Experiment: B1 Tablet Manufacturing

B1. Tablet Manufacturing

Contents:

1.       Aim……………………………………………………………………………………………………………………..2

   1.1     In-Process Control (IPC) in form of Quality Control Charts………………………………………2

1.2     Influence of tableting speed on tablet quality……………………………………………………..2

2.       Theoretical background………………………………………………………………………………………2

    2.1    In-Process Control (IPC) in form of Quality Control Charts………………………………………2

    2.2    Influence of tableting speed on tablet quality…………………………………………………………5

3.        Expectations

     3.1   In-Process Control (IPC) in form of Quality Control Charts……………………………………..8

     3.2    Influence of tableting speed on tablet quality………………………………………………………..8

4.         Materials and Methods………………………………………………………………………………………9

     4.1    In-Process Control (IPC) in form of Quality Control Charts……………………………………..9

     4.2     Influence of tableting speed on tablet quality……………………………………………………..10

5.         Results and Discussion

      5.1    In-Process Control (IPC) in form of Quality Control Charts…………………………………..11

               Preliminary experiment……………………………………………………………………………………11

               Production and quality control………………………………………………………………………….13

     5.2     Influence of tableting speed on tablet quality……………………………………………………..16

                Mass variation………………………………………………………………………………………………16

                Resistance to crushing…………………………………………………………………………………..17

                Friability……………………………………………………………………………………………………….18

                 Fore-time diagrams during the tableting process………………………………………………20

6.         Conclusion……………………………………………………………………………………………………..22

     6.1    In-Process Control (IPC) in form of Quality Control Charts……………………………………22

     6.2     Influence of tableting speed on tablet quality……………………………………………………..22

7.          References…………………………………………………………………………………………………….23

8.          Annexes…………………………………………………………………………………………………………23

1.      Aim

• In-Process Control (IPC) in form of Quality Control Charts

The aim of this experiment is to produce tablets on a large scale with a rotary tablet press and monitor the production process using In­-Process Control in the form of Quality Control Charts (x̅ and s charts).

• Influence of tableting speed on tablet quality

The aim of this experiment is to investigate the influence of tableting speed on tablet properties and characterization of tablets with regards to uniformity of mass (Ph.Eur.2.9.5), friability (Ph.Eur.2.9.7) and crushing strength (Ph.Eur.2.9.8).

2.    Theoretical background

• In-Process Control (IPC) in form of Quality Control Charts

Two thirds of all pharmaceutical products comprise of tablets hence making tablets the most frequently used drug dosage form. The major reasons why they are preferred to liquid and semi-solid dosage forms include ease of manufacture and dosing. They also show improved physical and chemical stability properties when compared with other dosage forms ^[1].

An important unit operation during tablet manufacture is compaction. It involves the formation of tablets through application of pressure on tablets or granules. A single axis compression using the upper punch, lower punch and die leads to the formation of tablets.

Different types of machines are used in the production of tablets and they include the eccentric and rotary tablet press. During development, eccentric presses are commonly used while production of tablets on large scale involves the use of a rotary tablet press ^[1]. There are some differences between these two types of presses. In the eccentric press, there are only two punches and only the upper punch moves downward to compress the powder or granules ^[1]. While, in the rotary press, there are large number of punches up to 60 or more and compression of the powders or granules is carried out by both the upper and lower punches.

The punches in a rotary press are attached in circle on the die table and by turning at the same time, they work with same number of pairs of punch. In contrast to the eccentric press, the hopper is fixed and powder moves directly onto the feed frame which transfers the powder into the die uniformly. Upper and lower punches move along the route where cams and rolls determine the amount of powder in the die and load exerted ^[1].

The process of tablet production can be divided into four stages: filling of the die, adjustment of powder volume in the die, main compression process and ejection or removal of the formed tablet from the machine ^[1].  Through the feed frame, the powder is moved into the die. The loaded die adjusts to the area that controls the volume of powder, where excess powder is removed from the die. Afterwards, the compaction stage commences. This includes: pre-compression, main compression and ejection steps ^[1].

Pre-compression: This involves an initial compression of powders to reduce the powder volume and get rid of excess air within the powder particles. During this stage, lower compaction pressure is applied to the powder bed by smaller rolls ^[1].

Main compression: This is the stage in which the tablets are formed. In this step, larger rolls apply high compaction load and the primary volume reduction occurs until all interparticle spaces are filled by repositioning of particles. After that, particles start to deform or to fragment ^[1].

Ejection: This is the removal of the tablet from the die. This stage requires a force to overcome the adhesion of tablets to the die wall and other attraction acting in the die ^[1].

