Six Sigma: Process of Understanding the Control and Capability of Ranitidine Hydrochloride Tablet

The process of understanding the control and capability (PUCC) is an iterative closed loop process for continuous improvement. It covers the DMAIC toolkit in its three phases. PUCC is an iterative approach that rotates between the three pillars of the process of understanding, process control, and process capability, with each iteration resulting in a more capable and robust process. It is rightly said that being at the top is a marathon and not a sprint. The objective of the six sigma study of Ranitidine hydrochloride tablets is to achieve perfection in tablet manufacturing by reviewing the present robust manufacturing process, to find out ways to improve and modify the process, which will yield tablets that are defect-free and will give more customer satisfaction. The application of six sigma led to an improved process capability, due to the improved sigma level of the process from 1.5 to 4, a higher yield, due to reduced variation and reduction of thick tablets, reduction in packing line stoppages, reduction in re-work by 50%, a more standardized process, with smooth flow and change in coating suspension reconstitution level (8%w/w), a huge cost reduction of approximately Rs.90 to 95 lakhs per annum, an improved overall efficiency by 30% approximately, and improved overall quality of the product.

A process that is six sigma (six sigma process quality is considered as world class quality) will yield just two instances of non-conformances out of every billion opportunities, provided there is no shift in the process average, and the same process will yield 3.4 instances of non-conformances out of every million opportunities with an expected shift of 1.5 sigma in the process average. A process at four sigma levels (considered average process) is expected to yield 63 instances of non-conformances for every million opportunities, without a shift in process average and 6210 instances of non-conformances with a shift in the process average. Contrary to the above, a process at the two sigma level is considered a poor quality process and is expected to yield 3,08,537 instances of nonconformances with the shift of 1.5 sigma in the process. [5][6][7] The data for the process at different sigma levels are given in Table 1.
Defect values in the Table 1 suggest that as the sigma level goes up the defect rate reduces, which means the product quality improves. Six sigma, therefore, is a powerful tool that can transform defect prone business / industry into an organization of perfection. Thus a journey toward sigma level means a journey toward making fewer and fewer mistakes in everything.
The PUCC framework is explained in Figure 1. The framework can be used to manage: current processes, process change, and new processes. Eight elements of PUCC [8,9] are shown in Figure 2.

DMAIC
The basic methodology consists of the following five steps: • Define the process improvement goals that are consistent with customer demands and enterprise strategy. • Measure the current process and collect relevant data for future comparison. • Analyze, to verify the relationship and causality of factors. Determine what the relationship is, and attempt to ensure that all factors have been considered. • Improve or optimize the process based on the analysis, using techniques such as the design of the experiments. • Control, to ensure that any variances are corrected before they result in defects. Set up pilot runs to establish process capability, transition to production, and thereafter continuously measure the process and its capability. [10][11][12]

Focus methodology
PUCC stands for three phases, process of understanding,  Six sigma process control, and process capability. These three phases cover the DMAIC methodology of six sigma. Instead of carrying the project in the phases of PUCC, the project was covered by the DMAIC method. [13] Ranitidine hydrochloride production falls in the following stages: Weighing and blending, Compression, Coating, and Packing.
Forty batches from NL461 -NL500 were monitored throughout these four stages, and enormous data was collected, to cover the measure phase of DMAIC.
The data collected was then analyzed using STATISTICA, MINITAB 14 (STATISTICAL PACKAGES), and MICROSOFT EXCEL.
On completion of the analysis phase, the improved phase is initiated, and then the action plan for the control phase of DMAIC is designed.

Define
The process improvement goals are consistent with customer demands and the enterprise strategy. The complete process of manufacturing is defined in terms of its various process flow diagrams; the definition of the problem must be stated in this step. Process capability parameters are defined and are critical to the customer and to the quality parameters that are defined.

Ranitidine hydrochloride (RHCL) tablet manufacturing
is monitored for a long run, up to 35 batches, with data regarding the characterization of raw materials, comparability study of alternative sources of raw materials, manufacturing process such as blending, compression, and packing, packing material characterization, packing line efficiency, and packing line yields. Data has to be collected and treated statistically, to study the trend analysis and define most of the contributing variables in the process variations. The present Sigma level of the overall manufacturing process is between 1.5 and 2.5, and the target Sigma value is 4.

Baseline of manufacturing process is defined using the following tools
The Ranitidine hydrochloride Process Capability Parameters are, Proposed CTQ Trait, Process Map of RHCL tablets, [ Figure 3], Flow diagram for parameters affecting the process, Process flow diagram for RHCL tablets, input process output (IPO) diagram for blending process, IPO diagram for compression process, blending parameters, data required, correlation analysis, variable factor analysis, multiple variable graphs, Pareto charts for variables, line plots, and trend plots.

