Increasing Plant Efficiency Through CIP

In biopharmaceutical and many pharmaceutical operations, post-production residues are primarily removed by chemical, rather than physical, means. Chemical cleaning is typically the most efficient mechanism for removing in-process material. Chemical cleaning methods rely on fully developed turbulent flow in pipelines and spray devices (often non-rotating sprayballs) in vessels and other processing equipment to supply rinsing and washing solutions to surfaces being cleaned. Cleaning is a mass transfer process that relies on good mixing and strong convection to produce turbulence. Turbulent flow promotes efficient mass transfer and thus is a key factor in optimizing cleaning cycles.

Clean-in-place (CIP) systems generate and deliver cleaning solutions to process equipment. Controlling the generation of specific concentrations, the distribution of consistent quantities, and the temperatures of rinse waters and cleaning solutions is automated. These rinsing waters and cleaning solutions are typically returned to the CIP system where they are either sent to drain or recirculated.

Advances in the application of cleaning technology to biopharmaceutical process systems have resulted in a new focus on the optimization of cleaning processes as a means to increase productive capacity. This article examines cleaning processes and theory and addresses how to reduce cleaning run times and increase capacity.

Figure 1. ESC CIP System - ESC, an Entegris Company

PROCESS SYSTEM DESIGN FOR CIP

CIP engineering begins with the overall definition of cleaning circuit and cycle strategy, continues with design and build of the manufacturing facility, and culminates in the development of optimized and validated cleaning circuits. For the purposes of this discussion, a CIP circuit includes the CIP skid, CIP supply piping, the process equipment being cleaned (including its interconnecting process piping), and the CIP return piping (Figures 1 and 2).

For the most effective use of CIP technology, cleaning circuits must be designed into the facility from the beginning. In many facilities, cleaning operations are designed as an afterthought. Design starts with process flow diagrams and continues in detail with piping and instrument drawings. The best time to incorporate CIP design is during these early design stages because the CIP and process piping are closely integrated and interdependent — although this is not always acknowledged.

Figure 2. Typical CIP Circuit Schematic

If the integration of CIP and process piping is not addressed during plant design, it will ultimately be handled in the facility — either during or following plant construction. Design features that could have been perfected with "pencil and eraser" must be addressed with "hacksaw and torch," which is extremely inefficient.

Specify new equipment designs so they are suitable for CIP. Ensure that vendors have experience with CIP operations and vendors and mechanical contractors comply with the guidelines of the American Society of Mechanical Engineers Biopharmaceutical Process Committee (ASME-BPE). Finally, always specify disc-type vortex breakers to ensure proper vessel drainage. The vortex breaker will help to assure adequate vessel drainage while it is being cleaned, eliminating residue and cleaning agent carry-over.

System instrumentation is essential for ensuring consistent CIP operations and enabling the validation effort. The following cleaning parameters — at a minimum — should be measured: supply and return temperatures of the wash solutions, solution supply flow rate return flow switch for automatic shutdown, solution supply pressure, and solution supply and return conductivity. Locations of instruments are sketched in Figure 3. Effective utilization of CIP instrumentation and control allows implementation of Process Analytical Technology (PAT), in accordance with recent FDA initiatives, for cleaning operations.

Figure 3. Instrumentation on a CIP Skid

An integrated design will clean the process tanks and transfer lines as one circuit, potentially reducing the number of cleaning circuits by a factor of two. Use process piping as CIP supply and return piping whenever possible (reducing the quantity of installed piping). Design the cleaning circuit to clean groups of paths on a vessel. For example, the O₂, CO₂, and addition lines may each be configured as one cleaning path into a bioreactor. These paths are usually cleaned individually in series, but, if designed correctly, they can be cleaned in parallel.

TYPICAL CLEANING SEQUENCE

Figure 4 shows the typical CIP phases for cleaning tanks, bioreactors, centrifuges and microfilters, as well as equipment used for media preparation and distribution, primary recovery, purification, and final bulk filling. An abbreviated, purified water rinse cycle is often used in cleaning buffer equipment or equipment with no proteinaceous residues. While some in-process residues are readily soluble in water alone, many are not. Accordingly, aqueous cleaning solutions are used to chemically degrade (via peptizing, saponifying, wetting, or emulsifying) non-water soluble residues.

Figure 4. Phases of a Common Chemical CIP Cycle

Phase 1 consists of pre-rinses and intermittent drains of the system. Ambient temperature water (potable or purified) is used to rinse water-soluble residues from process equipment and its interconnecting piping. The water is passed once through the CIP circuit and sent to a drain. The pre-rinse removes water-soluble post-production residues, minimizing the residue load in the subsequent alkaline wash (making it as short and effective as possible). Intermittent drains between rinses maximize the turbulence at the vessel bottom for optimum residue removal.

Potable water is used in some newer biopharmaceutical manufacturing facilities for all rinse operations during the CIP sequence except for the final water-for-injection (WFI) rinse. The use of potable water can reduce water costs and, with the proper controls in place, is a satisfactory method of rinsing the circuit.