Process parameters that were adjusted on the rotary tablet press used in this experiment include: the fill depth, immersion depth and tableting speed. The fill depth is the space in the die that the powder can flow into on a tablet press ^[2]. It defines the mass of the tablet can be controlled as part of the setting up procedure for the tableting process, by adjusting how high or low the lower punch is placed in the die during the fill step.  Tablet mass can be increased or decreased by adjusting the fill depth. It can be increased by increasing the fill depth and vice versa.

The extent of compression force can be determined by the immersion depth, which is the lower dead part of the upper punch ^[3]. The lower dead point of the upper punch is the immersion depth of the upper punch inside the hole of the die ^[15]. The compression force can be increased or decreased by adjusting the immersion depth. It can be increased by increasing the immersion depth and vice versa. If the mass or fill depth is changed, there will be an increase/decrease in the compression force. An increase in fill depth will require a higher compression force for the tableting process while a decrease will require lower compression force.  A higher compression force is required for the production of tablets with increased tensile strength while tablets produced with a lower compression force tend to have decreased tensile strengths and reduced hardness.

In-Process Controls (IPCs) are performed because it is challenging to achieve constant quality attributes during tablet production as tablets are usually produced in batches of several million ^[4].  IPCs are Quality Control tests or activities performed to monitor the production process and if necessary, adjust the process in order to ensure that the product conforms to its specifications ^[5].

To make a product defect-free, it is essential to minimize the variation in a process.  Hence, quantifying the amount of variation in a process is the first and the critical step towards improvement ^[6]. Generally, two types of variations are encountered in a process. They are special cause or assignable cause variation and the random or irregular type of variations ^[6].

Special Cause variation: These are variations that are relatively large in magnitude and viable to identify. This type of variation occurs infrequently, is unstable and avoidable ^[6].

Common Cause variations: This type of variation is the total of a large number of effects of a difficult interplay of causes that occur frequently or that are unpredictable. These kinds of variations are usually stable, can be corrected with the right adjustment and are unavoidable ^[6].

The best way of analyzing the special cause variation and common cause variation is the Quality Control Chart techniques. A control chart is a graphic that depicts whether sampled products or processes are meeting their intended specifications and if not, the degree by which they vary from those specifications ^[8].

A control chart is meant to be used during the production process and at the site of production. A Quality Control Chart can show if a process has one variable/deviation from the targeted process or if there are more than one deviation or variables from the targeted result. ^[8].

Control charts are used to ^[6]:

(1) track performance over time

(2) evaluate progress after process changes/improvements and

(3) focus attention on detecting and monitoring process variation over time ^[6].

Common forms of the Quality Control charts are the x̅ and s charts. These charts are used to detect special cause variations in an ongoing process. The x̅ chart is used for monitoring the mean while the s chart is used to monitor process variability in form of the standard deviation ^[4]. Control charts have one central mean line, the Upper Control Limits (UCL) and Lower Control Limits (LCL) ^[9]. These control limits are statistical limits set at ±3 standard deviations from the mean. The region above the UCL or below the LCL is known as the out-of-control region ^[7]. When a point falls in the out-of-control region, it is interpreted as evidence that the process is out of control and a proper corrective action is needed ^[7]. In this experiment, when a value is above the UCL or LCL during production of tablets, the filling depth is the process setting that has to be changed to minimize the deviation. When the value is above the UCL, the filling depth has to be decreased to allow less powder into the die. In contrast, when the value is below the LCL, the filling depth is to be increased to allow more powder into the die in order to maintain the target value during the process.

The Six Sigma process is a methodology used to eliminate defects in a production process. Its main goal is to identify and eliminate variations or defects in a production process ^[6]. It helps to measure how many defects that are present in a process and shows how to eliminate them and get as close to zero defects as possible ^[6]. The main goal of any Six Sigma project is improvement by reducing variation and the reduced variability ultimately leads to improved product quality. Six Sigma is described as a data-driven approach to reduce defects in a process as measured by six standard deviations between the mean and the nearest specification limits ^[6].

The define–measure–analyze–improve–control (DMAIC) approach is one of the frequently used method in the Six Sigma process, where ^[6]:

1. Define—The problem or project goals that need to be addressed are defined
2. Measure—The problem and process from which it was produced are measured
3. Analyze—Data and process to identify the root causes of defects and opportunities are analyzed
4. Improve—The process is improved by finding solutions to fix, diminish, and prevent future problems.
5. Control—Implement, control, and sustain the improvements and solutions

• Influence of tableting speed on tablet quality

An important step during tablet production is compaction which includes compression and consolidation. Compression is the decrease in volume of powder and readjustment of the powder particles. While consolidation is formation of bonds within the powder particles ^[10]. The deformation behavior of the Active Pharmaceutical Ingredients (APIs) and excipients as well as

the choice of the right settings on the tableting press determines the success of the compaction process ^[10].

Mechanical properties of the tablet such as tensile strength and friability are determined during the process of compaction ^[11].

