UNIVERSITI TEKNIKAL MALAYSIA MELAKA

INVESTIGATION OF EFFECTIVENESS AND CLEANLINESS OF AUTOMATED BLOW FILL SEAL PROCESS IN

PHARMAUCEUTICAL INDUSTRY

Thesis submitted in accordance with the partial requirements of the Universiti Teknikal Malaysia Melaka for the

Bachelor of Manufacturing Engineering (Robotic and Automation)

By

MOHAMAD HAFIZEE BIN YAACOB

Faculty of Manufacturing Engineering May 2007

SULIT

TERHAD

TIDAK TERHAD

(Mengandungi maklumat yang berdarjah keselamatan atau kepentingan Malaysia yang termaktub di dalam AKTA RAHSIA RASMI 1972)

(Mengandungi maklumat TERHAD yang telah ditentukan oleh organisasi/badan di mana penyelidikan dijalankan)

(TANDATANGAN PENULIS)

Alamat Tetap: PT 239 KG. KEDEMIT 16259 WAKAF BHARU KELANTAN Tarikh:18/05/2007

Disahkan oleh:

(TANDATANGAN PENYELIA)

Cop Rasmi:

Tarikh: _______________________ * Tesis dimaksudkan sebagai tesis bagi Ijazah Doktor Falsafah dan Sarjana secara penyelidikan, atau

disertasi bagi pengajian secara kerja kursus dan penyelidikan, atau Laporan Projek Sarjana Muda (PSM). ** Jika tesis ini SULIT atau TERHAD, sila lampirkan surat daripada pihak berkuasa/organisasi berkenaan dengan menyatakan sekali sebab dan tempoh tesis ini perlu dikelaskan sebagai SULIT atau TERHAD.

BORANG PENGESAHAN STATUS TESIS*

UNIVERSITI TEKNIKAL MALAYSIA MELAKA

JUDUL: INVESTIGATION OF EFFECTIVENESS AND CLEANLINESS OF AUTOMATED BLOW FILL SEAL PROCESS IN PHARMAUTICAL INDUSTRY SESI PENGAJIAN: 2006-2007 Saya _____________________________________________________________________ mengaku membenarkan tesis (PSM/Sarjana/Doktor Falsafah) ini disimpan di Perpustakaan Universiti Teknikal Malaysia Melaka (UTeM) dengan syarat-syarat kegunaan seperti berikut:

1. Tesis adalah hak milik Universiti Teknikal Malaysia Melaka. 2. Perpustakaan Universiti Teknikal Malaysia Melaka dibenarkan membuat salinan

untuk tujuan pengajian sahaja. 3. Perpustakaan dibenarkan membuat salinan tesis ini sebagai bahan pertukaran

antara institusi pengajian tinggi. 4. **Sila tandakan (√)

MOHAMAD HAFIZEE BIN YAACOB

√

APPROVAL

This thesis submitted to the senate of UTeM and has been accepted as partial fulfillment

of the requirements for the degree of Bachelor of Manufacturing Engineering

(Robotic and Automation). The members of the supervisory committee are as follow:

………………………………………….

Supervisor

Muhammad Hafidz Fazli b Md Fauadi

Faculty of Manufacturing Engineering

(Official Stamp & Date)

DECLARATION

I hereby, declare this thesis entitled “Investigation Of Effectiveness And Cleanliness Of Blow Fill Seal Automated Process In Pharmaceutical Industry

” is the results of my own research except as cited in the reference.

Signature : ……………………………………………..

Author’s Name : ……………………………………………..

