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Clean-in-Place Systems in the Processing Industries

Clean-in-place (CIP) technology offers significant advantages to manufacturing facilities, from efficient and reliable cleaning of process equipment and piping at lower cost to improved product quality. This summary highlights the important factors in CIP technology, identifying several designs of CIP systems and discussing the basic operation of the units. The controls incorporated into CIP systems are critically important, being required to provide a variety of cycle times, temperatures, composition and concentration of cleaning solutions. The clean-in-place systems may include current recycling and regeneration technologies, in order to reduce operating costs and control the cost of waste disposal.


The development of clean-in-place (CIP) technology, i.e., the automatic, reproducible and reliable delivery of cleaning solutions, rinse and wash water to and through process equipment and process piping, has improved both product quality and plant hygiene. Furthermore, the ability to clean a processing system, incorporating tanks, pumps, valves, filters, heat exchange units and process piping, without the need to disassemble all or part of that system, significantly reduces cleaning costs and minimizes the handling of chemicals to provide a safer environment for plant personnel. These systems may be integrated into existing processing systems, but more importantly, clean-in-place technology should be included in the design of any new process system, to be simultaneously incorporated with the design of the process flows, the controls and automation.

Clean-in-place technology may be applied to any equipment in which contact by a liquid can be achieved by way of spraying or recirculation of water and aqueous cleaning solutions under pressures ranging from 25 to 80 psig. Prior to cleaning a process system, it is economically beneficial to many processing industries to recover the residual product. Several approaches may be used, e.g., evacuation, “water flush,” “airblow” or “pipe pigging.” This latter term describes the propelling of a flexible, elastomer projectile through the piping system. The pig is usually driven by air, nitrogen, water or a cleaning solution. This technique reduces downtime between product runs or when formulations are changed and recovery of the product is economically significant.

Designs of CIP systems

There are several designs of CIP systems. The “single-pass” and the “recirculating” configurations are often utilized in the processing industries, since both require minimal capital investment, typically have a small footprint and are flexible, in that the unit can readily adjust to a range of cleaning protocols. However, the cost for the chemicals, water and steam and for disposal of the wastewater are higher than for other designs.

The dairy and food industries have consistently favored a “re-use design,” which provides for the recycling of the water and possible regeneration of the cleaning chemicals. These CIP systems have a larger footprint than “single pass” systems and there is a greater risk of cross- contamination during operation. The “re-use” systems also lack flexibility, in that a single temperature and a single concentration of cleaning solution is used for whole process system, unless additional vessels are included in the CIP unit.

The pharmaceutical and bio-pharmaceutical industries prefer to use a multi-tank configuration, with independent, stainless steel tanks being used to hold water of different quality, e.g., deionized water (DI), hot or cold water for injection (WFI) and water from reverse osmosis units (RO). These multi-tank systems are operated as if they were single-use systems, the tanks being drained between subsequent programs to minimize cross-contamination A single-use, eductor assisted CIP unit, which reduces the consumption of water and chemicals, was developed primarily for use in the dairy and food processing industries, but has recently found application for selected pharmaceutical processes. This system is capable of circulating small volumes of water at relatively high rates.

How does a CIP system operate?

The operation of the CIP system requires the control of several conditions, i.e., the fluid flow rates and velocities, temperatures, cleaning times and the concentrations of the cleaning chemicals (detergents, caustic soda). Fluid velocities in the process piping are typically approximately 5 feet per second, although some systems in the pharmaceutical and bio-pharmaceutical industries use higher velocities. In the case of tanks, the rates of flow of either water or cleaning solution are largely determined by the size of the tank, as well as the number and the properties of the spray devices. These flow rates usually range from 10 to 160 gallons per minute.

Spray devices come in a variety of designs. The traditional spray ball is commonly used and provides directional streams of water or cleaning solution from small, static nozzles. Rotational devices provide spherical spray patterns and direct impingement spray devices introduce high pressure streams at low flows, rotating through 360˚ The impingement spray devices represent an alternative to the removal of soils or deposits by cascading water or cleaning solution that cascade down the sidewalls of the tanks or vessels.

