copy of popular intern report

8/2/2019 Copy of Popular Intern Report

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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, avacuum 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

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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.

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Solid & Liquid Department

Main dosage forms manufacture by Popular Pharmaceutical in their Solid & LiquidDepartment given below.

Tablet

Capsule Syrup Suspension Dry suspension Cream Ointment

Machineries & Equipments List (Production for Solid & Liquid):

NAME OF MACHINE MODEL CAPACITY ORIGIN

Cosmic/Bin mixer Yenchen 500 liters 40rpm Taiwan

Drum blender Nipun 80 liters Bangladeshfluidized Bed dryer(FBD) Pam Glatt 120-1 50 kg/400 lit IndiaCone mill Yenchen 300 kg/hr TaiwanLifting & tilting machine Yenchen 150 kg/batch TaiwanSuper manufacturinggranulator(SMG/RMG)

Yenchen 120-150 kg/batch Taiwan

Tablet compression machine370

Sejong 50rpm,222000tab/hr

Korea

Tablet compression machine15S

Sejong 6orpm,61000tab/hr

Korea

Automatic film coatingmachine

N.R. Industries - Thailand

Blister machine Noak 800 strip/mm GermanyPrinting machine(lnnercarton batch printing)

Moricooverprinter

7000packlhr Japan

Powder loader Sejong 50-1 00 kg KoreaSieving machine Gansons 100 kg IndiaCapsule fillingmachine(powder & pellet)

Zansi 40F 6pm ,48 capsulebosh

Italy

Coating machine Yenchen 50-1 00 kg/batch TaiwanBottle washing machine Pharmalab 100-1 20

bottle/mm

India

Bottle filling & Cap lockingmachine

Pharmalab 6 channels,100bottles\min

India

Syrup manufacturingmachine

Pharmalab 1500 liters India

Ointment/Cream/Gel/Lotionmanufacturing machine

Pharmalab 100 liters India

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Ointment/Cream/Gel/Lotionfilling machine

Pharmalab 42 unit/min India

Bottle labeling machine Pharmalab 110-150 label/mm India

Table: 01

Materials Receiving System for Solid & Liquid Department:

Materials for production are received by following way

Fig: 01

Product Change Over:

4

Requisition for RM & PM

by production departmentaccording to BMR & BPR

Approved byProduction Manager

Issued by WarehouseManager

Dispensing by dispensingPharmacist

Checked by QAOfficer

Requisition for BMR & BPRby the production departmentto QA department

Received by ProductionOfficer


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Product change over means the changing and cleaning process of production machineriesparts, production room & other equipments after production of every batch or everyproducts.Example: In case of tablet compression, product change over includes the cleaning andchanging 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 differentproduct 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 cleaningroom.

In cleaning process the following materials are used:

1. Tape water, Purified water.2. Sodium lauryl sulphate 4% (SLS) for all machines3. JET4. 70% IPA (Iso-propyl alcohol).5. Sodium bicarbonate for coating machine6. 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, nosedimentation & 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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TABLET MANUFACTURING PROCESS


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Fig-02

Capsule encapsulation flow:

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Dry Granulation DispensingWet

Granulation

Dry mixing of API &Excipients by RMG

Wet mixing: By RMGBinder preparation:

Paste or solution form

Mixing is continued until alump formation is observed

Wet milling: by Cone Milldischarge of wet Granulesby using appropriate mesh(generally 8mm)

Drying: By fluidizedBed Dryer (FBD)

Sizing or crushing: According

to the - specification by BMRBlending: Bin mixerLubrication

Tablet compression

Coated TabletPackagingCore Tablet

Coating

API &

Sieving

Slugging: BycompressionMachine

Crashing: ByMulti Mill

Mixing: Drummixing

Direct compression

Sieving

Warehouse


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There are two types capsule filling:1. Pellet filling process2. Powder filling process

Pellet filling process

Vacuum pipe

Fig-03

Powder filling process

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Hopper containingPellets

Capsule shells(Body & Cap)

Separated by

Rotating disc

(upper & lower)

Cap to upperbush

Body to lowerbush

Body containing

Pellets

Check unseparated

Shell & rejected bysensor

Locking

Ejection

Packing

Dispensing


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Fig-04Ointment manufacturing flow & control:

Fig-04

BMR, BPR & its activity & regulations:

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Dispensing Sieving Blending Encapsulation Packaging

Dispensing

Oil: Hydrocarbons base

melting & mixing at 1000 Cinto manufacturing stainlesssteel vessel.

