Necessity of in-plant training:
A pharmacist is the person of drugs or the expert on drugs. He is the only expert on drugs, for expertise regarding drugs requires knowledge in depth in all the facts of pharmacy. It is her professional responsibility to know all about the drugs. No educational program other than that in pharmacy provides the background to understand completely all about drugs.
Among the professions of pharmacists like community pharmacy, institutional pharmacy, whole sale pharmacy, industrial pharmacy, government service, pharmaceutical education, organizational management, in my country industrial pharmacy offers great opportunity to the pharmacists.
Industrial pharmacy is a profession of unique hybrid of business and profession.
So an industrial pharmacist should have proper knowledge about drugs and also about medical progress, commence marketing and technology. To be a self-sufficient pharmacist beside academic knowledge, practical knowledge is essential.
This is why after appearing the Bachelor of Pharmacy examination in-plant training was arranged by the department in renowned pharmaceuticals industries. This training has sharpened my academic knowledge what I learnt in the last four years .I have completed my training in Popular Pharmaceuticals Limited a fast growing pharmaceutical company in Bangladesh.
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 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
The manufacturing site is built with strict compliance to WHO cGMP standards and also to meet US FDA and UK MHRA requirements.
The growing demand for new medicines is driven by increasing population and improved life expectancy as modern medicine supports an ageing population. Popular Pharmaceuticals Ltd. intends to focus its skills and resources on all major therapeutic areas that represent majority of the burden of disease profiles of Bangladesh.
Popular Pharmaceuticals Ltd. is also committed to delivering new, medically important and commercially successful products to the market every year. Along with its commitment to competitiveness and high performance, PPL will continue to be led by its core values to achieve sustainable success.
Major Therapeutic Area
Solid, Liquid and Injectable
- NSAIDs & analgesic
- Vitamines & minerals
- Human Insulin
- Calciam Acetate
- Oseltamivir 75mg
- Iron sucrose
- Fentanyl citrate usp
Popular Infusion Ltd.
Brand NameGeneric Name Pack Size
Amisol Amino Acid 500 ml
Amisol Gold Amino Acid, Glucose, Electrolytes 500ml
Glucolin IV Infusion Dextrose 5% 500 ml
Glucolin IV Infusion Dextrose 5% 1000 ml
Glucosal IV Infusion Dextrose 5% & NaCl 0.9% 500 ml
Glucosal IV Infusion Dextrose 5% & NaCl 0.9% 1000 ml
Glucolin DS IV Infusion Dextrose 10% 500 ml
Glucolin DS IV Infusion Dextrose 10% 1000 ml
Electrosal IV Infusion Hartmann`s Solution 500 ml
Electrosal IV Infusion Hartmann`s Solution 1000 ml
Fructolin IV Infusion Fructose 10% 500 ml
Kolosal IV Infusion Cholera Saline 500 ml
Kolosal IV Infusion Cholera Saline 1000 ml
Normalin IV Infusion NaCl 0.9% 500 ml
Normalin IV Infusion NaCl 0.9% 1000 ml
Metonid IV Infusion Metronidazole 0.5% 100 ml
Levobac IV Infusion Levofloxacin 0.2% 100 ml
Civox IV Infusion Ciprofloxacin 0.2% 100 ml
Solid & Liquid Department
Main dosage forms manufacture by Popular Pharmaceutical in their Solid & Liquid Department given below.
- Dry suspension
Machineries & Equipments List (Production for Solid & Liquid):
NAME OF MACHINE
500 liters 40rpm
fluidized Bed dryer(FBD)
120-1 50 kg/400 lit
Lifting & tilting machine
Super manufacturing granulator(SMG/RMG)
Tablet compression machine 370
Tablet compression machine 15S
Automatic film coating machine
Printing machine(lnner carton batch printing)
50-1 00 kg
Capsule filling machine(powder & pellet)
6pm ,48 capsule bosh
50-1 00 kg/batch
Bottle washing machine
100-1 20 bottle/mm
Bottle filling & Cap locking machine
6 channels,100 bottles\min
Syrup manufacturing machine
Ointment/Cream/Gel/Lotion manufacturing machine
Ointment/Cream/Gel/Lotion filling machine
Bottle labeling machine
1.Materials Receiving System:
Materials for production are received by following way:
2. 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.