The major factor of a tableting process is the compression force which has been shown to influence the disintegration and dissolution times of tablets and also affects tablet hardness and friability ^[11].  The instrumentation of a tablet press is important during tablet production because it provides relevant information about the compression force, hence enables monitoring and control of the tableting process ^[10].

Sensors also known as transducers equipped at certain locations on the machine are used to monitor and control a tablet press. A transducer is an equipment that transforms energy from one form to another (e.g., force to voltage). Applied force, speed of the turret and position of a punch can be measured by these transducers ^[11].

Examples of instrumentation for rotary machines include strain-gauge and piezoelectric crystals ^[10]. Piezoelectric transducers use quartz crystals and when exposed to stress, the crystal increases electrostatic charge that is corresponding to the applied force ^[11].

Presently, the use of strain-gages is the ideal method of instrumenting a tablet press or measuring the compression force. Strain-gages transform pressure or force into electrical voltage and can be in the forms of a thin sheet of metal, cable, or semi-conducting devices ^[11]. The principle used in strain- gages is that when the thin wire is exposed to stress, it increases in length and becomes thinner. These factors; increase in length and becoming thinner contribute to increased electrical resistance. If an electrical current is sent through this wire, it will be affected by the changes in the resistance of the conduit ^[11].

The compaction process is the most important step during production of tablets as it leads to the formation of tablets from powders or granules. Powder particles occupy spaces between them and are rearranged when load of compression is exerted on powder inside the die. Since there is no more space available for rearrangement of powder particles, they start to change their shapes or break into fragments with increase in load of compression ^[4].

Three ways by which powder particles can deform are: elastic deformation, plastic deformation, and brittle fragmentation ^[13]. In elastic deformation, the powder particles go back to their former shape when pressure of compaction is reduced and is therefore a reversible process. While plastic deformation is an irreversible process because the particles do not go back to their original shape and as a result, there is an unchangeable alteration in the shape of particles ^[13]. This process depends on how long the greatest pressure is exerted. Plastic deformations are time-dependent because of the tighter formation of bonds which results from extended application of compression load ^[4]. Brittle materials undergo fragmentation which is breaking into pieces or smaller particles. These smaller particles tend to go through another rearrangement, after which more deformation processes can occur ^[13]. Pharmaceutical APIs and excipients may deform by more than one of the ways mentioned above, and these mechanisms can take place at different stages of the compaction process.

Force-time and force-displacement diagrams are information obtained during compaction process from instrumented tableting machine. Force-time diagrams are used to describe behavior of active ingredients, excipients, and formulations during compression regarding their plastic and elastic deformation ^[10]. The force-time diagram on a rotary tablet press, is divided into three stages: compression, dwell time, and decompression (Figure 1) ^[10].  The time to reach the greatest force is the compression stage while dwell time is the time interval at which maximum displacement takes place. It is the time over which the flat part of the head of the punch comes in contact with the compression roller. In the decompression stage, both punches move away before the formed tablet is ejected ^[10].

The use of compression force against punch displacement diagrams is a common way of evaluating the compaction behavior of materials. Assessment of plastic and elastic behavior can be done using Force-displacement diagrams (Figure 2) ^[10].

Figure 2: Force-displacement diagram showing the plastic and elastic deformation areas ^[10]

Tablets must be able to keep their physical, chemical integrity and the dosing uniformity during the manufacture. They also should stay intact after production until they reach patients. Thus, mechanical strength is a vital feature of tablets and must be maintained for successful scale up process. Generally, crushing force/tablet hardness and friability describe the mechanical strength of tablets.

Crushing force is defined as the force applied across the diameter of the tablet in order to break the tablet ^[12]. The resistance of the tablet to chipping, abrasion or breakage under the condition of storage transformation and handling before usage depends on its hardness. Resistance to crushing of tablets is determined using a crushing force tester.

Friability is the loss of weight of tablet due to removal of fine particles from the surface. Friability test is carried out to access the ability of the tablet to withstand abrasion in packaging, handling and transport.  This a way of determining the ability of a tablet to withstand tumbling. A friability tester is used in determining the friability of tablets. The tablets are weighed before and after a specified number of rotations and the loss in the weight of the tablets is the measure of friability. Generally, the test is run once. If obviously cracked, cleaved or broken tablets are present after tumbling, the sample fails the test. A maximum loss of mass not greater than 1.0% is considered acceptable for most products ^[14].

One basic quality attribute of tablets is their uniformity of mass. During the compression process, dosing of tablets is conducted by volumetric filling of the die cavity. Thus, at a given bulk density the volume of tableting material will directly correspond to the tablet weight. Therefore, a low variation of the individual tablet weights is regarded as an indicator for adequate content uniformity ^[13]. One fundamental reason for poor tablet weight uniformity is inconsistent filling of the die cavity as a result of the tableting material showing insufficient flowability. Sticking of powder material to punch surfaces may also cause high tablet weight variations.  The problem of poor tablet mass uniformity may be solved by improving the flowability of the powder by addition of a sufficient amount of glidant or by optimization of the particle size distribution by means of granulation ^[13].

In industrial-scale tablet manufacture, problems such as capping, lamination or sticking are commonly observed. It is important to note that these problems may cause the rejection of whole batches for quality or safety reasons, and consequently commercial losses ^[13].

During production, handling or testing of tablets, capping or lamination of tablets are problems that happen constantly. Capping involves removal or breakage of the top parts of a tablet (Fig. 3a) whereas lamination refers to the tablet separating or breaking into two or more parts (Figure 3b) ^[13].

Figure 3. Tablet capping (a) and lamination (b) ^[13].

Sticking is another problem that is encountered during manufacture of tablets. It involves the adhesion of powder material to surface of the punch or the die wall ^[13]. Higher force of adhesion between the punch surface and the powder particles result to tablet sticking. To prevent sticking, the addition of anti-adherents/lubricants such as magnesium stearate to the tablet formulation is the most commonly used measure.

Compaction factors such as tableting speed can affect tablet properties such as weight of tablet, hardness and friability. The average weight of tablets decreases with increase in tableting speed. This can be explained by the mechanism of die filling in the rotational tablet machines. Flowing of the mixture into the die is affected by the speed of turret, because there is a less time available for filling of the die, compared to lower speeds ^[4].

A common example of the effect of compression speed is the deterioration in tablet quality, including reduction of tablet strength/hardness. However, not all materials are affected by increasing tableting speed. It is believed to be dependent on consolidation mechanism of materials to be compressed ^[4]. Plastic and elastic materials are mostly affected while the effect on brittle materials is insignificant because of the easy fragmentation of their particles.

As mentioned earlier, when pressure is applied materials consolidate exhibiting elastic, plastic deformation or express fragmentation of particles to smaller ones. Plastic deformation is believed to be time dependent because a long dwell time is essential to form strong bonds between powder particles resulting from prolonged applying of load. This in turn results to a stable solid compact or tablet. Plastic materials show a decrease in tablet strength with increasing tableting speed. This is because an increase in tableting speed results to a decrease in dwell time which is the time that the punch head remains in contact with the compression roller.  In contrast, brittle materials express less sensitivity to tableting speed and this is because of the quick fragmentation of particles, that is making duration of dwell time insignificant. For elastic materials since they are not time dependent and go back to their original shape once the force is removed, there is a plateau and the force during the dwell time is constants.

Tableting speed also influences friability of tablets since there is usually an inverse relationship between crushing force and friability. Increase in tableting speed results to tablets with a lower resistance to crushing force and a higher friability while at lower tableting speed, tablets with higher resistance to crushing force and lower friability are produced.

3.    Expectations

• In-process control (IPC) in form of quality control charts

It is expected that the mean and standard deviation values of the tablets produced fall within the UCL and LCL of the x̅ and s charts respectively so as to ensure that the production process is free of deviations and is stable.

• Influence of tableting speed on tablet quality

It is expected that higher tableting speed will affect properties of the manufactured tablets by increasing their friability, mass uniformity and resistance to crushing.

4.    Materials and methods

• In-Process Control (IPC) in form of Quality Control Charts
  • Materials

Table 1: List of excipients, their functions and quantity used in tablet Experiment 1

• Equipment used

Table 2: List of equipment used in the Experiment 1

• Method

First, fumed silica and magnesium stearate were sieved with a sieve size of 180 µm, then 5 kg of the powder mixture in Table 1 were weighed in a plastic bucket, and the mixture (except for magnesium stearate) was blended for 15 minutes using the L.B Bohle Mixer. 1 kg of this powder mixture was used for the preliminary experiment and 4 kg for the real quality control. Magnesium stearate was added to the mixture shortly before production and the mixture was blended again for 3 minutes. The reason for adding magnesium stearate shortly before production is because longer mixing time with magnesium stearate lead to an over lubrication which can decreases tablet hardness or produce delamination. Hence, it is recommended to mix powders with magnesium stearate during shortest possible time.

Then the Kilian rotary press was set up and the parameters were adjusted in manual mode before starting the process in the automatic mode. Adjustable settings are the tableting speed (set to 21,000 tabs/h in this experiment) of the machine, the fill depth and afterwards the immersion depth. The fill depth defines the mass of the tablet (desired in this experiment: approx. 300 mg per tablet) and the immersion depth defines the compression force (approx. 10 kN for this experiment).

Subsequently, the tablet production started in the automatic mode, and 30 random tablets were collected and weighed. The mean and standard deviation of the tablets were calculated, and the values obtained were used to set up the Quality Control Charts with the determined control limits.  Then, the remaining 4 kg of the powder mixture was used to start the production. It is important to blend the mixture again for 5 min with the L.B. Bohle Mixer. Magnesium stearate was added to the mixture which was blended again for 3 minutes. This was followed by the set-up of the rotary tablet press. The tableting speed was adjusted to 21 000 tablets/ h, the fill depth to get a tablet mass of approximately 300 mg and the immersion depth to reach a compression force of approximately 10 kN.

