Analysis of Leachable Compounds in Pharmaceutical Packaging Materials

Leachables are chemical entities that migrate into a drug product formulation from the packaging or delivery system and its components, and are subsequently delivered to patients along with each dose of medication. Leachables, therefore, present potential safety risks for patients, and in particular for the sensitive patient population using inhalation drug products to treat chronic diseases. The analysis and identification of leachables from medicinal packaging materials is conducive to solving the problems faced by pharmaceutical companies in the identification of unknown compounds. If a systematic workflow for the identification of extractables of pharmaceutical packaging materials is provided, then a comprehensive and accurate identification of all potential contaminants, or at least a clear understanding of the compound class will be available. Serious consequences such as product recall, economic loss or branding image damage will not be resulted.

Several studies have been reported that various analytical techniques including chromatography, mass spectrometry, and organic synthesis are commonly used in characterizing or identifying extractables and leachables from drug packaging and drug delivery devices.

For the analysis and identification of leachables for pharmaceutical packaging materials, the general procedure is as follows.

Using the reflux method, microwave method or supercritical fluid extraction method to select solvents with a wide range of polarities to ensure that both non-polar and polar analytes can be extracted. Then as much analyte as possible can be available.

Then the major extractables can be isolated by semi-preparative HPLC method combined with silica gel-based chromatographic methods. Secondly, NMR spectra including 1D NMR (1H, 13C, DEPT135) and 2D NMR (COSY, HSQC, HMBC) were introduced to identify the extractables, besides GC-MS, LC-MS/MS and HRMS. Finally, the extractables can be determined respectively.

The analyte data can be confirmed by a commercially available library (for example the NIST). However, when the target compound is not included in the library or the sensitivity of the single quadrupole MS is insufficient for analyte-positive identification, the challenge of volatile matter analysis arises. Additional techniques such as atmospheric pressure gas chromatography and quadrupole time-of-flight mass spectrometry can be combined. For example, F. Zhang et al. used GC-MS to analysis structural identi?cation of extractables from rubber closures used for pre-?lled semisolid drug applicator mass spectrometry data analysis process is as follows.

• Use MS data to obtain high-resolution chromatographic separation

• Clarify the molecular formula of the element

• Identify the structure of the compound

• Evaluate the proposed structure based on the fragment information

• Collect the standard data and compare it with the sample results

Finally, the migration testing of the extractables were performed to assess the leaching behavior of the pharmaceutical packaging materials. The level of the target compound in the sample is measured, and the amount of extractables is calculated to see if the TTC limit of a particular value is exceeded, ultimately determining whether the product is potentially risk to the patient health.

References

• F. Zhang, A. Chang, K. Karaisz, R. Feng, and J. Cai, (2004) ‘Structural identi?cation of extractables from rubber closures used for pre-?lled semisolid drug applicator by chromatography, mass spectrometry, and organic synthesis.’ Journal of Pharmaceutical and Biomedical Analysis, vol. 34, no. 5, pp. 841-849.

• D. R. Jenke, J. Story, and R. Lalani, (2006) ‘Extractables/leachables from plastic tubing used in product manufacturing.’ International Journal of Pharmaceutics, vol. 315, no. 1-2, pp. 75-92.

• D. L. Norwood, L. Nagao, S. Lyapustina, and M. Munos, (2005) ‘Application of modern analytical technologies to the identi?cation of extractables and leachables.’ American Pharmaceutical Review, vol. 8, no. 1, pp. 78-87.

• D. R. Jenke, J. M. Jene, M. Poss, et al., (2005) ‘Accumulation of extractables in bu?er solutions from a polyole?n plastic container.’ International Journal of Pharmaceutics, vol. 297, no.1-2, pp. 120-133.

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