Different types of tablet Coating:
IPC check during coating:
- Weight of tablet
- Inlet air temperature check
- Exhaust air temperature check
- Pan speed
- Spray gun atomizing air pressure check.
Critical parameters in coating:
- Inlet air temperature
- Exhaust air temperature
- Pan speed
- Atomizing pressure
- Spray rate
- Gun to bed distance
- program parameter
- Height of core sample after pre jag drying cycle
- Peristaltic pump speed.
Capsule encapsulation flow:
There are two types capsule filling:
- Pellet filling process
- Powder filling processPellet filling process:
Powder filling process:
3.Liquid, Cream &Ointment
This section is of the most important parts of PPL. It is separated from solid department .It involves in manufacturing of about many products including syrup, cream, ointment, Suspension, Dry Suspension and other semi solids preparation.
Liquid dosage forms formulated in PPL are as follow-
- Dry suspension
It can be broadly divided into three units in operation. These are as bellows-
1. Manufacturing Unit:
- Area for syrup manufacturing
- Area for cream manufacturing
- Area for ointment manufacturing
2. Filling & Packaging Unit:
- Cream, ointment ,syrup filling and packaging room
- Automatic bottle washing room
- Room for Pasteurization
- Washing room for small volume product manufacturing vessels and containers
Clean& dry vessel→ Addition of solvent & → Rising temp. to → Addition of preservative co-solvent 75-80°C
Volume Adjustment ← Addition of coloring ← Addition of active ← Cool & Flavoring agent ingredient down at ↓ 40°C
Adjustment of pH → Wait for Q.A approval →filtering → Storage for filling
Ointment manufacturing flow & control:
4. BMR, BPR & its activity & regulations:
BMR includes the following records:
- Product name
- Batch no.
- Batch size
- Batch Quantity
- Manufacturing procedure
- Name of product materials with required quantity & Pharmacopoeias or In-House Specification (IHS)
- Product order number
- Date of requisition
- Date of commenced
- Date of completion
- Product line clearance
- Change over checklist for production line
- 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:
- Product name
- Batch No
- Batch size
- Batch Quantity
- Name of packaging materials with required quantity
- Pharmacopoeias or IHS specification
- Date of requisition
- Date of commenced
- Date of completion
- Product order number
- Packaging line clearance
- Change over checklist for packaging line
- Bulk product received
- Carton over printing record
- Printing line clearance
- Over printing inspection
- It must be checked by QA officer etc.
5. 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.
6. 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
- Tape water,
- Sodium lauryl sulphate 4% (SLS) for all machine
- 70% IPA (Iso-propyl alcohol).
- Sodium bicarbonate for coating machine
- Compressed air for plastic bottle.
7. Prevention & Maintenance system:
- HVAC system maintains “Clean Corridor Concept” (Corridor with positive pressure).
- Gown, musk, hand gloves 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.
8. 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.
9. Productivity, Capacity utilization:
This plant, for now only uses 20% of its full capacity. It also does contract manufacturing for various companies (Healthcare Pharmaceuticals, Radiant Pharmaceuticals, Chemico Laboratories, NOVO Healthcare & Pharma, Aristopharma etc) utilize its capacities properly.
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. It’s 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 Sterilization filling & 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 machine||1500 bottle/hr|
|Bottle drying||Bottle Dryer||32 Trays|
|Filling||Auto Powder Filling machine||40 bottle/min|
|Cap sealing||Auto Cap Sealing machine||40 bottle/min|
|Lubrication(final blending)||Drum Blender||80L|
|Dispensing||Sartorius balance(Germany)||150 kg|
|Sieve||Sifter with mesh, Hand sieve (40 mesh)||NA|
|Dry mixing||Cosmec Blender, Drum|
|750 L, 80 L|
|Compression||Cadmach Compression machine||20000 tab/hr|
|Coating||Automatic film coating machine||up to 22 kg|
|Encapsulation||Auto capsule filling machine||40000 cap/hr|
|Polishing & Sorting||Sejong Cap|
Environment monitoring is depends on the –Temperature & Humidity.