Date : ……………………………………………..

i

ABSTRACT

This thesis describes the inspection process and requirement for Blow Fill Seal

Automated for the Pharmaceutical Industry. This thesis describes the cleaning process

which consists Clean In Place (CIP) and Sterilization In Place (SIP). The processes are

Clean In Place (CIP) and Sterilization In Place (SIP). Both the cleaning process is to flush

the all particle in Piping, inlet and of the machine. For the inspection process it is very

critical for the pharmaceutical products this to be inspected effective and in short time

before being delivered. Eye inspection by human is prone error. Therefore this thesis

propose the use of machine vision to carry out the inspection tasks. The digital camera is

use to capture image of product to be analyze using vision system. Automated inspection

would reduce human error in executing inspection task.

ii

DEDICATION

1 dedicate this PSM thesis to my beloved parents, Khadijah Mohd Yusoff and Yaacob

Awang,my beloved young brother Muhamad Khusyairie Yaacob

iii

ACKNOWLEDGEMENTS

Bismillahirrahmanirrahim. Alhamdullillah, with the helps and blessings from Allah

S.W.T., 1 had managed to complete this project succesfully. First of all, I would like to

thank my parents, for their concern and support, all over the time. Not forgotten my

brothers and sister, who had helps me a lot supporting me physically and morally.

I also want to thank Mr. Muhammad Hafidz Fazli Fauadi from Manufacturing

Engineering Faculty, UTeM, for supervised me all along this project, and provide helps,

guides, ideas, and suggestions to accomplish this project. All the supports and motivation

that been given to me are greatly appreciated.

Also not forgotten, Mr. Hamdan Nazeri Zainal Abidin and Mr. Rizal Mohd Nawi from

Production Department, Ain Medicare Sdn. Bhd for giving a cooperate for this case

study from beginning until finish this report.

With a deep sense of gratitude, I would also like to express my sincere thanks to my

colleague, Noorul Manan, Irwan Shah, Faizul, Hafizan and Muhammad Zhafran for the

helps and supports that been shown by them.

Finally, last but not least, thanks to all my friends who had helped me directly or

indirectly in completing this project and thesis in time.

