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A scientist performing tablet compression research on the NP-RD10A in the Natoli Scientific laboratory (Natoli Engineering Company, Inc.).
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Hata CVX triple layer and core tabletting press (Elizabeth Companies).
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Comprima high efficiency tablet press (IMA S.p.A.-IMA Active).
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Tool coatings are accepted industrywide as a solution for sticking (I Holland Ltd).
The tablet remains the most popular dosage form and tabletting equipment has evolved significantly over the last decade to accommodate the ongoing demand for its advancement. Big pharma and their generic opponents increasingly seek to gain the competitive edge, producing tablets that boast improved ‘drug delivery’ capabilities, attained through the application of taste-masking, enhanced solubility and timed/delayed release technologies.
EPM Editor Elizabeth Valero consulted key representatives at tabletting equipment providers on current trends and key factors for achieving the fast and economical production of high-quality tablets.
Participants:
Ryan Keefer, general manager at Elizabeth-Hata International, a division of Elizabeth Companies.
Steve Deakin, business development director at I Holland Ltd.
Stefania Barzanti, marketing manager at IMA S.p.A.-IMA Active.
Charles Kettler, director at Natoli Scientific, a division of Natoli Engineering Company, Inc.
‘Sticking’ and ‘picking’ (where product adheres to the punch faces or within the embossing of the tooling), are cited as the most common and costly issues during tablet production, resulting in substantial losses of product and lengthy periods of downtime, how can their occurrence be minimised or eliminated?
Keefer: Elizabeth’s tablet design staff work with customers to maximise the overall tablet design and eliminate areas in the tablet configuration that could cause sticking and picking. Certain tablet design characteristics can be utilised on the punch face to reduce and eliminate these issues.
Another alternative method is the use of specific tool steel coatings that can be used to reduce sticking and picking on the punches. Depending on the product application and type of tool steel being used to manufacture the punches, there are several good coatings that can be used to help resolve these issues.
Deakin: Good tablet design can often reduce the possibility of both sticking and picking. Whilst picking can normally be eliminated completely by design changes, the root cause of sticking can be attributed to many different factors associated directly with the type of formulation; Van der Waal Forces and capillary action for example. The use of anti-stick tool coatings is now accepted across the industry as these new and innovative coatings or treatments can eliminate sticking.
It has always been difficult to persuade people to try different coatings owing to the additional costs involved, but now there are good case studies available showing the increased production value of such coatings.
Specialised coatings can significantly increase the price of tooling but when successful, the savings clearly outweigh the additional costs as the increase in product yield and manufacturing efficiency is easily quantifiable.
When selecting the correct coating, it is essential to share the full details of the problems being experienced so the correct recommendation can be made.
Barzanti: Reasons for sticking and picking can be related to the product to be compressed, like quality and characteristics of the raw materials — for example, particle size and moisture content — plus inconsistent wetting and drying during granulation, lack of lubricant or inefficient blending.
A careful drying process is essential to achieve a more consistent blend. Lubricants must be properly screened to remove over-sized particles and must be evenly blended into the formulation. When sticking is related to a melting and/or hygroscopic powder, achieving compression at a low temperature and low humidity can help a lot in solving the problem.
Also, the tablet press can be adjusted to minimise these problems, reducing punch penetration and increasing dwell time; while with a gravity press to extend dwell time it is necessary to reduce the speed, with our Comprima tablet press dwell time can be easily extended by playing with the compaction and pre-compression axis.
In some cases, changing the tool surface finish is enough to stop sticking and picking; chrome plating, for instance, produces a smooth and non-adherent face on punches and this can be a solution.
Kettler: Many of the sticking and picking problems that we see are due to required changes in process variables as the product moves from clinical supply production to larger scale product launch manufacturing, often after the formulation has been submitted and accepted by the regulatory agency.
The desire to have a direct compression formulation, driven by the perceived capital and labour cost reduction, often prompts a speed to market mentality that limits the R&D required to design a formulation that runs with minimal problems at both production scales.
Adhering to a well-thought out drug product design process and flowchart can minimise future problems by identifying the potential risks and addressing them through thoughtful studies. Having qualified and experienced drug formulators who can utilise their experience of past successes and failures is key to knowing what studies are required and what the consequences are when data are not generated to address the risks identified during the drug product failure mode and effects analysis (FMEA).
To what extent is quality and consistency of tablets contributable to choice of excipient and granulation specs and flow?
Keefer: These are major factors. Pharmaceutical R&D groups are involved in many different product development processes, trying to determine the best excipient choice for a particular product. Formulation characteristics, tablet specifications and granulation flow are all important factors in order to achieve consistent quality during tablet production.
Deakin: With regard to sticking, spatial heterogeneity of the ingredients within the tablet is critical. This is because of the possibility of one ingredient causing sticking; so if this ingredient is concentrated in one area of the compressed tablet, then the Van der Waal Forces in bulk behavior could initiate sticking.
