By Carrie Meadows

In July, ATMI, Inc. (Danbury, CT) announced the launch of four High Productivity Development Centers in the United States and Asia, which the materials, process, and handling company plans to utilize to support customers integrating new semiconductor development and manufacturing processes.

At centers located in Connecticut, California, Taiwan, and Japan, ATMI personnel conduct experiments designed in collaboration with customers that can evaluate up to 192 different test chemistries at once, using fewer wafer materials.

By making it possible to assess large numbers of precisely varied chemical formulations concurrently, the technology generates large amounts of meaningful data in a very short period of time, explains Doug Neugold, CEO of ATMI.

“New materials are being introduced into manufacturing processes at an unprecedented pace

October 21, 2008

Dedicated equipment, minimal operator intervention, and single-use technologies are just a few keys to success in the aseptic processing of biopharmaceuticals.

By Bruce Flickinger

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Although biological products and their potential contaminants are fickle entities, the manufacture of sterile biopharmaceuticals has matured into a well-characterized, industrialized endeavor. Much of the uncertainty is gone, the constraints and opportunities are largely understood, and incidents of compromised products reaching consumers are relatively rare. These facts speak volumes about the technologies, training, processes, and ongoing research involved in bringing aseptically processed drug products to market

Ultra-trace bulk analysis of polysilicon helps meet production demands for high-purity silicon in solar-cell market

By J.D. Robertson, M.D. Glascock, and H. Newcomb, University of Missouri Research Reactor Center

The rapid growth in solar cell production has fueled demand for high-purity silicon. About 90 percent of the current solar cell market is based on solar cells using silicon, and the majority of the raw material for the process is derived from polycrystalline silicon. The demand for polysilicon from the solar industry is growing at up to 40 percent annually and it is anticipated that the use of polysilicon for solar cells will be three to four times that of the semiconductor industry in about 10 years.1 The projected global demands for polysilicon are such that the two largest polysilicon producers have announced plans to increase their production capacities to more than 58,000 metric tons in the next three years, and several other companies, with no prior polysilicon experience, are constructing facilities to enter the market.¹

Although the purity requirements of silicon for solar cells (five to seven 9s) are lower than those for semiconductors (nine 9s), the power conversion efficiency of solar cells is largely dependent on impurity levels in the silicon raw materials. Measurement of element concentrations in the polysilicon raw material and the process wafers is therefore essential as new polysilicon production technologies are developed to lower solar-cell production costs and for the maintenance of quality control during the manufacturing of solar cells. The quality control of the polysilicon is especially important as new producers of this high-purity material enter the market. Since it was first applied in 1960 for the analysis of tantalum,² instrumental neutron activation analysis (INAA) continues to be one of the most sensitive and accurate techniques for meeting industries’ needs for the trace element analysis of high-purity silicon. In keeping with the industry expansion, the demand for INAA of high-purity silicon at the University of Missouri Research Reactor Center (MURR) has more than doubled over the last three years. This article presents a brief overview of INAA of high-purity silicon.

INAA technique

The idea of using neutrons as an analytical probe for elemental analysis was first proposed and demonstrated by Von Hevesy and Levi for the analysis of trace quantities of rare earths in geological materials in 1936. Since then, the sensitivity, selectivity, and precision of INAA have made it a versatile and widely employed elemental analysis techniques. Because most materials are “transparent” to both the probe (neutrons) and the signal (gamma rays), there are few matrix effects associated with the analysis, and standardization of the measurement is simple and straightforward. Moreover, because little, if any, sample manipulation is required, INAA is a highly sensitive technique that can be applied to bulk samples and is relatively free of reagent and laboratory contamination.

In INAA, stable nuclei in the sample undergo neutron-induced nuclear reactions when the sample is exposed to a flux of neutrons. The most common neutron reaction is neutron capture by a stable nucleus (^AZ) that produces a radioactive nucleus (^A+1Z). The “neutron-rich” radioactive nucleus then decays, with a unique half-life, by the emission of a beta particle. In the vast majority of cases, gamma rays are also emitted in the beta decay process and a high-resolution gamma-ray spectrometer is used to detect these “delayed” gamma rays from the artificially induced radioactivity in the sample for both qualitative and quantitative analysis. A schematic illustration of the neutron capture INAA process is given in Fig. 1.