- Humidity – 22±2 °C
- Temperature – 45±5 %
Condition for different portion is given bellow:
Humidity: Bellow 50%
Temperature: Bellow 25°C
Humidity: Bellow 50%
Temperature: Bellow 25°C
Humidity: Bellow 45%
Temperature: Bellow 25°C
Humidity: Bellow 40%
Temperature: Bellow 25°C
Powder for Injection filling
Type of dosage form of sterile products:
- 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.
|Name of control measure|
|01||Zone concept||Class A(100),|
|02||Minimum Air change rate||Class B: 50 times/hr,|
Class C: 3Otimes/hr,
Class D: 10-15 times/hr
|03||Air pressure difference||Positive pressure must be maintained in the processing room & 15 Pascals higher than that of adjacent rooms.|
|04||HEPA filter integrity||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.
|06||Temperature & humidity|
|(22 ±2)°C, (50±5) % Relative humidity.|
|07||Laminar air flow cabinet||Placed under HEPA filter. Air velocity 0.45 m/sec|
Particle count at
Particle count operation m³
- 2. 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:
5. Surfacing materials
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.
- 3. Sterilization:
Sterile products can be classified in two classes:
- Products which can be sterilized in their final container.
- 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
250°C, 45 minutes. Glass container(vials),
18O°7 hr Closed mouth ampoule
Moist heat sterilization (Autoclave)
121°C, 30 minutes. Dress, machine parts, flips off slip, rubber stopper.
- 4. 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 stands for large volume parenteral liquid. Popular Pharmaceuticals Ltd. produces a variety of infusion products
v Glucolin- Dextrose 5% w/v
v Glucolin DS- Dextrose 10% w/v
v Glucosal-Dextrose 5%w/v and Sodium Chloride 0.9% w/v
v Electrosal- Hartmann’s solution
v Kolosal- Cholera saline
v Normalin- Sodium Chloride 0.9% w/v
v Civox- Ciprofloxacin 0.2% w/v
v Levobac- Levofloxacin 0.5% w/v
v Metonid- Metronidazole 0.5% w/v
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. 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 bio-accumulate and lead to reproductive problems.
Flowchart showing the manufacturing of infusions
Popular Pharmaceutical Ltd is one of the very few companies to produce Hemodialysis fluid. It currently produces 3 dialysis fluids
v Dialyte A- acidic component (pH 1.8-2.8)
v Dialyte AC- basic component (pH 8.1-9.1)
v Dialyte B – pH 7.5-8.5
Flowchart of the Dialyte manufacturing process
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 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.
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
Quality Assurance and Validation
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 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
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.
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.
Process Validation must have Repeatability
Meet pre-determined specifications.
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 ³. 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.
Manufacturing Process In-process control
a) Dispensing Room condition –Temperature
and RH should be within specifications.
b) Granulation Uniformity of the granules as well as granule
c) Drying LOD( Loss on drying)
d) Compression Room condition, appearance of tablets
(Absence of capping, lamination, picking, sticking)
Average weight, uniformity of weight and
RSD, hardness, thickness and diameter the
tablet. Friability of the tablet as well the
disintegration time are also checked.
e) Coating appearance of tablets( absence of bridging,
filling, sticking, color variation),
a) Encapsulation Room condition, appearance of shell, average
weight, uniformity of weight, RSD,
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.
a) Filling Fill volume
Powder for suspension
a) Bulk Appearance, odor, color
b) Filling Room condition, fill weight, reconstituted
volume, sealing of cap
a) Blistering, PP infusion bags Leak test
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
ü Clear title
ü An identification number
ü be approved by authorized person( eg. Director of industrial operations)
ü date of issue
Any batch record usually consists of the following:
ü Production order sheet
ü Batch manufacturing record (BMR)
ü Batch packaging record (BPR)
ü Packaging order sheet
ü Tablet or capsule inspection sheet
ü Weight or volume inspection sheet
ü Finished product test record sheet
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 progeny.
Site Master File
Site master file contains the complete layout and detailed information about the plant’s machineries, engineering, company’s structure etc. It contains:
- General information
ü Manufacturing licenses
ü Manufacturing activities
ü Manufacturing site
ü Number of employees
ü Outside technical assistance
ü Quality management system
ü Key personnel
ü Health check up
- Premise and equipments
ü Plant layout
ü HVAC system
ü Water system
ü Major equipments
ü Qualification and Validation
ü Preparation, revision, authorization, distribution
ü Document list related to product manufacturing
ü Production operation
ü Material handling
ü Reprocessing and rework
ü Handling rejected materials
ü Process validation
- Quality control
- Toll manufacturing
- Distribution, complaint handling, product release
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 analytically staffs. These activities actually ensure the product to be safe, effective, stable and acceptable to every person.
