Leachables Found in Parenteral Drug Products - Lyophilization Articles & Reports

Leachables Found in Parenteral Drug Products
March/April 2004
Jim Castner, Ph.D., Neal Williams, M.S. and Michael Bresnick, M.A.
Bristol Myers Squibb Medical Imaging
APR
Introduction
In the process of bringing a new drug to the clinical investigation stage, several steps occur in which the sponsoring company makes a sizable investment at the multi-million dollar level. These steps typically include the discovery of a patentable compound, development of a commercially viable synthetic pathway, characterization of the physiochemical and biochemical properties of the new compound, animal toxicology, formulation development and the list goes on. What is frequently overlooked in this list is an assessment of the chemical compatibility properties for the new drug substance and its formulation matrix. The justification given by project leaders for neglecting or delaying such studies until much later in the drug development program is for efficient use of resources. Cited examples from personal experience are "reduce timelines by focusing only on the time critical elements" or "get the biggest bang for each R&D buck spent." Chemical compatibility studies however are investments requiring relatively small expenditures of resources. From a time perspective, a majority of the work should be completed prior to the nomination stage for a new drug. Ignorance about incompatibilities between a drug product and the surfaces of the manufacturing equipment or the container/closure could put the program at high risk for failure. Options are limited to circumvent the potential problems of chemical incompatibility unless the R&D budget has a contingency fund for using equipment fabricated from noble metals such as gold or using Waterford crystal.
Addressing the potential problems of chemical incompatibility should start prior to initiating any drug product development program, as mentioned above. The investigator first needs to create a database from the published literature about the materials that are exposed to the drug product during the manufacturing process, as well as, the primary packaging components [1,2]. This database should also be supplemented with experimental data. In particular, data from extraction studies of the critical components is used in the manufacturing process and the primary packaging. These extraction studies need to be conducted using appropriate solvents and analytical methods as outlined in the guidance provided in the USP monographs <661>, <381>, <87> and <88>for the respective materials. Having established a database for the materials that are exposed to the drug product, the next stage in the compatibility assessment is to conduct drug substance exposure studies. In these studies, the stability and the ad/absorption properties of the drug substance are monitored, along with detection of leachables from the exposed materials. Leachables differ from extractables in that they are chemical substances, which migrate from an exposed surface into the drug product under typical or normal operating conditions. Extractables, on the other hand, are the chemical substances that are obtained by exposing the sample material to a variety of solvents under exaggerated incubation conditions of time or temperature. In a general sense, leachables can be considered a subset of extractables [3].
Currently limited guidance is available in the published literature and from the regulatory agencies about conducting leachable studies with regards to the level of identification and settings of threshold limits. Working groups within the nonprofit organization Product Quality Research Institute (PQRI) are developing a consensus among its membership (which includes participants from the FDA, professional organizations, industry and academia) on defining the types of analytical methods and the toxicological criteria that are to be used in conducting leachable and extractable studies. When the recommendations from the PQRI working groups are published, they are anticipated to have a significant impact on both regulatory requirements and industrial practice. In the interim, individual investigators are left to use good scientific judgement and follow the successful practices of others in executing these studies. To provide some further insight into the practice of conducting investigations of leachables, four case studies are presented as examples. The focus of these case studies will be to examine the analytical chemical techniques that can be used and the procedures for identifying the source of the leachable resulting from exposure to the primary packaging material or from the manufacturing equipment.
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