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The energies of the delayed gamma rays are used to determine which elements are present in the sample, and the number of gamma rays of a specific energy is used to determine the amount of an element in the sample. For example, when a sample that contains iron is irradiated, a fraction of the ⁵⁸Fe atoms in the sample will capture a thermal (or low energy) neutron and become ⁵⁹Fe. The ⁵⁹Fe atoms are radioactive and have a half-life of 44.5 days. When the ⁵⁹Fe atoms beta decay to ⁵⁹Co, a 1,099-keV gamma ray is emitted 56 percent of the time. The amount of iron in the original sample can be determined by measuring the number of 1,099-keV gamma rays emitted from the sample in a given time interval after the sample has been exposed to a flux of neutrons. A description of the procedures used to quantify an analyte in INAA is beyond the scope of this article. The physical principles of the analysis are so well understood that neutron activation analysis is one of the primary techniques used by the National Institute of Standards and Technology (NIST) to certify the concentration of elements in standard reference materials.

Although there are few matrix effects in INAA, direct and indirect interferences are possible. A direct interference occurs when the radioactive species or gamma ray of interest is produced by multiple nuclear reactions. For example, measurement of ²⁸Al that is produced by thermal neutron capture on ²⁷Al is frequently used to quantify trace amounts of aluminum in a sample. However, in polysilicon, ²⁸Al is also produced in significant quantities through a high-energy neutron absorption reaction followed by proton emission on ²⁸Si. To quantify aluminum in a high silicon matrix, one must account for the alternate production of ²⁸Al by this reaction. A direct interference can also occur when the same energy gamma ray is emitted by two different isotopes. This spectral interference can be easily accounted for by the difference in half lives between the two isotopes and/or by monitoring multiple gamma rays from each isotope. An indirect interference occurs when the activity generated by a dominant species in the sample impacts the signal-to-noise ratio of the analyte of interest by changing the background in the gamma ray spectrum. A detailed description of how direct and indirect interferences are resolved in the application of INAA to solar-grade silicon can be found in an article by Revel et al.³

Figure 2. Silicon samples for irradiation. Photo courtesy of University of Missouri Research Reactor Center.Click here to enlarge image

Scientists at MURR have been performing trace element INAA of silicon samples for more than 30 years. A complete description of our analytical protocol can be found in an article by Herrera et al.⁴ The most common samples are semiconductor silicon, polished wafers, ingot chunks, polysilicon blocks, and polysilicon beads. Samples with masses typically ranging from 10 to 80 g are loaded into individual graphite containers (Fig. 2). These containers are then bundled and placed in a reactor irradiation position where the samples are exposed to a neutron flux for 54 hours. After a decay period of 48 hours, the samples are either cleaned with deionized water in an ultrasonic bath or subjected to a mild or harsh etching procedure. The mild etch is used when a light surface cleaning of the sample is required by the client, and the harsh etch procedure is employed when the client requests that the entire sample surface be removed. After the cleaning/etching procedure, the samples are dried, weighed, placed in plastic containers, and counted on low-background, high-resolution gamma-ray spectrometers. Two counts are performed on each sample. The first 30-minute count is performed immediately after the cleaning/etching and is used to measure radionuclides having half-lives in the range of 12 to 48 hours. The second six-hour count is performed after a minimum decay of 14 days and is used to measure the longer-lived radionuclides. The sensitivities able to be obtained for 40 elements in high-purity silicon using INAA at MURR are given in the table.

