November 2009
Cover Story
Biotech breathes new life
Cleaner, longer processes instill new meaning to technical, scientific relationships
Fast Forward
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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.
RESOURCES
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Intricate processes in bio-pharmaceuticalsThe 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:
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 bioengineeringBioengineering 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. |
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