IMPROVING THE PERFORMANCE OF PHARMACEUTICAL TABLET PRODUCTION USING SIX SIGMA METHODOLOGY (MODULATION ON DIGESTIVE ENZYME TABLET)

IMPROVING THE PERFORMANCE OF PHARMACEUTICAL TABLET PRODUCTION USING SIX SIGMA METHODOLOGY (MODULATION ON DIGESTIVE ENZYME TABLET)

El-Menhawy A.¹, Mohamed N. M. ¹, Arafa H. A. ¹, and Abd Elmonem A. R ^*2

Arab Academy for Science and Technology and Maritime Transport¹, Productivity and Quality Institute, Cairo, Egypt

Department of Pharmaceutics and Industrial Pharmacy ², Faculty of Pharmacy, Misr University for Science and Technology, 6 October, Giza, Egypt

ABSTRACT: Each company is expected to develop specifications for their products to be accommodated with the inspection guide of pharmaceutical quality control. After product analysis for (X) pharmaceutical company it was noticed that 84.5% of defects were attributed to tablet department while 14.1% and 1.4% for ampoule and syrup departments respectively so it was valuable to solve the tablet department problems. Data was collected for three months for two types of tablets which were analgesic tablet (AT) and digestive enzyme tablet (D.E.T). D.E.T was chosen for further study due to its high percent of defect. By using six sigma methodology to analyze the collected data it was found that the major problem was in tablet microbiological test 85.9% rather than the physical problem 14.1%. D.E.T was subjected to study the variables affecting the bacterial count like raw material, process environment and microbiological analysis accuracy. It was found 66.7 of the problem caused by the variation in process environment. By using factorial design for three variables it revealed that the cleaning and disinfection methods were the most affecting factor that caused the total variation in the overall process. Seven remedies for cleaning were studied and each remedy was rated for each criterion using a special scaling system. It was noticed that the manual cleaning was the most effective method since it lowered the bacterial count of the coating solution to 285 cfu/ml and affected on sigma level to be 4.2 σ which exceeded the target (not more than 500 cfu /ml). Six Sigma methodology is a promising method for improving the pharmaceutical tablet production and achievement its quality control

Digestive Enzyme Tablet, Quality control, Six sigma, Performance, Tablet production, Coating solution, Manual cleaning, bacterial count

INTRODUCTION: Quality within all industries is important, but within the pharmaceutical industry, it is essential.  Because lives are at stake, quality, when it comes to creating and manufacturing medicines for individuals, is necessary¹ since drugs worldwide used either through prescription or as over the counter medication². Since 2002, FDA began an initiative to address cGMP for the 21st century³

cGMP focuses on manufacturing as a mean to produce a safe and effective products for the patient ⁴. The practice of industrial hygiene focuses upon the implementation of workplace safety solutions and control of workplace health risks and stressors by highly trained and experienced professionals skilled in the science and art of hazard anticipation, recognitions, evaluation and control within the workplace, the surrounding environment, and community⁵.

For drug products, specifications usually consist of test methods and acceptance criteria for assay, impurities, pH, dissolution, moisture, and microbial limits, depending on the dosage forms. They are usually proposed by the manufacturers and subject to the regulatory approval for use⁶. This effort involved taking new looks at both the regulatory and industrial systems for insuring drug quality⁷. Six Sigma as a measurement standard in product variation can be traced back to the1920's when Walter Shewhart showed that three sigma from the mean is the point where a process requires correction⁸. Six Sigma Projects are based on the DMAIC model. The DMAIC model is the generic model of six sigma methodology. It is an acronym that stands for; Define, Measure, Analyze, Improve and Control. Sometimes this model includes recognize as an awareness item to the model. Each of the components addresses a different aspect of the overall improvement and breakthrough strategy⁹.

