Medical imaging moves to the plant floor
Imaging technologies such as computerized tomography (CT), which won Peter Mansfield and Paul Lauterbur the Nobel Prize for medicine last month, have proven instrumental in diagnosing many illnesses. As pharmaceutical companies refine process analytical technologies (PAT), similar imaging technologies may soon be used routinely to optimize production of the medicines used to treat those ills.
A number of R&D projects are now underway to evaluate medical imaging techniques for pharmaceutical manufacturing "patients." In the U.S., Pfizer Corp. (New York) and the U.S. Food and Drug Administration (FDA) have launched a cooperative research and development agreement (CRADA) that could take near-infrared imaging to the shop floor for formulations development, process scale up, monitoring and control, quality assurance and verification of packaged product.
Where NIR spectroscopy, a well established lab technique, measures a single spectrum of a sample presented to it, NIR imaging takes multiple spectra from discrete points within the sample, providing a spectroscopic map of the sample. "We intend to take imaging based on lab-based spectroscopic techniques and apply it on line, throughout products' lifecycles" says Norman Winskill, vice-president of global manufacturing services at Pfizer. Pfizer and FDA plan to have an experimental NIR unit on line at a pilot plant in New Jersey within the next six months, with commercial instrumentation available within two years.
The CRADA is part of FDA's push to commercialize PAT and update its current good manufacturing practices (cGMP). NIR, like CT scanning, has become established in medicine for studying the brain and other parts of the human body, and analyzing ailments such as tumors.
Pfizer first began to use NIR spectroscopy in its pharmaceutical manufacturing operations back in the 1980s, to monitor and troubleshoot specific reactions. By 1990, the company had formed a dedicated NIR group, and roughly five years ago, began to evaluate mid-IR, acoustic and Raman spectroscopy as well.
One important goal of the CRADA is to automate quality control so that testing occurs during processing, rather than as a separate adjunct to each process step. NIR imaging offers the benefit of being able to analyze all components within a given solid, including active ingredient, lubricant and disintegrant simultaneously. When solids are dissolved in solution to prepare samples for HPLC or other analysis, solid-solid interactions are destroyed or reduced. NIR allows these interactions, instead, to be analyzed, providing much more data on bioavailability, Winskill says. Sample-preparation and laboratory test time also are eliminated.
Last year, at its Brooklyn, N.Y. plant, Pfizer installed a battery-powered, radio-communicating NIR spectrometer to take continuous online readings from a blender. The unit, controlled by a PC in another room, featured a sample-reading head that automatically collected between 200 and 300 milligrams of material from the blender. Readings allowed Pfizer technicians to track not only one, but all ingredients in the blend in real time. The installation achieved in one minute what would otherwise have required taking eight samples and running HPLC analyses on each, to determine product uniformity, explained Steve Hammond, head of the NIR group within Pfizer's global manufacturing services, at FDA's PAT Initiative meeting last year.
The company is also working with Bruker Optics (Billerica, Mass.) and Schleuniger Pharmatron of Switzerland to develop a fully automated, integrated system that would scan tablets directly at the tablet press, testing 300 tablets at a time, rather than the 10 typically tested using conventional methods. In evaluations at a company plant in Australia, the technology was used to trace problems with a specific batch, and ultimately found that a transfer chute was causing segregation in the blend, Hammond explained at the meeting. Traditional testing would have taken much longer to trace the cause of the problem.
Pfizer has worked extensively with other vendors such as Spectral Dimensions (Olney, Md.), and, previously, with academic researchers at London's University College and Imperial College to develop its in-house NIR imaging technology.
Meanwhile, in the U.K., pharmaceutical major GlaxoSmithKline is looking closely at the CT imaging offshoot, electrical resistance tomography (ERT), as a process-development tool. The company discussed its work at the third World Congress on Industrial Process Tomography held in Banff, Alberta, Canada in late September 2003. Leading chemical processing companies, including Johnson Matthey Catalysts and Syngenta, also presented results of applying ERT at the conference.
Based on lab-scale studies, Glaxo concludes that ERT technology can provide the mixing time data needed to characterize reactors and other process vessels more effectively than existing method. The technique can also be used to validate computational fluid dynamic (CFD) models. The company has used ERT online to monitor ethyl acetate hydrolysis, a single-phase process, in a 3.5-l reactor that mimicked pilot-plant equipment and operating conditions as closely as possible. Glaxo is now evaluating ERT on multi-phase systems. Supplying the imaging equipment and know-how for this work is Industrial Tomography Systems (ITS), a company spun off by the University of Manchester's Institute of Science and Technology, U.K., specifically to develop the commercial potential of ERT.
How ERT Works
Glaxo, working with Imperial College London, arranged platinum electrodes symmetrically in planes around the circumference of a model glass reactor. Glass was chosen for its transparency and because it is commonly used to line pilot- and full-scale pharmaceutical manufacturing vessels. Platinum was used because of its high chemical resistance and because its thermal expansion coefficient is close to that of glass.