API stirring at 40 rpm at

60C into another stainlesssteel vessel.

Mixing: Cooling to 60 C starringfor 30min

WIP

Filling

Packaging


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BMR means batch manufacturing record. In this documentation process the followingguideline is given about manufacturing of a batch of product:

BMR includes the following records:

1. Product name2. Batch no.3. Batch size4. Batch Quantity5. Manufacturing procedure6. Name of product materials with required quantity & Pharmacopoeias or In-House

Specification (IHS)7. Product order number8. Date of requisition9. Date of commenced

10. Date of completion11. Product line clearance12. Change over checklist for production line13. It must be checked by QA officer etc.

BPR means Batch Packaging Record. In this documentation the following guideline isgiven about packaging of a batch product:

BPR contains following records:

1. Product name2. Batch No3. Batch size4. Batch Quantity5. Name of packaging materials with required quantity6. Pharmacopoeias or IHS specification7. Date of requisition8. Date of commenced9. Date of completion10. Product order number11. Packaging line clearance12. Change over checklist for packaging line13. Bulk product received14. Carton over printing record15. Printing line clearance16. Over printing inspection17. It must be checked by QA officer etc.

Packaging Line Clearance:

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It means clearance of every packaging materials of previous batch of same or differentproduct 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. Tape water,2. Sodium lauryl sulphate 4% (SLS) for all machine3. JET4. 70% IPA (Iso-propyl alcohol).5. Sodium bicarbonate for coating machine6. Compressed air for plastic bottle.

Prevention & Maintenance system:

HVAC system maintains Clean Corridor Concept (Corridor with positivepressure).

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 theappropriate utilization of existing resource. And it also prevent system lose in theproduction 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. Injectable3. Powder for injection (Vial)

Environment Monitoring:

Environmental monitoring is one of the most important tasks in the sterile department. It isa regular check of view to take timely corrective measures for maintaining a favorablemanufacturing environment, minimizing the risk of product contamination. It is also a partof validation exercise.The environmental monitoring approach is also adopted to ensure that there is nosignificant risk of air borne cross-contamination.

Serial no Name of control measure Description

01 Zone concept Class A(100),ClassB(100),ClassC(10000),ClassD(100000) (Ft)

02 Air change rate Class A:60 times/hr, ClassB:50 times/hr, ClassC:3Otimes/hr,Class D:10times/hr

03 Air pressure difference Positive pressure must be

maintained in the processingroom & 10-15 Pascal higherthan in the adjacent rooms.

04 HEPA filter integrity 0.3 micron & 99.997%efficacy. It determines theeffectiveness or potential ofthe clean air to protect theaseptic area from externalcontamination.

05 Microbial growthmonitoring

Class A:


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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 isautoclave.

There are two types of sterilization:

Name of sterilization Description

Dry heat sterilization 250C, 45 minutes. Glass container(vials),18O7 hr Closed mouth ampoule

Moist heat sterilization (Autoclave) 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 specialgarments 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 varietyof 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/vFlowchart showing the manufacturing of infusions

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

Aseptic dispensing

Mixing in the 3500Lmanufacturing vessel

Filtration is done using 1.2mand 0.2m cartridge.

