The same scientific rationale supports the use of VRLs in a manufacturing facility. The main difference between pilot plant and commercial manufacturing facilities is equipment size. Acceptable viewing parameters for the larger manufacturing equipment, including distance, viewing angle, and light level, consistently detect VRLs for several marketed formulations (6).
The implementation of VRLs in the pilot plant and their potential use in the manufacturing facility were additions to established cleaning programs. The cleaning programs in both the pilot plant and manufacturing facilities established validation based on swab sample data using high-performance liquid chromatography (HPLC) for analysis. Visual inspections were part of the validation, but were qualitative determinations only.
It should be possible to demonstrate the correlation between the quantitatively determined VRL of either the API or formulation on the manufacturing equipment and the analytically determined swab recovery data. The data from the two determinations should be mutually supportive as part of a cleaning process validation. Therefore, a retroactive analysis of the pilot-plant validation study compared the previously obtained swab results with the more recently generated VRLs for the subject compounds.
In addition, a current cleaning validation study conducted in a clinical packaging area included VRL as an integral part of the study. The study used documented worst-case formulations to soil the equipment, followed by cleaning according to a standard operating procedure. Visual inspection used experimentally determined VRLs. Swab samples for the appropriate compound confirmed the equipment's cleanliness. Testing for each formulation was repeated twice to validate the cleaning procedure. The final report includes a comparison between the VRLs and the swab sample results.
Although the cleaning validation passed testing ( i.e., all swab results were lower than the ARL), the swab results for several metformin samples assayed higher than the experimentally determined VRL. An investigation reconciled the discrepancy.
The cleaning-validation study for the pilot plant selected worst-case formulations. One formulation was validated for a dry-granulation equipment train and another for the wet-granulation process. Each piece of cleaned equipment was visually inspected before swab testing and both formulations were tested three times for validation.
The compounds tested were simvastatin and rofecoxib (Whitehouse Station, NJ, Merck & Co., Inc.). Four observers viewed dried solution spots of known concentrations to determine the VRLs. The experimentally derived VRLs for the compounds were 0.485 and 0.871 μg/cm 2 , respectively (4). For a swab area of 25 cm 2 , the limits were 12.1 and 21.8 μg/swab. The VRLs for the base and neutral detergents used to clean the equipment were <0 .37=".37" and="and" cm="cm" g="g" sup="sup">20>
Eighty-four swabs were taken for rofecoxib, and all were below the VRL of 21.8 μg/swab. Of these, 55 had no rofecoxib detected (less than 0.02 μg/swab), 23 were less than 1 μg/swab, and only 6 were greater than 1 μg/swab.
Finally, of the 69 detergent swabs taken, 68 had no detergent detected ( <3 14-="14-" and="and" g="g" had="had" less="less" remaining="remaining" span="span" swab="swab" than="than" the="the" vrl.="vrl.">3>
Although all 231 swabs from the cleaning validation study showed agreement between the swab results and VRLs, only 5% of the swabs were greater than 1 μg/swab. The validated cleaning process reduced residues far below both the ARL and the VRL levels. Therefore, the pilot-plant cleaning-validation study did not seriously challenge the correlation between the swab results and the VRLs.
Cleaning validation. The current cleaning validation study established the requirements and acceptance criteria for the following equipment in the clinical packaging area: tablet counter, automatic filler, 8-track filler, and tablet elevator. The validation of the cleaning procedures was on equipment that had been used to fill and package clinical product and then cleaned. A development formulation and 500-mg metformin tablets served as representative worst-case formulations for validation. Both products are non film-coated tablets, which produce dust during the packaging process. The metformin tablets had a very high drug load (95%) and any residual dust was most likely to be API.
Investigation. The investigation into the VRL and swab numbers for metformin targeted the assay method, the cleaning method, and the VRL determination of the API and formulation. The swab samples' testing was by HPLC and the assay run was reviewed as well as the method validation data. The cleaning process used in the clinical packaging area was reviewed for potential chemical interactions. The VRL determination of metformin was investigated for potential issues.
