Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation - Pharmaceutical Technology

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Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation
A risk-management assessment of visible-residue limits (VRL) in cleaning validation of pharmaceutical formulations was conducted for both pharmaceutical pilot plant and manufacturing facilities. The authors discuss how potential risks were identified, analyzed for probability, considered for seriousness, and controlled through avoidance or mitigation. These opportunities for VRL implementation then were identified for both pilot plant and manufacturing settings.

Pharmaceutical Technology

Other uses of VRL in the pilot plant include technology transfer to a contract or other manufacturing facility. Since cleaning procedures between facilities are different, VRLs would be a quick, simple verification of cleaning in place of analytical method transfer and testing. This strategy applies more to early development where the number of manufactured batches is limited and for compounds that are relatively nontoxic.

VRLs also can be used for the introduction of new equipment into the facility. VRLs would be used to ensure baseline cleanliness and demonstrate equivalency with respect to the cleaning efficacy of a previously validated procedure. Developing the cleaning procedure for new or modified equipment in with VRLs is an efficient way to get equipment on line.

The optimization of new cleaning procedures during development is a potential application for VRLs. Cleaning cycle times could be challenged with VRL determination as the acceptance criteria. A more immediate benefit would be realized with manual cleaning procedures. Personnel who clean the equipment could effectively determine optimal scrub times and rinse volumes with a visual limit.

The cleaning-validation program of the pilot plant was based on qualitative visual inspection and swab-sample testing (9). A recent cleaning validation study (10) used VRLs along with swab-sample testing. The cleaned equipment passed both the swab testing and VRL inspection. Nonetheless, the swab-assay results were higher than expected based on the VRL data. An investigation concluded that the compound had reacted and formed an enantiomer with greater ultraviolet absorbance. The investigation demonstrated the value of establishing VRL data in conjunction with swab recoveries.

Uses of VRLs in a manufacturing facility

Several opportunities to apply VRLs as a surrogate to surface sampling have been identified in manufacturing facilities using good manufacturing practices (GMPs). Process controls and procedures also have been identified to mitigate the risks when applying VRLs in a GMP facility. Given that VRL determinations for drug-product formulations have been established (4, 6) and the relative accessibility to visual inspections with this equipment, the scope of these applications would be primarily applicable to pharmaceutical manufacturing and primary packaging operations.

As with pilot-plant facilities, VRL data may be used to develop new or optimize existing cleaning procedures. For manual cleaning procedures where the VRL is less than the ARL, the extent of routine documentation and cleaning records could be streamlined in a GMP facility. Once optimal scrub times and rinse volumes have been validated and incorporated into the cleaning procedure, visual cleanliness may be the only critical cleaning parameter that would require documentation on a routine basis. With VRL data, a check by a second person for visual cleanliness confirms performance and ensures that the level of residuals is below the acceptable residue level. This procedure may obviate the need to record actual cleaning parameter data (i.e., scrub times and rinse volumes) on a routine basis and reduce the volume of GMP documentation that must be maintained for marketed drug products.

VRL data and visual inspection may be applied to support the introduction of new products into existing validated product matrices. The use of product matrices or bracketing product residues to validate a "worst case" for multiproduct equipment modules is a common practice in industry and supported by regulatory guidance (2, 11–13). Best practices include an evaluation of the different products and intermediates with respect to solubility and cleanability. Laboratory studies may be performed to directly compare the relative cleanability between the targeted compounds and products. Methodologies for rapid and inexpensive testing for cleanability have previously been reported (14). The relative toxicity data for all compounds in the matrix should also be reviewed, with the ARL set using the most potent compound. To validate the matrix, validation studies would challenge the cleaning on the worst-case compound to remove using an ARL calculated for the most potent compound in the matrix. As new products are introduced, toxicity and cleanability must be assessed as to whether the compound represents a new worst case. If not a new worst case, the VRL of the new compound can be compared with the validated ARL. If the new compound is less than the ARL, visual inspection alone should be satisfactory for revalidation of the cleaning procedure for a new product.


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