Extractables and leachables (E&Ls) associated with parenteral drugs present an ongoing challenge to pharmaceutical manufacturers. Any time new materials are introduced into the extensive system that comprises parenteral manufacturing, which includes any and all filters, containers, and transfer tubing, and all components of the final drug product packaging, there is the potential that unknown leachable compounds will accumulate in the drug product. Even though leachables are typically present in minute quantities, some can cause significant problems for patients. Thus, E&Ls must be identified to the greatest extent necessary or possible and, if found to be a problem, eliminated or reduced to acceptable levels. The challenge, however, is clear: they can originate from any material that comes in contact with a parenteral drug during filtration, purification, formulation, transfer, filing, packaging, and storage, from a new additive in tubing or a container seal or a new ingredient in a washing solution used during syringe manufacture, and therefore can be continually changing.Supply-chain understanding critical
Recognition of the issues posed by E&Ls throughout the supply chain has been one of the most important advances with respect to managing this challenge, according to Carsten Worsøe, a principal scientist with Novo Nordisk. “The challenge is that every change in the composition and processing of a part of a device or a container-closure system potentially can change the leachable profile in the drug product. Such changes can be introduced by the supplier of the device or container-closure system or any number of subsuppliers or converters. The importance of bringing the changes forward to the pharmaceutical company can’t be overstated. This information is critical to a drug manufacturer’s ability to evaluate the risks associated with the change with respect to the leachable profile of the drug product,” he explains.Range of recent closure and device advances
The increased awareness in the supply chain has led to several advances in container-closure system and device technologies. “In each case, critical experiences with interactions of leachables with drug products led to the development of alternative technologies that minimize those interactions, and in turn, these examples have further underscored the role that participants in the extended supply chain have to play in managing extractables and leachables,” Worsøe observes.
The introduction of coated stoppers for vial products is one example of such a recent advance, according to Dennis Jenke, a distinguished scientist in the Technology Resources Division of Baxter Healthcare Corporation. These coatings retard the leaching of substances from the stopper’s base rubber material. In addition to the use of such barrier films and coatings, elastomer manufacturers are more closely evaluating the raw materials they use, including critical raw-material quality properties. “Enhanced controls on raw materials and the use of quality-by-design principles when manufacturing elastomers will result in cleaner, new elastomer formulations that should exhibit both reduced levels of extractables and greater lot-to-lot consistency,” notes Jennifer Riter, senior director of global analytical services with West Pharmaceutical Services. “The use of new films and coatings combined with these approaches will help further minimize extractables coming from an elastomer used in primary packaging for injectables,” she adds.
Advances have also been made in the chemistry of UV-cured adhesives used in device manufacture and the process used to form the needle channel of prefilled syringes, according to Worsøe. In the former case, the incomplete curing of the adhesives used to glue device parts together was leading to the interaction of unreacted acrylic acid with proteins. The solution to this problem was the optimization of the adhesive formulations and UV curing parameters to ensure that the amount of unreacted acrylic acid monomer was minimized, which in turn reduced the leaching of acrylic acid-related leachables.
For prefilled syringes (PFS) made of glass, the formation of the needle channel is commonly performed using a tungsten pin at high temperature (approximately 1200 °C). At this temperature, according to Worsøe, tungsten can be deposited on the surface of the glass as elemental/metallic tungsten or as tungstates/oxides. The presence of these tungsten compounds has been shown to lead to protein aggregation and oxidation in the PFS over time. Different approaches have been taken to minimize the deposition of tungsten, including optimization of the pin composition and design and more frequent replacement of the pins.
