Introduction
The Extractables and Leachables Safety Information Exchange (ELSIE), a consortium of pharmaceutical, biotech, and medical device companies has developed a database that will hold (i) safety information on extractables and leachables from a variety of materials; and (ii) controlled extraction study information from materials used in packaging, container closure systems, and devices, and components used in manufacturing processes. The ELSIE database offers a number of valuable potential benefits including reducing duplicative safety studies, streamlining the search for safety information for extractables and leachables, providing information that companies can use early in their development processes to facilitate the extractables evaluation process, and reduce the risk of resource-draining leachables issues arising at the end of development. Ultimately, these benefits will help companies deliver high-quality drug products to patients in a timely manner. The database has been developed under the premise that companies should not compete on issues of safety.
The safety portion of the ELSIE database currently contains summaries of safety studies on single chemical entities that ELSIE member companies have seen as leachables and/or extractables. These safety studies have been selected from the pool of published literature and government studies. It is planned that safety information from member companies as well as safety information jointly generated by ELSIE members will also be included in the database.
The materials portion of the database will contain extractables profiles as well as the ELSIE-developed protocol(s) used to obtain the extractables information. ELSIE has developed a pilot protocol and is conducting Controlled Extraction Studies at 11 different labs on four material types – a PVC and polyethylene, both in the un-molded state, and after the material has been molded under the extremes of the manufacturer’s recommended parameters (melt temperature and residence time). These material states would provide extractables profiles containing the universe of possible extractables from these materials, and therefore the universe of potential leachables for a variety of pharmaceuticals, devices and other medical products. In other words, these profiles would provide a “knowledge space” of extractables (and potential leachables) that companies could use as a starting point for materials selection, analytical method development, Controlled Extraction Studies, and Leachables Studies. Results from the pilot studies will be used to develop a streamlined protocol to populate the database.
Benefits of Sharing Extractables and Leachables Information
There are a number of challenges inherent in extractables/leachables evaluation, and chief among these is quick access to reliable safety and chemical information on individual compounds and materials. Access to safety information relevant to extractables/leachables can greatly facilitate toxicological risk assessments at early stages of materials selection, during conduct of Controlled Extraction Studies and later during leachables assessments. Access to materials information such as extractables profiles and study protocols can facilitate selection of appropriate materials early in product or process development, and development of extractables and leachables methods. A central database containing safety and materials information allows such access, and thus, can provide a fundamental basis for a “knowledge-based” approach to materials selection and management of leachables. The database will also help companies share information and thereby reduce the occurrence of duplicative studies and subsequent resource waste.
ELSIE’s Extractables and Leachables Database
The ELSIE database currently contains safety information for over 40 compounds and will eventually contain safety information for several hundred chemical entities (identified by the ELSIE consortium as priority extractables/leachables) and information on a large number of materials. The database will continue to expand as companies include more compounds and materials. The database thus addresses two significant challenges in pharmaceutical development: (i) the means to readily evaluate safety issues early in the development process; and (ii) ready availability of relevant safety and materials information on extractables and leachables.
For the safety portion of the database, each compound will have associated with it a summary of chemical information, a high-level summary of safety information, and finally, brief summaries of relevant safety studies regarding the given chemical, along with full reference information, and tracking of updates. The materials database will provide identification information for a given material; relevant dates, e.g., dates of manufacture and performance of extraction studies; and links to documents containing extractables profiles and study protocols. The materials database will also contain a list of single chemicals confidently identified in the profiles, which will be linked to the safety database.
Figure 1. ELSIE database entry page, showing links to safety database and materials database.
The ELSIE database is currently housed in a Microsoft Access™ platform, chosen since this platform is generally available. The database entry page (Figure 1) provides links to the safety portion of the database and the materials portions of the database. The safety database is described here in detail as this aspect of the database is currently fully developed.
The main search page in the safety portion of the database allows users to search on CAS number, chemical name (IUPAC, trade names, any other synonyms), molecular formula, and functional use, e.g., anti-2011oxidants, anti-static agents. The search function allows users to search on fragments of information as seen in Figure 2. For example, one may enter the word “palmitic,” which would provide search results on any compounds in the database with this string contained in the name. By clicking on the “Review” button, users can review detailed information on a specific chemical from the search results (in this case, Palmitic Acid). This action would take the user to the next screen, the main interface for individual chemicals, Figure 3.
Figure 2. Search page for ELSIE safety database
The main interface for individual chemicals (Figure 3) provides a summary of the chemical information – CAS number, molecular formula, molecular weight, chemical names, chemical structure – and also provides an index of safety information for the given compound (in the “Information Link” window). This index can be “clicked” on to provide the user with a Microsoft Word™ document containing the safety information. The safety information for each compound includes those categories relevant for the Common Technical Document (CTD), such as single-dose toxicity, repeat dose toxicity, genetic toxicity, reproductive and developmental toxicity, and carcinogenicity. There is also a category for “special studies,” for those studies that may be relevant, but are not easily grouped into the other categories. The safety report document also provides a high level summary of all safety information on the given compound at the start of the report.
Figure 3. Interface for individual chemicals. This window provides basic chemical information relevant for the search function, displays the “last update” date for all information (including safety) and a list of related compounds.
Conclusion
There exist a number of challenges to obtaining useful and relevant extractables and leachables information for medical products. Such challenges include obtaining extractables profiles that would provide an extractables “knowledge space” thereby assisting in the materials selection and method development processes, and obtaining relevant and quality safety information early in the development process. The ELSIE extractables and leachables database, developed by the ELSIE consortium, aims to assist companies in addressing these challenges. ELSIE’s goals are to create a database that will support companies’ regulatory submissions and enhance the quality of medical products for patients.Finally, the safety document includes a list of references for all studies included in the document. ELSIE chose to provide safety summaries in a Microsoft Word™ document because member companies noted the need for such information to be easily read in a prose style, easily printed, and easily transferred to other documents (applications, etc.).
Dr. William Beierschmitt received his B.S. in Biology from Mount Saint Mary’s University, and his Ph.D. in Toxicology from the University of Maryland. After completing post-doctoral work at the University of Connecticut Toxicology Program, he joined Pfizer’s Drug Safety Research and Development department in Groton, Connecticut. Bill is a Diplomate of the American Board of Toxicology. In his over 20 years experience in the pharmaceutical industry, Bill has been involved in a wide range of toxicology issues associated with impurities in drugs, including the development of strategies to risk assess extractables and leachables.
Dr. Shaw is currently working has an independent consultant. In 2010 he retired from Pfizer Inc. where he had held a number of positions in both the Pharmaceutical Sciences and Medical Device Divisions. He holds a B.S. and M.S. from Northeastern University, and Ph.D. degree from Purdue University in Chemical Engineering. He is an advisory board member of the University of Connecticut’s Institute of Material Science. Dr. Shaw is a team member of the PQRI Parenteral and Ophthalmic Drug Product team and leads the material team of the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium.