Koslow Scientific Company
 Portable tester verifies passivation of stainless-steel equipment


 Koslow Scientific Company’s Passi-Flash 3036 portable instrument for passivation testing works with all grades of stainless steel to verify that vessels, piping, and equipment are free from iron particles that can oxidize and contaminate products. The tester resembles an oversized pen and is designed for single-handed operation. It produces a pass/fail signal in less than one second and displays the measurement in millivolts. The built-in memory stores readings for download to a record-keeping system. Portable testers allow users to test equipment on-site, rather than at an outside testing facility, notes the company. 

Articles

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the May 2012 edition from Koslow Scientific Company and Vaisala.

May 2012 Editor's Picks: Products from Koslow Scientific Company

Q. We are using a vacuum oven to dry our wet-cake intermediate. At 120 °C, it takes 26 hours on average to dry the material from 80% to 10% moisture. Can we shorten our drying time, possibly by agitating the product to improve heat transfer?

A. Your instinct is right-agitating the material while heating it under vacuum accelerates the drying process. Mixing provides a mechanism for constantly exposing fresh material to areas where the rate of heat transfer is highest at the heated surfaces of the vessel.

A double planetary mixer has been proven to be successful in this application. The mixer is equipped with two identical blades that rotate on their own axes while also orbiting on a common axis. After only 36 revolutions, in about one minute, the blades contact virtually every point in the vessel. This mixing action is very efficient, thorough, and predictable. 

The double planetary mixer is a relatively low-speed device, which is an advantage in vacuum drying applications where generation of fines should be avoided. Its gentle blending action can adequately turn over the batch contents, whether they are in the form of a thin slurry, a sticky paste, a wet granulation, or dry, fine powders. The mix vessel can be removed from under the mixer for full access to the agitators and the product. Clean design features such as highly polished wetted parts, a sealed and purged gearbox assembly, flush discharge valve and sanitary charge ports all contribute to minimizing the risk of contamination. If liquids need to be added and mixed into the batch prior to the drying stage, atomizing spray nozzles may be installed on dedicated ports for controlled and spill-free addition.

Vacuum-rated double planetary mixers are supplied in capacities as small as ½ pint and as large as 750 gal. The straightforward scalability of these systems allow R&D scientists to conserve expensive ingredients while following a repeatable, consistent mixing and drying process that can be easily replicated in pilot and production scale. 

Drying times vary depending on the raw materials, product quantity, temperature, vacuum level, final moisture content, and other variables. However, cycle times in the range of 1–2 h are fairly common, especially for laboratory batches. Testing is recommended to confirm drying time for a specific application.

—Christine Banaszek, application engineer, Charles Ross & Son Company.

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

We are using a vacuum oven to dry our wet-cake intermediate. At 120 °C, it takes 26 hours on average to dry the material from 80% to 10% moisture. Can we shorten our drying time, possibly by agitating the product to improve heat transfer?

Reducing Wet-Cake Drying Time

Although continuous manufacturing offers strong potential for solid-dosage manufacturing, additional development is still needed. Continuous tableting, granulation, and coating can and are in some cases being done, but questions and challenges remain. Two related challenges are how to analyze and control product quality in line and how to define lots for release.

Process analytical technology (PAT), which evaluates product quality on line in real time, is a key to enabling continuous processes. Process models correlate analysis of measured characteristics to product attributes that can be controlled by changing process variables. Genzyme, for example, used a fiber-optic probe (Lighthouse Probe, GEA Pharma Systems) to control high-shear granulation by correlating near infrared measurements to moisture content, bulk density, and particle size, explained GEA in a case study (1).

While process analytical technologies are well developed for individual unit operations, a remaining challenge is achieving control of the overall, integrated system, said Fernando Muzzio, director of the Engineering Research Center for Structure Organic Particulate Systems and professor in the Department of Chemical and Biochemical Engineering at Rutgers University, during a panel discussion on best practices and regulatory expectations in continuous processing at Interphex 2012. The central control systems that would allow a true plug-and-play system of multiple unit operations in a continuous stream, in which measurements downstream are fed back to control systems at earlier process steps, have not yet been fully translated into pharmaceutical applications, said Muzzio.

How to define a batch or lot of material for release when using in-line quality measurements is another challenge. For a particular process and application, a manufacturer must choose in advance what the lot size will be, whether it is one shift, one day, or some other time. With a larger lot size, more product is at risk if there is a problem, but with a smaller lot size, more testing must be done to qualify it.

