In-plant Training Report at Ziska Pharmaceuticals Ltd. by~ Waliullah

Assalamu alaikum
Welcome to Our Presentation on

By…
MD. Waliulah Wali
Department of Pharmacy
Southeast University
waliseu31@gmail.com
https://www.facebook.com/pages/Warinas-
Pharmaceuticals/245690832271163

Introduction
Production Department
Warehouse
Profile about Ziska Pharmaceutical Ltd.
Engineering department
Quality Assurance Department
Quality Control Department
Packaging Department
Finished Good

Training Period:
From August 06, 2014 to August 19, 2014
Duration: 14 Days
Training Areas:
Warehouse
Production Department
Quality Assurance & Quality Control Department
Product Development Department
Maintenance & Engineering Department
In- Plant Training Program at ZISKA PHARMACEUTICALS LTD.

 In Bangladesh the pharmaceutical sector is one of the
most developed hi-tech sectors within the country's
economy.
 This sector is also providing 97% of the total medicine
requirement of the local market.
 Recently few new industries have been established with
high tech equipment’s and professionals which will
enhance the strength of this sector.
 Ziska Pharmaceutical Ltd. is one of them.
In- Plant Training Program at ZISKA PHARMACEUTICALS LTD.2/10/2015 6

 Company Name: Ziska Pharmaceutical Ltd.
 Factory Location: Karol Surichala, Safipur, Gazipur
 Head Office: Nurul tower, 34- Purana Paltan line,
Dhaka-1000
 Corporate Setup: Private Limited Company.
 Manufacturing areas: 146500 sft.
 Established Year: 1986
2/10/2015 7

2/10/2015 8

In- Plant Training Program at ZISKA
PHARMACEUTICALS LTD.
2/10/2015 9

The Engineering department deals with the complete
maintenance of the production and companies total
working environment .
The Engineering section of Ziska Pharmaceuticals Ltd.
covers the following Utilities :
Production machineries.
Electricity supply
Air Handling
Water supply
Emergency supply
Repairing, restoring and reporting
Worker distribution and pest control.
2/10/2015 10

Electricity:
Required electricity mainly obtained from DESA, incase of
load shedding heavy duty generator provide electricity.
Generator:
Name: Cummins
Type: diesel operated.
Capacity: 1750 kilowatt.
Requirement: 1500 kilowatt.

A boiler is used to boil water to
110◦C and produce steam for
production area.
Heat is generated by using gas.
Generated steam is used in fluid
bed dryer, FBP and in coating pan.
Name: Fulton (Tube less boiler)
Origin: America
2/10/2015 12

It means Heating Ventilation Air Conditioning (HVAC). It
maintains optimum temperature and humidity throughout
the factory.
All seeks to provide thermal comfort , acceptable indoor air
quality and reasonable installation operation.
2/10/2015 13

HVAC:
Controlling of temperature and Relative Humidity in deferent
areas-
 Dispensing: 22±2°C 45±5% RH
 Solid &Liquid: 22±2°C 55±5% RH
 Sterile: 22±2°C 50±5% RH
 Low humidity requiring rooms: 22±2°C 25±5% RH
 Minimum air change rate:
Class B 30/hr
Class C 30/hr
Class D not less than 15/hr
2/10/2015 14

HVAC system:
Spoiled
Air
Back Filter
Added
with
natural air
Pre-filter
Fine Filter
Pass through
Cold Water
Coil
Hepa
Filter
Fresh Air
2/10/2015 15

HVAC system:
2/10/2015 16

Chiller system:
This system is involved for the production of chilled water which is
supplied through the pipe to produce air conditioning system.
Process:
Fan
Chilled water
supplied through
coil
Air flow inhibitor,
which hold air and
helps to remain with
the contact of coil
and cool them
Conditioned air
2/10/2015 17

Chillers
2/10/2015 18

HEPA Filter
High-efficiency particulate air Filter or HEPA filter is an air
filter that must remove (from the air that passes through)
99.97% of 0.3 µm size particles.
Smaller and larger particles are filtered at even greater
efficiency.
The efficiency of H30 HEPA filter is about 99.99% and
The efficiency of H40 HEPA filter is about 99.999%.
2/10/2015 19

HEPA Filter :
2/10/2015 20

Environment Monitoring:
Environmental monitoring is one of the most important tasks in
the sterile department.
Name of control
measure
Description
Zone concept Class A(100),Class B(1000),Class C(10000),Class D(100000) (Ft³)
Air pressure
difference
Positive pressure must be maintained in the processing room & 10-
15 Pascal higher than in the adjacent rooms.
HEPA filter
integrity
0.3 micron & 99.997% efficacy.
Temperature &
humidity
(22 ±2)°C, (50±5) % Relative humidity.
2/10/2015 21

Water
Portable water
Purified Water
Water for Injection
(WFI)
2/10/2015 22

Schematic Diagram of Purified Water and WFI Plant:
Feed
water
Alum
dosing
Sand
bend
Softener
(strong cation
resin)
UV lamp
(single)
254 nm 26 W
Anti-scalant dosing
NaOH
dosing
Cartridge
filter
5µ
RO-1
membrane
0.0001µ
RO-2
membrane
0.0001µ
2/10/2015 23