Table 1: INAA limits of detection for high-purity silicon Click here to enlarge image

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Advantages and disadvantages of INAA

The major advantage of INAA is that it provides accurate results for large, bulk samples (tens of grams) without having to dissolve or digest the sample. Moreover, by employing an appropriate surface etch procedure, it is possible to ensure that the trace elements observed in the INAA measurement are coming from the bulk material and are not a result of surface contamination at the production facility or in the analytical lab

The inherent cleanliness and properties of stainless steel enhanced by preparation processes make it the material of choice for critical applications

By Ken Sullivan, PB Power

Stainless steel has historically been the material of choice for the pharmaceutical industry due to its unique metallurgical composition, which is inherently hygienic and chemically resistant. The objective of this article will be to review pharmaceutical quality requirements and examine some of stainless steel’s intrinsic properties and the benefits that make this material well suited for pharmaceutical water systems. The focus will be on 304, 316, and 316L AISI stainless-steel pipes as they apply to high-purity (HP) water systems used for critical applications.

Pharmaceutical water is one of the most important of all pharmaceutical utilities and is an essential component in most pharmaceutical processes, used in preparations, products, processing, and cleaning.

There are two basic grades of pharmaceutical water commonly used: purified water (USP) and water for injection (WFI), which is the most purified water. USP water is used in the preparation of non-sterile products and as feed water in the preparation of WFI and pharmaceutical-grade pure steam; it cannot be used for preparations intended for injections. It is also used for rinsing purposes (cleaning of containers) and for preparing cleaning solutions. WFI is used to dissolve or dilute other drugs, which may be delivered intravenously. The primary difference between these grades is the absence of bacterial endotoxin requirements for USP water, degree of system control, and final purification techniques for bacterial removal. Water quality standards for USP water have been established by a number of professional organizations. The standards that the pharmaceutical industry must comply with are the United States Pharmacopeia (USP), the official public standards-setting authority for all prescription and over-the-counter medicines, dietary supplements, and other health-care products manufactured and sold in the United States.

All in the family

In metallurgy, stainless steel is defined as an iron-carbon alloy with a minimum of 10 percent chromium by weight.1 It is the addition of chromium that gives stainless steel excellent resistance to corrosion and good strength at high temperature and pressure. The three main classes of stainless steels, designated in accordance with their metallurgical structure, include martensitic, ferritic, and austenitic; however, all are not suitable for pharmaceutical-grade water systems.

The austenitic family of stainless-steel alloys includes more than 70 percent of the total stainless-steel production. It generally has much greater toughness than the ferritic type, such as the 400 series, which cannot be hardened by heat treatment. While martensitic types are not as corrosion resistant as the other two grades, they are extremely durable as well as highly machinable and can be hardened by heat treatment. Because austenitic stainless-steel pipes are excellent in terms of mechanical strength and abrasion and heat resistance, they are the preferred choice for pharmaceutical water systems.

The 300 series of austenitic stainless steels is an iron-based, low-carbon alloy that is non-magnetic and owes its very high corrosion resistance to its chromium content. Nickel is required to stabilize the austenite, which forms at elevated temperatures so that it can be retained when cooled to room temperature. The basic composition of the 300 series is 18 percent chromium, 8 percent nickel alloy, and 0.10 percent carbon (commonly known as 18/8 stainless). The nickel and chromium content can be increased to improve corrosion resistance; in addition manganese, nitrogen, and molybdenum can also be added to further enhance the corrosion resistance properties. A lower carbon content reduces carbide precipitation during welding.

These steels cannot be hardened by heat treatment although cold work will cause an increase in both hardness and strength. After cold working, the material is annealed to preserve the structural integrity. Also, if any carbon precipitate occurs while slow cooling (sensitization) from a high temperature, they may be reheated and quenched to re-dissolve the carbon and keep it in solution. These steels exhibit excellent structural integrity and thermal stability.

The 300 Series consists of the following types of austenitic chromium-nickel alloys:

• Type 304 is also known as “surgical stainless steel.” The most common grade is the classic 18/8 stainless steel with excellent strength, formability, fabricability, and ductility. 304 stainless steel is typically used in brewery, dairy, food, and pharmaceutical production equipment applications. 304 costs less than 316 stainless steel.
• Type 304L is similar to 304 grade but specially modified for welding and fabricability.
• Type 316 contains molybdenum and a higher nickel content (10 percent) than 304. Molybdenum, in conjunction with chromium, provides superior resistance to attack by most chemicals and an increased resistance to chloride corrosion compared to type 304. The additional nickel content aids in repassivation of the passive layer in case of damage.
• Type 316L is the most common material used in the pharmaceutical industry. The corrosion resistance of 316L is the same as standard 316. However, low-carbon “L” grade is used to avoid possible sensitization corrosion in welding.