Filling in Pluemet Filling andsealing Machine

Arranging the infusion bags inthe trolleys for autoclave

Autoclave at 121C for 30 minsin the Fedegari autoclave

Packaging

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When filling starts the first 8 to 10 bags are rejected to make sure the cleaning WFI is fullyexpelled 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 testpH and weight/ml. The first and the last filled bags are sent to QC for bio-burden (endotoxin andmicrobiological 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 PVCbags that are widely used because the plasticizers PVC bags used have been shown to bio-accumulate and lead to reproductive problems.

Dialysis

Popular Pharmaceutical Ltd is one of the very few companies to produce Hemodialysis fluid. Itcurrently produces 3 dialysis fluids

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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

Fig-06

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

Dispensing

Mixing

Samples sent to QC totest pH and wt/ml

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

Filling using Pharmalabfilling machine .

Manual labeling

Packaging

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Manual capping

IPC: weight should bewithin specifications


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water , than Clotech solution and then with hot purified water. After that they are left to dry and then theyare ready to be filled.

Integrity test: This test is carried out to test the efficiency of the cartridge after filtration of every batch. TheBubble point test is carried out using the machine Sartocheck Junior.

Amino acid production flowchart

Fig-07

Cephalosporin

Dispensing

Mixing in themanufacturingvessel

Samples sent to

QC

Filling in Pluematfilling machine

Bottles washed in Yenchen

Bottle washing machine

Sealing and rubberstoppering

Terminal sterilization inCelester Sterimega at 121C

Visual Inspection

Samples sent toQC for bio-burdentest

Packaging

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Cephalosporins are a group of semisynthetic antibiotics derived from cephalosporin-Cobtained 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 Name of Equipment Capacity

Vial washing Sterilizationfilling & Sealing

Macofer (Italy) 9000 /hr

Label printing (vial) Jet Printer (Image) 2800 /hr Vial blistering Hoonga 6000 /hr Bottle washing Semi automatic Rotary

bottle washing machine1500 bottle/hr

Bottle drying Bottle Dryer 32 TraysFilling Auto Powder Fillingmachine

40 bottle/min

Cap sealing Auto Cap Sealing machine 40 bottle/minLubrication(final blending) Drum Blender 80LCrushing Multi Mill NADispensing Sartorius balance(Germany) 150 kgSieve Sifter with mesh, Hand sieve

(40 mesh)NA

Dry mixing Cosmec Blender, DrumBlender

750 L, 80 L

Compression Cadmach Compressionmachine

20000 tab/hr

Coating Automatic film coatingmachine

up to 22 kg

Encapsulation Auto capsule filling machine 40000 cap/hr Polishing & Sorting Sejong Cap

Polishing &Sorting

100000 cap/hr

Blistering Hoonga 25 unit/min

Table-05

Environment monitoring

Environment monitoring is depends on the Temperature & Humidity.

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Generally: Humidity - 222 C Temperature - 455 %

Condition for different portion is given bellow:

1. Tablet

Humidity: Bellow 50%Temperature: Bellow 25C

2. Capsule


3. Drysyrup


4. VialHumidity: Bellow 40%Temperature: Bellow 25C

Powder for Injection filling

Fig-08Powder for suspension:

20

Vial washing

Vial sterilization

Vial filling

Vial sealing

Vial inspection

Vial labeling Packaging

Dispensing

SievingDry mixingFillingCap sealingPackaging


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Fig- 09

Quality Assurance

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

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efforts are required. The whole process of assuring, that the quality of the product will beas stated or perceived, consistently, can be called quality assurance.

ROLE of QA

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

Specified raw and packaging materials

Sampling by QC

Testing for specification compliance byQC

Released

Stored in warehouse

Bulk Manufacturing Packaging

QA inspection

QA inspection

Bulk product

Packaging

QA inspection

Finished product

QA releaseQA inspection

Release of finished product

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Raw material specifications Packaging material specifications


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Purpose of Validation: Validation is carried out to have better control of the manufacturingand related operations to ensure minimum deviations in actual production from the onesrequired by design. The benefit of such validation exercises therefore include better systemcontrol and maintenance and a high degree of assurance that a specific process will

consistently produce a product meeting its predetermined specifications and qualitycharacteristics.

