Film-Coated Tablets Process Map and Validation

The processing and manufacture of tablets is an elaborate yet lengthy process. The research and development lab is tasked with coming up with a definitive stepwise process through which a given molecule will undergo from its active pharmaceutical ingredient to form a tablet that is film-coated and can be taken by a patient. The tablet must be visually appealing, free of impurities and formulated in such a way that it can remain viable for long. The powders have to undergo various processes to be able to form compact tablets that can later be coated. Each of these processes must meet a given prior set standard lest the drug fails in the final set quality control parameter.

Innotab 100mg means that the tablet has 100 micrograms of the given active ingredient. The 100 micrograms are, however, a very minute mass of negligible size that must be combined with other elements in order to make up a tablet. The additional materials used in tablet making are called the vehicle. The vehicle must be inert to the active ingredient as well as the film coating material that will be used on the tablet. The mixing of the various components follows a set procedure; this is to ensure that all the components of the mass powder, that will later be divided and made into tablets is uniform in the entire tablet. Through the process, multiple tests are done on the tablet materials and the tablet itself to confirm that the process is within the acceptable parameters.

The process through which a tablet undergoes is illustrated in the flow chart indicated. After the dedusting of the tablets, they are now ready for film coating, which is another process by itself. These functions are done within a large scale unit of processing and a single mishap results in thousands of erroneously made tablets. In order to minimize the occurrence of scenarios where millions of tablets fail to meet the set standards, in-process quality control is done. This is made possible by various process analytical technologies that are devices placed within the manufacturing line that are able to pick on any slight adjustments of the critical parameters and inform the operators of the possibility of a production error.

Figure 1 indicating the process map for the wet granulated film-coated tableting process.

To ensure a flawless process, various technologies are used; they are the process analytical technologies. The technologies assess critical process parameters that are known to directly affect critical quality attributes. They ensure any deviations from the desired standard are easily detectable and rectified to avoid mass production of defective tablets. These technologies are incorporated in the processing line and do not require samples for them to detect an error. They ensure continuous monitoring that is concurrent with the manufacturing process only alerting the operators when there is an error. The technologies are connected to computer monitors away from the actual machine making it possible to monitor the process remotely.

A critical parameter such as weight is an indicator of a critical quality attribute, for example, the content of active pharmaceutical ingredient. A PAT that monitors the parameter of weight ensures that there will be no rejects based on the quality attribute of content of active pharmaceutical ingredient. The technologies used for this in-process or on-process controls must be able to generate results in a rapid manner, unlike traditional laboratory techniques.

In the granulation stage, the particle size and distribution (PSD) are the necessary critical quality attributes that are measured. The PSD is informed by the moisture content as a key critical parameter. Therefore, a technology that effectively measures the moisture content can be used to determine the particle sizes. Notably, technologies that measure particle size help define how the distribution will occur. Use of focused beam reflectance and near-infrared spectroscopy on line helps monitor these parameters. Near-Infrared Meters measure reflectance and absorption of light waves to determine moisture levels.

High amounts of moisture is known to result in high absorbencies, therefore the higher the moisture, the higher the absorbance. The meter produces a near-infrared wavelength from a stabilized source, which is focused on the material to be measured. The materials absorb some of the energy while reflecting a portion of it. The reflected energy is then filtered on two distinct wavelengths. One of the two wavelengths is calibrated for moisture, while the other is used as the test wavelength. In the course of using this methodology, an algorithm is created that ensures the energy is converted to a moisture value that can be read from a computer screen. The process is fast making the monitoring process easy to implement.

The use of visual light, which can detect differences in concentration of active ingredient within a tablet is used to check for uniformity of content ensuring there is no production of high potency tablets that can pose a danger to patients. This works by flashing the tablet with light and collecting the transmitted radiation using fiber optic cables. The data can then be printed into high definition images from the charged couple devices. The photons collected vary with the location of the excessive concentration of the active ingredient, the piling together of the active ingredients can be on either side of the tablet. To ensure effective monitoring, the light sources are placed as three points at a 120-degree spacing on the sides of the production line ensuring the data is collected from all sides of the tablet. The images are differentiated between those with normal concentration and those that have the active components clustered in one part of the tablet.

Weighing involves determining the mass of the various components that will go into the whole tableting process. The weights are informed by the number of tablets expected to be manufactured. The weighed masses are then broken down into uniform sizes. The sizing is done using various forms of grinders. The ground powder is then taken through sieves that ensure only the required sizes are used. The unification in the size of the powder particles ensures that there is miscibility of the various different components. Extremely small particles tend to flow in between the big particles making it difficult to generate a uniform mixture of the two. To get over this hurdle, the powder is ground into equal sizes.

The subsequent step is blending. This is the mixing together of the powder mass with the binder. The binder is prepared by mixing a suitable liquid together with the various tablet components. This results in a damp mass that can be pushed through a robust sieve to produce smaller pieces of the damp mass. The taking of the damp mass through the solid mesh is called wet massing.6-12 mesh screens are used for this process in order to generate pellets or granules. The conversion of the powder into granules offers multiple advantages to the manufacturing process, it makes it possible for the mixing to be uniform and the powder to flow with ease through the machines involved in manufacturing. Granulation also improves the tablet appearance, reduces dust formation and eases the tablet compression process.

