The cleaning parameters for a cleaning process include:
- Water quality
- Water temperature
- Water pressure
- Detergent
- Detergent concentration
- Cleaning aids (brushes, wipes)
- Duration (time)
- Force (manual force)
- Initial rinse
- Wash
- Second rinse
- Final Purified Water rinse
- Drying
- Personnel (for manual cleaning)
The CPPs are a subset of these parameters and should be determined during development.
Soil Load
The amount of product residue on the equipment can have an impact on the effectiveness of the cleaning; however, the soil load is not generally considered a CPP for cleaning.
Before cleaning begins, the soil load on the equipment must be defined to ensure consistency in order to better determine the CPPs. To ensure consistent product deposits on equipment, the manufacturing batch record should include steps to recover/remove any remaining batch material from the equipment. For liquid dose equipment
this could be as simple as thoroughly draining all equipment. For solid dose equipment, vacuuming and scraping equipment surfaces is often employed, followed by wiping all surfaces with solvent (e.g., 70% IPA) to remove remaining residue, minimizing dust when moving the equipment to the cleaning area, and drying the equipment surfaces.
Residue removal after manufacturing can be subjective but when considered as part of batch reconciliation, a consistent batch yield reflects consistency.
If the batch material removal is completed immediately after manufacturing, there are several advantages: The batch yield is consistently higher; the equipment cleaning personnel are exposed to lower levels of product residue, and the amount of API going into the drain during cleaning is decreased.
The DHT is impacted by the soil residue load and timing of batch material removal. The DHT is much easier to define, defend, and manage when the batch material removal occurs as part of the manufacturing batch record. The DHT begins after manufacturing, so the residue level is much lower and the equipment is dry when a solvent wipe is used. If batch material removal waits until the beginning of cleaning, the DHT will reflect the higher, more variable residue level, and any residual moisture in the residue will dry, potentially making the equipment harder to clean and the DHT as well as the cleaning validation harder to defend.
Water Quality
The water quality is usually based on the local municipal water supply. For cleaning equipment, this is generally satisfactory. The hardness (high mineral content) or softness of the water can impact the effectiveness of detergents. Water quality cannot be controlled for cleaning and is not generally considered a critical cleaning parameter, but the consistency of the local water supply should be monitored by engineering to ensure consistent plant operations.
The quality of water used for the final rinse of the equipment after cleaning should be the same as used for manufacturing (e.g., purified or better).
Water Temperature
Water temperature for CIP systems and some COP systems can be measured and monitored, and automated systems can be programmed to shut down if the water temperature goes outside the programmed range.
Controlling water temperature for manual cleaning is necessary from a cleaning validation and safety perspective. The system should supply water at a certain temperature and then cleaning is validated at that temperature.
Manual cleaning may be conducted under controlled temperature conditions. Installing a temperature gauge in the water line is an option, but unless it is monitored and recorded, its value is limited. There are certain circumstances when cold water works better than hot water for cleaning. An example is some enteric coating components. On the other hand, soft-gel gelatin requires hot water of > 60°C for effective, efficient cleaning.
Establishing water temperature as a CPP for cleaning should be determined during cleaning development. If truly a CPP, then it needs to be measured and controlled. If water temperature is not thought to be critical, then a wide range of temperatures should be considered during development to demonstrate that it is not a cleaning CPP.
Detergent
Note: Other cleaning agents are sometimes used, for example, water, chemicals (e.g., NaOH), or solvents. Detergents are addressed here but appropriate controls should be implemented when other cleaning agents are used.
Alkaline detergents are more effective for cleaning the majority of APIs and excipients. Acidic detergents are more effective for certain excipients; however, neutral detergents can also be effective for cleaning. Since a chosen detergent is a constant for a cleaning process, it would not be considered a cleaning CPP.
Ideally, one detergent is chosen for all cleaning. The goal is to choose a detergent and use a rugged cleaning process to clean the worst-case soil to levels well below the cleaning limit. Use of one detergent simplifies the approach to cleaning and cleaning validation. A low-foaming detergent that is compatible with CIP and COP systems can also be used for manual cleaning and is advisable for the same reasons. If a new worst-case soil is introduced, the use of additional detergents may be necessary, but this should be minimized, since each detergent used requires a separate validation.
