Concerns and Innovations in Tablet Splitting and Scoring

PharmTech spoke with Tim Freeman of Freeman Technology; David Beach, technology advisor and consultant to Accu-Break Pharmaceuticals; and Thierry Menard, lab manager, and Bruno Villa, president, both at Medelpharm, about challenges and innovations in tablet splitting and scoring.

Analytical technologies

PharmTech: How has the development of new analytical technologies influenced the quality criteria and standards for the uniformity of dosage units? Have more accurate systems led to greater focus on tablet scoring?

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Freeman (Freeman Technology): Tablet scoring enables patients to control their drug dosage and could potentially deliver cost savings for healthcare providers. It also makes larger tablets easier to swallow. However, the production of a scored tablet undoubtedly adds complexity to the manufacturing process. This issue was brought into focus by recent FDA guidance on tablet scoring, for both general tableting, and more specifically, the manufacturing of generics.

Whilst a key aspect of tablet splitting has always been on how uniformly the active ingredient is distributed within the finished product, it is equally important to understand how to produce tablets with the required mechanical integrity and properties. Advances in spectroscopic techniques, such as near infrared (NIR) and laser-induced breakdown spectroscopy (LIBS), mean that it is now possible to analyse content uniformity across the surface of a tablet. In addition, advances in powder characterization techniques can assist in the development of truly robust manufacturing processes.

Poor content uniformity is often attributed to the difficulty of achieving a homogeneous blend to begin with, which may be because the active ingredient is present at very low levels or is cohesive and prone to agglomeration. Alternatively, if the API has significant particle size or density difference to the excipients in the blend, it may be liable to segregation post blending. Dynamic powder characterization can help optimize the blending process (1) and also predict the likelihood of segregation. It, therefore, brings real insight into how to address these issues.

Furthermore, dynamic parameters in combination with shear and bulk properties, support a comprehensive understanding of powder behavior, whether during the blending process itself, or when processed through the tablet press. Together these properties help manufacturers to rationalize and control powder performance during discharge from the hopper, whilst flowing through the feed frame, and during filling of the die. In addition, they provide information relating to the compressibility characteristics of the blend, as well as quantifying the ease with which air is entrained and released, both of which impact finished tablet quality. This information can be extremely helpful in ensuring compatibility between the process equipment selected and the properties of the blend, a match that is crucial for ensuring content uniformity in scored tablets.

PharmTech: When manufacturers are developing a tablet designed to be scored or subdivided, what tests are necessary to ensure stability? How does patient compliance factor into these decisions?

Freeman (Freeman Technology): Stability raises issues around the mechanical properties of the tablet, for example, can it be broken into two equally useful doses without crumbling, and is the finished product stable despite the score? Once again, powder characterization can play a useful role here in product and process optimization. For instance, one of the factors that influences tablet hardness and friability is the consistency of the die filling, which in turn is impacted by the characteristics of the powder blend. Even if the die can be filled uniformly at a commercially viable press speed, it is vital that the entrained air is rapidly released during compression and compaction, as retention can lead to capping and lamination. Retention is especially a problem for larger tablets that are more likely to be scored. The ability of the blend to release air can be quantified using parameters such as permeability and through dynamic characterisation of aerated powders. Finally, the response of the powder to compression can be directly measured via compressibility testing. In summary, comprehensive multifaceted powder characterization supports the development of optimized formulations and more exacting processes, both of which are required to produce well-engineered, mechanically stable scored tablets that are easy for patients to use.

PharmTech: FDA is currently working on draft guidance for tablet scoring. If implemented, how could such guidance affect analytical approaches for scored tablets, both in terms of new developments and demands from the industry?

Freeman (Freeman Technology): Increased focus by the FDA on scored tablets intensifies the requirement for manufacturers to adopt a rigorous quality-by-design (QbD) approach to their tablet development processes. Analytical approaches that can lead to a better understanding of critical-to-quality parameters, such as content uniformity and mechanical stability as outlined above are, therefore, likely to become increasingly important. Properties that predict blending performance and how the blend will subsequently perform in the tableting press are especially valuable. For example, returning to the issue of air entrainment and release, processing powders with low permeability at high rates can ultimately lead to trapped air building up in the powder at all stages of the press due to fast powder flow rates and recycle. The net result is an eventual degradation in tablet quality. This is just one of many illustrations of how powder property data can help processors make sound decisions about what equipment to use and what production rates to target for efficient scored tablet manufacture.

Common challenges

PharmTech: What are the common challenges involved in the formulation, manufacturing, and testing of scored tablets?