Rectify

Shipment

Fig-11

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URS: User RequirementSpecification. Specifying the haveand the have-nots of a machine

DQ: Design Qualification. Thevendor and the company agreeingon the details of a machine

FAT: Factory Acceptance Test.This is basically a checklist whichensures the machine purchased is

SAT: Site Acce tance Test

IQ: Installation Qualification

OQ: Operational Qualification

PQ: Performance Qualification

Machine gets qualified inpursuit of validation


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Computer System Analytical MethodValidation Validation

(accuracy, precisionspecificity, sensitivity,ruggedness)

Fig-12

Process Validation must have RepeatabilityReproducibilityMeet pre-determined specifications.

In a validated process critical parameters are optimized. Each step of the manufacturingprocess 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 individualweights 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 settlingplates. The particle count in Class A room should be below 100/f . All filling head shoulddeliver 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 themanufacturing of a product by carrying out tests to ensure certain specifications of theproduct are met. IPC basically guarantees that the validated process is running smoothlyand the product has the desired quality. In-process controls are particularly importantwhere a process may vary with time such as tablet weights, fill volume etc.

Process

Validationn

System Validation Cleaning Validation

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Outside technical assistance Quality management system

Personnel 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 complianceswith specifications. The responsibility of the quality control is to ensure that the startingmaterials, intermediates and final products are promptly tested to confirm compliance withspecifications before their release. To perform functions of the QC, PopularPharmaceuticals Ltd has a well equipped QC laboratory which is supported with trainedanalytical staffs. These activities actually ensure the product to be safe, effective, stable andacceptable to every person.

Equipment used in Quality Control Department:

Equipment Company Origin Use

HPLC(Quarternary)Model: [0-201OAHT

Shimadzu Japan Analytical Test: Identification Qualification Separation

HPLC(lsocratic) Shimadzu Japan Analytical Test: Identification Qualification Separation

HPLC(Binary)Model:1100 series

Agilent Germany Analytical Test: Identification Qualification Separation

Water preparationforHPLC

Barnstead USA To reduceconductivity& particle size ofwater

Atomic absorptionspectrophotometerModel :AA-6300

Shimadzu Japan To identify andmeasure minerals.

Pressure machineModel: SSP-10A

Shimadzu Japan To prepare disc of IR

FT IR Shimadzu Japan Materialidentification &purity tests

TOC Analyzer Shimadzu Japan To measures total

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Model: TOC-V cpH organic Carbon inpurified water

UV-VisibleSpectrophotometerModel: UV_1650PC

Shimadzu Japan A wide rangeanalytical test.

Conductivity TesterModel: PP-20

Sartorius Germany To test conductivity

Seiving machine Fritsch Germany To do sieve analysisAutomaticPolarimeterModel: AP-l 00

Atago Japan To determine Opticalrotation

ViscometerModel: RVDV-I

Brookfield Viscositydetermination

pH meterModel:RSP-42

Mettler Toledo Switzerland To determine pH

Dissolution TesterModel: PTWS Pharmatest Germany Dissolution testing

Melting PointAnalyzerModel:FP62

Mettler Toledo Switzerland Identification

RefractometerModel: DR-Al

Atago Japan To determinerefractive index

Water bathModel:1083

GEL Germany Controlled tempreaction

Centrifuge machineModel:Z400

Hermle Germany Separationtechniques

Muffle Furness Linn Hitherm Germany To determine ashcontentMicroscopeModel:CX-21 FSI

Olympus Japan Identification

Precision ovenModel:0V453

Channel Germany Drying

Drying Oven Model:100-800

Memmert Germany Drying

Horizontal ShakerModel:3017

GEL Germany Shaking

Weghing Balance

ModelI:PB4002-s

Mettler Toledo Switzerland Analytical weighing

Potentiometrytitrator Model:DX53

Mettler Toledo Switzerland Potentiometrictitration for ions

Karl Fischer titratorModel:DX3I

Mettler Toledo Switzerland Moisturedetermination

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 arediscussed 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 ofapproval or rejection of each batch of starting, packaging and final materialson the basis of testing.