How long the tableting process time will run is calculated according to the following:

The mass variation of the tablets during the process was monitored using the Quality Control Charts. Therefore, IPC was performed every 5 minutes till the 35th minute, with a sample size of 10 tablets for each time period.

Tablets were weighed individually and the mean as well as standard deviations were calculated. The average mean and standard deviations for each group of tablets were charted on the Quality Control charts which were created through computer aid with excel in order to determine any variation in the production process.

• Influence of tableting speed on tablet quality

4.2.1 Materials

Table 3. List of excipients, their functions and quantity used in tablet Experiment 2

4.2.2 Equipment used

Table 4. List of equipment used in the Experiment 2

4.3 Methods

First, fumed silica and magnesium stearate were sieved with a sieve size of 180 µm, then 2 kg of the powder mixture in Table 3 were weighed in a plastic bucket and this mixture (except for magnesium stearate) was blended for 15 minutes using the L.B Bohle Mixer. Shortly before production, magnesium stearate was added and the mixture was blended again for 3 minutes. During a longer storage of the powder mixtures, there is a potential for the powders to segregate over time therefore another blending process is required.

Then the Kilian rotary tablet press was set up and at first, the mass was adjusted to approximately 300 mg per tablet, while the immersion depth was adjusted in order to set a compression force of approximately 5kN. Afterwards, the production of tablets started and a force time diagram was measured. A slow tableting speed of 22,000 tablets/h was used and the tablets produced were collected and kept for further characterization.  Then the tableting speed was increased to 52,000 tablets/h and the manufactured tablets were set aside for tablet characterization.  The tablets were then characterized with regards to uniformity of mass, friability and resistance to crushing according to the European Pharmacopoeia using the procedures outlined below:

• Uniformity of mass for single-dose preparations (Ph. Eur. 2.9.5):

Twenty tablets were weighed and the average mass calculated. The tablets were then weighed singly, no more than two of individual masses deviate from ±5.0% and none deviates from ±10.0%.

• Resistance to crushing (Ph. Eur. 2.9.8): Each tablet was placed between the jaws of the crushing force tester which crushed the tablet when turned on. After crushing the tablet, the crushing force was then displayed on the apparatus. The measurements were carried out on 10 tablets for each batch and before each measurement; fragments of previous tablets were removed.
• Friability test (Ph. Eur. 2.9.7): A sample of whole tablets corresponding as near as possible to 6.5 g was taken and dedusted prior to testing. The tablets were weighed and placed in the friability tester which was rotated at 25 revolutions per minute (rpm) for 4 minutes. Afterwards, the percentage friability was calculated.

5.    Results and discussion

• In-process control (IPC) in form of quality control charts
  • Preliminary Experiments:

The mass value of in total of 30 tablets was taken for IPC. Therefore, Quality control charts (and x̅ /s-diagram) was created by using the following data:

Table 5. Determined mass by weighing the tablets

The upper and lower control limits for the control charts were calculated according to the equations given below. Therefore, tabulated anti-biasing factors were taken into account for the statistical significance of the limit values.

x̅-chart:

Upper control limit (UCL): Mean + A3 x SD (equation 1)

Lower control limit (LCL): Mean – A3 x SD (equation 2)

s-chart:

Upper control limit (UCL):  B4 x SD (equation 3)

Lower control limit (LCL): B3 x SD (equation 4)

Table 6: Tabulated Anti-Biasing Factors for Sample Size n=10

The calculated values for the upper control limit (UCL) and the lower control limit (LCL) for the mass variation analysis are given in Table 7 and the exemplary calculation based on the calculations given below.

Resulting, for preliminary experiments, the upper and lower control parameters regarding IPC-mass variation experiments were determined.

• Production and quality control

During the tablet production, In-Process control were taken to monitor the process, using the Quality Control Charts. Therefore, IPC is performed at defined time points (every 5 minutes) with a sample size of 10 tablets.

Table 8: Weight of tablets during production

The results Control charts for IPC of the production are given below.

Figure 4: Results of x̅-chart for mass variation control during IPC, mean values, n=10

Figure 5: Results of s-chart for mass variation control during IPC, standard deviation, n=10

The x̅-chart and the s-chart serve to monitor the mass variation during tablet production.  Therefore, it provides constant quality over the entire process.

The x̅-chart showed the mean mass of 10 tablets randomly taken during the production process. In this case, most of the mean values were in the range except for the second one (10 minutes), which can be defined as a special cause variation in a Six-Sigma process At that point, the adjustment took place by reducing the filling depth and decrease the powder into the die, thus reduces the tablet mass, it can be observed that the adjustment was sufficient and the following means of the samples were within the control limits.

