Technologies for Aseptic Filling: The Choice is Clear

Introduction

Over the last forty years technologies for the aseptic production of sterile products have advanced significantly. Where staffed clean rooms once provided most of the operational capacity, new production means have been gradually introduced. Isolator use began in the 1980s, to be followed shortly by Restricted Access Barrier Systems (RABS), their somewhat simpler descendant. In 2007, Agalloco, Akers, and Madsen outlined criteria to be used in selecting a suitable aseptic filling technology.¹ When originally written there was a paucity of experience and limited comparative data available for use in the decision process. With the passage of time, it is now possible to draw upon published content to assist in the selection process. This publication relies upon the experience and analysis of others to provide a clear picture of the appropriate technology choice to make for aseptic processing.

First and foremost, it should be apparent to all that the era of staffed cleanrooms for aseptic processing is over. There is no justification for the construction of a new aseptic facility where the operator is not physically separated from the critical environment in 2024. Any new aseptic process should adhere to the precepts of advanced aseptic processing.

“An advanced aseptic process is one in which direct intervention with open product containers or exposed product contact surfaces is not required and never permitted by operators wearing conventional cleanroom garments.”²

Secondly, this might suggest that all versions of RABS satisfy the precepts behind this definition. That is not the case, RABS which allow for ‘open door’ interventions by aseptically garbed personnel are not advanced technologies. The definition excludes “open” RABS which require operator intervention for set-up and mid-process interventions. Even some “closed” RABS fail to meet the criteria, largely because of the invasive manual decontamination processes utilized. The cRABS design in which the enclosure is decontaminated after set-up and is never entered during aseptic processing would be considered advanced.

There are only two serious technology contenders meeting the advanced aseptic process expectations for the commercial production of sterile products - cRABS and isolators. These technologies are the subject of this publication and we have chosen to rely heavily on comparative assessments performed by others to define the preferred processing technology. We believe this approach increases objectivity and reduces the significance of our personal opinions. We have considered only comparisons based upon filling of small volume parenterals with the following features:

• continuous infeed of containers and discharge of closed containers
• use of transfer devices for material/component entry/exit
• automated decontamination of the critical zone
• line automation for weight checks / remote adjustment
• no gowned personnel access for decontamination or operation

Evaluation Criteria

We have elected to utilize the same criteria employed in the original document, using the referenced documents wherever possible to determine preference. The importance of the aseptic technology selection process is of such import that considerable deliberation should be given to each of the relevant factors.

The evaluation process should address each of the following: facility lead time; initial facility cost; qualification duration; qualification obstacles; operating cost; operational hurdles; line preparation; environmental sanitization; line operation; environmental monitoring; process simulation; impact of personnel; cleaning; change over; suitability for campaign usage; system maintenance; complexity; novelty; regulatory expectations; industry perspectives and intangibles.

Rather than create a lengthy narrative on each criterion, we have included a description, the suggested preference, and a brief rationale statement. The references we have used are listed in the Bibliography and a thorough reading of this collection supports the stated preference.

Comparative Assessment

The superiority of isolation technology to cRABS as outlined in the table is evident. The opinions stated above are derived from numerous publications comparing the technologies (see the accompanying bibliography). RABS designs evolved from substantially older staffed cleanroom facilities as something that would avoid the then prevalent negative concerns of adopting isolation technology to an existing facility. These concerns are related to difficulties with leak detection, and decontamination, and the uncertainties that these might present in project execution. Given the limited sophistication of many early RABS designs, that simplicity had a certain appeal to those uncertain of the new obstacles that isolators might entail. Contemporary cRABS designs now incorporate operation in a fully closed mode, with no operator access during aseptic operations and automated decontamination, making them more isolator-like.

