Introduction In the last twenty years, pharmaceuticals have developed into a major sector in Bangladesh, contributing 11% to its

economy. A large number of multinational and local pharmaceutical industries have proliferated during this time. Due to this rapid growth, a vacuum for pharmacists has been created which is being increasingly met by private universities in addition to the public sector. East West University (EWU) is one of the pioneers in this field, operating its Bachelors in Pharmacy program since 2003. As par of the curriculum, students are required to complete an in-plant traineeship of six weeks which is aimed at gearing them towards gaining practical experience and consolidating theoretical expertise. As students of EWU, we chose to do our traineeship at Popular Pharmaceutical Ltd., because of its cutting-edge technology, and compliance with global quality standards. In this report, we discuss our insights into the structure, functioning of the plant Tongi. About Popular Pharmaceutical Popular Pharmaceuticals Limited is established in compliance to all the norms to become a Global Company. This is the only company in Bangladesh having five separate and dedicated facilities on over 6 acres of land for the manufacture of variety of formulations like Human Insulin, Low molecular wt heparin, Cephalosporin, Penicillin, Ophthalmologic, SVP, Dialysis Fluids, and LVP etc. Besides its regular formulations like solids (Tablets, Caplets, Capsules), liquids (Syrup, Suspension, powder for suspension), creams & ointments. PPL has the highest initial investment to establish the most modern, State-of-The-Art Pharmaceutical manufacturing facilities in Bangladesh and already marketed more than 150 formulations with first time introduction of a number of molecules and formulations in the country. There are also good numbers of novel products and formulations in the pipeline to be launched shortly in the market. Popular Pharmaceuticals Ltd. (PPL) has developed its export portfolio from the very 1st year of its operation capitalizing on its strict compliance to WHO cGMP standards and initiated proceedings for export its products to the developed countries that demand stringent regulatory requirements, in addition to the less and moderately regulated countries 1

where products from Bangladesh are currently being exported. PPL has started moving Global by exporting its first commercial consignment to Kenya during the first week of December, 2006. This is the quickest export for a pharmaceutical company in Bangladesh, within the 16th month of its commercial launching in local pharmaceutical market. Popular Pharma started exporting its products to Sri Lanka from September 2007 and to Macao from December 2007. Products from Popular Pharmaceuticals Ltd. are also expected to become available soon in Singapore, Philippines and some other African countries including Libya Tanzania, Nigeria etc.

Solid & Liquid Department Main dosage forms manufacture by Popular Pharmaceutical in their Solid & Liquid Department given below. Tablet Capsule Syrup Suspension Dry suspension Cream Ointment

Machineries & Equipments List (Production for Solid & Liquid): NAME OF MACHINE Cosmic/Bin mixer Drum blender fluidized Bed dryer(FBD) Cone mill Lifting & tilting machine Super manufacturing granulator(SMG/RMG) Tablet compression machine 370 Tablet compression machine 15S Automatic film coating machine Blister machine Printing machine(lnner carton batch printing) Powder loader Sieving machine Capsule filling machine(powder & pellet) Coating machine Bottle washing machine Bottle filling & Cap locking machine Syrup manufacturing machine Ointment/Cream/Gel/Lotion manufacturing machine MODEL Yenchen Nipun Pam Glatt Yenchen Yenchen Yenchen Sejong Sejong N.R. Industries Noak Morico overprinter Sejong Gansons Zansi 40F Yenchen Pharmalab Pharmalab Pharmalab Pharmalab CAPACITY 500 liters 40rpm 80 liters 120-1 50 kg/400 lit 300 kg/hr 150 kg/batch 120-150 kg/batch 50rpm,222000 tab/hr 6orpm,61000 tab/hr 800 strip/mm 7000packlhr 50-1 00 kg 100 kg 6pm ,48 capsule bosh 50-1 00 kg/batch 100-1 20 bottle/mm 6 channels,100 bottles\min 1500 liters 100 liters ORIGIN Taiwan Bangladesh India Taiwan Taiwan Taiwan Korea Korea Thailand Germany Japan Korea India Italy Taiwan India India India India

Ointment/Cream/Gel/Lotion filling machine Bottle labeling machine

Pharmalab Pharmalab Table: 01

42 unit/min 110-150 label/mm

India India

Materials Receiving System for Solid & Liquid Department: Materials for production are received by following way Requisition for BMR & BPR by the production department to QA department Requisition for RM & PM by production department according to BMR & BPR

Approved by Production Manager Issued by Warehouse Manager

Dispensing by dispensing Pharmacist

Checked by QA Officer Dispensing Pharmacist Received by Production Officer Fig: 01

Product Change Over:

Product change over means the changing and cleaning process of production machineries parts, production room & other equipments after production of every batch or every products. Example: In case of tablet compression, product change over includes the cleaning and changing process of tablet compression machine such as die, punch and all of the contact surface. This function is very important to prevent product to product cross contamination. Packaging Line Clearance: It means clearance of every packaging materials of previous batch of same or different product before packaging started. - Previous product must be removed. - Previous packaging materials must be removed. - Check by QA officer. Machine operation & cleaning: Most of the machines are PLC (Programmable Logic Control) controlled. Some machines are manually controlled. Operated by skilled operator. Some machines have CIP (Clean in process) system such as coating machine. Some movable parts such as dies, punches and disc are discharged to clean in cleaning room. In cleaning process the following materials are used: 1. Tape water, Purified water. 2. Sodium lauryl sulphate 4% (SLS) for all machines 3. JET 4. 70% IPA (Iso-propyl alcohol). 5. Sodium bicarbonate for coating machine 6. Compressed air for plastic bottle. Prevention & Maintenance system: HVAC system maintains Clean Corridor Concept (Corridor with positive pressure). Gown, musk, hand gloves, ear muffle are used to prevent contamination. Sandwich wall (45 mm diameter) maintains pressure; prevent passage of air, dust, no sedimentation & ease to clean. Epoxy paint in the production floor facilitate easy clean & dust free. Cleaning room with every production floor. SOP for all important activities. Skilled operators. Regular training for operators.

