Last update on November 15, 2024
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
The initial step in designing a cleaning validation program involves defining its scope and objectives. This foundational phase sets the direction for the entire validation process, ensuring that it is both comprehensive and focused on critical areas.
Developing a cleaning protocol is the initial step, detailing procedures, agents, equipment, and personnel involved, along with acceptance criteria. Manufacturers must create a validation protocol specifying tests, criteria, sample size, locations, methods, and limits for each cleaning procedure. It should also determine the number of validation runs needed for effectiveness. Consistent training of operators on this protocol is crucial for accurate execution of cleaning validation procedures.
Before cleaning validation starts, a risk assessment should be done to pinpoint potential contamination sources. This guides which facility areas need the most attention during cleaning. Prioritizing based on this assessment ensures critical areas posing the highest risk to product quality and patient safety are focused on.
Manufacturers must create custom cleaning procedures for each equipment or process, specifying cleaning agents, methods, and frequencies. These procedures should account for material compatibility, validation limits, and regulations.
The next step is to follow the cleaning protocol and thoroughly clean and sanitize all equipment and surfaces. This should be done by trained personnel and in accordance with the cleaning agent’s manufacturer’s instructions.
- After completing the cleaning process, samples must be taken from different parts of the facility and tested to verify if the acceptance criteria are met. This involves analyzing the samples for contaminants and documenting the results. Manufacturers need to develop a sampling plan determining where and how often samples are taken during cleaning.
- Both visual inspection and analytical testing are important to ensure effective removal of residues and contaminants, often using methods like chromatography or spectroscopy. The cleaning validation process involves several steps to ensure equipment and processes are thoroughly cleaned and free from contaminants.
Manufacturers start cleaning validation after setting up procedures, sampling plans, and validation protocols. They perform the cleaning as per the protocol, collect samples, and analyze them for contaminants. This process is repeated to ensure consistency.
- After cleaning validation runs, manufacturers analyze test data to compare against acceptance criteria in the validation protocol. Meeting criteria validates the cleaning process.
- A detailed report documenting procedures, results, and conclusions is required for regulatory compliance. The process is iterative, requiring investigation and resolution of any deviations or failures before validation. This ensures cleaning procedures are effective and consistent in removing residues and contaminants.
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.
- In the pharmaceutical industry, manual cleaning is the primary method for cleaning parts in direct contact with solutions. It involves physically scrubbing components with brushes, sponges, or cloths using detergent-based solutions to remove contaminants.
- Nondedicated equipment like mixing vessels, granulators, and blenders can be cleaned manually due to their smaller size and portability. Tablet compression machines, filling machines, and other equipment are also cleaned manually. Water, particularly purified and distilled water, is commonly used for cleaning soluble residues, while other agents are used for insoluble residues. The choice of cleaning agent depends on factors such as the previous product, equipment compatibility, ease of use, residue removal, required contact times, and microbial targets.
- CIP cleaning is a method used in pharmaceuticals to clean equipment without disassembly. It circulates a detergent-based solution through the equipment while assembled, effectively removing contaminants. This system utilizes fixed or rotating spray devices along with a wash tank, recirculation pump, and piping to ensure thorough cleaning, even in difficult-to-reach areas. Large processing equipment such as sterilization tanks, mixing tanks, storage vessels, etc. are equipped with automatic cleaning-in-place (CIP) facility.
- CIP (Cleaning in Place) typically involves using fresh distilled water sprayed through fixed spray balls for thorough vessel cleaning or directly into pipework. Critical parameters like flow velocity, temperature, and cleaning duration need verification and documentation for each validation test. Installations with CIP flow switches should ensure proper alarm functionality.
COP cleaning involves disassembling equipment and cleaning parts individually, typically in a tank with cleaning solutions and sometimes using mechanical or ultrasonic devices. It’s commonly employed in automated parts washing systems like cabinet or tunnel washers, which include cleaning, rinsing, and drying cycles.
- Ultrasonic cleaning utilizes high-frequency sound waves to agitate cleaning solutions and eliminate contaminants from surfaces and equipment.
- Widely employed in the pharmaceutical industry, this method immerses components in a cleaning solution and exposes them to sound waves, generating microscopic bubbles that implode and scrub away dirt. It’s highly effective, environmentally friendly, and suitable for sterilizing processing and packaging equipment, provided it’s compatible with the process.
High-pressure cleaning involves using high-pressure water jets to remove contaminants from equipment and surfaces.
- Steam cleaning sterilizes machines and equipment by using high-pressure steam to remove contaminants. It’s widely employed in pharmaceutical processing and packaging to ensure hygiene and safety. Typically automated, this process is integral to equipment design by most manufacturers.
- Cleaning agents, like detergents and chemicals, are best reserved for situations where water or solvents alone aren’t effective due to factors like insoluble materials or challenging equipment. Approved cleaning agents with known compositions are recommended for easy removal of residues. Ensure only approved sanitizers are incorporated into your cleaning procedures.
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)
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)
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)
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.
- 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.
Sagar Pawar
Sagar Pawar, a Quality Specialist at Zamann Pharma Support, brings over 11 years of experience in Quality domain for the pharmaceutical and medical technology industries. Specializing in qualification, validation, Computer System Validation (CSV), and Nitrosamine activities, Sagar is currently focused on enhancing the Zamann Service portfolio by developing and implementing robust strategies to address Nitrosamine-related challenges. Outside of work, Sagar enjoys trekking and cooking. Connect with Sagar on LinkedIn to discuss topics related to equipment qualification, GMP Compliance and Nitrosamine-related challenges.
