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www.biopharminternational.com June 2018 BioPharm International eBook 27 Single-Use Systems Quality approach is still a little bit scattered, and there is a great deal of effort in coming to an agreement and stan- dardizing these systems. Regardless of the system, there is always a challenge in defining the materials of construction, par- ticularly if there is a change for any reason. The goal is to drive toward integrity and reliability of these sys- tems. ANALYTICAL CHALLENGES BioPharm: What analytical chal- lenges are involved in qualifying single-use systems? How are these challenges addressed? H owe r a n d Lu (SGS): T he a na- lytical challenges when qualify- ing single-use systems are mainly driven by the product that is in contact with the single-use system. The degree of challenges faced is derived from the dosage informa- tion of the product, the formulation components, and the manufactur- ing process conditions. The dosage information of the product is used to determine the analytical thresh- old for detecting and quantifying E&L compounds. Certain dosage forms require that the reported concentration level for these com- pounds be set very low. The for- mulation matrix of a product can cause interference when perform- ing analysis on samples and may result in certain E&L compounds being overlooked. Most formula- tion matrices are composed of more complex matrices, including surfac- tants like Polysorbate 80 (PS-80). Those complex matrices could eas- ily interact with the plastic surfaces of the single-use system as well as create analytical challenges to dis- cover leachables at trace levels with a high analytical background. The conditions used in the manufac- turing of these products will deter- mine the design of the extraction process to generate a worst-case potential extractable profile but may also produce a large quantity of compounds that need to be char- acterized. These analytical challenges can be addressed in two ways—through a complete understanding of the product and by using high-end analy tical instr umentation. By understanding the manufacturing process and the formulation com- ponents of the product, a proper study to characterize the single- use systems components may be designed. In this way, an extrac- tion procedure can be selected to more closely mimic the real-use conditions of the single-use systems while still providing a comprehen- sive extractable profile. In addition to having a proper study design, the necessity of using high-end analyti- cal instrumentation, such as high- resolution, accurate-mass (HRAM) mass spectrometers, is undeniable. With the increasing complexity of drug matrices and the diverse nature of single-use system com- ponents, high-end mass spectrom- eters are an absolute requirement to achieve the necessary sensitivity and accurately perform chemical characterization of the manufactur- ing components. A suitable sam- ple preparation procedure is also necessary to minimize the matrix interference when injecting into analytical instruments. Pora (Pall Biotech): From an ana- lytical standpoint, there are a few challenges. They are heavily linked to the determination of E&L pro- files, understanding the materi- als of construction, and having unknowns kept to a minimum. As you get deeper into implement- ing single-use systems, there is still much to be determined and stan- dardized. Bulpin (MilliporeSigma): Several different types of instruments (i.e., gass chromatography-mass spec- trometry [GC-MS], liquid chro- matography [LC]-MS) are used to identif y extractable compounds from single-use systems. The identi- fied compounds can be evaluated from a patient safety perspective to qualify the single-use systems. However, it is not always possible to know if the extractable com- pound poses a concern from a pro- cessing perspective. An example of this is the extractable compound bis-di-tert butyl phenol phosphate (bis-DtBPP). This compound is a breakdown product of the anti- oxidant Irgafos 168 and has been found to retard cell growth, thereby reducing the productivity of the bioreactor. Though this compound is easily detected by LCMS, it was not easily recog nized that the compound would impact bioreac- tor productivity. MilliporeSigma obtained this knowledge by testing different cell lines with various con- centrations of the compound. MilliporeSigma has addressed this challenge by identifying an internal model cell line that is sen- sitive to extractable compounds. We can then expose this internal model cell line to extracts from our single-use systems to see if the extractable compounds impact cell growth. If retarded cell growth is observed, more analytical testing can be done to identify the com- pound of concern and determine the source. We recognize that this approach is not fool-proof, as there may be some extractable com- pounds that may not impact our sensitive cell line and still impact our customers. As the industry matures, more knowledge of these troublesome compounds will be known, and analytical methods can be established to test for them. In some cases, there are analyti- cal challenges in achieving the ana- lytical evaluation threshold with the different analytical methods.