TABLET MANUFACTURING PROCESS

Dry Granulation

Dispensing

Wet Granulation Dry mixing of API & Excipients by RMG

API & Excipients

Sieving

Binder preparation: Paste or solution form

Wet mixing: By RMG

Slugging: By compression Machine Crashing: By Multi Mill

Mixing is continued until a lump formation is observed Direct compression Wet milling: by Cone Mill discharge of wet Granules by using appropriate mesh (generally 8mm) Drying: By fluidized Bed Dryer (FBD)

Sieving

Mixing: Drum mixing

Lubrication

Blending: Bin mixer

Sizing or crushing: According to the - specification by BMR

Tablet compression Coating Core Tablet Packaging Coated Tablet

Warehouse Fig-02 Capsule encapsulation flow:

There are two types capsule filling: 1. Pellet filling process 2. Powder filling process Pellet filling process Hopper containing Pellets Dispensing Capsule shells (Body & Cap) Separated by vacuum pump Vacuum pipe Rotating disc (upper & lower)

Body to lower bush Check unseparated Shell & rejected by sensor Body containing Pellets Locking

Cap to upper bush

Ejection

Packing Fig-03

Powder filling process

Dispensing

Sieving

Blending Fig-04

Encapsulation

Packaging

Ointment manufacturing flow & control:

Dispensing

Oil: Hydrocarbons base melting & mixing at 1000 C into manufacturing stainless steel vessel.

API stirring at 40 rpm at 60C into another stainless steel vessel.

Mixing: Cooling to 60 C starring for 30min

WIP

Filling

Packaging Fig-04

BMR, BPR & its activity & regulations:

BMR means batch manufacturing record. In this documentation process the following guideline is given about manufacturing of a batch of product: BMR includes the following records: 1. 2. 3. 4. 5. 6. Product name Batch no. Batch size Batch Quantity Manufacturing procedure Name of product materials with required quantity & Pharmacopoeias or In-House Specification (IHS) 7. Product order number 8. Date of requisition 9. Date of commenced 10. Date of completion 11. Product line clearance 12. Change over checklist for production line 13. It must be checked by QA officer etc. BPR means Batch Packaging Record. In this documentation the following guideline is given about packaging of a batch product: BPR contains following records: 1. Product name 2. Batch No 3. Batch size 4. Batch Quantity 5. Name of packaging materials with required quantity 6. Pharmacopoeias or IHS specification 7. Date of requisition 8. Date of commenced 9. Date of completion 10. Product order number 11. Packaging line clearance 12. Change over checklist for packaging line 13. Bulk product received 14. Carton over printing record 15. Printing line clearance 16. Over printing inspection 17. It must be checked by QA officer etc. Packaging Line Clearance:

It means clearance of every packaging materials of previous batch of same or different product before packaging started. Previous product must be removed. Previous packaging materials must be removed. Check by QA officer.

Machine operation & cleaning: Most of the machines are PLC (Programmable Logic Control) controlled. Some machines are manually controlled. Operated by skilled operator. Some machines have CIP (Clean in process) system such as coating machine. Some movable parts such as dies, punches and disc are discharged to clean in cleaning room.

Following materials are used for the cleaning 1. 2. 3. 4. 5. 6. Tape water, Sodium lauryl sulphate 4% (SLS) for all machine JET 70% IPA (Iso-propyl alcohol). Sodium bicarbonate for coating machine Compressed air for plastic bottle.

Prevention & Maintenance system: HVAC system maintains Clean Corridor Concept (Corridor with positive pressure). Gown, musk, hand gloves, ear muffle are used to prevent contamination. Sandwich wall (45 mm diameter) maintains pressure; prevent passage of air, dust, no sedimentation & ease to clean. Epoxy paint in the production floor facilitate easy clean & dust free. Cleaning room with every production floor. SOP for all important activities. Skilled operators. Regular training for operators.

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Shop floor planning: The overall arrangement of production floor during production which involve Packing material scheduling Machine scheduling Product scheduling Manpower scheduling

And this planning occurs by the three phase in a month. This is very much useful for the appropriate utilization of existing resource. And it also prevent system lose in the production area. Productivity, Capacity utilization: This plant, for now only uses 20% of its full capacity. It also does contract manufacturing for various companies (Healthcare Pharmaceuticals, Novo Pharmaceuticals, ACI, etc) utilize its capacities properly.

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Sterile Department Type of dosage form of sterile products: 1. Ophthalmic 2. Injectable 3. Powder for injection (Vial) Environment Monitoring: Environmental monitoring is one of the most important tasks in the sterile department. It is a regular check of view to take timely corrective measures for maintaining a favorable manufacturing environment, minimizing the risk of product contamination. It is also a part of validation exercise. The environmental monitoring approach is also adopted to ensure that there is no significant risk of air borne cross-contamination. Serial no 01 Name of control measure Zone concept Description Class A(100),Class B(100),Class C(10000),Class D(100000) (Ft) Class A:60 times/hr, Class B:50 times/hr, Class C:3Otimes/hr,Class D:10 times/hr Positive pressure must be maintained in the processing room & 10-15 Pascal higher than in the adjacent rooms. 0.3 micron & 99.997% efficacy. It determines the effectiveness or potential of the clean air to protect the aseptic area from external contamination. Class A:<1 per plate per 4 hours, Class B:<5 per plate per 4 hours, Class C: <50 per plate per 4 hours, Class D: <100 per plate per 4 hours. (22 2)C, (505) %

