Expert detection of impurities can improve product safety and regulatory success.
Driven by Patient Safety
Drug manufacturers have as their primary goal the development of high quality, safe, and efficacious medicines that improve patient health and quality of life. As such, during the drug development process it is important to identify any potential for product adulteration that could present a risk of toxicity or affect product stability or efficacy.
In addition to process-related impurities, manufacturers must consider the impact of impurities that may arise from packaging materials, drug delivery systems, manufacturing conditions, and storage. Ideally, packaging materials and other materials in contact with the drug product or the drug substance are resistant to chemical attack, UV and other forms of radiation, moisture, and heat. Their performance must be confirmed, however.
A combination of risk assessment and analytical testing is employed to systematically determine the potential for contamination of the drug product due to extraction and leaching of harmful compounds from containers, container closures, drug delivery systems, and other materials used in drug product or drug substance packaging or delivery.
The analytical testing work involves performance of extractables and leachables (E&L) studies to determine what, if any, compounds migrate from the packaging or other materials into the drug product or drug substance and at what levels. The overall goal is to provide a safer product. And while E&L studies can be complex, challenging, labor-intensive, and time-consuming, failure to perform risk assessments and appropriate analytical testing can lead to the delay of product launches or, even more significantly, harm to patients.
Understanding Extractable and Leachable Contamination Sources
Extractables are compounds present in packaging materials (and medical devices, such as pre-filled syringes) that can be forced to migrate out of the material under stressful conditions, for example exposure to strong solvents and high temperatures. Typical extractables include surfactants, plasticizers, antioxidants, dyes, heavy metals, and curing agents.
Leachables are compounds that migrate from packaging materials into drug products under normal storage, handling, and use conditions over the lifetime of the drug product.
All packaging components – and components of medical devices – have the potential to act as sources of extractables and leachables. Plastic (or glass) bags, bottles and vials, foil pouches, rubber stoppers that serve as container closure systems (CCSs), and the ink and adhesives used in product labels and secondary packaging all have the potential to provide unwanted contaminants that can leach into drug products. Even the needles used in pre-filled syringes can serve as an E&L source.
Applicable Regulations, Guidance and Standards
In 1999, following extensive studies on the propellants used in metered dose inhalers, the FDA mandated that pharmaceutical manufacturers demonstrate the safety of materials used in production systems, container-closure systems, and drug delivery devices. Since that time, numerous compendial standards and guidance have been issued that outline the requirements for conducting E&L studies for packaging materials. Similarly, many analytical methods have been developed for use in E&L studies.
Two important US Pharmacopeia (USP) chapters are USP <1663> “Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems” and USP <1664> “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems.” USP <1663> outlines who is responsible for extractable studies, potential sources of extractables, guidelines for conducting extractable studies, and how extractables should be characterized. USP <1664> provides similar guidance on leachables studies.
Additionally, USP <661> presents analytical standards and performance criteria specifically for polymers use in plastic packaging. Many other regulations, such as ICH M7(R1), CFR 21 Part 211.65, and ISO 10993-1:2018 are used to guide E&L studies.
The Nature of E&L Studies
E&L studies are performed to identify and quantify compounds that have the potential to migrate from packaging materials into the drug product. They also involve determination of the impact that these compounds may pose to human health and drug stability and efficacy.
Each study must be designed for the specific drug/device and packaging combination to be sure that the risks associated with the specific potential leachable impurities are properly evaluated.
Study designs must take into consideration several different factors that can impact the migration of compounds from packaging materials: the materials of construction used in the packaging; the physical characteristics of the drug product (solid, liquid, presence of solvents and excipients); the conditions under which the packaged product will be stored, handled and used during its lifetime; and the sterilization process to be used for the product (filtration, heat, radiation, chemical).
Given the involvement of multiple materials of construction and the many other factors that must be considered, E&L studies comprise a series of experiments using a variety of conditions. In addition, no single analytical method can detect and identify all possible extractables and leachables. As a result, E&L studies require the use of multiple analytical techniques and detection platforms.
Analytical technologies used in E&L studies include gas chromatography-mass spectrometry (GC-MS), headspace GC-MS, high-resolution accurate mass (HRAM), liquid chromatographymass spectrometry (LC-MS), and inductively coupled plasma mass spectrometry (ICP/MS).
A safety concern threshold (SCT) is calculated based on data provided by the client and informed by ICH M7(R1). The SCT is then used to determine the analytical evaluation thresholds (AET) for each extraction and test, which are the levels above which extractables must be monitored in a leachable analysis or leachables must be reported for toxicological assessment.
Step-by-Step Evaluation
The overall concept of E&L studies is simple – expose the material to ‘worst case’ extremes of pH, solvents, and temperature to reveal all potential extractables, and follow up with analysis of the subset of extractables that may leach into the drug product under normal storage conditions.
In practice, however, E&L studies encompass a complex array of individual experiments that require their own specific conditions. Instrument settings, spiking solutions, and other conditions must be modified according to each material studied. In addition, the appropriate limits of detection must be established so that potential leachable compounds can be detected at the levels at which they are considered harmful to patients.
An understanding not only of the chemicals involved, but also of the capabilities of different analytical techniques and instruments, is needed to ensure that the appropriate extraction processes are employed and all potential contaminants can be accurately detected and quantified.
The first step in preparation for E&L studies is to carefully consider the materials of construction. All known materials can be searched across libraries of existing data to guide appropriate experiments. When available, data from material suppliers can also provide insight into the expected extractables and leachables.
The more data that can be gathered in advance of the study, the easier it is to predict which extractables and leachables might be present and therefore to choose the most appropriate analytical techniques.
For materials that are not already known or characterized, experience plays a critical role in devising a strategy for analysis. In this case, a broad screening strategy is generally used to identify and characterize relevant extractables for later quantitation studies.
Once the potential extractables are identified, it is necessary to determine whether trace amounts of these compounds may migrate into the drug product. After the leachables have been quantified, the potential risk they may pose to the integrity of the drug product is then assessed. Detected extractables are also examined against literature data to identify target leachables.
Leachables testing is generally conducted using either freshly prepared product or product subjected to accelerated storage conditions. If any compounds not previously identified are found to be present above a predetermined threshold level for unknown leachables, the source of those compounds must be identified.
The greatest attention is paid to leachables that are classified as presenting a high risk to patients, such as carcinogens and heavy metals. E&L studies for these compounds must provide quantitative evidence to demonstrate they exist in the product below regulated levels or not at all.
A series of experiments must be designed for each material of construction. Study designs can be quite complex as a result, particularly for medical devices such as pre-filled syringes, which typically consist of many different components, each of which may be made from several different materials.
Experience and Expertise Ensure Success
Extractables and leachables studies are an essential component of regulatory filings and are needed to demonstrate product safety. Depending on the choice of container, container-closure system, labels, and secondary packaging, E&L studies can be very complex.
Access to and knowledge of how to leverage libraries of available data to conduct thorough examinations of containment-closure systems, packaging materials, and medical devices provide a distinct advantage. Broad experience is also essential in choosing the best techniques to give a full picture of the relevant extractables for a given drug product and container system.
Experience from previous studies is a critical advantage when designing a targeted analysis of a product containment system that may have unknown materials. Expert knowledge of materials improves the ability to predict which chemicals might be present in order to begin detection.
Often, the best way to complete these studies and have the most successful results is to work with an experienced contract development and manufacturing organization (CDMO) that has worked with a broad range of drug products and finished formulations. An experienced CDMO will have historical documentation of E&L studies, as well as being versed in the latest regulatory requirements to complete successful studies and bring a safe, efficacious drug product to market in the desired formulation.