Alfa Laval
 Magnetic mixer enables high yields


 Alfa Laval’s (Lund, Sweden) magnetic mixer is designed to provide high yields and reduce operating costs. Magnetic coupling between the impeller and the driving magnets causes the impeller to levitate. As a result, the impeller has no direct contact with axial bearing surfaces. The design allows the unit to continue mixing until a tank is empty, and it helps achieve a validated mix to a lower tank level than other mixers. 

The absence of friction and the eight-winged impeller permit the mixer to achieve run rates higher than 750 rpm. These speeds are appropriate for applications that require heavy mixing and vortex. The mixer also is efficient at speeds as low as 5 rpm in applications that require gentle agitation for sensitive products. 

Operators do not have to stop the mixer after a batch to begin clean- or steam-in-place cycles. Because cleaning fluid flows over all surfaces freely, operators do not need to submerge the mixer in cleaning solution.

Gems Sensors and Controls 
 Solenoid valves use little power


The E Series of pneumatic solenoid valves from Gems Sensors and Controls (Plainville, CT) were designed for air and dry-gas applications such as in printing machinery, sorting equipment, automated packaging equipment, and air-monitoring systems. The valves’ power consumption is 0.65 W. The products offer fast response times and high-pressure and high-flow capabilities.

Each unit features a compact, nickel-plated, cylindrical body and coil housing designed for durability and corrosion resistance. The solenoid valves are available in diameters smaller than 0.75 in. and lengths less than 2 in. The units’ seal and O ring options include nitrile, ethylene–propylene rubber, and silicone. They are available in various two- or three-way configurations, including normally open, normally closed, and multipurpose and directional-control three-way models. The E Series valves’ orifice sizes range from .032 to .078 in., and their port configurations include #10-32 straight thread, M5 x 0.8 threads, manifold mount, and bottom under-seat port.

Articles

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the September 2010 edition from Alfa Laval and Gems Sensors and Controls.

September 2010 Editor's Picks: Products from Alfa Laval and Gems Sensors and Controls

Stainless steel is the primary construction material for pharmaceutical and biopharmaceutical processing equipment. Prized for its ability to resist corrosion, stainless steel comes in hundreds of types and subtypes. Austenitic stainless steel is the most common type in these applications. It is nonhardened, nonmagnetic, and easily welded, and it resists heat and chemical sterilization and corrosion. The most common austenitic stainless steels are 304, 304L, 316, and 316L. “L” refers to low carbon content (i.e., 0.03% instead of 0.08%). The base metal of 304 and 316 stainless steels is iron (62–65%), which is combined with chromium (16–20%), nickel (8–14%), and other components such as carbon, silicon, and molybdenum (1). 

Stainless steel becomes corrosion-resistant during a process called self-passivation, when the metal surface, which must be clean, comes into contact with oxygen to form a nonreactive chromium-enriched passive layer. In addition to naturally occurring passivation, chemicals such as nitric acid, phosphoric acid, citric acid, and formulated phosphoric acid–citric acid blends can passivate stainless steel (2–4). 

The quality of the passive layer can be assessed through various methods, including X-ray photoelectron spectroscopy (XPS). XPS commonly helps scientists validate chemical treatments. Before passivation, operators rinse mechanically polished stainless-steel panels with isopropyl alcohol, high-purity water, acetone, and again with high purity water. After passivation treatment, operators remove the panels, rinse them with high-purity water, and allow them to air dry. Figure 1 shows the results of an XPS analysis (5, 6). The chromium–iron ratio at the surface of the untreated sample is approximately 0.25 Å, while that of the samples treated with formulated or commodity citric acid is approximately 2.0 Å. 


 Rouge is a corrosion product of stainless steel that ranges in color from reddish brown to blue or black. The general types of corrosion are galvanic, pitting, stress, intergranular, crevice, and microbe-induced. Rouge can be classified into the following three types (7, 8): 

Oxidized metal particles, generated by an external source through erosion or corrosion, that are deposited on downstream surfaces. This rouge generally is easy to wipe off, leaving the underlying stainless-steel surface intact (see Figure 2).

 oxidation, which generally adheres strongly and sometimes indicates underlying surface damage or pits. 

 Black-oxide rouge generated by high temperatures or steam. The top layers of this rouge wipe off, but full removal often requires specific chemical treatment.

