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Less manual intervention, more automation: Annex 1, which has been mandatory since August 2022, promotes the pursuit of increased pharmaceutical safety. What impact can new automation solutions have? Will these solutions have a positive effect on the ongoing shortage of skilled workers?
New challenges lead to new solutions – often through a phase of incremental improvements until the benefits clearly outweigh any potential drawbacks. The introduction of isolator technology is one example; initially several hour-long decontamination cycles were opposed to the first reproducible decontamination results.
A new approach to isolator systems has emerged that eliminates the need for glove ports and opens up new possibilities. While manual intervention can have both benefits and drawbacks, those who have the chance to manually retrieve a costly drug batch will likely opt for GMP-compliant glove ports. However, there is no guarantee of consistent intervention and the gloves themselves pose a pharmaceutical risk, which is addressed through established methods.
Glove ports: Less is moreThe idea of an isolator without glove ports is fascinating. GMP-compliant operation via glove ports can be trained, but ultimately people cannot be “programmed”. Even the slightest mistake, such as handling a decontaminated but not steam-sterilized glove over a stopper sorting bowl, could compromise the “first air principle” as outlined in Annex 1 for product contact parts.
This creates a demand for automation innovations that minimize potential pharmaceutical risks while reducing the number of needed personnel to counteract the shortage of skilled workers.
It is certain that no single technology can be used to implement additional pharmaceutical processes automation. Differentiated technical solutions will be necessary for various sections of the system.
Optima Pharma understands the importance of ensuring that high output systems have access to these functions. This has significant advantages, since the vast majority of aseptic liquid drugs for patient care will be produced using such systems. Therefore, it is a priority for Optima Pharma to minimize, not eliminate, the number of glove ports.
Regulatory reference: With new technical functions, Optima Pharma wants to offer users, who know their aseptic processes and the potential contamination risks, to develop an appropriate production strategy or production rationale, as described in Annex 1.
Optima Pharma is using pilot projects to put the first new functions into practical use. The priority in developing new automation solutions is to minimize glove ports on production systems wherever possible – especially for medium and high output filling and closing systems.
Optima Pharma also envisions the benefits of introducing glove port minimization technology in systems for personalized medicine, including systems with a lower output. While keeping individual glove ports for product recovery may be necessary for processing expensive drugs, the benefits of glove ports should be weighed against their drawbacks. If safer and more efficient alternatives exist, glove ports should be avoided.
Optima Pharma achieves the minimization of glove port with new functions and technologies. A glimpse of what’s to come from Optima: For example, Petri dishes are still placed over glove ports to record a potential germ load in the isolator-protected area. This process can be risky and laborious, as machine operators must manually remove the dishes from the isolator through the glove ports for incubation and evaluation at regular time intervals. In contrast, a new system targets the automatic detection of germ occurrence in the isolator in real time. This method analyzes a large volume of air per minute, guiding air through an isokinetic funnel, and detecting and documenting potentially present germs using laser light and biofluorescence particle counting, while counting non-living particles parallel and analogous. This means there is potential in the near future to (almost) automate environmental monitoring of aseptic processes - avoiding glove ports, which are otherwise necessary for the production isolator or upstream for handling Petri dishes.
Optima Pharma has installed this new system at various pharmaceutical companies, parallel to the “traditional” germ collection system using Petri dishes. Data is currently being generated that will allow comparisons and lead to independent findings with regard to the precision and reliability of the measurement results of the new system.
Thinking ahead: artificial intelligenceIn order to reduce glove ports, Optima Pharma uses robots controlled by artificial intelligence. This system is already proven to correct misaligned stoppers in the infeed to the pick-and-place transfer station that would cause an error message. Controlled by cameras, the system recognizes whether and where stoppers are incorrectly positioned. If intervention is required, it is done inline, i.e. in the continuous high-speed process with a robot, equipped with a steam-sterilizable tool complying to high technical and pharmaceutical standards.
The performance or movement speed of the intervening robot must be synchronized with the process speed of medium and high-performance filling and closing systems – which would not be feasible with a “conventional” technical approach. Conventionally controlled robot movements would simply be too slow to intervene with a running process in real time without interrupting or risking errors. First, the robot movements must comply with pharmaceutical GMP requirements. This means that moving parts, in this case the robot arm or head, must not be located or move over the stopper. Here, too, the “First Air Principle” applies according to GMP guidelines, meaning that the HEPA-filtered air must first flow over the object to be processed without any deflection as it will later come into direct contact with the product. Second, the robot must not run the risk of touching any other system components.
How do you reconcile these complex requirements? The solution lies in the artificial intelligence that Optima Pharma incorporates into the process control. Virtual planning using a digital twin that runs ahead of the real process, mapping out the exact processes that the real system will undergo. This provides a look into the future, and the opportunity to simulate various scenarios to identify potential problems before they arise - without the risk of negative consequences. This prevents pharmaceutical integrity from being violated by robot intervention or collisions in the real system. Critical robot movements and processes would be recognized in advance in the digital twin.
The robot technology, which is initially too slow for medium and high outputs, is harmonized with the use of artificial intelligence, interaction with the comparatively faster processes of the filling and closing system - without duplicating robot stations. This additional automation function avoids the need for glove ports in this area. Here again, Optima Pharma is looking at systems in the field that are already equipped with this new technology.
An automatic feeding system for sterilized stoppers or other container components is another option to avoid glove ports. If the stoppers are fed into the system conventionally in bags and docked to the RTP ports, operators have to manually operate the inside of the RTP port, using glove ports to transfer the stoppers into the system. With a new transfer solution, this process can be automated and glove ports completely avoided directly at the system. Optima Pharma has already equipped several machines with this system.
New technologies in useThere are already several options to reduce the number of glove openings in isolator-protected systems – explicitly in systems with medium and high output.
Another possibility are rescue ports. Rescue ports are only installed at locations without regular hands-on work through glove ports. These fallback locations serve as reinsurance, to intervene manually in the event of a fault and to “save” a batch in a GMPcompliant and documented manner through glove ports. As a result, except for situations where manual intervention is necessary, the potential disadvantages and complex decontamination process of glove ports are largely eliminated.
The development of machines designed with a reduced number of glove ports, including systems with low, medium and high outputs, has picked up speed. These systems meet today’s GMP requirements – and reduce operator intervention as much as possible to counteract the shortage of skilled workers. These systems do not rely on any singular new technology – more exciting innovations in system automation are to come!