Medelpharm: It is challenging for drug manufacturers to identify a robust formula that creates correct hardness and satisfies quality requirements for splitting. Being able to screen rapidly is key in order to test many formula, formats and options. The challenge here is to perform tests quickly and efficiently.

Dosage units

PharmTech: How easy is it for manufacturers of traditional tablets to ensure that the dosage units of subdivided tablets fall within the accepted criteria of USP, EP, and other guidance documents?

Beach (Accu-Break): Traditionally, tablet scores have been applied more as an aesthetic/marketing feature than with the expectation of any functional purpose. With the advent of regulatory changes begun first in Europe and now also proposed in the US, functional scoring of tablets has taken on a new meaning and placed additional requirements on manufacturers wishing to market tablets with a score. Achieving the requirements currently set out for functionally scored tablets is no simple matter for tablet manufacturers because tablet design, processes, and expected testing of the finished dosage form have all taken on new complexities. Data now must prove that the score results in a fraction of the whole dosage form that meets the same requirements as the intact or unscored tablet. This requirement has placed additional testing requirements on those manufacturers who wish to have functionally scored tablets. Issues such as segment content uniformity, friability of the tablet segments, in vitro dissolution performance and stability of the fractured tablet segments must all be investigated and documented as part of development.

Medelpharm: The content uniformity is even more critical with a dose becoming smaller and an already higher weight variance due to splitting tablets. This variance adds more pressure in scale-up and formulation, requiring more robust processes.

Medelpharm for example did some experiments for a customer with progressive-shape tooling where we examined the ideal shape (angle of indent), as well as single- or double-side scoring and the benefits of using a "narrow waist" tablet. Producing small batches at production speed, we were able to predict which upper and lower pairs of punches and die selection produced the best tablets for meeting regulatory requirements. At the same time, we tested the efficiency of shaped dies and of different punch tips to find the best compromise between quality acceptance and tooling costs.

Meeting requirements is tricky, however, since quality guidelines take into account human action in breaking tablets. And, as we all know, the regulatory-defined process for breaking a tablet is rarely followed in everyday life.

PharmTech: To ensure tablets can be split evenly with good dosage content uniformity, what factors do tablet manufacturers need to take into account?

Medelpharm: As always, monitoring and knowing key critical parameters are crucial to quality. During research and development of the compression stage, it is important to use final production tools (punches), use similar compression parameters than during production (e.g., forces, compression cycle/speed and pre-compression), and use similar weight regulation systems to control filling and weight homogeneity. Different compression forces or speeds between research and development and production will create different hardness and density inside the tablets, which will impact dissolution and breakage.

Powder flow in the feeding systems, and inside the tablet during compression, is another parameter that should be measured. High-speed production press simulators can monitor these parameters.

Splitting unscored tablets

PharmTech: What are the problems or risks associated with splitting unscored tablets, especially if they are film-coated or modified release tablets?

Beach (Accu-Break): Splitting unscored tablets is fraught with unpredictability, regardless of the splitting method engaged. Unscored tablets are not designed to be subdivided into reliable and consistent partial doses, and often result in splintered parts with significant loss of mass. Splitting unscored film-coated tablets or modified-release tablets will, in most cases, result not only in an inaccurate medicine dosage, but could also have other undesirable effects. In the case of film-coated tablets, particularly if the film coat is functional (e.g., an enteric coat), the tablet contents could be hydrolysed in the stomach, resulting in profound drug degradation. Similarly with modified-release tablets, fracturing the intact tablet could result in a markedly faster release profile from the broken segments and the production of unwanted side effects because of the overly rapid absorption of the tablet contents. In general, unscored, film-coated tablets should be swallowed whole to avoid untoward effects.

Medelpharm: The main risks are:

• API dosage control. The risk of uneven pieces and fragments with varying dosages is very high compared with scored tablets. Risks are measured in quality-assurance processes according to the pharmacopoeias.

• Modification of timed release characteristics. These characteristics can, in some instances, be totally destroyed when a tablet is broken.

To lower the risks and ensure QbD on multilayer tablets designed especially to be split without score marks, you have to create tablets that are real production prototypes and browse the behavior in the whole design space using tableting robots like STYL'ONe.

PharmTech: How different is the tabletting process for scored tablets compared with unscored tablets in terms of the technology and equipments involved, quality control and quality assurance protocols, and stability testing requirements?

Medelpharm: Precision and reliability are even more critical than usual when producing scored tablets. The sensitivity to variance is increased in upscale process, as well as in tablet production. It is important to take note of the following:

• Before compression, it is crucial to ensure that processes are in place to avoid demixing, segregation, and over-lubrication; classical issues during processing.

• During compression, there should be tighter regulation control and rejection rules.