02

Air change rate

03

Air pressure difference

04

HEPA filter integrity

05

Microbial growth monitoring

06

Temperature & humidity

12

07

control Laminar air flow cabinet Table: 02

Relative humidity. Placed under HEPA filter. Air velocity 0.45 m/sec

Particle count: Class Particle count at rest m 0.5 5 3500 0 3500 0 350000 2000 3500000 20000 Particle count operation m 0.5 5 3500 0 350000 2000 3500000 200000
Not defined Not defined

Microbial growth (cfu) -<1 <5 <50 -

A B C D

Table: 03 Aseptic Room Preparation: The purpose of the aseptic technique is to prevent microorganisms from the environment. To design of an aseptic room the following factors must be borne in mind: 1. Site 2. Size 3. Windows 4. Doors 5. Surfacing materials 6. Services 7. Corridors The aseptic procedure comprises the following steps: 1) Sterilization of equipments 2) Sterilization of containers 3) Sterilization of gown. 4) Filling of the solution in the containers under aseptic conditions 5) Double door air lock system. 6) Pass box for materials. Filling containers under aseptic conditions is the most critical step in the production cycle. This technique is filtration sterilization. HEPA (High Efficiency Particulate Air) filter is used. The most effective ones are claimed to retain 99.997% of the particles. Laminar Air flow cabinet is used under HEPA filter. Filling area is class-A zone whereas the background is class-B zone. The processing rooms must be supplied and flushed with air under controlled positive pressure. Sterilization: Sterile products can be classified in two classes: 13

1. Products which can be sterilized in their final container. 2. Products which must be processed under aseptic conditions since they cannot withstand the common methods of sterilization. Most sterile preparations are aqueous solutions and the method of choice for sterilization is autoclave. There are two types of sterilization: Name of sterilization Dry heat sterilization Moist heat sterilization (Autoclave) Description 250C, 45 minutes. Glass container(vials), 18O7 hr Closed mouth ampoule 121C, 30 minutes. Dress, machine parts, flips off slip, rubber stopper. Table: 04 Gowning System: In the manufacture of sterile drugs Gowning System is most important. 1) The gown must be sterilized and made of material which will not shed particles. 2) Everyone entering a clean or a sterile area must change gear garments and wear special garments which includes head, musk and footwear. 3) The number of people must be as low as possible and restricted to authorized people.

LVPL

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LVPL stands for large volume parenteral liquid. Popular Pharmaceuticals Ltd. produces a variety of infusion products Glucolin- Dextrose 5% w/v Glucolin DS- Dextrose 10% w/v Glucosal-Dextrose 5%w/v and Sodium Chloride 0.9% w/v Electrosal- Hartmanns solution Kolosal- Cholera saline Normalin- Sodium Chloride 0.9% w/v Civox- Ciprofloxacin 0.2% w/v Levobac- Levofloxacin 0.5% w/v Metonid- Metronidazole 0.5% w/v Flowchart showing the manufacturing of infusions

Aseptic dispensing

Mixing in the 3500L manufacturing vessel

Filtration is done using 1.2m and 0.2m cartridge.

Filling in Pluemet Filling and sealing Machine

Arranging the infusion bags in the trolleys for autoclave

Autoclave at 121C for 30 mins in the Fedegari autoclave

Packaging

Fig-05 Cleaning and Maintenance: The manufacturing vessel is fitted with a mobile auto cleaning in place (CIP) and sterilization in place (SIP) unit from Pharmalab. CIP is done with 80-90 C WFI. 15

When filling starts the first 8 to 10 bags are rejected to make sure the cleaning WFI is fully expelled from the system. In-Process Control: a leak test is carried out on the infusion bags by random sampling. Quality Control (QC): After mixing and before filtration 250ml of solution are sent to QC to test pH and weight/ml. The first and the last filled bags are sent to QC for bio-burden (endotoxin and microbiological test) .After autoclave around 23 bags goes to QC for sterility tests. Popular infusion products use Poly propylene (PP) bags which is of better quality than the PVC bags that are widely used because the plasticizers PVC bags used have been shown to bioaccumulate and lead to reproductive problems.

Dialysis Popular Pharmaceutical Ltd is one of the very few companies to produce Hemodialysis fluid. It currently produces 3 dialysis fluids 16

Dialyte A- acidic component (pH 1.8-2.8) Dialyte AC- basic component (pH 8.1-9.1) Dialyte B - pH 7.5-8.5

Flowchart of the Dialyte manufacturing process

Dispensing

Mixing Samples sent to QC to test pH and wt/ml

Filtration using 1.2m (pre-filter) and 0. 2m (final filter) cartridge.

Filling using Pharmalab filling machine .

Manual capping IPC: weight should be within specifications

Manual labeling

Packaging

Fig-06 Package cleaning: The primary packaging of dialyte fluids is canisters. The outside of the canister and cap is wiped with Clotech (sodium hypochlorite 5.25%). The inside of the canisters is first washed with portable

17

water , than Clotech solution and then with hot purified water. After that they are left to dry and then they are ready to be filled. Integrity test: This test is carried out to test the efficiency of the cartridge after filtration of every batch. The Bubble point test is carried out using the machine Sartocheck Junior. Amino acid production flowchart
Dispensing

Mixing in the manufacturing vessel Samples sent to QC Filling in Pluemat filling machine Bottles washed in Yenchen Bottle washing machine

Sealing and rubber stoppering

Terminal sterilization in Celester Sterimega at 121C Samples sent to QC for bio-burden test Visual Inspection

