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As regulatory bodies extend the oversight of E&L testing, companies working with drug products need to make provisions on how to best comply with the evolving expectations.
Extractables and leachables (E&L) testing, to a certain degree, is a requirement for nearly all drug product submissions to the relevant regulatory bodies, unsurprising given the fact that patient safety is of paramount importance. Guidance documents provided by regulators, however, do not detail how E&L evaluations should be performed by companies, and expectations by regulators have become more stringent in recent years.
“Nearly all drug products submissions require at least some level of E&L evaluation, with the possible exception for lower-risk items, such as oral solid dosage forms,” says Derek Wood, associate director, PPD Laboratories. “Failure to comply with regulatory expectations regarding E&L evaluation can result in drug product approval delays.”
Used to determine whether unwanted, and potentially harmful, compounds can migrate into a drug product from packaging, delivery system, or manufacturing surface, under normal or extreme circumstances, E&L testing is of critical importance in drug development, confirms Andrew Kolbert, president and chief technology officer at Avomeen. “E&L testing results must be included with FDA drug submissions, for example,” he states.
“The main driver of all regulatory authority in drug registration, such as product approval and drug/device combination approvals, is patient safety. Product efficacy also provides a basis for regulatory involvement,” notes Frank Hoffmann-Geim, director regulatory affairs at Schott Pharmaceutical Systems. “One critical parameter of patient safety, as well as for avoidance of loss of efficacy, is to avoid any kind of negative interaction between the inner surface of the drug container and the medicine inside.”
Ultimately, compounds that have extracted or leached into the drug product can not only result in direct toxicity to the patient but can also impact the efficacy of the drug product, which has the potential to also impede patient safety, emphasizes Wood. “To ensure controls for protecting patient safety, E&L evaluation is a key requirement for most regulatory filings and is critical for consideration of drug product safety, efficacy, and quality,” he adds.
However, even to this day, Wood explains that there are many instances where insufficient or incomplete E&L testing is occurring and, as a result, causing delays or even complete rejections of regulatory submissions. In illustration of his point, Wood raises an example from the late 1990s, involving a leachable vulcanizing agent in an Eprex anemia drug product. The leachable agent was found to cause an increase in cases of pure red-cell aplasia (PRCA) in some patients, which resulted in the product being recalled from 17 countries (1).
“The source of the problem in the Eprex anemia example was determined to be due to a change in the formulation that was made wherein the original biologically derived solubilizing agent, human serum albumin, was replaced by polysorbate 80,” Wood says. “Along with the formulation change, the manufacturer changed the rubber material of the syringe from a coated plunger to that of an uncoated plunger. These modifications enabled an interaction between the rubber plunger and the polysorbate 80 in the new formulation, resulting in a vulcanization agent (2) within the rubber to leach into the drug product.”
Giving a further example, Wood highlights the cases in 2010 and 2011, where multiple lots of Lipitor, Glumetza, and Tylenol were recalled when patients noticed a musty odor coming from opened drug product bottle containers (3). “It was found that the musty odor was from 2,4,6-tribromoanisole (2,4,6-TBA), a byproduct of a chemical preservative used for the wooden shipping pallets on which the products were stored and shipped,” he reveals. “The preservative byproduct (2,4,6-TBA) leached out from the wooden pallets and migrated into the drug products’ containers.”
It is widely known that increasing numbers of large-molecule drugs are entering the development pipeline and being presented to regulatory bodies for review. However, these complex molecules present a variety of potential concerns relating to E&L testing.
“Although it is best practice to perform leachable testing as part of your registration stability for all drugs, it is especially more important to do this for biologics,” emphasizes Kolbert. “This is because in addition to leachable toxicology, large-molecule drug substances pose greater risks of interacting with the packaging, delivery system, or manufacturing surface in ways that can compromise drug activity.”
Biopharmaceutical products are generally developed as parenteral formulations, which is an administration route considered to be higher risk for E&L by regulatory bodies. “Although many small molecules are parenterally administered as well, the uniqueness of large-molecule drugs is they more often include certain excipients that are present to enhance the stability or solubility of the active ingredient,” explains Wood. For example, surfactants such as polysorbates and poloxamers, which are used to help prevent protein aggregation or degradation and aid with solubilization or emulsification, can enhance the migration of leachables, he adds.
Additionally, biopharmaceuticals present challenges due to the number of active sites present within the molecules themselves that have the capacity to react with leachables, Wood iterates. “The activity-dependent, tertiary structure of biopharmaceutical products can be negatively impacted by leachables, such as silicone oil,” he says. “Biopharmaceutical products can be denatured by exposure to inorganic leachables such as certain metals.”
Another important consideration for Wood is drug product manufacturing. “Biologic drugs typically are manufactured using a single-use system, in which disposable plastics and bags are utilized instead of traditional stainless-steel vessels,” he asserts. “The disposable manufacturing components have a higher propensity to leach compared to the stainless-steel components.”
Companies may also be cautious in terms of the amount of materials available for E&L evaluations. For many cell-based production techniques, small amounts of product are manufactured with a high cost-per-unit volume, which means that a laboratory must approach E&L testing with an appropriate study design so that the sensitivity required can be attained at a scaled-down volume compared with traditional small-molecule products, Wood stressed.