B. Personnel at all levels have accountability to carry out their responsibilitiesto meet the quality goal.

2. Personnel:

Qualified personnel are a key factor in ensuring quality. Personnel have threeimportant 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. Adequate space allocations.B. Easy to cleanC. Safety facilitiesD. Storage facilitiesE. Segregation of activities

F. Proper environment for testingG. Every equipment has safety distance from othersH. Microbiology lab is isolated from Analytical lab

4. Equipments:

The laboratory is well equipped for performing all tests according to BP, USP. Tomaintain all equipments & machineries following measures are taken:

A. Every equipment has a log book for records.B. Regular maintenance is done.C. All equipments are calibrated at specified intervals.

D. Most of the equipments & machineries are connected with printers thus thereremain no chance of manipulation.

5. Reference standards:

Reference standards are substances with known purity or potency. Certified referencestandards are available from many official sources. For routine laboratory tests it is worthconsidering working standards prepared by standardizing some good quality rowmaterials 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 controlprocedure (MCP) for every materials. It has SOP for every action. SOP is constrictlyfollowed by analysts.

8. Sampling:

Appropriate sampling is a vital step in GLP. To facilitate correct and appropriate samplingprocedures 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 asper requirement laid down specifications.

10. DocumentationAll test results are recorded on a test record sheet (TRS). All Q.C. records relating to abatch analysis are a part of the batch documentation. The purpose of documentation is torecord important information with evidence. It is preserved at least one year after batchexpired 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 adefinite binding on the part of the supplier that the materials meet the requiredspecifications. Now a day, many reagents certificates are found on internet.After receiving the raw materials, a GRN (Goods Receive Note) recorded with details suchas: materials name, suppliers name, total quantity, number of containers, manufacturersbatch number (s), physical condition of the containers etc.The raw materials should remain in quarantine until sampled, tested and released orrejected by the laboratory.

2. Sampling:

It is important that the QC personnel independently inspect the raw materials duringsampling.Sampling is done by using sampling thieves. It takes materials from three positions fromtop, middle and bottom. If there is large numbers of containers sampling is done from n+2containers, 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 redlabel.

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 offinished product for compliance with predetermined standards is a critical factor forproduct release.

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Microbiology

Equipment used in Microbiology:

1. Airborne Particle Counter: Used for 0.5 and 5; Climet Cl-20(USA)2. Dry Heat Sterilizer: Used for dry sterilization; Memmert (Germany)3. Autoclave: Used for preparation; Hiclave HV-85; Harayama, Japan4. Autoclave: Used for destruction; Hiclave HV-25; Harayama, Japan5. Incubator : For incubation; Memmert (Germany)6. Microscope: Max magnification l000x; Olympus CX-41 (Philipines)7. 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 formaintaining a favorable manufacturing environment, minimizing the risk of productcontamination.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 toproduction area. Then it is incubated for 5 days at 30c. This visualize the microbialgrowth.C) Surface swabs technique:Sterilized swabs of cotton buds are moistened in a sterile diluents or a suitable liquidculture media. A specific area is then swabbed and the organism sampled from the surfaceis then smoothly rubbed over the supporting agar surface and incubated. This technique isemployed to evaluate solid surface, garments, equipment, personnel for microbiologicalgrowth.D) Air sampling:Done for microbial growth in air.

Airborne particle limit:

Class Particle count at

rest

m

Particle count

operation m

Microbial growth

(cfu)

0.5 5 0.5 5 --

A 3500 0 3500 0


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D 3500000 20000 Not defined Not defined -

Table-08Laboratory test:

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 Time Temperature

Fungus 5 days 22C 25CBacteria 3 days 30C 35C

Table-09

B) Limit test/Contamination test:This test is done for checking raw materials. Three types:1) Pour plate2) 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 asfinished products are kept at their optimum storage condition. Raw materials are tested asthey enter the warehouse and they are transferred to the manufacturing department byrequisitions.