The 16 electrodes in each plane were repeatedly oven-fired, ensuring minimal protrusion into the process fluid to avoid disturbing the flow. During trials, current applied in a very fast predetermined sequence between the electrodes provided data which, fed through a specially-written algorithm, gave a real-time picture of material distribution in that plane on a computer screen. Using electrodes in several planes offered a 3-D view of the whole reactor (Image). In mixing evaluations, ERT can cover the whole vessel, rather than summing values taken in many different locations, as with other techniques using local conductivity probes.
Monitoring a Reaction
Ethyl acetate hydrolysis was chosen for testing ERT because the hydroxide ions consumed and acetate ions produced during the reaction have very different conductivities, and ERT can track the change. Glaxo compared the ERT results in a stirred tank with a tried-and-tested on-line monitoring technique: Raman spectroscopy. Starting materials and products have different Raman spectra. Trials made allowance for the relative insensitivity of the Raman system and its long spectrum acquisition time, but the graphs of conversion against time for the two systems were virtually identical.
ITS is working to make ERT more flexible, so that users won't have to line electrodes around a vessel and wire them up. Along with the glass-lined reactor manufacturer, Pfaudler, ITS is developing a glass Optomix probe (Photo) that would be placed inside a glass-lined reactor, and would play the same role as a baffle. The Optomix electrodes would perform the same function as those on the circumference of the vessel, but the data-conversion algorithm would take their different geometries into account. The probe promises greater flexibility and could be used in any vessel where two phases, such as solids and liquids, are being mixed or are reacting together.
ITS team members and a laboratory-scale version of the Optomix probe. Photo courtesy of ITS
A Bright Future for Bioseparations
According to October forecasts by Business Communications Co. (BCC), Norwalk. Conn., demand for bioengineered protein drugs will move from nearly $40 billion this year to almost $71 billion by 2008; monoclonal antibody demand will account for most of that growth. Demand for separations technologies in the U.S., meanwhile, should grow from $2.1 billion today to $3.6 billion by 2008. (Bar graph)
Filtration suppliers adapt to bioprocessing needs
Filtration specialists are developing new products, or adapting existing ones to the biotech market, all aiming to allow manufacturers to streamline complex bioprocesses, reduce scale-up costs and simplify regulatory compliance. At September's Biophex/Interphex show in San Jose, Calif., in late September, a number of innovations in disposable single-use filtration systems were showcased by Camarillo, Calif.-based Meissner Filtration Products Inc., Millipore Corp. (Billerica, Mass.) and Pall Corp. of East Hills, N.Y.
Disposable systems simplify biopharmaceutical process validation, because they eliminate the need to validate sterilization and clean-in-place procedures, according to Suraj Baloda, Ph.D., group manager for process microbiology and sterile applications at Millipore. In addition, he says, the systems reduce cleaning downtime, filter assembly and cleaning costs.
By minimizing operator intervention, disposables ensure ultraclean processing. Typically, such systems are presterilized, or, at least presterilizeable via autoclave or gamma irradiation, and many are designed to fit easily into multistage filtration systems. Meissner's UltraCap single-use disposable capsule filter, for example, features a T-style configuration.
Disposable fittings, such as Millipore's Lynx ST, Pall's Kleenpak and St. Paul, Minn.-based Colder Products' Steam-Thru also were showcased. Millipore takes an integrated approach to disposable aseptic fill and finish processing solutions. Its Lynx connector was introduced last July, augmenting a line of disposables including its Opticap filter capsules and SafePass rapid sterile transfer system. Disposable Acerta filling technology is now in advanced beta testing and is expected to be commercially available by the end of this year. Meissner, meanwhile, is focusing on "engineered disposables," customizing disposable filtration systems using UltraCap, which typically features either a SteriLUX polyvinylidene fluoride (PVDF) or a polyethersulfone (PES) membrane.
Membrane filtration suppliers are exploring new bioprocessing markets. Millipore, for example, is developing systems based on its scaleable tangential flow filtration technology (TFF), and integrating TFF with chromatography, virus clearance and sterile filtration for mammalian cell culture, fermentation, plasmid DNA and viral vector-based processes.
Microfiltration systems are being developed to improve virus removal from bioprocess streams. Currently, microfiltration removes viruses effectively, explains Meissner's director of business development, Barry Bardo, but removal typically takes a long time, and requires a large membrane surface area. Meissner currently sells the STyLUX PES membrane, with a high flow rate of 0.04 micronm for virus reduction and is now developing a virus-removal membrane with an even higher flow rate, Bardo says.
Ultrafiltration suppliers, meanwhile, see conjugate vaccine manufacturing as a promising bioprocessing outlet. The technology promises to streamline the 30 or more steps needed to separate and purify the vaccines, according to Ian Sellick, director of product marketing for Pall Biosciences.
Conjugate vaccines require processing a protein portion and a polysaccharide portion, then combining them. Polysaccharides, from the cell wall of the infecting bacteria, when combined with a protein toxoid, help children's immature immune systems recognize and "remember" the required response when exposed to the microbes. Even though conjugate vaccines are widely used in the U.S., expensive manufacturing processes currently limit their distribution worldwide, Sellick says.