If a cleaning process uses two detergents (e.g., an alkaline detergent wash followed by a rinse, followed by an acidic detergent wash or an alkaline detergent wash followed by a rinse, followed by a neutral detergent wash), consider using the dual detergent approach for all products. The dual detergent approach is inherently more rugged and consequently lowers the risk of introducing a new worst-case soil.
Detergent Concentration
The detergent supplier has a recommended concentration (e.g., 2%) and dilution scheme for their detergent. Cleaning development studies, either by the end-user or by the detergent supplier, should confirm the appropriate concentration of detergent that will effectively clean the worst-case product in the facility manufacturing portfolio.
A detergent supplier could have literature showing the criticality of the detergent concentration. Otherwise, a range around the recommended concentration can be tested during development to establish whether the detergent concentration is a cleaning CPP.
Cleaning Aids
Manual cleaning is accomplished with the use of cleaning aids. Brushes of different sizes and functions need to be defined and sourced. Examples of brushes include: long and short-handle scrub brushes for cleaning flat surfaces and large and small bottle brushes for cleaning valves and pipes. Non-abrasive, non-shedding scouring pads or wipes can also be used. All cleaning aids must be specifically designated and sourced from the same supplier and used for validation to avoid questions about the effectiveness of the cleaning process. If the cleaning aid is used consistently, it is not a CPP. However, if different cleaning aids are used or are not specifically identified in the cleaning procedure, they might be considered critical.
The determination to designate cleaning aids as single-use or reusable is a major decision. Single-use is easier to understand and defend. To reuse cleaning aids, cleaning, drying and storage must be defined. The number of times the aids can be reused needs to be defined and justified. The use of the cleaning aids must be tracked and documented.
Initial Rinse Technique/Time
Note: The timing of rinse and cleaning steps should be considered CPPs and captured individually or as a group on a case-by-case basis.
The soiled equipment is initially rinsed with water or solvent following a top to bottom pattern to remove any loose residue. The length of the rinse should be defined during development, and measured and documented during validation.
Equipment Cleaning Technique/Time
The equipment is washed with the prepared detergent solution per the equipment SOP. CIP and COP systems have cleaning programs for the equipment. Manual cleaning should use a top to bottom or inside to outside pattern and overlapping strokes. The length of the wash should be defined during development, and measured and documented during validation.
The level of detail should be enough to ensure consistent cleaning. Added detail is appropriate for those pieces of equipment requiring more specific instructions based on their complexity or known history of cleaning problems.
Second Rinse/Time
The cleaned equipment is rinsed with water following a top to bottom pattern to remove any remaining residue and the detergent. The length of the rinse should be defined during development and measured and documented during validation.
Final Purified Water (PW) Rinse/Time
The rinsed equipment is final rinsed with PW for better results following a top to bottom pattern to the rinse water from the equipment. The grade of water used for the final rinse reflects the grade of water used for manufacturing. This prevents dried water residue marks on the equipment. The length of the rinse should be defined during development, and measured and documented during validation.
Drying
The cleaned equipment can be dried using a drying room, compressed air, or solvent (e.g., 70% IPA) to remove remaining PW from the equipment. Equipment can also be left to air dry, which takes longer. If solvent is used, it takes about 15 min for the solvent (e.g., IPA) to completely evaporate. The equipment surfaces should be inspected as clean and dry prior to covering and storing. Drying is not considered a cleaning CPP as long as the equipment is dry.
Documentation
All CPPs for a cleaning process should be recorded. Some cleaning parameters are outside the cleaning area control, including the water quality and hot water temperature. The lot and expiration date of the detergent should be recorded along with the routine preparation of the working detergent.
Recording times for rinsing and washing can range from recording the timing for each part, to recording one time for the entire piece of equipment. The greater the level of detail, the better the demonstration of consistent control of the cleaning procedure. Each facility must decide the level of detail they can record to demonstrate reliable, consistent equipment cleaning without adversely impacting cleaning activities.
