Smart Strategies for Handling Indirect Product Contact Components
Excerpt from the GMP Compliance Adviser
Click here to view the complete chapter: Handling indirect product contact components in aseptic filling processes
7 min. reading time | by Dr. Birte Scharf
Published in LOGFILE 15/2026
Aseptic filling processes: Handling indirect product contact parts in compliance with the revised Annex 1 of the EU GMP Guide.
In addition to parts that come into direct contact with the product, aseptic filling processes involve parts that do not come into direct contact with the product but do, for example, contact sterile primary packaging. These parts are referred to as indirect product contact components. Typical examples include stopper bowls, vibratory conveyors, chutes, or conveyor belts.
Although there is no direct product contact, these surfaces represent an increased hazard (“hazard” as defined by ICH Q9(R1)). Contaminants can be transferred to sterile primary packaging via contact with such components and thus ultimately enter the sterile product.
With the revision of Annex 1 of the EU GMP Guide in August 2022, sterilisation of components that come into indirect contact with the product is therefore required in addition to the sterilisation of direct product contact parts:
Figure 1 | Excerpt from Section 5 (Equipment) of Annex 1 of the EU GMP Guide
This requirement is clearly formulated in the new Annex 1 and is leading to intense discussions within the industry regarding suitable practical implementation strategies, particularly regarding the use of isolators and closed RABS (Restricted Access Barrier System) with automated bio-decontamination systems.
Sterilisation of indirect product contact components
In isolators, Annex 1 requires automated bio-decontamination using a gaseous or vaporised sporicidal agent [1]; vaporised hydrogen peroxide (vH₂O₂) is most commonly used for this purpose. However, it should be noted that this is not a sterilisation procedure, but rather surface bio-decontamination. Its efficacy depends heavily on factors such as the exposure of surfaces, potential shadowing effects, and the process parameters [2]. To ensure the sterility of indirect product contact surfaces, vH₂O₂ bio-decontamination alone is therefore insufficient; components must be subjected to a suitable sterilisation procedure [1, 3].
In contrast to bio-decontamination, sterilisation procedures are characterised by achieving at least 12-log reductions and having a penetrating effect. The sterilisation procedure to be used depends on the material, geometry, and thermal stability of the components. Commonly used sterilisation methods utilise steam, dry heat, or radiation.
In many cases, the components are sterilised while enclosed in appropriate sealed packaging, for example in Tyvek®. This allows the sterile status of the components to be maintained until their installation and reduces the risk of recontamination during transport [4].
Timing of unpacking sterilised components
In practice, the question often arises as to when the sterile-packed indirect product contact components should be unpacked. This question is particularly relevant when using isolators, as different cleanliness conditions apply during various phases of the set-up process.
Generally, two different approaches have become established in the industry, which are explained below.
Unpacking after bio-decontamination
In this approach, the previously sterilised components are introduced into the isolator while still in their packaging. Subsequently, the bio-decontamination cycle is performed while the components remain in their packaging. Only after the cycle is complete and the aeration phase is over are the parts removed from their packages and assembled [5,6].
This approach is often justified by the following passage from Annex 1, since grade A conditions are not achieved within the isolator until the bio-decontamination process is complete:
Figure 2 | Excerpt from Section 8 (Production and Specific Technologies) of Annex 1 of the EU GMP Guide
In practice, however, several potential drawbacks are subject to discussion. When opening the packaging, particles may be released in the grade A zone at levels exceeding acceptance criteria. Furthermore, the presence of a large amount of packaging material during bio-decontamination can lead to shadowing effects, preventing certain surfaces from being fully exposed. There is also discussion that hydrogen peroxide residues may remain inside or below the package, particularly with Tyvek® materials. These effects may potentially require extended aeration times or additional process controls. The presence of vH₂O₂ residues negatively affects oxidation-sensitive products; therefore, they must be accurately and reproducibly quantified, and rinse times must be adjusted accordingly [6].
Unpacking before bio-decontamination
An alternative approach is to unpack and install the sterilised components during system set-up. In this case, the packaging is removed immediately before the bio-decontamination cycle, which encompasses both the barrier system and the installed components [5,6].
The advantage of this procedure is that all surfaces are fully exposed during bio-decontamination and no shadowing by packaging material can occur. Additionally, the potential generation of particles by opening of the packaging does not occur within the final grade A environment.
Since unpacking in this scenario takes place before the final bio-decontamination, appropriate measures must be taken during this process step to minimise recontamination as much as possible. In practice, this involves, for example, additional sterile clothing, controlled work procedures for operating personnel, and continuous particle and microbiological monitoring during set-up [6]. Even under worst-case conditions, the risk of microbial recontamination is on a scale that is completely mitigated by the subsequent bio-decontamination cycle. This procedure is widely used and accepted by regulatory authorities and is recommended due to its numerous advantages.
Alternative: Introduction via rapid transfer ports
An alternative option is to introduce sterile-packed components directly into the barrier system via rapid transfer ports (RTPs). In this process, the components are first sterilised in beta containers and transferred without additional packaging via alpha ports into the (bio-decontaminated) system or grade A area. This complies with the requirements in Annex 1, 8.12, while simultaneously avoiding the disadvantages of unpacking after the fumigation cycle. A disadvantage of this approach is the need for a sufficiently large alpha port in the immediate vicinity of the installation site. This is particularly difficult or impossible in existing facilities because large or unwieldy components can be introduced through standardised ports or passed through the plant to the point of installation only to a limited extent. This approach is therefore to be considered an alternative for future projects and requires a targeted facility design.
Evaluation within the context of the contamination control strategy
Which approach is chosen in a specific case should be evaluated within the context of the manufacturer’s contamination control strategy (CCS). The goal is to establish an overall concept that reliably ensures both microbiological safety and particle control [5].
Special considerations for existing facilities
Practical limitations may arise with existing plants, particularly if certain components (such as large stopper bowls) cannot be removed and sterilised externally [4]. In such cases, a risk-based approach can be carefully considered.
Accordingly, following an appropriate assessment and in consultation with the competent authority, a strategy may be acceptable in which these components are first cleaned in situ to achieve a very low level of residual contamination, before a validated vH₂O₂ bio-decontamination cycle is performed. In this case, the bio-decontamination step serves as an additional microbiological safeguard for the surfaces [5].
Summary
- Annex 1 requires the sterilisation of indirect product contact components.
- Two strategies are discussed: unpacking before or after bio-decontamination.
- Selection of the approach is made within the context of the contamination control strategy.
Literature
- European Commission. (2022). EudraLex Volume 4: EU guidelines for good manufacturing practice for medicinal products for human and veterinary use – Annex 1: Manufacture of sterile medicinal products. European Commission.
- Hopkins, A. (2018). VHP (vapour hydrogen peroxide) fragility. MHRA Inspectorate Blog.
- Hopkins, A. (2025). Vapour hydrogen peroxide, still fragile? A retrospective follow-up on a 2018 MHRA blog. Lachman Consultant Services, Inc.
- Pierobon, C. (2025). Challenges in sterilizing indirect product contact surfaces. PDA Letter.
- Pharmaceutical and Healthcare Sciences Society. (2020). PHSS Clarity in GMP Guidance Note No. 2: Assuring sterility of indirect product contact parts. Pharmaceutical and Healthcare Sciences Society.
- Blumenstock, M., Burkart, F., Greiner, M., Lehmann, F., Moser, B., Schiessl, R., Schoenenborn, S., Staub, J., Storn, V., & Wieland, N. (2026). Smart strategies for aseptic filling line setup. ISPE Pharmaceutical Engineering (iSpeak Blog).
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