Six sigma is a statistical concept which helps us to define the problems systematically, provides tools to measure and analyze the influential factors, identifies the improvements that can be implemented easily and ensure that the changes which have been made, are kept alive through a control process and maintains the gains over the time. It is a known fact that in a process with six sigma capability, process variation is not reduces more than 3.4 defects per million opportunities¹⁰. Six Sigma has evolved over time. It's more than just a quality system like TQM or ISO. It's a way of doing business. As Geoff Tennant describes in his book Six Sigma: SPC and TQM in Manufacturing and Services: "Six Sigma is many things, and it would perhaps be easier to list all the things that Six Sigma quality is not. Six Sigma can be seen as: a vision; a philosophy; a symbol; a metric; a goal; a methodology." We couldn't agree more¹¹.

The goals of Six Sigma for improving customer satisfaction relay on accelerating process cycle times and time-to-market, reducing defects, controlling variation and improving predictability, reducing costs – without "unintended consequences", and improving end-to-end process management and measurement¹².

The pharmaceutical market in Egypt It started around 1940 when the Misr Company of Pharmaceutical Industries was founded. In the 1980’s and 1990’s, the Egyptian market was over flooded by a huge amount of private sector pharmaceutical companies.

According to the report of IMS Health (2006), the pharmaceutical organizations in Egypt fall into three categories:

• Public sector categories, the Drug Holding Company (D.H.C.), which have their roots in the first national pharmaceutical Industry
• Local private sector companies.
• Transnational private corporations.

According IMS the pharmaceutical market, in 2006, consists of around 47 pharmaceutical companies, of which 8 are publicly owned. The Egyptian ministry of Investment speak about 30 private and 8 public pharmaceutical companies, source; IMS Health, unpublished Statistical report, March 2007GlaxoSmithKline has the largest market share, an estimated 7.5%, followed by Novartis,6.7% and Sanofi-Aventis which possesses nowadays an estimated 6.3% of the Egyptian pharmaceutical market, due to the international merger of Sanofi and Aventis in August 2004. Sanofi-Aventis is now both the world largest and Egypt’s third largest pharmaceutical company and it also ranks number 1 in Europe.

Egypt's exports of pharmaceuticals have grown steadily in recent years, topping USD 270 million in FY2011/2012Compared to USD 238 million in FY 2006/2007. Investments in Egypt's pharmaceutical industry currently stand at EGP 26 billion, with the industry employing a total of 39,500 professional staff and production workers. Egypt has the largest drug manufacturing base in the MENA region accounting for around 30% of the regional market.

Local production covers around 93% of the market with 7% made up of highly specialized pharmaceuticals not produced locally. Annual production is recorded to be EGP15 billion in 2009 in 2010, the market size has reached USD 4.1 billion at retail prices that represented 1.9% of GDP and 30.6% of health expenditure. The number of pharmaceutical factories has increased from 90 factories in 2006 to 120 factories in 2010 with other 70 plants that are under construction¹³.

Large multinationals as Glaxo Smith Kline (GSK) is the leading company in the Egyptian market with 9% of the market share. Sanofi-Aventis and Novartis, Pfizer, Servier, and Bristol- Myers   are also among the top multinational manufacturers in the market. Holdipharma have 1700 types of medicine, 42.1% of them are sold in cheap prices, with LE 1.3bn. annual losses because of its low prices the total capital of Holdipharma and its affiliates is about LE 2bn, with a cumulative growth rate over the last five years 50%. Egyptian pharmaceutical exports in 2008 reaching US $ 120.4 million. Imports have reaching US $ 1018.4 million in 2008¹⁴.

MATERIALS AND METHODS:

Materials: produced by (X) company:

• Ampoules: sample = 60,000 ampoule/batch.
• Tablets: sample = 3000 tablet/batch.
• Syrup: sample = 1500 bottles/batch.
• Methods:
• Classification of the company pharmaceutical product formulations Pharmaceutical products were classified into:
• Sterile products:
• It is the pharmaceutical dosage form that contains therapeutic agent and must be free of microorganism. It includes ampoule production only.
• Non Sterile Products:
• It is the pharmaceutical dosage form that contain therapeutic agent that have microbial loading. It includes tablet and syrup production.
• Problem analysis:

Samples are pulled from different sections of production (Ampoule – Syrup - Tablets). Samples were drawn from batches to analyze. Result of analysis indicated batch rejection or acceptance according to the specification limit.