In this experiment, when it was detected that values are out of control an adjustment of the process took place by changing the filling depth. However, the mass variation control shows that there is a systematic deviation from the targeted value after 25 minutes of production and this behavior is normally observed at the end of the process when the hopper is running out of the powder which leads to an uneven and improper filling of the dies since the gravitational force becomes lower, this might cause changed in the filling degree, it is also known that when there is a small amount of powder in the hopper the flowability of powder is changed, resulting in decreasing compression force as well as mass variation in the process and it could be that tablets produced at the end of the process do not meet the criteria15. Therefore, the process can be successful by adjusting the filling depth and by lifting the position of lower punch during production.

In the s-chart, the standard deviation confirms the record of the variation in Six-Sigma process, the spread of data with a given measurement such as production batch in which it can be observed that all the values are within the quality control limits (Figure 5), this chart illustrates that the variability of the process is within the limits for the product. The standard deviation represents the degree of variation and data extension in a specific range. During the tableting process, the determined values were within the range in s-chart, and according to Six-Sigma, statistical control of the process means that it will continue to produce a consistent product so long as it stays in control.

In the x̅/s chart, s-chart always considered first. Since s-chart represents the average standard deviation of control limits therefore if s-chart values are in out of control limits that indicate the values of x̅-chart are not correct. If only one point of the s-chart is beyond the limits but not of the x̅-chart, it means there is no accurate estimation of standard deviation therefore the process should be stopped. Accordingly, special cause variation should be determined plus identify and control of the variation needed. Also, the subgroups from the calculations should be withdrawn. When the s-chart values are in control limits thereby the points can be assigned to analyze the x̅-chart ₁₇.

Additional to the IPC, all batches must be tested according to their applicable test in the Pharmacopeia, in case of tablets for mass variation, friability, resistance to crushing, etc, since the IPCs serve just a way of control during the production.

• Influence of tableting speed on tablet quality

In order to determine the influence of the tableting speed on the tablet quality, two speeds were evaluated, 22,000 tabs/h and 52,000 tabs/h, random samples were taken from each process to characterized them.

Table 9 shows the mass variation and resistance to crushing at different tableting speeds.

• Mass variation

According to Uniformity of mass of single-dose preparations (Ph. Eur. 2.9.5), since the average mass of the tablets in this experiment is higher than 250mg, no more than 2 individual tablets should deviate from ±5% of the average mass and none deviates by more than twice that percentage.

There are no values out of the deviation percentage of the average mass, nevertheless, a higher variability in the mass tablet can be observed in the boxplot at higher tableting speed; which was expected because when using a rotary tablet machine the filling of the powder into the die is affected by the turret speed, which means that a higher tableting speeds there is less time available for the powder to fill the die homogenously, compared to lower speeds and is also known that as the peripheral speed increases the centrifugal forces acting on the material in the dies result in uneven packing or loss of material from the die cavity; the first phenomena is represented by greater variability in the mass (higher SD with 52,000tabs/h), while the second can be seen that the average mass is below the target value (300mg) when the tableting speed is 52,000tabs/h in comparison with the lower speed at 22,000tabs/h (Table 9).

A mean closer to the target value and a narrower box were obtained for the lower speed (Figure 6), nevertheless, some outliners were found (represented by dots), which are unusually large or small observation that are at least 1.5 times the interquartile range (Q3 – Q1) from the edge of the box[1] and should be further investigated, therefore these values are not consider as the minimum and the maximum in the boxplot.

When considering a tableting process of a verum product (containing API), using higher tableting speeds not only leads into a high mass variation, but also a high uniformity of dosage since segregation of the powder can take place due to the vibrations in the machine.

It is also important to consider that the faster tableting speed was performed at last on the experiment when the hopper is not well filled, the gravitational forces are reduced and this can lead into a reduction of the filling degree results into a higher mass variation and a tendency to the lower limits.

Figure 6: Bloxplot of weight at different tableting speeds

• Resistance to crushing

The resistance to crushing of the tablets was measured using Erweka® crushing force tester and results are shown in Table 9. Resistance to crushing of the tablets is directly influenced by the tableting speed due to the fact that successful formation of a tablet is time-dependent specially for plastic materials to create an enough hard bonding across particles.

The powder compressed in this experiment was a mixture of mainly Lactose and Microcrystalline cellulose, which are excipients showing a brittle fracture deformation and mostly plastic deformation respectively, in combination can provide a mixture with good tabletability properties. It is known that some deformation processes are time dependent (plastic), so once the elastic limit of the material is exceeded, the plastic deformation occurs and the particles remain irreversibly deformed upon removal of the applied pressure ^[15], which leads into a “stable” tablet. This means that the rate at which load is applied and removed may be a critical factor, so an important role plays the dwell time, which is define as the time the punch head remains in contact with the compression roller, thus is influenced by the tooling (punch flat head size) and the speed of machine, at this time interval, the maximum displacement occurs; the lower the tableting speed, the longer the dwell time and the higher the tableting speed, the shorter the dwell time, therefore this should be long enough to achieve the plastic deformation to avoid structural failure of tableting.

