Editorial | Open Access | Published 26th April 2024

GUEST EDITORIAL : Sterilisation and Bio-decontamination, roles and challenges in Aseptic manufacturing

Author : James Drinkwater, Franz Ziel GmbH Head of GMP compliance and Honorary member and ex-Chairman of the PHSS, Co-leader of PHSS Aseptic processing, Annex 1 implementation and Control Strategies focus groups

Sterilisation in Aseptic manufacturing is applied for sterilisation of Direct and In—direct product contacting parts and surfaces whilst Bio-decontamination is primarily applied to the Barrier technology (Isolators or RABS) and installed process equipment non-product contacting parts.

There has been a long-standing challenge related to in-direct product contacting parts e.g. stopper bowls, chutes and trackways if the bio-decontamination process of applying vaporised hydrogen peroxide (VHP/vH₂0₂) that can inactivate Geobacillus stearothermophilus biological indicators with 6log sporicidal reduction can be claimed to deliver ‘Surface sterilisation’ as such replace the need to sterilisation. It is accepted all direct product contacting surfaces must be sterilised but can the rules change and risk be accepted as lower for in-direct product contact parts so an alternative method of bio-decontamination can be applied?

When the MHRA published the Blog on ‘Fragility of VHP’ was this message that such a process is fragile and not suitable in aseptic manufacturing or are the strengths of vaporised hydrogen peroxide bio-decontamination not managed through good scientific knowledge and process understanding so the application becomes ‘fragile’. Fragility in knowledge and process uncertainty can lead to increased risk to product sterility and patient harm and is a fundamental principle within quality risk management; QRM -ICHQ9(R1) that applies over the product life cycle; ICHQ12.

Sterilisation is a penetrative process with method references in Pharmacopeia’s e.g. Moist Heat, Dry Heat, Gamma irradiation and ETO (Ethelene oxide, a true gas applied under vacuum). In variance to terminal product sterilisation the alternative of Aseptic manufacturing applies sterilisation of product by filtration, where PUPSIT; pre-use and post use filter integrity testing applies and sterilisation processes are applied for both direct product contact parts (Filling pumps, fluid paths and filling needles) and in-direct product contacting surfaces e.g. container closure feed bowls, chutes and trackways. Without exception direct product contact parts must be sterilised by a pharmacopeia method. By default, in-direct product contact parts present a risk of sterile product contamination hence should also be subjected to a process that assures sterilisation of surfaces without compromise to assurance of sterility of products and patient safety.

Moist heat sterilisation applied to in-direct product contacting parts such as container closure feeder bowls, chutes and trackways in Aseptic manufacturing does have it challenges in qualification i.e. to present loads for air removal and exposure to moist heat with avoidance of water retention and to develop suitable cycle parameters including appropriate equilibration times. Although such processes are long established in GMP manufacturing the need for scientific understanding and process knowledge is still as important today and essential in following QRM principles and documenting the application, method, qualification approach and control/ monitoring as part of the Contamination Control Strategy (CCS).

Bio-decontamination via VHP/vH₂0₂ is not a ‘true’ sterilization process as it has limited penetration capability hence appropriate as a surface treatment only that under certain conditions can achieve ‘surface sterilisation’ and certainly zero CFU recovery in environmental monitoring (EM). Both the limitations in VHP/vH₂0₂ penetration and EM recovery, impact the efficacy claims made for surfaces in process environments on barrier technology and process equipment (non-product contact and in-direct product contact surfaces).

Regulators have seen too much focus on biological indicators (BIs) efficacy claims without consideration to bio-decontamination process limitations that may apply to the critical process surfaces in Grade A processing environments and on processing equipment.

In efficacy qualification studies ‘Rogue’ BIs (BIs that have spore clumping issues and increased resistance to inactivation because of the lack of spore availability/exposure), fig1. underline the penetration limitation of VHP/vH₂0₂. In addition, soiled surfaces e.g. fatty acids from finger touch, if not properly cleaned before VHP/vH₂0₂ exposure may protect/shield biocontamination that could later be exposed in processing operations. Add to that the challenges of VHP/vH₂0₂ distribution as a condensable vapour that is subjected to hydrogen bonding characteristics, hence poor at passive diffusion the challenges to achieve surface sterilisation are not to be underestimated.

Fig 1. Scanning electron Micrographs (SEMs) of spore inoculations on biological indicators for VHP Bio-decontamination cycle development and qualification.

Without due regard of target surface exposure and inherent limitations of VHP/vH₂0₂ any claims of ‘surface sterility’ will not be valid. One of the main reasons the MHRA released the ‘Blog’ on ‘Fragility of VHP’ was not to characterise the bio-decontamination process as unsuitable as an application in Aseptic manufacturing but to challenge the ‘fragility’ of scientific knowledge and process understanding for VHP/vH₂0₂ as a bio-decontamination process.

