Aseptic Processing: A Review of Current Industry Practice

This article reviews current industry practices and regulatory expectations for the aseptic processing of sterile drugs. It provides comparisons and outlines points of tension between curent manufacturing technology and capabilities with regulatory “requirements” for this important activity. n 1988, the Parenteral Drug Association (PDA) published a position paper on aseptic processing in response to intense interest in aseptic processing in the industry at that time and in partial response to the publication of the Food and Drug Administration’s (FDA’s) 1987 guideline on aseptic processing (1, 2). The intent of this review is similar to that of its 1988 predecessor: to identify and discuss the current capabilities of aseptic processing technology. The improvements to aseptic processing operations described in the 1988 position paper were characterized in the opening section of that document as “evolutionary.” The improvements in aseptic processing technology that have occurred since 1988 would perhaps be better characterized as “revolutionary.” We believe that the practices described in 1988 are, by and large, as valid now as they were then. We also believe that products manufactured in compliance with the underlying principles outlined in the 1988 document are still inherently safe. The aseptic manufacture of sterile products is perhaps the most difficult challenge faced within the healthcare industry. Aseptic processing requires the careful application of microbiological contamination control principles to exclude infectious organisms from sterile products. We reaffirm our belief stated in 1988 that, “the major variable in the control of aseptic processing arises not from the sterilization processes, the cleanroom, or the filtration processes that are so often the subject of technical papers and regulatory guidelines, but rather from the workforce itself ” (1). Industry findings since 1988 confirm the earlier statement that humanborne contamination is the most critical risk factor in aseptic processing. Numerous industry surveys and technical articles published since that time are in accordance with this statement. (3–8). Since the publication of the 1987 guidance, firms have continued to implement new technologies and aseptic processing improvements to better control humanborne contamination. At the same time, the industry has implemented expanded microbial-test regimens and more comprehensive process simulation testing to ensure that aseptic processing systems have adequate process capability and that this capability is consistent and as reproducible as possible within the technical constraints that are inherent in the measurement of aseptic performance. This article describes the improvements in conventional and new technologies that have occurred since the late 1980s. It also describes the improvements that have been made in aseptic process validation and control. Finally, the paper discusses the technical limitations that still exist in the evaluation of aseptic processing and raises concerns regarding the increasing regulatory tendency to ignore the existence of those limitations.