GMP Annex 1 and bio-decontamination: considerations on technology and decon process engineering

12 August 2024

With the review of GMP Annex 1, the bio-decontamination of barrier systems has certainly taken on a key role, but not all solutions available on the market offer the same answers in terms of results, process management and validation. In the article below, we are going to consider some aspects that should be evaluated before choosing the most suitable system for your aseptic process.


GMP Annex 1 and VPHP biodecontamination

Almost a year after GMP Annex 1 came into force, there are still several open questions and problems to be solved. From one hand, there are some aspects whose interpretation gives rise to debate within the pharmaceutical industry but, on the other hand, some messages emerge with the utmost clarity.

One of them is certainly the need to use the most advanced technologies on the market. It’s nothing new, since from the 2001 and 2003 versions of the document, the so-called “Marketing Authorization Holders” companies were required to use updated processing technologies. But, after the latest review of this document, it has become clear that this kind of choice is considered today as a crucial element for contamination control by identifying the use of isolators and RABS as a preferential choice in the drafting of the Contamination Control Strategy (CCS).

Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.
(GMP Annex 1, Premises 4.3, p. 06)

In this context, it appears clear that the engineering approach towards the barriers systems represents a key element of the contamination control strategy required by the document, so much that GMP Annex 1 identifies some critical points that should be specifically considered in the CCS drafting. Among them, there is also the bio-decontamination program.

Key considerations when performing the risk assessment for the CCS of an isolator should include (but are not limited to); the bio-decontamination programme, the extent of automation […].
(GMP Annex 1, Premises 4.20, p. 10)

The characteristics of the bio-decontamination process of the internal surfaces of barrier systems are defined in section 4.22 of the document.

The bio-decontamination process of the interior should be automated, validated and controlled within defined cycle parameters and should include a sporicidal agent in a suitable form (e.g. gaseous or vaporized form).
(GMP Annex 1, Premises 4.22, p. 11)

If the message contained in these two lines is quite clear, the same cannot be said for its practical application. The sentence “controlled within defined cycle parameters” contains several implications related to the performance and characteristics of the technology used. There are cycle parameters that should be taken into consideration and which strictly depend on the engineering process.

 

Furthermore, not all the solutions offer the same response in terms of results, process management and validation. Below are listed several useful considerations about GMP Annex 1 and VPHP biodecontamination in order to evaluate the right solution for any need.

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Vapour Phase Hydrogen Peroxide – VPHP

By evaluating the various bio-decontamination processes in barriers systems, the one that seems to have the best characteristics – considering its performance, versatility and control – is based on the use of Vapour Phase Hydrogen Peroxide – VPHP. In fact, it brings several advantages compared to the other two technologies in use, based on ethylene oxide and ozone.

Hydrogen peroxide, unlike the other two components, is in fact in the liquid state at ambient temperature. This characteristic makes it easier to transport and storage it, it is not toxic if released into the environment and it is not polluting, given that the only products related to its decomposition reaction are oxygen and water vapour. These characteristics, combined with the huge sporicidal action, have made the VPHP-based devices the preferential choice in order to integrate the barrier systems.

 

Bio-decontamination cycle: the peroxide concentration is not the only parameter to take into consideration

 

Despite the advantages linked to the use of VPHP, the challenge consists in adapting the bio-decontamination cycles to the different pharmaceutical processes, which are different for process parameters, materials and production times to respect.

Efficiency in bio-decontamination cycle does not depend only on hydrogen peroxide concentration in the environment, but also on relative humidity, temperature and kind of materials within the machine.

For example, it is possible to reach high concentration and reduce the cycle time in a process where decontamination of many glass vials is needed, because this material is not permeable to VPHP.

On the contrary, in a process where permeable plastic materials are present, it is best to keep a lower concentration in peroxide, preventing it from penetrating the plastics, protecting any sensitive components inside them and accelerating the final aeration phase. In fact, the bio-decontamination cycle should be managed by taking into account this final phase, because an effective cycle may not be effective in the final elimination of the peroxide from the barrier system, which must reach lower values than 1ppm.

For all these reasons, lowering the relative humidity as much as possible and maximizing the VPHP ppm does not represent the most effective solution in all cases. By controlling the VPHP ppm, it could be possible to have not only faster final ventilations, but also more effective cycles. For example, for each case, this can be possible by finding the ideal relative humidity value to start the injection of VPHP and its final value. This approach allows to manage the microcondensation process on surfaces, which efficiency is confirmed by several industry literature studies (Unger-Bimczok 2008, D. Walting 2002), and to evaluate with precision the maximum concentration of peroxide to reach.

Versatility and integration: the solution for consistently high performance

The ideal solution to reach high and consistent performances, even in multiple different cases, seems to be the adoption of a VPHP generator as versatile as possible, deeply integrated with the different barrier technologies to which it is connected.

For temperature-sensitive processes, it is possible to integrate the generator with the facility’s compressed air network, guaranteeing low relative humidity values in a short time without excessively heating the air to vaporize the peroxide. On the contrary, for processes where temperature is not a significant parameter, or the facility does not have large quantities of compressed air, it is possible to integrate the generator with a silica gel dehumidifier, which heats the air during the dehumidification process, thus helping the desorption of the peroxide during the final aeration. This last phase is often the bottleneck of the cycle and, if mismanaged, it can last longer than all the other phases combined together. Integration between barrier system’s ventilation and VPHP generator offers enormous advantages in developing a bio-decontamination cycle.

 

Integrated Bio-decontamination generator
 

The importance of choosing a partner able to managing all the parameters involved

The picture that emerges is that multiple situations can arise, making it difficult to research the different ideal cycle parameters, which depend not only on the VPHP generator, but also on the process and the barrier system itself.

The partner choice therefore represents a crucial aspect for the success of an aseptic process. Only the use of a system that deeply integrate the VPHP generator with the barrier system allows a high level of the process engineering, being able to manage, under a single manufacturer and in the most efficient and safe way possible, the following installation, validation and development phases, by guaranteeing the more and more demanding regulatory standards on the market.

The synergistic integration of the bio-decontamination technologies, barrier systems and knowledge of the involved parameters in an aseptic process represents the key strategy to face the future challenges of the pharmaceutical industry.

 

Discover HYPER, our integrated bio-decontamination system

 

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