What is Cleaning in Place or CIP Cycle? Light on Automation Prospect

The cleaning of systems at the place where they are installed is called Cleaning in Place (CIP).

Meanwhile, systems, sub-components, ancillary systems, and accessories that are unable to clean in their dedicated space or required to be dismantled and cleaned outside is called Cleaning out of Place (COP).

A successful CIP cycle guarantees that these systems are free from previous batch residues. It also improves the efficiency of production cycle time. However, to achieve this, CIP requires solid control from development to automation.

Establishing and demonstrating an effective cleaning procedure requires thorough cleaning validation studies. We’ll just stick to the Clean In Place (CIP) system instead.

Typical Cleaning In Place Cycle Steps

CIP is generally carried out after completion of a batch in that equipment to remove the previous batch residues typically known as soiling. Every healthcare industry develops and employs its own cleaning procedures.

Utility for cleaning in place is selected based on requirements such as Water For Injection (WFI), Purified Water (PW), Potable Water (PoW), etc.

Due to product complexities, we can’t define a fixed set of operations in cleaning in place cycles. In fact, below are some of the common steps. Again, they are optional unless otherwise justifiable to label the equipment status “CLEANED”.

Traditional vs. Automated

Before pharmaceutical manufacturers adapted to automation, CIPs were manually performed. From preparing cleaning solutions to final rinsing with offline measurements.

Due to manual handling, assuring the same cleaning effect every time was a challenge. Overcoming this, automated cycles would make the business sustainable in the long run.

The table below outlines the benefits of following the automation approach.

Traditional Approach	Automation Approach
Product Contamination Probabilities	Reduced Product Contamination
Longer Cleaning Cycle Times	Short Cleaning Cycle Times
Increased Regulatory Concerns	Reduced Regulatory Concerns
Maintaining offline measurement systems	Replaced with online measurement
Longer Production Cycle Times	Shorter Production Cycle Times
Consistency and Repeatability is a Challenge	Similar cleaning effects every time
Chemical exposure to operating personnel	Exposure free operations
Trouble with resource optimization	Resources such as WFI can be optimized effectively

Automated Cycle

There are various ways to perform Cleaning In Place based on the system architect.

1. Mobile Systems (Movable on the floor)
2. Stationary Systems (Fixed directly on the floor)

Stationary systems may have dedicated arrangements for the CIP cycle through automation as they can’t move from one location to another.

Sometimes, equipment is docked to the specialized cleaning stations called CIP skids. Based on this, there are two ways to perform cleaning in place of the equipment.

1. Using CIP Skid (For mobile systems)
2. Using an in-built automated CIP cycle (for stationary systems)

Drug manufacturing involves complex process systems from process vessels to finished product processing units such as lyophilizers, filling machines, etc. Every piece of equipment may undergo either dedicated or an integrated cleaning in place treatment.

To easily understand this, we’ll look at the in-built CIP of a dedicated process vessel. While cleaning steps remain constant, the philosophy for an integrated approach is different than single-vessel CIP. Just put the picture below to give you a rough idea.

Recipe Based Approach

The best way to drive and control your cleaning cycles is through recipe management. The recipe is a step-by-step sequence of operations with conditional logic that behaves as per user set points.

Suppose we’ve got a 600L working volume process vessel to do the cleaning in place. So a typical recipe should look like this:

The values and steps entered above are just examples, you may want to edit your recipe according to your cleaning requirements.

Equipment with an in-built CIP would require manual caustic and acid solution preparations or any other automated alternative.

When using CIP stations, it takes care of caustic and acid solution preparation with a dosing system arrangement. So the steps shown above may be modified.

Prior to starting execution, it is important to check the readiness of the system including:

1. Input/Output testing
2. Proper concentration of cleaning agents
3. Pressurized conditions of clean utility such as WFI
4. Drain lines are connected properly
5. Equipment is empty and no product present

Once the recipe loads successfully, it is time to execute it.

Execution

Based on the selected utility, the cleaning process is initiated. Purified water, if selected, would require heating during the caustic wash to effectively disengage high soiling at high pH.

