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22 BioPharm International ® Quality and Regulatory Sourcebook eBook March 2024 www.biopharminternational.com Manufacturing BPSA guides cover irradiation and sterilization vali- dation, determination of E&L, and disposal of SUS. BPSA has published quality assurance templates that look at quality requirements and product specifications. ASTM is working on a standard for the determination and char- acterization of extractables from single-use materials with considerable input from BioPhorum and BPSA. ASME, ASTM, and BioPhorum are looking at leachables. USP and ASTM are addressing sub-visible particles from single-use components. ASTM, ASME, and BPSA are working on system integrity testing issues. Patient safety concerns The next major concern is patient safety from E&L that might migrate from the product contact parts of the single-use components used in disposable systems into the drug product. Regulatory scrutiny of patient safety assessment from process equipment related leachables (PERLs) is stringent when using single-use components for final formulation and filling processes. Matching the risk that PERLs could adversely affect the quality of the drug product to the required level of testing and assessment is achieved by an initial risk as- sessment followed by a risk assessment. The initial risk assessment establishes whether component testing is required. Once the need to perform a testing is estab- lished, a risk assessment is performed to establish what testing must be performed. The testing proceeds as per section 4.1 of USP <665> (18) and the BioPhorum E&L protocol (19). BioPhorum published two key guidance documents to help control potential risks associated with leachable impurities released by single-use com- ponents: Best Practices Guide for Evaluating Leachables Risk from Polymeric SUS Used in Biopharmaceutical Man- ufacturing and Standardized Extractables Testing Protocol for SUS in Biomanufacturing (19). The results of the extractables profiling are then in- terpreted in the context of suitability for use and patient safety assessment via the toxicological assessment. PERLs will be further evaluated for patient safety by the toxicity assessment. If the results are proven safe to the patient, the documents are then ready for regulatory submission, and one can use the single-use components in the manufacture of drug products. USP chapters <665> (18) and <1665> (20), when com- bined with International Council for Harmonisation principles Q8 Pharmaceutical Development and Qual- ity by Design and Q 9 Quality Risk Management, early in the component selection and drug development stages, will ensure and confirm that the single-use manufacturing systems selected are suitable for their intended purpose. Summary The biopharma industr y has matured as a global community with an increased focus on monoclonal antibodies, recombinant proteins, biosimilars, and vaccines. SUTs have become an integral element in most of the bioprocessing steps, including upstream processing, harvesting, buffer storage, purification, mixing, filtration, formulation, and fill/finish. While some of the steps are completely in SUT mode, many of them are yet in a hybrid mode, used with conventional stainless-steel equipment. The manufacturers adopt- ing SUTs have various guidance documents that can be used from the start of setting up a business case, to a changeover to SUT, to being compliant in regula- tory submissions related to E&L, patient safety, and disposal of the used plastics in a sustainable manner. Single use is a promising technology, and the adoption of this technology is evolving rapidly, leading to the eventual evolution of the next stages: modular biopro- cessing and continuous bioprocessing. References 1. Rathore, A. S.; Agarwal, H.; Sharma, A. K.; Pathak, M.; Muthukumar, S. Continuous Processing For Production Of Biopharmaceuticals . Prep. Bio- chem. Biotechnol. 2015, 45 (8), 836 – 849. DOI: 10.1080/10826068.2014.985834. 2. Klutz, S.; Magnus, J.; Lobedann, M.; et al. Developing the Biofacility of the Future Based on Continuous Processing and SUT. J. Biotechnol. 2015, 213, 120–130. DOI: 10.1016/j.jbiotec.2015.06.388 3. Langer, E. S.; Rader, R. A. Biopharmaceutical Man- ufacturing is Shifting to SUS. Are the Dinosaurs, the Large Stainless Steel Facilities, Becoming Extinct? Am. Pharm. Rev. online, Oct. 23, 2018. 4. Lim, J.; Cox, S.; Leveen, L.; Monge, M.; Sinclairm A. The Environmental Impact of Disposable Technolo- gies. BioPharm Int. supplement 2008, 7. 5. Single Use Support. Pioneering Biopharma. www. susupport.com (accessed Jan. 21, 2024). 6. Das, S. The Appeal of Single-use Tech. BioSpectrum India online, Nov. 30, 2022. 7. Parenteral Drug Association. Technical Report Num- ber 66: Application of Single Use Systems in Pharma- ceutical Manufacturing. Technical Report, September 2014. 8. ISPE. ISPE Good Practice Guide: Single-Use Tech- nology (2018). 9. Barbaroux, M.; Horowski, B.; Mokuolu, S.; Petrich, M.; Whitford, W. The Green Imperative: Part One— Life-Cycle Assessment and Sustainability for SUTs in the Biopharmaceutical Industry. BioProcess Int. 2020, 18 (6). 10. Budzinski, K .; Constable, D.; D'Aquila, D. et al. Streamlined Life Cycle Assessment of SUTs in Bio- pharmaceutical Manufacture. New Biotechnol. 2022, 68, 28–36. DOI: 10.1016/j.nbt.2022.01.002 11. Scott, C. Cell Culture. BioProcess Int. 2011, 9 (10). 12. Andersen, O.; Hille, J.; Gilpin, G.; Andrae, A. S. G. Life