Rouge occurs in most biopharmaceutical facilities and often is associated purified-water systems, clean-steam systems, buffer-preparation tanks (especially sodium-chloride or glycine-solution preparations), filling lines, vial washers (which typically are cleaned with hot purified water), and steam sterilizers. Rouge results from exposure to highly aggressive environments such as purified-water or -steam systems, chloride or corrosive products, and high-temperature stress or erosion. Other factors that cause rouge are nonstainless-steel components or inserts, improper welding, surface defects, and inadequate cleaning or passivation.


Facilities should have procedures in place for cleaning, derouging, and passivating new equipment, as well as for periodically inspecting in-use water systems and process equipment. New equipment often arrives with particulates and oily residues from buffing, polishing, and lubricating compounds. These residues must be removed, and the chromium-enriched passive layer restored.

Qualified engineering or maintenance staff should inspect in-use equipment for rouge. Surface inspection will help determine whether the equipment needs to be derouged and passivated. If no program is in place, a semiannual inspection is recommended as a starting point.

Laboratory evaluation can help determine the best conditions (e.g., chemistry, concentration, time, and temperature) for removing specific types of rouge. A facility’s routine acid cleaner, when used at a higher concentration and for a longer time, may effectively remove the rouge and restore the passive layer. 

Low-level preventive derouging and passivation 


 Formulated alkaline cleaners are effective at removing most biopharmaceutical-process residues from stainless-steel surfaces. The standard approach for routine cleaning is to remove organic residues with an alkaline cleaner and perform an acid rinse to remove inorganic residues and neutralize the alkaline cleaner. Although this acid rinse is performed at a lower concentration and for less time than during derouging and passivation, it also can be an effective method for removing rouge and enhancing the passive layer (see sidebar, “The general procedure for derouging and passivation of 304 and 316 stainless-steel surfaces.”) (9). 

The author generated laboratory rouge by suspending a preweighed 304 stainless-steel coupon and mild steel coupon in a 1% sodium-chloride solution while mixing for one week. The laboratory-generated rouged coupons were then treated with water, citric acid, formulated citric acid, or phosphoric-acid detergent at 60 °C for 30 min. The results, shown in Figure 3, indicate that low-level concentration and temperature conditions can remove rouge.

A low-concentration acid rinse after an alkaline wash step has potential benefits for regular preventive maintenance, derouging, and passivation. Compared with removing the equipment from the production line completely to deal with rouge buildup, a low-level clean-in-place approach can save time, cost, and labor in the long run. In addition, preventive-maintenance programs that include routine inspection of equipment surfaces and piping, and specific derouging and passivation procedures, can reduce costly equipment downtime significantly. 

ASME, “Nonmandatory Appendix E: Passivation Procedure Qualification,” in 

ASTM, A 967 – 99, Standard Specification for Chemical Treatments for Stainless Steel Parts (ASTM, West Conshohocken, PA, 2001), pp. 1–6. 

ASTM, A 380 – 96, Standard Practice for Cleaning, Descaling, and Passivation of Stainless Steel Parts, Equipment, and Systems (ASTM, West Conshohocken, PA, 1996), pp. 1–12. 

STERIS, “Lab Report 410-300-3308, The Effect of ProKlenz TWO on Passivation of 316 Stainless Steel,” (STERIS, Mentor, OH, 2009). 

P. Lopolito, INTERPHEX Puerto Rico 2010 (San Juan, Puerto Rico, 2010). 

J.C. Tverberg and J.A. Ledden, Proceedings of Tube 2000 (Dusseldorf, 2000). 

STERIS, “Lab Report 410-300-3313, Laboratory Derouging of Simulated Rouge Using ProKlenz TWO,” (STERIS, Mentor, OH, 2009).

Paul Lopolito is a technical services specialist at STERIS, Mentor, OH,

In the Mixer

The author describes the types and sources of rouge and explains ways to prevent and mitigate this problem.

Addressing Rouge in Biopharmaceutical Manufacturing Systems

Needlephobes, take note. The Georgia Institute of Technology and Vyteris (Fair Lawn, NJ) are developing thermal-ablation technology that may one day enable proteins to be delivered through the skin. Their cooperation is a sign that transdermal drug-delivery techniques continue to evolve and hold the promise of greater convenience for patients. Transdermal systems also could benefit pharmaceutical companies that seek to reformulate their drugs for delivery by alternate routes, thus extending the lives of their patents.