Results and discussion
Cleaning validation. A cleaning-validation study was completed successfully in a clinical packaging facility. The study used the worst-case packaging situations and all swab samples assayed below the ARL of 100 μg/swab (see Tables II and III) for the three executions (including 7-day idle time before cleaning). The cleaning processes used in the clinical packaging area are considered validated for hold times as long as 7 days.
The only problem was the discrepancy between the swab results for metformin and the VRL. The VRL data indicated that anything greater than 25 μg/swab should have been detected visually. A visual inspection of the equipment before sample swabbing concluded that it was visually clean.
Investigation. The investigation into the discrepancy between the metformin VRL and swab data began with the HPLC assay of the samples. Nothing was consistently present in the samples to suggest contamination of the swabs or solvents because the majority of the samples (58 of 69) had assay values below the VRL (see Figures 1a, 2a). Nothing in the sample chromatograms indicated the presence of an intermittent extraneous peak, which might explain the high results. The chromatogram of a control containing a swab, swabbing solvent, and extraction solvent showed no peaks. The system suitability data were within testing parameters. The HPLC assay did not indicate a potential cause.
The method-validation data and documentation review indicated that all validation parameters were within accepted guidelines, including recoveries from stainless steel coupons. Forced degradation studies of metformin showed no degradate peaks to explain the observed swab results.
The cleaning process for equipment in the clinical packaging area consisted of an appropriate amount of equipment disassembly such that all surfaces were accessible. A dry vacuum removed most residue from the equipment. The equipment surfaces were cleaned with an appropriate solvent and then dried before reassembly. A sample of metformin prepared in the cleaning solvent showed no evidence of degradation.
The correlation between swab assay results and visible-residue limits (VRLs) for cleaning validation was examined. A review of previously completed validation studies was inconclusive because swab results were much lower than the more-recently determined VRLs. A current cleaning-validation study evaluated both swab testing and VRLs. Unexpectedly, high swab results led to an investigation that showed the value of establishing the VRL in conjunction with swab recoveries for cleaning-validation programs.
Richard Forsyth* is an associate director in Global Clinical GMP Quality with Merck & Co., Inc., WP53C-307, West Point, PA 19486, tel. 215.652.7462, fax 215.652.7106, firstname.lastname@example.org [email@example.com]
Julia Roberts is a research chemist in Vaccine Pharmaceutical Research, Tara Lukievics is a global sourcing project leader in the Global Clinical Supplies Organization, and Vincent Van Nostrand is a research chemist in medicinal chemistry with Merck & Co., Inc.
*To whom all correspondence should be addressed.
Submitted: May 16, 2006. Accepted: May 25, 2006. Keywords: cleaning, validation, visible-residue limits
1. D.W. Mendenhall, "Cleaning Validation," Drug Develop. Indust. Pharm. 15 (13), 2105–2114 (1989).
2. US Food and Drug Administration, Guide to Inspection of Validation of Cleaning Processes (Rockville, MD, Office of Regulatory Affairs, 1993).
3. D.A. LeBlanc, "'Visually Clean' as a Sole Acceptance Criteria for Cleaning Validation Protocols," J. Pharm. Sci. and Technol. 56 (1) 31–36 (2002).
4. R.J. Forsyth, V. Van Nostrand, and G. Martin, "Visible Residue Limit for Cleaning Validation and its Potential Application in a Pharmaceutical Research Facility," Pharm. Technol. 28 (10), 58–72 (2004).
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6. R.J. Forsyth and V. Van Nostrand, "Application of Visible Residue Limit for Cleaning Validation in a Pharmaceutical Manufacturing Facility," Pharm. Technol. 29 (10), 152–161 (2005).
7. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, www.nvbi.nlm.nih.gov.