RHCL process capability parameters
Critical to Customer (CTC): Defects that would make the customer question the quality or effectiveness of the product. [14] Proposed CTC trait Color (uniformity, right color) legibility of print / embossing, broken / chipped tablets, thick or thin tablets, efficacy, shape. [15] • Critical to Quality (CTQ): Defects that would cause a batch rejection, batch re-work or FDA action. • Critical to Process (CTP); an item that if not held within a certain range as determined through process development would cause out-of-specification results. [16] Batch reconciliation in dispensing (per raw material), blending time parameters met, blending yield, tablet weights (individual, average), tablet thickness, tablet hardness (individual, average), tablet friability, tablet disintegration time, tablet shape, tablet size, debossing, foreign product / material, uncoated tablet, broken tablet, compression accountability, compression yield, QC assay, equilibrium relative humidity, press speed, pre-compression force, main compression force, blending yield, blending accountability, blending LOD, and tablet assay.

Measure
Evaluation of granule [17] Tables 2 and 3 indicate data for raw material and blending.  Evaluation of tablet [18] The features evaluated were: Tablet thickness and diameter, tablet hardness, friability, uniformity of weight, and uniformity of content.

Analyze
Data collected from 38 batches was analyzed on a statistical tool called 'Statistica'.
Data was analyzed for the following phases and in the following order: • Raw material and blending • Compression • Coating • Packing Verification of relationships and causality of factors were carried out by using various statistical tools. [19][20][21] What the relationship was also determined and an attempt was made to ensure that all factors had been considered. (All representative figures of each phase mentioned above had been attached in the same sequence).

Improve
The process was improved or optimized based on the analysis, using techniques like design of experiment [22] and so on. With the help of the above analysis done by various statistical tools and techniques, various UDEs (undesirable effects) were discovered, and the severity and causes of these UDES were discussed. Desirability of various improvements was checked and certain suggestions  [15][16][17][18][19][20][21][22][23][24][25] should remain in control, that is, they should be sustained. An action review is important for that, and this was carried out in this phase.

RESULT AND DISCUSSION
Undesirable effects were observed during the analysis of the process using different statistical tools. For minimization of undesirable effects, various changes in terms of process alteration and corrective measures for manual handling of the process were made in the process, for making it more capable and robust.
In order to improve process capability, in the following stages different parameters are targeted and their exact role is discussed.
• Blending • Compression • Coating • Packing (All representative figures of each phase mentioned above have been attached in the same sequence).

Blending
During the blending process, assay variation [ Figures 4 and 5] was observed in the range of 146 -152. In order to overcome this variation, the existing blender had to be replaced with a new blender of higher capacity, it was validated and a measurement system analysis of the blend was performed.
Particle size distribution of Ranitidine Hydrochloride (RHCL) and microcrystalline cellulose (MCCP) was not available to manufacturing heads. This had been informed to the Manufacturing Department on the browser, for RHCL as well as MCCP, from the Quality Assurance Department, with the help of the Information Technology Department.
High cycle time for the activity of weighing, sifting, and blending was required and more manpower was used in this stage for weighing, sifting, and blending. To avoid this, load charting of the weighing, sifting, and blending stage had to be carried out, for minimization of manpower, Recalculation of the cycle time at the installation of the new blender was carried out. Parameters for the granule evaluation are as shown in Table 4 and Figures 6 and 7.
Magnesium stearate [ Figure 8] distribution in the batch at the top, middle, and bottom was also observed. For even distribution of magnesium stearate, the angle of repose were made for improvements, which were then discussed. Subsequently, these improvements would be implemented and their impact would be observed on the improvement of yield and sigma level. The major U.D.E's discovered during the analysis phase and their suggestion for improvement made the process more capable and robust.

Control
All actions taken in the above-mentioned four phases     and tablet hardness was observed in Table 5, Figures 9 -13.
In order to solve the variation in the compression stage of different machines, data was observed and entered simultaneously on a run chart after replacement of a punch set. Checking the thickness of the tablets on the first two rotations of the machine, every time the machine was restarted, and also collection of data on punch height was done.
Average U.R (Utilizable Residue) produced per batch was 3.5%, that led to extra man hours for rework. In order to overcome this variation, interlinking the speed of the machine and force feeder was done and also inspection of  whether the tablets were taken out, each time the machine was adjusted or not was checked.
Considerable variation in friability was found and in order to solve this variation, monitoring of moisture content was done regularly and data was generated for CHEMFILED, to compare it with the existing RANQ.
More unaccounted time and minor stoppages were observed and to minimize this, Time value mapping of the cleaning activity on a daily and weekly basis was done and operator attitude and awareness was addressed.
Rotation of the machine operator was observed daily. To minimize this, the staff was fixed for a period of two weeks.
Time wasted while the first shift ended (30 minutes closing time) and the second shift started (15 minutes starting time) was observed. To utilize that time, overlapping between these two times were challenged.
The Present Overall Equipment Effectiveness (OEE) is 28.75%, and 28.30% for Compression machine CM26 and CM27 was observed. To improve the Overall Equipment Effectiveness (OEE) level up to 45% for CM26 and CM27 as a first target, the project had to be taken by the manufacturing heads.

