Industry perspective on a holistic container closure integrity approach to parenteral combination products.

Biologics are being developed more and more as parenteral combination products with drug delivery devices. The maintenance of sterility is imperative for such medical devices throughout their life cycle. Therefore, the container closure integrity (CCI) should, preferably, be built into the overall process, and not just demonstrated during the final testing of the combination product. The integrity is an important Critical Quality Attribute (CQA) and in the scope of specific considerations and studies during the combination product life cycle i.e., design robustness, assembly processes, storage (to end of shelf life), and shipping prior to patient use. The goal of this paper is to summarize an industry holistic approach to ensure CCI, for a combination product, and to build a scientifically based justification that Quality (in terms of CCI) is built into the overall process. Current analytical approaches used for characterization or Good Manufacturing Practice (GMP) CCI testing during combination product development will be described. However, the use of quality by design (QbD) during product development can reduce or eliminate routine batch level or stability testing of the combination product.

A Multicompany Survey Study for Helium Leak Container Closure Integrity Test.

All products labeled as sterile are required to be free of microbial contamination throughout their shelf life (obligatory critical quality attribute). Container closure integrity (CCI) needs to be addressed with a holistic life cycle strategy comprising adequate primary packaging components selection and the assessment of critical unit operations and critical process parameters (CPPs) according to quality by design (QbD) principles. The helium leak method is currently the most sensitive CCI test method and preferably used for the initial container closure system (CCS) qualification and characterization studies. Currently, two different measuring principles are used in the pharmaceutical industry, and no data is available in the public domain for typical method performance parameters such as accuracy, precision, intermediate-precision, and limit of quantification of the method. Furthermore, the performance of different types and sizes of artificial leaks as well as certified helium leak standards have not yet been characterized across different test laboratories. In this multicompany study, we shared 17 artificially prepared leak samples using the most common types of artificial leaks in relevant nominal size ranges that are commercially available or can be easily prepared in a laboratory. Each participating company generated results according to their in-house methods, applying their established test parameters as the aim of the study was not to create a standard for helium leak measurements, but to compare real-world performance between different laboratories. Consequently, this study is not an interlaboratory study using the same test method across laboratories.

Zinc distribution within breast cancer tissue: A possible marker for histological grading?

PURPOSE: Focusing on the trace metal zinc as a potential biomarker for breast cancer, the literature describes bulk zinc concentrations in breast cancer tissue to be higher than in normal tissue. From a histopathological point of view, cancer cells are intermingled with normal cells of the stroma within breast cancer tissues; therefore, bulk analysis cannot reflect this situation adequately. To address this problem, analysis of zinc distribution in histological sections is the method of choice. METHODS: In the present study, nine samples of invasive ductal and lobular breast carcinoma of histological grade 1-3 were investigated, clearly differentiating between cancer and stroma areas. Zinc concentrations were determined by laser ablation inductively coupled plasma mass spectrometry applying a calibration technique based on spiked polyacrylamide gels. RESULTS: Direct comparison between hematoxylin- and eosin-stained tissues and zinc contour plots revealed that zinc is enriched in cancer tissue containing tumor cells in contrast to normal stroma. Moreover, zinc concentration in carcinomatous tissues directly correlates with the histological malignancy grade. CONCLUSIONS: Differentiation between carcinomatous tissue and stroma by determination of zinc content and the correlation of zinc concentration with the histological malignancy grade not only provides a key feature for clinical decision making for cancer therapy but also suggests the trace metal zinc as a potential biomarker for breast cancer.