Cleaning Validation – Product and Equipment Grouping and Worst-Case Product Selection
Introduction
This procedure defines the criteria that should be considered when grouping Active Pharmaceutical Ingredient (API) and Drug Product (DP) equipment or product for the purposes of cleaning validation.
The ability to group products or equipment for the purpose of reducing the amount of sampling and testing during cleaning validation is dependent on scientific, documented rationale.
Similarly, scientific, documented rationale is also required when determining a worst-case product for the purposes of cleaning validation of API and DP manufacturing equipment.
Recommendations and Rationale
The primary objective of grouping related items in validation is to be able to identify a ‘worst case’ or representative item that allows the results of a particular validation exercise using that item to be applied to the remainder of the items in that group. In doing so, the overall burden of validation is reduced while at the same time objective evidence is obtained that supports validation of grouped products or equipment.
Equivalent Cleaning Procedures
Any plan to group products or equipment for the purpose of cleaning validation should be based on the premise that the items grouped share the same cleaning procedure. Use of the term ‘same’ in this context means equivalent and applies to the cleaning methodology and parameters. If two or more procedures or automated programs share the same methodology and parameters, but have different titles, document numbers or program identifiers then it should be possible to apply the results of the cleaning validation across all those procedures. When determining if two procedures are equivalent, the following points should be considered as to their criticality in achieving the final result:
- Cleaning agent and cleaning agent concentration
- Liquid used for rinsing
- Temperature
- Scrubbing, rinsing and drying times
- Flow rate
- Agitation
- The extent of manual intervention required to produce expected results
Product Grouping
For the purpose of cleaning validation a group of related products to be identified and a single product selected as ‘worst-case’ or representative of the product family The rationale for the grouping must be documented. Types and examples of product grouping include:
Once products are appropriately grouped, the worst-case product or products can be selected from among the group for the purpose of executing the cleaning validation protocol. A number of scenarios are possible:
Within a group, two or more products may be determined to provide an equivalent ‘worst-case’ challenge to the cleaning procedure. Once the rationale for equivalency has been documented and approved by the Quality Authority, the equivalent products are used to demonstrate the effectiveness of the cleaning procedure during validation.
Example: Product A and Product C are established as equivalent worst-case challenge products for the cleaning procedure used for products A, B, C, D and E.
During validation, any lot combination of Products A and C are used to fulfill the 3 validation cleanup requirement (e.g. 3 of A or C, 2 of A and 1 of C or1 of A and 2 of C).
- Within a group, two or more products are determined to be ‘worst-case’ challenges, but are not equivalent. Each worst-case product should be subjected to the 3 validation cleanup requirement.
- The same cleaning procedure is used for two or more groups of products. Each worst-case product within each group should be subjected to the 3 validation cleanup requirement, unless a rationale is documented and approved by the Quality Authority that the worst-case product of one particular group is clearly a worst-case product for all groups.
- Other scenarios may be possible and each product, or any new product introduced to the site, should be evaluated on a case-by-case basis. The criteria that should be considered when selecting a worst-case product or products include:
- Solubility of the residues in the cleaning agent, including cleaning and rinse solvents – the least soluble residue among a group is the most common approach.
- Ease of removal by a detergent, if applicable.
- Cleaning History – residues that have been demonstrated to be difficult to clean within a group of products cleaned with a given set of instructions. This information could be obtained from interviews with operators, failure history during validation, or trends in failure that have been identified during periodic review of a cleaning procedure that had been previously validated.
- Potential presence of difficult to remove excipients (e.g., polymers, dyes)
- Ease of detection of residues by visual inspection
- Potential for biofilms or the other side products, or degradants, to form during or prior to the cleaning operations
- The Residue Acceptablity Limit (RAL) required for cleaning
- Manufacturing processing parameters (e.g., high temperature, use of carbon) Selection of the most difficult to clean product/process should be documented. In the event that after application of the worst case selection criteria, the material that is chosen is infrequently produced (e.g. one lot per year), consideration may be given to the advantages of creating a separate cleaning validation protocol for that individual material. The benefit to this strategy is that validation data can be obtained and summarized in reports for all other materials at an accelerated rate due to more frequent production of the other materials. Alternatively, interim reports may be used to document the results on the worst case cleanups and the next-to- worst case cleanups completed to date. This interim report would support the partial completion of the validation.
Equipment Grouping
In order to reduce the burden of repetitive, unnecessary sampling and testing, equipment with the same design and operating principle used in the same manufacturing process may be grouped for the purposes of cleaning validation. Once a group of equipment is identified, samples taken from an individual piece of equipment may be considered representative of the remainder of the group for purposes of validation. These groupings and representative sampling sites should be documented and justified. The documentation should be approved by the Site Quality Team and Site Production Team. If equipment grouping is used, cleaning validation should be performed using three (3) executions of the same cleaning procedure using any combination of equipment within a group. Document and justify if the number of cleaning executions to be used for validation is different than 3 (three).
Equipment design (e.g., Heating/cooling, Mixing, gross function) and geometry (e.g., shape and size)
The ability of an individual procedure to produce expected results, i.e., uses the same cleaning instructions.
A change in the sequence of cleaning cycles constitutes a different cleaning recipe and should not be considered equivalent for the purpose of validation.
CIP design including spray device pattern, pump size, and supply line diameter.
Process piping routing and aggregate surface area is sufficiently similar. Pipe routing and size should be considered and appropriate test cases identified. If a scientific rationale can be justified with approval by site Quality, that a set of piping is sufficiently similar, a worst test case selection is appropriate for the purpose of validating the set. Otherwise, multiple piping configurations should be represented within the test cases to represent the variability inherent in the pipe sets.
Verify if all equipment groupings and cleaning procedures are being included on the selected test cases for each family group. If not, add additional test conditions to include all equipment and cleaning procedure considerations. This process may result in several combinations selected as “worst cases” for each group of products, and also to include the different equipment and cleaning procedure considerations.
During any failure investigation activity, consider the possibility of an inappropriate grouping strategy as the root cause of failure, and revise the rationale for the grouping strategy as necessary. For example, if the failure rate for an equipment unit is higher than the failure rate for the other equipment in the same group, the equipment grouping should be re- evaluated to determine if it is defendable.