The relatively recent commercialization of “low extractables” plastics such as cyclic olefin copolymer is another example of the development of new materials for use in the extended supply chain that are specifically designed to address the E&L issue, according to Jenke.Analytical advances
To effectively screen for E&Ls, it is essential to use a number of orthogonal analytical methods, or those that will complement each other with respect to the detection of different compound classes, according to Worsøe. Such analytical methods include high-performance liquid chromatography–ultraviolet spectroscopy (HPLC–UV), liquid chromatography–mass spectroscopy (LC–MS), gas chromatography–mass spectroscopy (GC–MS), gas chromatography–headspace–mass spectroscopy (GC–HS–MS), inductively-coupled plasma-atomic emission spectroscopy (ICP-OES), inductively coupled plasma mass spectrometry ICP–MS, and ion chromatography (IC). Mass spectroscopy is often coupled with chromatographic techniques for the identification and accurate mass detection of organic E&Ls. He adds that recent improvements in gas chromatography time-of-flight mass spectroscopy (GC–QToF–MS) have enabled this technique to be used as an important method for the identification of unknown organic E&Ls. “More recently, liquid chromatography-nuclear magnetic resonance (LC–NMR) spectroscopy and liquid chromatography-solid-phase extraction-nuclear magnetic resonance (LC–SPE–NMR) spectroscopy have been shown to be valuable techniques for identifying unknown organic E&Ls,” Worsøe says.
Many of these latest analytical techniques used for extractables and leachables determinations are improvements on current technologies; more modern equipment and electronics offer greater sensitivity, according to Paul Cummings, laboratory operations manager for West Pharmaceutical Services. West is implementing ultra-high pressure liquid chromatography (UHPLC), which is a next-generation HPLC technique that requires less solvent and has higher sensitivity, so also enables the use of smaller sample quantities. Accelerated solvent extraction, which is an improvement over the reflux extractions used in the past, is also providing West with more control over temperature, pressure, and time, thus yielding more reproducible results.
For Jenke, it is the coupling of high-efficiency chromatographic techniques with information-rich detectors that continues to be an interesting area of development for E&L analysis. He points to the coupling of UHPLC with high-resolution MS detectors capable of providing accurate mass information, which enables the determination of the empirical formulas for otherwise unidentified extractables and leachables as being a noteworthy recent advancement in E&L test methods. “This development makes the LC screening process more broad-scope and information-rich, and thus more productive," Jenke comments.
Even with such advances in the resolution and accuracy of analytical techniques, there are concerns that remain. One of the most important issues, according to Jenke, is the fact that the screening methods commonly employed for organic extractables (GC and LC) are not 100% efficient in capturing all E&Ls. “Even if one were to identify all of the peaks in GC and LC chromatograms, it is possible ̶ and in fact likely ̶ that there would be extractables that the LC and GC methods did not detect. The questions then are: ‘How does one know whether such uncaptured extractables exist?’ and ‘How does one find these uncaptured extractables?’ Scientifically sound and universally applicable answers to these questions are not currently available.”The volume challenge
Large-volume parenterals (LVP) present additional issues when it comes to E&Ls in the form of the so-called “'volume challenge.'” “The main challenge for LVPs is the need to develop scientifically based toxicological acceptance criteria for E&Ls that can be met using currently available analytical techniques,” Worsøe notes. With LVPs, such as a dialysis bag used by patients with kidney failure, the daily volume of the parenteral drug that is consumed can be several liters compared to injection volumes for a small-volume parenteral (SVP) down to 100 µL.
If both an SVP and LVP each contain 0.1 mg/L (0.1 ppm) of a leachable compound, and the two drugs are dosed at 0.05 L and 1 L per day, respectively, the patient would be exposed to 0.1 mg/L x 0.05 L = 0.005 mg in the case of the SVP and 0.1 mg/L x 1 L = 0.1 mg in the case of the LVP. “Thus,” says Jenke, “all things being equal, leachables would need to be measured in LVPs to much lower levels than SVPs in order to establish the same degree of safety.”
In fact, the ‘volume challenge’ can result in a detection limit for the same leachable that is 10,000 times lower for an LVP compared to that for an SVP, according to Worsøe. “Because it is often the case that such low detection levels cannot be achieved using existing analytical methods, the approach must be taken to accept the level that is as low as practically possible,” he concludes. Although such an approach is a practical necessity, Jenke notes that adopting this approach increases the uncertainty of a toxicological safety assessment based on the chemical data. It is appropriate to address this uncertainty with alternate or additional testing. For example, if a leachable in an LVP drug product cannot be measured down to a toxicologically safe level, then it might be possible and appropriate to measure the same compound as an extractable by extracting the test system with an extraction medium that is more analytically viable than the drug product.