Phase 2 is the alkaline wash. Water is circulated within the circuit, and cleaning agents are added to a predetermined concentration. Then the cleaning solution is heated to a chosen temperature by a heat exchanger. The circuit-return temperature (as measured at the CIP skid) is monitored and used as an interlock to ensure that all inline piping and equipment is washed at the specified temperature for a specified time. The alkaline wash removes water-resistant residues.

Phase 3 consists of air blowing and draining the circuit. Air blowing clears the alkaline solution from the CIP supply lines, and draining clears the CIP return lines. This reduces the rinsing time and the amount of water required to clear the alkaline chemical from the circuit during subsequent rinses and drains. Effective air blowing and draining also results in more repeatable and reliable rinsing and residue clearance.

Phase 4 consists of rinsing with ambient-temperature or hot water and intermittent draining. The rinses pass once through the circuit and to the drain, removing the bulk of the alkaline cleaning agent.

Phase 5 is the acid wash. Similar to the alkaline wash, water is circulated within the circuit with acidic cleaning agents, and the cleaning solution is heated to a chosen temperature by a heat exchanger. The acid wash is used to neutralize any residual alkaline cleaning agent, demineralize the surfaces of process equipment, and provide some passivation. Some manufacturing facilities have eliminated (or considered eliminating) the acid wash from the CIP sequence to reduce cycle time. However, this increases the time and water consumption needed to remove the alkaline cleaner and the risk of accumulating mineral deposits on process equipment surfaces.

Phase 6 consists of air blowing and draining to clear the acid solution from the circuit. This reduces rinsing time and water consumption.

Phase 7 is the final rinse step, using WFI that is passed once through the circuit in bursts with intermittent drains. The WFI rinse removes the acid cleaning agent and all other residues prior to cycle completion. Return conductivity is used to determine the end point of the rinse.

Phase 8 is a final air-blowing and draining, leaving the system "drained and dry."

CLEANING CYCLE STRATEGY

Let us now focus on the optimization of cleaning processes. Some of the greatest gains in plant efficiency can be made in this area. CIP strategies and objectives are often overlooked before the commissioning and startup of pharmaceutical manufacturing facilities — leading to use of the "neutron bomb" approach to cleaning. This approach results in the usage of large quantities of cleaning agents and time during cleaning operations to achieve acceptable results. Unfortunately, once circuits are commissioned and validated, optimizing — or even adjusting — them is difficult and rarely done because of the time and effort required for revalidation.

The four most significant factors that affect the efficiency of the cleaning process are cleaning solution temperature, cleaning agent concentration, cleaning solution contact time, and the external energy put into the cleaning solution in the form of velocity and pressure, resulting in momentum and turbulence. The effective specification and control of these factors results in efficacious, repeatable, and reliable cleaning.

These four factors are used to optimize cleaning operations. For example, increasing the cleaning solution temperature can result in significant reduction of cleaning time. Increasing the temperature increases reaction rates, decreases bonding strength and decreases solution viscosity, which results in increased turbulence. Increases in cleaning-agent concentration and the external energy put into the cleaning solutions can also result in reduced cleaning time, potentially increasing the facility's productive capacity.

To define CIP strategies, evaluate the equipment being cleaned. Complete CIP cycles (incorporating all eight phases) are used for cleaning protein-contacting equipment and vessels (bioreactors, centrifuges, and product transfer lines). Water rinses alone can be used to clean buffer- and sometimes media-contacting equipment. Salt-based buffers are extremely water-soluble and typically do not require cleaning agents except on a periodic maintenance basis. This strategy significantly reduces cleaning agent usage, water cost, and cleaning-cycle time.

CLEANING CYCLE DEVELOPMENT

Once cleaning cycle and circuit strategies are established, CIP cycle development can begin. This incorporates a number of factors, including hydraulic balancing of circuits, specification of rinse durations, circuit-fill volumes, cleaning agent concentrations, wash temperatures, and wash contact times. When setting and fine-tuning cleaning parameters, one should start with low values and increase cleaning agent concentrations, exposure time, solution temperatures, and other variables only as required. Finally, automate the cycles as much as possible for efficiency, reproducibility, and reliability.

Hydraulic balancing ensures optimal cleaning performance and helps attain maximum cleaning capability. A cleaning circuit is hydraulically balanced when the incoming rinse or wash flowrates and the drain flowrates are equivalent. This ensures that CIP solutions do not accumulate in the vessel being cleaned. Tanks that accumulate liquid during CIP do not clean as well as free-draining tanks, and this accumulation of cleaning solutions results in residue carryover and unreliable cleaning operations.

Establish CIP circuit-fill volumes as part of the hydraulic balancing operation, and modulate CIP supply pump speeds to maintain setpoints for flowrates. Fill volumes (the volume of water required to fill the supply and return piping) should provide adequate net positive suction head (NPSH) to the CIP return pump. The fill volume should be minimal to avoid "puddling" in the equipment and inadequate turbulence.

