A primary mission of the PDA Journal of Pharmaceutical Science and Technology is to disseminate new information pertaining to advancements in the improvement of product quality that ultimately benefit patient health. One such area that is covered by the journal is the interaction of pharmaceutical products with their manufacturing, packaging, and/or delivery systems; specifically, the extent to which substances can migrate (leach) from these systems and into the drug during its manufacture, storage, and/or administration. These interactions are assessed as part of extractable studies and/or leachable studies, whose purpose is to characterize the materials used in these systems and/or analyze the drug product that contacts them to ultimately confirm that any leaching, if it has occurred, will not negatively impact the quality of the drug or safety of the patient.
The design, execution, reporting, and interpretation of extractables studies and leachables studies requires expertise in such diverse fields as polymer science, analytical chemistry, solution chemistry, thermodynamics, kinetics, and regulatory science. Thankfully, significant advancements in the design of these studies has occurred in the past 20 years, with the publication of the Product Quality Research Institute’s (PQRI’s) Orally Inhaled and Nasal Drug Product (OINDP) in 2006 (1) often regarded as a breakthrough resource in this area. More recently, substantial revisions of the United States Pharmacopeia chapters (2⇓⇓⇓⇓–7) have been made, much of which have incorporated and expanded on the good practices established by the PQRI OINDP to other formulations and delivery routes. Similarly, part 18 of ISO Standard 10993 (8) was substantially revised, providing expanded guidance on the assessment of extractables and leachables (E/L) for medical devices, which, for the most part, has been recognized and accepted by the U.S. Food and Drug Administration (9). In the future, a revision of part 17 of ISO 10993 (10), which pertains to the toxicological assessment of leachables, and a new International Conference for Harmonisation (ICH) guideline that will cover E/L impurities, ICH Q3E (11), are anticipated.
Despite the progress that has been achieved in the E/L field, there is still plenty of work to be done. For example, in my opinion, the following is a list of questions, albeit an incomplete one, that need further investigation to support advancement of the field:
What are suitable surrogate matrices for complex and analytically challenging drug product excipients/active ingredients that could be used to prepare simulation solvents that would have solubilization properties similar to the drug product vehicle without the analytical challenges? Is this even possible?
Similarly, is it possible to establish simulation matrices that adequately mimic biological products, which are analytically challenging and/or cannot be tested because of the nature of the contact (implanted devices), so that simulated extractable studies can be performed with the goal of accurately understanding what leaching is occurring?
Does leaching in various packaging systems occur continuously over the life of a product or is an equilibrium, and thus maximum concentration, achieved more quickly? If so, can shorter or accelerated leachable studies be justified? Can models be established? If not, what are the specific leachable trends and to what specific materials and/or systems are they applicable?
What improvements in speed, sensitivity, and other characteristics can be made to analytical methodologies based on experience working with E/L samples, new instrument technologies, and/or leveraging advancements in other fields?
Is the standardization of methods across all E/L practitioners possible? Can we eliminate the perceived (but poorly documented) lack of reproducibility in E/L data between labs?
Can we establish appropriate uncertainty factors to account for analytical variability without going overboard and increasing the burden on the analytical chemist or unnecessarily producing false positives? Are uncertainty factors even necessary for well characterized screening methods?
Can alternate safety concern thresholds/thresholds of toxicological concern be established above the current 5 µg/day sensitizer threshold?
What are the extraction methods and procedures best suited for the generation of representative extract samples? Specifically, what solvents, techniques, and extraction stoichiometries should be used? Can this be standardized based on sound scientific justifications?
What is the most appropriate and expedient way to execute E/L studies to achieve the ultimate goal of ensuring patient safety and product efficacy? Do formal leachable methods need to be validated and used if it is clear leaching is not occurring? Similarly, can screening studies be used as the primary mode of assessing this interaction? Are leachable studies needed for well characterized and established container closure systems?
I believe it is important to note that the task of answering these questions is not limited to the expert panels and working groups responsible for setting standards and publishing recommendations. It should be thought of as the responsibility of the entire pharmaceutical scientific community. In fact, it has been noted that the establishment of these standards and recommendations has been limited by the lack of published data in the aforementioned areas. As such, it is important that everyone takes responsibility for the advancement of this field. In truth, this is being done to some extent, based on my experience with excellent technical presentations related to these (and other) questions. However, presentations are not adequate substitutes for the publication of research because they do not undergo a rigorous peer review process, do not contain the same level of detail as a full publication, and often contain opinion mixed with facts.
The lack of published studies notwithstanding, it is important that the stakeholders in these studies, namely the product sponsors, labs performing the work, and regulatory bodies, continue to work together in an open and communicative manner to advance the field based on good science. On the sponsor/lab side, this can be achieved in many ways, including the aforementioned need for publications, open communication through organized events, and collaboration in public and private activities, such as working groups with goals that align with the advancement of the field. On the regulatory side, it would be beneficial for regulators to provide better insight into expectations, which oftentimes are not clear or are even contradictory from one case to another, as well as be more open to the perspective and feedback of the E/L community as opposed to strictly taking a role of dictating actions, a paradigm that may contradict the purpose of these studies.
Ultimately, the goal of the progress that has been made, and the progress yet to be made, is to establish E/L testing practices that utilize the appropriate studies to quickly and unequivocally ensure the safety and quality of all pharmaceutical products. In turn, this will ensure these beneficial therapies will be safe and can be brought to market as quickly and cost effectively as possible.
- © PDA, Inc. 2021