Packaging

Fig-07

Cephalosporin

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Cephalosporins are a group of semisynthetic antibiotics derived from cephalosporin-C obtained from a fungus Cephalosporium. They are chemically related to penicillins. Popular Pharmaceuticals Ltd. has a dedicated plant for cephalosporin manufacturing & packaging. Its has the facility to manufacture a wide range of dosage forms. Cephalosporin manufacturing floor is maintained as aseptic room & entry is restricted to authorized person. EQUIPMENTS USE IN CEPHALOSPORIN PLANT: Process Vial washing Sterilization filling & Sealing Label printing (vial) Vial blistering Bottle washing Bottle drying Filling Cap sealing Lubrication(final blending) Crushing Dispensing Sieve Dry mixing Compression Coating Encapsulation Polishing & Sorting Blistering Name of Equipment Macofer (Italy) Jet Printer (Image) Hoonga Semi automatic Rotary bottle washing machine Bottle Dryer Auto Powder Filling machine Auto Cap Sealing machine Drum Blender Multi Mill Sartorius balance(Germany) Sifter with mesh, Hand sieve (40 mesh) Cosmec Blender, Drum Blender Cadmach Compression machine Automatic film coating machine Auto capsule filling machine Sejong Cap Polishing & Sorting Hoonga Table-05 Capacity 9000 /hr 2800 /hr 6000 /hr 1500 bottle/hr 32 Trays 40 bottle/min 40 bottle/min 80L NA 150 kg NA 750 L, 80 L 20000 tab/hr up to 22 kg 40000 cap/hr 100000 cap/hr 25 unit/min

Environment monitoring Environment monitoring is depends on the Temperature & Humidity. 19

Generally: Humidity - 222 C Temperature - 455 %

Condition for different portion is given bellow: 1. Tablet Humidity: Bellow 50% Temperature: Bellow 25C 2. Capsule Humidity: Bellow 50% Temperature: Bellow 25C 3. Drysyrup Humidity: Bellow 45% Temperature: Bellow 25C 4. Vial Humidity: Bellow 40% Temperature: Bellow 25C Powder for Injection filling Vial washing

Vial sterilization

Vial filling

Vial sealing

Vial inspection

Vial labeling Fig-08 Powder for suspension: Dispensing

Packaging

20 Dry mixing Cap sealing Sieving Filling Packaging

Fig- 09

Quality Assurance Quality Assurance (QA) means that products used by consumers should fulfill the need for which it was acquired. To achieve this end, a whole gamut of organizations, methods and

21

efforts are required. The whole process of assuring, that the quality of the product will be as stated or perceived, consistently, can be called quality assurance. ROLE of QA
Raw material specifications Packaging material specifications

Specified raw and packaging materials

Sampling by QC

Testing for specification compliance by QC Released Stored in warehouse QA inspection Bulk Manufacturing QA inspection Bulk product Packaging QA inspection Finished product QA release Release of finished product QA inspection Packaging

Fig-10 Validation may be defined as a means to prove that an equipment or process actually performs as per design or requirement. This is achieved by measuring any attribute that is possible to quantify. 22

Purpose of Validation: Validation is carried out to have better control of the manufacturing and related operations to ensure minimum deviations in actual production from the ones required by design. The benefit of such validation exercises therefore include better system control and maintenance and a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
URS: User Requirement Specification. Specifying the have and the have-nots of a machine

DQ: Design Qualification. The vendor and the company agreeing on the details of a machine

FAT: Factory Acceptance Test. This is basically a checklist which ensures the machine purchased is going to be fit the conditions of the

Rectify Shipment
SAT: Site Acceptance Test IQ: Installation Qualification

OQ: Operational Qualification

PQ: Performance Qualification

Machine gets qualified in pursuit of validation Fig-11

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Process Validatio nn

System Validation

Cleaning Validation

Computer System Validation

Analytical Method Validation (accuracy, precision specificity, sensitivity, ruggedness) Fig-12 Repeatability Reproducibility Meet pre-determined specifications.

Process Validation must have

In a validated process critical parameters are optimized. Each step of the manufacturing process should be qualified to validate the complete process. Dispensing: All the used balances are calibrated. The formulation is correct and authorized. All ingredients are dispensed in front of a QA officer. Encapsulation: Temperature and relative humidity are specified. Average and individual weights are monitored as per requirement. Filtration: The integrity of filters is checked after completion of the filtration. Filling/ Sealing: The condition of the room is checked by particle counters and settling plates. The particle count in Class A room should be below 100/f . All filling head should deliver the predetermined volumes as specified. Packaging: Line clearance is obtained prior to start up. All the stereos used for overprinting are of the current product lot. In-process control (IPC) is an integral part of Quality Assurance. IPC is done during the manufacturing of a product by carrying out tests to ensure certain specifications of the product are met. IPC basically guarantees that the validated process is running smoothly and the product has the desired quality. In-process controls are particularly important where a process may vary with time such as tablet weights, fill volume etc.

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Manufacturing Process In-process control ______________________________________________________________________ Tablets a) Dispensing b) Granulation c) Drying d) Compression Room condition Temperature and RH should be within specifications. Uniformity of the granules as well as granule size LOD( Loss on drying) Room condition, appearance of tablets (Absence of capping, lamination, picking, sticking) Average weight, uniformity of weight and RSD, hardness, thickness and diameter of the tablet. Friability of the tablet as well the disintegration time are also checked. appearance of tablets( absence of bridging, filling, sticking, color variation), disintegration time Room condition, appearance of shell, average weight, uniformity of weight, RSD, disintegration time

e) Coating Capsules a) Encapsulation

Liquid dosage forms, Ointment, creams, gels a) Bulk Appearance, odor, color and pH b) Filling Fill weight, fill volume, sealing, appearance of filled liquids, presence of foreign materials. Ophthalmic a) Filling Fill volume Powder for suspension a) Bulk b) Filling Packaging a) Blistering, PP infusion bags Appearance, odor, color Room condition, fill weight, reconstituted volume, sealing of cap Leak test Table-06