To ensure improved tablet quality and consistency, and to avoid the possibility of sticking and picking, one should check the moisture content of the granule and increase lubrication in the granule if necessary. Also, check humidity within the compression room.
Granule characteristics will always play a major part in the behaviour of the product during compression. Quality product, formulation and process controls will always assist in the compression of a successful tablet.
Barzanti: To obtain a tablet, the powder to be compressed must possess very precise physical and mechanical properties. A good flowability is required for consistent filling of the product in the die, while at the same time the granulate must feature enough compressible and cohesivene properties to form a tablet. As a general note, a high content of fines should be avoided as it is one of the major causes of problems during tabletting and this is why a granulation process is normally required.
The choice of excipient and granulation specs are of major importance to obtain a tablet of good quality and consistency and of course these are different from product to product. Performing tests of the complete process — granulation, blending and tabletting — can be of great help in understanding how the processing parameters can be adjusted to achieve the best result. With this aim, IMA makes available to customers a team of process specialists and a process and development laboratory where all the appropriate instrumentation is available to carry out different technological tests.
Speed is critical in today’s tabletting production environment, what have been the most effective speed-increasing developments in recent years and what is the outlook for bettering the production rates currently being achieved?
Keefer: Production speed is definitely a key factor, however making consistent quality tablets to certain specifications with limited machine downtime seems to be even more important. High production speeds without maintaining quality is a recipe for disaster. The tablet presses and automation features continue to improve as far as mechanical capabilities, but sometimes the product granulation can be a major limiting factor due to poor flow characteristics that ultimately affect the machine production speeds.
Deakin: Whilst increased tablet output is a main driver for most tablet manufacturers, increased tablet press speed is not always the answer. Productivity can be increased by the use of multi-tip tooling without the need to increase tablet press speed.
Increased tablet press speeds can have a negative impact on tablet quality because of a reduction in dwell time, which reduces with increased speed. This may cause issues such as air entrapment, leading to capping and scrapped tablets, sticking and tablet weight variation caused by poor flow.
There are available solutions for reduced dwell time, an example being the EU441 extended dwell tooling, although these types of innovation mean considerable outlay as the turret and associated parts of the tablet press have to be changed to accommodate the tooling design.
There is an option to modify the head flat of a standard B or D type punch, which has to be done in a controlled way but can increase dwell time without the need for major modifications to the tablet press. This is a relatively small enlargement of the head flat and it can help reduce the negative effect of increased press speed.
Barzanti: Speed depends on two main factors — accurate feeding of powder into the die and dwell time, i.e. the time during which compression is applied, ejecting the air contained in the powder and locking the particles in place.
In 1994, IMA introduced the COMPRIMA tablet press, which we believe still represents the real innovation in tablet compression at high speed. The powder is fed from an upper loading hopper into the central rotor area and moves towards the dies through the specially shaped radial channels, pushed by the centrifugal force generated by turret rotation. This system ensures accurate and consistent feeding of the dies, even at high production speeds and with difficult-to-handle products, while at the same time minimising the quantity of air incorporated into the powder and to be ejected during the compression process.
It is a unique system owing to the fact that if offers an extended dwell time, made possible by the combination of compression wheels and bearings applied on punch heads, which results in a longer compression time, even at high speeds.
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.
Barzanti: The concept of QbD is strictly related to critical quality attributes (CQAs) of the product and to the critical process parameters (CPPs) that are controlled in order to ensure that the product attributes are within the desired limits. Most tablet presses are now fitted with indirect weight control through compression force, allowing 100% in-line control of the most important CQAs of a tablet, such as the weight, as well as self-adjustment of machine working parameters to keep the process within the proper design space. Tablet hardness and thickness can be statistically controlled with an IPC auxiliary unit. In the future, an increasing number of process parameters will be controlled on-line, with the aim of ensuring the quality of other critical tablet attributes and possibly to achieve a real-time release.
Concerning continuous manufacturing, this is not an issue for the tabletting process as this is already running continuously. Probably one of the most important changes will be an increasing integration with upstream and downstream processes (granulation and coating) as soon as they have been developed to operate in a continuous mode.
Again, a very important presupposition for such an integration is a good control of the process and a quick feedback on the machine parameters, therefore avoiding any disturbance in the upstream parameters to propagate downstream.
Kettler: QbD will be adopted, in one form or another, by all drug providers who recognise the need to present their drug development process in a format that is expected by the regulatory agencies. Continuous manufacturing offers opportunities for companies to better leverage return on their capital assets as well as produce drug products on a reduced timeline.
QbD will play an integral part in continuous manufacturing. The formulation generated by a continuous process must perform on the tablet press without problems so that the tablet manufacturing process is indeed continuous. Powder flow and compression must be designed to meet the needs of all of the unit operations, not just the tablet press.