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.


 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      short water rinse to remove alkaline cleaner

A water      rinse to remove acid cleaner

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 

D.A. Seiberling and J.M. Hyde, “Pharmaceutical Process Design Criteria for Validatable CIP Cleaning,” in 

 (Institute of Validation Technology, Duluth, MN, 1997), pp. 38–58. 

Clean-in-Place for Biopharmaceutical Processes,

 D. Seiberling, Ed. (Informa Healthcare, New York, NY, 1st ed., 2007). 

G. Verghese and P. Lopolito, “Cleaning Engineering and Equipment Design,” in 

 P. Pluta, Ed. (DHI Publishing, River Grove, IL, vol. I, 2009), pp. 123–150. 

PE 006-3: Validation Master Plan Installation and Operational Qualification Non-sterile Process Validation Cleaning Validation

Guidance for Industry-Process Validation: General Principles and Practices

, (Rockville, MD, Jan. 2011), pp. 1–19. 

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, 

Articles

In the Mixer

The author describes the benefits and challenges inherent to cleaning in place (CIP). The article also describes the development and validation of a CIP cycle.

Basic Equipment-Design Concepts to Enable Cleaning in Place: Part I

Meissner
 Filter system reduces cleaning requirements


 Meissner’s inline UltraCap H.D. assembly is a ready-to-use, integrally sealed filter and housing system. The system’s filter element is welded into a disposable polypropylene housing unit to form an assembly without O-rings. The assembly’s absence of O-ring materials and its construction from natural polypropylene material help reduce extractables and leachables.

The UltraCap H.D. assembly is completely disposable, thus reducing cleaning and cleaning validation costs and enabling faster and more convenient change-outs than traditional cartridge and filter housing systems. In addition, the inline capsule filter was designed to withstand higher temperatures and operating pressures than conventional high-capacity capsule filters. The unit’s inline flow configuration is intended to provide high flow rates by reducing housing pressure loss.

The UltraCap H.D. filter is available in lengths from 10 to 50 in. and pore sizes ranging from 0.04 through 99 µm. Users can choose the new inline version or the existing T-style version of the system depending on their requirements.

Telstar
 System loads and unloads lyophilized vials


Telstar’s new automatic vial-loading and -unloading system operates under aseptic conditions and is compatible with conventional cleanroom and barrier technologies. The vial-loading technology incorporates mechanisms driven by a set of three flexible, curved steel bands that make it compact and easy to clean. The entire system is situated outside the lyophilizer when not in active use. The lateral curvature of the bands gives them high stiffness, which reduces requirements for guidance and makes system elements accessible for cleaning.

The system can be configured in a pass-through layout that makes it possible to segregate loading and unloading in areas in terms of aseptic classification and degree of operator protection. The system integrates easily with isolators designed to separate operators from toxic chemicals. Under isolated conditions, operators can access all working areas easily and safely using gloves for activities such as changes of format and sampling.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the June 2011 edition from Meissner and Telstar.

June 2011 Editor's Picks: Products from Meissner and Telstar

Q: Our company is getting low and unpredictable cycle life out of our diaphragm valves. This problem has caused us to implement standard operating procedures for frequent replacement of the diaphragms, which is costly and time consuming. What could be happening, and what are our options?

A: This is a common problem for diaphragm valves that are used in steam applications. In many nonsteam service applications, weir-style diaphragm valves may last as long as 40,000 cycles, but they fail quickly when placed in steam applications.

Diaphragm failure has two common causes: cycle life failure due to the diaphragm and valve design, and diaphragm failure due to steam cycling, whether from mechanical stresses or aging of the diaphragm in steam service. In a sanitary valve, the diaphragm acts as the body seal and the inlet-to-outlet seal; it plays a big role in how the valve functions. Diaphragms are typically either PTFE or elastomer. The standard PTFE design is a two-piece diaphragm with a PTFE diaphragm and a backup elastomer diaphragm to reduce cold flow. The elastomer is often best for cycle life, but the PTFE typically holds up better with the temperature requirements of steam sterilization. The pure elastomer design often provides higher cycle life, but cycle life may be significantly reduced under steam-sterilization conditions.

Look for a diaphragm valve that features a single-piece PTFE diaphragm designed for high temperatures and high cycle life. This design will give you the best of both worlds and help your company avoid costly change-out procedures. You may need to ask some pointed questions when you are specifying or purchasing valves, but that should help you avoid line shutdowns, system contaminations, and high maintenance costs in the long run.

