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

Cleaning of manufacturing equipment has great importance in the pharmaceutical and biotechnology industries. It is required to clean manufacturing equipment thoroughly between batches to prevent cross-contamination and ensure the product quality. Non disassembling systems and production equipment are cleaned using the clean-in-place method. It is an automated system that cleans the interior surface of vessels, tanks and process lines without disassembling them.

A clean-in-place system is not reliable until it is validated. Validation of this system is required to demonstrate that the cleaning procedure is effective and reliable to produce reproducible results. In this article, we will understand the validation strategy, sampling techniques, regulatory expectations and best practices for clean-in-place cleaning validation for pharmaceutical equipment and systems.

What is CIP (Cleaning-in-Place)?

A clean in a place is an automated or semi-automated cleaning system that cleans equipment without dismantling them. A clean-in-place system involves:

• Pre-rinsing with water to remove residues
• Detergent cycle to remove remaining product residues
• Post-rinsing to remove detergent traces
• Final rinsing with purified water or water for injection
• Sanitization or disinfection cycle if required

Clean in place is a widely used method for cleaning of fermenters, reactors, tanks, piping systems, especially in clean rooms and liquid oral dosages plants.

Why Cleaning Validation is Essential

Cleaning validation helps to ensure that the cleaning procedure removes all residues of previous product, cleaning agent used for cleaning and microbial contamination. The goals of cleaning validation are:

• Prevents cross-contamination between products
• Ensures product safety and efficacy
• Complies with regulatory requirements
• Maintains equipment reliability and reduces batch failures

Regulatory Expectations

Regulatory authorities like FDA, EMA, WHO, PIC/S and MHRA expect the documented evidence of cleaning procedure validation. The FDA guideline says that cleaning procedures must be validated to ensure that they consistently control contamination to acceptable levels.

Key Elements of CIP Cleaning Validation

1. Validation Protocol Development

As we know, a validation protocol is a detailed plan outline containing the scope, methodology and acceptance criteria. It must include:

• Objective
• Equipment and product details
• Cleaning procedure and parameters
• Sampling plans and locations
• Analytic method and detection limits
• Acceptance criteria
• Number of validation runs (generally 3 consecutive runs)
• Revalidation criteria

The cleaning procedure validated for a specific product is not considered validated for all products. The protocol should be product-specific when the same equipment is used for multiple products.

2. Worst-Case Product Selection

When equipment or a system is used for the manufacturing of multiple products, it is essential to identify the worst-case product. Worst case product is one that is hardest to clean or has insoluble ingredients or is highly toxic. Consider the following factors to select a worst-case product.

• Solubility of API
• Exposed surface area of equipment
• Potency and toxicity of the product

Cleaning validation against the worst-case product ensures the cleaning efficiency for all the products.

3. Sampling Methods

There are two main types of sampling used in the cleaning validation of pharmaceutical equipment

A. Swab Sampling: It is the physical wiping of a defined surface area with a sterile swab. It is suitable for hard-to-clean areas, gaskets and valves. It allows recovery studies and targeting specific equipment locations.

B. Rinse Sampling: In the rinse sampling, the final rinse solution from the CIP system is collected. It is useful to determine overall system cleanliness. It detects water soluble product residues or detergent remains.

Both methods are used in cleaning validation and help to determine the overall performance of the cleaning method.

4. Analytical Method Validation

The method for analysis used to detect the residues must be validated for its specificity, sensitivity, recovery, linearity, accuracy and precision. Common analytical methods used for detection are:

• High-performance liquid chromatography (HPLC)
• Total organic carbon (TOC) analysis
• UV-visible spectrophotometry
• Conductivity (for detergent verification)

5. Establishing Acceptance Criteria

Acceptance limits in cleaning validation are established on the following criteria.

A. No visible residue: Equipment must be visually clean and there should not be any visible residue on the equipment surface.

B. Maximum Allowable Carryover (MACO): It is calculated on the basis of therapeutic dose, batch size, safety factor and worst-case conditions. The following formula is used to calculate the maximum allowable carryover.

MACO (mg) = (Minimum daily dose of previous product × Batch size of next product) / (Safety factor)

MACO ensures that drug residues carried over are below the safety risk.

C. Microbiological Limits

• For non-sterile systems, acceptable microbial count limits must be defined and pathogens must be absent.
• For restaurant systems, microbial count limits should be zero.

D. Detergent Residues: Residues of cleaning agents must be below acceptable toxicological limits.

6. Execution and Documentation

Cleaning validation of CIP systems must be executed exactly as given in the protocol.

• Properly document equipment ID, date, time, lot number and cleaning agents used properly in cleaning validation report.
• Record actual parameters like flow rate, temperature and contact time.
• Log sweep samples and their analytical results.
• Attach raw data, chromatograms and other related documents with the report.
• Record any deviation and investigation reports if applicable.

7. Revalidation and Continuous Monitoring

Revalidation of the cleaning procedure is required in the following conditions.

• If the cleaning procedure is changed
• Any modification in equipment or relocation
• A new product is added to the product list
• Deviations or any failures are observed

Best Practices for CIP Cleaning Validation

1. Design Equipment for Cleanability

Equipment should be designed to make cleaning easy. Avoid dead legs and rough welding using sanitary design principles.

2. Use Validated Detergents

Select a cleaning agent that is effective against product residues and ensure its compatibility with the equipment material.

3. Automate CIP Processes

Automatic programmable logic controllers (PLCs) should be used for the reproducibility of the cleaning results. Record cleaning process data electronically to make it traceable.

4. Perform Cleaning Hold Time Studies

Determine the hold time of the equipment after which the cleaning procedure becomes ineffective. Define maximum hold time for dirty and clean equipment.

5. Train Operators and QA Personnel

Ensure everyone involved in the cleaning procedure understands everything about validation requirements.

Challenges in CIP Cleaning Validation

There are some challenges in clean-in-place systems cleaning validation, like inadequate sampling due to equipment design, poor documentation, inconsistency in cleaning cycle parameters, variability in water quality or cleaning agent concentration. These issues must be considered during the cleaning validation. Across functional teams should be created involving QA, production, validation and engineering departments to reduce the occurrence of issues during cleaning validation and overcome these challenges.

Clean-in-place system cleaning can be automated to effectively remove product residues, contaminants and microorganisms. Cleaning validation of clean-in-place equipment and systems is essential like other systems. By following the above strategies using a validated analytical method and every step documentation, companies can have confidence in their cleaning procedures and prevent product recalls and regulatory findings.

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