Two out of every three prescriptions in the United States are administered via solid dose form, and nearly 50% of these solid dose prescriptions are administered in the form of compressed tablets. This makes compressed tablets the single most popular dosage form in the world.
While many factors contribute to the enduring popularity of compressed tablets, simplicity is not one of them. Commercial tablet manufacturing is a complicated, multi-stage process that demands strict adherence to cGMPs (current Good Manufacturing Practices). Even when cGMPs are closely maintained, manufacturing defects and other pitfalls can complicate the process.
Errors can occur at any stage of the commercial tablet manufacturing process.
Most drug substances must be pre-treated in order to properly flow into the tablet press’ die cavity. Excipients are often added to improve the flow of the granules. Even a minute error in dose measurements or the purity of the raw starting materials may compromise the entire batch.
This is why quality control begins long before the tablet press is turned on. Only after the APIs and excipients are tested and found to be of sufficient purity does the process begin in earnest.
Mechanical equipment can slip up at any point, from the initial dispensing and sizing of tablets through powder blending and granulation. If this occurs the dosage of the tablets can be critically altered. Care must be taken to ensure that dried granules are passed through the precise mesh screen, and that screened wet granules are dried at the exact right temperature.
Once the materials reach the tablet press, the potential for error rises even higher. Tablet compression may seem straightforward, but all manner of issues can arise. Even a properly calibrated tablet press can produce defective products that must be discarded.
The defects that occur during tablet compression are often cosmetic, such as variation or errors in the punching, printing, or embossing. Double impressions are common, as are mottled coloring, unseemly stains, and even the presence of foreign materials such as dust, hair, or fibers. Tablets may stick in the die cavity, chipping apart when they are removed.
More serious issues that can compromise the tablet compression process arise from poor mixing or flow. Fluctuations in weight based on the size and distribution of granules can retard proper dose distribution. Variations in hardness can impact the physical strength of some tablets, producing an inconsistent batch. Mechanical errors can lead to improperly layered tablets, or prevent them from being properly laminated or capped.
Standardized pharmacopoeial testing is the cornerstone of quality control in commercial tablet manufacturing.
These procedures must meet the strict guidelines of the FDA, the U.S. Pharmacopeia (USP), the European Pharmacopeia, the Food Chemical Codex, or other peer-reviewed publications. Tests are conducted to confirm the composition of any given tablet, as well as how the active component will be released in vitro.
Content of active ingredient testing is the first trial for any tablet batch. A small sample of tablets are selected at random, the exact number determined by the individual guidelines. This sample is then typically crushed and dispersed in solvent in order to accurately assay the active drug content.
The exact testing procedures for each aliquot will vary depending on the protocols laid out in each individual drug’s monograph, but High-Performance Liquid Chromatography and spectrophotometry are most common. As with certain other testing methods, this trial can only provide an average and not the content of every individual in a batch.
Disintegration testing is performed to confirm that tablets will properly disintegrate when immersed in liquid. This test is performed using in vitro equipment that simulates the human digestive system.
Tablets must completely dissolve in a set period of time with no remaining particles suspended in the solution in order to pass the test. This time period varies depending on the individual drug monograph or classification of tablet. Disintegration time testing alone is not sufficient, however as dissolving in liquid does not guarantee the dispersal of the active ingredient.
Dissolution testing measures how quickly the active ingredient of a tablet enters a solution under various sets of parameters. Various pieces of equipment were developed to gauge and predict the speed and efficacy with which drugs become available once ingested.
The rotating paddle, the rotating basket, and the flow-through cell are among the most common dissolution apparatuses. Meticulous care must be taken during these trials, as anything from the physiochemical properties of the drug to the method of granulation to the temperature of the solution can impact the results and potentially skew the data.
Uniformity testing must also be performed to confirm that the weight and content of a batch is consistent. Weight variation testing is easily accomplished with a random sample weighed against the control.
Content uniformity testing is more complex and depends entirely on the individual drug monograph. A random sample is taken from the batch and tested to confirm that the active ingredient of any given tablet falls within the acceptable range.
Commercial tablet manufacturing also relies on non-pharmacopoeial testing to deliver the best possible product.
These tests may not be required by official guidelines, but they are widely considered best practice. Many of the trials involve the physical qualities of tablets.
Friability testing determines how well tablets withstand the friction of being jostled against one another in a bottle, and breaking force tests measure the hardness of individual tablets. Other non-pharmacopoeial quality control tests may be performed to confirm that batches of tablets have the desired shape, thickness, size, color, taste, and even smell.
Individual labs may develop and require all manner of additional quality control tests before determining the success of an individual batch. After all, responsible manufacturers understand it is not sufficient for a tablet to merely meet the minimums–drugs must be as effective, safe, and consistent as possible.