Equipment used in Quality Control Department:
Model: [0-201 OAHT
|Water preparation for|
|Barnstead||USA||To reduce conductivity|
& particle size of water
|Atomic absorption spectrophotometer|
|Shimadzu||Japan||To identify and measure minerals.|
|Pressure machine Model: SSP-10A||Shimadzu||Japan||To prepare disc of IR|
|FT IR||Shimadzu||Japan||Material identification & purity tests|
|TOC Analyzer Model: TOC-V cpH||Shimadzu||Japan||To measures total organic Carbon in purified water|
|Shimadzu||Japan||A wide range analytical test.|
|Conductivity Tester Model: PP-20||Sartorius||Germany||To test conductivity|
|Seiving machine||Fritsch||Germany||To do sieve analysis|
Model: AP-l 00
|Atago||Japan||To determine Optical rotation|
|pH meter Model:RSP-42||Mettler Toledo||Switzerland||To determine pH|
|Dissolution Tester Model: PTWS||Pharmatest||Germany||Dissolution testing|
|Melting Point Analyzer Model:FP62||Mettler Toledo||Switzerland||Identification|
|Atago||Japan||To determine refractive index|
|Water bath Model:1083||GEL||Germany||Controlled temp|
|Centrifuge machine Model:Z400||Hermle||Germany||Separation techniques|
|Muffle Furness||Linn Hitherm||Germany||To determine ash content|
|Microscope Model:CX-21 FSI||Olympus||Japan||Identification|
|Precision oven Model:0V453||Channel||Germany||Drying|
|Drying Oven Model: 100-800||Memmert||Germany||Drying|
|Horizontal Shaker Model:3017||GEL||Germany||Shaking|
|Weghing Balance ModelI:PB4002-s||Mettler Toledo||Switzerland||Analytical weighing|
|Potentiometry titrator Model:DX53||Mettler Toledo||Switzerland||Potentiometric titration for ions|
|Karl Fischer titrator Model:DX3I||Mettler Toledo||Switzerland||Moisture determination|
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:
- Organization & management:
It is a basic requirement for establishing an effective QC system.
- 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.
- Personnel at all levels have accountability to carry out their responsibilities to meet the quality goal.
Qualified personnel are a key factor in ensuring quality. Personnel have three important characteristics:
- 3. Premises:
A well designed premise is an essential part of GLP.
- 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:
- 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 good stock of reference standards is maintained and used.
To maintain reagents QC department has taken following initiatives:
- Laboratory has a complete list of all the reagents needed.
- Solid reagents are stored in alphabetic orders and separated from liquid reagents.
- The reagents need to be stored at low temperature is refrigerated.
- Flammable reagents have segregated area.
- Moisture sensitive reagents are stored in desiccants.
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 con strictly followed by analysts.
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.
The incoming goods and finished products are tested according to BP, USP, EP as per requirement laid down specifications.
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: material’s name, supplier’s name, total quantity, number of containers, manufacturer’s 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.
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 don’t 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.
• 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:
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.
Equipment used in Microbiology:
- Airborne Particle Counter: Used for 0.5μ and 5μ; 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:< -120°c
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 30°c. This visualize the microbial growth.
C) Surface swabs technique:
Sterilized swabs of cotton buds are moistened in a sterile diluent’s 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|
|0.5µ 5µ||0.5µ 5µ||—|
|A||3500 0||3500 0||<1|
|B||3500 0||350000 2000||<5|
|C||350000 2000||3500000 200000||<50|
|D||3500000 20000||Not defined Not defined||–|
A) Sterility test:
It is done for raw materials and product materials. 14 days are require for sterility test.
a) Direct method.
b) Filtration method (mostly used).
Condition require for microorganism test given below:
Type of Organism
22°C – 25°C
30°C – 35°C
B) Limit test/Contamination test:
This test is done for checking raw materials. Three types:
1) Pour plate
2) Spread plate.
