Pharmaceutical production increasingly involves the use of highly-active ingredients. This is also accompanied by increased demands on containment. Cross-contamination in particular becomes a risk for patient safety and product quality. But what requirements actually apply here and what technologies offer effective protection during tableting?
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 tumor therapy and hormone treatment. But patent expiration will also mean that manufacturers of generic products will increasingly enter the market.
This development will also be accompanied by increased requirements on manufacturing processes. Pharmaceutical manufacturers will be obliged to adjust to more frequent product changes involving highly-active substances, whereby this will be accompanied by a general risk that active substance residue in the plant is transferred to other products. The tolerances for such cross-contamination are however practically zero in the case of HPAPIs.
Evaluating the risks of cross-contamination
The regulatory authorities have also set their sights on the issue of cross-contamination which likewise appears several times in chapters 3 and 5 of the EU GMP Guidelines revised in 2015. These chapters emphasize the responsibility of companies when it comes to undertaking toxicological analyses and comprehensive risk management against cross-contamination.
However, the toxicological analysis is a challenge for many companies. To date, for example, standard practice involved specifying one-thousandth of the therapeutic dose as the maximum value for tolerable residue. The general rule that maximum ten PPM (Parts Per Million) of another product could be contained in a medicinal product also applied. In the case of HPAPIs, however, new approaches are required which consider the individual active agents. An alternative approach is represented by the PDE value (Permitted Daily Exposure, also ADE value, Acceptable Daily Exposure) which defines the dose which most likely does not display any adverse effects when someone is exposed to it all their life. Information for the calculation of such limits, users can derive for example from the Annex 1 of the EU GMP Guidelines. Having said that, the expertise for such limits still needs to be developed in many companies.
Protecting against cross-contamination in tableting
In order to satisfy the requirements on contamination protection in production, suitable technological concepts are vital. "Comprehensive containment with Wash-in-Place facilities is the best protection against cross-contamination", explains Jörg Gierds, Senior Product Manager at Fette Compacting. "As a machine manufacturer, we work intensively on such systems which can be fully integrated in the process flow, whereby 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."
Nowhere for production residue to hide
In order to minimize the risk of cross-contamination, Fette Compacting has realized special design concepts which start as soon as the plant is set up, as Gierds outlines: "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, e.g. valves, seals and welded connections. In its capacity as a process apparatus, a tablet press is under a certain degree of pressure. This means that powder can even reach places you would never imagine it to be. Consequently, all components need to be coordinated even more precisely and their transfer points continuous. These requirements can be satisfied using double-flap valves and hollow-profile seals, for example. A WiP Center ensures optimal hygienic results for washable systems by Fette Compacting, whereby product residue is practically eliminated thanks to a combination of diaphragm valves and orbital welded pipes.
Safe, automatic washing
Where encapsulated plants are involved, individual components must be recorded and washed by a single program. The washing programs for the Fette Compacting WiP and Containment tablet presses can be configured and programmed accordingly depending on the respective product. A special rotation and spray jet design ensures that the cleaning agent reaches every area of the process chamber. Even the dust extraction pipes can be washed, preventing particles from falling back into the machine. In addition, tight spaces which are difficult to access can be rinsed using a manual spray gun.
On the basis of these concepts, users can also press highly-active agents safely and efficiently. Ultimately, cross-contamination is then no longer an acute risk but rather a calculable aspect of prevention.