CIP Systems Raise the Bar on Cleanliness

Nick Basta, Contributing Editor

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.

CIP, CAD and CFD

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.