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.
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 shipment’s 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 company’s logo are destroyed. For raw materials that are the rejected the vendor is contacted immediately.
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 (2-8°C) eg. insulin
– cool room (8-15°C)
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.
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(FEFO)’ basis.
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.
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.
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:
25°C, 60% Relative Humidity (RH)
a) Real time stability
30°C, 65% RH
b) Accelerated Stability: 40°C, 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
Water is pulled 470 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.
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 85°C 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.
Conductivity: at 25°C <1.2µs/cm
TOC < 500 ppb/Li
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 90°C at 4-5 bar. The WFI pipes are sterilized after every 15 days at 121°C for 30 minutes.
Conductivity: at 20°C <1.1µs/cm
Bacterial endotoxin <250 IU/Li
Microbial load <10cfu/0.1L
Schematic Diagram of Purified Water Plant
Heating Ventilation Air Conditioning (HVAC) maintains optimum temperature and humidity throughout the factory.
Area Temperature Relative Humidity
Dispensing: 22±2°C 45±5%
Solid &Liquid: 22±2°C 55±5%
Cephalosporin: 22±2°C 55±5%
Sterile: 22±2°C 50±5%
Low humidity zone: 22±2°C 25±5%
Minimum air change rate: Class B 50/hr
Class C 30/hr
Class D not less than 15/hr
Effluent Treatment System
The purpose of an Effluent Treatment Plant (ETP) is to reduce Biological Oxygen Demand (BOD) & Chemical Oxygen Demand(COD) of pharmaceutical unused chemicals & powders and waste materials which may cause severe harmful effect on environment as well as human health.
Effiuent management in Popular Pharmaceuticals Ltd. is carried out through bio-spiral technology as aerobic treatment process. The capacity of the plant is 30 m3/day.The quality of output is dischargeable into the public sewer or re-useable for gardening & land scarping.
All the waste water passing through a bar screen is collected. Raw sewage from the source is usually received in to the bar screen chamber by gravity. Screen provide will remove all floating and big size matter such as plastic bottles, polythene bags, glasses, stones etc.
Sewage transfer pumps transfer sewage from equalization tank to bio-spiral unit.
The Primary Settlement zone reduces the suspended solids by 75% and the BOD by 25% to 30%. The recirculation from the system and the return of humus sludge into the primary settlement zone inhibits the settled effluent from becoming anaerobic which prevents bad odor.
▪Aerobic Treatment (Reducing Process of BOD & COD):
The primary settled sewage is then treated by the Aerator. It is a biological treatment zone. It is a combined fixed film reactor and active aeration system mounted on a horizontal shaft. The Aerator is fitted on the sludge storage tank and covered. The rotational media is a spiral formation enclosed in an outer drum to provide active aeration.
The final settlement or humus tank is a discrete compartment denying ingrees of untreated or partially treated liquor. Treated sewage is then passed to Treated Sewage Tank and the sludge goes to the Sludge holding Tank.
▪Sludge Holding Tank:
Sludge Holding Tank is provided in the base of units. It’s capacity is approximately 12 weeks capacity provided. De-sludging from the holding tank can be carried out by centrifugal pump.
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
Schematic Diagram of ETP
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, employee’s behavior, clothing etc.
• 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.
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.
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.
General Security Instruction:
a) Entry of unauthorized people is restricted.
b) Entry of transport inside plant is restricted except up to transport parking area. However, entry of transport during rain is allowed only to drop/pickup their persons.
c) No one is allowed to enter inside the Production areas except any cause of fire or any accident.
d) Spiting, smoking, sleeping, urinating etc. other than specified places are strictly forbidden for any one.
e) Duties: 24 hours duty have been divided in the following manner:
A- shift ——— from 6am to 2pm
B- shift ———- – 2pm to 10 pm
C- shift ———— – 10pm to 6 am
D- Shift ———– – 6am to 5 pm
Popular Pharmaceuticals Ltd. the pioneer manufacturer of generic Biotech formulations (Human Insulin) in Bangladesh, is a company of Popular Group, the leading corporate house in private sector Health Care Management in the country. Popular Pharmaceuticals Ltd. (PPL) has five separate and dedicated facilities for the manufacture of wide variety of formulations like Human Insulin, Low Molecular Weight Heparin, Anesthesia Products, Cephalosporins, Penicillins Opthalmologics, Injectables, Dialysis Fluids, etc. besides its regular formulations like solids (Tablets, Caplets, Capsules), liquids (Syrup, Suspension, powder for suspension), creams & ointments. Two more facilities are also being erected for the manufacture of Oncology Formulations and Hormones. Popular Pharmaceuticals Ltd. (PPL) exports its high quality products to a number of countries in Asia and Africa and continuously invading newer markets round the globe.
