Cleaning Validation of Clean-in-Place (CIP) Systems

The clean-in-place cleaning method is used to clean equipment that can not be disassembled or displaced like pipelines, tanks and large vessels. Cleaning validation ensures that our cleaning method is capable of removing the residues and contaminants from the equipment or vessel. Cleaning validation of such equipment as great importance because we can not move them for proper cleaning and some parts of these equipment can’t be checked visually. In this article, we will understand the whole process of cleaning validation step by step.

Step 1: Cleaning Validation Protocol

Create a validation protocol having the following sections.

1. Define Cleaning Procedure

Create a sampling procedure for the equipment, pipeline or vessel including the cleaning steps, cleaning agent, temperature and cleaning time according to the characteristics of the material and residue.

2. Selection of Worst-Case Product

This is the most critical part of any cleaning validation. Select the difficult-to-clean product manufactured on the equipment on factors like its solubility, concentration and difficulty in cleaning.

3. Sampling Plan

Select a sampling plan to take swab samples from the surface and rinse samples from difficult-to-reach areas. Define critical parts, sample quantity and sample storage conditions in the protocol.

4. Analytical Method

Select an analytical method to detect the residue of the worst-case product samples. The method should be sensitive and specific and validated for its accuracy, precision and linearity.

5. Acceptance Criteria

Establish acceptance criteria on the basis of product toxicity, allowable residual limits and regulatory guidelines and it should be scientifically justified.

Step 2: Validation Studies

1. Cleaning Parameters Determination

Conduct a study to determine the critical cleaning parameters like concentration of cleaning agent used, temperature of water, water quantity used in cleaning, and contact time of cleaning agent.

2. Residue Removal Study

Perform a study to determine that the cleaning method is capable of cleaning the residues from the equipment. Spiking methods are generally used to demonstrate the residual removal study in which the worst-case product is spiked to the equipment and swab or rinse samples are analyzed.

3. Rinse Recovery Study

Evaluate the efficiency of the rinse method to clean the residues from the equipment surface.

4. Swab Sampling Studies

Collect the sample of residues using swabs from the equipment surface and analyze it for recovery. It will help to determine how much residues are collected from the surface in percentage.

Step 3: Sampling and Analysis

Take the sample using a swab and rinse the method from the locations as described in the protocol. Analyze the samples using the validation analytical method to quantify the residues. Compare the analytical results against the acceptance criteria to determine the validation result and effectiveness of the cleaning method.

Step 4: Documentation and Reporting

Document every step of the validation process including procedure, analytical results, any deviation and corrective action taken during the validation process. Prepare a validation report to summarize the results of the validation study and conclude the recommendation for improvements.

Step 5: Ongoing Monitoring

1. Routine Monitoring

Monitor the CIP cleaning system routinely to ensure the effectiveness of the cleaning procedure. This monitoring may include the visual inspection, TOC test of rinse sample or periodic verification of critical parameters.

2. Change Control

You must implement a change control system to manage the changes in equipment, cleaning procedure or any change in product formulation that may impact the cleaning procedure.

3. Revalidation

Create a schedule for periodic revalidation of CIP equipment to confirm its continued regulatory compliance. Revalidation may be initiated due to any significant change in process, equipment or any regulatory requirement.

Regulatory Requirements

1. FDA Guidelines: Follow FDA guidelines on cleaning validation i.e. FDA's Guide to Inspections of Validation of Cleaning Processes.

2. ICH Guidelines: ICH Q7 guidelines for Good Manufacturing Practice (GMP) for Active Pharmaceutical Ingredients is another regulatory guideline on cleaning validation for pharmaceutical manufacturing equipment.

3. EU GMP Guidelines: EU GMP Annex15 on Qualification and Validation must also need to comply that includes the requirements for cleaning validation in pharmaceutical manufacturing.

Cleaning validation of clean-in-place (CIP) manufacturing equipment and systems is essential to prevent cross-contamination through the residues of previous products. By following the above CIP validation steps a pharmaceutical manufacturer can ensure product quality, patient safety and regulatory compliance.

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