Lyophilization may also be an attributing factor to consider for E&L testing, as many biologics are lyophilized to improve shelf-life storage stability. “Although perhaps counter-intuitive to the typical expectation that liquid solvents would promote more leaching than dry powder, our research (4,5) has revealed that in the case of lyophilized products stored in a vial with rubber septum, there can be a greater propensity for volatile and semi-volatile leachable compounds migration into the lyophilized cake than there would be for the product in liquid form,” Wood says.
Furthermore, packaging and packaging systems are being affected by the increasing demands of biological products, and consequently are becoming more complex. “Of particular importance is the use of different materials for components of such packaging,” confirms Hoffmann-Geim.
“Much of the United States Pharmacopeia (USP) regulations and norms concerning E&L testing arose from the use of glass vials, because they were the most common container for injectable drugs,” he continues. “Over the years, primary packaging manufacturers have introduced syringes made of glass as well as of polymer, both comprising rubber components as stoppers, tipcaps, or plungers. Now, the norms are evolving so that pharmaceutical companies have to not only consider the packaging itself, like the glass barrel of a syringe, but also the additional components made of different materials and which will come into contact with the drugs.”
Multiple guidance documents have been published by FDA and the European Medicines Agency (EMA) to support industry with the legal requirements of ensuring that impurities in drug substances and drug products, above a certain threshold, are monitored and/or characterized. However, the guidance is generally not prescriptive and can be open to interpretation in terms of implementation, stresses Kolbert.
Highlighting experiences with FDA specifically, Kolbert continues to explain that as a result of the non-prescriptive nature of the guidance, it is possible for E&L testing expectations to change readily without regulations changing. “Over time, FDA has increased the scope of products for which it expects E&L testing results,” he says. “The agency used to be concerned only with the most high-risk products. FDA has now moved on to also focus on products that are low risk-such as oral capsules and tablets.”
Additionally, Kolbert reveals that FDA has expanded its oversight of E&L testing to include components that are not necessarily associated with risk factors, such as manufacturing components involved in the drug production process. “So, if a drug product has to pass through a gasket or hose for any amount of time, FDA expects E&L testing to be performed on those components,” he adds.
“Due to the lack of detail and clear direction in the evaluation of E&L, various industry group guidance documents also have been established over the years to help complement the regulatory guidance with best practice ‘how-to’ approaches for conducting E&L studies and reporting thresholds,” Wood notes. A main industry group whose approaches to E&L testing have been adopted by regulatory bodies globally is the Product Quality Research Institute (PQRI) (6).
“One of the more recent developments over the past few years is the ongoing establishment in the USP of more extensive E&L general chapters and related monographs that are aligned with PQRI and regulatory documents, regarding the approach and reporting of leachables,” Wood says. “This has helped to add consistency to the approach for these types of studies, bringing together the accepted industry group and regulatory guidance.”
Pharma and drug-device companies have a tendency to outsource E&L testing to laboratories that have extensive experience with a wide range of systems and materials for a variety of administration routes, Wood reveals. “A contract E&L laboratory should be able to provide effective consultation for proper study design to help navigate regulatory expectations,” he says.
In agreement, Kolbert adds that for the majority of pharma companies the expertise required for E&L testing of materials, such as plastic, polymer, and rubber, are not typically core competencies. To address the evolving E&L testing expectations of regulatory bodies, he specifies that contract research organizations (CROs) should be employing experts from the metals, plastics, and polymer industries.
“It is often difficult for pharma companies to keep up with changing E&L guidance because regulatory bodies can take issue with the E&L testing methods used without precedent,” Kolbert explains. “Usually a CRO finds out about these things because one company receives a finding and word gets around the industry through the CRO. When a company submits a product for review, then learns there is a regulatory requirement to consider additional factors, it can cost the company a great deal of additional time and money. Often, the entity must ask the CRO to do the work in a compressed timeframe. Such rush requests can be quite costly.”
In light of the evolving regulatory stance on E&L testing, greater time and effort is required by companies and outsourced partners to learn and understand how to meet regulatory expectations. “The best way for CROs, in particular, to prepare for more stringent standards in E&L testing that may come in the future is to hire experts from a wide variety of industries to provide a greater scope of expertise,” Kolbert says.
“For companies with large drug product pipelines especially, there are benefits to arriving at a list of platform material components to be used to save time and cost on performing separate extractables studies later,” adds Wood. “We have seen this with multiple large pharmaceutical companies, where they establish a material platform for container/closure or device components, such as vial stoppers used for storing liquid injectable products. All the potential stoppers to be used for all their products are collected and a large controlled extraction study is performed, and then that data can be leveraged for many products in the future, saving time and cost. Leachable studies are still required, but the extractables piece is already in place. The component extractables data can be leveraged for use on new products, thereby helping to shorten the overall E&L timeline.”
From the primary packaging manufacturer perspective, Hoffmann-Geim highlights the potential challenges of biologics, which are very sensitive to chemical interactions with other materials. “The importance of E&L assessments is going to grow in coming years,” he summarizes. “It’s of increasing importance that providers of primary packaging work closely with pharma companies to understand which ingredients and molecules are being used in our containers. It’s not enough to only sell a piece of glass or a piece of polymer. Primary packaging must also be tailored directly to a specific drug, the needs of the patients, and the therapy to ensure patient safety.”
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6. PQRI, “Publications,” pqri.org [accessed Nov. 11, 2019].