Bio-decontamination with VHP/vH₂0₂ – ‘Strengths’

With good scientific knowledge and process understanding the limitations of VHP/vH₂0₂ can be managed and the strengths of VHP/vH₂0₂ can be fully realised for applications in aseptic manufacturing. The key strengths are considered as;

·         Bio-decontamination with the automated application of a sporicidal agent with broad-spectrum efficacy having oxidising potential and a free radical attack mechanism that inactivates, bacteria, fungi/moulds, spores and viruses (subject to DNA cleaving).

·         Cycle development via iterative studies can characterise inherent process variables to facilitate minimising variables to improve the process and provide a recipe for control parameters suitable for routine production use.

·         Efficacy can be qualified with biological indicator challenges and overkill applied to assure a robust and repeatable bio-decontamination process

·         Together with the efficacy the breakdown components of VHP/vH₂0₂ are the safe components of water and oxygen that are not persistent hence can deliver a residue free bio-decontamination process; subject to starting agent elemental impurities and oxidising impact on resident residuals e.g. from cleaning agents.

·         For Aeration and residual removal VHP/vH₂0₂ can be broken down by simple catalysts and dilution via venting to the outside environment where breakdown occurs to the safe components: oxygen and water. The same characteristics cannot be claimed for ‘true gases’ that readily diffuse and have lower OEL e.g. 0.1ppm. 

As VHP/vH₂0₂ for isolators is applied as an automated process with parameters of control subjected to cycle development, to characterise inherent process variability and applied overkill such a process is possible to qualify for 6log sporicidal efficacy with biological indicator challenges. Automated process limit operator variability and provide a higher level of assurance of repeatability.

In addition, increasingly Enzymatic Indicators (EIs) as used to support cycle development to characterise worst case locations and efficacy challenge location to location efficacy profiles.  

As a condensable vapour VHP/vH₂0₂ that is poor at passive diffusion the vaporised agent can managed and be applied safety in closed spaces including within barrier technology and material transfer devices have a defined and qualified leak integrity with operators present in the surrounding environment. With an OEL of 1ppm any leakage is limited in terms of spread and exposure to operators.

These combined attributes ‘Strengths’ of VHP/vH₂0₂ together with many peer-reviewed published articles relative to different microbiological species bio-decontamination and regulatory acceptance of a process capable of qualification by biological indicator efficacy challenges then VHP/vH₂0₂ still remains the most commonly applied bio-decontamination process for Barrier technologies, Material transfer devices and Cleanrooms.  

Summary

When the PHSS prepared the ‘Clarity of GMP Guidance note no.2’ Assurance of sterility of in-direct product contact parts in Isolator Barrier technology Aseptic manufacturing and submitted to the MHRA before publication the PHSS were told this is exactly what is was hoped would happen following the Blog e.g., the industry started to think more about gaining and sharing scientific knowledge together with building process understanding of VHP/vH₂0₂ as a bio-decontamination process so limitations and process variables are understood and risks managed; by design, characterised for application and qualified to deliver a repeatable and robust bio-decontamination process that follows QRM principles.

Process understanding means it is important to understand both the ‘Fragility and Strengths’ so process variables and limitations can be managed and claims met that underpin the requirements of assuring product sterility and patient safety.

This editorial provides an introduction to an upcoming article in the EJPPS looking into more details on strengths and fragility of VHP/vH₂0₂ Bio-decontamination, relationship with sterilisation and cleaning (a pre-requisite for both process steps). In addition, the term Bio-decontamination as a combination of cleaning and high-level sporicidal efficacy is also applied to RABS: Restricted Access Barrier Systems as a manual process and key points to consider are covered in comparing applications for Isolators and RABS.

As control strategies develop with an increased application of QRM principles we also need to consider the relationship between control strategies, what is documented and justified within and what confidence such strategies can provide auditors and regulators that there is a fundamental understanding of related science and process knowledge for any given application. Each aspect of cleaning, sterilisation, bio-decontamination needs such knowledge with attention to their interactions as well as individual process steps so a more holistic approach to control is applied.

We are moving to a new paradigm in GMP regulations and connections with CMC taking a more risk-based approach; via implementation of the revised ICHQ9(R1), holistic approach; with collective and effective control and monitoring measures and proactive approach where digitalisation of data supports improved data analysis and trending to address adverse trends or avoid adverse outcomes. Only with thorough knowledge of relevant science and process understanding can we meet such a new paradigm delivering product quality, patient safety and supply over a product life cycle.

James Drinkwater, Franz Ziel GmbH Head of GMP compliance and Honorary member and ex-Chairman of the PHSS, Co-leader of PHSS Aseptic processing, Annex 1 implementation and Control Strategies focus groups

Charles River Laboratories | Every Step of the Way. (criver.com)