iv

TABLE OF CONTENTS

Abstract ………………………………………………………………..i

Dedication …………………………………………………………… …ii

Acknowledgement …………………………………………………… iii

Table of Contents ……………………………………………………….iv

List of Figures ………………………………………………………………vii

List of Tables ………………………………………………………………..x

1. INTRODUCTION ………………………………………………...1

2. LITERATURES REVIEW ………………………………………...5

2.1 Introduction ………………………………………………………...4

2.2 Bottle Producing Process………………………………………………… ...5

2.2.1 Water Production ……………………………………………....5

2.2.2 Line Process …………………………………………………....8

2.3 Automation Element ………………………………………………….21

2.4 Machine Vision…………………………………………………………… ..23

2.4.1 Introduction………………………………………………………….23

2.4.2 Basic Component…………………………………………………….23

2.4.3 Working Procedure…………………………………………………..25

2.5 Application ………………………………………………………………… .31

2.5.1 Inspection…… ………………………………………………………..24

2.5.2 Case Study For Vision System Inspection…………..………………...32

3. METHODOLOGY........................................................................................35

3.1 Problem Definition………………………………………………………….37

3.2 Choosing the Thesis Title…………………………………………………....38

3.3 Propose and Submit the Thesis Title………………………………………...38

3.4 Literature Review……………………………………………………………38

v

3.5 Data Collection from Company…………………………………………….40

3.6 PSM 2…………………………………………………………………..…..41

3.7 Project Analysis (Current Condition)…………………………………..…..41

3.8 Automation Improvement………………………………………………..…42

3.9 Testing the Improvement…………………………………………………...42

3.10 Conclusion……………………………………………………………..….45

4. COMPANY BACKGROUND……………………………………………46

4.1 Manufacturing Facilities……………………………………………………..48

5. RESULT…………………………………………………………………....49

5.1 Data Collection………………………………………………………………..49

5.1.1 Leak Bottle Head……………………………………………………...49

5.1.2 Dirty Body Defect.………………………………………………...…..50

5.1.3 Dirty Cap Defect.……………………………………………………...51

5.1.4 Volume Defect.………………………………………………………..51

5.1.5 Scratch Defect.………………………………………………………...52

5.1.6 Particle Defect..………………………………………………………..52

5.2 Defect Analysis…………………………………………………………….….53

5.2.1 Leak Bottle Head…………………………………………………..….53

5.2.2 Dirty Body…………………………………………………..…..…….55

5.2.3 Dirty Cap…………………………………………………….………..56

5.2.4 Volume.………………………………………………………….…....57

5.2.5 Scratches……………………………………………………………....58

5.2.6 Particle………………………………………………………………...59

5.3 Vision System Testing Result…………………………………………………..67 5.3.1 Experimental Layout…………………………………………………..67

5.4 Image Processing……………………………………………………………….75

vi

6. DISCUSSION………………………………………………………………..79

6.1 Introduction ………………………………………………………………….....79

6.2 Layout Proposal For Vision System Inspection………………………………...79

6.2.1 Effectiveness Calculation…………………………………………………81

6.3 Layout operation Flow Chart…………………………………………………...83

6.4 Image Processing…………………………………………………………….…86

6.5 Conclusion……………………………………………………………………....86

7. CONCLISION…………………………………………………………….....87

7.1 Project Summery………………………...……………………………………87

7.2 Recommendation For Future Work Study……………………………………88

REFERENCE

APPENDIX A

APPENDIX B

APPENDIX C

APPENDIX D

APPENDIX E

APPENDIX F

APPENDIX G

vii

LIST OF FIGURES

2.1 Water Treatment Flow Chart Process 5

2.2 The whole process for bottle pack line 8

2.3 Dispensing Raw Material 9

2.4 CIP Scheme of the product lines of bottle pack 13

2.5 Sterilization of the product and air system of bottle pack 14

2.6 Scheme of the sterilization path: connection bottle pack 15

2.7 Bottle Transfer 16

2.8 Mirror Welding 16

2.9 Loading Inspection 17

2.10 Sterilization and Autoclaving 17

2.11 Visual Inspection 18

2.12 Labeling Product 18

2.13 Sealing and Packaging 19

2.14 Palletizing 19

2.15 Quarantine Process 20

2.16 Delivery 21

2.17 Mandrel Die-ring 22

2.18 Raster Scan of Machine Vision System 26

2.19 The shape of object is irrelevant in array of its histogram 31

of pixel count at each gray level

2.20 A Machine Vision View the Printed Circuit Board 33

2.21 Actual Size a 100-pin gull-wing Bumpier 33

Quad Flat Pack (BQFP)

2.22 Machine Vision System close-up of 100-pin 34

2.23 Robotic Flexible Assembly 34

3.1 Project Methodology Flow Chart 37

4.1 Organization Chart 47

5.1 Leak Bottle Head Defect 50

viii

5.2 Dirty Body Defect 50

5.3 Dirty Cap Defect 51

5.4 Volume Defect 51

5.5 Scratch Defect 52

5.6 Particle Defect 52

5.7 Leak Bottle Head Defect 53

5.8 Bottle Miss Position after Release From BFS Machine 54

5.9 Over Air Pressure for Blowing Process 54

5.10 Dirty Body 55

5.11 Dirty Cap Defect 56

5.12 Volume Defect 57

5.13 Filling Process 57

5.14 Scratch Defect 58

5.15 Mould Release Bottle 58

5.16 Particle Defect 59

5.17 January BFS Rejection Percentage 60

5.18 February BFS Rejection Monitoring Percentage 60

5.19 Conventional Visual Inspection 65

5.20 Puncher Location 65

5.21 Optical Chart 66

5.22 Experimental Layout 68

5.23 Good Product Testing 71

5.24 Scratch Result 71

5.25 Dirty Body Result 72

5.26 Volume Defect Result 73

5.27 Result of Particle Defect 73

5.28 Vision System Testing Graph 74

5.29 Grab Object Coding 76

5.30 Convert The Image To Black And White Image 76

5.31 Comparing Image 77

5.32 Decision Making 78

ix

6.1 BFS Vision System Layout 80

6.2 The Vision System Sequences for BFS 80

6.3 Layout Distance 81

6.4 BFS Vision System Flow Chart Operation 85

x

LIST OF TABLES

2.1 The processes executed by BFS machines 10

5.1 Parameter of Experiment 68

5.2 Vision System Testing Result 70

6.1 Measurement and Timing for BFS Layout 81

1

CHAPTER 1 INTRODUCTION

1.0 Introduction

In the modern medical treatment, pharmaceutical solutions were the packed usually

