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www.biopharminternational.com Quality and Regulatory Sourcebook eBook March 2024 BioPharm International ® 21 Manufacturing A 2018 survey from BioPlan Associates (3) reports five downsides or potential problems with SUS as cited by more than 50% of respondents. These down- sides include breakage of bags and loss of production material, cited by 75% of survey respondents; extract- ables and leachables (E&L), cited by 73.3% of respon- dents; and high cost of disposables, cited by 68.8% of respondents. Material incompatibility with process f luids and reluctance to becoming "vendor-depen- dent" (i.e., single-source issues) were tied for fif th place w it h 56.7% of respondents citing bot h as a downside to SUTS. The main challenge is the security of the single-use component supply chain. Suppliers of single-use com- ponents are as critical to ensuring that drug products reach patients in both a reliable manner and with on-time deliver y and consistent qualit y. A second challenge is the time, cost, and regulatory approvals needed when changing over from traditional stain- less-steel systems to the construction material for SUS. The third challenge is the regulatory require- ment and validation or qualification costs needed wh i le establ ish i ng a lter nate vendors dur i ng t he changeover. The fourth challenge is the realization that SUTs might not always be the most effective or economical solution for the manufacture of low-cost formulations such as ophthalmic products and tradi- tional large-volume parenteral injectables. In those cases, a hybrid approach using a combination of dis- posable and traditional stainless steel becomes more viable option. Industry guidance T here are g uidance documents avai lable to work around overcoming these challenges. PDA's Techni- cal Report Number 66, Application of Single Use Systems in Pharmaceutical Manufacturing, describes a risk- based decision-making process for determining if implementation of SU Ts is appropriate for a given process (7). ISPE's Good P ract ice Guide: Single-Use Technology (8) provides a roadmap for efficient im- plementation of SU T w it h m in imum disr uptions to existing operations. The guidance document is structured with two major sections. The first section describes process f low for arriving at the design of assemblies/systems. The activities described in this section include the selection of components with the design of assemblies and systems, the qualit y requi rements for SU T equipment, assessment of supplier quality, defining the criteria for audits, and developing the user requirements specifications. The second section deals with implementation and use of SUTs, the regulations typically applicable with pro- cesses using SUTs, training programs and when to apply them during the implementation process, and the criteria that lead to a robust and reliable supply chain. The guide also includes specific chapters and appendices that contain tools to support the two main sections, including the evaluations of extractables, criteria to evaluate and apply in a risk assessment, and the overall implementation schedule and de- tailed schedules for specific activities. Another concern is the waste disposal and sustain- ability related to single-use components. Compared to global plastic waste in total, the consumption of SUTs in the biopharma industry is negligibly small (0.03 x 10 6 t); never theless, the high consumption of plastic material per unit of product and during research and process development is becoming a major concern among more and more scientists and biopharma market stakeholders (9). There has been increased use of SUTs in recent years, and concerns have been expressed on the environmental aspects of single use. A detailed study has been conducted to address this concern (10). The study revealed that the environmental aspect of end-of-life due to use of plas- tic is quite small, and the highest contribution to en- vironmental pollution is from the energy required for electricity generation for the manufacturing plant. The achievement of a solution to solve environmen- tal issues and improve sustainability among all pro- duction steps might be possible by instilling a sense of ownership among workers across industry and beyond to encourage a feeling of taking responsibility for sus- tainability (11). International Standards Organization (ISO) established a standard for life cycle assessment (LCA) that provides general principles for the method- ology and content of an LCA. ISO 14040 contains the principles and framework for an LCA, while ISO 14044 considers the requirements and guidelines for carry- ing out an LCA study (12–15). ISPE's End-Of-Life Man- agement for Single-Use Products in Bioproduction Part 1 (16) and Part 2 (17) discuss the details of the current disposal practices for SUTs, successful best practices for end-of-life management, and opportunities to im- prove single-use waste in the future. There are two regulatory requirements impacting components used in SUS from a biological safety and patient safety perspective, material biocompatibil- ity and E&L. Biological reactivity and safety are re- quired to be performed in compliance as per United States Pharmacopeia (USP) <88>, Biological Reactivity Tests for Class VI Plastics. Biocompatibility testing requirements fall within USP <87>, USP <88>, and ISO 10993, depending on the application. The following organizations are actively involved in developing workable standards related to the use of disposable technologies, Bioprocess Systems Al- liance (BPSA), BioPhorum, PDA, US Pharmacopeial Convention (USP), ISO, ASTM International, and the American Society of Mechanical Engineers (ASME) (with its Bioprocessing Equipment group).