CIP Systems Raise the Bar on Cleanliness

July 1, 2004
As Specs Continue to Tighten, Suppliers Keep Pace With New Design Tools and Materials
Cleaning systems for pharmaceutical production are being refined, driven by bioprocessing's more demanding requirements, and the evolution of new materials and technologies for performing cleaning, or for measuring contamination in process units or final products.

Nevertheless, the pressure remains on to meet basic FDA requirements for process cleanliness. A handful of the dreaded Form 483 letters that FDA sends out each month to manufacturers continue to note inadequate cleaning procedures, or insufficient documentation of how cleaning is supposed to be performed.

"Clean in place" (CIP) evolved as manufacturers learned to deal with the complexity of opening up or taking apart production units in order to clean them. Obviously, it's less effort to clean the system without elaborate disassembly; the challenge is to ensure that the parts that come in contact with ingredients are indeed clean.

A Moving Target

"CIP is a great example of why the letter c for current is in cGMP standards," notes John Lohnes, marketing vice president of Purity Systems, Inc. (San Jose, Calif.). "While the actual FDA code on cleaning is very simple, the standards that FDA investigators consider as current continually evolve." Lohnes' company gets involved with the qualifying of CIP and related pharmaceutical equipment, both at the original fabricator and as-installed at a client's plant. He says that his company has performed 700 such inspections in the past 15 years or so.

The design of cleaning systems depends heavily on the size and type of pharmaceutical production going on. Small, batch-oriented processes can often make do with a portable CIP unit that contains cleaning solutions, steam or purified water for rinsing, and the pumps and controls necessary for running the process. Cleaning solutions are either detergent-based, for removal of organic residues, or a combination of acids and/or caustic solutions, for inorganic contaminants. The unit can be wheeled from station to station, manually hooked up and turned on.

Larger or more complex manufacturing processes usually have an integral CIP system that is designed to operate much as the process itself does, with automated controls and multiple processing steps. Although representing a higher capital cost, the integral systems offer the advantages of faster cleaning cycles and higher throughputs. A more subtle, but very powerful, advantage is that the CIP systems have all their process steps documented in the same fashion as regular production, enabling recordkeeping to be performed in a more consistent manner.

During a recent expansion, Novocol Pharmaceutical of Canada (Cambridge, Ont.) converted from a manual cleaning process to an integral CIP system from ESE, an Entegris Company (Chaska, Minn.).The cleaning system alone accounted for part of the capacity increase, according to Paul Ricciatti, director of operations, because it cut the cleaning cycle in half. "We also realized that with larger tankage installed during the project, manual cleaning would be even more time-consuming," he says. Start up has gone smoothly, and operators are now used to its programmable controller-based control system. The company is about to install a second CIP system as part of a subsequent expansion.

How Clean Is Clean?

FDA's basic guidance does not specify levels of residue after a cleaning process, other than to say that the residue should not adulterate the final product. In practice, however, pharmaceutical manufacturers have adopted a group of standards that enable them to assess the quality of cleaning.

A very basic part of the cleaning process is visual inspection. In cases of organic residues in vessels, a common practice is to spray the inner surfaces with a solution of riboflavin (vitamin B6), which adheres to the residue. When a UV light is shone on the surfaces, adhering riboflavin fluoresces, providing an easy to detect indicator. The riboflavin test is frequently performed during initial qualification of the process unit, and then intermittently as a check on cleaning completeness.

Beyond this test, cleaning suppliers suggest 10 ppm for any active agent in the final formulation, and/or a maximum level of 1/1,000th of the active agent in a maximum daily dose of the product. This entails testing to see how much residue can actually be retained in the next production batch going through a system.

For ongoing production, a verification of the completeness of cleaning is necessary. With CIP systems, the check is simple: run the process until the rinse solution coming out of the system equals the purity of the process materials, such as water-for-injection (WFI) purity. Mass spectrometry or high-performance liquid chromatography can be used to verify this purity.

Recently, instrumentation vendors have begun proposing faster alternative tests. Smith's Detection (Warren, N.J.) has developed the Ionscan ion mobility spectrometry (IMS) system (Pharmaceutical Manufacturing, April/May, 2004; p. 9), which identifies concentrations based on how quickly sample ions move through a gas subjected to an electric field. Bristol Myers Squibb, GlaxoSmithKline, and Forest Laboratories found that the system reduced cleaning validation time from over a day to a few hours.


The use of riboflavin as a qualification step points to a critical part of CIP system design: ensuring that all the interior surfaces that contact process materials are being washed by the CIP system. In some cases, it is only when the CIP system and the tanks and process vessels are installed together on the plant floor that this testing can be performed definitively. In other cases, systems or components suppliers are using computer tools to evaluate vessel or component geometries to at least estimate how overall cleaning will function.

"I've seen some CIP vendors use the computer-aided design (CAD) files of the process equipment to determine things like the preferred spraying pattern of a spraying ball," says High Purity's Lohnes.