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Documentation Documentation is an all pervading feature of Good Manufacturing Practices. It defines a system of information and control so that misinterpretation or error in oral communications is minimized. Documentation encompasses all the aspects of pharmaceutical production: Building and premises: installation, validation, cleaning, maintenance Equipment: installation, validation, cleaning, maintenance. Materials: specifications, testing, warehousing, use, rejection /disposal. Processing controls: individual steps in the process of manufacturing. Finished goods: specifications, testing, storage, distribution, rejection. These documents are designed and prepared with utmost care. All document have a Clear title An identification number be approved by authorized person( eg. Director of industrial operations) date of issue Any batch record usually consists of the following: Production order sheet Batch manufacturing record (BMR) Batch packaging record (BPR) Packaging order sheet Tablet or capsule inspection sheet Weight or volume inspection sheet Finished product test record sheet Retention Samples These samples of the final packaged formulation are kept with the objective, should the need arise at a future date during the declared shelf-life of the material or product, that they can be tested. Retention samples are preserved in the archive room along with the batch record for the duration of shelf-life plus 1 year. The quantity of the each sample is taken at least twice that necessary to carry out all the required tests, except those for sterility and pyrogens. Site Master File Site master file contains the complete layout and detailed information about the plants machineries, engineering, companys structure etc. It contains: General information Introduction Manufacturing licenses Manufacturing activities Manufacturing site Number of employees

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 Personnel

Outside technical assistance Quality management system Organogram Key personnel Training Health check up Premise and equipments Plant layout HVAC system Water system Major equipments Qualification and Validation Sanitation Documentation Preparation, revision, authorization, distribution Document list related to product manufacturing Production Production operation Material handling Reprocessing and rework Handling rejected materials Process validation Quality control Toll manufacturing Distribution, complaint handling, product release Audit

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Quality Control (QC) Quality control is the sum of testing and assessment. It is a part of Quality Assurance. Starting materials, intermediates and final products are tested to confirm their compliances with specifications. The responsibility of the quality control is to ensure that the starting materials, intermediates and final products are promptly tested to confirm compliance with specifications before their release. To perform functions of the QC, Popular Pharmaceuticals Ltd has a well equipped QC laboratory which is supported with trained analytical staffs. These activities actually ensure the product to be safe, effective, stable and acceptable to every person. Equipment used in Quality Control Department: Equipment HPLC(Quarternary) Model: [0-201 OAHT HPLC(lsocratic) Company Shimadzu Origin Japan Use Analytical Test: Identification Qualification Separation Analytical Test: Identification Qualification Separation Analytical Test: Identification Qualification Separation To reduce conductivity & particle size of water To identify and measure minerals. To prepare disc of IR Material identification & purity tests To measures total

Shimadzu

Japan

HPLC(Binary) Model:1100 series

Agilent

Germany

Water preparation for HPLC Atomic absorption spectrophotometer Model :AA-6300 Pressure machine Model: SSP-10A FT IR TOC Analyzer

Barnstead

USA

Shimadzu Shimadzu Shimadzu Shimadzu

Japan Japan Japan Japan

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Model: TOC-V cpH UV-Visible Spectrophotometer Model: UV_1650PC Conductivity Tester Model: PP-20 Seiving machine Automatic Polarimeter Model: AP-l 00 Viscometer Model: RVDV-I pH meter Model:RSP-42 Dissolution Tester Model: PTWS Melting Point Analyzer Model:FP62 Refractometer Model: DR-Al Water bath Model:1083 Centrifuge machine Model:Z400 Muffle Furness Microscope Model:CX-21 FSI Precision oven Model:0V453 Drying Oven Model: 100-800 Horizontal Shaker Model:3017 Weghing Balance ModelI:PB4002-s Potentiometry titrator Model:DX53 Karl Fischer titrator Model:DX3I Shimadzu Japan

organic Carbon in purified water A wide range analytical test. To test conductivity To do sieve analysis To determine Optical rotation Viscosity determination To determine pH Dissolution testing Identification To determine refractive index Controlled temp reaction Separation techniques To determine ash content Identification Drying Drying Shaking Analytical weighing Potentiometric titration for ions Moisture determination

Sartorius Fritsch Atago Brookfield Mettler Toledo Pharmatest Mettler Toledo Atago GEL Hermle Linn Hitherm Olympus Channel Memmert GEL Mettler Toledo Mettler Toledo Mettler Toledo

Germany Germany Japan

Switzerland Germany Switzerland Japan Germany Germany Germany Japan Germany Germany Germany Switzerland Switzerland Switzerland Table-07

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Major responsibilities of QC: Sampling adequately for testing purpose. Issuing release, reject or quarantine advice for each batch of raw, bulk and packaging materials. Assessment of the finished products for their release, reject etc. Maintaining batch wise full quality control test records with signature of the person(s) who performs the tests. Batch documentation. Performing Environmental monitoring checks. Calibration and standardization of laboratory equipment. Control of laboratory reagents. Analysis of complaint samples with their corresponding keeping samples.

GLP norms and regulations: To ensure a wide range of testing disciplines the laboratory has some facilities which are discussed in GLP. The major considerations that accounts for GLP functioning involves: 1. Organization & management: It is a basic requirement for establishing an effective QC system. A. QC department is a well organized department. He has the authority of approval or rejection of each batch of starting, packaging and final materials on the basis of testing. B. Personnel at all levels have accountability to carry out their responsibilities to meet the quality goal. 2. Personnel: Qualified personnel are a key factor in ensuring quality. Personnel have three important characteristics: A. Education. B. Experience. C. Training. 3. Premises: A well designed premise is an essential part of GLP. It has:

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A. B. C. D. E. F. G. H.

Adequate space allocations. Easy to clean Safety facilities Storage facilities Segregation of activities Proper environment for testing Every equipment has safety distance from others Microbiology lab is isolated from Analytical lab

4. Equipments: The laboratory is well equipped for performing all tests according to BP, USP. To maintain all equipments & machineries following measures are taken: A. B. C. D. Every equipment has a log book for records. Regular maintenance is done. All equipments are calibrated at specified intervals. Most of the equipments & machineries are connected with printers thus there remain no chance of manipulation.

