The cleaning procedures used the appropriate cleaning standard operating procedure to verify the repeatability of the cleaning
processes to control residue. In addition, during one of the three validation trials for each piece of equipment, a seven-day
"dirty" hold time established the longest allowable time between the completion of the filling and packaging process and the
start of the subsequent cleaning process.
Table III: Residual development formulation (μg/swab).
The acceptable API limit for the clinical packaging equipment was 100 μg/swab (25 cm2 ). This limit was based on adulteration of the subsequent batch of packaged material. The adulteration limit was used exclusively
because any material with a potential safety concern is packaged in an isolated facility and equipment cleaning is addressed
on a case-by-case basis. In addition, product contact with the equipment was limited in this case compared with manufacturing
equipment because the formulation was in final market image.
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.
A review of the VRL determination for metformin noted that the VRL samples were dried under nitrogen to prevent potential
oxidation of the material, which had been noted on a previous compound. The VRL study was repeated using API and formulation
dispersed in alcohol, but the samples were air dried rather than under nitrogen to simulate drying conditions in the packaging
area. Sample concentrations were at the VRL of 25 μg/swab level and at the approximate level of the highest sample obtained
during the validation studies, 75 μg/swab. Spots were applied in triplicate to 3 × 6-in. stainless steel coupons.
Table IV: Metformin visible residue limit recovery study.
A visual examination of the metformin residues confirmed that the 25-μg/swab spots were visible. The 75-μg/swab spots exhibited
a proportionally greater amount of visible residue. The metformin residues were swabbed and assayed by HPLC. The swab results
from the formulation (see Table IV) matched the nominal residue amounts. Nonetheless, several swab results for the 25-and
75-μg API spots were significantly higher. As with the HPLC assays for the cleaning validation samples from the packaging
area, no contaminants or extraneous peaks were present to explain the intermittent high results.