Cleaning Validation: 8 Steps for FDA Compliance Success

Read the full article here: https://zamann-pharma.com/2024/07/17/cleaning-validation-7-steps-for-fda-compliance-success/

What is Cleaning Validation?

Cleaning validation is a systematic process to demonstrate that a cleaning procedure consistently and effectively removes residues such as active ingredients, excipients, and cleaning agents so as to ensure product quality in future batches is not compromised.

Cleaning validation covers the entire cleaning process, from the selection of cleaning agents, sampling procedures, setting up acceptance criteria, testing, and recording.?

Cleaning validation is done before new product launches or major cleaning process changes. It’s not routine; instead, it’s done when necessary, like when switching products or upgrading equipment.

A successful cleaning validation results in a validated cleaning procedure, which is documented and used as a standard operating procedure (SOP) for routine cleaning.

Cleaning verification confirms that a cleaning procedure has effectively removed residues from equipment, focusing on specific batches rather than the overall cleaning process. It ensures cleanliness criteria are met at the end of each cleaning cycle.

Steps to Cleaning Validation Compliance

Step 1. Defining the Scope and Objectives

Step 2. Develop a Cleaning Validation protocol

Step 3: Conduct a risk assessment

Step 4. Cleaning Procedure Development

Step 5: Clean and sanitize the facility

Step 6. Conduct sampling and testing

Step 7. Performing of Cleaning Validation

Step 8. Involves analysing data from cleaning validation runs

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What types of cleaning methods are used in Cleaning Validation?

Cleaning methods are selected based on equipment, facility, product, and contamination sources. They’re vital for thorough cleaning, removing contaminants, and reducing product contamination risk.

Manual cleaning:

CIP (Clean-in-place) cleaning

COP (Clean-out-of-place) cleaning

Ultrasonic cleaning

High-pressure spraying

High-pressure cleaning involves using high-pressure water jets to remove contaminants from equipment and surfaces.

Steam cleaning

Cleaning agents

Cleaning Validation Guidelines

Most regulatory agencies and industry bodies publish guidelines on how to conduct cleaning validation. Ensure pharmaceutical quality through science-based quality systems. Conduct risk assessments to identify contamination sources and validate cleaning processes for effective contaminant removal. Regularly perform and document cleaning validation to maintain quality standards.

Their principles could be summarized as follows.?

1) Food and Drug Administration (FDA)

• FDA Cleaning Validation Guideline from CFR 211.67
• Here is a link to the entire code.?21 CFR Part 211
• Inspection References: Guide to inspections validation of cleaning processes

2) European Medicines Agency (EMA)

• EMA guidelines?(10.1 -10.15)
• EMA Cleaning Validation Guideline on setting HBELs

3) Pharmaceutical Inspection Co-operation Scheme (PIC/S)

• Cross-contamination in shared facilities – PI-043-1
• Guideline on Setting HBEL for use in risk identification in the manufacture of different medicinal products in shared facilities

4) World Health Organization (WHO)

• Good Manufacturing Practices: Guidelines on Validation Annex 3 – See appendix 3

5) International Society For Pharmaceutical Engineering (ISPE)

• Baseline Guide Vol 7: Risk-Based Manufacture of Pharma Products 2nd Edition
• Cleaning Validation Lifecycle – Applications, Methods, and Controls?ISPE Cleaning Validation Guideline

6) Parenteral Drug Association (PDA)

• PDA Technical Report 29: Points to Consider for Cleaning Validation?PDA TR 29
• PDA Technical Report 49: Points to Consider for Biotechnology Cleaning Validation

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What do FDA require regarding Cleaning Validation?

As almost always, the FDA quotes 21 CFR 211.67 when it comes to cleaning validation deficiencies. What did the FDA criticize? It was criticized that the company could not demonstrate that contaminants could be removed with the cleaning/disinfection procedures used. The only measure applied was visual inspection of surfaces.

FDA quotes 21 CFR 211.67

• Equipment and utensils must be regularly cleaned, maintained, and sanitized or sterilized as needed to prevent malfunctions or contamination that could affect the safety, quality, or purity of the drug beyond set standards.
• Procedures for cleaning and maintaining equipment used in drug product manufacturing must be established and followed. These procedures cover responsibility assignment, maintenance schedules, detailed cleaning methods, disassembly and reassembly instructions, removal of previous batch identification, protection of clean equipment, and pre-use cleanliness inspection
• Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified

What is contained in a Cleaning Validation Protocol?

A Cleaning Validation Protocol typically includes procedures and criteria for verifying the effectiveness of cleaning processes used in pharmaceutical or food manufacturing facilities.

The Cleaning Validation Protocol varies based on facility, equipment, and products. It requires approval from Plant Management and Quality Assurance.

• Objective of the Validation Process: This section delineates the goals and provides an overview of the cleaning validation process, emphasizing its purpose and summarizing pertinent regulatory requirements.
• Scope Definition: This section precisely defines the boundaries of the cleaning validation, specifying the equipment, surfaces, systems subject to cleaning, and the associated products manufactured on them.
• Responsibilities: Outlining the roles and duties of personnel involved in the cleaning validation process is the focus of this section.
• Downtime Interval: This aspect addresses the time lapse between the conclusion of production and the initiation of cleaning procedures.
• Cleaning Procedures: Here, the prescribed cleaning protocols for each product, manufacturing system, or equipment piece are detailed.
• Sampling Plan: This section elaborates on the sampling strategy, encompassing the number of samples, sampling locations, and methods utilized.
• Analytical Methods: Description of the analytical techniques employed for sample testing, encompassing detection limits, precision, and accuracy parameters.
• Acceptance Criteria: Defining the parameters for acceptance in the cleaning validation process, including maximum allowable levels of contaminants, falls within this section.
• Record Keeping: Procedures for meticulous record maintenance throughout the cleaning validation process, covering documentation of all cleaning activities, sampling, testing results, and any deviations or corrective measures taken, are delineated here.
• Bracketing Concept Application: This section discusses the application of a “bracketing” concept to extend the validation to other products, processes, and equipment.
• Re-validation Requirements: Clarification on circumstances necessitating re-validation is provided here.

A Final Validation Report, approved by Plant Management, assesses the cleaning success and any limitations. The process must be documented in an SOP. Cleaning records include details like area/equipment cleaned, cleaner, time, SOP, and previous product. They must be signed by the cleaner and production supervisor, then reviewed by Quality Assurance.

Conclusion

Cleaning validation in the pharmaceutical industry is essential for ensuring that equipment cleaning procedures effectively remove all residues and maintain product quality. The process involves creating a detailed protocol that covers objectives, equipment details, testing methods, and safety measures. The FDA provides guidance on this process, emphasizing the need for written procedures and validation reports. Key considerations include a risk-based approach, using approved cleaning agents, and periodic monitoring. Overall, cleaning validation is critical for product integrity and regulatory compliance, helping to minimize risks such as cross-contamination and quality defects.