The temperature of the CIP process may vary from 135 to 175˚F and control is usually critical. The necessary heat transfer demands are met either by incorporating heat exchangers (plate-and-frame or shell-and-tube) into the CIP system, or by direct injection of steam. Chemicals may be added using peristaltic or pneumatic diaphragm pumps and the concentrations of the cleaning solutions are monitored by the measurement of the pH or electrical conductivity of the solution.

The CIP process involves a sequence of cycles that includes an initial and final drain step, a pre-rinse, wash and post-rinse. The duration of the rinse and wash cycles vary from 5 minutes to 1 hour. In the pharmaceutical, bio-pharmaceutical, dairy and food industries, the CIP process may include a “sanitize” cycle to reduce the levels of bacterial contamination. This cycle necessarily uses aqueous solutions of strong oxidants such as hydrogen peroxide, ozone, chlorine dioxide and other chlorine-containing compounds. When a “sanitize” cycle is included, thorough final rinse cycles are required to avoid corrosion of the stainless steel tanks, vessels and process piping, due to the presence of traces of the strong oxidant, particularly the chlorine containing compounds or chloride ions. In order to efficiently drain process equipment and process piping, the system should be designed and installed to either allow the fluids to flow out under gravity or be pitched to drain points. It is also very important to avoid sections of the piping and equipment in which fluid flow is restricted. Split flow designs also adversely affect the flow of solution through a piping system. Any problem areas should be identified and the piping modified or an appropriate cleaning method developed. The pre-rinse uses recycled water to flush out loosely adhering particulates and soil. This water is often flows directly to the drains as it leaves the CIP system. The wash cycle may use more than one chemical, depending upon the degree of fouling and nature of the deposits in the process equipment and piping. The post-rinse cycle provides the final flush for the system. The effluent from this final cycle may be discharged to the drains, directed to a solution recovery tank or to a pre-rinse tank, as has been described earlier. The effluent may flow to the drain or recovery points under gravity, but some CIP systems include return pumps or eductor devices.

How important is the control system to the operation of the CIP unit?

The importance of the controls incorporated into the CIP system cannot be overstated. It is necessary to include a variety of instruments and devices, i.e., resistors that are dependent upon temperature, pH probes, conductivity meters, flowmeters, timers, level sensors and alarms. Fully automated control must provide for variable times for rinse and drain cycles and for recirculation of the various solutions. The system must also have the capability to change the temperature, flowrates, composition and concentration of the cleaning solutions. The main control unit is usually based upon PLC equipment, often as multiple panels to service operator stations and for valve and I/O termination. The process control system is critical to controlling or minimizing hydraulic shock, a common problem in CIP units. The proper sequencing or “pulsing” is required to clean the valves, lip seals, o-rings and valve seats. A correctly designed and installed control system may eliminate the problem of hydraulic shock, leading to lower maintenance costs and longer component life. A&B Process Systems has recognized the importance of providing user-friendly controls and instrumentation with any CIP system. The Automation and Controls group at A&B works with the design engineers and the customer to ensure that this objective is realized and that the proper level of operator training is provided.

What is meant by “process validation?

Process validation is an important aspect of a properly managed CIP system. Three questions should be asked of the operating CIP unit; Is the CIP system working as intended?

Has the CIP process cleaned/ sterilized to the level required?

Have residual chemicals been removed from the process equipment and process piping?

The answer to question (a) is provided by the array of instruments in the CIP system.The probes, devices and meters monitor fluid flows, times, temperatures and concentrations of the cleaning solutions and the data obtained establishes that the system is, or is not, working as intended. The answers to questions (b) and (c) are obtained from analysis of the effluents, using such techniques as TOC (total organic carbon) analyses, atomic absorption, HPLC (High Pressure Liquid Chromatography) and GC (Gas Chromatography). Efficient cleaning of the tanks in the process system requires that the interior surfaces be totally covered by the sprays introduced through the spray devices. The surface coverage is determined by the “Riboflavin Validation” process, a visual analysis based upon the response of the organic compound to ultra-violet light.

Are other factors or components significant to CIP processes?