The technical excellence of PPL is being reflected by the toll manufacturing of specialty product ranges of six leading pharmaceutical companies of the country.
Bangladesh Pharma market is very dynamic with an interesting growth rate. It is worth US$ 593M (approx) with 16% growth over last year (IMS 4 Q MAT 07).
PPL is now looking for tapping pharmaceutical import market in Bangladesh in association with reputed research based companies and their products. Depending on the level of involvements of the principals in Bangladesh, these products might be marketed with the help of dedicated/shared product management team along with the highly professional and experienced medical representatives of Popular Pharmaceuticals Ltd. Our principals will also have access to the data on doctors and pharmacies maintained by PPL. PPL also own a distribution network having 9 distribution centers throughout the country and capable of supplying products to 40,000 retail pharmacies.
Popular Pharmaceuticals Limited (PPL), has exclusive authorization to market and distribute the world renowned brands of Merck KGaA, Germany in Bangladesh. Should you be interested to associate with a visionary company in Bangladesh, we shall appreciate your views and comments at firstname.lastname@example.org
International Marketing Department (IMD)
Pharmaceutical Industry is one of the areas where Bangladesh has achieved remarkable advancement. Subsequent to the WTO-TRIPS agreement, Bangladesh and other 38 LDC’s are allowed to manufacture patented drugs till 2016. This opened up the window of opportunity for export of these patented molecules to the LDC’s as among these countries, Bangladesh has the best infrastructure with regards to manufacturing of pharmaceutical formulations.
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 where products from Bangladesh are currently being exported.
PPL 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 now available in Kenya, Sri Lanka, Macau & Somalia. Products from Popular Pharmaceuticals Ltd. are also expected to become available soon in Singapore, Philippines and some other African countries including Libya, Tanzania, Nigeria, and Yemen etc.
Popular Pharmaceuticals Limited welcomes the leading Importers and Distributors of Pharmaceutical Finished Formulations all over the world who intend to explore the opportunities to develop long lasting and mutually beneficial business relationship with a visionary organization of Bangladesh.
Key features of PPL Distribution
12 Distribution centers
Covering 45 thousand chemists
First time manufacturer of cold chain products in Bangladesh.
Fully capable of distributing all kind of pharmaceutical products
Although the four weeks time of our training in Popular Pharmaceuticals Limited flew very quickly, with the co-operation of the authority and all the personnel, we have learnt a great and gathered a lot of experience which will be helpful for our future practical purposes. In every section, the respective authority cordially received us. They initiated our curiosity and interest regarding the relevant subjects. We are pleased with the behavior of every person involved in the factory. Thus, we have completed our training with great satisfaction and hope that the feeling is mutual.
The plant layout of the Popular pharmaceuticals Limited plant at Tongi is in a word, excellent. It was, no doubt, a very well planned layout that provides an optimum use of space and ease of operation and thus contributes highly towards optimum productivity.
The plant is very well organized and the internal environment is very supportive to the employee, which is very nice since a congenial atmosphere increases the productivity of a company. The canteen is also very nice and the food menu was found to be very good, although there is always room for improvement in this regard.
One of the impressive things about popular Pharmaceuticals Limited is its wide range of products and its quality. I was also very impressed with the maintenance of GMP and the extensive documentation of all the works kept in the in the company, complying with the ISO 9001 requirements.
Another most impressive things about popular Pharmaceuticals Limited is that they are trying to commence such kind of product which are valuable and they are marketing it in lower price. For example the anti-cancer drug Enliven.
I would like to end with a note of thanks, again, to Almighty Allah, and to everyone involved, for successful completion of this training and I hope that popular Pharmaceuticals Limited will continue its co-operation to allow In-plant Training in future.
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