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24 Pharmaceutical Technology ® Quality and Regulatory Sourcebook eBook March 2024 PharmTech.com Aseptic MAnufActuring • using single-use aseptic connectors/disconnec- tors for filtration in Grade-A • making sure no open products or product contact surfaces in the area when operator is inside the Grade-A area to performs the setup activity or any other intervention • using split butterf ly valves and alpha-beta con- nections for API transfer and pH buffer additions. This will still call for validation activities and reg- ulatory approvals to proceed with; however, this can save a long waiting time for a new set of equipment and subsequent facility qualification efforts. Table VIII is the example of IREM evaluation in such a sce- nario [Click here to view Table VIII]. Discussion and conclusion The ability to make decisions based on relative risk to product quality and patient safety is a sound business principle. It is essential for the compliant manufac- turing of regulated sterile pharmaceutical products. It is important that relative risk can be accurately de- termined. Without an objective, measurable means to do so, companies may unwittingly use subjective, inaccurate assessment methods that are prone to bias and predetermined outcomes. These methods can be inaccurate, incomplete, and of little practical value. At worst, they can lead to poor decisions. In addition, the practicality of the risk assessment method is im- portant because risk assessment should not be merely considered as a regulatory requirement and should not become a 'check the box' exercise. It should have production and quality related effectiveness value. A scient i f ica l ly sou nd a nd ea s y to use r isk a s- sessment tool is not on ly valuable for traditional large-scale sterile product manufacture, but also for smaller-scale aseptic processing, where unique risk conditions and concerns do exist. Such tools should be understandable and useable by all levels of stakeholders to promote process and process con- trol awareness and understanding. As the industry progressed through the past several decades, more emphasis was placed on improving output through large-scale manufacturing and automation. However, there are important processes that still require man- ual aseptic activities. Where these occur, the authors recognize there are risks associated with human ac- tivities. This means that the use of sound methods for the assessment of risk and the implementation of controls to mitigate those risk is essential. Practical and objective risk assessment methods such as IREM can be effective for the assessment and evaluation of more manual aseptic process activities including those used in aseptic compounding and filling. It helps those performing the assessment rec- ognize unique aspects of the process that can indicate or contribute to quality risk. It can provide a higher level of awareness to those that are responsible for implementing and performing the control measures determined to mitigate those risks. And it can pro- vide valuable information needed to determine, im- plement, or change those controls, thus improving manual the aseptic manufacturing process. References 1. Baseman, H.; Chakraborty, S.; and Long, M.A. Inter- ventions Risk Evaluation and Management in Asep- tic Manufacturing. PDA J. of Pharm. Sci. and Technol. 2022 November/December. 2. EC. Annex 1: Manufacture of Sterile Medicinal Prod- ucts. EudraLex. European Commission: Brussels, 2022. Vol. 76. 3. EMA. Concept Paper on the Revision of Annex 1 of the Guidelines on Good Manufacturing Practice— Manufacture of Sterile Medicinal Products. Euro- pean Medicines Agency and Pharmaceutical In- spection Convention/ Cooperation Scheme (PIC/S); EMA, 2015. 4. Baseman, H; Hardiman, M; Henkels, W.; Long, M. A. Line of Sight Approach for Assessing Aseptic Pro- cessing Risk: Part III. PDA Letter, 2016. 5. Ljungqvist, B.; Reinmueller, B. Microbial Risk Assess- ment in Pharmaceutical Clean Rooms; PDA: Bethesda, MD, 2001. 6. Akers, J.; Agalloco, J. P. A Revised Aseptic Risk As- sessment and Mitigation Methodology. Pharm. Tech- nol. 2017, 41 (11), 32–39. 7. Katayama, H.; Toda, A.; Tokunaga, Y.; Katoh, S. Pro- posal for a New Categorization of Aseptic Processing Facilities Based on Risk Assessment Scores. PDA J. Pharm. Sci. Technol. 2008, 62 (4), 235–243. 8. Akers, J. E.; Agalloco, J. P. The Simplified Akers– Agalloco Method for Aseptic Processing Risk Anal- ysis. Pharm. Technol. 2006, 30 (7). 9. Whyte, W.; Eaton, T. Microbial Risk Assessment in Pharmaceutical Cleanrooms. Eur. J. Parenter. Pharm. Sci. 2004, 9 (1), 16–23. 10. Hussong, D.; Madsen, R. E. Analysis of Environ- mental Microbiology Data from Cleanroom Samples. Pharm. Technol. 2004, 2004 Suppl. (3). Further reading • FDA. Guidance for Industry, Sterile Drug Products Pro- duced by Aseptic Processing — Current Good Manufac- turing Practice (CDER, CBER September 2004) • PDA. Points to Consider for Aseptic Processing of Sterile Pharmaceutical Products in Isolators; Bethesda, MD, 2020. • PDA. Points to Consider for Aseptic Processing: Part 2, PDA, Bethesda, MD, 2011. • PDA. Technical Report No. 22, Process Simulations for Aseptically Filled Products. Parenteral Drug Associ- ation, Bethesda, MD, 2011.■