There currently are no regulations prohibiting the use of continuous manufacturing, commented another panelist, Elaine Morefield, deputy office director for review and operations in FDA’s Office of New Drug Quality Assessment. There are some challenges when utilizing continuous manufacturing such as communicating control strategies and risks clearly and in defining a lot of product. This is because the technology and approaches for continuous manufacturing differ from most current manufacturing and control approaches and because of the complexity of the controls used, Morefield noted.

Maintaining data integrity of a batch is a challenge with continuous processing, agrees Fred Murray, president at tablet-press manufacturer Korsch America. Korsch is currently working on continuous process technology that integrates granulation preparation, tablet compression, in-line tablet measurement, and tablet coating, along with integrated PAT monitoring.

Equipment manufacturers see continuous tableting and coating being used today for some vitamins and over-the-counter drugs, but not as much for pharmaceuticals in which expensive APIs and regulatory concerns make defining and testing lots a more complex issue. Finding solutions to these issues is key to enabling manufacturers to use continuous systems.

1. GEA Pharma Systems, "Case story: Genzyme - In-Line Control of High Shear Granulation," 

www.gea-ps.com/npsportal/cmsdoc.nsf/webdoc/webb8g67x8

Production Lines

Advances in process analytical technology and in defining lots for release are key for enabling use of continuous processes in solid-dosage manufacturing.

Ongoing Challenges in Continuous Manufacturing

Rouge is a common phenomenon in water for injection (WFI) and clean-steam systems and can often be found in equipment and piping connected to these systems. While the root cause of rouging in high-grade stainless-steel equipment is a contentious issue, it is generally agreed that rouge is a form of surface corrosion that can form on stainless steel when exposed to high-purity water at elevated temperatures. This corrosion can manifest itself as a glazed, immobile discoloration or as a powdery reddish deposit (1).

Investigators should first determine that the observed problem is indeed rouge and not product residue or another type of contamination. Reddish-brown residue from a surface swab can be analyzed using Fourier transform infrared spectroscopy (FTIR) for the presence of iron oxide, which would indicate rouge. Close visual inspection should also be used to assure that there is no pitting or flaking in the affected area, which would indicate an advanced level of corrosion beyond the scope of rouging. 

If rouge is present, the most critical determination is whether the rouge is additive to the process or not. Is the rouge firmly adhered to the surface of the equipment or could it instead come off into the process stream either slowly or as a result of water hammer or another shock? If the rouge is glazed and smooth in appearance and does not wipe off or is not found on downstream filters or gaskets, then it would be safe to conclude that it is not an additive problem. If, on the other hand, the rouge wipes off easily on a swab or a glove, or is found downstream on filters or gaskets, then it can also be found in the water-for-injection or process stream. The equipment can indeed be said to be “additive, reactive, or absorptive,” which is a violation of 21 

 211.65(a), and further investigation and remediation is required (2).


 Different companies use numerous classifications of rouge, and many do nothing to help the operator or mechanic on the floor define the problem or determine if it really is a problem. Saying that the rouge is “shiny and black” or “a glazed purple” may help to identify the visual anomaly as rouge, but it does nothing to say if the material is additive to the process. Instead, a standard operating procedure (SOP) should give steps to determine a classification using visual criteria, roughness measuring, swabbing, or other straightforward methodology to see if the rouge is mobile or fixed. An SOP should use simple categories: one category should be for rouge that can impact a process and requires an investigation and another category for rouge that does not. If the rouge is not additive, reactive, or absorptive and does not affect cleanability or operation, then it should be documented and processing should proceed.

Quality assurance personnel are not expected to be experts in the metallurgy of stainless steel, but must ensure that equipment is in good order, cleanable, and not contributing to contamination of products. Implementing clear procedures will ensure that rouging does not paralyze operations and lot-release schedules.


 1. R.W. Revie and H.H. Uhlig, “Iron and Steel,” in 

Corrosion and Corrosion Control: An Introduction to Corrosion Science and Engineering, 

(John Wiley & Sons, Inc., Hoboken, NJ, 4th ed., 2008) pp. 115–148. 
 2. 

 Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 211.65(a).

John Anderson is a validation manager at Lonza in Visp, Switzerland, tel: +41 79 893 94 48, 

In the Mixer

Properly identifying and classifying rouge, a form of surface corrosion that comes in many forms, is important in determining whether it may be affecting product quality and whether further actions are necessary.

Equipment and Processing Report-05-16-2012

May 2012 Editor's Picks: Products from Koslow Scientific Company

Reducing Wet-Cake Drying Time

Ongoing Challenges in Continuous Manufacturing

Classifying Rouge Aids in Determining Maintenance and Remediation Procedures