5. Reference standards: Reference standards are substances with known purity or potency. Certified reference standards are available from many official sources. For routine laboratory tests it is worth considering working standards prepared by standardizing some good quality row materials against certified reference substance. A. A good stock of reference standards is maintained and used. 6. Reagents: To maintain reagents QC department has taken following initiatives: A. Laboratory has a complete list of all the reagents needed. B. Solid reagents are stored in alphabetic orders and separated from liquid reagents. C. The reagents need to be stored at low temperature is refrigerated. D. Flammable reagents have segregated area. E. Moisture sensitive reagents are stored in desiccants. 7. Procedure: For every operation in QC written instructions are available. It has master control procedure (MCP) for every materials. It has SOP for every action. SOP is constrictly followed by analysts. 8. Sampling: Appropriate sampling is a vital step in GLP. To facilitate correct and appropriate sampling procedures sampling must be done at conditions same as production environment e.g. sterile raw materials & products are sampled under laminar air flow.

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9. Testing: The incoming goods and finished products are tested according to BP, USP, EP as per requirement laid down specifications. 10. Documentation All test results are recorded on a test record sheet (TRS). All Q.C. records relating to a batch analysis are a part of the batch documentation. The purpose of documentation is to record important information with evidence. It is preserved at least one year after batch expired date. Quality control of raw materials: To achieve desired goals following measures are taken: 1. Materials receiving System: Raw materials of every batch must require with a full certificate of Analysis which is a definite binding on the part of the supplier that the materials meet the required specifications. Now a day, many reagents certificates are found on internet. After receiving the raw materials, a GRN (Goods Receive Note) recorded with details such as: materials name, suppliers name, total quantity, number of containers, manufacturers batch number (s), physical condition of the containers etc. The raw materials should remain in quarantine until sampled, tested and released or rejected by the laboratory. 2. Sampling: It is important that the QC personnel independently inspect the raw materials during sampling. Sampling is done by using sampling thieves. It takes materials from three positions from top, middle and bottom. If there is large numbers of containers sampling is done from n+2 containers, where n is the no. of the containers. 3. Batch release: The raw materials should be released in a batch fashion and with proper status labeling. Approved raw materials are marked green and available to warehouse staffs. If the raw materials dont comply with specifications, they are rejected and marked red label. Control of Packaging materials: Following characteristics are checked in packaging materials: Text of the printed materials. Color of the materials. Locking of cartoons. Compatibility of closures with bottles. Thickness of foils.

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 Real materials are used. Pasting of cartoons. Weight (gram per m2) of cartoons for checking materials. Control of Bulk Products: Each lot of bulk product is tested to ensure: Identity. Quality. Potency. Purity. Bulk products are tested following their MCP. Some products require compendial (BP/USP) procedures for testing. Control of finished products: Final testing of finished product is made in the quality control laboratories. The testing of finished product for compliance with predetermined standards is a critical factor for product release.

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Microbiology Equipment used in Microbiology: 1. 2. 3. 4. 5. 6. 7. Airborne Particle Counter: Used for 0.5 and 5; Climet Cl-20(USA) Dry Heat Sterilizer: Used for dry sterilization; Memmert (Germany) Autoclave: Used for preparation; Hiclave HV-85; Harayama, Japan Autoclave: Used for destruction; Hiclave HV-25; Harayama, Japan Incubator : For incubation; Memmert (Germany) Microscope: Max magnification l000x; Olympus CX-41 (Philipines) Refrigerator: Two compartment is available: Refrigerator: 2-8 c Freeze:< -120c

Environmental monitoring: Environmental monitoring is a check with a view of taking timely corrective measures for maintaining a favorable manufacturing environment, minimizing the risk of product contamination. Following techniques generally employed for monitoring: A) Airborne particle count (non-microbiological): This is done by using particle counter. B) Settle plate technique: Petridishes containing sterile microbiological growth media in agar are exposed to production area. Then it is incubated for 5 days at 30c. This visualize the microbial growth. C) Surface swabs technique: Sterilized swabs of cotton buds are moistened in a sterile diluents or a suitable liquid culture media. A specific area is then swabbed and the organism sampled from the surface is then smoothly rubbed over the supporting agar surface and incubated. This technique is employed to evaluate solid surface, garments, equipment, personnel for microbiological growth. D) Air sampling: Done for microbial growth in air. Airborne particle limit: Class Particle count at rest m 0.5 5 A 3500 0 B 3500 0 C 350000 2000 Particle count operation m 0.5 5 3500 0 350000 2000 3500000 200000 Microbial growth (cfu) -<1 <5 <50

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D Laboratory test:

3500000

20000

Not defined

Not defined

Table-08 A) Sterility test: It is done for raw materials and product materials. 14 days are require for sterility test. Two types: a) Direct method. b) Filtration method (mostly used). Condition require for microorganism test given below: Type of Organism Fungus Bacteria Time 5 days 3 days Table-09 Temperature 22C 25C 30C 35C

B) Limit test/Contamination test: This test is done for checking raw materials. Three types: 1) Pour plate 2) Spread plate. 3) Filtration. C) Endotoxin test/LAL test: It is an in-vitro test method for pyrogen, has been developed utilizing the gelling property of the lysate of amoebocytes of limulus polyphemus. Single test