• Uniformity of mass and filling are important parameters. Different weight or uneven filling creates different hardness, which in turn impacts friability and the quality of breaking, as well as uneven filling.

Tooling design is of course crucially important and computer simulation can provide information on stress line inside tablets.

However, only studies of real tablets, opposed to virtual models, on a fully instrumental press like STYLCAM or STYL'One can provide you with data and results rapidly. To further limit your risk, a 'tableting robot' like a STYL'One can browse the design space and help you rapidly select the ideal punch design and production parameters.

Regulatory challenges

PharmTech: With tablet splitting gaining greater attention from FDA and other regulators, what will be the challenges for tablet manufacturers?

Beach (Accu-Break): The challenge for pharmaceutical tablet manufacturers with the advent of the new regulations is to prove that their products meet or exceed the proposed requirements. This challenge can only be met by custom designing formulation and tablet tooling to meet the enhanced testing required of split-tablet segments following tablet breakage. For those manufacturers desirous of labelling a product as 'functionally scored,' the new regulations will require additional diligence during product development, the generation of appropriate data to provide regulators with the confidence to approve the 'functionally scored' tablet, and continued enhanced testing after approval to demonstrate that the 'functionally scored' product continues, in commercial manufacture, to meet the required specifications.

Nearly half of all Americans aged 55 and above are taking at least one prescription drug, and 25% of those above 55 are taking four or more prescription drugs. The elderly demographic as a whole is responsible for approximately 30% of prescriptions filled in the US. The need for dose flexibility, especially within this demographic, is indisputable. We recognized a paradox in the pharmaceutical industry: while dose flexibility is clearly important, most manufacturers were not commercializing dosage forms that enabled easy and accurate dose adjustment. The vast majority (estimated to be greater than 85%) of oral dosage forms were marketed as either unscored tablets or capsules. Many of the remaining scored tablets often bear a cosmetic score that indicates the middle of the tablet, but that score has proven to be poorly functioning.

The European Union recognized the need for functional scoring over a decade ago and implemented the European Pharmacopeia's Monograph 0478. In the US, the need for the efficacious and consistent scoring of tablets has recently come into sharp focus with the USP's publication of Pharmacopeial Standards for the Subdivision Characteristics of Scored Tablets, and the FDA's guideline titled Guidance for Industry, Tablet Scoring: Nomenclature, Labeling, and Data Evaluation.

Our Accu-Break technologies were designed to create dosage forms that could be subdivided easily by hand into exact smaller doses. In developing the various technologies, we focused on adhering to the following parameters for our tablets:

• The tablets must split into exact partial doses, including ¼ doses if desired.

• The partial doses must pass content uniformity.

• The tablets must be easy to break by patients.

• The tablets and partial doses must pass friability, dissolution, and stability tests.

• The intact tablet must be swallowable (i.e., not too large).

• The unit production cost per tablet must be comparable to conventional tablets.

• Controlled-release formulations and film-coating must be an option.

We have developed two distinct multilayer-tablet technologies, known as 'Accu-B' and 'Accu-T,' both of which incorporate a strategic drug-free layer that serves as a break layer within the tablets.

With the Accu-B technology, the dosage form has two layers, one of which is drug-free. The second layer contains drug and is deeply scored. The drug-free layer provides several unique features: first and foremost, given the deep score in the drug layer, the drug-free layer forms a backbone that gives the finished dosage form mechanical strength to withstand packaging and shipping operations. Secondly, the drug-free layer is the fracture plane for the Accu-B tablet. The tablet can be broken through the score, and the fracture occurs in the drug-free layer. Compared with a conventionally scored tablet, the Accu-B bilayer design ensures partial dosing accuracy and eliminates concerns over loss of mass. The scored tablets can also satisfy the testing and data requirements for both the EP's Monograph 0478 and the FDA's new scored tablet guidance.

Our Accu-T technology uses up to five layers in a taller-than-wide tablet, and the incorporation of drug-free layers serve one of two purposes:

A drug-free breaking layer is incorporated into the middle of an Accu-T tablet and is used to separate the drug-containing layers. Since the drug-containing layers are physically located at the 'top' and 'bottom' of this taller-than-wide tablet, breaking the tablet through the middle placebo layer separates the dose into exact halves.

The drug-free layer provides a physical barrier between active ingredients. This barrier allows the formulation of incompatible actives with no worries about co-mixing and resultant physical or chemical stability issues. The technology utilizes machinery that can produce tablets with up to five compressed layers so the use of more than one drug-free layer can facilitate a 'poly pill' with three different API-containing formulations.

Reference

1. Freeman Technology, Blending white paper, http://www.freemantech.co.uk/en/literature-and-downloads/articles-and-white-papers.html#white-papers