From Manual to Modern: US FDA's View on 25 Years of Aseptic Processing

When Rick Friedman joined the US FDA in the early 1990s, aseptic processing looked nothing like it does today. Filling lines were staffed by multiple operators working in close proximity to open products, relying on manual dexterity, reusable gowns, and preventing hazards from various ancillary cleanrooms to maintain the sterility of sterile medicines. At the 2026 ISPE Aseptic Conference in Washington, D.C., Friedman—now Deputy Director for Manufacturing Quality in US FDA's Center for Drug Evaluation and Research—offered a detailed retrospective on the quarter century of transformation that followed, while delivering a clear-eyed assessment of where the industry still sometimes falls short.

A Legacy Built on Risk

To understand where the industry stands today, it helps to understand where it started. Friedman described the aseptic processing landscape of around 2000 as heavily shaped by facilities built decades earlier, many dating to the 1950s through the 1980s, that were designed before major evolutions in contamination prevention.

Lines were manually intensive. Unit operations were common, meaning people physically moved sterile components from one process step to the next, each transfer creating a fresh opportunity for contamination. Multiple operators worked in direct proximity to the aseptic zone, often protected only by flexible plastic curtains or plexiglass panels that provided, at best, partial barriers. Cleanrooms themselves were vulnerabilities: bidirectional gowning rooms, poor material-flow design, and lapses in disinfection could all allow contamination to migrate from ancillary spaces into the critical filling zone.

The consequences were not abstract. These low-capability operations resulted in processes exhibiting sporadic or chronic sterility failures, contributed to supply chain instability, and placed an enormous burden on human performance under inherently difficult-to-control conditions. While other industries, such as biomedical laboratories, nuclear, and electronics, had adopted isolators and glove boxes, pharmaceutical aseptic processing had not yet made the leap.

"Direct human-machine interactions were common in the year 2000," Friedman told conference attendees. He added that installation of lines with this type of process design is becoming obsolete in 2026. “We've come a long way."

Transformation: Separation, Automation, and Integration

This broad modernization was driven by a convergence of technological advancement, regulatory expectation, and industry leadership. A handful of trailblazing companies in the late 1990s and early 2000s began installing the first isolators and restricted access barrier systems (RABS), demonstrating that a fundamentally different approach to aseptic manufacturing was both possible and practical.

The conceptual framework underpinning this shift rests on three pillars: separation, automation, and integration.

Separation means physically protecting the ISO 5 critical zone from the surrounding environment and the operators working nearby. Isolators achieve the highest level of protection by creating a fully enclosed, independently controlled environment. Closed RABS provide strong protection; open RABS offer meaningful improvements over traditional lines while preserving some degree of operator access for necessary interventions. Each step up the separation ladder corresponds to a meaningful reduction in contamination risk.

Automation reduces the frequency and complexity of manual interventions, the steps most vulnerable to human error. Robotic systems, automated lyophilizer loading, integrated rapid transfer ports, and sterilize-in-place (SIP) connections have collectively removed many of the riskiest manual steps that once defined aseptic manufacturing. Where human action was often required for a hundred or more discrete interventions in a single batch in the past, automated systems now execute those steps with consistent, repeatable precision.

Integration eliminates the transfers between unit operations that once required operators to carry sterile components through cleanroom spaces. Modern lines process materials from component preparation through filling in a connected, protected sequence, dramatically reducing exposure to contamination hazards at every stage.

The ISPE's own 2020 barrier technology survey captured the scale of this industry shift: by 2020, virtually no new aseptic filling lines were being delivered without some form of RABS or isolator. From a market where traditional open-access lines once dominated, the industry had arrived at a point where those barrier technologies are the default expectation.

When Modernization Didn't Happen

Despite this industry-wide transformation, Friedman was clear that many facilities have not kept pace and that the US FDA has seen the consequences firsthand.

He described two recent warning letter cases that illustrate what an inadequate aseptic processing design looks like in practice. In the first, a facility operating without RABS or isolator technology had excessive personnel present during aseptic production, improper aseptic technique, and a line design that could not adequately protect the critical zone. The firm had accumulated multiple sterility test failures; when the US FDA tested an imported lot in its own laboratories, that lot also failed sterility testing. The firm was placed on import alert.

The second case involved a partial barrier concept, which included a rigid wall enclosure supplemented by cleanroom curtains. The inspection uncovered a system requiring several hundred manual interventions into the ISO 5 environment during a single batch, with doors open for extended periods, and aseptic connections performed outside ISO 5 air classification. The US FDA concluded that the facility, equipment, and process had fundamental design flaws.