One of the most cost-intensive processes is fractionating polysaccharides, or breaking them down into specific size classes so that they can be attached to proteins. Fractionating generally requires size-exclusion chromatography, or staged membrane processing, both of which are expensive and labor-intensive steps. Ultrafiltration offers a simpler, faster method, Sellick says. So far, Pall has developed some cassette holders for semidisposable ultrafiltration membranes, which it also is selling in India and China.
Meanwhile, the PallSep membrane (Photo), based on VSEP technology licensed from New Logic Research, Inc. of Emeryville, Calif., has been tailored to process the plant and animal sources used to manufacture some "transgenic" protein drugs.
PallSep is composed of a sealed stack of flat, circular membrane plates connected by a torsion bar to a seismic mass. A motor applies a controlled torque to the mass so that the membrane stack oscillates at about 60 Hz. This oscillation helps prevent fouling, according to Pall Biosciences' Sellick, since transgenic sources typically contain a high percentage of solids. In competing filtration separation processes, fluid is typically pumped at higher velocities or pressures to prevent fouling. For a typical 400 ft2 installation, Sellick says, PallSep could allow users to save some 30 to 40 percent in capital costs.
Pall is developing a fully enclosed PallSep unit to bring a barrier process to first-stage clarification and recovery, Sellick says, making it easier to meet both FDA and USDA regulations and eliminating workplace odors inherent with some tissue-extraction processes. A disposable cartridge is also being developed for smaller scale units. Several European biotech companies are currently licensing PallSep for transgenic protein drug manufacturing. One biopharmaceutical company has reportedly standardized on PallSep for a new generation of recombinant vaccines.
Research, Training Keep Pace With Puerto Rico's Growing Pharmaceutical Base
Currently 80% of the top-selling drugs in the U.S. are made in Puerto Rico, according to the island commonwealth's industrial development company, PRIDCO. However, that number is soon expected to reach 90%. The island attracted $1.5 billion in biopharmaceutical investments last year, and currently both Abbott Laboratories and Eli Lilly are building major new biotech facilities, expanding existing manufacturing capacity on the island.
New training programs and research facilities will help ensure that the future Puerto Rican pharmaceutical and biotech labor force, some 9,000 science and engineering graduates each year, can meet the challenges of a rapidly expanding manufacturing base. In January, the University of Puerto Rico will begin constructing a Molecular Sciences Complex at its Rio Piedras Campus that is expected to become the island's top research facility. Included will be a laser and spectroscopy facility, biotesting and materials characterization centers, and areas for molecular modelling and computational chemistry.
At its Mayaguez campus, home to the island's Industrial Biotechnology Learning Center (IBLC), the University inaugurated a $350,000 protein spectroscopy laboratory, the first of its kind on the island, last year. GlaxoSmithKline and the National Institute of Health participated in the project, as did scientists from the Mayo Clinic and Northwestern University in the U.S.
At IBLC, Pall Corp. (East Hills, N.Y.) is offering intensive technical training courses focused on enhanced filtration practices during process-scale manufacturing. Students at the Center will attend lectures and receive hands-on training using various types of tangential flow filtration equipment, filtration media and integrity test equipment. "Pall is committed to this emerging market," said Edward Hoare, president of Pall Biopharmaceutical Division, Western Hemisphere. "By sharing our experience and knowledge of process-scale manufacturing, we hope to advance the growth of the Puerto Rican biotechnology community."
The growing biopharmaceutical base adds to a well-established pharmaceutical manufacturing infrastructure that dates back to the 1970s. Currently, the island is home to over 65 pharmaceutical manufacturing plants. Not surprisingly, the Interphex convention is moving to Puerto Rico. Reed Exhibitions will launch its first Interphex on the island on January 29 and 30.
The event will take place at the Caribe Hilton Hotel and Resort in San Juan. Sponsored by the Society for Life Science Professionals (ISPE), the event will feature a number of workshops and showcase new products and services for professionals based on the island, and their peers around the world.
Of particular interest is a conference on Risk-Based Approach to cGMP, to be led by Paul D'Eramo, executive director of Johnson & Johnson, on the 29th. On the 30th, separate programs will focus on packaging issues, enhancing pharmaceutical maintenance, 21 CFR Part 11, and current trends in biotechnology. For more information, visitwww.interphexpuertorico.com.
The following Pharmaceutical Manufacturing advertisers are among companies that will be at the show, exhibiting at the booth numbers indicated:
AES Clean Technology (106), AdvantaPure (119), Allegheny Bradford Corp. (201), AssurX, Inc. (610), DuPont (419), FabTech Inc. (514), Fette America (308), Honeywell (520), IPS (423), ITW Texwipe (400), Rytec Corp. (212), Serail (319), Sparta Systems(311), Stelex (524), Transcat (402), USFilter (203) and Vector Corp. (102)