An important component of the CIP system is the transfer panel. This is actually a “routing station,” which controls the distribution of the various fluid streams. Today’s transfer panels are the result of continued modification and development of “cleaning hook-up stations” used for solution distribution in early CIP systems. There are several geometric configurations used for the ports in the design of the transfer panel, the simplest and most common arrays being triangular or radial. The incorporation of “proximity sensors” into these designs has become an industry standard, the sensors interfacing with the process control system, as well as providing verification of the connections to the transfer panel for product and operator safety.The utilization of chemicals, water and energy is an important consideration in CIP systems. Manufacturing facilities are concerned with controlling consumption of the chemicals and water to reduce the cost of operation and waste disposal and to maintain compliance with respect to the environmental regulations. In CIP processes large volumes of the solutions are brought into contact with the contaminated surfaces and economic operation often requires recycling and re-use of the rinse water, wash water and chemicals in the cleaning solutions.

Passivation Techniques

Aim : To establish the method to evaluate that the pharmaceutical equipment and high purity water pipe linescontact surfaces are rendered non reactive, additive or absorptive so that drug product is not adversely altered.
Brief description of Passivation Process:
1. Solvent decreasing
2. Water Washing
3. Passivation ( acid wash)
4. Final Water Rinse.
Treat the metal part at RT with solvent or water-soluble detergent and remove dirt, oil, grease from the surface. Wash the decreased surface with water at RT to remove loosened particles and detergents.
Passivate the metal surface with suitable passivating agent (oxidizing agent). This will remove free ions, metallic residue, oxides and other corrosion products.Rinse the metal surface with water to remove all extractable residues.


Method used for passivation: Cleaning and passivation solutions are sprayed onto the interior surfaces of the vessels, containers and equipment for minimum of 30 minutes per each rise stage. Repeat each stage three times.
Testing Method:
Pour 1000 ml de-ionized water over the surface at RT collect for testing. Repeat the step three times for each of the steps mentioned below.
A. Filter through 0.2 to 0.5 filter and inspect.
B. Check the conductivity before spraying and after spraying.

SIP Validation Protocols
The Validation of Sterilization-in-Place (SIP) Processes

When process equipment reaches commercial-scale proportions, the sterilization of essential units by autoclaving becomes impractical and some means of sterilizing the equipment in situ is needed. Such installations, in order to comply with cGMP, must be design, installation, and operationally qualified (DQ, IQ, and OQ) and the sterilization process must be validated. So, here is a short introduction to the SIP validation procedure.

SIP installations will usually comprise one or more pieces of processing equipment, such as a fermentor and a centrifugal separator to handle harvests, connected by rigid stainless steel or flexible Teflon®-lined piping. The installation will be capable of withstanding steam pressure up to, say, 20 psi and corresponding sterilizing temperatures in the 121° to 125°C range. There will be a supply of steam suitable for the procedure, under pressure control, and a "trapped" drain at a low point on the system, which will pass condensed water, but not steam. Suitable safety valves or "burst disks" will control the safe operation of the installation.

Design qualification of a SIP installation will require confirmation that the process equipment, pipe work, and steam supply equipment meet preset specifications for materials and for pressure and temperature resistance. Attention must be paid to the quality of the steam which will be used. This usually means that the steam is generated in a dedicated "clean-steam" generator. The steam may also pass a micro-filter before use. The cleanliness of the steam must be maintained by the use of pressure-grade stainless steel or Teflon®-lined tubing and suitably constructed pressure control and shut-off valves and pressure gauges.

Other design aspects of the equipment intended for SIP will include ensuring that the steam can reach all parts of the equipment in contact with product and that air is not trapped in the plant during sterilization. There must also be a means for the easy clearance of condensate during the heating process, through the steam trap. Finally, temperature sensors must be sited where they will represent reliably the state of the equipment during the sterilization cycle. Often, the most favored point for temperature measurement is at the condensate drain, since this will be the last area to reach operating temperature. However, there may be good reasons for siting thermo-sensors in difficult-to-reach areas of the plant.

Installation qualification of a well-designed SIP system will involve confirming the proper installation of the process equipment and correct siting and connections for all pipe work, including ensuring that proper condensate drainage can occur.