Materials Receiving System:

a) Upon receiving the shipments labeling should be carefully checked to make surethat they belong to the same batch. Only materials from the same batch receive thesame Good receival note (GRN) number. The GRN is the identification number forthat 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 samplesfrom each and every container. However for excipients as well as packagingmaterial the sampling is done n +2. The containers from which the QC hassampled are labeled sampled.

e) After the materials have conformed with the specification they are released by QCauthorities and are labeled released meaning they are ready to be used inmanufacturing.

f) Rejected materials should be clearly separated from the released materials.Rejected packaging materials containing the companys logo are destroyed. For rawmaterials that are the rejected the vendor is contacted immediately.

Storage:

Raw materials and finished products are stored according to their chemical or physicalproperties. Some raw materials and finished products are kept at normal room conditionwhereas 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 keyand access is restricted to authorized personnel only.

In order to prevent mix-up of printed containers and labeling materials, each printedpackaging material is stored properly identified with the specific GRN number and codenumber 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 aredone in the presence of an authorized personnel from production and QA.Materials are dispensed according to the Batch manufacturing record (BMR). Theremaining 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 humidityand temperature are optimum for the raw material .Dispensing is done under laminar airflow to minimize dust generation and microbial contamination. All raw materials aredispensed 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 effectiveformulation of a drug. The stability, efficacy of a drug depends on its formulation. PDconsists of two parts: Galenical & Analytical. PD is also responsible for creating BMR andBPR.Launching a new product involves a lot of work.

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Proposal fromProduct ManagementDepartment (PMD)

Market study ofthe newproduct byPMD

Evaluation ofexisting facilities

Feasibility studyby PD

Evaluation of theManufacturingDepartment

Consulting with theEngineeringDepartment

Cost EvaluationFeasibility study byPMD

Proposal Approved

Product File Open

Raw materials procurement requisitionaccording to QA specifications

Lab batch produced by PD Stability testing

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Fig-14

During formulation PD has to undertaken intensive research. Literatures have to besearched 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 recipeundergoes various corrections.

Pilot Batch: The manufacturing procedure should be validated on at least three pilot lots toidentify the critical parameters in the product and process. Tentative limits fixed for thecritical variables may be modified from the data available by stability studies.

Galenical and Analytical methoddevelopment and validation

Pilot batch production (3consecutive batches)

Accelerated Stabilitytesting (6 months)

Recipe sent to Drugs RegulatoryAuthority (DRA) for approval

Annexure approval

Commercial production

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PMD approval


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Stability Study:

There are two methods by which stability is tested: Real-time stability study, andAccelerated stability study.

Products are kept in the stability chamber at three different conditions:25C, 60% Relative Humidity (RH)

a) Real time stability30C, 65% RH

b) Accelerated Stability: 40C, 75%RH

The product stays in the stability chamber for 6 months. If the degradation of the product isless 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

Fig-15

Maintenance

Fig-16

Portable water

Utility SystemMachine Maintenance Safety and Environment

protection

PreventiveMaintenance

BreakdownMaintenance ETP Fire safety

Power Generation

Steam generation

Nitrogen supply

Water System

Compressed airgeneration

HVAC

Preventive Corrective

Predictive Routine basedmaintenance

Breakdownmaintenance(unplanned)

Planned corrective

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Water is pulled 430 feet below ground by a submersible pump. The water is thenchlorinated to destroy bacteria and filtered through a multimedia filter. USP 28/27 qualityPortable 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 at85C for 30 to 35 minutes every 15 days to take the microbial count to 0 cfu/ml. At thepoint of feed at PW sodium hypochlorite is dosedSpecifications:Conductivity: at 25C less than 1.2s/cmTOC- 500 ppb/LMicrobial Load- 100 cfu/ml