The phenomenon of passivity

Historically, pharmaceutical companies have chosen high-polished stainless-steel for pure water piping systems because of its inherent hygienic properties that render it non-reactive, non-additive, non-absorptive and non-corrosive (see Fig. 1). Their goal is to choose a material that will not release contaminants and thus lower the water purity. The way stainless steel achieves this is the chromium content of the steel combines with oxygen in the atmosphere to form a thin, invisible film of chrome-containing oxide, called the passive layer. The sizes of the chromium atoms and their oxides are similar, so they pack tightly together on the surface of the metal, forming a stable layer only a few atoms thick.

Figure 1. Pharmaceutical companies have typically chosen high-polished stainless-steel for pure water piping systems because of its inherent hygienic properties that render it non-reactive, non-additive, non-absorptive, and non-corrosive. Photo courtesy of Plymouth Tube Co.Click here to enlarge image

The protective layer is too thin to be visible, meaning the surface appears glossy. If the metal is cut or scratched and the passive film is disrupted, more oxide will quickly form and recover the exposed surface, protecting it from oxidation corrosion. This phenomenon is called passivation by materials scientists and is similar to the oxide layer on aluminum. However, high steam velocities, vibration, and thermal shock all can have adverse effects on the film’s continuity.

Corrosion resistance

Corrosion is a primary concern for HP water systems because its presence contaminates the water quality. That is why stainless steel is used more often in place of other available materials. Because pharmaceutical water is so pure, deionized or “ion hungry,” a concentration gradient is established between the de-mineralized water and the stainless steel with only the passive layer preventing the diffusion or leaching of minerals (free iron) from the pipe into the water. This contamination could be potentially dangerous to the process or the final product. The types of corrosion that can occur include general, concentration cell (crevice), pitting, intergranular, stress, de-alloying, erosion, and microbial-induced corrosion.

Stainless steels perform best under fully aerated or oxidizing conditions, which enhance the passive layer. The lower alloyed grades of stainless steel resist corrosion in atmospheric and pure water environments, while high-alloyed grades can resist corrosion in most acids, alkaline solutions, and chlorine-bearing environments, properties which are utilized in the process industries. Fortunately, the corrosion-resistant properties of stainless steel can be further enhanced to meet the requirements of the pharmaceutical industry by increasing the chromium content and the addition of other elements such as molybdenum, nickel, and nitrogen.

Stainless-steel piping is susceptible to “rouging,” an extremely fine rust that produces a red/brown discoloration on the internal, wetted surfaces of the pipe, which results from the aggressive action of hot (typically above 65°C) pure water on the ferrite content of the stainless steel, breaking it down. This condition is typical for hot/purified/WFI/clean-in-place systems where less dissolved air is carried by the water. For rouging to occur, it may be assumed that either the protective chromium oxide layer has either not been established or that it may have been disrupted. Water systems that operate at ambient temperatures do not typically exhibit any rouge formation in their lifetime.

Hygiene

The easy cleaning ability of stainless steel makes it the first choice for strict hygiene conditions. Keeping the alloy surface clean and free from contamination helps eliminate concentration cells that might cause pitting.

Organisms exist in water systems either as free floating or attached to the walls of the pipe where they can grow in the rough pipe surfaces or crevices. When they attach themselves to the pipe walls they are known as biofilm. The pipe surface finish is often cited as one of the critical factors in the proliferation of bacteria colonies; the smoother the finish is, the more difficult it is for biofilm to attach to the pipe’s internal surface. Hygienic design factors such as maintaining a constant turbulent (3 to 5 ft/s) flow, smooth pipe-joining methods, and minimizing deadlegs and air pockets will all reduce the risk associated with bacterial growth and contamination.