in plastic bottle. It very safe compares with former time them usually using glass as a

packaging container or the empty plastic by using conventional filing process. Such

process required extensive precaution for manufacturing pharmaceutical sterile

product due to the difference local positioning the individual manufacturing steps,

which usually in relatively high production costs.

In the current technology, the Blow Fill Seal Process (BFS) is characterized

by the fact that the sterile plastic container production as well as the sterile filling and

closing of the container of the performed at the same place.

This technology was developed by the Germany Company called Rommelag

group since 1960s and it was already at the end of the 1960s. On 1970s when the

bottle pack Blow Fill Seal (BFS) machine were applied for pharmaceutical solution.

Start from early day, the solution used were mostly large volume products like post-

sterilized influence. However today, the Blow Fill Seal machine can produce many

type of volume, such small volume unit-dose for injection, contact lens cleaning

solution, food industry, eye drop solution and other solution.

The plastic materials for manufacturing the container offer a considerable

higher flexibility in the design of packaging compare to the glass packaging. When

using plastic as a bottle pack material, every thing is possible to containers with

2

round, oval, angular cross section or bellow bottle design. The flexibility also allows

mould closure design which can meet the requirement of a special product

application.

For the course time, diversification of blow fill seal machine program took

place in order to cover difference capacity needs. At the same time, the individual

components were developed further in the order to meet the increasing requirement

of the clients and authorities of the pharmaceutical sector.

The Blow Fill Seal machines normally operate after water preparation,

product preparation and sterile filtration. The filling product is fed in sterile condition

to the bottle pack blow fill seal machine. The plastic granulate is transported from the

resin material storage to the blow fill seal machine. This processed there to plastic

packaging, filled with the filling product and sealed immediately.

The essential components of the blow fill seal machines themselves are a

resin-extrusion equipment and container molding system with the integrated dosing

process as well as separated cabinet modules where motors, pump, ventilator, valves,

and electrical installation to control the machine.

The blow fill seal process start with the forming of the plastic container.

Usually they use the low, medium and high density polyethylene as well as melted,

homogenized and extruded as plasticized parisons. In the blow process, the extruder

parisons are molded as container in the mold. After that, they are filled immediately

at the same position by dosing needles with the requested filling quantity. After

completion of dosing, the filling mandrels rise vertically to their upper rest position

and special closing tools weld the container hermetically, where the requested

closure is welded by vacuum. After that the entire mold opens and the container is

discharged the cycle begins again. The duration time to complete this process is

depending on the container design and the filling quantity between 10sec until 18sec.

3

In the pharmaceutical industry, the Blow Fill Seal product called Intravenous

Solution (IV Drips). The IV Drips function is to supply of nutrition with or without

medicine direct into the blood stream of the patient. This solution must be clean from

any contamination, sterile from any microorganism and non-pyrogenic substance and

temper bottle. The nutrition content can be one or a mixture of carbohydrate, mineral

salts, protein, fats and vitamins which are needed daily for patient’s survival. The

nutrition in IV drips is in the simplest form and can be absorbed by the human body

direct without with other process. This solution administered intravenously cannot be

removed from the patient by any mechanical or other means. In medical field, IV

drips is very importance because patients need nutrition daily to survive, recover and

recuperate their body. They also cannot and drink by usual means. They must used

this IV Drips to produce energy to survive. The IV Drips is a vehicle for antibiotic

and medicine treatment to treat the patient ailment.

