Of the 78 swabs taken for simvastatin, all were below the VRL of 12 μg/swab. This finding confirms that the equipment was
visually clean when swabbed. Of the 78 swabs, 64 had no simvastatin detected (less than 0.1 μg/swab), nine had less than 1
μg/swab, and 5 had more than 1 μg/swab.
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 μg/swab) and the remaining swab had less than the
14-μg/swab VRL.
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.
Experimental
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.
Table I: Formulation residue concentration and visibility.
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Before the first cleaning trial, a VRL was established for both compounds. Each formulation was dispersed in methanol and
spotted on 3 × 6-in. stainless steel coupons at appropriate concentrations. A stream of nitrogen dried the spots to facilitate
the drying process and prevent potential degradation of the material. Oxidative degradation had occurred on several in-house
compounds in the past. The areas of the dried spots determined the amount-per-unit area (μg/cm2 ) value for each spot of material (Table I). The VRL determined for the development compound was 0.51 μg/cm2 (12.75 μg/swab) and 0.97 μg/cm2 (24.25 μg/swab) for metformin.
Table II: Residual metformin (μg/swab).
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The cleaning validation was performed in triplicate on representative pieces of equipment. Validation consisted of overall
visual inspection and swab sampling in the areas identified in the protocol. These areas had been identified as hard-to-clean
areas of the equipment to confirm that the cleaning procedure removed residue to acceptable levels as predetermined by the
established 100 μg/swab (25 cm2 ) acceptance criteria for the API. The swab samples were assayed with a validated HPLC method (Agilent 1100 HPLC, Agilent
Technologies, Palo Alto, CA) with ultraviolet diode array detection (Tables II and III).
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