Cleaning In Place

by Pietro Perrone
Cleaning In Place

This article introduces CIP operations, the top-rated technical topic identified by a recent readers’  survey (see June 2005 newsletter). It is intended as a general introduction to CIP and identifies general, but important topics that are considered in defining appropriate CIP protocols. The more in-depth CIP issues and concepts and how they apply to specific unit operations will be featured in future newsletters.

Since cleaning is a big part of any processing plant, there should be many readers experienced in CIP operations. If this describes you, we invite you to submit an article that could be used in a future column. The article should deal with CIP and focus on specific unit operations such as vessels, fermentors, filtration systems, heat exchangers, chromatography equipment, etc. Please forward your article to christine_ lindberg@yahoo.com.

Cleaning is one of the most prominent operations in pharmaceutical/ biotechnology plants. Although it is often one of the first operations done during a processing plant’s commissioning activities, it typically gets addressed after the processing functions are defined and detailed. This can result in an operation that does not use the equipment at its optimum design point relative to all of its operating situations. Most processing equipment spends a substantial amount of its lifetime in a cleaning mode. The best operating process can consist of a cleaning time in the range of 10 to 20 percent of the processing time.

However, it is more typical that the cleaning time is in the range of 30 to 50 percent of the processing time. In some extreme cases where batches are small, the equipment could spend more time cleaning than processing. This causes a significant impact in the efficiency of the operations and one that warrants attention. A proper cleaning design will minimize the time (and cost) that the processing equipment needs to stay in clean mode while maximizing the productivity of the equipment.

During the design of processing equipment, it is best to keep the critical parameters that can impact the cleaning of the equipment at the forefront of the PFD and the P&ID development. An understanding of the primary factors of a proper cleaning should help in identifying areas that need attention during the design phase of a process.

Contributors to effective CIP protocols include the following:
1. Temperature
2. Chemical Concentration
3. Fluid Motion/Agitation
4. Time

These factors and their interdependence have a direct impact on the effectiveness of the cleaning operation. Although each factor may take a leading role in a specific step of the cleaning cycle, they are all interactive and all contribute to overall cleaning effectiveness. For example, in a rinsing protocol, the temperature of the solution and fluid motion have the leading roles. The chemical concentration and time, although important, have a secondary role.

A chemical solution protocol is most dependent on the chemical concentration. However, temperature is a close second as the activity level of the chemical solution is impacted by the temperature: a higher temperature results in higher chemical activity. Once the chemicals loosen the contaminants, maintaining the level of chemical activity depends on moving the contaminants away from the surface. The fluid motion/agitation comes into play for this function. At the base of all these actions is the amount of time the surface to be cleaned is exposed to the chemical solution. A longer amount of exposure time is not always best since re-deposition can occur if the contaminants removed are allowed to re-circulate on the surface. An optimum time of exposure is usually developed for the cleaning operation. This time is optimized for getting the most chemical exposure activity in the fastest time.

A generalized cleaning protocol consists of the following steps:
1. Rinse
2. Chemical Solution
3. Rinse
4. Chemical solution
5. Rinse

This simple protocol is the foundation upon which most cleaning programs are based. Although variations (more steps) may be implemented, the return-on-investment for the additional steps is often only justified for very difficult-to-remove contaminants or the need for an extremely low level of residual contaminants. A brief description of each step is provided below.

Rinse
This is the initial rinse that flushes out any residual process fluid. Promptly executing a rinse operation after finishing processing maximizes cleaning effectiveness and minimizes the chemical solution concentration needed in subsequent steps.

Chemical Solution
Typically, the first chemical solution consists of an alkaline (NaOH orequivalent) solution that removes proteinaceous components from the surface. The high pH level is most effective at removing oils, fats, and proteins. Other additives such as detergents and/or sodium hypochlorite (NaOCl) also may be added.

Rinse
This rinse is to flush out any chemical solution remaining after that cycle is complete and the solution drained. Chemical Solution Typically, the second chemical solution consists of a low pH solution that targets the removal of mineral components that become soluble in acidic conditions. Rinse - This final rinse is to flush out any chemical solution remaining after that cycle is complete and the chemical solution drained. Complete drainage at the end of this step will minimize the presence of any residuals contaminants. The effectiveness of the chemical cleaning is dependent on the quality of the chemicals used in making up the solutions. It is important that any additives and their effects be understood before incorporating them into the cleaning protocols. Additives, such as chelating agents or detergents, may resolve one issue while creating another. It is also important that the water used for the cleaning protocols be of reasonably good quality.

Two deleterious effects can result from poor quality water. The first is that the chemical cleaning solution may be impacted by the chemicals/ components present in the source water. The second is that the effectiveness of the rinsing steps may be compromised by contaminants present in the water. The quality or purity of the rinsing water is especially critical during the later rinses. The final rinse is best done with WDI or WFI to eliminate any trace of chemicals.

Conclusion
Efforts directed at developing and properly executing cleaning programs can pay significant dividends. These efforts include: addressing CIP concerns at the design phase of projects, selecting cleaning operations consisting of a combination of
1. proper chemical selection,
2. sufficiently elevated cleaning temperature, and
3. high fluid turbulence, and using these in CIP sequences that systematically remove the various contaminants. Following these simple rules will maximize equipment utilization and minimize operating costs.