The manufacturer must have relevant license certificate from National

Pharmaceutical Control Biro (NPCB) from Malaysia Ministry of Health. The issued

must issue by Malaysia Ministry of Health Director. Their certificate must renew for

annually. Manufacturer must conform to the requirement for good practice in the

manufacture and quality control as recommended by World Health Organization

(WHO) and the Malaysian guideline on Good Manufacturing Practice. If any

manufacturer not fulfills the Malaysian guideline or their product fails such as not

sterile, pyrogenic, wrong labeling, wrong concentration and Good Manufacturing

Practice by NPCB, the line process can be close.

4

CHAPTER 2 LITERATURE REVIEW

2.1 Introduction

When we look at the plastic bottle, can we think how to produce that bottle?

What the material they used? For this project we want to describe how to make it?,

what the machine they used? What the automation element at the machine?.

Basically, the plastic bottle produce by lower density plastic (LDPE). The main

industry used this bottle is the pharmaceutical industry and food industry.

For this thesis we want to describe effectiveness and cleanliness of blow fill

seal (BFS) technology in pharmaceutical industry. In pharmaceutical industry the

cleanliness is very important to use it because it must sterile process to avoid any

contaminations and sterile from microorganisms in the product.

The automation element also we discuss in this thesis. We can research about

the automation to support the product produce. This thesis also can discuss about the

down time for machining process.

5

2.2 Bottle Producing Process

2.2.1 Water Production

The bottle pack line process beginning with water treatment process. In this

process it involves their water producing for mixing with raw material at line mixing

room. The flow chart process shown in figure 2.1:-

Figure 2.1: Water Treatment Flow Chart Process

2.2.1.1 Raw Water Collection

It function is sucking up water from the ground (ground water) to the

Tubewell tank. It used one pump to operate this process. All water after

sucking keeping in storage tank to avoid for any contaminations and chemical

reaction. The tubewell capable to suck water 30m3/hour or 720m3/day. The

capacity of is 3500L/ period. Equipment involved are Tubewells and

Tubewell Storage Tank.

Raw Water Collection Equipment involved:

• Tubewell • Tubewell

Storage Tank

Treatment 1 Equipment involved:

• Aeration Tower

Treatment 2 Equipment involved:

• Dynasand Filter Tower

Treatment 3 Equipment involved:

• Softener

Treatment 4 Equipment involved:

• Ultraviolet Disinfection

Treatment 5 Equipment involved:

• Reverse Osmosis System

Treatment 6 Equipment involved:

• Mixed Bed Tank

Treatment 7 Equipment involved:

• Distiller

Treatment 8 Equipment involved:

• Deionizer Storage Tank

6

2.2.1.2 Treatment 1

The process of this treatment is to carry the water and air combining to

remove Ferum (Fe) and Mangan (Mn). In this process, Ferum (Fe3+) curve to

produce ferum Hidrokside [Fe(OH)3] at packing tower. This process very

importance because to increase the O2 dissolved. For remove Hydrogen

Sulfur (H2S) gas and carbon Monoxide (C2). Equipment involved is Aeration

Tower. The tower capacities are:-

- Input = 30m3/hour

- Output = 30m3/hour

- Total supply = 720m3/day

2.2.1.3 Treatment 2

Dyanasand Filter function is to filter and remove Suspended Particle in raw

water. This process is very important because to avoid their water from

microorganisms contaminations. Equipment involved is Dynasand Filter

.The Dynasand Filter capacities are:-

- Input = 30m3/hour

- Output = 27m3/hour

- Total supply = 648m3/day

2.2.1.4 Treatment 3

After raw water filter at the Dynasand Filter, the function of softener is to

mixing with raw water they move to the softener to softening process with

ion changing in the raw water with Natrium (Na+) supply by softener tank.

The main function of softener is to remove the bad particle from the raw

water. Equipment involved is Softener. The capacities of Softener are:

- Input = 4m3/hour

- Output = 4m3/hour

7

2.2.1.5 Treatment 4

To make sure a microorganism free, UV Disinfection using UV radiation to

activate the microorganism in the water the free the water from bad

microorganism. It can supply 12 000 l/day. Equipment involved is Ultra

Violet (UV) Disinfection.

