Pharmaceutical packaging: Extractables & Leachables case study - inhalation products

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 then 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 primary pharmaceutical packaging under study are 2.5 ml blow-fill-seal LDPE (Low Density Polyethylene) respules, which are used as the primary packaging for inhalation drug products. BFS technology is often used for the manufacturing of liquid-filled containers, either for small or large volumes, and is widely employed in the pharmaceutical industry. Generally, BFS containers are made of either polypropylene or polyethylene.
Inhalation solutions, especially those orally inhaled, but also those delivered through the nasal cavity, have been given the highest level of risk due to their route of administration and their likelihood of interacting with their packaging. Furthermore, the container closure system could represent a high risk to introduce impurities, as LDPE is a semi-permeable material.

Aim of the study
The aim of the study is the characterization of extractable compounds possibly released by blow-fill-seal respules for pharmaceutical use.
Extraction studies are the overall laboratory processes required in order to create extractables profiles of packaging. Extractables could be organic and inorganic chemical entities that are released from a pharmaceutical packaging/delivery system into an extraction solvent under laboratory conditions meant to stress the packaging beyond normal conditions of use. Extractables, or substances derived from extractables, have the potential to leach into a drug product under normal conditions of storage and use, and thus become leachables. Therefore, extractables profiles can be used in order to simulate a worst-case leachables profile of the drug product.

Mérieux NutriSciences strategy for Extractables & Leachables studies

Inhalations products have the highest level of risk, so our experts have developed a full-integrated testing strategy, together with a toxicological assessment and risk analysis.

1. Extractables & Leachables study
2. Toxicological evaluation
3. Identification of probable pharmaceutical risks

Results
The analytical study, that can be considered a “worst case” approach, is a useful support for the risk assessment of materials in contact with drug products.
The extracts obtained have been analysed for elemental impurities, S-VOCs, N-VOCs, and for anions, while the packaging as it is was analysed for VOCs. The study was conducted ensuring that the quantification limits of the analytical procedures met the calculated AET (Analytical Evaluation Threshold) based on a Safety Concern Threshold officially indicated for inhalation drug products:

• No metal shows values higher than the LOQ of the method.
• No anion shows values higher than the LOQ of the method.
• Several organic compounds (VOCs, SVOCs, N-VOCs) have been detected at concentrations equal to or higher than the AET.

The results obtained have been subjected to a toxicological evaluation to establish the safety of the packaging or the need for further investigations.