Charles N Kettler presents some considerations for oral solid dosage
The evolution of a new molecule through the discovery and drug development stages requires attention to all details of the many processes required to deliver a medicine that is safe and effective. Quality by design (QbD) is a term that has been embraced as an overarching methodology to ensure that the remedy supplied to the patient is the result of a logical process based on sound science. Results from the clinic define the product profile that provides the safety and efficacy of the medicine for the patient. The critical quality attributes of the formulation must be understood and risks to any degradation of these attributes must have been identified and mitigated. For a solid oral dosage form due diligence has resulted in a design space for the formulation that will produce a tablet that meets patient needs. However, the patient is rarely a part of the solid oral dosage development process. The challenge may be to not only deliver efficacy, but also a tablet that meets requirements that are often not correctly identified to ensure patient tolerance, satisfaction and compliance to prescription.
Patient expectations
The patient has an expectation that the medicine in their hand will deliver the proper dose of the active ingredient in the defined period of time. The patient also has the expectation that the tablet presentation will have an acceptable appearance, will be geometrically designed to enable easy consumption and will meet their needs with respect to handling and storage of the tablets under varied conditions. In addition, the patient population expects that once the medication is offered to the marketplace the supply will be such that shortages will not exist. Tablet design and related compression tools must be selected to ensure these patient expectations are met or exceeded.
Oral dosage forms that contain a large dose of active pharmaceutical ingredient (API) are often difficult to formulate into a powder that can be compressed into a tablet that is easy to swallow simply due to the size of the resulting tablet. Perhaps the tablet will require a coating due to the unpalatable taste of the uncoated tablet. In these cases the size, shape and appearance of a tablet can be paramount to the acceptance of the patients and their probability of maintaining compliance with the required dose regime. A tablet must be designed to meet patient acceptance as well as meet the required tablet breaking force specification that impacts tablet friability and for many presentations determines the dissolution profile and disintegration of the tablet. Many tablets require bisect scores as well as identifying letters or numbers to be embossed on the surface of the tablets. The engraving cuts must be designed keeping in mind the need for tablet coating as well as the potential for sticking and picking problems, which can impact the tablet compression process.
Sticking and picking can also become a problem when the compression process is scaled up to meet full production for patient population supply. Modern high-speed rotary tablet presses can produce tablets in large numbers, but high-speed operation means shorter dwell times and the potential for problems with powder compaction. The dwell time, which is defined as the period of time that a formulation is under maximum compression, is often the key to proper compaction of a powder. Often the marketplace demand for a product requires the production department to run their tablet presses at higher and higher output. If a formulation has not been designed to compensate for shorter dwell time by adding compression force to meet tablet breaking force and friability targets, then problems arise and production expectations cannot be met. In addition to tablet physical properties, there are often sticking and picking issues. These result because the compaction of the powder is insufficient and this has resulted in a situation whereby some of the powder from the tablet is compelled to remain in the punch cup or in the letters of the embossing instead of staying with the tablet. This results in tablet defects and decreased production yields. Unfortunately, this problem may be identified after the product has been submitted to the regulatory agencies and changes to the formulation are challenging.
Part of the QbD process requires the definition of product design space. When a post submission problem is identified, it can sometimes be traced to insufficient development data that led to incorrect design space. To avoid these problems, it is in the best interest of the R&D staff to include their compression-tooling provider early on in the development process to alleviate future problems. Tablet design considerations such as embossing prepick and taper, engraving cut angles and radii and considerations for the cup depth and tool land need to be discussed to identify and mitigate potential risks in the initial and final designs. If the formulation is likely to provide sticking and picking problems, then the investment in proper identification of tool steel and coating is a worthy venture given the cost of remediating any sticking problems at a later date. Running a small performance batch using the production equipment at full rate will go a long way toward limiting the angst of having to solve a sticking problem post submission when demand for the product is high.
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Charles N Kettler is director of Natoli Scientific.
