Unlocking the Key to Sterile Manufacturing: Optimizing Cleaning-in-Place Processes

Introduction;

In routine sanitization practices for sterile manufacturing, all product contact surfaces, such as pumps, tanks, and relevant piping, must undergo a thorough cleaning process. One common and effective method for achieving this is Cleaning-in-Place (CIP). CIP is a set of activities conducted to clean all or parts of processing system without removing or disassembling them, this process facilitates cleaning of the process equipment, vessels, inter-connection pipes, valves and fitting after batch processing of the production fully or semi- automated cleaning technique that allows to clean closed or open circuits without dismantling equipment.

CIP recipe;

The CIP "recipe" refers to the specific set of parameters and a series of sequential steps required to effectively clean and sanitize a piece of equipment or a processing system. A CIP recipe defines the cleaning process in a pharmaceutical manufacturing facility. It involves the use of cleaning agents, such as detergents or sanitizing solutions, and specifies particular temperatures, flow rates, and durations for each stage of the cleaning cycle.

The CIP recipe is a critical component of the overall cleaning and sanitization process, as it ensures the consistent and thorough removal of any residual product, impurities, or microbial contaminants from the equipment. The recipe determines the order in which different parts of the equipment are cleaned and rinsed. It is typically developed and validated during the initial commissioning of the equipment or cleaning processing system and regularly reviewed and updated as necessary.

Key Elements of the CIP Process;

The CIP process involves the jetting or spraying of surfaces or circulation of cleaning solutions with some key points as follows:

1.???? Flow rate and pressure

2.???? Temperature and contact time

3.???? Cleaning/sanitizer solution composition

4.???? Rinsing steps

5.???? Quality of water for cleaning/rinsing

Below we explain each one;

1.???? Flow rate and pressure;

The flow rate and pressure at which the cleaning solution is circulated through the equipment. These parameters are critical in ensuring the thorough wetting and contact of the cleaning solution with all internal surfaces of the equipment. All spray devices should be oriented so that the cleaning solution is directed at the intended location with enough flow and pressure to clean the vessels.

2.???? Temperature and contact time;

The required temperature of the cleaning solution and the duration for which it is circulated through the equipment. This is typically set to anywhere between 50 to 75 °C to break down fats or proteins the salts and the minerals. The temperature and duration are carefully controlled to ensure the effective dissolution and removal of the contaminants.

3.???? Cleaning/sanitizer solution composition;

We use suitable chemicals such as detergents, acids or alkalis to break up and remove any remaining residues through chemical actions. The type and concentration of these cleaning agents is based on the specific requirements of the equipment and the manufacturing process.

4.???? Rinsing steps;

The number and duration of the rinsing steps required to remove any residual cleaning solution from the equipment. Proper rinsing is essential to ensure that no cleaning agent residues are left behind, which could potentially contaminate the next batch of product.

5.???? Quality of water for cleaning/rinsing;

According to the European Medicines Agency's (EMA) "Guideline on the quality of water for pharmaceutical use"(1), the quality of water used for cleaning and rinsing equipment, containers, and closures is a critical factor in ensuring the safety and efficacy of pharmaceutical products. In sterile pharmaceutical manufacturing, the quality of water used for cleaning and rinsing is critical to ensure the safety and efficacy of parenteral products. According to EMA guideline the following water quality standards should be applied for cleaning and rinsing processes;

Purified Water (PW); PW should be used for the initial rinse, CIP of equipment, containers, and closures.

Water for Injection (WFI); WFI is required for the final rinse, including CIP of equipment, containers, and closures, in sterile parenteral products. contaminants. In this regard take a look at the following table;

We can combine above key elements in the following CIP process steps which conduct sequentially before Sterilize-in-Place (SIP);

The 1st step; Pre-Rinse;

The first step, Pre-Rinse, involves an initial flush of the equipment and surfaces with purified water (PW) or recycled Water for Injection (WFI) at ambient temperature to eliminate visible product residues, debris, and gross soil contamination. This process helps loosen any dried or baked-on contaminants before further cleaning and sanitization steps. To ensure effective cleaning, achieving the correct velocity is crucial. Laminar flow, characterized by velocities below 1.5 m/sec, does not provide adequate cleaning characteristics. Turbulent flow, achieved between 1.5-2.1 m/sec, yields better results, with no significant gain observed beyond 2.1 m/sec. Additionally, the design should prioritize eliminating dead leg zones or undrainable pockets in the piping, as these can harbor stagnant water and potentially contribute to microbial growth or other contamination issues.