3. Data collection and analysis before applying six sigma on tablet department (For Three Months). Two types of tablets were subjected to study their collected data. The first type was analgesic (A.T) tablet and the other was digestive enzyme tablet (D.E.T). Data for both of them were collected and analyzed.

4. Applying six sigma methodology on D.E.T collected data.

Six Sigma projects enhance technological innovation of the firms; however, they are beneficial for firms in stable environments¹⁵. So this study aims to increase the internal customer satisfaction by identify the main causes of out of specification. The suggested reason was the variation in the Bacterial count of Digestive enzyme tablet (D.E.T) which also caused dramatic effects on the tablet production process due to bacterial count got out of specification. That was reported through internal customer (quality control microbiology). Focus on the processes using six sigma methodology was done to achieve the customers’ expectations. The application of six sigma includes the following¹⁶:

Define Phase:

This phase deals with defining processes, key customer requirements, and process “owners”¹¹. At this phase three issues were studied which were:

• Identify Customer Critical to quality.
• Develop Project Charter.
• SIPOC Analysis
• Measure Phase:

This phase considered as measuring performance against customer requirements and key performance indicators¹¹. It consists of three main steps:

• Critical to Quality Characteristics.
• Define Performance Standard.
• Measure System Analysis.
• Analyze Phase:

This phase was related to Analyze data to enhance measures and refine process management mechanisms¹¹. This phase consists of three main steps:

• Establish Process Capability.
• Process Performance.
• Identify Variation Source.
• Improve Phase:

The main steps of the improve phase were:

• Generation of Ideas.
• Rating of ideas.
• Design of experiment.
• Improvements recommendation.
• Control Phase:

Controlling process performance was done by monitoring process inputs, process operation, and process outputs, and responding quickly to problems and process variations¹¹. This phase contained the following:

• Define and Validate Measurements.
• Determine Process Capability.
• Implement Process Control.

5. Implementing Integrated Approach of Six-Sigma at tablet coating solution.
6. Manual cleaning.

RESULT AND DISCUSSION:

Company products were classified into sterile and non sterile. The sterile product was ampoule and the non sterile subdivided into tablet and syrup. Table 1 showed the problem analysis of the products for one month production.

TABLE 1: PROBLEM BATCH ANALYSIS

FIG.1: PARETO CHART DEPARTMENTS DEFECTS ANALYSIS

As shown from Fig.1 84.5% of the defects were attributed to tablet department that's considered the biggest problem rather than the other departments. Ampoule and syrup departments defect ratios were 14.1 and 1.4% respectively. The previous data showed that the major problem was related to tablet department. The sorting of tablet department

data revealed that 14.1% of the tablet defect was related to physical problem and 85.9% was related to microbiological problem so the main issue for further study was the defect related to microbiological reason. Data was collected for three months for both of D.E.T and A.T for further analysis. As shown in Table 2 the microbiology defect and nonconformity for the digestive enzyme tablet was higher than the analgesic tablet.

Digestive enzyme tablet was taken for further study. Process analysis for digestive enzyme tablet was done to recognize the reasons of the microbiological defect. Table 3 and Fig.2 showed that the main reason for the highly bacterial count was the coating solution since it had 80% of the total bacterial count.  So we had to solve the problem of the coating process to improve the tablet process.

TABLE 2: DATA COLLECTION OF TABLET DEPARTMENT FOR THREE MONTHS

TABLE 3: PROCESS ANALYSIS OF D.E.T

Six Sigma fundamental phases (define, measure, analyze, improve and control) applied on the problem of D.E.T in tablet production line through defining the scope and goals of improvement, measuring the process and analyze the problem.

This study aimed to increase the internal customer satisfaction by identifying the main reasons led to out of specification focusing on the processes using six sigma methodology.

