Kettler: Multi-tip tooling has presented an opportunity to quickly increase tablet production. The cost difference is not significant relative to the increase in production as well as the value of the drug product delivered. If a formulation performs well with single station tooling, then the probability of encountering problems when shifting to multi-tip tooling is low. It is low as long as the tablet press operators realise that there will be a measurable increase in the need to be diligent in press setup as well as the need to run trial lots of material to ensure tablet weight uniformity and hardness meet the specifications for tablet disintegration and content uniformity.
As with any formulation design, the potential for sticking and picking is reduced during the development process. For a presentation that will be manufactured using multi-tip tooling, consideration for that reality should be addressed during drug product development.
Also, multi-layer is significantly slower and has a far greater scrap rate than single-layer tabletting, do you foresee the speeds and scrap rates for multi-layer improving in the near future?
Keefer: Yes, Elizabeth has developed a very good mechanical design on the Hata tabletting press for multi-layer production. The Hata press has single-, bi- and tri-layer production capabilities.
More recently, tablet press speeds have been able to increase along with tablet quality because of better tablet rejection methods and enhanced tablet layer sampling. Scrap rates should also continue to decrease owing to these mechanical improvements.
Barzanti: Definitively, speed and scrap rates are well-known problems when dealing with layered tablets; first layer compression, sampling, final compression and both hardness of layers and their separation are all issues. Some technical solutions trying to improve these are available, although so far there is no real solution. This is why, as a global supplier, we see an increasing trend of capsule filling machines for dosing product combinations, as this process can be accurately controlled and performed without affecting machine speed.
However, fixed dose combination drugs are becoming increasingly popular as part of the lifecycle management strategies to extend intellectual property and minimise generic exposure of mature pharmaceutical products. For sure, technical solutions have to be developed in the tabletting process to really exploit the potential of this market trend.
Interest in multi-layer tabletting has increased considerably in recent years — mainly because of its ability to accommodate multiple and often incompatible products — do you envisage this continuing and are there any recent or pipeline developments worthy of mention?
Keefer: Yes, we do think that this trend will continue for multi-layer products. Multi-layer tabletting is a unique way to extend the life of a product’s patent or combine two different drugs for an extended release or slow release product. Many companies are involved in multi-layer and some newer core-tabletting developments for tablet-within-a-tablet technology. These are all unique methods for specific product applications that should continue in the future.
Barzanti: If we think of fixed dose combination drugs as a way to treat two closely related diseases or to improve compliance and thus efficacy of prescribed medicines, we believe that this trend will continue. However, multilayer tablets could be a less frequent option if in the future the drugs to be combined are designed for being mixed in a unique powder to be processed in a standard tablet press.
In fact, today most of the combined actives are existing drugs, while in the future a higher number of combinations will be achieved with new formulations specifically designed to be combined from the development stage. In this case, the properties of the different compounds are optimised to be combined, minimising possible interactions so that it is not necessary to keep the different drugs separated in layers.
Quality by Design (QbD) and continuous manufacturing are steadily gaining traction in the pharmaceutical industry, how do you predict these strategies will affect or change tabletting in the future?
Keefer: Continuous manufacturing seems to be a key buzz phrase right now. We believe a stronger focus on reducing machine downtime and performing equipment cleaning processes off-line is paramount, as these will continue to be key to bettering overall tablet production efficiency.
This falls in line with the methodology behind continuous manufacturing. Tablet press machinery providers must continue to focus on reducing machine downtime and improving cleaning methods as these will be important factors in tablet press selection.
Deakin: The ethos of QbD will most certainly have an impact across the tablet manufacturing marketplace and we are beginning to see this initiative take shape already. We expect this to result in more stringent demands on suppliers of tablet tooling and the associated services we offer such as tablet design.
QbD by definition is that quality can be planned and that most quality crises or problems relate to the way it was planned in the first place. This is exactly the philosophy that we have applied day in, day out to our tablet and tooling design process for many years, trying to design out any potential production problems through adopting best practice techniques before the tooling hits the compression room.