Spraying Systems Inc. (Wheaton, Ill.) uses CAD-type systems to analyze spraying patterns. But it also has a fairly comprehensive laboratory that includes wind tunnels, atomization analysis and other tools to analyze sprayer performance.

Swagelok, Inc. (Solon, Ohio) has performed extensive computer testing of its fittings, using computational fluid dynamics (CFD) to model flow patterns. In one case, CFD showed that limiting the dimensions of fittings improved the downstream flow of fluid, says marketing manager Timothy Warrell.

ESC/Entegris has also used CFD, CAD and other techniques, says engineering director Lyle Clem. However, he finds that the greatest improvements are possible when users treat CIP systems as integral parts of the production lines. Working closely with one client, for example, the company developed a new eductor valve that can be used to draw a vacuum on CIP return lines, allowing less cleaning solution, and smaller pumps, to be used.

Specifications Getting Tighter

The trend toward a higher, more repeatable level of cleanliness challenges pharmaceutical system providers. An example of this is the guideline for "dead legs"--lengths of pipe or tubing where fluid stands still, either during the manufacturing process or during a CIP cleaning. "A decade ago, the guideline we went by was not to have a dead leg longer than six times the pipe diameter," says High Purity's Lohnes. "Now, it's one-third that." A similar tightening of requirements has led to the development of so-called zero-static valves, he says, which are designed to have no fluid hold up, and shorter tees and other couplings generally.

Lohnes, whose company has worked in all three fields, says pharmaceutical manufacturers are learning a lot from biopharmaceutical and microelectronics manufacturers. A case in point, he says, is monitoring the quality of atmospheric gases, such as nitrogen used for blanketing, or oxygen for fermentation processes.

Meanwhile, it's easy to overreach with regard to tighter specs and higher standards, says ESC/Entregris' Clem. "There's a tendency to specify things like exotic alloys, high levels of electropolishing and other standards almost as if CIP couldn't be done."

Stronger Magnets Field Metallic Contaminants

A widespread worry of pharmaceutical producers is the presence of metal in the final product, either as an impurity that entered with other raw materials, or as a contaminant from erosive wear, rust or other metal shedding from the production equipment.

The tool of choice for metal removal tends to be high-power, rare-earth-based permanent magnets, which can be positioned as a roller above a conveyor line, as a grate through with granulated material falls, or as a set of tubes through which liquids flow. In most cases, the magnet picks up the metal particle, and the process operator only has to worry about cleaning the magnet periodically, usually by swabbing it down.

The news in magnets, say several providers, is that the magnetic power has gone up substantially in recent years. Eriez Magnetics (Erie, Pa.) is rolling out a new unit called the Xtreme, which has a force rating of 11,000 Gauss. "At a power level like that, you can think about reducing the number of passes to clean a quantity of material, or removing micron-sized metal particles," says communications manager Keith Jones.

Bunting Magnetics (Newton, Kan.), which also markets rare-earth-based magnets, has packaged one of its units on a roller cart, as well as made it quick to disassemble for cleaning. "This is intended for laboratory or pharm-prep locations, where the unit could be moved from station to station," says Michael Wilks, marketing manager. Wilks notes that the current generation of high-power magnets makes it possible to remove "rust dust"--metallic dust that is small enough to be floating in the air.

Oxides like rust, or ferrous metals, are only part of the story for metal removal, of course. Nonferrous materials are commonly encountered in process equipment and need to be addressed. According to various manufacturers, these can be removed either with eddy-current devices or radio-frequency-based metal detectors. At least two instrument suppliers offer metal detectors specifically designed for inspecting pills or capsules flowing along conveyor lines. Bunting has licensed the Pharmatron 05 in the U.S. from the German company, Mesutronic; and Lock Inspection Systems (Fitchburg, Mass.) offers a unit called the Met 30+. The Bunting unit runs with a 1-MHz frequency, said to provide high throughput rates, while the Met 30+ unit is rated for line speeds of up to 30,000 tablets/min.

Biogen Automates, Validates Small-Parts Cleaning

CIP is a solution for large equipment, but, for small parts such as end caps, clamps, tees elbows or hose, many companies still rely on manual washing--a time-consuming process that can be even more time-consuming to validate. Biogen IDEC (San Diego, Calif.) recently opted for an alternative: a clean-out-of-place (COP) washer developed by Sani-Matic (Madison, Wis.) that automates small parts cleaning.

The company needed an effective cleaning method for its Zevalin and Rituxan production lines, since residual bacteria from monoclonal antibody production tend to adhere to process equipment and other surfaces. "IDEC was looking for a more-consistent method of cleaning parts," says manufacturing supervisor John Keller.

The washer cleans parts by submersing them in a highly agitated bath of water and chemical solution. Sensors verify flow, temperature, and chemical strength, making it easier to validate the system.