Editorial | Open Access | Published 20th December 2023
GUEST EDITORIAL : VHP biocontamination – a fragile process or unsuitable measurement system
Author : Aled Jones; Director MSAT. Fin Vector Oy; Microkatu 1 S, FI-70210 Kuopio, Finland
Key words: Vaporised Hydrogen Peroxide (VHP), Biological Indicators (BI’s)
The use of VHP as a sporicidal surface bio-decontamination process has been regarded as a “fragile” process1, due to issues with failures in requalification of systems due to BI growth. This has resulted in significant challenge by authorities, resulting in significant technical modification to the requirements for this process driven by Annex 1. Yet, there are a number of experts who disagree with this opinion, with Jim Agalloco2 even calling for the MHRA to withdraw these comments and review sterilization claims for VHP with greater diligence. There have been many excellent articles3 on the issue of rogue BIs and how to reduce their impact by use of multiple biological indicators in the same locations, as described in PDA Technical report 514 and recommended by PIC/S5. However, I do not believe that as an industry we have had a robust discussion on whether we can truly establish whether we have a “fragile” process or whether the measurement system we are utilising for the assessment of VHP effectivity is suitable for purpose.
A measurement system is typically described as being data that describes a process where the quantity may be compared with a standard unit (calibration) and that the data should be repeatable (variability caused by the measurement device) and reproducible (variability between occasion of use or users).
USP6 states that a standardized BI for vapour systems is not available and only under well-defined conditions in relation to an individual cycle, can a reliable D-value be established. For BIs, the equivalent to a calibration coefficient would be the D-value, a value that is absolute for wet steam sterilisation irrespective of cycle, however it is known that BIs with the same nominal D-value will give different recovery7 when supplied from different manufacturers. As the D-value cannot be used across different cycles, we have no known calibration standard to refer to.
Much discussion has been had by BI manufacturers as to designing BI systems for VHP cycles. As cellulose reacts with VHP and can combust, Tyvek® is commonly used as the primary packaging for the inoculated carrier to protect it from external contamination and prevent spores being released into the manufacturing area. Unfortunately, Tyvek® has a significant impact on the ability of VHP to penetrate into the inoculated stainless steel carrier8, especially when the BIs are exposed to humidity, handling or even the ink that is used to write on them, which may catalyse VHP. Most commercial VHP cycles have extensive dehumidification steps prior to the decontamination phase, driven by the need to control humidity for the Tyvek® surrounding the BI strips. A typical spore log reduction by 1-3 log would be expected by removing the Tyvek® and exposing a naked carrier8, so a BI with a spore count of 106 potentially behaves closer to 109 due to this packaging; or conversely, we can reduce the resistance to VHP for the BI strip by exposing the naked carrier. For example, if we have a VHP requalification that fails with BIs in Tyvek® packaging, should we recommend that the study is repeated with naked carriers as the cycle will then pass? The impact of the packaging we currently use for BIs means that the measurement system is not repeatable.
Typically, hundreds of BIs are used in a single bio-decontamination cycle requalification. Driven by the requirement for each location to have triple BIs, the positioning of the BIs inside an isolator can be extremely challenging from an ergonomic perspective and from personal experience, very tiring. It is critical to not touch the BIs with bare hands to avoid transfer of grease or sweat to the BI, which makes positioning multiple BIs with tape very difficult. A full description of best practice is given by Mesa Labs9, however even with these detailed instructions, variability may be introduced to the BI recovery due to operators placing strips with very small differences, for example small changes of the angle of the BI strip to the plane of the surface impact the resistance of the BI. I would thoroughly recommend validation personnel practise BI placement in a test isolator prior to the formal process qualification, especially if they are more familiar with autoclave sterilisation where the technique of placing of BI strips is not so critical. The ergonomics of our current system challenges the measurement system to be reproducible.
In conclusion we have a measurement system that does not meet the expected requirements for an industry that is moving towards the adoption of closed system aseptic processing, and if we do not have a suitable measuring system we cannot determine when we have true process failures and conclude that we have a fragile process. The consequence of this is that across the industry, VHP requalification remains increasingly challenging, resulting in extensive downtime for investigations where BI recovery is obtained during requalification, with a single or any root cause rarely being established.
For isolator decontamination, cycles are required to have significant overage of VHP to ensure that the cycles are robust enough to account for the variability of the process capability of the measurement system (BI’s) and setting the cycle at a minimum of 10-8 to 10-10 is not uncommon10. This then has the impact of the overage of VHP interacting with the materials used in the manufacture of the isolator (see: “Investigation of the Visual Impact of the Combined Exposure to Residual Cleaning Agents and Vaporized Hydrogen Peroxide on Materials used in Barrier Systems” in this edition) resulting in shorter equipment lifetime. Also, as the industry moves towards biological products the requirement to move to lower and lower residual peroxide levels will become critical.
I would suggest that an industry wide best practice recommendation is undertaken to agree or develop new standards for VHP cycle assessment. Examples could be to:
Redesign the BI strips with alternative primary packaging that does not give a different response to naked strips, or packaging that can be opened for the VHP cycle once placed in the isolator and then closed after the cycle.
An industry wide agreement to account for the 2-log increase with the Tyvek® packaging and standardise VHP cycle qualification with 104 BI strips.
The adoption of the use of alternatives to endospore biological indicators, such as enzymatic indicators based on thermostable adenylate kinase (tAK)¹¹ (see: “Enzymatic Indicators in Vaporized Hydrogen Peroxide Decontamination Cycles” in this edition) and chemical indicators¹⁰ which show good equivalence.
Jim Agalloco Open Letter to MHRA on May 11, 2018 (Open Letter in Response to MHRA blog on Vapour Hydrogen Peroxide Fragility | LinkedIn)
Sandle, T. (2020) Rogue Biological Indicators: Are They A Real Phenomenon? Journal of Validation Technology, 26 (1):
PDA Technical Report No. 51: Biological Indicators for Gas and Vapor Phase Decontamination Processes: Specification, Manufacture, Control and Use. Bethesda: PDA, 2010
PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME PI 014-3 25 September 2007 Section 184.108.40.206
USP <1229.11〉 VAPOR PHASE STERILIZATION
Reich, R; Caputo, R. Vapor-Phase Hydrogen Peroxide Resistance of Environmental Isolates. Pharmaceutical Technology, Aug 2004: 50-58
BI Placement During VHP Decontamination Cycles | Mesa Labs
Jones et al (A practical methodology to assess VPHP cycle effectiveness during routine qualification European Journal of Parenteral & Pharmaceutical Sciences 2021; 26(2))
Hesp et al, Thermostable adenylate kinase technology: a new process indicator and its use as a validation tool for the reprocessing of surgical instruments, J Hosp Infect. 2010 Feb;74(2):137-43