Set water rinse durations to minimize rinse times and water use. Return conductivity, measured at the CIP skid return piping, is used to set rinse durations.

• The first pre-rinse (Phase 1) is used to remove the bulk of the residues in the process equipment and piping. Rinsing of the residues should continue until the return conductivity reaches 75-50 µS/cm.

• The post-alkaline-wash rinse (Phase 4) removes the bulk of the alkaline wash. Set the duration by rinsing until the return conductivity reaches 75-50 µS/cm.

• The final rinse (Phase 7) removes all the remaining residues. Return conductivity should be less than 2 µS/cm.

Residues take the form of cell debris, denatured proteins, lipids, sugars, salts, nucleic acids, endotoxins, and possibly viable organisms. Alkaline concentrations should be based on the quantities and types of residues left in post-production process systems. The highest concentration of cleaner should be used with the worst-case residues. Attention to cleaning chemical concentrations can reduce operating costs and minimize chemical usage. Offline analysis and understanding of the process residues will help determine the wash chemical concentrations.

Cleaning-agent concentrations usually fall within these ranges (measured as supply conductivity):

• Alkaline cleaning agents:
• * 20 to 25 mS/cm for bioreactors and harvest systems (highest concentration of residues)
• * 10 to 12 mS/cm for media preparation (moderate concentrations of residues)
• * 8 to 10 mS/cm for purification systems (lower concentrations of residues)
• Acid cleaning agents 4 to 6 mS/cm
• Buffer vessels and lines are often only water rinsed.

Cleaning temperatures and contact times must be based on the chemical characteristics of the residues (including protein denaturation) and the cleaning agents. Alkaline wash temperatures are typically 60 to 70°C. However, if silicon-based antifoam agents are present, alkaline wash temperatures are 70 to 80°C.

Acid wash temperatures are typically 25 to 35°C as this is adequate for neutralization and de-mineralization, the purpose of the acid wash. A temperature just above ambient gives little cleaning benefit but helps ensure better temperature control. Some companies specify higher acid temperatures, which provide little benefit but are not harmful.

The alkaline wash should remove most product residues in 5 to 15 min (8 to 10 iterations through all sub-circuits). Difficult residue areas may receive 15 to 25 min of alkaline exposure. Easier residue areas may receive 5 to 10 min of alkaline exposure. Acid washes should remove alkaline and mineral residues in 5 to 10 min (recirculate 4 to 6 circuit volumes).

Figure 5. Typical Bioreactor with a Plethora of Lines Requiring Cleaning

CAPACITY GAINS

Optimization of cleaning operations can increase the productive capacity of existing process equipment through the reduction of downtime. Just how much capacity can be gained? CIP cycles that are not optimized can take more than 4 hr for a single piece of equipment, such as the one in Figure 5. By optimizing the cycle and fine-tuning run parameters, a 2.5-hr reduction in cleaning time can translate into eight additional production runs per year. The example in Table 1 shows a 5 percent capacity increase.

Additional advantages of optimizing CIP cycles include reductions in water usage, cleaning-agent usage, lot-to-lot and product-to-product turn-around times, and labor and plant operating costs. However, there are costs associated with cleaning optimization, including some upfront labor hours for cycle development. Additionally, if the optimization is not planned properly, commissioning schedules (and thus overall time requirements for bringing facilities on-line) may suffer. The advantages still outweigh the disadvantages.

Table 1. Batch Run Time

Avoid manual cleaning whenever possible. Manual cleaning can be plagued with inconsistency and is a hot issue with regulatory agencies. Manual cleaning operations are difficult to validate and require extensive operator training and qualification. To deal with these issues, manually cleaned equipment may be handled in parts washers or automated COP (clean out-of-place) equipment that employs processes very similar to those used for CIP cleaning.

A number of facilities rely on manual cleaning of centrifuges, but CIP cleaning of centrifuges provides better control of the cleaning parameters and generally yields shorter cycle times.

APPLY CIP TECHNOLOGY

As biopharmaceutical companies rush to bring new products to market, productive capacity can become a significant bottleneck. Manufacturing and engineering personnel routinely address process efficiency, aiming to decrease run times and increase yields. These efforts often lead to plans for added manufacturing space and process equipment at substantial capital cost.

Significant manufacturing capacity can be added without the addition of capital equipment by focusing on cleaning. These gains can be fully realized when effective CIP engineering is incorporated into the design and startup of new and retrofitted facilities. ?

Simon Forder is west coast director at JM Hyde Consulting, Inc., 400 Oyster Point Blvd #211, South San Francisco CA 94080, 415.748.8753, fax 650.588.2857, simon.forder@jmhyde.com

John M. Hyde is president and founder of JM Hyde Consulting, Inc., 6685 Gunpark Road, Suite 230, Boulder CO 80301, 303.530.4526, fax 303.581.0839, john.hyde@jmhyde.com