Examining the Growing Challenge of Extractables and Leachables

Extractables and leachables (E&L) are a growing area of concern for regulators, necessitating more oversight from pharmaceutical manufacturers. Pharmaceutical Technology conducted an industry roundtable to find out more about how extractables and leachables are being approached in the pharmaceutical industry. Participating in the roundtable were: Piet Christiaens, scientific director at Toxikon Europe; Andrew Feilden, chemistry operations director, at Smithers Rapra; Allen Kesselring, scientific director at EAG Life Sciences; Paul Killian, analytical technology R&D manager at EMD Millipore Corp.; and Wayland Rushing, senior scientific advisor at ABC Laboratories.

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At-risk products

PharmTech: What are the most common causes and types of E&L? Are certain drug-delivery and packaging components or product types more at risk?

Feilden (Smithers Rapra): Leachables can come from any part of the supply chain or manufacturing process. Issues can arise from the container–closure system itself, the secondary packaging, the manufacturing process, and even the storage environment. Typically the longer the contact time and larger the contact surface area the higher the degree of risk of leachables. The drug-delivery systems most at risk are inhalation aerosols and injectable suspensions. As a rule of thumb, the container–closure systems for these types of products have a large elastomeric content that tends to produce more leachables. Another area of major concern for regulators is biological formulations. Even though a leachable in its own right may be safe, it may have a significant impact on the properties of a biological formulation, such as aggregation, particle formation, or other product quality issues.

Kesselring (EAG Life Sciences): E&L studies are traditionally associated with orally inhaled nasal drug products, ophthalmic products, and injectable products. The quick and efficient transport of material to the bloodstream, which make these drugdelivery routes highly effective, also makes them susceptible to impurities arising from the packaging (this neardirect exposure concern also extends to many topical, transdermal, and implantable products). In addition to route of delivery, exposure quantity, and length of use are other key considerations that must be evaluated during E&L testing.

Killian (EMD Millipore): I perform E&L studies on single-use processing equipment. The most common types of E&L are small-oxygenated compounds, such as ketones, aldehydes, and organic acids generated from the gammairradiation process. The compounds and concentration will vary based on the strength of the gamma irradiation; the higher the dose the greater the number and concentration of these compounds. Other common compounds may include breakdown products from antioxidants added to protect the plastics, siloxanes from silicone tubing, and residual solvents from filters.

Rushing (ABC Laboratories): Some drugdelivery systems are at higher risk for E&L issues. Liquid-based parenterals and inhalation products (specifically metered-dose inhalers and inhalation solutions) tend to attract the greatest regulatory scrutiny. Because of the nature of these formulations, it is not uncommon to observe leachables above the recommended safety concern thresholds set for the toxicological evaluation of leachables in final-drug products. A second common source of E&L problems we have seen at ABC Laboratories is the actual labels that are applied to the drug product bottles. The inks and glues used in labeling have been a common source of leachables in several drug-device configurations.

Analytical testing

PharmTech: How are analytical tests today able to take a risk-based approach with E&L? What has changed in this area compared with 10 years ago?

Christiaens (Toxikon Europe): To take a "riskbased" approach, it is necessary to understand what the real risk is. Several years ago, risk-based approaches were often taken solely based on a paper evaluation of the known composition of a raw material (e.g., anti-oxidants, slip agents, nucleating agents, and other processing aids) or on the results of limited extraction studies. Today, the risk of finding leachables in the drug product and the harm it can cause to the patient is much better understood. As a consequence, more emphasis is placed on the risk evaluation of actual leachable data.

Feilden (Smithers Rapra): Taking a risk-based approach to E&L has been aided by the implementation of ICH Q8, Q9, and Q10. Aspects of quality by design are also being introduced that could help reduce the overall testing burden, but these studies are very intensive at the start of an E&L project.

It is now much easier to implement a risk-based approach to testing, but regulators are still very risk averse, so reducing the amount of testing can be challenging. Often, the risk of not carrying out the testing outweighs any associated cost or time savings that can be achieved.