0.25 ml in LAL and dissolve

Incubation at 37 C for 1 hr

Gel formation

Indicate presence of endotoxins

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Fig- 13 Warehouse Warehouse is the place where the bulk raw materials, packaging materials as well as finished products are kept at their optimum storage condition. Raw materials are tested as they enter the warehouse and they are transferred to the manufacturing department by requisitions. Materials Receiving System: a) Upon receiving the shipments labeling should be carefully checked to make sure that they belong to the same batch. Only materials from the same batch receive the same Good receival note (GRN) number. The GRN is the identification number for that raw material. b) The shipment should be inspected visually for damage. c) The materials are than carefully labeled Quarantine with the GRN number. d) The first people allowed opening the material labeled Quarantine are Quality Control (QC) officials. For active pharmaceutical ingredients QC takes samples from each and every container. However for excipients as well as packaging material the sampling is done n +2. The containers from which the QC has sampled are labeled sampled. e) After the materials have conformed with the specification they are released by QC authorities and are labeled released meaning they are ready to be used in manufacturing. f) Rejected materials should be clearly separated from the released materials. Rejected packaging materials containing the companys logo are destroyed. For raw materials that are the rejected the vendor is contacted immediately. Storage: Raw materials and finished products are stored according to their chemical or physical properties. Some raw materials and finished products are kept at normal room condition whereas products which are temperature sensitive are kept in - Cold room (2-8C) eg. insulin - cool room (8-15C) Finished products such as solid dosage forms are kept under lock and key. Pethidin containing product, because of the risk of abuse, is kept under strict lock and key and access is restricted to authorized personnel only. In order to prevent mix-up of printed containers and labeling materials, each printed packaging material is stored properly identified with the specific GRN number and code number and at the time issues the identity is checked very carefully.

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Dispensing: Close attention is paid to dangers of cross-contamination. Dispensing of raw materials are done in the presence of an authorized personnel from production and QA. Materials are dispensed according to the Batch manufacturing record (BMR). The remaining stock is recorded to make reconciliation of the stock possible at any time. During dispensing QA officer also checks the room condition to make sure the humidity and temperature are optimum for the raw material .Dispensing is done under laminar air flow to minimize dust generation and microbial contamination. All raw materials are dispensed in a first-expiry-first-out basis.

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Product Development Product Development (PD) is the department that is a responsible for the effective formulation of a drug. The stability, efficacy of a drug depends on its formulation. PD consists of two parts: Galenical & Analytical. PD is also responsible for creating BMR and BPR. Launching a new product involves a lot of work.

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Market study of the new product by PMD

Proposal from Product Management Department (PMD)

Evaluation of existing facilities Evaluation of the Manufacturing Department

Feasibility study by PD

Consulting with the Engineering Department Feasibility study by PMD

Cost Evaluation

Proposal Approved

Product File Open Raw materials procurement requisition according to QA specifications Lab batch produced by PD
Stability testing

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PMD approval

Galenical and Analytical method development and validation Pilot batch production (3 consecutive batches) Accelerated Stability testing (6 months) Recipe sent to Drugs Regulatory Authority (DRA) for approval Annexure approval Commercial production Fig-14 During formulation PD has to undertaken intensive research. Literatures have to be searched for Stability assay, key solubility data Bulk properties, solubility and stability profile and compatibility PD also has to do process research to Improve yield Bulk scale-up And finally from an experienced trial-and error method a formulation is developed. Lab Batch: a lab batch is produced to see if the formulation is effective. The recipe of the lab batch is sent to the DRA. It is also done for a feasibility study. The lab batch recipe undergoes various corrections. Pilot Batch: The manufacturing procedure should be validated on at least three pilot lots to identify the critical parameters in the product and process. Tentative limits fixed for the critical variables may be modified from the data available by stability studies.

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Stability Study: There are two methods by which stability is tested: Real-time stability study, and Accelerated stability study. Products are kept in the stability chamber at three different conditions:
25C, 60% Relative Humidity (RH)

a) Real time stability

30C, 65% RH

b) Accelerated Stability: 40C, 75%RH The product stays in the stability chamber for 6 months. If the degradation of the product is less than 5% in 6 months then the shelf life is 2 years The Analytical method development requires demonstration of suitable Accuracy Precision Specificity Sensitivity Ruggedness

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Engineering Engineering Department

Utility System

Machine Maintenance

Safety and Environment protection

Preventive Maintenance

Breakdown Maintenance

ETP

Fire safety

Power Generation Steam generation Nitrogen supply Water System Compressed air generation HVAC

Fig-15 Maintenance

Preventive

Corrective

Predictive

Routine based maintenance

Breakdown maintenance (unplanned)

Planned corrective

Fig-16 Portable water 42

Water is pulled 430 feet below ground by a submersible pump. The water is then chlorinated to destroy bacteria and filtered through a multimedia filter. USP 28/27 quality Portable Water is produced Purified Water: Portable water is further treated to produce purified water which is used in manufacturing & cleaning processes. The purified water pipes are cleaned by hot water sterilization at 85C for 30 to 35 minutes every 15 days to take the microbial count to 0 cfu/ml. At the point of feed at PW sodium hypochlorite is dosed Specifications: Conductivity: at 25C less than 1.2s/cm TOC- 500 ppb/L Microbial Load- 100 cfu/ml

Water for Injection (WFI) The raw material for WFI is purified water. Purified water is vaporized and chilled to make WFI. The WFI at the loop is at a temperature of 90C at 4-5 bar. The WFI pipes are sterilized after every 15 days at 121C. Specifications: Conductivity: at 20C less than 1.1s/cm Bacterial endotoxin less than 250 IU/L Microbial load less than 10cfu/0.1L

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Schematic Diagram of Purified Water Plant

Portable water Automatic Multimedia filter Break Tank Inventor (p-60) pump pump Coreless filter (10) Automatic Softener A64B Automatic Softener A64A Automated Carbon Filter (absorbs Cl and organic molecules

Soften Water tank

Circulation pump

Heat exchanger (chilled water at 7-8 C

Cartridge filter (5)

Reverse Osmosis Booster pump

Storage tank (600L) Purified Water

Continuous Electro deionizer

Loop circulation pump User Point (25

Heat exchanger

feed purified water

Heat by steam

Pure Steam Chilled

Fig-17

WFI

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Schematic Diagram of ETP

Raw sewage from Cepha+Peni
Neutralization basin (conc.NaOH)

Sewage from production floor

Bar screen chamber

Equalization Tank Sewage transfer pump

Chlorination tank (NaOCl dosing)

