Paul Hardman, managing consultant at Broughton outlines why extractables and leachables (E&L) testing is critical for identifying potentially harmful leachable impurities from pharmaceutical container closure systems (CCS) and drug delivery devices.
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A strong E&L strategy analyses the nature of all present substances and their toxicity, quantifying patient exposure to each chemical and the corresponding risk. Important considerations when designing an E&L strategy include material candidates and study design.
Pressurised metered dose inhalers (pMDIs), a common treatment for conditions such as asthma, consist of a drug formulation (in suspension or solution) with a closure that delivers the required dosage efficiently and consistently. When using a pMDI, the correct administration of an active substance depends on factors including drug formulation, device design, and patient use.
For the treatment of lung disease, aerosol droplets must be of a size where they are not deposited on the back of the throat or in the bifurcations of the bronchi. However, this means that any potential toxicants from leachables in the device packaging could also be administered to the alveoli rapidly and enter the bloodstream.
Devising an E&L strategy
pMDIs carry a high risk of the potentially harmful materials in packaging, posing a risk to the user and potentially impacting drug delivery. These devices often contain materials and plastic components with a range of polymerisation catalysts, antioxidants, pigments, and slip agents from their manufacture that may leach, all of which may carry varying toxicological risks.
An E&L assessment is a controlled extraction study using various solvents to identify compounds that can be extracted from the packaging. Information gleaned from these studies is vital for the design of the appropriate leachables studies. Standards and guidelines for pMDI manufacturers to follow during E&L investigations include USP <1663>, USP <1664>, USP <1664.1> and ISO 10993.
Study design
Typically, E&L evaluation is performed during late-stage drug product development. However, an early assessment allows inappropriate materials to be replaced quicker, reduces risk by allowing time to react to extractables findings, and can help manufacturers accelerate their product’s route to market.
Once pMDI manufacturers have identified the material candidates, they can start investigating their E&L implications. Early consideration of method development and the validation of bespoke methods for the analysis of targeted leachables is essential.
Having finalised the container closure system design, the manufacturer can begin stability studies to analyse the targeted leachables and determine if the identified substances migrate from the container into the drug product.
Working with a science and regulatory consultancy can help you design and implement an effective E&L strategy for your inhaled products. To find out more, visit www.broughton-group.com/
