Flexible batch operation: Producing many productions with one set of
batch equipment
As you increase levels of automation, you increase complexity, with a
resulting increase in cost and schedule, as well as in requirements for
technical expertise.
Utilities, especially clean utility systems, offer automation
challenges, such as limited access to instrumentation and valves. These
could be hidden behind walls or in ceilings to reduce cleaning
requirements. There is also a high demand for reliability, since many
parts of the process may depend upon the utility. And of course,
cleanliness is of the utmost importance; this means no particulates and
chemical residues.
The clean-in-place (CIP) system is responsible for supplying cleaning
solutions to various parts of the process. This usually includes the
supply of acidic and basic cleaning fluids, high-purity water, and/or
lower purity water.
It is critical to keep all cleaning solutions at appropriate
temperatures and pressures to allow for rigorous cleaning action within
the piping and vessels you are cleaning. The piping may range from small
chemical addition lines to large vessel flow paths. Spray balls can
provide full coverage of vessel internals.
Temperature, pressure, and flow set points could change throughout the
cleaning cycles. Some biological processes may leave proteinaceous
residues. If biotech engineers try to clean these materials with hot
cleaning fluids, they could bake the proteins, leaving a deposit difficult
or impossible for the CIP system to remove.
A typical CIP cleaning cycle may contain a preliminary flush with
water, caustic cleaning, hot water flush, acid flush, and final rinse. You
would apply these steps to each flow path within the equipment you are
cleaning. You may also use them in combination to provide the most
effective cleaning for a system.
Prepare cleaning fluids to appropriate concentrations, store them at
specific conditions, and distribute them as needed to the process. In some
cases, you can recycle cleaning fluids to reduce costs. The return fluid
flows must be balanced with the supply to avoid pooling of fluids at any
point in the process. Proper maintenance of the material mass balance
during the CIP cycle is critical. A balance tank can keep an adequate
supply of materials during the recycle phase.
During system commissioning, it is typical for cleaning development and
cleaning validation activities to rigorously test the operation of the CIP
system, and establish set points for temperatures, flows, pressures,
conductivity/composition, and timers. It is important the automation
system allows for this experimentation during commissioning and then
allows for the user to lock down parameters to be used during routine
production.
Finally, in heavily automated systems, the CIP system may keep track of
equipment status (clean/dirty), acceptable clean hold time, and may be
required to print cleaning reports.
Steam in place
The steam in place (SIP) system is responsible for repeatedly steaming
areas of product contact, including vessels, flow paths, and sample ports,
to reduce the bio-burden on the system or to kill harmful materials at the
end of a batch. A typical SIP system will ensure all steamed have been
exposed to live steam for an adequate time to ensure the kill.
The steam system must be able to measure and control steam temperature,
pressure, and/or flow to ensure adequate steaming. Calculation of Fo or
other measures is often required to meet process needs.
The SIP sequence usually involves path confirmation, purge of
non-condensables, steaming, cool-down, and hold in steamed state.
Temperature measurements are most important in the SIP operation because
they confirm the step’s completion.
Proper placement of temperature measurements is key to the success of
the SIP automation. In addition to temperature measurements in place for
process purposes, the system must measure temperature at all
representative locations, as well as measure and confirm the temperature
at the coldest points of the system being steamed. Consult heavily with
validation, quality, and regulatory personnel to determine the appropriate
number and location of sensors.
To hold costs down and minimize the blockage of small piping,
thermocouples often see use for temperature measurement throughout the SIP
operation. Often the coldest points of measurement are just prior to steam
traps located at the ends of small sample lines or drain lines. These may
be very small diameter tubing, and even a small thermocouple may restrict
steam and condensate flow.
SOURCE: Automation Applications in
Bio-Pharmaceuticals, by George Buckbee, P.E., and Joseph Alford,
Ph.D., P.E., CAP, ISA, 2008. |
Futures in bioengineering
Bioengineering today is driving clinical and economic improvements,
especially in healthcare. The field exists at the interface of the
classical disciplines of science—chemistry, physics, biology,
mathematics—but bioengineering plays a vital role in the future of
biotechnology and medicine. In rubbing shoulders with these old masters in
research labs and R&D departments around the world, it is sparking new
ideas that are shaping the future of healthcare.
Evidence-based medicine
Connecting the disjointed dots of gathering comparative data from
patient outcomes is a critical role for bioengineering, the authors said.
Bioengineering contributes to the development of electronic medical
records to gather these fragmented pieces of information, integrate and
archive them in accessible formats, and layer them in intelligent
analytics to inform decision-making.
Evidence-based protocols are reducing mortality and morbidity rates and
lowering the cost of care in studies at medical institutions of all sizes.
Bioengineering plays another vital role in pulling together data in
today’s disjointed healthcare system. With patient records, test results,
imaging studies, and other vital data points existing in separate silos,
isolated by geographic and digital divides, bioengineering helps gather
data from millions of medical events to make sense of it so evidentiary
medicine can become useful and practical on a larger scale.
Molecular imaging
Bioengineers are instrumental in enabling companies to develop imaging
technologies of increasing performance and diagnostic molecules of
increasing specificity that enable physicians to identify cancer, heart
disease, and other threats early, when treatment options are more
abundant, more effective, and less costly.
Along with genomics and bioinformatics, molecular imaging is one of the
most potent tools in advancing early health. While most traditional
imaging reveals anatomy, molecular imaging provides insight into
physiology or function, where the earliest markers of disease are often
seen. With 70 to 80% of healthcare resources devoted to managing
symptom-based, advanced disease, this shift in resources can help doctors
identify and treat disease before symptoms appear and potentially increase
survival rates and reduce the cost of care.
Healthcare at home
A need for hardcore bioengineering in home health can help millions of
people take greater control of their independence and quality of life.
Hospitals are now specialized centers of acute care, clinics function like
mini walk-in hospitals, and patients are being discharged to nursing and
assisted living facilities and even to their homes sooner, yet they are
still sick and need careful monitoring. As a result, there is a critical
need for patient monitoring platforms functional and adaptable to
non-medical settings and lay users. This means a need for low-cost devices
that are easy to use and able to communicate data to central processing
stations for analysis so appropriate caregivers can be alerted to relevant
changes in patient status.
Cell-based therapy
Since the 1980s, drug therapy has progressed from small molecule drugs
(most of which treat disease symptomatically) to biopharmaceuticals,
antibody, or protein-based drugs, which target the disease pathway. Today,
we anticipate the development of the next generation of biological
therapeutics—cell-based drugs that may embody the cure itself. Biology and
engineering can help develop therapeutics with stem cells, the
flag-bearers for this new class of treatment options, with stunning
potential to repair damage in the body and literally grow a healthy part
to replace a diseased one.
SOURCES: “At the Interface: Where Bioengineers are
Shaping the Future of Medicine,” by Michael J. Harsh, chief technology
officer at GE Healthcare, Healthcare Systems; and Nadeem A. Ishaque,
business programs manager at GE Research Center, GE Healthcare, in
Wauwatosa, Wis. |
Related Files
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