—Mike Bridge, biopharmaceutical market manager at Swagelok

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

 and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

Our company is getting low and unpredictable cycle life out of our diaphragm valves. This problem has caused us to implement standard operating procedures for frequent replacement of the diaphragms, which is costly and time consuming. What could be happening, and what are our options?

Dying Diaphragm Valves

The drug industry’s future could lie in large molecules. The introduction of new biopharmaceuticals and a predicted rise in patient spending on biosimilars indicate an industry with a strong potential for growth. Companies that manufacture biopharmaceuticals must ensure that their products do not contain protein aggregates, which can trigger harmful immune responses or potentially dangerous side effects. Two popular methods for detecting protein aggregates are analytical ultracentrifugation (AUC) and size-exclusion chromatography–multiangle light scattering (SEC–MALS). These techniques’ results correlate relatively well, but each one has its own strengths.

To perform AUC, scientists load a sample into a cell, spin the cell, and analyze the product with ultraviolet-light (UV) absorption or refractometric detection. “The big advantage of analytical ultracentrifugation over SEC–MALS is that it offers matrix-free separation and minimal sample handling,” says Mark Staples, principal and consultant for Cusp Pharmatech Consulting. The technique does not rely on calibration standards or interactions between the drug surface and chromatography media. 

Because AUC can detect aggregates within the matrix of the final-product formulation, some scientists believe that it presents a truer analysis of aggregation in the product than SEC–MALS does. “With AUC, you’re more likely to get a much more accurate picture as far as the type of aggregates that are present and the quantity of these aggregates,” says Mario DiPaola, chief scientific officer and chief operating officer of BlueStream Labs.

Scientists who need quick results are more likely to choose SEC–MALS, however. The time required per run for adequate SEC resolution of each species limits SEC throughput, but may produce results in minutes—usually less than an hour—per run, says Staples. In contrast, it may take between six and 48 h to complete AUC analysis, depending on the experiment.

In SEC–MALS, a scientist separates a sample by passing it through an SEC column. Next, the scientist places the sample into a cell and shoots a laser light through it. Detectors catch the beams as they exit the sample, and a computer indicates the presence of aggregates based on the angles at which light is refracted. 

SEC–MALS is much easier to adapt and use than AUC, says Michelle Chen, director of analytical services at Wyatt Technology. The method also covers a wider molecular weight range (i.e., 500–10 million Da) than AUC does. For smaller molecules, the sample concentration must be higher. In addition, MALS is often sensitive in detecting the aggregates and is a good technique for measuring the aggregate size.

But the method’s biggest drawback is that it may filter certain types of aggregates out of the sample. During SEC, the column frits remove insoluble aggregates, and the sample is diluted by the mobile phase. By the end of the process, the sample’s matrix composition has changed, and scientists may have an inaccurate picture of the number and types of aggregates in the product.

Manufacturers are not limited to these two techniques. Microflow imaging (MFI), which Brightwell Technologies originated, could be a valuable complement to SEC–MALS, says Wendy Saffell-Clemmer, director of research at Baxter Healthcare. MFI captures digital images of particles, displays them in real time, and stores them for further analysis. The technique detects particles between 0.75 and 400 µm and stores information particle count, size, level of transparency, and shape. MFI requires only 1 mL of sample, and it allows users to distinguish between bubbles, silicone droplets, and protein aggregates. MFI may require samples to be diluted, however, and it may have difficulty handling highly viscous samples.

SEC–MALS and AUC would be difficult to adapt for on-line analysis. But MFI “seems ideal for a [process analytical technology] application because of the speed of analysis, the lack of a requirement for sample preparation, and the small volume of sample required,” says Saffell-Clemmer. 

AUC, SEC–MALS, and MFI each have strengths and weaknesses, but a combination of these methods could give scientists needed information about a final drug product. Equipment improvements are enhancing the quality of the information that these techniques can provide. In addition, other analytical techniques are available, and companies can compare the results of various analyses for a broader perspective. As the biopharmaceutical market is poised to expand, manufacturers can be fairly confident about their ability to detect potentially harmful protein aggregates.

Production Lines

Two popular methods for detecting protein aggregates are analytical ultracentrifugation (AUC) and size-exclusion chromatography?multiangle light scattering (SEC?MALS). These techniques? results correlate relatively well, but each one has its own strengths.

Equipment and Processing Report-06-15-2011

Basic Equipment-Design Concepts to Enable Cleaning in Place: Part I

June 2011 Editor's Picks: Products from Meissner and Telstar

Dying Diaphragm Valves

Analyzing Aggregate-Detection Methods