Regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) are dedicated to ensuring the safety and efficacy of drug products delivered to patients. This has led to the development of regulatory guidelines for the use of container closure systems (CCS) for parenteral drug products. Parenteral drug products are packaged as a solution, suspension, emulsion, or lyophilized powder and are administered in liquid form. Two of the main considerations for delivering parenteral drug products are stability and sterility, which can be achieved by using the proper CCS. CCS should be transparent to allow for visual inspection prior to usage and they should also be compatible with the drug product formulation. In this instance, compatibility means that the drug solution should not be compromised by anything that may leach from the CCS due to direct contact. In addition, there are certain packaging forms that pose a higher risk of interfering with the drug product (Table 1). While it is possible to have non-toxic levels of certain leached compounds, there is a chance some compounds may interfere with the efficacy of the drug product[1-3]. Thus, to ensure the compatibility of a formulation with a CCS, extractables and leachable studies (E&L) can be performed[2, 4].
Table 1. Risks associated with drug product administration route and CCS. Adapted from FDA guidance document: Container Closure Systems for Packaging Human Drugs and Biologics
Extractable studies evaluate the safety of the CCS whereas leachable studies evaluate the safety of drug product within the CCS. Extractable studies allow for the identification of potential leachables, which are chemicals released from the CCS into the formulation under normal conditions. Extractables are chemicals which are forcibly released from CCS under exaggerated conditions which can be induced by using strong solvents and high temperatures[2-5]. Analytical testing is then used to identify and quantify the extracted compounds. This data is then used to develop and validate a method for leachable testing and analysis. A leachable study is executed to ensure the drug product formulation is not impacted by any chemicals released under normal storage conditions. Leachable studies are usually performed under “real-time” and accelerated conditions. Furthermore, the leachable study can also be incorporated as a part of the normal drug substance and product stability testing. A risk-assessment toxicological report is then prepared based on the leachable study data. Leachable studies also help validate the findings in the extractables studies, since extractables are considered a “worst-case scenario”[1, 2, 6].
Figure 1. Interaction between extractables and leachables
To attain a meaningful compound profile from E&L studies, highly sensitive analytical techniques are required[1, 6]. Analytical methods need to be able to quantify compounds down to parts per billion (ppb) and possibly parts per trillion (ppt). In addition, the analysis method needs to be able to distinguish between isobaric compounds. MS based analysis is popular due to its reproducibility, sensitivity and high throughput capability and if often coupled with chromatographic techniques[2, 4]. Following separation, MS can identify compounds based on how they fragment and, with increasing mass resolution capabilities, such as is provided by Sannova’s state of the art Thermo Exploris 240 Orbitrap, the structure of extractables and leachables can be readily identified with high levels of confidence using sophisticated software and rich databases. GC is also widely accepted as an appropriate separation method due to expected volatile substances present in E&L samples[1-4, 6].
Due to the importance of maintaining the quality of the final drug product, regulatory authorities and organizations such as the International Conference on Harmonization (ICH), FDA and EMA are constantly updating their CCS guidelines (Table 2)[2, 5, 7]. In fact, some regulatory agencies require E&L data to be included in new drug applications (NDA) and biologics license applications (BLA). While inclusion of this data is becoming an industry standard, current guidelines do not dictate how to design and execute E&L studies. Furthermore, understanding the analytical data generated from E&L studies requires highly skilled analytical scientists. Thus, it is critical for sponsors to have the resources necessary to ensure E&L studies are compliant with regulatory guidelines.
Table 2. Quality guidelines relevant to E&L studies. Note: Not all guidelines relevant to E&L studies are included in this table.
Sannova has years of experience in developing and validating methods using MS based analysis and is well prepared to aid sponsors in the E&L study process. We have a state-of-the-art facility equipped with multiple MS instruments, including GC/MS, HRMS, LC/MS/MS and ICP/MS. In addition to our expertise in analytical methods, Sannova provides guidance in designing and executing E&L studies. We can help develop an extractable study protocol and based on the results we can suggest which leachables for which testing should be conducted.
It is evident that E&L testing is an integral part of delivering safe and efficacious products to patients. While some leachables may be expected in the final drug formulation, it is important to understand how those compounds may affect the final drug product. Biologics in particular are sensitive to their environment and may be prone to aggregation and other changes, which is why understanding its interaction with the CCS on physicochemical level is essential. In order to have a comprehensive understanding of these interactions, techniques such as MS are critical. Their high sensitivity allows for small amounts of chemical compounds to be detected and quantified. Furthermore, with the appropriate analytical chemistry background, this data can be interpreted to ensure there are no adverse effects to the final product. Thus, it is important for sponsors to reach out to companies such as Sannova which have expertise in these types of studies and analysis.