The presence of leaks in isolators, which was an obsession decades ago, has largely disappeared. Recognition that the alternative systems, whether staffed cleanrooms or RABS, rely on air flowing from the critical zone towards the operators meant that leaks were not strictly an isolator problem. In fact, given the sustainable pressure differential between the isolator interior and the surrounding environment leaks are far less significant with isolators.

The concerns voiced by some regulators regarding enclosure decontamination uncertainty extend to their use with both cRABS and isolators. Thus, any perceived faults in the use of H2 O2 for enclosure decontamination are shared by both technologies.

The first RABS were designed to provide the operational performance of isolators at lower cost with simpler execution. Industry experience has shown that while the performance of cRABS can approach that of isolators, the cost of operating a cRABS is higher. One could argue that the increasing desire to reliably decontaminate cRABS systems after set-up (a premise of the above comparison) has resulted in more challenges than in a comparably sized isolator (where design standardization and independent HVAC systems make for simpler execution of the decontamination process).

Isolation technology has been successfully implemented worldwide many times and regulatory authorities have indicated a preference for its use over all other aseptic technologies. Industry surveys indicate that more isolators have been installed than RABS. Several multinational firms have made isolation technology their default choice for new installations as they have recognized their superiority in most applications. The introduction of gloveless isolators relying upon robotics and automation takes the separation of personnel from sterile materials to levels far beyond that of prior technologies.

RABS technologies can provide a means for the gradual upgrade of ordinary staffed cleanrooms as the ancillary classified environments needed for both are identical. Gowning, sterilization / depyrogenation, material airlocks, corridors, and other classified areas would be virtually unchanged by the replacement of a conventional staffed line by a RABS. Introducing an isolator into a pre-existing facility would ordinarily require more extensive modifications.

The real-world experience gained with both RABS and isolators makes the selection of suitable technology simpler than it once was. There’s little reason to choose a cRABS system in any new installation given the numerous advantages of isolation technology. Isolators are clearly the best available technology for aseptic processing and containment application.

References

1. Agalloco, J., Akers, J., Madsen, R., “Choosing Technologies for Aseptic Filling - Back to the Future?” Pharmaceutical Engineering, Vol. 27, No. 1, p 8-16, 2007.
2. Akers, J., Agalloco, J., Madsen, R., “What is Advanced Aseptic Processing?” Pharmaceutical Manufacturing, Vol.4, No.2, pp 25-27, 2006.

Bibliography

1. Agalloco, J., Akers, J., Madsen, R., “Choosing Technologies for Aseptic Filling - Back to the Future?”, Pharmaceutical Engineering, Vol. 27, No. 1, p 8-16, 2007.
2. PDA. “Technical Report No. 34, Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products.” PDA J. Pharmaceutical Science & Technology. 55(5, Supplement). 2001.
3. Akers, J., Agalloco, J., Madsen, R., “What is Advanced Aseptic Processing?”, Pharmaceutical Manufacturing, Vol.4, No.2, pp 25-27, 2006.
4. ISPE, Restricted Access Barrier Systems (RABS) for Aseptic Processing Definition, 2005.
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Author Details 

James Agalloco, President- Agalloco & Associates; Phil DeSantis, Principal- DeSantis Consulting Associates

Jim Agalloco is a pharmaceutical manufacturing expert consultant with 50+ years of experience. He has assisted more than 200 firms with validation, sterilization, aseptic processing, and compliance. He has co-edited 5 texts; written 40+ chapters; published more than 170 papers and lectured extensively.

Phil DeSantis is a pharmaceutical consultant, specializing in Pharmaceutical Engineering and Compliance. Phil retired in 2011 as Senior Director, Engineering Compliance for Global Engineering Service at Merck (formerly Schering-Plough) located in Whitehouse Station, NJ. He continues to work on standards and practices for all facility and equipment-related capital projects and site operations, as well as in the areas of sterilization and contamination control.

Publication Details 

This article appeared in American Pharmaceutical Review:

Vol. 27, No. 2

March 2024

Pages: 36-39

 

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