Top Three Cleaning Processes That Must Be Validated
What are cleaning validations?
Cleaning validations are a form of microbial contamination control. Cleaning validation protocols are essential for good manufacturing practice (GMP) facilities and certified cleanrooms. In essence, cleaning validations are the validation of cleaning processes to ensure that potential contaminants are removed to acceptable levels for container use, equipment use, or post-cleaning sterilization processes. The following article details an overview of cleaning validations and cleaning validations guidelines for FDA-approved cleaning validations.
Why are cleaning validations important?
Cleaning validations are critical for successful maintenance and control of cleanrooms for medical device and product manufacturing. In particular, aseptic cleanrooms require easily sanitized rooms, surfaces, and equipment. Any containers or equipment in contact with product formulations or parenteral preparations must be cleaned thoroughly to prevent dust, fiber, chemical, and microbial contaminants. Additionally, all residues between product batches must be eliminated before reuse. Dedicated equipment is used and cleaned for sterile product use only. Validation of cleaning procedures is a “hot topic” for GMP regulatory inspections. Hence, cleaning validation guidelines are imperative to create and follow for GMP manufactured products such as medical devices.
What are the top three cleaning processes that must have cleaning validation Guidelines?
#1: Cleaning of Containers
Generally, containers are loaded (sometimes manually), cleaned, and then removed for sanitizing. Often an automated container washer (such as a Bosch) is used for cleaning sterile product containers. Container washers and validated cleaning settings for them are created based on container shape, size, desired processing time, and contamination type. Detergents leave residues and thus are avoided for new containers. Instead, thermal-shock washing sequences are used to loosen container wall debris. Only an air rinse is needed for new containers with minimal and loose particulates.
Cleaning containers requires:
- First requires introducing a liquid or air to the container. This liquid or air is used to strike an inverted container’s bottom, spread in all directions, flow down the walls, and exit through the container’s opening, thus providing a “sweep” of the container. Often jet stream pressure is used as it allows for little to no splashing and prevents the redeposit of loose waste during the cleaning process.
- A liquid or air is introduced to provide an outside rinse to the container.
- A cleaning cycle switches between hot and cool treatments, with the final rinse treatment using water for injection (WFI). The final rinse must be ultraclean so that the rinsing agent leaves no particle residues.
- Metal cleaning equipment components are composed of a noncorroding, noncontaminating material, such as stainless steel.
The wet, clean containers are specially handled to avoid recontamination during the drying process. These containers are protected by storing in a laminar flow of clean air until covered. Ideally, wet, clean containers are dry heat sterilized as soon as possible after washing.
Automated cleaning machines move wet and clean containers into a sterilization and depyrogenation dry-heat tunnel. Automatic cleaning machines are more expensive but minimize recontamination risk (since they remove human interaction) and increase container cleaning processing rates. In fully automated cleaning systems, wet and clean containers are protected by filtered, laminar flow air. This laminar flow air protects clean containers from the preparation area through the tunnel sterilizer to the filling line.
It is the parenteral product manufacturers’ responsibility to establish scientifically justified acceptance criteria for cleaning validations for parenteral products. Arbitrarily set target residues are concerns for the Food & Drug Administration (FDA) quality auditors. Appropriate sampling methods (e.g., swabbing, final rinsing, testing of subsequent batches) is needed to acquire the necessary data for cleaning acceptance criteria.
#2: Cleaning of Closures
Cleaning for container closures is more challenging than container cleaning itself. For example, rubber closures are hard to clean because their shapes have intricate channels and apertures. The first step to cleaning a container closure is to agitate the closure in a hot bath of mild water softener or detergent. The agitation process continues for multiple cycles with filtered WFI. A large agitator or horizontal automatic washing machine is used for this process. If closures are sensitive to abrasion, closures are heated in kettles along with a detergent solution, followed by a long, pressurized rinse. In the case of rubber tubing, WFI is passed through the tubing lumen. After agitation, the closures are rinsed to eliminate any loose particulates. No matter the item, the last rinse in the closure cleaning cycle should always be with low-particulate WFI. Next, wet closures are traditionally steam sterilized using an autoclave and stored until use. Closures must be free from pyrogens, so the combined cleaning and sterilizing processes must be validated for both microbe and endotoxin removal. Steam sterilization does not remove pyrogens. Thus, the cleaning process is responsible for pyrogen removal from container closures. As closures must be dry for use, they may experience vacuum drying at 100◦C after autoclaving completes. Higher drying temperatures are used for closures containing freeze-dried products. Automated closure processors can simultaneously wash, sterilize, and transport closures directly to the filling line. Cleaning validations guidelines are particularly essential for closure cleanings designed to remove pyrogens.
#3: Cleaning of Sterile Processing Equipment
Equipment cleaning can be tricky due to all the internal parts (e.g., joints, crevices, screw threads, and other structures where debris collects). Clean steam supports dislodging residues from equipment walls, such as stationary tanks, fixtures, pipes, and other comparable items. After equipment steaming, cleansed items go through a thorough rinsing with distilled water. Most equipment is cleaned using automated Clean-in-Place (CIP) systems. These computerized systems process through programmed steam and distilled water rising cycles to clean sterile processing equipment. More specifically, high-pressure spray nozzles are used to wash equipment with hot detergent solution, followed by WFI rinsing. For thorough cleaning, stainless-steel equipment with smooth, rounded internal surfaces must be selected for use. After CIP, a sterilizing-in-place (SIP) cycle is initiated for sanitizing or sterilizing the equipment. Note that any rubber tubing, rubber gaskets, or other rubber parts are washed using the methods described above for container closures.
Summary
All in all, cleaning validations are the validation of cleaning processes. Cleaning validations ensure that potential contaminants (dust, fiber, chemical, and microbial) are removed to acceptable levels for container use, equipment use, or post-cleaning sterilization processes. The successful maintenance and control of cleanrooms for medical device and product manufacturing hinge upon the use of fully validated cleaning processes. The top three cleaning processes that must have cleaning validations are container cleansing, container closure cleaning, and cleansing of sterile processing equipment. Manufacturers can ensure consistent product sterility with appropriate cleaning validations in place and meet FDA auditing requirements. Ensure you choose a contract testing organization that can provide proper cleaning validations for your unique medical device or product needs.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Sterilization Validations, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
