Keep it clean: Comprehensive containment with Wash-in-Place facilities is the best protection against cross-contamination, says Jörg Gierds, Fette Compacting
The demands on containment in the pharmaceutical sector continue to grow. Jörg Gierds, Fette Compacting, looks at effective protection against cross contamination in tabletting
Pharmaceutical production increasingly involves the use of potent to highly-potent ingredients. This is accompanied by increased demands on containment. In the future, manufacturers will be required to an even greater extent to safeguard production processes using appropriate containment technologies. Cross-contamination in particular represents a risk for patient safety and product quality. New developments in tabletting reveal the applicable requirements and technologies offering effective protection.
HPAPIs (high potency active pharmaceutical ingredients) remain a growth driver for the pharmaceutical industry. By 2022, the HPAPI market is likely to grow from 11 billion euro (2014) to 24 billion euro, according to a forecast by Grand View Research. This will mainly be attributable to advances in tumour therapy and hormone treatment. Another study – by Transparency Market Research – projects that the global market for HPAPIs will grow by an average of 10% by 2018 (Compound Annual Growth Rate, CAGR). In contrast, the pharmaceutical market is likely to grow by a mere 6%. Furthermore, numerous patents for pharma products containing high-potency ingredients will be expiring in the years to come with the result that manufacturers of generic products will continue to increase their investments in HPAPIs.
Safe guards: A high-containment plant with integrated process equipment offers effective protection against cross-contamination to OEB Level 5
This development will also be accompanied by increased requirements for manufacturing processes. Pharmaceutical manufacturers will be obliged to adjust to more frequent product changes involving highly-potent substances, which will be accompanied by a general risk that potent substance residue in the plant can be transferred to other products. However, the tolerances for such cases of cross-contamination are practically zero in the case of HPAPIs.
Authorities focus on cross-contamination
The regulatory authorities have also set their sights on the issue of cross-contamination which subsequently appears several times in chapters 3 and 5 of the EU GMP Guidelines revised in 2015. These chapters emphasise the responsibility of companies when it comes to undertaking toxicological analyses and introducing comprehensive risk management.
However, toxicological analysis represents a major challenge for many companies. To date, for example, standard practice has involved specifying one-thousandth of the therapeutic dose as the maximum value for tolerable residue. The general rule that a maximum ten PPM (parts per million) of another product could be contained in a medicinal product still applies. In the case of HPAPIs, however, new approaches are required which consider the individual active agents. An alternative approach which would gradually replace the current official acceptance criteria is represented by the PDE value (Permitted Daily Exposure) or the ADE value (Acceptable Daily Exposure), which defines the dose least likely to display adverse effects when someone is continually exposed to it. Users can derive information on how to calculate such limit values from Annex 1 of the EU GMP Guidelines, for example. In many companies however, expertise in terms of this validation method still needs to be developed.
Clean and clear: During automated washing of the process area, all parts coming into contact with the product are cleaned in an encapsulated area
Comprehensive containment in tabletting
In order to satisfy the requirements of contamination protection in production, suitable technological concepts are vital. I believe that comprehensive containment with Wash-in-Place (WiP) facilities is the best protection against cross-contamination. As a machine manufacturer, we work intensively on such systems which can be fully integrated in the process flow, where contamination risks lurk in every pipe and seal. For this reason, all machine components must be designed so as to prevent residue from arising in the first place as well as being fully washable.
In order to minimise the risk of cross-contamination, Fette Compacting has realised special design concepts which start as soon as the plant is set up. For example, we have designed the pipe system to be very transparent in washable tablet presses. As a general rule, pipes are difficult to examine for residue on the inside which is why we use a single-pipe piping system, which directs the water via a single, easy-to-control line through the plant.
Inside the tablet press, product loss can be particularly prevalent where machine components intersect, eg valves, seals and welded connections. In its capacity as a process part, a tablet press is subject to the corresponding pressure. This means that powder can even reach places you would never imagine it to be. Consequently, all components need to be coordinated precisely and their transfer points to be continuous. These requirements can be satisfied using double-flap valves and hollow-profile seals, for example. A WiP centre ensures optimal hygienic results for washable systems by Fette Compacting – product residue is practically eliminated thanks to a combination of diaphragm valves and orbital welded pipes.
Automated washing and easy handling
Where encapsulated plants are involved, individual components must be recorded and washed by a single program. The washing programmes for the Fette Compacting WiP and containment tablet presses, for example, can be configured and programmed depending on the respective product in order to achieve optimal results. For example, the washing system is comprised of six separate circuits through which the product and dust residue is fully bound during the washing cycle. A special rotation and spray jet design ensures that the cleaning agent reaches every inch of the process area. Tight spaces which are particularly difficult to access can be rinsed using a manual spray gun or WiP gun. The rotor, pressing tools and add-on parts can be easily dismantled after washing and, depending on requirements, subject to final cleaning and conservation in a separate cleaning area. This automated washing process and simplified handling of the machine components also enables manufacturers to enjoy significant savings in time.