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Extractables/Leachables Study for a Controlled Drug Solution in a PET Bottle

To gain the information necessary to submit their Abbreviated New Drug Application (ANDA) to the FDA for approval, a pharmaceutical company turned to Avomeen for their extractables & leachables testing. This study identified any compounds leached from their pharmaceutical’s packaging into their drug product. The results of the study determined that the pharmaceutical company was able to move their product into production using their current form of packaging.

Necessary E&L Testing Performed in 3 Steps

Step 1: Method Validation

Avomeen’s chemists had to choose and validate an analytical method that would be utilized to test the Polyethylene Terephthalate (PET) bottles and the drug solution for extractable and leachable compounds. The method was validated for specificity, linearity, accuracy, precision, and robustness through a series of tests under a specific protocol. All methods were validated and shown to tolerate changes including ±10% injection volume, ±10% in column temperature, and ±5% of organic concentration in the gradient.

Step 2: Extractables Study

In order to determine the quantification and characterization of the extractables in the PET bottles, a controlled extraction study was performed. Gas Chromatography Mass Spectroscopy (GC-MS) revealed no significant peaks, thereby determining the volatile chemical extractables to be insignificant. Using Liquid Chromatography Mass Spectrometry (LC-MS) the Total Ion Chromatogram (TIC) revealed peaks matching the extracted ion chromatograph peak fragments of cyclic oligomers. The m/z value of each oligomer was then extracted from the solvent’s extracts’ TIC individually and matched to the retention times of the TIC’s significant peaks. The oligomers were quantified by comparing the analyte peak areas from data collected using High Performance Liquid Chromatography (HPLC) and Ultraviolet–visible spectroscopy (UV-Vis), to that of the external toluene standards.

UV-Vis Chromatograms of a Reflux Extract Concentrate


The sample concentrate oligomer concentration (6.77ppm) was determined via comparison of peak areas between the analyte and an external standard of toluene. The Analytical Evaluation Threshold (AET) per bottle was determined by multiplying the minimum number of days necessary to consume a bottle of the drug product (4.73 days), by the Safety Concern Threshold (SCT) for an oral drug product, 1.5 µg/day. The calculations yield peaks with a daily consumption well above the AET, the largest peak representing 2.81 µg/day. This process allowed for both characterization and quantification of the analytes detected within the PET bottles.

Step 3: Leachables Study

Next, a leachables testing study was performed on the drug solution via HPLC as per the validated method. The HPLC chromatograms of the extracts from the PET bottles obtained during the extractables analysis were compared with that of the drug product extract. Despite the extractable results, no leachables were found above the AET. There was also no PET oligomer analyte peaks matching the retention times of the peaks detected in the drug product extract.

Conclusion of the E&L Study

The conclusion of the extractables and leachables study showed that the pharmaceutical company’s drug product was clear for FDA submission, as all levels of extracted and leached compounds were below the AET. Though the extractables study did reveal that oligomers were extracted from the PET bottle, the leachables study showed that no compounds of concern were leached from the bottle into the drug solution. This finding allowed the company to pursue an ANDA submission in order to gain approval for their product’s production.

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