EU GMP Annex 1 has been revised and provides clarification on the regulatory requirements regarding the manufacturing of sterile products. Many important topics have been discussed and revised by the authorities during this update. Process monitoring, cleaning/disinfection, integrity testing of product sterilizing filter, aseptic holding time are only some of the topics covered.
In addition, the Annex 1 revision will have an important impact on the design of future aseptic filling lines. The method of sterilization of filling machine stoppering parts has been thoroughly discussed and analyzed in order to provide more specific guidance to pharmaceutical companies.
This article explains how the expectations of the regulatory authorities will change regarding the management of machine components.
In this article guidance will be provided to process engineers for the design of filling machines and isolators, which will comply with the new stricter regulations.
To clearly understand what will change, there are some definitions and concepts that must be understood properly. Let us start with that first.
What is an aseptic filling line?
An aseptic filling line is a complex group of automated machines, which are integrated one to another, with the purpose of dispensing a medicinal product into vials under sterile conditions.
The filling machine is integrated with the following equipment:
Filling isolator: it encapsulates the filling machine, it is able to perform bio-decontamination of inner surfaces with hydrogen peroxide vapors, provides filtered air and grade A environment for the aseptic filling operation.
Sterilizing tunnel: positioned upstream from the filling machine, it is responsible to heat-sterilize the vials and transfer them to the filling line.
Vial crimping machine: positioned downstream from the filling machine, it is responsible to perform crimping of filled, stoppered vials.
The main parts of an aseptic filling machine are:
Vial transport system: able to transport the vials from the start of the filling line (downstream the sterilization tunnel) until the end of the filling line (upstream the crimping machine).
Vial filling system: able to fill the exact quantity of product inside the vials, to carry on in process controls and to reject incorrectly filled vials.
Vial stoppering system: able to transfer, correctly orient, transport stoppers and close the pre-filled vials.
The stoppering part of a filling machine is usually encapsulated in a «side arm» of the filling isolator and meets the vial transport system approximately with a 90 degrees angle. This part of the machine is composed by the following features (see figures 1 and 2):
Stopper transfer system: transfers sterilized stoppers from outside the isolator into the stopper hopper via an aseptic rapid transfer port system.
Stopper hopper: collects and stores the stoppers that have been transferred into the isolator. The size of this element needs to be carefully designed in order to guarantee a sufficient buffering capacity for the filling line.
Stopper bowl: this element receives the stoppers from the hopper and, with a system of vibration, orients and transfers the stoppers to the linear tracks. Also the size of this element is crucial for the speed of the filling line. If the size is not well designed, the filling machine speed can be negatively impacted.
Stopper tracks: guides the previously oriented stoppers from the bowl to the actual stoppering location.
Stoppering feature: This part is ultimately responsible to receive the stoppers from the linear track and to place them on the vials.
Surfaces classification inside an isolator
Surfaces inside an automated filling machine encapsulated within an aseptic isolator can be divided into three typologies:
Non-product contact: surfaces that do not have direct or indirect contact with the product, like the inner isolator surfaces
Non-direct product contact: surfaces that have indirect contact with the product, like stopper bowl and stopper tracks
Direct product contact: surfaces that are in direct contact with the product, like filling needles and piston pumps.
Different surfaces, different risks
Direct product contact surfaces carry much higher risk of transferring pathogens and endotoxins to the product and therefore they must be sterilized via an autoclave (dry heat or steam) or by gamma irradiation. These methods are able to penetrate deeply into the material.
Non-product contact surfaces carry minor risk to contaminate the product and therefore these surfaces can be sterilized via hydrogen peroxide vapor. This method is only able to decontaminate the surface of the material, but it has no possibility to penetrate deeply or to eliminate the endotoxins.
Isolator loading and bio-decontamination
Cleaned, non-direct product contact components are transferred and installed into the isolator via the isolator door (see figure 3).
Once the isolator is loaded and sealed, hydrogen peroxide vapors will be sprayed into the isolator in order to decontaminate all the surfaces within the isolator (see figure 4). These surfaces will mainly include non-product contact parts like internal isolator surfaces, vial transport system, balances and gloves. Although stoppering parts of the filling machine cannot be considered as non-product contact parts, they are not direct product contact parts either. Therefore prior to the Annex 1 revision, it was deemed acceptable to sterilize these components with hydrogen peroxide during isolator bio-decontamination.
Aeration phase, aseptic transfer of equipment and assembly
After the decontamination phase, an aeration phase will follow. Catalytic converters will help the isolator ventilation to break down and clear the excess of hydrogen peroxide. The level of hydrogen peroxide must be sufficiently low before the process can carry on. Once the measured level of hydrogen peroxide is below the specification limit, the filling line assembly can start.
As direct product contact parts (like product piston pumps and product needles) cannot be sterilized via decontamination, they need to enter the isolator after the decontamination in an aseptic way.
Modern aseptic isolators are equipped with rapid transfer ports that allow to dock pre-autoclaved metal containers (canisters) in order to transfer sterilized components and machine parts without breaking the isolator containment. These ports are made of stainless steel and are embedded into the isolator outer wall. Although they are robust, they cannot sustain an excessive weight. These rapid transfer ports have usually a diameter of about 30cm and are suitable to transfer small parts and tools. Use of aseptic canisters is the first choice to transfer product path components inside the sterile isolator. These parts have relatively small dimensions and can easily fit into these containers (see figure 5).
