James Agalloco, Agalloco & Associates
I first worked on vaporized H2O2 decontamination beginning in 1992 and then repeatedly over the next decades. Following the recommended practices for the process was initially problematic, but rejection of misguided precepts, and modifications to the decontamination process and system configurations eventually resulted in consistent results. A gradual learning process certainly, but one that focused on a singular objective - the acceptance criteria was always complete destruction of G. stearothermophilus spores with a minimum population of 106 distributed across the target system.* This performance was paralleled by others resulting in many successful installations. Properly designed decontamination processes have had great success, and FDA’s 2024 acknowledgment of vaporized H2O2 processes is proof of their reliability.1
I believe that the difficulties associated with vaporized H2O2 process are associated with the persistence of the belief in its presence in as a ‘gas’ rather than the two-phase system which is the present day understanding. With the expiration of the core patents on vaporized H2O2 in the mid-2000’s, numerous decontamination systems were introduced by industry vendors Processes and systems designed for a ‘gas’ ignore the many challenges the two-phase vaporized H2O2 process presents and make consistent results less likely. The use of unidirectional air during isolator decontamination compounds the problem.2 The use of isolators increased substantially as did the complexity of their design. With the increased usage, came increased reports of positive results from decontamination studies. Here, the story turns ugly, some of those encountering the non-conforming results adopted a workaround relying on multiple BI’s and a Most Probable Number approach to discount the positives.3,4 Dealing with ‘rogue’ BI’s became common practice. Admittedly, vaporized H2O2 decontamination processes are complex, and inquiries into the nuances of their design and execution is no simple task. There is almost no mention of process focused investigations when BI positives are encountered. The positive outcomes were attributed to BI anomalies dismissing the potential shortcomings of the various decontamination processes and system designs.
The reported difficulties with vaporized H2O2 processes drew the attention of MHRA, and eventually EMA suggesting that these processes are insufficient robust for sterilization of product contact materials and equipment.5,6 Recently, there’s been publicly stated positions that lower the performance threshold tolerating ‘rogues’ as unresolvable and accepting their presence as a matter of routine with vaporized H2O2 processes.7 That this further undermines the utilization of these processes something which EMA has already discounted is problematic. It forces system modification, added manipulative activities, increased cost and makes the use of isolators for aseptic processing less attractive.
The superiority of isolation technology over other means for aseptic processes being unquestioned, despite EMA’s lukewarm to almost negative stance suggests some measures be taken.
- Vendors of decontamination systems should deliver systems capable of the consistent kill as has been routinely achieved by others for decades. Complete kill of bioindicators should be mandatory for all vaporized H2O2 systems.
- Explaining away positive results as the result of unconfirmed ‘rogues’ should cease. Systems operating without BI positives rely on the same suppliers with no difficulty.
- Objective guidances and standards for system performance should be prepared by end users. Vendor participation should be limited.
- Investigations into process failures should give equal weight to the biological indicators and the decontamination process.8
It is widely accepted that isolation technology offers the most capable and cost-efficient means for aseptic processing of sterile products.9 Obstacles to their expanded use, such as denigrating their performance by fixation on inferior systems as representative of all need to be reconsidered.
*The biological indicators used in these systems, then and now, are identical to those available to other users. That these users and systems did not experience the ‘rogue’ behavior that was increasingly prevalent in others suggest process weaknesses were at ‘root cause’ rather than something attributable to biological indicator.
References
1FDA, Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile, January 2022.
2Agalloco, J., “Paradise Lost: Misdirection in the Implementation of Isolation Technology”, Pharmaceutical Manufacturing, Volume 15, No. 4, p. 34, 2016. Continued online at Pharmmanufacturing.com. Reprinted in Aseptic Processing Trends eBook, pp 9-17, July 2017.
3PDA Technical Report No. 51: Biological Indicators for Gas and Vapor-Phase Decontamination Processes: Specification, Manufacture, Control and Use. PDA, Bethesda, Md, 2010.
4Sigwarth. V., & Moirandat, C., Development and Quantification of H2O2 Decontamination Cycles. PDA Journal of Pharmaceutical Science and Technology, Vol. 54, No. 4, pp 286-304, 2000.
5Medicines and Healthcare Products Regulatory Agency. MHRA Inspectorate Blog: VHP (Vapour Hydrogen Peroxide) Fragility. https://mhrainspectorate. blog.gov.uk/2018/04/20/vhp-vapour-hydrogen-peroxidefragility/, 2018.
6EMA Annex 1, Manufacture of Sterile Medicinal Products, 2022.
7PHSS, Bioindicator (BIs) strategy to use in VHP/vH2O2 Bio-decontamination cycle development, performance qualification and ongoing re-qualification, 2025.
8Agalloco, J., “Ridding the World of ‘Rogues’: Improving Vapor Phase H2O2 Sterilization and Decontamination Processes”, PDA Journal of Pharmaceutical Science & Technology, Vol 77, No. 5., pp 412-419, 2023.
9Agalloco, J., & DeSantis, P., “Technologies for Aseptic Filling: The Choice is Clear”, American Pharmaceutical Review, Vol. 27, No. 2, pp. 36-39, 2024.
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