Diane Paskiet, director, scientific affairs, West Pharmaceutical Services explains how to understand risk from extractables and leachables (E&L) and the key quality considerations when designing E&L studies
Materials that have direct or indirect contact with a drug or biologic product can leach harmful substances into the final pharmaceutical product. Substances that leach can originate from various materials, at any point in the supply chain and throughout the product’s lifecycle. Constituents that migrate from primary packaging into the final product when manufactured and stored under its normal conditions are referred as leachables. Typically, leachable compounds are found in trace amounts yet can have a negative impact on pharmaceutical quality with potential to compromise patient safety. Any component used during manufacture, storage, shipping and administration to the patient can be implicated as a source of leachables.
Compatibility issues
There are multiple types of components to be considered throughout the manufacture, storage and delivery to patients. Primary classes of materials used to manufacture and store drugs and biologics include elastomers, plastics, glass, metal and paper board components. These components must be compatible with the final product and function properly for intended use as well as provide protection over the drug’s shelf life. A pharmaceutical product can be affected by chemical substances migrating from material into final product with distinct outcomes. The leached substance can be toxic, affect the product stability or react with active pharmaceutical ingredients or excipients to form a new chemical entity. Patient risk needs to be assessed and mitigated based on understanding potential for leaching. This is accomplished by designing systematic studies to identify and quantitate extractable substances.
Component profiles have many levels of complexity, which may become more varied once the component is formed, washed, sterilised and assembled. Common sources of extractables include residuals and by-products from the material. Processing aids and additives such as stabilisers, antioxidants, lubricants, curatives and their breakdown products are all examples of species contributing to the chemical profile. An extractable study will establish the chemical profile, which reflects risks relative to potential toxicity and incompatibility. Toxicity will depend on the leachable concentration in the final product and patient total daily intake; incompatibility is fundamentally dependent upon the pharmaceutical matrix and conditions of use. Often compatibility issues are manifested by different end points such as pH shift, degradation, oxidation, aggregation, foreign particles and other impurities that can become evident over a period of time. All materials will leach to some degree under certain conditions. The goal of an extractable study is to provide evidence that materials are suitable for intended use by understanding how risk for leaching correlates to patient harm and eliminating or mitigating that risk.
Key considerations for E&L studies
An extractable and leachable strategy consists of multiple steps in which voluminous information is acquired and builds until final drug product stability studies are completed. This can span a period of five years or more from discovery to confirmation. The objective of an E&L study is to identify and communicate risks by conducting controlled extractable studies, which can be correlated to drug/biologic safety and quality. Formal risk assessment tools such as flow diagrams, control charts, risk ranking/filtering or hazard analysis, and critical control points can add value in assessing components for intended use, although these tools are not required. The studies should be designed so the various components are evaluated commensurate with the level of risk to final product quality and safety. Criticality should be justified based on the likelihood of component interaction with the drug or biologic product during manufacture, storage or when in contact with a patient.
Once the components are deemed critical for evaluation, the chemical make-up of each material should be understood. This will feed into the component sampling, preparation of extracts and analysis techniques. Multiple solvents that encompass organic as well as aqueous solutions should be employed to explore a comprehensive chemical profile. Multiple analytical techniques and those that are orthogonal should detect a wide range of extractable species with various sensitivities. Analytical methods should be robust and fit for purpose; that is, having a system capable of detecting certain predetermined targets at specified levels as well as detecting unexpected extractables.
Understanding a material’s chemical profile is necessary to enable detection of leachables. The chemical characterisation of a component should include extraction solvents and conditions that are aggressive enough to indicate the basic chemical ingredients and by-products of the material; however, this is not often indicative of actual leachables. In certain applications, it can be an advantage to simulate or mimic final product under exaggerated conditions to define targets better. The purpose of an extractable study is to provide comprehensive data to indicate risk for leaching and guide a leachables assessment. Methods need to be optimized to measure trace leachables which are easily masked and difficult to detect in a complex matrix. Spiking and recovery studies are necessary to confirm the presence or absence of target compounds. Correlation of the component extractables with confirmed leachables under worst-case conditions will lead to the necessary control strategy.
Setting acceptance limits
There are limits in various compendia for certain materials used in pharmaceutical and medical device industries; however, these limits are considered a starting point to identify materials that might be acceptable. The final drug or biologic product will influence appropriate specifications and acceptance criteria. Acceptance criteria should be set based on the observed range of variation according to ICH guidance Specifications: Test Procedures and Acceptance Criteria for New Drug Substances, New Drug Products (Q6A); Biological Products (Q6B). The guidance establishes the criteria to which a drug and biologic product should conform to be considered acceptable for its intended use. There is a provision for control of extractables from container/closure systems in which parenteral products are considered significantly important. The guidance indicates that where development and stability data show evidence that extractables are consistently below levels demonstrated to be acceptable and safe, the elimination of this test can be accepted but should be reinvestigated if the container/closure system or formulation changes. The guidance also recommends collecting data for components as early in the development process as possible. This is consistent with quality guidelines on Pharmaceutical Development (ICHQ8 (r2), Risk Management (ICHQ9) and Pharmaceutical Quality Systems (ICH Q10).
Acquiring appropriate evidence to demonstrate suitability of materials is necessary for each pharmaceutical product. Extractables are a function of the material chemical make-up, physicochemical properties, configuration of the delivery systems, various environments and length of exposure. Risk variables include component proximity to the final product, area of direct contact, dosage form and conditions of use throughout material processing, manufacturing, filling and storing. Risk for leachables can be indicated based on identifying those extractable compounds with the highest propensity to leach into final product. The extraction and analysis methods should be tailored to substantiate that leachable levels are below quality and safety concerns. This allows risk of toxicity or poor quality needs to be identified and mitigated. It is not practical to assume a standard method or even suite of methods can provide all the essential evidence. Nonetheless, a standard strategy has been conceived by the Product Quality Research Institute (PQRI). In 2006, Recommendations for Safety Thresholds and Best Demonstrated Practices for Leachables and Extractables in Orally Inhaled and Nasal Drug Products (OINDP) was published (www.pqri.org). This is currently being extrapolated for parenteral and ophthalmic drug products (PODP). Recent USP guidelines <1663> Assessment of Extractables Associated with Pharmaceutical Packaging and Delivery Systems; and <1664> Assessment of Leachables Associated with Pharmaceutical Packaging and Delivery Systems were also published in USP PF 39 in September 2013 and are consistent with PQRI approaches.
To set acceptance criteria for extractables and/or leachables, relevant data must be collected and assessed. It is important to justify specifications based on impact to final product and patient. Control points can be considered early on, but the nature of leaching often occurs over time. Variability will exist from component to component as well as the extractables’ propensity to leach. Control points are not easily derived until there are multiple lots of components representing full shelf-life stability studies. Once an analytical target profile (ATP) is established for leachables methods should be optimised and measurements fully validated. Statistically relevant data is necessary to establish acceptance criteria.
A range of sophisticated analytical technologies can be employed for extractable and leachable testing. While all-purpose methods can be a starting point, these will not address distinct applications. Pertinent information is acquired by understanding the materials and intended use to enable specific extraction and analytical methodology to be justified.
Upcoming advances may be a combination of improving technologies for identifying/qualifying leachables along with development of new materials that are engineered to fit a purpose in a quality by design (QbD) paradigm. Accurate and precise analytical measurements will be the means to enable the future of applying the right knowledge at the right time to materials used in the manufacture, containment and delivery of high-quality pharmaceutical products.