What’s the impact of the Annex 1 revision?
With the revision of Annex 1, hydrogen peroxide has been questioned as a method of sterilization. Concerns of experts towards hydrogen peroxide decontamination has caught the attention of regulatory authorities. In particular, it was established that it is not acceptable to rely uniquely on hydrogen peroxide for the sterilization of critical surfaces, also including indirect product contact parts. This means that stoppering parts also would require to be heat sterilized prior to enter the isolator.
Although this might seem just a simple statement, it has significant consequences on the design of the isolator and the set-up of the filling machine, especially for stoppering system.
What are the main challenges?
Progress of the technology of filling and transport equipment has led to faster and faster filling lines. To avoid that the stoppering step could become a bottle neck in the process, the buffering capacity of these elements had to increase. Higher demand of efficiency of filling machines has led to design large capacity stopper hoppers and bowls. Stopper bowls and hoppers became quite bulky parts in order to minimize downtime and to reduce the number of stopper transfer interventions required. As these parts are manufactured in solid stainless steel, they can weight up to 20 kg. This makes the transfer into the isolator and the assembly already quite complex operations.
The addition of the pre-sterilization step and the management of the bioburden during the transfer/installation operations adds a further layer of complexity to the picture.
How to meet the expectations?
The expectations can be achieved in different ways. Each of these ways will have their own pros and cons:
Loading and installing pre-autoclaved components in the isolator prior to sealing and prior to the start of the bio-decontamination (when isolator is open and therefore not sterile).
+ Simple design (no need for aseptic transfer technology)
+ Less risk for isolator (transfer is performed when isolator is not sterile)
- Manual operation (rely on procedure for compliance)
- Additional protective measures (required to protect the parts during transfer)
- Management of bioburden risk for the pre-sterilized components
Bringing in stoppering parts via canisters after the isolator is sealed and bio-decontamination and aeration steps are completed (when the isolator is closed and sterile).
+ Process is safer for the machine components (enclosed in a steel container)
+ Less prone to human error (transfer via validated aseptic transfer system)
- Design of canisters (effort, customization, cost)
- Method cannot be used for big, heavy parts
- Installation of the machine components might be difficult via isolator gloves
Which approach to choose?
Both 'open door' and 'closed door' transfer approaches are actually valid. The best strategy to follow could be a hybrid one. This would allow to use the advantages of both methods.
Pre-sterilized bigger stopper product contact parts might be transferred when the isolator is still not sealed shut. Parts like hopper and bowl might be sterilized with a heat-resistant cover to protect inner surfaces during the transfer inside the isolator and during installation (see figure 6). Only after the installation of these machine components the cover could be removed, just before (or just after) sealing the isolator and starting the hydrogen peroxide bio-decontamination cycle (see figure 7).
Smaller and lighter stopper product contact parts (e.g. stopper tracks) can be easily fitted inside a canister and heat sterilized in order to be transferred when the isolator is sealed and in sterile condition (after the aeration phase) (see figures 8-10).
Focus on the design phase is crucial
'Open door' transfer of bulky, heavy stopper parts into the isolator
Stopper hopper and bowl shall be designed to allow easy installation, according to SMED (Single Minute Exchange of Dies) principle without the need to remove the cover.
The isolator and the line shall be designed to have ergonomical features to allow transfer of these heavy ad bulky components in a safe way both for operators and processes.
Trolleys could be designed to facilitate the transfer of the heavy parts into the isolator. This would allow to reduce human intervention, to lower the bioburden risk and to provide the best ergonomics.
Extra precautions may be taken in order to protect the pre-sterilized stopper components and the isolator. Extra gowning for operators transferring the components with open doors would be required.
Protective airflow would also be necessary to manage bioburden contamination of the clean isolator during transfer. Number of open doors must be minimized during transfer of stopper hopper and bowl in order not to disrupt the protective airflow.
'Closed door' transfer of lighter, smaller stopper parts into the isolator
Design of the parts has to follow the SMED principle. No tools should be needed to assemble the parts. No adjustments or fine-tuning should be required as dexterity of operators is reduced when assembling parts with isolator gloves.
Careful design of the rapid transfer port is crucial to allow closed door transfer of smaller parts. The positioning of the rapid transfer port is very important for ergonomics. This needs to be evaluated during the isolator mock-up study.
The mock up study is also important to decide suitable positioning of isolator gloves. The operator needs to be able to install the parts in a comfortable and safe way.
Canisters need to be designed to minimize the number of transfer operations (maximizing the number of parts contained in one canister).
Revision of Annex 1 and the new requirements for the management of stoppering parts will have important consequences on the design of future aseptic filling machines and isolators. For the existing, older generation filling machines a dialogue with regulatory authorities will be necessary to understand how compliance can be achieved with retrofitting of features and modifications of process flows. For new machines, clear user specification requirements, punctual collaboration with machine suppliers and a well thought design phase are crucial to comply with the new requirements right first time.
Associate Manager @ pi
EU GMP guidance: Annex 1 – Manufacture of sterile medicinal products
MHRA blog: Fragility of VHP (2018)
PHSS (Pharmaceutical and Healthcare Sciences Society): Clarity on GMP guidance, Assurance of Sterility of indirect product contact surfaces in aseptic process filling