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10 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2020 P h a r mTe c h . c o m Manufacturing I n the late 1970s, media fill studies began to be used in asep- tic processing for the expressed purpose of evaluating sterility assurance levels in filling activities. These initial studies were simplistic. In response to regulatory expectations, the activity grew in sophistication to address perceived vulnerabilities (1). The Parenteral Drug Association (PDA) interpreted the guidance and conducted periodic surveys of practices (2–6) to assist firms in the design of their process simulation studies. In 2007, FDA proposed and later implemented changes to 21 Code of Federal Regulations 211.113 (b), which updated the agency's perspectives on aseptic pro- cessing (7, 8) to emphasize the importance of validation. Central to revised validation was the belief that the media fill could somehow provide definitive proof of sterility for all processes, an unre- alistic expectation. Microbiology is a logarithmic science, with methods incapable of a limit of detection of one viable cell. Regulators have not recognized that zero growth in microbiology does not mean 'sterile', it just means that nothing was detected. Industry interpretations of sterility assurance have continued to emerge with the first PDA survey on aseptic processing in 15 years (9–12). The author and others have weighed in on the subject as well (13, 14). The most recent regulatory positions are outlined in the European Medicines Agency's (EMA's) proposed revision to Annex 1 (15, 16). This draft revision elicited a number of industry com- ments because it presents a vision of aseptic processing that seems to be at odds with many existing practices (17). This article reviews aspects of media fill execution in which regulatory expectations have created artifi- cial compliance concerns and resulted in significant practical difficulties. James Agalloco is principal of Agalloco & Associates. With nearly 50 years of industry experience with companies that include Merck, Pfizer, Squibb, and Bristol-Myers Squibb, he has served as an officer or director of PDA and is a member of Pharmaceutical Technology's editorial board, jagalloco@aol.com. GORODENKOFF-STOCK.ADOBE.COM Complications in Process Simulation Execution James Agalloco Regulators have exaggerated expectations for simulated media fills.