Possibly the most common reason that companies fail at generating a Quality by Design (QbD)-based NDA or ANDA is that the wrong measurements are taken at the wrong place at the wrong time. All too often, a given pharma producer’s “QbD team” depends on classic techniques to build a Design Space. That means those folks may try to determine blend uniformity by stopping the blender and using a sample thief to gather samples (despite the fact that even the U.S. Food and Drug Administration believes that this is the worst way to sample bulk powders), or checking content uniformity by assaying 20 tablets with a HPLC, and so forth. However, if one wants to design good tablet-based drug-delivery systems, manufacturers need to gain a better understanding of what happens in the making of the beasties, not after-the-fact assays. “Quality by Testing” is not QbD.
Because the process of making a tablet is, for the most part, a physical exercise and not a chemical one (most of the chemistry takes place in the synthesis of the API); after-the-fact tests like HPLC, hardness, friability and dissolution tell Pharma processors literally nothing about how the powder blends, flows, granulates, compresses and is coated. For these data, one requires in-process monitors that provide real insight into the “living process” that is solid dosage form manufacture. This is where PAT comes into the picture; before a product goes into production, PAT gives us knowledge and a tool to control the process/product.
Let us assume that you or your colleagues have taken the time to actually characterize the raw materials, not merely perform USP tests on them. That is, measured the particle size distribution, the polymorphic profile, moisture situation (surface or structural), levels of crystallinity, and any other physical characteristic that may affect mixing and other steps. Ironically, the industry performs porosity and these other tests for the API, which is usually the smallest ingredient in the mix. The excipients are almost regarded as “passive” and not worth characterizing.
MEANWHILE, 30 YEARS LATER
Looking at mixing the ingredients (blend uniformity is a legal requirement and generic houses must, by law, test every batch for uniformity), we have slowly accepted near-infrared (NIR) as a reasonable test of uniformity (it only took 30 years, after all). The work that Pfizer did (over a decade ago) with Zeiss gave us the first wireless, portable NIR instrument. Several other models are also available and also have been accepted (by the FDA) in NDAs and ANDAs. The development of blend uniformity by wireless NIR was performed on products with 5%-50% API content. These levels are also quite within the wheelhouse of Raman instruments and have been the standard range of APIs for decades. There are a number of fine hand-held units on the market, easily adapted for blend uniformity work, although most published accounts are for NIR applications.
LIF FOR LOW LEVEL
However, with more potent drugs being developed and tested, the API level in the mix is often below 1%, making NIR or Raman detection (in a moving bed) problematic. A better technology for low-level API concentrations is Light-Induced Fluorescence (LIF). Until recently, LIF units had only a single wavelength operational range and induced most organic molecules fluoresce (to varying degrees). There were some specificity questions that slowed its acceptance.
With newer units (see Figure 1), tunable, multiple wavelengths and wireless operation are now available. This newer type of instrument allows the formulator/operator to tune the incident light to the excitation wavelength of a low-level API, a lubricant (often in the 0.1 to 1.0% range), or any other organic ingredient in the mix. Since not all ingredients mix at the same speed (varying densities, sizes, shapes), this specificity allows any or all components to be monitored for completeness of blend.
Another way of measuring powder characteristics (after mixing) is with an automated Powder Rheometer. Pharma has been testing the viscosity of liquids for decades with similar devices, but now the technology exists where the industry can test the interactions between particles in a powder mixture. The unit combines shear, bulk, dynamic and axial powder testing methodologies for comprehensive powder characterization. This information gives us insight into parameters such as flowability, compressibility, and may even be correlated to dissolution characteristics. This can be a boon for developing the amount of lubricant (as well as type) in a manner that is no longer “hunt and peck,” but based on actual flow characteristics.
The tablet cores themselves may need to be tested prior to coating for a number of parameters: hardness, friability and tensile strength, for example. One interesting device, made to non-destructively measure parameters such as Tensile Strength (see Figure 2) of a (finished) tablet is to use ultrasonic waves. The speed with which the sound travels through the tablet is measured and correlated with standard (destructive) testing technologies. The calibration curve generated is then used to analyze process samples rapidly. The obvious advantage is the ability to measure many more doses, non-destructively. Figure 3 shows calibration curves for tablets made from DiCalcium Phosphate and Microcrystalline Cellulose. These data can be used to quickly predict physical parameters and allows formulators to understand what component ratio changes or compression changes are doing to the finished dosage form.