Reverse Osmosis
Storage Tank
(1000L)
Mixed Bed
(strong cation
& anion resin)
Filter
132µ (Cartridge
Net type)
Filter
45 µ (Cartridge Net
type)
Cartridge
filter
1µ
Cartridge
filter
0.2 µ
UV lamp
(double)
254 nm 26 W
Purified
Water tank
(3000L)
Multicolumn
distillation
WFI storage
tank
(500L)
2/10/2015 24

2/10/2015 25

2/10/2015 26

Distillation Column :
2/10/2015 27

WFI storage tank:
2/10/2015 28

Pharmaceutical unused chemicals & powders and waste
materials may cause severe harmful effect on environment
as well as human health.
An Effluent Treatment Plant (ETP) manages or treats the
waste materials into neutralized molecule or reduces the
harmful ingredients below toxic concentration.
2/10/2015 29

Process Flow Chart of Effluent Treatment Plant (ETP)
2/10/2015 30
Raw sewage from
Cepha & Peni
Neutralization (conc. NaOH)
Sewage from
production
floor
Bar screen
chamber
Equalization
Tank Sewage transfer pump
Primary clarifierAerotor BiozoneSecondary
clarifier
Chlorination tank
(NaOCl dosing)
Clarified Water
Tank
Treated sewage
pump
Multimedia
Filter
Carbon
filter
Discharge to
Public sewer or
recycle

2/10/2015 31

 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 and packaging material are tested as they
enter the warehouse and they are transferred to the
manufacturing department by requisitions.
 The storage department of Ziska Pharmaceuticals Ltd.
includes the following sections:
1. Raw materials store
2. Packing material store and
3. Finished product store
2/10/2015 32

Generally three types of labels are used in ware house.
They are-
Passed
Rejected
2/10/2015 33
Under test

Storage Condition:
Generally four Storage Condition are maintained according
do products sensitivity. These are:
2-8 oC
8-15 oC
15-25 oC
≤50 oC
Cool room
2/10/2015 34

2/10/2015 35

2/10/2015 36

Tablets are solid dosage forms consisting of active
ingredient(s) and suitable pharmaceutical
excipients. They may vary in size, shape, weight,
hardness, thickness, disintegration and dissolution
characteristics.
2/10/2015 37

Name of Machine used in Tablet section:
NAME OF MACHINE MODEL CAPACITY ORIGIN
Rapid Mixer Granulator Saral Eng. 100kg/80L India
Fluidized Bed dryer(FBD) Alliance 60 kg India
Fluid Bed Processor (FBP) Solate 250kg Korea
Multi Mill Shifter Kothari Pharma 60kg/hr India
Double Cone Blender (DCB) Mark Inds. 150kg Bangladesh
Tablet compression machine 35 S Jaguar 60rpm India
Tablet compression machine 27 S Cadmach 50rpm India
Automatic Film coating machine Intilligent 60-80kg China
Blister machine Buchon 28rpm Korea
2/10/2015 38

The Tablet section performed the following steps to
manufacture a complete tablet dosage form.
Dispensing Granulation Compression
Packaging
Coating
2/10/2015 39

1. Dispensing
It is one of the most important and the first step to
prepare any type of dosage form.
Purpose: -
To evaluate the correct quantity of drug and
excipients .
To prepare an unit dosage form.
To obtain standard dissolution, disintegration and
other test done.
2/10/2015 40

2. Granulation
Granulation is the process where the granules are
prepared from the powders.
Types:
A. Wet granulation
B. Dry granulation
C. Direct compression
2/10/2015 41

A. Wet granulation
Steps:
Weighing
Granulating in
rapid mixing
granulator(RMG)
Drying in
fluid bed
dryer(FBD)
Multi Milling Screening
Lubrication
(In Blender)
Compression
2/10/2015 42

Double cone blenderFBDRMG
2/10/2015 43

B. Dry granulation
Steps:
Requisition of raw materials
Weighing/Dispensing
Compression into slugs or roll
compaction
Milling and screening of slugs
Lubrication/Blending
2/10/2015 45

C. Direct compression
Steps:
Weighing of the
ingredients
Mixing & Sieving according
to desired mesh size
Mixing with
Lubricant
CompressionTablet is prepared
2/10/2015 46

3.Compression:
Compression is the process to prepare tablet by
compacting the masses.
Purpose:
For the preparation of tablet
To prepare accurate uniformity and tablet
dosage form.
2/10/2015 47

TABLET COMPRESSION MACHINE(JAGUAR):
2/10/2015 48

Compression Process :
Weighting of granules
↓
Put the materials into the hopper
↓
Filling of dies
↓
Tablet is prepared by compression between the rotating area of
punch and dies
↓
Ejection
↓
Checking size, shape and hardness, thickness, D.T, Friability of
the tablet.
2/10/2015 49