All required services and monitoring devices should be in place. Operational qualification starts with the start-up of the steam generation set-up and confirmation that correct pressure and steam volume is achieved. The sterilizing cycle is then run. Steam under pressure is passed through the entire installation while allowing the escape of air through properly placed vents in the piping or on the equipment. Steam-resistant bacterial filters usually protect these vents. After a suitable period of steaming, the air vents are closed and steam pressure is allowed to build to the required level. Pressure is maintained during a preset period, then the steam is released through a condenser. Temperature sensors in the system should indicate that the recorded pressure resulted in the required temperature being reached for sufficient time to ensure destruction of all contaminants. Cooling down of the equipment requires that air be allowed to pass back into the system through one or more of the sterilizing filters on the vents, to prevent the development of a vacuum.

Validation of the system operations will require the use of chemical and biological indicators, which should be placed in sections of the plant determined to be difficult to free of air, and near the condensate drain. The prescribed sterilization cycle should always yield sterile indicators. The process can be challenged by "worst-case" conditions, such as a reduction in sterilization period or steam pressure. Eventually, a set of operating conditions that have been shown to produce sterile plant reproducibly can be adopted as the validated process. Minimum and maximum limits on the steam pressure, indicated temperature, and exposure time will be set. If appropriate, the final evidence of the validity of the sterilization process may be achieved by running culture medium through the sterilized set up in imitation of the manufacturing processes and then incubating a large number of media samples, or the entire batch, to ensure no bacterial growth occurs. In any event, the regular manufacture of product batches that pass sterility and endotoxin tests after processing in the SIP plant will confirm PQ of the system. These records, however, will not substitute for proper SIP process validation.

Like all validation procedures, the DQ, IQ, and OQ of the system, as well as the validation run parameters and test results, must be fully documented. Measurement devices must be properly calibrated in reference to an accepted standard. If sections of the plant are rebuilt or changed, the entire SIP set up must be revalidated. Given the critical nature of the SIP procedure, it is probably a good idea to schedule revalidation of the installation at regular intervals anyway.


Electropolishing is an effective way to passivate a stainless steel surface. This process creates a passive surface, enhancing corrosion resistance and reducing particle generation via anodic dissolution. Electropolishing removes a microscopic amount of material from the surface, forming a smooth, passivated and chromium rich surface. This must be controlled in order to achieve an ideal passive surface.

Electropolishing is the improvement in the surface finish of a metal in a suitable solution. With the proper selection of current density, temperature and other conditions, the surface is smoothened and brightened while metal is removed. Electropolishing will produce a chemically clean, lustrous-to-mirror bright surface.In fact, because it removes surface metal,electropolishing tends to displace surface inclusions arising from stamping, machiningetc. The electropolishing surface also ismore passive and decidedly more corrosion resistant than a mechanically polished surface.

In electropolishing, both micro and macro-asperities are preferentially removed.The removal or reduction of the surface micro-asperities increases surface reflectivity and reduces surface friction.Burrs may be regarded, to some degree, as asperities and during electropolishing they are dissolved at a more rapid rate than the rest of the surface. Deburring is one of the common applications for electropolishing.

Electropolishing is exceptional useful for polishing complex and convoluted parts.Because electropolishing will occur wherever the process solution contacts the work piece and the appropriate current density much more readily than they could be treated by mechanical polishing. Difficult parts can be finished by electropolishing .

The more homogeneous and fine-grained the structure of an alloy or metal is, the better the result of electropolishing will be. Because of their basic metallurgical make-up, nickel-containing stainless-steels(300 series) have a structure that is particularly well suited for electropolishingand thus constitute a large portion of the commercial applications for electropolishing.Applicants include the reduction of gearwear, and the use of electropolishing toproduce desired dimensional requirements. Electropolishing does not “flow” the metalsurface. Deep scratches or surface imperfections are not smeared over and hidden as they are by mechanical electropolishing. Because Electropolishing provides a passivating oxide film roughly 15-50 angstroms thick, it creates better corrosion resistance. In fact good passivation of the surface typically requires chromium-rich oxide thickness in the 25-40 angstrom range.

Surface smoothness is also increased.Because electropolishing is a liquid bath,it wets to surface thoroughly and better than mechanical polishing. Finally, an electropolished surface provides betterclean ability because the surface is smoother and therefore can better release chemicals, dirt and bacteria. The flatter surface is free of points, cracks and crevices where organic contamination can build up, and where stress corrosion often occurs. One of the special features of Electropolishing is possibility of getting bright surface irrespective of roughness grade.