Dissolution testing can help manufacturers confirm that a dosage form releases the correct amount of drug at the intended rate. The testing also improves control of product quality and batch-to-batch consistency. 

 apparatuses 5, 6, and 7 were developed to test the dissolution of transdermal systems. 

Despite differences in design, apparatus 5 (i.e., paddle over disk), apparatus 6 (i.e., cylinder), and apparatus 7 (i.e., reciprocating holder) operate on the same principle. An operator secures the transdermal patch to a physical support and submerges it into an appropriate buffer, which typically is maintained at 32 °C. The instrument agitates the buffer through stirring or reciprocating, and the operator takes samples manually or automatically at predetermined intervals. After a scientist analyzes the samples for drug content using a chromatographic or ultraviolet method, he or she can determine the dissolution curve for the transdermal patch. 

Apparatuses 5, 6, and 7 are appropriate for testing passive transdermal patches, including matrix and membrane- or reservoir-based transdermals, says Jerry Zhang, CEO of Zyleris PharmaTech (Lake Bluff, IL). The instruments also are suitable for testing the dissolution of emerging systems based on active technologies such as iontophoresis or sonophoresis, provided that the patch portion of the system can be removed from the delivery device. If the operator can’t separate patch from the device, he or she might use a holder to attach the transdermal system to the apparatus, but the holder could be noncompendial, Zhang observes.

 apparatuses produce good, reproducible results, yet some scientists believe that further modifications could improve the instruments’ suitability for testing transdermal drugs. “Dissolution into a vessel of medium may be a better approximation of the digestive tract than it is of the skin,” says Paul Johnson, senior director of analytical research at Noven (Miami, FL). Matrix transdermals rely on the skin to control the delivery of the drug. It would be helpful if, in place of the screen in apparatus 5 or the cuprophan in apparatus 6, operators could use a reproducible membrane that mimics the skin, says Johnson. The skin-like membrane could be made of a polymer, and it would make dissolution-test results more meaningful, he adds.

New drug-delivery technologies have made it possible to develop transdermal therapies for biologics and highly potent water-soluble small molecules. When these molecules are formulated as transdermal systems, the patches often are small or contain low amounts of drug. This design could prove problematic. “The current systems for evaluating dissolution are not optimal for the detection of low amounts of drug due to the relatively large amount of buffer volume required,” says Frank Tagliaferri, head of research and development at Altea Therapeutics (Atlanta, GA).

Manufacturers therefore need low-volume apparatuses to test patches that deliver these drugs, especially if they require accurate drug-dissolution data at early time points, when the drug concentration is low. These low-volume instruments could share their designs with apparatuses 5, 6, and 7, but would incorporate smaller vessels and use less buffer than the latter. The new machines also might need modified stirring or mixing capabilities, depending on the sizes of the patches to be evaluated, says Tagliaferri. 

An alternative to a low-volume apparatus is to use highly sensitive analytical methods for drug detection. On the other hand, methods such as liquid chromatography, mass spectrometry, and electrophoresis may have practical drawbacks such as low throughput or high cost that limit their suitability for common quality-control applications.

In general, the pharmaceutical industry seems satisfied that current instruments provide valuable dissolution data for transdermal drugs. To manufacturers’ knowledge, no new apparatuses to test the dissolution of transdermal drugs have been proposed. The industry seems open to the idea, however. Several dissolution-device suppliers have offered to help Altea Therapeutics design instruments that better meet the company’s current needs, says Tagliaferri. Innovations in transdermal delivery technology, and the need to stave off generic competition, might one day spur improvements in dissolution-testing equipment. If new devices yield more accurate results than current instruments, they could enable drugmakers to provide convenient alternatives for patients.

Production Lines

US Pharmacopeia apparatuses for testing the dissolution of transdermal drugs produce good, reproducible results. Yet some scientists believe that further modifications could improve the instruments? suitability for this application.

Equipment and Processing Report-09-15-2010

September 2010 Editor's Picks: Products from Alfa Laval and Gems Sensors and Controls

Addressing Rouge in Biopharmaceutical Manufacturing Systems

How Can We Improve Dissolution Testing for Transdermals?