EU GMP Annex 1 compliance: should you get new equipment or upgrade?

Published: 4-Jun-2024

Buy a new machine or upgrade the existing equipment? In light of Annex 1, pharmaceutical manufacturers and contract manufacturing organisations are facing this question more than ever. Steffen Mueller discusses the solution Syntegon worked on with AJ Vaccines

The Danish pharmaceutical company AJ Vaccines and its long-term partner Syntegon showed that upgrades can yield great results.

They modernised an older MLF 3002 vial filling and closing machine with a complete RABS and made it fit for future challenges.

On August 25, 2023, the new Annex 1 of the EU Good Manufacturing Practices for the production of sterile medicinal products came into force.

It explicitly recommends pharmaceutical manufacturers to apply barrier systems as part of their contamination control strategy.

The document now comprises 58 pages instead of previously 16, while the size of the chapter on barrier technology has even quadrupled.

The document clearly recommends the use of appropriate barrier technologies

This has far-reaching consequences for sterile filling operations. Overall, the new Annex 1 sends a clear signal in direction of the highest possible product quality. Its primary objective is to prevent product contamination.

One rationale in this regard is the separation of the aseptic process area from the operator environment. For the first time, the document clearly recommends the use of appropriate barrier technologies – isolators and RABS (Restricted Access Barrier Systems) are considered equal. Pharmaceutical manufacturers will therefore require at least RABS for the approval of new products; new approval on existing cleanroom lines will only be possible in exceptional cases.

A trend towards RABS upgrades

Since its publication, Annex 1 has been triggering high demand for new machines and barrier technology upgrades, which continue to date.

Pharmaceutical manufacturers and contract manufacturing organisations must comply with the regulation and make sure they have all technologies in place for maximum product and operator protection – which is quite a challenging task.

One solution is to invest in a completely new line with pre-installed barrier technology. However, many drug manufacturers still have very good equipment running reliably in their manufacturing facilities.

Many drug manufacturers still have very good equipment running reliably

Against the background of cost pressure and sustainability targets, disposing of machines that still perform well is out of the question for most companies.

Hence, the current trend clearly points towards upgrades of existing equipment. In most cases, isolator upgrades are too complex or costly. Hence, many pharmaceutical manufacturers and contract manufacturing organisations have already opted for or are currently planning an upgrade of their existing equipment with RABS.

The options are manyfold and range from an open or closed system in passive or active design with associated air handling unit to individually specified components such as glove ports, material locks, or transfer ports. Syntegon offers all these options and analyses customer requirements in detail to recommend the ideal solution.

Action instead of reaction

For AJ Vaccines, a pharmaceutical manufacturer with headquarters in the heart of the Danish capital Copenhagen, the choice was obvious: their MLF 3002 vial filling and closing machine from Syntegon has been running smoothly in previous years.

Following a technical audit and some optimisations in the infeed and outfeed areas, the machine still had a very high life expectancy. However, AJ Vaccines was aware of the upcoming changes through Annex 1 at an early stage. So, the company took advantage of the technical audit session with the Syntegon experts to inquire about a RABS upgrade. 

Following a technical audit and some optimisations in the infeed and outfeed areas, the machine still had a very high life expectancy

The experts at AJ Vaccines develop and manufacture vaccines to prevent polio, tuberculosis, and other infectious diseases, as well as diagnostics and therapeutic solutions.

The pharmaceutical pioneers’ mission: finding new ways of providing the whole world the same opportunities for safety and prevention through vaccination that exist in Denmark.

To continuously be able to achieve this, AJ Vaccines always has an eye on new trends, developments, and regulations in the field.

Consequently, AJ Vaccines did not wait until the new Annex 1 was implemented or even published. Instead, they decided to proactively prepare for all regulatory changes well in advance.

The challenges of Annex 1

According to the revised Annex 1, sterile production must take place under RABS or isolator conditions to ensure better product and operator protection. Glove ports are needed to avoid opening of the glass doors, for example to change settle plates for environmental monitoring or in the case of a manual intervention through glove ports.

These requirements are subject to regulatory audits either through local authorities or through the European Medicines Agency (EMA) and had to be fulfilled by the date of the Annex 1 implementation to ensure validated production processes.

Following the mock-up phase, AJ Vaccines decided to implement a passive open RABS

Danilo Bongiovanni, service project manager at Syntegon, confirms the rising number of inquiries for new barrier systems or upgrades: “In Denmark alone, we have already realized several RABS upgrades and often receive requests for new machines with integrated barrier technology,” he reports. 

Of course, this is not a Danish phenomenon. All over the world, drug producers and CMOs are looking for effective and cost-efficient measures to comply with Annex 1 as quickly as possible.

Since new machines are a cost-intensive acquisition and require significant qualification and validation efforts, many pharmaceutical manufacturers are looking to update or upgrade their existing equipment.

Prior to the project kick-off, AJ Vaccines visited other Syntegon customers in Denmark to see the results of similar upgrades and was soon convinced that Syntegon was the right partner for their project as well. The dedication of the Syntegon team during the technical audit underlined this evaluation.

Focus on user-friendly operation

The first step consisted in the mock-up phase, which is essential to determine the exact scope of the upgrade, including the type of RABS, the position of the glove ports, and further details. “For new machine projects, we would usually draw up a virtual 3D model.

AJ Vaccines is among the first customers Syntegon supported in getting “Annex 1-ready”

Existing machines, however, require up to a week at the customer’s site. Every inch of the equipment needs to be checked and documented thoroughly since older machines often only come with 2D constructional drawings,” Bongiovanni explains.

A mobile mock-up frame helped determine the exact height and position of the glove ports. “The upgrade brings a number of changes for the operating staff. We used the chance to make their work with the new system as ergonomic and user-friendly as possible by testing the work steps beforehand with a selected group of operators to find the ideal average position.”

Following the mock-up phase, AJ Vaccines decided to implement a passive open RABS. The team then established a project plan and defined milestones.

During the subsequent design phase, the Syntegon engineers developed a comprehensive 3D model, which was challenged and discussed in several design review meetings to adapt it precisely to all customer requirements.

Apart from the new RABS, the design further included the exchange of the former rotary valve piston pump with RTU filling paths and the connection to a third-party pump trolley. Again, the project team paid special attention to user-friendliness by optimizing the processes to transfer equipment into the machine.

Annex 1-ready well in advance

In August 2022, the installation was successfully completed. Syntegon provided the comprehensive documentation, while AJ Vaccines revalidated its MLF line.

Apart from new machines, the numerous RABS upgrades offer customers an extensive choice of options

In October, the Syntegon experts were on site again to accompany the first batch and check whether the machine was running according to plan. “The entire project was completed on time, despite some issues with supply chain bottlenecks,” Danilo Bongiovanni recalls. “AJ Vaccines even manufactured some sheet metal parts themselves for the project to remain on schedule.

This was one of my highlights of this project: the joint commitment of Syntegon and AJ Vaccines, excellent communication, and very clearly defined requirements and milestones.”

AJ Vaccines is among the first customers Syntegon supported in getting “Annex 1-ready”. Syntegon is currently working on many more projects to prepare further pharmaceutical manufacturers for the challenges of Annex 1 with high flexibility, a dedicated project team, and profound technological expertise – in Denmark and all over the world.

Apart from new machines, the numerous RABS upgrades offer customers an extensive choice of options, including peripheral topics such as viable monitoring, new stopper infeed solutions, or glove integrity testing devices.

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