A higher mean for the resistance to crushing was observed at the lower tableting speed (77N), this was expected because the dwell time is long enough to form a “stable” tablet, nevertheless, a higher variability was obtained (SD. 4N) and a broader box is observed (Figure 7), which was not expected for the lower tableting speed, however the blox plot shows that most of the values obtained (between the first and third quartile) are higher than the ones obtained for the higher speed. On the other hand, when the product is compressed at a higher speed a lower mean was obtained (72N), so it can be said that reducing the dwell time leads to a lower resistance to crushing.

As for mass variation, it is important to consider that the higher speed was performed at last, when the hopper is not well filled, the reduction of the filling degree results in less hardness and consequently higher friability, therefore, this could be another factor to consider.

Figure 7. Bloxplot of resistance to crushing at different tableting speeds

• Friability

A friability test for both tableting speeds were conducted since it is important due to the fact that tablets are usually subjected to mechanical stress in subsequent steps, either in coating process or packaging process. Results are shown in Table 10.

For both tableting speeds the friability test according to the Ph. Eur. 2.9.7 was successful (less than 1.0%), nevertheless, a lower friability was obtained at the lower tableting speed, which was expected since there is an inversely relationship between resistance to crushing and friability.

Usually the higher the resistance to crushing, the lower friability, so a higher resistance to crushing (77N) for the lower speed was seen, a lower friability was expected, and on the contrary, a higher friability was expected for the higher speed with low resistance to crushing (72N).  As for resistance to crushing, dwell time is an important factor in friability, increasing the dwell time a plastic deformation of the materials can take place forming a stable tablet that leads to lower loss of material after mechanical stress (lower friability), which was obtained for the lower tableting speed (friability 0.03%) in comparison with the higher speed (friability 0.22%), as it was already mentioned when the tableting speed is increased the punches pass faster below the compression rollers, which is important not only for the main compression force to form the tablet, but also for the pre compression process that is useful to remove the air from the powder, if the air is not removed, once the tablet is ejected will lead into tablet defects, which can range from high friability to lamination or capping, however with the values obtained (less 1.0%), such problems are unlikely.

Table 10. Friability results from random samples (n=1)

Friability (%) calculation at 22,000 tabs/h:

Friability (%) calculation at 52,000 tabs/h:

• Force-time diagrams during tableting process

During tableting process, the force-time diagram can be used to determine the consolidation time which is the time to reach the maximum force; dwell time and the decompression/relaxation time, these parameters are important to obtain tablets with good mechanical properties.

The force-time diagrams from the two different speeds were obtained; two punches were blinded to visualize a whole rotation of the rotary press, which is represented by the horizontal lines in the diagrams, from this diagrams several information can be obtained, such as dwell time, the behavior of materials and the force during tableting, Figure 8 show the consolidation time (blue line) when the upper punch get in touch with the powder in the die until achieve the maximum force, then the dwell time (green line) and the relaxation/decompression time of the elastic materials (red line).

It is also observed a drop in the force during the process, which is representative of plastic behavior (microcrystalline cellulose) since these materials does not require so much force after the dwell time and the material flow together, so this deformation is irreversible, in contrast with elastic materials that usually present a plateau and the force during the dwell time is constants.

In theory, once the upper punch is removed, the force would drop to zero for a 100% plastic material, since no relaxation occurs; in contrast, for an elastic material a symmetrical curve would be observed, since the time for compression would be the same as that for the relaxation.

Figure 8. Force-time diagram at 22,00tabs/h; [Blue line: Consolidation time; Green line: Dwell time; Red line: relaxation time]

In general, increasing the tableting speed the punches pass more times below the compression roller in the same amount of time, resulting in narrower curves and smaller dwell time (Figure 9).

Finally, despite that all parameters are correctly adjusted and remain the same during the tableting process at the two different speeds it is a certain variability of the compression force from punch to punch observed which is attributable to the variation of the mass in the die, each process has a certain variability due to the characteristics of the powders, and it is known that the mass variations lead to variation in the compression force.

In automatic rotary tableting machines each tablet is compressed to the same thickness and a larger compression force would imply a heavier tablet ^[16], so the compression force can be used as a process analytical technology to assure tablets of the desire mass.

