Jörg Gierds, Fette Compacting looks at the rising demands on tablet presses for highly potent agents and explains how efficiency can be achieved through seamless containment
Jörg Gierds and Fette Compacting's FE55 rotary press which has an optional containment package
More and more tablets contain potent and highly potent substances (High Potency Active Pharmaceutical Ingredients, HPAPIs) which can be bound to powders and granulates through methods such as hot melt extrusion. After consumption, these formulations release precise doses of the active ingredients – painkillers, hormones or cytostatic drugs – into the body. Medications of this sort offer new hope to many therapies, since their action in the body is both accurately targeted and low in dosage.
A study by the trend researchers at Transparency Market Research predicts a global growth of about 10% annually until 2018 for high potency substances. By comparison, it is predicted that the pharmaceutical market as a whole will only grow by about 6% over this period. On top of this, manufacturers of generic medicines are increasingly entering this market as many patents for medication with high potency substances will expire in the next few years.
Growth creates standards
Pharmaceutical manufacturers will not, however, be able to obtain a share of this growth without adjusting their production processes. The regulating authorities have laid down clear requirements in order to assure working safety, product safety, and environmental protection for processing high potency substances. On 1 March 2015, for example, supplements to the EU-GMP guidelines came into force. These relate primarily to the question of cross-contamination, referring to the unintentional transfer of active ingredients to other products. With active or toxic substances this involves high levels of risk.
Companies often find it hard to assess what is involved in the evaluation of such contamination risks. It is even more difficult to implement the guidelines into a practice that is both effective and efficient. The latest example of this is the "Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients" (ICH Q7), which has been incorporated into the GMP guideline. This resulted in a number of uncertainties, with the result that the authorities arranged for the publication of a comprehensive Q&A, containing the most important answers, in June 2015. One of the topics highlighted is the relevance of technical and process-oriented measures to effective contamination protection.
Requirements of the tableting process
The active and toxic ingredients present in the tableting process necessitate strict requirements if the associated powders and granulates are to be compressed safely and efficiently. This presents a particular challenge to the makers of tablet presses, since it is their job to ensure that pharmaceutical manufacturers are supplied with GMP-conforming technology. They must also demonstrate pharmacological competence, so that directives – such as the European Pharmacopoeia, or "Pharmacopoea Europaea" – can reliably illuminate production planning. One important criterion for tableting technology here is the integration of a containment solution into the full processing sequence. If the focus is only placed on individual machines the likelihood of faults will rise and efficiency will fall.
Fette Compacting has defined binding containment targets which not only satisfy the official guidelines but also the commercial requirements the manufacturer has of the production process. In this context, the features of containment components must be such that the release of dust during the production process cannot occur, and also that the cleaning process cannot result in contact with toxic substances. On top of this, the compression chamber must be waterproof and dustproof and must offer a maximum of safety to the equipment operators. Due to the rising number of active and toxic ingredients, in the future a dustproof machine will be looked on as the minimum standard for pharmaceutical production.
Interaction of containment components
Integrating the containment solutions seamlessly into the production process also presents new challenges to the makers of tableting machines. The fundamental principle is that all the technical interfaces must be conceived and designed in such a way that their connections are sealed without any gaps. The FE55 high-performance rotary press from Fette Compacting, which is available with an optional containment package, illustrates how this can be achieved. In its standard form, this high-performance rotary press can manufacture about 90% of all products. Since 2015, this has now also been true for toxic or potent ingredients, with dust contamination outside the machine measuring between 10 and 100 micrograms per cubic meter.
A number of special components have proven themselves for ensuring tight sealing of the connections. From OEB Level 3 upwards, tablet presses must be totally sealed. For this purpose, Fette Compacting has developed a lockable, encapsulated compression chamber with double-lip seals which prevents the release of even extremely small dust particles. The locking is monitored automatically to ensure maximum safety for the operators.
The window flaps of the FE55 are in turn provided with Rapid Transfer Ports (RTP). This quick-transport connection system provides the basis for fast, repeated transfers. Operators can, for example, safely introduce tableting tools into the tablet press and replace them through an RTP. A hollow-section seal between the RTP and the window flap ensures that containment is maintained.
As far as possible, the tableting process should continue automatically. Ideally, there should be no intermediate manual steps that might risk contamination from the filling of the machine until the tablets are transported away. If, however, manual intervention is unavoidable, gloveports in the window flaps are essential in order not to break the containment. An automatic monitoring system ensures that the operator is protected, and stops the tablet press in the event of any interventions. Thanks to double seals, it is also possible to replace the gloves without contamination. The OEB-3 concept of the FE55 also provides for a split valve for secure product supply, a HEPA H13 filter with a real-time display of the vacuum, and a dustproof tablet outlet integrated into the pillar. There are three more components that can be integrated into the process with dust proofing: an upwards tablet deduster, a metal detector and an IPC unit for in-process monitoring of the weight, hardness, diameter and thickness of the tablets. The parameters for all the components of the FE55 can be adjusted centrally via the HMI terminal. Operators can conveniently monitor the individual steps of the compression cycle and the in-process control through the terminal.
Through an analysis of the production process in respect to possible sources of contamination, followed by optimisation of the system for maximum dust proofing, the FE55 aims to ensure that both the maximum permitted dust contamination of up to 100 micrograms is maintained and that the product quality needed for medications with active substances is achieved.
The future of containment
Pharmaceutical technologists predicted some two decades ago that the importance of containment would grow. Numerous components and methods that have made pharmaceutical production safer and more efficient have been developed since then. This process is still a long way from coming to an end, and trends can even now be detected which will improve containment even further. As one example, the production process will become even more closely assimilated to containment, allowing containment production to be performed in a very small space. This promises advantages for both cleaning and refitting. There will also be an increased emphasis on continuous manufacturing. One effect of this is to link the process steps together, thereby requiring fewer potential containment interfaces.
The FE55 from Fette Compacting already implements some of the central aspects required for dustproof pharmaceutical production. As a high-performance rotary press, the system, together with the optional containment package, unites the aspects of compliance with operations and high-efficiency that are crucial to the pharmaceutical sector.
Fette Compacting also offers reliably compliant solutions for the higher toxicity of OEB Level 4 and Level 5. WiP/Containment tablet presses are available with standard process equipment for OEB 4. For highly toxic substances up to OEB 5, users can take advantage of tablet presses with complete containment and integrated process equipment. Pharmaceutical manufacturers can participate in the growth of the active substances sector by using machines of this sort.