Secondary clarifier

Aerotor Biozone

Primary clarifier

Clarified Water Tank Treated sewage pump

Multimedia Filter

Carbon filter

Discharge to Public sewer or recycle

Fig-18 Effluent Treatment System Pharmaceutical unused chemicals & powders and waste materials may cause severe harmful effect on environment as well as human health. An Effluent Treatment Plant (ETP) manages or treats the waste materials (usually chemicals & powders) into neutralized molecule or reduces the harmful ingredients below toxic concentration. It is very important that the BOD and COD be kept under limits specified. At the primary clarifier 75% of suspended solids will be retained. 20-30% COD and BOD will also be reduced at the primary clarifier. The aerobic bacteria present in the Aerotor Biozone further reduces the COD and BOD. Then it is passed through sewerage line. Specifications: pH 6.5-8.5 Total suspended solids (TSS) NMT 150ppm Total dissolved solids (TDS) NMT 100mg/L Chemical oxygen demand (COD) NMT 200mg/L Biological oxygen demand (BOD) NMT 30mg/L

HVAC 45

Heating Ventilation Air Conditioning (HVAC) maintains optimum temperature and humidity through out the factory. Dispensing: 222C 455% RH Solid &Liquid: 222C 555% RH Cephalosporin: 222C 555% RH Sterile: 222C 505% RH Low humidity requiring rooms: 222C 255% RH Minimum air change rate: Class B 30/hr Class C 30/hr Class D not less than 15/hr

Factory Administration

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The overall tasks of the factory administration are as follows: House keeping: means keeping the whole administration unit as well as the premise clean and attractive looking. The support staff deployed for this purpose is responsible for many a things starting from gardening to keeping the washrooms clean. Canteen management: the company has a yearly contact with a caterer who supplies meals as well as snacks. The raw food that is brought in every day is checked by supervisors to ensure desired quality. Safety and security: The Company has its own security personnel. It currently has 1 inspector, 5 supervisors and 13 well-trained guards. The guards work on around the clock in 3 shifts; from 6 am to 2 pm, from 2pm to 10 pm and from 10pm to 6 am. There are 7 posts around the premise where a guard is deployed. For safety there are fire extinguishers and water hoses at specific location as well as emergency exits for safe evacuation. Vehicle management: the vehicles work on a fixed pickup and drop schedule. They are routinely maintained at fixed workshops. Event management: basically consists of inviting reputed doctors, other pharmaceuticals as well people from regulatory bodies to the plant. This helps to build a lasting reputation for the company. Documentation: the factory administration is in charge of renewing licenses such as warehouse license, environment clearance, boiler license, trade license, taxes (city corporation tax, land tax, holding tax etc). Protocol: the administration looks over the visas, accommodation, and transportation of international bodies that want to visit the plant. Waste Management: Pharmaceutical industries are in the Orange B and Red category which means that the waste they produce can cause significant environmental damage. Thus waste management is carried out to ensure that the wastes are properly separated, recycled and disposed to maintain a pollution free environment according to regulatory requirements. All employees working at the plant are expected to follow the factory rules and norms. The rules and norms consist of the working hours, overtime, employees behavior, clothing etc. Leave policy: Casual leave -10 days annually Annual leave- 15days Sick leave (14 days/year) Maternity leave (up to 2 children) - 16 weeks Waste is of two types solid waste and liquid waste. By assessing various parameters regulatory authorities have defined waste to be of two kinds- non-hazardous waste and hazardous waste.

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Solid wastes are usually papers, boxes, cartons, empty blisters, glass bottles, vials, ampoules, plastic and HDPE containers, canteen wastes. They may also be metal and wooden scrapes from packaging air filters, scrapes of rubber, plastic, nylon, teflon, acrylic, GP sheet, SS sheet, GI & MS piping from maintenance. Liquid wastes are usually cleaning and washing liquid, reagents, solvents, printing ink, lubricants from generator, air compressor, gearbox of different machinery, diesel from generator. Disposal methods Solid wastes are firstly separated into wastes that can be recycled, that can be incinerated, that are hazardous and that can be sold. As Popular does not have an incinerator, incineration is carried out by a third party. Non-hazardous waste is sold off. Hazardous wastes are buried. Liquid wastes from production are sent off to ETP. Normal container rinsing, sewerage water directly discharge into the municipal drain. Conclusion Our training at Popular Pharmaceutical Ltd. gave us a wonderful opportunity to observe how a GMP-run plant operates. We felt that PP Ltd. has sincerely tried to build and operate a world-standard pharmaceutical plant in an impoverished country such as ours. We got to understand PP Ltd. vision of providing high-quality low-priced medicine. PP is the first pharmaceutical to introduce the Omeprazole (Omegut) and Pantoprazole (Pantogut) injection in Bangladesh. It is also the first to bring the much-needed Insulin (Insul) injection. We were impressed to see that PP Ltd be the first to bring the bi-layered tablet technology to Bangladesh. Throughout our training we felt that each and every member of the Popular family cares deeply about the growth of the company. With such hard-working and dedicated member it is only a matter of time before Popular Pharmaceutical Ltd. becomes the leading pharma company in our country. We do however would like to impress upon a few developments PP Ltd. should make and they are: The validation department should be a multidisciplinary unit. Experienced personnels from QA, production, engineering, QC should be actively involved in process validation and machine qualification. Machines or equipments that fail to work properly should be fixed immediately as broken machine only incurs loss. Women should be employed in production as well as packaging. That way the companys image will grow as one that encourages women empowerment. Labels reading the purpose of the machine or of a room should be put in the Solid and liquid department for the convenience of visitors We would also like to mention that we are very grateful to all the Managers and officers of all the departments for giving us their time regardless of their busy schedule. We hope we were successful in representing East West University well. We also humbly apologize for any disturbance that we might have caused.

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Our heartiest wishes to Popular Pharmaceuticals Ltd.

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