Whereas, WFI itself is in hot condition approx. 80°C and hence not included in a recipe. The mixer is kept ON till the completion of the cycle at a suitable RPM.

Pre-Rinse

1. PW or WFI introduced in the system through the main header and then sub-header. Flushing of the vessel along process lines ensures large-sized soiling or residue is easily removed.
2. The soiled water then leaves the system through the drain point and therefore this step is once through. The effectiveness of this step can be confirmed by installing a suitable turbidity meter in drain locations.
3. Upon complete draining, process-grade air is flushed through the system to ensure no moisture remains inside the surface of the piping and equipment.
4. The system then depressurizes and gets ready for the next step.

Caustic Wash

1. PW or WFI is filled to the set point.
2. Caustic has been added to prepare a 0.5N NaOH solution. Explained further on how to make it 0.5N.
3. If PW is used, then the system is heated to the temperature range of 60-80°C with the help of an appropriate heating medium through the jacket. In the case of WFI, this step is not required.
4. Once the solution is heated, it is then recirculated through various process lines for a set time to ensure all the residue is dissolved and disengaged from product contact surfaces.
5. After recirculation, the system is drained completely.
6. Upon complete draining, process-grade air is flushed through the system to ensure no moisture remains inside the surface of the piping and equipment.
7. The system then depressurizes and gets ready for the next step.

Intermediate Rinse

1. PW or WFI is filled to the set point.
2. Recirculation is done from the same path that was employed during the caustic wash to ensure remaining residue traces were removed along with the caustic solution.
3. After recirculation, the system is drained completely.
4. Upon complete draining, process-grade air is flushed through the system to ensure no moisture remains inside the surface of the piping and equipment.
5. The system then depressurizes and gets ready for the next step.

Acid Wash

1. PW or WFI is filled to the set point.
2. Acid is added to prepare 0.05N Ortho-Phosphoric Acid solution. Explained further on how to make it 0.05N.
3. It is then recirculated through process lines for a set time. Protein residue that may have escaped from caustic wash gets removed here.
4. After recirculation, the system is drained completely.
5. Upon complete draining, process-grade air is flushed through the system to ensure no moisture remains inside the surface of the piping and equipment.
6. The system then depressurizes and gets ready for the next step.

Intermediate Rinse

Similar to the previous intermediate rinse.

Final Rinse (Once-Through)

1. The system and process lines are flushed with PW or WFI and drained simultaneously for a set time to remove all the residue of cleaning agents accumulated during cleaning.
2. pH and conductivity are monitored during flushing. Sometimes, conductivity can dictate that equipment and associated process lines are free from any residue.
3. The conductivity of less than or equal to 1.3 µS/cm will terminate the cycle upon successful monitoring for the set time.
4. Once the conductivity is achieved, the system is drained completely.
5. Upon complete draining, process-grade air is flushed through the system to ensure no moisture remains inside the surface of the piping and equipment.
6. The system then depressurizes and gets ready for the next batch.

Once the final rinse is over, Cleaning in Place is considered complete. Intermediate rinses add one layer of cleaning assurance and can be considered optional. Also, caustic washing is sometimes called alkali wash.

If the critical process parameters for pharmaceutical cleaning operations are not meeting the acceptable limits, the cleaning cycle will have to be re-executed. Following are the critical process parameters generally considered for cleaning in place.

• Flowrate
• Pressure at Utility Supply
• Temperature and sometimes pH
• Acid and Caustic concentrations
• Acid and Caustic contact times
• Final rinse Conductivity demonstrating all cleaning agents removed completely

Velocity is the Key

Velocity no more than 2 m/s and no less than 1.5 m/s would achieve better results in cleaning. Recirculation pumps and flowrates at supply should have a flowmeter with velocity measurement capabilities to ensure the required fluid velocity is achieved during practical use.

A velocity of less than 1.5 m/s is considered laminar flow and would not promote proper cleaning. While a velocity of more than 2 m/s would not obtain additional effectiveness.