Kesselring (EAG Life Sciences): The heightened sensitivity and widespread prevalence of mass spectroscopy as a detector for analytical techniques such as gas chromatography, liquid chromatography, and inductively coupled plasma has had big impact on E&L evaluation. While this improved technology, together with enhanced libraries (both commercially available and proprietary), allow for faster, and more efficient and accurate assessment of E&L, they have also led to a significant increase in regulatory expectations.

Killian (EMD Millipore): As analytical instrumentation improves, so does the ability to detect compounds at lower concentrations. In some ways, this has created new challenges with E&L studies, when it comes to identifying and quantifying small peaks observed in chromatographs. In the past, these compounds would not have been detected by the instrumentation.

However, one currently accepted practice to address this issue is to develop an analytical evaluation threshold, which allows the chemist to disregard small peaks and to instead focus on the larger peaks.

Rushing (ABC Laboratories): A risk assessment of the known compounds used in the manufacture of the container–closure system, such as processing aids (e.g., slip agents and mold-release agents) or other additives to the product, may determine that there is no need to monitor for these compounds during the E&L program. This approach can, in some cases, significantly simplify analytical tests. However, these compounds may contain impurities or react unpredictably in the presence of the drug product formulation. As a result, care should be taken when performing these assessments to ensure they are performed using the proper data and appropriate justifications.

During the past 10 years, we have seen significant advances in analytical technologies. Newer instrumentation can gather qualitative structure information while simultaneously meeting the low sensitivity commonly required for E&Ls and reducing the length of time required to perform toxicological assessments on observed leachables.

PharmTech: Are you seeing more trends in simulation studies to predict and prevent E&L with certain drug-packaging components, and what are the benefits?

Christiaens (Toxikon Europe): There is a growing consensus that simulation studies, as suggested by the Product Quality Research Institute–Parenteral and Ophthalmic Drug Products work group, are a very relevant addition to the traditional E&L approach, typically as a step in between extraction studies and formal leachable studies (using validated methods). Filling the containers with a relevant simulant and studying the migration behavior of the pharmaceutical packaging under accelerated storage conditions will help to understand which compounds (found in the initial extractable studies) are actually leaching out of the packaging components into the drug product. In the ideal case, the drug product itself can be selected (e.g., in an accelerated leachable study using screening analyses) because this approach should not only predict the real leachables profile, but also reveal potential interactions between the leachables and the drug product.

Feilden (Smithers Rapra): Nothing can be done to prevent extractable testing at some point in the development process. However, simulation studies are being more widely used to predict if there are going to be any leachable issues before the end of the shelf life or if there are issues with the formulation. This is happening more with biological and parenteral formulations.

Killian (EMD Millipore): Simulants (or model solvents) are very useful in E&L studies because they reduce the matrix interference with the analytical assay and are less expensive and safer to use than actual product streams. Simulations are especially useful when evaluating new packaging material. Several candidates can be evaluated side by side, and those with the most extractables can be eliminated from consideration early in the process.

Rushing (ABC Laboratories): The performance of leachable simulation studies to predict and potentially prevent leachables is increasing. The products that would typically benefit from these studies are liquid-based formulations such as parenterals, oral solutions, and inhalation solutions.

These studies are typically set-up by using the actual drug product formulation (or a justified simulant) to mimic a worst-case scenario interaction between the container–closure and the formulation. Accelerated conditions can be employed, but should not be overly aggressive. An aggressive extraction approach typical of a controlled extraction study can lead to dozens, if not hundreds, of observed compounds above the reporting threshold. From experience, we know that most of these compounds are unlikely to extract under typical storage conditions. Traditionally, determining which compounds would actually leach required performing stability studies on the actual drug product, but this approach can be time-consuming and costly, especially when evaluating multiple container–closure configurations.

Simulation studies allow for better decision making process during the development program. As a result of the study design of simulation studies, the compounds observed are more likely to be representative of the compounds that that can be expected to leach. By using these data, we can make decisions on which packaging may result in overall leachable levels and which methodologies will likely need to be employed to monitor for actual leachables in the drug product.

