Pharmaceutical packaging: Extractables & Leachables case study – ophthalmic solution in multidose packaging
Both primary and secondary containers used for drugs must ensure product safety until their expiry date, protect them from the environment, and avoid transferring possible harmful contaminants into the drug.
Extractables studies take on a central role in the technical dossier that eventually allows drug products to be released on the market, by serving as the basis for a toxicological risk assessment on the pharmaceutical packaging that acts as a framework for subsequent leachables studies on the drug product.
What about the packaging?
The drug product object of the leachables study is an ophthalmic solution, packaged in a multidose HDPE/LDPE container (nominal volume 10 mL).
Ophthalmic drug products are administered directly to the eye, so the focus is on leachable substances that might cause irritation or sensitization. The pharmaceutical packaging typically used for storage of ophthalmic solutions is semi-permeable and squeezable primary containers. Due to the semi-permeable character of the primary container material, compounds coming from the secondary packaging can also easily migrate into the ophthalmic drug.
Aim of the study
The aim of the study is the characterization of leachable compounds possibly released by the HDPE/LDPE multidose packaging for ophthalmic drug products.
Characterization is the discovery, identification, and quantification of each organic and inorganic leachable chemical entity. Leachables were characterized if present in a concentration higher than the LoQ, and reported for toxicological evaluation if present in a concentration higher than the Analytical Evaluation Threshold (AET), calculated on the basis of an appropriate Safety Concern Threshold (SCT). The study was conducted ensuring that the quantification limits of the analytical procedures meet the selected Analytical Evaluation Threshold of 1.0 μg/mL, based on FDA recommendations for ophthalmic drug products, and the SCT level is set at 1.5 μg/day, as indicated by the PQRI working group (Diane Paskiet, 2013) for Parenteral and Ophthalmic Drug Products (PODP).
Mérieux NutriSciences strategy for Extractables & Leachables studies
In the case of ophthalmic drug products, administered directly to the eye, the focus of the study are the leachable substances that might cause irritation or sensitization.
- Extractables & Leachables study
- Toxicological evaluation
- Identification of probable pharmaceutical risks
The analysis of the drug product considered both organic and inorganic entities, and the chromatographic techniques used for screening are coupled with appropriately sensitive, universal, and information-rich detection methods to ascertain the leachables identity and concentration as follow:
- HS-GC/MS – Headspace Gas Chromatography coupled with mass spectrometry detector
- GC/MS – Gas Chromatography coupled with mass detector
- HPLC/HR-MS Q-Orbitrap – Ultra Performance Liquid Chromatography coupled with high resolution mass detector
- ICP/MS – Inductively coupled plasma coupled with mass detector
Results
The analytical study, that can be considered a “worst case” approach, is a useful support for the risk assessment of packaging materials in contact with drug products, focused on investigation of leachables.
- Nickel is the only metal present at concentrations above the limit of quantification (0.001 μg/mL), but the correspondent PDE is several order of magnitudes below the PDE limit reported in ICH Q3D “Guidelines for elemental impurities”.
- No organic compounds have been detected at concentrations equal to or higher than the AET.
Since no organic compounds were found in concentrations above the AET, and the only metal above LoQ did not pose a health risk according to ICH International Guidelines, the need for a toxicological evaluation can be forgone.
