August 25, 2023 will go down as an important date in the history of the pharmaceutical industry. On this day, the new Annex 1 of the EU Good Manufacturing Practices for the production of sterile medicinal products came into force.
The document has far-reaching consequences for sterile filling operations. So, what do pharmaceutical manufacturers need to consider – and how can equipment suppliers like Syntegon help with the implementation?
15 years after the previous version came into force, the new Annex 1 “Manufacture of Sterile Medicinal Products” of the EU GMP guidelines has become effective on August 25, 2023.
One rationale of the new Annex 1 is the separation of the aseptic process area from the operator environment
Its scope alone suggests numerous implications for sterile manufacturing processes. The document now comprises 58 pages instead of previously 16, while the size of the chapter on barrier technology has even quadrupled.
Long before its publication, the new Annex 1 was the source of controversial discussions that continue to this day. On the one hand, the document leaves room for interpretation; on the other hand, many players in the pharmaceutical industry fear overregulation.
EU guidelines with global consequences
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. The transition period of one year shows that implementation is not easy; for the loading and unloading of freeze dryers, this period even amounts to two years.
However, these relatively long deadlines also underline the expectations on the part of the authorities: the changes should not only be planned or considered; they should also be implemented in practice – both for the installation of new plants and for retrofitting existing ones.
Although Annex 1 is an EU guideline, the document has consequences for the global pharmaceutical industry. For one thing, the specifications affect the manufacturing processes of drugs imported into the EU.
In the year following the publication of the guideline, the industry witnessed a veritable “run” on RABS upgrades of existing cleanroom lines
For another, the coordination of the document between EMA, WHO and PIC/S and the publication of equivalent documents by these organisations underscore its global relevance.
Accordingly, Annex 1 has created a stir throughout the world. Inspectors from all regions derive the requirements for their market – and are confronted with the same questions regarding their implementation.
Focus on barrier technology
One rationale of the new Annex 1 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.
In the year following the publication of the guideline, the industry witnessed a veritable “run” on RABS upgrades of existing cleanroom lines, which continues to this day.
First Air refers to a flow of filtered air that must not be interrupted prior to contact with exposed product and product-contacting surfaces
The aim is to fulfil the requirements of Annex 1 for the operation of RABS as completely as possible – which is quite a challenging task.
Pharmaceutical manufacturers must decide whether to retrofit an existing cleanroom line for a new product or invest in new filling equipment that runs with isolator (or RABS).
Isolator technology will become the new “normal”, as automatic bio-decontamination processes and the pressure difference from the operator environment provide additional safety. RABS is more likely to come into play for frequent product changes and with experienced operators.
A question of sterility
To establish and maintain sterility as required by Annex 1, pharmaceutical companies must conduct a contamination risk analysis and document it with measures in the form of a Contamination Control Strategy (CCS).
Advanced equipment makes an important contribution here. In the second chapter of Annex 1, automation and robotic systems are highlighted under the heading “Appropriate technologies”.
By using these technologies, gloves and human intervention in barrier systems can be reduced to an absolute minimum or even eliminated.
The fully automated isolator production cell fills between 120 and 500 containers per hour with virtually no product loss
The issue of gloves presents many challenges, which are acknowledged in separate paragraphs. For example, gloves are to be additionally tested in operation during longer campaigns – which is not possible with the glove testing equipment used to date without risking the integrity of the sterile room.
In fact, the new Annex 1 requires high level disinfection as soon as the gloves have been exposed to the RABS environment. Besides the aseptic setup situation, this also concerns the intervention involving door opening during production.
This makes the disinfection process very demanding, as the final steps must be performed with the doors closed. At the same time, the disinfection reagents should not affect packaging materials, components, and unsealed products.
A switch to gloveless systems with robotics that handle these manipulations represents the “grail of solution scenarios”. One example is Syntegon’s new Versynta microBatch for processing very small batches.
The fully automated isolator production cell fills between 120 and 500 containers per hour with virtually no product loss and 100 percent in-process control. Glove interventions are no longer necessary in this solution.
“First Air” as a major challenge
Annex 1 also sets clear requirements for air flow: unidirectional air flow (UDAF) is mandatory for open isolators and RABS in all class A areas and should not be interrupted between the air inlet and the open product.
The new Annex 1 will change sterile filling significantly
The air velocity (0.45 m/s +/- 20%) and its measurement are located “at working position”. This does not refer to the vertical position (“working height”), but the area of the critical, quality-relevant processes on the machine, such as filling, stoppering, and gassing. UDAF has the task of carrying any potential residual particles away from the product. This can also be achieved well at lower air speeds at product height.
However, especially the “First Air” principle, which is addressed for the first time in a European GMP guideline, poses new challenges for manufacturing companies.
First Air refers to a flow of filtered air that must not be interrupted prior to contact with exposed product and product-contacting surfaces. This ensures that the air reaches the product without turbulence or contamination.
Yet this uninterrupted flow is not possible everywhere. A typical exception is the filling needle together with the filling needle holder, which must be positioned exactly above the open, pre-sterilised packaging material in order to achieve loss-free filling.
It is expected that these components are aerodynamically designed to minimise turbulences and that these items can be sterilised separately and installed aseptically.
Considering QRM and CCS from the start
Further important topics covered in the new Annex 1 are Quality Risk Management (QRM) and the aforementioned CCS, which are intended to provide pharmaceutical producers with more options for defining the optimal manufacturing process for their products.
After all, one thing is certain: the new Annex 1 has come to stay.
Overall, the new guideline has a stronger focus on a holistic, risk-based approach. CCS not only addresses the working practices in the immediate production process to prevent microbial, particulate, and endotoxin/pyrogenic contamination in the final product.
It also includes the entire manufacturing chain from raw material to components and packaging materials to the finished drug.
When it comes to QRM, however, machine manufacturers also have their responsibilities. Good design of the machine, equipment, and process is crucial for Annex 1-compliant production.
Suppliers such as Syntegon offer extensive support in this regard: in accordance with QRM principles, potential quality risks can be proactively identified, scientifically evaluated, and controlled.
Qualification and validation measures confirm that both the design and the procedures have been implemented correctly and meet expectations.
Outlook
The new Annex 1 will change sterile filling significantly. Many new, mandatory details require innovative solutions, while advances in automation enable further optimisations.
In addition, the introduction of CCS and QRM in the document also opens up regulatory space for product-specific solutions. In the early phase after the guideline has come into force, the main objective for all players – from pharmaceutical companies to inspectors to equipment suppliers – is to remain in close exchange and to learn from each other.
After all, one thing is certain: the new Annex 1 has come to stay. And despite certain challenges and contradictions, it has a clear intention: to provide patients around the world with the highest quality medicines.
