Today drug developers and manufacturers are under unprecedented pressure to ensure the safety and quality of their products, thanks to increasing FDA safety regulations and consumer lawsuits. These have led to increasingly rigorous testing requirements and scrutiny of finished pharmaceutical products prior to sale.
Regulatory authorities have recently been increasing their requests for evaluation of extractables and leachables, in particular, that go beyond what is in the base ISO tests.
The government’s concern is understandable. Extractables and leachables have the potential to interact with a pharmaceutical product at multiple stages during development and production. That could impact efficacy, safety and quality.
Based on the problems these factors can cause, their presence must be evaluated in those components which come into contact with the product during formulation, intermediate storage, and final packaging for any sign of extractables or leachables. This evaluation enables a greater understanding of how to manage these compounds during development and assists with ensuring they fall within regulatory requirements for container closure systems and packaging materials.
Extractables migrate from a material under stressed conditions such as elevated temperature, extreme surface exposure and/or aggressive solvent systems. Leachables migrate from the product or packaging under normal conditions of exposure over the course of the product’s shelf-life.
There is generally an overlap such that the leachables involved may be classified as a subset of the extractables. However, if the leachable interacts with the drug product or packaging materials, new components can be present.
Such chemicals can have an impact on the safety of individuals. Leachables may cause a change in the protein in the pharmaceutical product causing conformation, aggregation, or degradation, and may have an immunomodulatory effect.
Extractables and leachables studies quantify potential leachable impurities from pharmaceutical container closures and medical device packaging. Such studies help to identify, quantify, and minimize harmful impurities which could leach from pharmaceutical container closure systems and packaging into pharmaceutical products.
The FDA typically requests that potential impurities are identified and then monitored throughout the life of the product. However, there are many variables that determine the type of extractable and leachable study to perform and to what degree a product or packaging is tested.
As pharmaceutical packaging can be extremely complex – with mixtures of plastic, polymer, rubber or glass materials, printed surfaces and coatings used – it is critical that these studies are designed specifically for the drug product and the container materials.
Lessons from the past
Prior to the implementation of more stringent regulations regarding extractables and leachables in pharmaceutical packaging or containers, there were several incidents in which potentially harmful leachables were identified, such as those with:
- Polycyclic aromatic hydrocarbons (PAHs), contamination within chlorofluorocarbon (CFC)-filled metered-dose inhalers (MIDIs);
- Vanillin being detected in inhalation solutions contained within primary low-density polyethylene (LDPE) containers; and
- Diethylhexyl phthalate (DEHP) being found in the total parenteral nutrition (TPN) fat emulsions used to help patients gain weight, as it can migrate from the PVC infusion lines into the emulsion and enter the body of the patient. DEHP incidents were especially worrying, as infants are known to be particularly sensitive to DEHP-triggered toxicity.
These are just a few examples of the potential risks that extractables and leachables present. Implementation of regulatory guidance has clearly been a necessity and detailed testing of all components involved in the construction of end products is now required. However, testing for extractables and leachables can still be a challenging process and requires a significant level of expertise.
Types of extractable/leachable studies
Extractable and leachable studies identify several key components such as semi-volatile organic compounds, non-volatile organic compounds, volatile organic compounds and metals. Analytical techniques to detect the extractables and leachables, such as gas chromatography mass spectrometry (GC/MS), liquid chromatography mass spectrometry (LC/MS), inductively coupled plasma-mass spectrometry (ICP/MS), and headspace GC/MS, are useful tools for such studies.
The results of such tests can be compared against industry standards to assess the impact on patients. For example, the Extractables and Leachables Safety Information Exchange (ELSIE) was formed in 2007 and provides a database of safety information on various extractable and leachables, as well as standardized protocols for generating controlled extractables data. Including extractables and leachables from packaging components in an overall assessment of product risk is important in ensuring patient safety.
For more information about how GERSTEL equipment can help your lab quickly and accurately analyze extractables and leachables in pharmaceutical products, contact us for a conversation.