Pharma Grade Water

The goal of any high-purity water system is quite simple: Remove as many contaminants as you can, as easily and as economically as possible. The question is how ? As in any any challenge, ‘there are many tactical issues to consider. The first step is to analyze the source’s of the feed water. Consistency is a critical issue, especially if the source is surface, water, which may be subject to seasonal variation.

Removing particles, ionic impurities, and organic contaminants is important, but the biggest challenge facing pharmaceutical-grade water systems is removing bacteria and pyrogens and keeping them under control. And, it’s not simply a matter of running the water through a prescribed series of isolated treatment steps to theoretically meet the criteria. Bacteria can grow almost anywhere and eventually will multiply into numbers that would overwhelm any water treatment system.

USP standards for purified water & water for injection


Chloride (mg/I)

Sulphate (mg/I)

Ammonia (mg/I)

Calcium (mg/I)

Carbon Dioxide (mg/I)

Heavy Metals (mg/I)

Oxidizable Substances

Total Solids (mg/I)



Bacteria (cfu/ml)



Endotoxin (Eu/ml) by LAL




5.0 to 7.0






0.1 as Cu*

Pass USP Permanganate Test




















50 ppb

1.25 uS/cm







*Numerical values are interpretations of procedures listed in the Standards in United States Pharmacopoeia XXII edition.
** Guideline only.
+ Replaced by conductivity measurement.
++ Replaced by TOC measurement.

The harsh reality is that different components of a water purification system do not operate independently of one another. Depending on the system, it may be critically important to know how the diggerent treatment steps can affect one another. The most difficult concept to grasp may be that every phase of the process has the potential to not only remove certain contaminants, but to add others. Finally, there’s the issue of compliance. Whatever their needs, pharmaceutical manufacturer need water purification systems that produce consistent, reproducible results that are easily validated.

Figure 1. The typical treatment system design for producing pharmaceutical-grade water demonstrates that there's more than one way to produce USP water, as can be seen by the options in this schematic incoming water quality and the needs of the manufacturing process will dictate which steps are most appropriate.

The parts of Typical System

1. Primary filtration: Multimedia or sand filters remove particles larger than 5 microns from incoming feed water. If there are high levels of iron, greensand filters are needed. bacteria risk is minimal of chlorine residual is maintained and the filter is back-washed regularly.

2. Softening:Softening removes hardness and trace metals that would otherwise form scale on downstream equipment (particularly detrimental to reverse osmos. membranes). This step also eliminates the need for acid addition to control scale, so a downstream reverse osmosis system can reject a higher percentage of bicarbonate. bacteria risk is minimal if chlorine residual is maintained. Because a carbon filter removes chlorine, in most pharmaceutical water system designs, the softener is typically placed a head of it.

3. Activated carbon filtrationCarbon filters can reduce TOC levels to below 1 ppm (part per million), remove 1- to 5-micron particles, and reduce chlorine to sub-ppm levels. This is particularly important if there are any composite menbranes downstream. Bacteria risk is high, because the lower part of the carbon media can be a bacteria breeding gorund. Therfore, it is absolutely essential to include provisions for frequent hot water or steam sanitization procedures, which will control bacteria growth.

4.Primary chemical treatment: Multimedia or sand filters remove particles larger than 5 microns from incoming feed water. If there are high levels of iron, greensand filters are needed. bacteria risk is minimal of chlorine residual is maintained and the filter is back-washed regularly.

5.Ultraviolet (UV) sterilization:UV radiation reduces viable bacteria levels and cuts TOC to parts-per-billion (ppb) levels in high purity water. UV can also be used to remove residual ozone that has been used as a sanitizing agent. Ultraviolet sterilizers should not be used to remove large bacteria concentrations. The accompanying dissociation of TOC into ions can degrade water quality. Bacteria risk is minimal, provided the lamps function properly and are replaced regularly.