FIG.2: PARETO CHART FOR PROCESS ANALYSIS OF TABLET

 Table 4 showed the project time frame for the five phases. The define phase concerned with identify the customer. Customer was classified into:

 i)Internal Customer, quality control microbiologist who was responsible for microbiological analysis at sterile product drug as ampoule and non-sterile drug as syrup and tablet (D.E.T), (A.T).

1. ii) External Customer, Ministry of Health, public hospitals, private hospitals, and medical centers.

Customer critical to quality (CTQ) was the internal customer for three variables which were

1. i) Raw material, which revealed that the microbiological analysis of raw materials was required to meet specification of analysis, raw materials that were internal process.

1. ii) Process environment, which was proceeded during the manufacturing production areas have ability to causes contamination of (D.E.T).

iii) Microbiological analysis accuracy, which reported that all microbiological tests must be under sterile aseptic conditions (sterilized equipment, laminar air flow, microbiologist free from infection pathogen). Technical process flow chart was prepared by dividing the production process into four phases as the following: raw material, compression, coating, and blistering and packaging. After a deeply look through the detailed process steps a process drill down tree was developed as shown in Fig.3.

FIG.3: TABLET (D.E.T) PRODUCTION PROCESS DRILL DOWN TREE

The project leader selected the team indicated the business case, mentioned the problem statement, indicated the goal statement, indicated the project scope, and put the project time plan for each phase to implement six sigma projects as shown in Table 5.

TABLE 5: PROJECT CHARACTER

The team was selected to represent the main branches affecting the (D.E.T) production on the selected tablet. The following individuals were responsible for the production process of (D.E.T) with high quality and were chosen according to their awareness and responsibility of work in each of the four processes of the (D.E.T) production process.

• Quality Controls Team Leader: Responsible for follow up of all quality activities in the selected (D.E.T) production and the microbiological lab for the company.

• Production Shift Leader: Responsible for distributing workload among the workshop and tablet production in the company.

• Planning & Scheduling Team Leader: Ensure that the projects achieve their goals on schedule.

• Supply Manager: Responsible for ordering and follows up of all departments.

A SIPOC Process Definition helps the Process Owner and those working on the process to agree the boundaries of what they will be working on. It provides a structured way to discuss the process and get consensus on what it involves before rushing off and drawing process maps¹⁷.

So the SIPOC diagram was prepared to provide a summary of the key factors of the process (D.E.T). The SIPOC simply was identified to ensure that selected employees in this project were aware with the problem parts as shown in Fig 4.

The team focused on how to reach the main defects in the (D.E.T) production process to determine root causes of (D.E.T). The measure phase consisted of three main steps which are critical to quality, define performance standard, and measure system analysis. The main factors effecting the tablet composition and bacterial count variation from microbiological point of view was coating solution which measured by CFU/g. The team studied the data collected from September 2012 to October 2012.

As shown in Fig.5 the median was centered in the IQR box. The confidence intervals for the precipitated data indicated that 95% confident that: The mean was 500.48; standard deviation was 199.24 which revealed that on average, the values of data tended to differ from the mean by ±199.24. Q1 was 450, Q3 was 600 and the IQR was 150.   The maximum value was 1000, minimum value was 10 and the range was 990 so the lower specification limit LSL would be 10 cfu/g, and upper specification limit would be 1000 cfu/g, target would be 500 cfu/ml, and as the standard deviation of coating solution of the (D.E.T) feed according to the company quality control requirement was 500 cfu/ml to keep the bacterial count of (D.E.T) at safety limits.  The defect was defined as the value of the bacteria of (D.E.T) process that had to be more than 1000 cfu/g for the selected tablet productions. Run Chart and individual control chart were done as shown in Fig. 6, 7.

FIG. 6: RUN CHART OF COATING SOLUTION

FIG.7: I CHART OF COATING SOLUTION

As shown in Fig. 6, 7 the average of the Standard deviation of bacterial count of (D.E.T) during the measure period was 1341which was out of the company quality control reference limits (standard deviation of bacterial count was 500cfu/ml) which gave an indication for high variation on (D.E.T). Regarding to the analysis phase in term of establish process capability since there was process instability so there was no need to study the capability of the process, ppm is equal to 387096, so sigma levels 1.77 that's give yield 60.85%.