Six sigma
Journal of Young Pharmacists Vol 3 / No 1     [Tables 6 and 7, Figures 14 and 15] as well as individual gun spray rate variation (50 ml -450 ml) was observed, in order to solve this variation, Gun maintenance and replacement was done and when required chocking of guns to be minimized or eradicated and also gun cleaning frequency and its effectiveness to be addressed.
Considerable variation in the parameters like: inlet air temperature, outlet air temperature, inlet air cfm, outlet air cfm, tablet bed temperature, and so on were observed. In order to minimize these variations, the same parameters were kept in PLC for both the coating pan and calibration of velocity. The sensor for filter cleaning was done. Also standard parameters values were set.
No robust method of measurement was available to measure gun distance from tablet bed, In order to solve this problem; Collection of data to see the validated results was done.
Uneven weight gain while coating was observed and     to solve this variation in weight gain, interaction of controllable parameter in coating that results in more or less weight gain, for e.g. spray rate ,inlet and outlet air temp, inlet and outlet air cfm, atomizing air pressure was observed.
In order to improve the Overall Equipment Effectiveness (OEE) level up to 50 -55% for both the pans as a first target, the project was taken up by manufacturing heads.
There was need felt to apply Design of experiment (DOE)  for change in coating suspension Reconstitution Level. In order to carry out the six sigma tool, design of experiment (DOE) for change in coating suspension Reconstitution Level, a separate project had to be handled. For that an STP (Situation, Target, and Plan) was prepared and also a trial protocol prepared.

Packing
The Average Overall Equipment Effectiveness (OEE) of packing lines [ Table 8, Figure 16 In order to achieve Overall Equipment Effectiveness (OEE) level in the range of 50 -65% for all the packing lines as a first target, the project had to be taken by the Packing Department heads.
It has been observed that the Roll change time contributes to 25 -34% of total stoppage time while completing a batch. To minimize this time period, the procedure was standardized for changing the rolls. Also efforts were made by the Engineering. Department to bring automation in the process of roll change and the process mapping was carried out at least once in a fortnight.
A run time (on a single shift basis of 570 minutes) of 320 minutes was observed and to increase this run time, the stoppages due to machine adjustment, tablet problem, and other miscellaneous factors were minimized. Also process mapping was carried out once in a month. Mapping of micro-stoppages, morning-evening tea breaks, and ground level exit was carried out, to minimize unaccounted time, and a BRAVO CARD system was implemented, to give recognition to the line operator who was providing the maximum output in a week. Loose winding of plane and printed rolls were observed. In order to solve this problem, the issue was addressed at the time of procurement of the rolls from the supplier.
The average foil rejection per batch was 12 kg and the average weight of the defoiled tablets was 6 kg per batch.
[ Figure 16]. To minimize this rejection, the variation in tablet thickness, hardness, weight, and coating, was reduced, which made the compression and coating stage more robust, to produce minimum number of defects. The operator attitude and awareness was also addressed, and machine issues that led to tablet and foil rejection, were taken care of by the Engineering Department.

CONCLUSION
As various UDEs (Undesirable effects) were discovered and discussed in the analysis, an improved phase of DMAIC, recommendations, and suggestions came about, to make the present process more robust against defects, either by bringing new steps in the process or by improving the same existent current process. This will result in benefits, some tangible and some non-tangible.
• Given here are some value additions from the process of RHCL production obtained by the implementing of PUCCInstallation of high capacity blender of 1000 kg, replacing the current 300 kg blender, thus saving the man-hours by 66% (approximately). • Introducing high capacity tote-bins of 200 -300 kgs, which would result in reducing the unloading time from the blender, coating the pan to one-third. Man and material motion would be reduced to one-third. Time of loading and unloading of tote-bins, to lifts, and to and from the mezzanine floor would be one-third. Batch changeover time would be reduced to 33% of the current time, and hence, less amount of U.R would be generated. • OEE improvement for compression, coating, and packing stage, which would lead to 30 -35% increase in OEE for RHCL 150 MG tablets production. • Set up time reduction for the whole process by 40 -50%. • Release of 20 -30% of the manpower. • Process waste reduction, both in compression and packing by 35% • Rework reduction by 50 -70%. • Reduction in packing line stoppages. • Improved process capability due to improved sigma level. • A more standardize process.