The wet granules are then oven-dried to a desirable weight. The drying level decision is informed by the active ingredient within the drug and the desired level of moisture that ensures proper tablet formulation. Drying can be done using tray driers or fluidized bed dryers. The dry granules are then passed through another sieve screen. This screen is of a smaller size than the initial screen. Screen sizes of 14- and 20- are used in this dry screening procedure. The next step is usually the lubrication of the granules. The granules are shaken through a 250 mm mesh; this ensures that all the small granules fall through while the coarser ones are retained. The lubricant is added to the finer granules first, mixed then the coarse particles are later incorporated. The amount of lubricant used varies depending on the machines being used in tableting as well as the formulation scientist involved.

Moisture content is controlled through the use of the thermogravimetric technique. This is done by taking a sample of the powder and placing it in a dryer. The dryer heats up and expels all the water content within the powder granules. The weight of the granules prior to drying and after is contrasted and the difference is the moisture content of the powder. The content should be such that it conforms to the required percentages for that specific powder.

To determine the effectiveness of the granulation process, sieving is used. The dried samples are placed in an air jet sieve or a shaking sieve, and the components separated depending on their sizes. Effective granulation should reduce the size ranges of the particles ensuring the whole powder mix bears a near equal size. The presence of a tiny powder size range indicates a failed granulation process. Granulation is also meant to increase the powder flow, which can be measured and used to demonstrate the effectiveness of the granulation process. Powder flow is measured using the angle of repose. The powder is poured from a container and is expected to form a heap as a result of the interplay of gravity and the inter-particle cohesion forces. The angle of repose is the angle between the flat bottom surface and the side of the heap. The greater the angle, the poorer the flow properties of the powder. Granulation should be able to increase the followability of powder significantly.

Disintegrants are a critical component of a tablet. These are the compounds within a tablet that make it possible for the tablet to break up once inside the body and release the necessary active ingredients. In wet granulation, they can be incorporated as either intragranular or extragranular. Intragranular means the disintegrant is within the granules and this is done by adding the disintegrant at stage one of the process. When done extra granularly, the disintegrant is in between the various granules, the integration is done during the addition of the lubricant. The choice between either of the two methods of incorporation is informed by the speed with which the tablet is expected to release its components into the body system.

To determine the effectiveness of the incorporation of the disintegrant, a tablet’s disintegration time is determined. This is done using 6 random tablets that are placed in disintegration tubes and vertically raised and lowered 50-60mm, 28-32 times a minute in a water bath set at 37 degrees Celsius to mimic the human body. The integration of the disintegrant was successful if all the tablets disintegrate within the specified time, and in case any do not, the process fails. Different tablets should disintegrate based on the intended design as to whether they were dispersible, effervescent, enteric-coated or uncoated tablets.

The next step is the compression of the powder granules into the tablets. This is done using a multi station tablet press that is able to produce several hundred tablets in a single second. The tablet press is fitted with multiple dyes and punches. The dye is a hollow space that holds the required amount of powder within it, the punch then hits on the powder causing compression that results in the powder sticking together into a solid dosage form that is referred to as a tablet. The compression should be done in such a way that the pressure applied ensures the tablet does not break too fast neither does it make it impossible for the tablet to break.

To determine how well the compression is done, resistance to the crushing test is carried out on the tablets. This determines the minimum diametric force that when applied crushes and breaks the tablet. 10 tablets are picked as sample, and each is individually placed in a reproducible manner in the jaws of a crushing instrument. The force causing the crushing of each is determined, and the tablet’s tensile strength and mean standard deviation calculated.

The uniformity in the weight and size of the tablet is a critical component in the manufacturing process. Excessive weight of the tablet means the tablet has more than the necessary active ingredient for the given tablet, whereas a lower weight means a below necessary amount of active ingredient. To thus have quality tablets, the compression stage is keenly monitored. Whenever there is a need for inscriptions on the tablet, it is achieved at this stage, the dyes and punches are fitted with the necessary inscriptions such as the name of the tablet and the strength of the tablet.

To ensure uniformity of weight, a test is carried out. The test is referred to as the uniformity of weight test. This involves taking the already finished tablets as the representative sample size. Twenty tablets are usually picked, and all of them weighed. The average weight of all the tablets is then determined. No individual tablets are allowed to deviate from the central mean with over a specific limit. The standard, therefore, is the weight deviation from the central average weight of the tablets.

Another method that validates the compression process, as well as all the preceding stages, is the determination of the component of the active pharmaceutical ingredient. The finished tablets before coating are used to test for this. The tablets are subjected to various qualitative parameter checks such as high-performance liquid Chromatography; this determines the content of the active ingredient in each of them. No tablet is allowed to have over 110% or less than 90% of the targeted active pharmaceutical ingredient.

Film coating involves the addition of a covering on the tablets. The cover helps in masking any undesirable taste or color of the tablet. Coating is also used to control tablet release, determining whether the tablet breaks down in the upper gastric region or the lower enteric region. In order to test the effectiveness of the cover, the tablet must be tested in conditions that mimic its environment of use. If it is an enteric coating that is supposed to break and open up in the small intestines, when tested in mild hydrochloric acid the cover remains intact; however, when tested in alkaline solution, it breaks open in less than 5 minutes. The sample here is the already covered tablets, and the measured parameter is the length of time it takes a given tablet to break open.

The entire process of tableting is a delicate one through which standards must be maintained. An array of tests in the course of and after completion of production is used to ensure quality. The test results demonstrate the effectiveness and robustness of the process. Errors and shortcomings indicated by the results are used in adjusting bits and units within the process design.

Figure 2: Table showing the various tests carried out and samples used.