The process performance showed a gap between the current state for the standard deviation of coating solution (512) and the target from the study (500) which is less than the specification of the company (not more than 1000). Identification of the variation sources was obtained by Study the measured values of standard deviation of coating solution during the period April to June 2013, and he found that 12 measured values from 31 are out of limit, Meeting with the team member and brainstorming take place with the selected company team to review the problems and factors that may be affect the variability of the kiln feed during taking the samples.

FIG.8: CAUSES THAT AFFECT THE BACTERIAL COUNT OF COATING SOLUTION

As shown at Fig. 8 the data was collected from the team revealed that the source of variation was the process environment. By using cause effect study on the mentioned variable as in Fig. 9 it was noticed that Raw materials for pharmaceutical products was a source for some forms of microbial growth, depending on the nutritive properties and moisture contents. Peoples who involved on every step of all process in manufacturing areas of (D.E.T) affected on bacterial count. Methods of analysis used to ensure that contamination of the manufacturing process is kept under control, with frequency of environmental analysis. Sterile petri dishes containing (T.S.A) media were added on production areas (compression, coating solution preparation, and packaging area) to evaluate air contamination. Swabs were taken from the machinery parts and walls before and after cleaning and sterilization to assess cleaning and disinfection method and evaluation of personnel Gown. Finger print was used to evaluate personnel hygiene through applying personnel fingers on sterile petri dish containing (T.S.A) media. Machine and equipment were very important factors in contamination control because it's direct contact with drug in every step of processes, so through cleaning and disinfection and control of air supply with gown and hygiene control could lead to decrease bacterial count. Environment was include deionized water system that are used in process and cleaning, and air supplementation which was direct proportional on bacterial count in machine and equipment and keep personnel hygiene with disinfection.

FIG.9: CAUSE-EFFECT DIAGRAM OF ENVIRONMENT PROCESS

Improvement phase of (D.E.T) production line were done by generation of ideas as shown in Fig. 9. One of the three vital factors which was necessary and vital to be eliminated (air contamination), the other two factors are personnel gown & hygiene, and parameters that need to be increased or decreased (increase technicians experience and reduce the time spent in documentations recording).

A design of experiments with two levels, full factorial design was performed to test the significance of the suggested vital factors and the interaction between them. Three factors (Changing the training method, increase technicians experience and reduce the time spent in documentations recording) are put into experiment with two possible levels for each factor, as in Table 6.

TABLE 6: FACTORS LEVELS

The level of each factor had to be-identified in order to know the actual meaning of each factor and level before applying the experiment. Air supply divided into two levels, the first level is the air contamination, which means that, uncontrollable bacterial count in tablet manufacturing. The second level is Applying HVAC system, which means that, air will prevent aerosol contamination by bacterial spores, and mold these can be achieve through applying HVAC system in tablet manufacturing.  Obviously, the second level is the proper level in the first factor. Personnel Gown & Hygiene divided into two levels; the first level is uncontrolled personnel gown & hygiene, which means that, the personnel gown & hygiene holds a number of microbes that may interference of tablet through direct contact.

The second level is a personnel control gown & hygiene, which mean that reduces the microbial load on Gown and prevents bad behavior of personnel's. Obviously, the second level is the proper level in the second factor. Cleaning and disinfection method divided into two levels, the first level is the unregulated cleaning and disinfection , which means that cleaning is  prevent product integrity, remove dust , any waste can be carried microorganisms, disinfect are used to kill microorganisms in environment and on personnel's obviously, the second level is the proper level in the third factor.

Experiments had performed in the (D.E.T) production of coating solution and microbiological samples collected from these areas and transferred  to microbiology laboratory to be examined by plate count method, all testes were happened under sterile equipment's and under laminar air flow. Experiment results were as shown in Table 7 below.