Regulatory requirements

Pharmtech: What are the current regulatory expectations (for example among FDA and EMA) for E&L testing and removal?

Christiaens (Toxikon Europe): Ten years ago, there was a general consensus that leachables were a subset of the list of extractables that could be detected in a properly designed extractable study. FDA and EMA guidance documents issued based on this assumption placed much emphasis on performing risk evaluations on extractable results. However, a better understanding on the interactions of drug products and packaging materials has made it clear that leachables are not always a subset of extractables. As a result, regulators are requesting more leachables data that better reflect the actual risk to the patient.

Feilden (Smithers Rapra): The basic premise for carrying out E&L testing from both FDA and EMA remains the same whether it is for the container–closure system or manufacturing environment. However, expectations have increased over the years, but have recently accelerated for biological formulations because of the possible interactions of leachables with these formulations.

Kesselring (EAG Life Sciences): There are several areas in which regulatory expectations regarding E&Ls and general impurity assessments are changing. Through initiatives such as the forthcoming USP General Chapters <232> & <233> involving elemental impurities, regulatory expectations of specificity, accuracy, and control are being implemented. Also, initiatives such as the recently "published for comment" glass delamination document of USP <1660> and the increase in requests for routine extractables testing of incoming lots of container material demonstrate that the concept of control and prevention is being driven by regulatory agencies.

Killian (EMD Millipore): Regulatory bodies put the onus on drug companies to demonstrate that E&Ls do not pose a risk to the patient. As a rule, agencies like to see leachables as low as reasonably achievable. They also like to see that the drug companies have thought out their approach to E&L.

One noticeable increase in E&L expectations comes with the expanded use of single-use components. In the past, there was little interest in E&L from process equipment because most facilities used stainless steel. Now, as more stainless steel is replaced with single-use equipment, regulatory bodies want more E&L data, including data from the same filters that were not a concern in stainless steel systems.

Rushing (ABC Laboratories): Regulatory expectations continue to increase. Drug–device combinations that historically garnered little regulatory attention in regards to E&L are now receiving more in-depth scrutiny. Over the past couple of years, several oral and dermal solution formulations have received either deficiency letters or specific information requests from FDA asking for in-depth E&L information for drug products. It is likely that this trend will soon spread to affect products that were traditionally considered to be at a lower risk of E&Ls as emphasis in this area continues.

PharmTech: How do regulatory expectations for E&L testing and toxicological assessments vary between EMA and FDA?

Christiaens (Toxikon Europe): The regulatory expectations in Europe (EMA) and the US (FDA) are very similar. However, in my experience, variability between different reviewers within the same authority regarding what level of documentation they expect is higher than the difference in official standpoints concerning what documentation to submit with regard to the qualification of the pharmaceutical packaging materials between FDA and EMA.

Feilden (Smithers Rapra): The significant differences between the two regulatory authorities are in the amount of information supplied on how to conduct testing. FDA points to the Product Quality Research Institute (PQRI) recommendations, but the EMA guidance is a lot shorter and doesn't go into specifics. Generally, PQRI recommendations tend to be followed because they are more stringent than EMA. PQRI has a level of 0.15 µg/day for identifying species whereas the EMA has 1.5 µg/day. There doesn't appear to be any difference between toxicological assessments for either regulators, but a toxicologist would be able to confirm this.

Kesselring (EAG Life Sciences): Although it is difficult to predict how developing regulatory requirements may contrast, I have found the current expectations for E&L testing between EMA and FDA to be more similar than different. I believe the background that has allowed this to occur is that the development of industry E&L study concepts has coincided closely with the development of the International Conference on Harmonization. It is also notable that the E&L industry driving force of the PQRI has been a multinational effort both in its recommendation development, as well as its promotion of the developed concepts.

Killian (EMD Millipore): There are some differences between EMA and FDA. EMA is quicker to incorporate ICH documents and is more willing to put out guidance documents (e.g., the 2009 CHMP Guideline on the Limits of Genotoxic Impurities). FDA is more noncommittal, leaving it up to the drug company to demonstrate that E&Ls do not pose a risk to the patient.