2.2.1.6 Treatment 5

In this part were using membrane separation processes. This process is

removing impurities with semi permeable membrane to produce Reverse

Osmosis (RO) water. This water also call mineral water and properly to

drink. The equipment involved is Reverse Osmosis System.

2.2.1.7 Treatment 6

In the Mixing Bed Deionizer, the processes operate to change positive ions

and negative ions in the RO water with hydrogen supply by resin. The water

in this system called Purified Water. Equipment involved Mixing Bed

Deionizer

2.2.1.8 Treatment 7

The distiller function is to deionizer the water with heating process for

deionizer water in Evaporator Column with raw steam supplying from Boiler

House to produce distillate water. Equipment involved is Distiller.

8

2.2.1.8 Treatment 8

The function of this tank is to store the distillate water before mixing process

with their raw material. The capacity of this tank is 20000L/tank in 800C.

Equipment involved is Deionizer Storage tank.

2.2.2 Line Process

After water treatment process complete, Water in Deionizer Storage Tank must flow

to the mixing tank before mix with raw material. The block diagram following figure

2.2:-

Figure 2.2: The whole process for bottle pack line

2.2.2.1 Raw Material

Raw Material can categories for the two types, first category is bottle pack

material. The material using is LDPE for producing bottle. Second category

is water solution raw material. The raw material will be mix with deionizer

water in mixing tank. All raw materials coming from raw material warehouse.

Dipensing

Granulate

Mixing

Raw Material Blow Fill Seal Process

Transfer Bottle

Mirror Welding

Sterilization Labeling Sealing And Packaging

Loading Inspection

Visual Inspection

Pallettizing Finish goods Quarantine

Delivery

9

2.2.2.2 Dispensing

Figure 2.3 shown the Dispensing Process to produce the water solution.

Dispensing mean weighing process. The weighing process is to weight

their raw material for the water solution. [ European Pharmacopoeia

Commission 2005 ]

Figure 2.3: Dispensing Raw Material

2.2.2.3 Granulate Tank

The granulate tank which is a storage for bottlepack material. This tank

connected with BFS machine. When the BFS machine operate, the machine

suck with in a one tube to the material hope at the machine. [ European

Pharmacopoeia Commission 2005 ]

2.2.2.4 Blow Fill Seal Process

BFS machine is the main part for the bottlepack process. It is place where the

raw material for water solution and bottle producing will be combining. Table

2.1 show the processes executed by BFS machines. [Dr. R. Oschman, Dr.

Willmar Schwabe Gmbh, D-Karlsruhe, Germany, Dr. O.E. Schubert,

Hoffmann, CH Basel (1999)]

10

Table 2.1: The processes executed by BFS machines

Figure For Step Process Description

Step 1

Extrusion

• The transparent polyethylene containers of medium density

allow a post a post-sterilization of up to approximately

1100C.

• In the extrusion system, the resin is heated up to 1700C-

2300C, whereas pressure of up to 350 bar exist. The

container result in the sterility of the resin which is

discharged as parisons. In various challenge tests in which

bacterial inoculated resin contamination with the

endotoxines were used, no growth of germs was discovered

after evaluation and no endotoxines was proven to be in the

plastic granulate are surrounded by the plastic melt and

therefore cannot migrate from the packing into the product

Step 2

Molding

• When the parison is taken over by the mold, it is separated

by an incandescent cutting knife below the extrusion die and

within a second the mold with the parison move to the filling

position. Sterile air with which the parison was kept under

pressure escape at the upper opening of the parison and

avoids the surrounding air entering into the parison and the

sterility within the parison is kept.

• The mold has reached the blowing/filling position, the

combined blowing/filling mandrel moves from the upper rest

position into the open parison. The parison is then blown up

with sterile air and is pressed against the mold wall.

The machine preparation, the blowing and filling mandrel

are sterilized. Except during the blowing and filling. The

combined blowing and filling mandrel are the upper rest

position in a special sterile chamber where they are flushed.