The presence of biofilm on the pipe surface leads to microbially induced corrosion (MIC) and occurs when microbes create colonies and remove pipe material, forming deep pits with small pinhole openings on the interior of the pipe. Microbial contamination can result in the loss of millions of dollars in pharmaceutical products.

Finish

The corrosion resistance of the stainless steel is affected by the roughness of the pipe surface. Roughness average (Ra) indicates the average distance between the microscopic peaks and valleys on the surface of the stainless steel: the lower the value, the smoother the finish.

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There are two surface finish conditions used for these systems: mechanical polishing and electropolishing. Mechanically polished surfaces retain the basic alloy composition with only slight depletion of the other alloy elements, whereas electropolished surfaces contain essentially only chromium and iron.

In a mechanical polishing process, the internal diameter of the tube is polished by a number of progressively finer abrasives passed through the tube via a pneumatic bellows. For the initial pass a coarse grit is used to remove surface imperfections such as weld splatter and slag formations. Finer grits are used for the final passes to enhance the finish.

The surface irregularities of stainless steel can be improved by electropolishing, which is an electrochemical method of polishing stainless steel in which surface iron is removed by anodic dissolution, a chemical reaction that removes surface metal, more simply electroplating in reverse. By removing these peaks and surface contaminates, electropolishing will improve and smooth the surface finish and restore the passive layer.

Electropolishing is required for the pharmaceutical industry because surface smoothness, with fewer sites for trapping impurities, means a purer product without the danger of bacteria growing in surface defects. Oxygen is a critical component in creating the special properties of electropolished surfaces, both to increase the depth of the passive layer and to produce a true passive layer (see Fig. 2).

The rougher the pipe surface, the easier it is for bacteria to adhere to it and resist flushing; a smoother finish allows for easier sanitization. A smooth internal surface finish would be a 20-Ra average and 25-Ra maximum. Similarly, the outside diameter of the pipe is polished to meet cleanroom standards.

Following electropolishing, the tubes are water-rinsed then further passivated in hot nitric acid. This additional passivation is necessary to remove any residual nickel sulfite and to improve the surface ratio of chromium to iron. Following passivation, tubes are rinsed with process water, placed in hot deionized water, dried, and packaged. If cleanroom packaging is required, the tubes are further rinsed in deionized water until a specified conductivity is met then dried with hot nitrogen gas before packaging.

Pipe joints

There are two types of fitting joints commonly used in hygienic piping systems: fusion-welded butt joints and sanitary tri-clamp connections. Prior to the advent of CIP systems, manual cleaning of piping systems and equipment required disassembly of the piping system and reassembly after internal cleaning. Potential issues have arisen associated with gasket extrusion’s effect on drainability and flow turbulence. Hygienic design requires that pipe joints should not trap impurities that might allow microbial growth and contaminate the process, such as threaded joints or even sanitary clamps; therefore, the preferred pipe-joining method is fusion butt-welding.

The 300 series stainless steels have a high degree of weldability; with a higher expansion rate and a lower thermal conductivity than plain carbon steel, the heat is not dissipated as fast from the weld region, which reduces the required welding current. The austenitic stainless steels are susceptible to intergranular corrosion at welding temperatures between 800° and 1,600°F because of carbide precipitation in the grain boundaries. This phenomenon is known as sensitization and occurs from the absence of chromium at a region immediately adjacent to the grain boundaries. Chromium and carbon, originally distributed through the austenitic structure, combine to form chromium carbide. These chromium carbides are not as corrosion resistant as the base austenitic structure. The sensitization can rapidly occur at temperatures of about 1,200°F; at higher temperatures the process is reversed and the precipitate is re-dissolved and kept in solution. The time when precipitation can occur is dependent on the amount of carbon present; low-carbon, 316L-grade stainless steel increases resistance to sensitization and is the material of choice for welded pipe systems.

