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Today’s pharmaceutical and biopharmaceutical industries use various methods to clean process equipment. Cleaning devices range from manual wipes and brushes to sprayers, baths, and washers. Cleaning methods differ mainly in the mechanical action applied on the surfaces and the degree of personnel involvement. Even though international regulatory agencies accept these validated cleaning methods, many companies are switching from their existing cleaning processes to clean-in-place (CIP) systems. The main reasons for this conversion are that CIP systems are more effective, consistent, and reliable than traditional cleaning methods (1).

The food industry has used CIP systems for decades. Their effectiveness in this industrial application had been proven long before they were introduced to pharmaceutical companies (2). The systems achieve consistent cleaning results because they minimize operator intervention, thus reducing the likelihood of human error, and enable consistent control of critical parameters. CIP systems have become standard, particularly for facilities regulated by good manufacturing practice (GMP).

The principal objective of a CIP system is to achieve the desired cleanliness without disassembling the process equipment. Generally, CIP cleaning is performed by circulating cleaning solutions through pipes, pumps, valves, and spray devices that distribute the cleaner over the surface areas of the equipment. The cleaning process may include steps such as preparing cleaning solution to a pre-established concentration, heating the cleaning solution, circulating wash and rinse solutions over all equipment surfaces, and drying as needed.

A CIP system includes equipment and various components. These systems can be fully or semiautomated for minimal operator intervention. They can be fixed installations or portable systems that clean several pieces of equipment in the same manufacturing train. Figure 1 shows a fixed CIP skid unit connected to manufacturing equipment. CIP systems can also be designed and integrated into the equipment itself. Figure 2 illustrates a large vessel with the necessary components to perform cleaning without a separate CIP unit. All cleaning steps, particularly cleaning-solution preparation and heating, are performed in the same process vessel. Part II of this article will describe CIP systems in greater detail.

Benefits and challenges of CIP cleaning
CIP systems control, monitor, and document critical parameters in automated cleaning processes. Typically, parameters such as time, action, detergent concentration, and temperature (TACT) determine the cleanliness achieved by a CIP process (3). Controlling these parameters results in consistent cleaning performance. In addition, the cycle documentation that is critical for process validation and product-batch release is generated automatically in a CIP process.

Another benefit is that cleaning parameters can be easier to optimize when using a CIP system. A CIP process allows the user to set more aggressive TACT parameters than are possible with cleaning methods that involve manual intervention. For example, alkaline or acidic chemistries can be used for CIP instead of the neutral products that are safe for manual applications. Higher concentrations and temperatures can also be applied to achieve more efficient cleaning.

In addition, CIP systems offer operator- and process-safety benefits. For example, cleaning processing equipment without dismantling it reduces operator exposure to potent drug residues and hazardous cleaners. It also minimizes the risk of damaging process equipment because assembly and disassembly are subject to human error. Moreover, CIP systems may eliminate the need for personnel to enter the vessel to clean sharp parts such as agitator blades or hard-to-clean locations. This factor reduces the risk of personal injury.

Although the disadvantages of CIP systems are minimal, some companies still resist adopting this technology (4). One of the most common reasons is the physical limitation of these companies’ process equipment. Not all manufacturing equipment can be completely cleaned in place without engineering modifications. Even with modifications, cleaning out of place may still be needed. Time and cost are also factors: CIP equipment must be qualified, which consumes time and resources. In addition, the required software and hardware may be complex and may need to be custom-designed for each process. No one-size fits all solution is available. Consequently, a CIP system requires an initial capital project investment for acquisition, installation, and qualification of the unit before operators can run it in a GMP-regulated environment.

If a facility chooses to invest in a CIP system, several design guidelines will optimize the system’s operation and cleaning effectiveness.

CIP cycle development and validation for GMP applications
Once a CIP system has been thoughtfully designed, it must be tested. Equipment qualification should be successfully executed before placing the CIP system into full operation (5, 6). The installation qualification, operational qualification, and computer qualification ensure that all the CIP components will operate as designed.

In addition to testing the mechanics of the system, it is important to determine the cycle phases and cleaning formulations that will be most effective. Prevalidation studies are helpful for establishing the cleaning chemistries and cycle parameters in a CIP cycle. A standard CIP program can include the following items:

• A once-through flush-to-drain to remove bulk soil load

• A recirculated alkaline wash

• A short water rinse to remove alkaline cleaner

• A recirculated acid rinse

• A water rinse to remove acid cleaner

• A high-quality water rinse to drain

• Drying by heat or nitrogen purge.

Validation demonstrates that a series of steps and parameters will consistently produce the expected results. An internally reviewed and approved protocol should be developed for this testing that includes objectives, methodology, and acceptance criteria. Validation should follow the protocol, and the data developed during its execution must be collected and attached to the final validation-closure package. Many reference books and training materials are available to assist with the development of cGMP cleaning protocols and procedures (7).

Take advantage of all CIP design resources
An effective CIP process design depends on the correct identification of system components and an understanding of how these components can help or hurt a successful cleaning configuration. Having these guidelines at hand can simplify the understanding of requirements for designing and implementing a reliable and effective CIP process. Quality, technical, and production personnel can all use these guidelines.

CIP system designs, however, are far more complex than the concepts discussed in this article; they usually require the involvement of subject matter experts to ensure that all necessary aspects of the process are addressed. The principles discussed in this article, even when supported by published references, cannot replace the advice and expertise of manufacturers and project-design professionals who can provide direct, practical, and cost-effective guidance during an on-site review. It is wise to take full advantage of the available expertise, which can save time, resources, and aggravation in the long run.

Note: Part II of this article, which describes the characteristics of equipment that can be cleaned in place, will appear in the July issue of Equipment & Processing Report.

References

1. D.A. Seiberling and J.M. Hyde, “Pharmaceutical Process Design Criteria for Validatable CIP Cleaning,” in Cleaning Validation (Institute of Validation Technology, Duluth, MN, 1997), pp. 38–58.
2. D.A. Seiberling, Clean-in-Place for Biopharmaceutical Processes, D. Seiberling, Ed. (Informa Healthcare, New York, NY, 1st ed., 2007).
3. G. Verghese and P. Lopolito, “Cleaning Engineering and Equipment Design,” in Cleaning and Cleaning Validation, P. Pluta, Ed. (DHI Publishing, River Grove, IL, vol. I, 2009), pp. 123–150.
4. G.J. Cerulli and J.W. Franks, Chem. Eng.109 (2), 78–82 (2002).
5. PIC/S, PE 006-3: Validation Master Plan Installation and Operational Qualification Non-sterile Process Validation Cleaning Validation (Geneva, Sept. 2007), pp. 1–26.
6. FDA, Guidance for Industry-Process Validation: General Principles and Practices, (Rockville, MD, Jan. 2011), pp. 1–19.
7. D.A. LeBlanc, Validated Cleaning Technologies for Pharmaceutical Manufacturing (Interpharm/CRC Press, Boca Raton, FL, 1st ed., 2000).

Elizabeth Rivera is a technical service specialist for STERIS, 7405 Page Ave., St. Louis, MO 63133, tel. 314.290.4783, fax 314.290.4650, [email protected].