The human cost of these failures is not theoretical. Friedman referenced a 2022–2023 outbreak linked to contaminated ophthalmic products (artificial tears and eye ointments) that affected more than 80 patients, caused at least four deaths due to septicemia, and resulted in at least 14 cases of vision loss. US FDA testing confirmed that 18 batches of artificial tears were non-sterile, and clear linkages were established with isolates from three different batches matching the clinical strains in the national outbreak database. Container-closure integrity testing further confirmed that the packaging itself allowed microbiological ingress.

"These tragic events occurred very simply because of poor manufacturing practices and inadequate container closure integrity," Friedman said. "This is a reminder of why the job all of us do every day, both regulatory agencies and the industry, is so consequential."

The Failure Modes of Modern Technology

A significant portion of Friedman's remarks focused not on legacy failures but on the failure modes that have emerged in modern barrier systems, a subject less frequently discussed but equally important. As he noted, all technologies have vulnerabilities, and knowledge of hazards increases with experience with a given technology.

Today's failure modes are increasingly mechanical rather than manual, reflecting how successfully the industry has reduced its reliance on direct human intervention. Glove integrity in isolators and RABS remains a critical concern. Friedman cited cases in which a company continued manufacturing after failing glove-integrity tests rather than stopping to resolve the issue. Gasket and O-ring wear at transfer ports, doors, and panel seals represent a persistent maintenance challenge requiring proactive preventive maintenance programs. Drain valve failures have caused back-siphonage and resulted in contamination. Loss of pressurization, whether due to a power failure or a utility issue, constitutes an immediate breach of integrity that building management systems (BMS) must detect without delay.

Single-use systems are also more common in modern operations, and they introduce their own risk profile. Bags can be damaged in shipping; vacuum loss may not be apparent on visual inspection; and any integrity failure must be treated as a critical deviation. Decontamination cycle effectiveness (e.g., vaporized hydrogen peroxide systems) can be compromised by occluded surfaces, non-optimized cycles, or an insufficient sterilizing phase. Blow-fill-seal systems require rigorous preventive maintenance for cooling water systems, where pinhole leaks have allowed gram-negative contamination to migrate directly into product containers.

While mechanical failure modes have become more significant in a more technologically advanced age, human factors have not been eliminated from modern barrier systems. Friedman described ergonomic challenges in RABS setups, breaches in aseptic technique during open-door interventions, and contamination risks from unplanned maintenance work during batch manufacturing. As an example of the latter, one firm removed a star wheel during production, which liberated contamination from underlying areas that were never decontaminated. Other firms were found conducting routine open-door RABS interventions without documented justification or duration limits. He also flagged a systemic problem with facilities claiming RABS status while opening doors frequently, which functionally resembled traditional lines. Some companies even claimed they had RABS, but the units did not have integrated gloves. The US FDA's compliance program is explicit on this point: if doors are routinely opened during filling or the system lacks installed gauntlet gloves (a basic design requirement for any RABS), the system does not meet the definition of a RABS.

A recently cited warning letter also illustrated the cleaning dimension of RABS and isolators. Gram-negative, biofilm-forming organisms were recovered over a two-year period in a RABS ISO 5 environment. This problematic contamination was traced to dead legs in the cleaning-use-point piping, moisture accumulating behind gaskets that provided a protective environment for microbes, and an inadequate cleaning-system design. The contamination residue posed a risk not only in itself but also to the efficacy of the VHP decontamination cycle, compounding the hazard.

2026 Expectations

Friedman's summary message was direct. Manufacturing capability determines the quality of medicines. Robust technological capability and vigilant lifecycle quality risk management, as codified in the recently revised ICH Q9(R1) guideline, are essential, not optional. The quality system is the foundation: without sound management oversight, data integrity, preventive maintenance, corrective and preventive actions discipline, and supplier qualification, even well-designed technology can fail over time. ICH Q9(R1) is also clear-eyed about emerging technology, noting that digitalization, automation, and isolation can reduce risk when properly validated, but cautioning against treating any new technology as a panacea without first establishing fitness for intended use.

The US FDA expects to see modern design principles in 2026: optimized cleanroom layouts, separative equipment, process automation, integrated material transfers, SIP in place of manual aseptic connections, robust BMS with continuous monitoring and prompt alarming, and rigorous interpretation of smoke studies as the foundation for intervention hazard identification and risk reduction. Facilities that fall short of these expectations should expect closer inspection and compliance scrutiny.

The message from the 2026 ISPE Aseptic Conference opening session was one of earned progress and continuing responsibility. The industry has accomplished a remarkable transformation. The technologies available today are profoundly more capable than those that came before. But capability is not the same as control, and control demands constant vigilance over design, maintenance, monitoring, and the human factors that remain present in every manufacturing operation, however automated it becomes.