The 2nd step, Detergent circulation cleaning: After the pre-rinse, practically the CIP process is initiated as the 2nd step. This step typically involves using Caustic/ Acidic cleaning detergents or cleaning solutions that are specific to the equipment and process being cleaned to remove any remaining product residues, microbial contaminants, and other impurities. It can be organized as follows:

The cleaning solution is circulated for a specific time and temperature determined by the validated cleaning process. The in-line sensors will monitor the temperature to ensure the media is at the correct temperature, Pressure to ensure there is correct pressure exist through the piping system and flow to confirm the correct flow velocity is achieved. Furthermore, the amount of cleaning solution Caustic/ Acidic cleaning solution or Detergent concentration to be monitored by conductivity sensor with milli-Siemens sensitivity which is usually located after the recirculation CIP pump via the CIP supply and returns via the CIP return It’s justified that conductivity sensor wound not exposed to CIP process so it is recommended that dosing position of detergents or cleaning agents/ detergent dosing pump to be considered after this specific sensor. ?

The 3rd step, Intermediate Rinse; Following the CIP, an intermediate rinse as 3rd step is conducted to remove the cleaning agents and any remaining debris from the equipment surfaces using PW at temperature around 60 C°. This step is crucial to ensure that no cleaning solution residues or Sanitizer solution left behind, which could potentially impact the subsequent steps and the final product quality.

The 4th step, Final Rinse with the CIP verification: The 4th step before SIP is the final rinse. In this step, water for injection (WFI) is used to flush the system and remove any remaining traces of cleaning solution or debris. The final rinse ensures that the equipment and surfaces are thoroughly cleaned and free from any potential contaminants that could compromise the sterility of the subsequent production batch. This step to be monitored with conductivity sensor with micro-Siemens sensitivity in the drain to verify and confirm the end of the CIP process when the WFI water conductivity used for the final rinse is reached to equal or less than 1.3 micro-Siemens or defined set point.

CIP verification;

In a GMP environment, verifying the effectiveness of the CIP process is crucial to ensure that the equipment and systems are properly cleaned and ready for subsequent sterilization processes. Two common methods for CIP verification are:

1.???? Conductivity Curve Monitoring: During the final rinse step, the conductivity of the WFI water is continuously monitored and plotted on a graph, creating a conductivity curve. This curve should exhibit a characteristic shape, with an initial high conductivity value due to the presence of cleaning solution residues, followed by a sharp drop as the cleaning solution is flushed out, and finally a stable low conductivity value indicating the complete removal of contaminants (Below picture);

The CIP process is considered successfully verified when the conductivity curve stabilizes at or below the predefined set point (usually ≤1.3 micro-Siemens for WFI). Any deviations from the expected curve shape or failure to reach the set point conductivity value may indicate incomplete cleaning or residual contaminants, requiring further investigation and corrective actions.

2.???? Sampling and Analysis: In addition to conductivity monitoring, samples of the final rinse water can be collected and analyzed for the presence of residual contaminants, such as cleaning agents, product residues, or microbial contaminants. These samples are typically subjected to various analytical techniques, such as pH testing, total organic carbon (TOC) analysis, or microbiological testing, depending on the specific requirements and validation protocols.

If the analytical results of the samples meet the predefined acceptance criteria, the CIP process is considered successfully verified, and the equipment is deemed ready for sterilization. However, if any samples fail to meet the acceptance criteria, further investigation and corrective actions, such as additional rinsing or re-cleaning, may be required.

Take-Home Message;

By focusing on the Cleaning-in-Place (CIP) ?method, we can ensure effective cleaning and preparation of equipment for subsequent sterilization processes in sterile manufacturing environments.

To ensure effective CIP in pharmaceutical manufacturing:

1. Monitor detergent concentration during the cleaning step using a milli-Siemens conductivity sensor, which is usually located after the recirculation CIP pump with injection points for dosing detergents placed after the sensor.
2. Conduct a final rinse with WFI and verify CIP completion using a micro-Siemens conductivity sensor, ensuring WFI water reaches the defined set point (equal to or less than 1.3 micro Siemens).

These practices help maintain equipment sterility, prevent contamination, and adhere to Good Manufacturing Practices (GMP), ultimately contributing to product quality and patient safety.

Reference;

1-???? European Medicines Agency's (EMA) Guideline on the quality of water for pharmaceutical use, EMA/CHMP/CVMP/QWP/496873/2018?