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

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Schematic Diagram of ETP

Fig-18

Effluent Treatment System

Pharmaceutical unused chemicals & powders and waste materials may cause severeharmful effect on environment as well as human health.An Effluent Treatment Plant (ETP) manages or treats the waste materials (usuallychemicals & powders) into neutralized molecule or reduces the harmful ingredients belowtoxic concentration. It is very important that the BOD and COD be kept under limitsspecified. At the primary clarifier 75% of suspended solids will be retained. 20-30% CODand BOD will also be reduced at the primary clarifier. The aerobic bacteria present in theAerotor Biozone further reduces the COD and BOD. Then it is passed through sewerageline.Specifications:pH 6.5-8.5Total suspended solids (TSS) NMT 150ppmTotal dissolved solids (TDS) NMT 100mg/LChemical oxygen demand (COD) NMT 200mg/LBiological oxygen demand (BOD) NMT 30mg/L

HVAC

Raw sewagefromCepha+Peni

Neutralizationbasin(conc.NaOH)

Sewage fromproduction floor

Bar screenchamber

EqualizationTank

Sewage transfer pump

Primary clarifierAerotorBiozoneSecondaryclarifier

Chlorination tank(NaOCl dosing)

Clarified WaterTank

Treated sewage pump

MultimediaFilter

Carbonfilter

Discharge to Publicsewer or recycle

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Heating Ventilation Air Conditioning (HVAC) maintains optimum temperature andhumidity through out the factory.Dispensing: 222C 455% RHSolid &Liquid: 222C 555% RHCephalosporin: 222C 555% RH

Sterile: 222C 505% RHLow humidity requiring rooms: 222C 255% RH

Minimum air change rate: Class B 30/hrClass C 30/hrClass 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 isresponsible 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 bysupervisors to ensure desired quality.

Safety and security: The Company has its own security personnel. It currently has 1inspector, 5 supervisors and 13 well-trained guards. The guards work on around theclock 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 thereare fire extinguishers and water hoses at specific location as well as emergencyexits 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 tobuild a lasting reputation for the company.

Documentation: the factory administration is in charge of renewing licenses such aswarehouse license, environment clearance, boiler license, trade license, taxes (citycorporation tax, land tax, holding tax etc).

Protocol: the administration looks over the visas, accommodation, andtransportation of international bodies that want to visit the plant.

Waste Management: Pharmaceutical industries are in the Orange B and Redcategory which means that the waste they produce can cause significant

environmental damage. Thus waste management is carried out to ensure that thewastes are properly separated, recycled and disposed to maintain a pollution freeenvironment according to regulatory requirements.

All employees working at the plant are expected to follow the factory rules and norms. Therules 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 parametersregulatory authorities have defined waste to be of two kinds- non-hazardous waste andhazardous 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 andwooden 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 fromgenerator.

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. Hazardouswastes are buried.Liquid wastes from production are sent off to ETP. Normal container rinsing, seweragewater directly discharge into the municipal drain.

Conclusion

Our training at Popular Pharmaceutical Ltd. gave us a wonderful opportunity to observehow a GMP-run plant operates. We felt that PP Ltd. has sincerely tried to build and operatea world-standard pharmaceutical plant in an impoverished country such as ours. We got tounderstand PP Ltd. vision of providing high-quality low-priced medicine. PP is the firstpharmaceutical 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 tablettechnology to Bangladesh. Throughout our training we felt that each and every member ofthe Popular family cares deeply about the growth of the company. With such hard-workingand 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 andthey are:

The validation department should be a multidisciplinary unit. Experiencedpersonnels from QA, production, engineering, QC should be actively involved inprocess validation and machine qualification.

Machines or equipments that fail to work properly should be fixed immediately asbroken 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 Solidand liquid department for the convenience of visitors

We would also like to mention that we are very grateful to all the Managers and officers ofall 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 humblyapologize for any disturbance that we might have caused.

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Our heartiest wishes to Popular Pharmaceuticals Ltd.

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