Figure 9. Force-time diagram at 52,00tabs/h

6.    Conclusion

• In-process control (IPC) inform of quality control charts

In conclusion, Six-Sigma is a problem-solving approach with proactive and reactive improvements during production. In a Six-Sigma project, at the beginning of the project and in the improvement phase, we can use a Control Chart to keep the process under control. Control Charts tend to make a process simple while skipping the assignable causes and helps to detect the process average and the variation. According to the x̅/s charts, the masses during production were stable, except from one point (10min), at this point, the proper adjustment was done to have again the process under control, nevertheless, the variability of the process was within the control limits (s-chart). The control chart not also serves to adjust the process if needed but also can be a tool to show process performance as it is like an integrity check of the process. It is very difficult to obtain a variation free process, nevertheless, maintaining the process within the control limits will assure not defect-free but with high quality.

• Influence of tableting speed on tablet quality

In industry is always desire to increase the productivity, regarding tablet production this can be achieved by increasing the tableting speed, but this is not always a good idea as it was observed in the characterization of the tablets.

Increasing the tableting speed could affect its quality, which results in tablets with a greater mass variation, since a higher speed does not allow homogeneous filling in the die and increases the centrifugal force that leads to the loss of powder. In the same way tablets with less resistance to crushing and greater friability were obtained at the higher tableting speed because the dwell time is decreased; this time is important for the formation of a stable tablet when having materials with plastic properties.

Therefore, it is important to consider a tableting speed that is high enough to have an effective process and results in high quality tablets that meet critical quality attributes (CQAs).

7. References

[1] Kosimov, Y. (2016). Effect of the compaction speed on the compressional behaviour of binary  mixtures containing microcrystalline cellulose and starch. Doctoral thesis, University of Helsinki, Helsinki. pp 13-16, 23-24, 50-51.

[2]https://www.lfatabletpresses.com/articles/tablet-making-definitions (last access on 01.05.2020)

[3]https://regi.tankonyvtar.hu/hu/tartalom/tamop412A/20110016_01_the_theory_and_practise_of pharmaceutical_technology/ch24.html (last access on 01.05.2020)

[4] Julian Quodbach et al, (2020). Pharmaceutical Manufacturing Practical Manuscript: B1, Tablet Manufacturing.

[5]https://elsmar.com/elsmarqualityforum/threads/ipc-in-process-control-definition.48147/ (last access on 27.04.2020)

[6] Muralidharan, K. (2015). Six Sigma for Organizational Excellence: A Statistical Approach. Springer India, New Delhi.

[7] https://www.jstor.org/stable/2291529?seq=1 (last access on 03.05.2020)

[8] https://www.investopedia.com/terms/q/quality-control-chart.asp ( last access on 27.04.2020)

[9] Chitranshi, U. An Ultimate Guide to Control Charts in Six Sigma. In: Grey Campus. (26.10.2018)

[10] Sarsvatkumar P., Aditya Mohan Kaushal, A. M., Bansa, A. K. (2006). Compression Physics in the Formulation Development of Tablets. Critical Reviews TM in Therapeutic Drug Carrier Systems, 23(1):1–65.

[11] Levin, M. (2008). Tablet Press Instrumentation. Encyclopedia of Pharmaceutical Technology, Volume 6: Ed. Swarbrick, J. New Jersey (USA), pp. 3684-3685.

[12] Asian Journal of Pharmaceutical and Clinical Research: Vol 9, Issue 1, 2016, 19-26. Received: 16 September 2015, Revised and Accepted: 23 October 2015

[13] Saniocki, I. (2014). New Insights into Tablet Sticking: Characterization and Quantification of Sticking to Punch Surfaces during Tablet Manufacture by Direct Compaction. Doctoral thesis, Universität Hamburg, Hamburg

[14] Pharmacopeia European, European Pharmacopeia, 2020, 10^th edition, 1^st supplement, 2019, Deutscher Apotheker Verlag, Stuttgart, Govi-Verlag – Pharmazeutischer Verlag GmbH, Eschborn

[15]https://regi.tankonyvtar.hu/hu/tartalom/tamop412A/20110016_01_the_theory_and_practise of_pharmaceutical_technology/ch24.html (last access on 09-05.2020)

[16] Fahr, A., Scherphof, G. L.  (02/2018). Voigt’s Pharmaceutical Technology [VitalSource Bookshelf version].  Retrieved from vbk://9781118972441, p.356

[16] Tablet Compression Force as a Process Analytical Technology (PAT): 100% Inspection and control of Tablet Weight Uniformity, Leo Manley, Jon Hilden, Pablo Valero, Tim Kramer, Journal of pharmaceutical science, January 2019Volume 108, Issue 1, Pages 485–493.

[17] https://sixsigmastudyguide.com/x-bar-s-chart/ (last accessed 11/5/2020)

8. Annexes

• Batch record of the tableting process for In-process control.

[1] https://support.minitab.com/en-us/minitab/19/help-and-how-to/statistics/basic-statistics/supporting-topics/data-concepts/identifying-outliers/ (Last access on 11.05.2020)