Importance of Cleaning Agents

The selection of a cleaning agent plays an important role in the effective cleaning of your healthcare equipment.

Finished product processing plants generally consider using 0.5N NaOH as a caustic and 0.05N OPA as the acid solution. They are adequate in dissolving proteins and other commonly associated residues.

Please note, they can’t remove scaling formed on the surface of the equipment or process lines. For that purpose, we generally carry out passivation with the help of Per-acetic acid or Nitric acid.

The caustic solution is generally 0.5N. Consider the dissolution of 20g of NaOH in 1L of PW to calculate the total required quantity of NaOH. Simply multiply the cleaning volume by a factor of 20 and that will give you the total grams of required NaOH.

You can calculate this for solid compounds pretty straight, but liquids like acids need additional calculations.

Commonly practiced acid for CIP is 85% concentrated ortho-phosphoric acid (OPA) of 0.05N.

In the case of Ortho Phosphoric Acid (H₃PO₄), a simple way to calculate the required amount of acid is to multiply by a factor of 1.137 (This value has arrived after a few pre-calculations). So the formula would be:

Volume of H₃PO₄ required (ml) = 1.137 * (Volume of Total Solution Including Acid (L))

The concentration and composition of cleaning agents used should demonstrate the effectiveness of your cleaning in place cycle.

Find Optimization Opportunities

Once set does not mean settle. Find opportunities to optimize your existing cleaning cycles both time and cost-wise.

Companies should always monitor their cycle behaviors over a period of time and may keep a trend with them. Trends are the best one-page source for finding potential risks as well as opportunities to improve.

Recipe parameters are another way to look at optimization. Excessive cleaning is nothing but a waste of time and resources. A systematic study of current CIP cycles would definitely bring something new to the table that may have been missed earlier.

Riboflavin or Spray Ball Coverage Test

Purpose

This test is used to evaluate the cleaning effectiveness of the spray ball for particular equipment. Moreover, to ensure the cleaning in blind spots of the equipment created by shadows due to agitator, baffles, nozzles, mechanical fittings, etc.

Scope

This cleaning pattern applies to the Cleaning In Place (CIP) of process vessels, mainly demanding the documented evidence of cleaning effectiveness.

Pre-requisites

• As part of the procedure, equipment must already be cleaned to avoid false reporting of fluorescence under ultra-violet light.
• Riboflavin solution with the required quantity filled into the spray device. Prepare Riboflavin solution by dissolving 1 gm of Riboflavin in 10 Lit. water for 100ppm solution.
• CIP Pump on the supply side to deliver at least 2.5 to 3 bar(g).
• Electropolishing has been completed and approved.
• Availability of pressure gauge, flow meter, and control valves.
• Identify and define critical or worst-case areas of the equipment.

Background

Riboflavin is most widely used for this test. It is a yellow vitamin that gives fluorescence under UV light. It is mixed with water and sprayed on the inside surface of the equipment being tested for cleanability. Rinsing is then delivered through the spray ball in a burst-rinse method.

Maintain the designed flow and philosophy of cleaning when performing the riboflavin test. The cleaning in place cycles must run under the bracketing of system design to confirm the results as repeatable.

Procedure

Steps to perform riboflavin testing:

1. Spray the solution on the inside surface of the equipment including all critical areas.
2. Perform cleaning through a spray ball at the specified flow rate, time, pressure, and frequency.
3. Inspect visually with the help of UV light for any fluorescence post-cleaning.
4. Note down the observations and conclude as pass/fail.

If riboflavin is still present post-cleaning, then it would appear like this under UV light and the cycle would be considered a failure. Else, the testing is considered as Pass.

Conclusion

Designing and implementing automated cleaning in place cycles is a complex process backed by appropriate conductivity measurements.

Though development platforms and measurement systems have been upgraded over time, the fundamentals remain the same. The steps explained in this article are just the tip of an iceberg and actual digging starts while developing them right from the valve activations till conductivity measurement.

How do you conduct your CIP cycles? What challenges are you facing in assuring your systems clean? Comment below.