Product grouping is a way to reduce validation activities in sites with multiple products and processes. Products may be grouped together if they are cleaned by the same process. If a product in that group requires a more aggressive cleaning process, that product becomes the worst-case product in that group. All products in that group should be cleaned using the worst-case products parameters.
If the cleaning process has yet to be determined, group products by type and determine the worst-case product by performing a risk assessment considering solubility, ADE/PDE levels, and cleanability. Each group of products may have a different cleaning process. They may be kept as different processes; however, future errors may be reduced or avoided if one cleaning process using the worst-case product residue requirements is chosen.
The worst-case product is a combination of the product residue that is the hardest to clean and the lowest cleaning limit for the products manufactured at a facility.
The hardest-to-clean formulation can be assessed in a number of ways. Formulations can be assessed for cleanability based on the physical properties of the formulation components. The assessment looks at the physical properties of all formulation components including solubility in water and their composition percentage to determine which formulations are considered hardest to clean. Operator cleaning experience regarding hard-to-clean formulations is subjective but often correct.
Laboratory coupon cleanability studies can be conducted on several candidates for worst-case to arrive at the hardest-to-clean product(s) and recommended cleaning conditions for the product. Once the hardest-to-clean residue from a risk assessment has been determined, design the cleaning process based on the removal of that soil. If the hardest-to-clean product can be cleaned down to the level of the product with the lowest acceptance criteria, then all products with the common cleaning process are considered validated.
Equipment grouping strategies (also referred to as family approaches) are often used to simplify aspects of cleaning validation. Establishing through scientific rationale that equipment sharing the same design and construction can be grouped for validation purposes may reduce the total number of validation runs necessary to demonstrate consistency of the cleaning process. For example, five 500 L formulation tanks with the same dimensions can be grouped for validation purposes. Although all pieces of equipment are cleaned during validation, less runs are needed to complete cleaning validation.
The basic purpose of product grouping determines the representative or worst-case products manufactured on a particular piece of equipment or in an equipment train. Assurance that the cleaning method removes those products to an acceptable level can also provide assurance that the cleaning procedure removes residues of the other products within that group to the same or better level. A single validation study utilizing a worst-case approach can then be carried out, which takes account of critical issues.
These approaches are supported by PIC/S and others. For cleaning validation purposes, cleaning procedures for products and processes that are very similar can be grouped together with proper justification, and may not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes. Strategies that could be followed include grouping by product or grouping by equipment.
1. Residue Types
Residues can have various characteristics or conditions that may affect the chosen cleaning process. Residues may be classified as easy to clean in water or very soluble in water; too easy to clean and highly mobile in liquid state; moderately easy to clean; having viscosity issues too difficult to clean, oily substance, builders or excipients; hard to clean such as denatured proteins, dyes, titanium dioxides, and thin film formers.
The condition of the soil may impact the cleaning process. Typical conditions are wet, dry, steamed, baked, and compacted. As residues dry on the surface or are baked on the surface through jacketed vessels, they may become harder to clean.
It is important to model laboratory evaluations after processing conditions with respect to residue conditions and amount on the surface. Ensure worst-case conditions are tested during the laboratory evaluation. Cellulose-based products become harder to clean as they dry whereas denatured proteins and polymers are harder to clean if they are heated and baked onto the surface. For example, if the process residue is wet granulation, ensure the product is reconstituted with the appropriate concentration of solvent prior to testing since dry wet-granulation is easier to clean than when re-wetted and applied to the surface.
1.1 Soil Residue Load
High levels of the residue may saturate the cleaning solution. This may be due to a large surface area cleaned using a low volume to surface area ratio of cleaning solution, or from the level of soil remaining on the surface per surface area. In these instances, an initial rinse step may be required or higher volumes of wash solutions used. The typical volume of cleaning solution to use is approximately 20%–30% wash solution compared to total hold-up volume of the equipment.
Additionally, a single-pass wash step versus a recirculated wash step, at least initially, may aid in removing gross soil from the equipment surface. Higher residue levels may also be encountered on equipment surfaces due to design issues such as splashing above the liquid level line from the lack of, or use of, an inappropriately sized dip tube; use of reducers either restricting flow or causing a reduction in flow rate; or j tubes directing flow above the liquid level line, horizontal surfaces, and residue located along the air-liquid interface.
1.2 Materials of Construction
The MOC should be considered as part of the cleaning process development. Some residues may be more difficult to clean from certain surfaces due to surface interaction, roughness, or porosity, as in the case of some plastics. The MOC should be assessed to determine if they are compatible with the cleaning agent and temperature.
2. Laboratory Evaluation/Confirmation
A laboratory evaluation will help determine the starting cleaning parameters of a product from an equipment surface using representative surface or coupons to base the initial cleaning trial on during the design phase.
A laboratory evaluation or coupon study may also be used to optimize a current cleaning process, to establish corrective action in the event of a cleaning failure, or as a worst-case product determination. The evaluation should provide a cleaning recommendation at normal operating range and an understanding of the design space or proven acceptable range.
The laboratory study should simulate the residue amount, manufacturing conditions, and cleaning method. The evaluation will determine which cleaning agent to use along with optimal cleaning parameters such as how long to clean the equipment, temperature to use for wash and rinse steps, and concentration. DHTs should also be assessed as part of this evaluation.
A laboratory evaluation starts by selecting coupons to match the MOC found in the manufacturing process; however, testing should initially be performed on the predominant MOC (e.g., SS) to assess if visually clean. Ensure coupons are thoroughly cleaned and if stainless, passivated if necessary. Cleanability is assessed by coating coupons with the product in a manner where the amount of residue per surface area is controlled and recorded. The product is then conditioned on the coupon to simulate equipment surface conditions during the process including the DHT. The cleaning process is then screened initially in a beaker to test various conditions that may be optimized or assessed in other representative systems.
3. Equipment Dirty Hold Time (DHT)
Worst-case hold times should always be evaluated during cleaning validation studies, but this can be mitigated if there is information from product development that the nature of the soil does not change during extended holds. Typically, moist soil becomes more difficult to remove when dry. The total DHT should be evaluated as opposed to the time it takes to dry onto the surface, since what appears dry is not always completely dry. The soil may undergo environmental changes during the elapsed time, which should be considered during validation. For example, in oral solid dose manufacturing, dry powders may absorb moisture and cake or harden, becoming more difficult to clean; conversely, some soils may be easier to clean after time.
There is no standard duration for typical DHT. Consult with the Operations Group to determine the optimal and achievable DHT. The length may be schedule driven where equipment may not be able to be committed for validation purposes for an extended length of time. DHT duration may range from 1 hour to 30 days (which is extreme), with 3 to 7 days being typical since potential contamination risk increases with time. Microbial proliferation and equipment condition should also be considered when establishing DHTs.
Once DHT is validated, the equipment must be cleaned prior to exceeding the DHT limit. If the equipment DHT limit is exceeded for any reason, the equipment requires verification that it meets the established acceptance criteria outlined in the original cleaning validation protocol. This may be a onetime verification test with reduced testing to ensure the equipment is back to baseline.
When possible, establish DHTs in increments greater than 24 hours. This allows for the end-user to calculate the delta dirty hold in days rather than in hours, which may minimize calculation errors and verification testing if DHTs are exceeded when in operation.
Consider all process equipment used in the equipment chain, and establish DHTs so all pieces of equipment in the operation are able to be cleaned in the allotted amount of hold time due to resource constraints, whether they be operators, utilities, or number of CIP skids.
Read also: Bracketing and Worst Case Rating in Cleaning Validation