Under the Quality by Deign (QbD) paradigm, new pharma product must be correctly designed to take into account the disease and its impact on the patient; the patient population; the drug properties; the preferred route of administration (from a clinical and a marketing perspective); and the requirements of the organization manufacturing the product. The preferred dosage form will usually be an oral solid dosage form (OSD), usually a tablet, which are relatively cheap to manufacture and administer, and can be produced with a wide range of release profiles.
Drug substance properties must be taken into account when developing the product formulation and manufacturing process. Selection of a sub-optimal process or formula may result in considerable extra costs and delays, and even failure. The principal manufacturing methods for tablets are summarized in Table 1.
Each process has its own Critical Process Parameters (CPPs), and is affected by the Critical Quality Attributes (CQAs) of the drug substance. The Product Control Strategy (PCS) is based on understand the links between the formula and process, and the CPPs and CQAs, so generating the data to support the PCS is key to meeting the regulatory expectations of QbD.
The development of the formulation and process is usually an iterative one in which the formulation or process is adjusted based on evaluation of intermediates and products. This is summarized in Figure 1.
All products and intermediates must be carefully evaluated to understand the impact of changes to the formulation and process on product quality, and to support the QbD process. The manufacturing scale used during formulation development depends on the amount of drug substance, and the equipment, available.
Material characterisation is key to understanding the impact formulation and process changes. Characterisation methods include the basic, such as loss on drying, tapped and bulk density, and sieve analysis, through to the sophisticated such as X-ray powder diffraction, microcalorimetry and solid state NMR. The technique(s) selected depends on the product properties and the resources available and should be selected on the basis of the drug substance and product CQAs. For example, if the API can be converted from one morphic form to another then it will need to be monitored at key steps including milling, granulation and compression. Likewise stability-related parameters such as water content or drying temperature may need detailed evaluation using an appropriate methodology. These data will need to be submitted to support the product whether the developer is adopting the QbD approach or not.
Small scale drug substance mixing
Mixing is part of every OSD pharmaceutical manufacturing process. Mixing is classified by the degree of intensity used in the process – low (tumbling), medium (convective) and high speed. Free flowing materials can be successfully tumble blended on the 10-20g scale using a Turbula blender or similar, but blending cohesive materials on the small scale is unlikely to be successful. Use of a convective mixer such as the Vrieco or a planetary mixer is likely to be necessary, giving a lower limit on batch size of a few hundred grams.
Small scale assessment of blend uniformity also presents a challenge. Use of high tech methods such as NIR is not practical on the small scale, and any sampling regime developed on the small scale will not necessarily work on the large. So in practice, the simplest manufacturing process is paradoxically difficult to evaluate on a small scale.
Direct compression processes
Direct compression tablets are made by blending the drug with compressible excipients, followed by lubrication and compression. The process is simple, but subject to variations in drug substance properties and limited by the compressibility and proportion of the active ingredient. Most APIs do not compress well, and vary from batch to batch. However the economic advantages of direct compression are considerable so the incentive to find a good formulation is strong. We regularly evaluate formulations using a “one tablet at a time” approach which is only possible using a direct compression system.
Small scale dry granulation
Dry granulation is becoming increasingly popular because it is cheaper and simpler than wet granulation, In dry granulation, an initial powder blend is compressed, the product is milled, blended with lubricant, and compressed a second time. The uniformity of the initial blend is important as it determines the uniformity of the final product.
The first compression step can be done on either a tablet (or slugging) press, or a roller compactor. The scale of operation can be very small. For example using the Gamlen Tablet Press we have recently been making batches from as little as 5g of material, compressing a 15mm slug of 1-2mm thickness. The properties of the slugs gave been found to correlate well with ribbon from the smallest scale of operation for a roller compactor which was 100g upwards.
Slugs or ribbon produced on the small scale can be milled using a hand or oscillating sieve, or on a small scale mill. The aim is to produce a product in the size range 0.1-1mm.
This is the most flexible, and most widely used tablet manufacturing technique in which the drug and excipients are mixed with a binder solution, sieved, dried, lubricated and compressed. This is lengthy but flexible process which can be adapted for use with the vast majority of APIs. A number of systems are available for small scale wet granulation including medium shear systems such as the Mixer Torque Rheometer from Caleva, and the Bohle mini granulator used for high speed mixer granulation down to a 5g scale. Instrumented high speed mixer granulators are available from Procept. Granulation endpoint by torque control is highly desirable; the main limitation of wet granulation in a QbD environment is the difficulty of controlling the process in real time.
Small scale drying is usually in a tray dryer or a small scale fluid bed drier, and milling and blending are as per a dry granulation process. Water content on the dried granule is critically important to ensure that results obtained on the small scale can be repeated on scale up.
Small scale compression under controlled conditions requires instrumentation using an instrumented tablet press, a compaction simulator, or the Gamlen Tablet Press.
The simplest way to compare formulations is assessing their “tabletability” – the relationship between compaction pressure and the tensile fracture stress of the tableted product. This provides a sensitive measure of both formulation and process effects. Figure 2 shows data from a recent study performed comparing paracetamol tablets prepared by direct compression, dry granulation and wet granulation. The superiority of wet granulation is clearly seen, with little difference in product quality between dry granulation and direct compression.
In another study we compared ten different wet granulations of a clinical trial material at 25% drug loading. The tabletability differences, seen in Figure 3, were substantial. Interestingly the worst formulation was very similar in behavior to the un-processed drug; the best material was twice as compressible as the worst. This enabled us to select the best formulation which met the challenging dissolution requirements for the product.
The Gamlen Tablet Press is uniquely suited to studying the ejection behavior of materials prepared on the small scale. The ejection profile (force and displacement) of each tablet is recorded from which both the ejection stress and the work of ejection can be calculated. This is very useful for selecting well lubricated formulations and processes. The range of ejection forces for different direct compression agents is truly huge.
Small scale formulation is an important phase of the development process, and essential for generation of the large volume of data needed to support the new requirements of Quality by Design. It will lead to more robust and reliable process, save time and money, and result in real patient benefits. We recommend more widespread adoption in the industry.
About the author
Michael Gamlen is Managing Director of Gamlen Tableting Ltd, who provide a specialist small scale product development service including free tabletability testing of customer samples. www.gamlen.co.uk.