6. Reverse osmosis (RO): RO uses semi-permeable membranes to remove upto 95 percent of the dissolved ions, organics, bacteria, and pyrogens. It can significantly reduce the volume of chemicals reduce the volume of chemicals used in water purification systems, that normally reject about 25 percent of their feed water as waste. The first pass of an RO system is often considered pretreatment to a further deionization step-eityher continuous deionization, second-pass RO or ion exchange. During RO, bacteria risk is low to moderate. It can be minimized with proper sanitary design, regular effective sanitization, and optimum pretreatment. But, because most RO used in pharmaceutical applications requires dechlorinated water, it is possible for bacteria to collect and grow in the system, especially during extended shutdown periods. Additionally, selection of RO membranes must be based not only on the types and concentrations of contaminants to be removed, but also on their compatibility with cleaning chemicals. For instance, cellulose acetate (CA) RO membranes are generally more resistant to chemical cleaning, but have relatively low rejection rates. Polymeric thin-film polyamide and composite RO membranes have composite RO membranes have higher rejection rates, but are more sensitive to chemical degradation, particularly from chlorine-containing chemicals.

7. Ion exchange (demineralization): Ion exchange systems replace ionic contaminants with more “compatible” H+ and OH- ions. There are three different type of systems: cation, anion, and mixed-bed. cation exchangers replace cationic (positevely charged) contaminants such as sodium, calcium and magnesium ions with H+ ions. Anion exchangers replace anionic (negatively charged) contaminants such as chloride and sulphate with OH- ions. And, mixed-bed exchangers do both. Thesed resin-based treatment methodes, however, do not offer a barrier that actually removes organics, ions, bactria and pyrogens. Demineralizers are resonably tolerant to improper operation. This major disadvantage is the need to handle acid or caustic. Bacteria risk is minimal with proper design of piping and valves, regular regeneration (often before exhaustion) and proper pre-treatment. The regeneration process can be used to sanitize the system, but it need to be done frequently.

8. Continuous deionization (CDI):This is a relatively new technology which has gained wide acceptance. CDI avoids many of the problems associated with ion exchange and even produces higher quality water than a secon-pass RO system. The patented CDI process uses a combination of ion exchange membranes, ion exchange resins, and electricity to produce high-purity water continuously and without the need for hazardous chemicals. It uses electricity instead of acid and caustic to continuously regenerate the resins and produces consistent, high-purity water. In pharmaceutical applications, CDI is normally used as a polishing step after RO and is capable of producing upto 18 megaohm water. CDI systems can operate with 95 percent water recovery by recirculating the reject stream. Like ion exchange, CDI does not rely on a membrane barier and, therefore, is limited in its ability to remove organics, bacteria and pyrogens. Bacteria risk is minimal with proper design, frequent operation, regular sanitization, and adequate pretreatment.3

9. De-pyrogenation for WFI:The system components described up to this point can generally be used in systems that produce both USP-grade and WFI-grade water. But to meet the official WFI-grade water specifications (as specified in USP 23), a de-pyrogenation step is required. In the pharmaceutical industry, distillation, which is very effective in killing bacteria and removing pyrogens, has long been the standard method for producing water for injection. But this has begun to change, in part, because of the high operating costs associated with this energy-intensive operation. Furthermore, distillation processes require significant pretreatment equipment to protect them from scaling and corrosion-usually carbon filtration, sodium sulfite addition (dechlorination) and deionization. RO has also been used as a de-pyrogenation step, but hasn’t been nearly as well accepted, because it is generally perceived to have operating temperature limits too low to control bacterial growth. The temperature limits on these polymeric based membranes also preinclude the use of steam-in-place (SIP) sterilization procedures, another widely used technique in the pharmaceutical industry.

10.Ultrafiltration (UF):Is a membrane process that can produce highly purified water at a continuous rate equal to about 95 percent of the incoming feed water. It is similar to reverse osmosis, except that it does not remove dissolved ions. but it can be used to remove bacteria, pyrogen-free USP-grade water. Furthermore, recent tests on a Membralox ceramic-based UF system revealed that this type of memebrane (starting with DI water that has passed through a 2.0 micron prefilter) is able to remove pyrogens to levels that meet WFI criteria, Significantly, ceramic membranes can be used at high temperatures and pressures, so they can be easily sterilized with steam.