TABLE 7: FACTORIAL DESIGN EXPERIMENT RESULTS

FIG. 10: EXPERIMENT RESULT CUBE REPRESENTATION

FIG.11: EXPERIMENT'S FACTORS VARIATION

As illustrated in Fig. 10, 11 the cleaning & disinfection method was the most affecting factor that caused the total variation in the overall process.

Improvement Methodology (Cleaning and disinfection method):

Disinfection is a process that reduces the number of pathogenic microorganism with an inanimate object to a level, which is not harmful to health, It is generally more reliable than chemical processes, leaves no residues, is nontoxic, shows lack of emergence of resistance, and the process is automated and validated, similar to the process of sterilization. Several remedies for cleaning process were studied as shown in Table 8.

 TABLE 8: REMEDIES OF CLEANING PROCESS

shown in previous table the seventh remedy (manual cleaning) was the best solution as it has a solution for all problems, but with some of competition with remedy one  especially that the (cleaning in place) in terms of will reduce process contamination, easy to implement, so the team also approved the first remedy. Selection between the two remedies was done by using selection matrix

Table 9. In remedy selection matrix, each remedy had been rated for each criteria using 1-2-3 scale.

• Bad remedy at this criterion.
• Not bad and not good remedy at this criterion.
• Good remedy at this criterion.
• TABLE 9: REMEDY SELECTION MATRIX

FIG.12: REMEDY SELECTION MATRIX

As shown from Fig. 12 the most suitable cleaning method was manual cleaning.

Control Phase.

This phase explains the implementation of Six-Sigma control phase. A measurement bacterial count had been developed, implemented and carried out on a three months to measure standard deviation of bacterial count at (D.E.T) at all process. The bacterial count relied on the formation of the (D.E.T).

TABLE 10: CONTROL PHASE MEASUREMENT RESULTS

Process capability, I Chart for individual and Run Chart with statistical summary for (31 samples) for coating solution , using the data collected in the control phase from the Table 10 were done to assure the control phase process capability as shown in Fig.13, 14, 15, 16.

Table 11 showed that the Cp value 2.45 and the Cpk value 1.36 which indicated that, the process of bacterial count at coating solution is stable and capable after applying the improvement methodology. In additions, the mean value 284.84 for the bacterial count after improvement is less than the desired target 500 cfu/ ml. which means, the target was achieved. According to the calculation of Sigma Level using Z-Type method Cpk value 1.36 is an indication for Sigma Level value 4.2 with non-conforming PPM value 26.7082 so the current process Sigma Level after the improvement is 4.2 σ.

TABLE 11: COLLECTED DATA FROM CONTROL PHASE PROCESS CAPABILITY

TABLE 12: DATA COMPARISON BEFORE AND AFTER IMPROVEMENT AT BACTERIAL COUNT OF COATING SOLUTION

 As illustrated in Table 12, we can clarify the following: The sample mean after the improvement took place was decreased from 1340.6 to 284.84, which mean that we reached the target 500 cfu/ml. The sample standard deviation after the improvement took place was decreased from 512 cfu/ml which considered a high value to 166 cfu/ml.. Variations in the control chart figure (17) before improvement took place have obviously-been eliminated in control chart Fig. 18 which means, there are no points out of control.

The approximate P values for Mixtures were-increased to be higher than 0.05 after improvement took place.

CONCLUSION: After identifying, the root causes of the bacterial count of coating solution, the Systematic use of the Six-Sigma Methodology through the research, ensured savings in terms of money and give safety (D.E.T) for patient.

ACKNOWLEDGMENT: We are so grateful to the staff members of Misr University for Science & Technology and Arab Academy for Science and Technology, for their kind support.

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    How to cite this article:

    El-Menhawy A, Mohamed NM, Arafa HA, and Abd Elmonem AR: Improving the Performance of Pharmaceutical Tablet Production Using Six Sigma Methodology (Modulation on Digestive Enzyme Tablet). Int J Pharm Sci Res 2015; 6(8): 3580-93.doi: 10.13040/IJPSR.0975-8232.6(8).3580-93.

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