Figure 3. Orbital welding ensures full penetration welds with no overheating occurring that could undermine the corrosion resistance of the weld zone. Note the pulsed arc finish on the weld surface. Photo courtesy of Pro-Fusion Technologies Inc.Click here to enlarge image

Pharmaceutical process piping is orbitally/autogenously welded in place, a fusion-welding process using heat without the addition of filler metal to join two pieces of the same metal (see Fig. 3). This welding is fast and avoids the crevices and potential for corrosion common with mechanical couplings where bacteria can grow and contaminate the system.

After welding, the “sensitized” steel should be annealed to re-dissolve the carbide and rapidly cooled through the sensitizing range. The heating causes the carbides to go back into solid solution and the quenching stabilizes the structure. Water quenching is important in order to pass through the sensitization temperature range (1,800° to 8,000°F) as rapidly as possible.

Orbital welding results in an area within which the alloy chemistry is not balanced for optimum corrosion resistance. Passivation is necessary to remove the manganese and to boost the chromium/iron ratio. Unless this is done, there will be an area where accelerated corrosion can occur, and in those environments containing electrolytes galvanic corrosion may also take place.

Cleaning

The final operation after fabrication or heat treatment is cleaning to remove surface contamination and restore corrosion resistance of the exposed surfaces. Degreasing to remove cutting oils, grease, crayon markings, fingerprints, dirt, grime, and other organic residues is the first step. When degreasing, only non-chlorinated solvents should be used in order to avoid leaving residues of chloride ions in crevices and other locations where they can initiate crevice attack, pitting, and/or stress corrosion later on when the system is placed in service. And only deionized water at 1,800°F should be used as a final flushing and sanitizing rinse.

Conclusion

Pharmaceutical piping systems deliver high-purity water to their processes and this requires high-quality materials that ensure a source of water that is free of bacteria, rust, or other contaminants. Stainless steel’s inherent hygienic properties and the ability to enhance these features with electropolishing and passivation have made it the leading material for pharmaceutical water systems. The main advantages of stainless-steel systems are mechanical strength within a wide temperature range and a low coefficient of thermal expansion. This simplifies equipment and piping design and allows for sanitization of the piping system. Potential disadvantages for consideration are the high cost of sanitary stainless-steel components, susceptibility to rouging, and the need for periodic chemical passivation to restore the oxide film that provides stainless steel with its corrosion resistance.

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Ken Sullivan is a senior engineer with PB Power (www.pbworld.com), a division of Parsons Brinckerhoff NYC. He has 30 years of industry experience in design and construction of mechanical systems for research and industrial facilities including laboratories, cleanrooms, and pharmaceutical facilities, and has managed capital projects with an international cosmetics manufacturer. He is a graduate of Farmingdale State University and Dowling College, and is currently teaching at the Institute of Design & Construction in Brooklyn, NY.

Reference

1. Steel Glossary, American Iron and Steel Institute (AISI).

By George Miller

To some consumers, it’s becoming a rock-vs.-hard-place choice in food safety: Risk Salmonella and other types of microorganism contamination or choose irradiation as a means to protect against it.

But for food producers, importers, shippers, and regulators, another option involves the use of more sophisticated risk-based techniques to identify problem areas in the food supply chain, monitor them closely, and eliminate the problems at their source. Successful risk-based systems should eliminate the need for lengthy, complicated, and expensive trace-back efforts when contaminated food begins making people sick.

“At the food processor level, we believe in risk-based programs,” says Tom Chestnut, vice president for supply chain, food safety, and quality programs at NSF International (Ann Arbor, MI). NSF is a not-for-profit organization that writes standards for food, water, and consumer goods protection.

“For example, the import system for seafood safety inspections in the U.S. looks at about 2 percent of imports,” he says. “But they use risk-based systems to determine where to look.”

Reactive efforts involve testing at the port of entry or further down the chain, according to Chestnut. However, in the approach developed by NSF and the Global Food Safety Initiative (GFSI), “We’re trying to be proactive, to work with suppliers to ensure safety before the product is shipped.”

GFSI is a retail-led network coordinated by CIES