4.Coating
It is the process to put an outer surface or coat on
tablet. We observed the coating of “Ranitidine” tablet.
Purpose:
To mask the bitter and
unpleasant taste
Protect the ingredients from the environment
Produce prolonged duration of action
Increase pharmaceutical elegance
2/10/2015 50

Coating Process :
Tablets to be coated is taken in coating pan
Temp. of pan, inlet & outlet air pressure, RPM of pan etc are
adjusted
Solution is connected to machine by tubes
Solution is sprayed onto the tablets by spray guns of the
machine.
Coating
2/10/2015 51

Coating Machine : Sejong
2/10/2015 52

5.Packaging
Packaging is the last step of tablet section. It is the
process that protects product from environment (dust,
foreign particles etc.) during distribution, storage, sale
and use.
Purpose
To provide convenience to user.
To ensure satisfactory sealing.
2/10/2015 53

Blister packaging machine
2/10/2015 54

Process of Blister Packaging:
PVC
sheet
Heating (temp. 125
to 145 C)
Formation of pocket
by air pressure
Tablet or capsules are filled into
the pocket automatically
Sealing with aluminum
top foil
labeling & Batch
Printing
Auto feed checker Cutting
2/10/2015 55

Capsules are solid preparations with hard or soft shell of
various shapes and capacities, usually containing a single
dose of active substance(s).They are intended for oral
administration.
2/10/2015 56

Types of capsules:
1.Hard gelatin capsule
(double piece)
2.Soft gelatin capsule
(single piece)
2/10/2015 57

Manufacturing process of Hard Capsule in Automatic
machine:
Empty
capsule
shell
Shells in
hopper
Caps and bodies are separated
by the force created by vacuum
pressure
powder are automatically filled
in body of shell
Enclosing
of cap and
body
Ejection
Finishing Inspection Packaging
2/10/2015 58

Capsule filling Machine: Automatic
HUASHILI NJP- 2000
2/10/2015 59

Manufacturing process of Hard Capsule: Manual
Capsule shells are set into the plate through in setter
↓
Plate set into the hand filler
↓
Body and cap separated by scissor
↓
Fill the body with materials
↓
Attached body and cap
↓
Capsules
2/10/2015 60

Capsule filling Machine: Manual
2/10/2015 61

This is a powder dosage form of oral drug used because the
drug is unstable in solution. It must be reconstituted
before use. It is mainly sugar based preparation.
We observed the preparation of Quinitor dry syrup
(Ciprofloxacin).
Purpose:
For the easy administration of drugs
To obtain the effectively of the drug completely after
reconstitution
2/10/2015 62

Process:
Milling and drying of sweetener
Transfer to a drum blender
Sieving and addition of active ingredients and other excipients
Proper mixing
Bottle filling and sealing
2/10/2015 63

A drug administer in solution is immediately available for
absorption and in most case is more rapidly and efficiently
absorbed than the same amount of drug administered in
tablet and capsules.
In Liquid processing unit two types of liquid dosage form
are manufactured. This are-
1. Syrup
2. Suspension
2/10/2015 64

Machineries Used in Filling & Packaging Unit of Liquid
department:
NAME OF MACHINE MODEL CAPACITY
Bottle washing machine Laxmipharma 100-120
bottle/min
Bottle washing machine Pharmalab 100-120
bottle/min
Bottle filling & Cap locking machine Pharmalab 100 bottles/min
Bottle filler & Capper machine United 80bottles/min
Bottle filler & Capper machine Kingfisher 70bottles/min
Bottle labeling machine Ambica 110-150 label/min
Syrup Mixing Machine Silverson Mixer 3000L
2/10/2015 65

Manufacturing Process of liquids:
Weighing of active ingredients along with excipients.
Excipients are mixed in a Charge vessel
Active is added to the vessel & mixed
Passing through a Pump to the storage vessel
Transfer of the solution to the filling vessel through 0.5µ Cartridge filter
Filling, Flushing of Nitrogen (N2) & Sealing of Bottles containing oral
liquid.
2/10/2015 66

Filling & Sealing Machine: Pharmalab
2/10/2015 67

Process of Liquid Filling:
Transfer of Prepared liquid preparation into the filling machine
from the processing vat by the use of transfer pump.
Set the machine according to filling volume
Filling of bottles
Sealing of bottle using sealing machine
Labeling & Packaging of bottles

Ointments are the soft semisolid preparations meant for
external application to the skin or mucous membrane.
Creams are viscous semisolid ointment like preparation
but have lighter body than the ointment. Due to the
presence of water soluble base in oil in water type creams
they can be easily removed from the skin.
2/10/2015 69

Water Phase Prepare in
Container (A).
Filling & Packaging
Transferring
&Weighing Milky Appearance
Main Vessel (Mixing): stirring at 800Cfor 30min
[High Speed=1500 rpm & low speed=43 rpm]
Congealing For 1 Hour
QA Approval
Oil Phase Prepare in
Container (B).
2/10/2015 70

Sterile pharmaceutical products are very critical and
sensitive products. These products should be free from
living micro-organisms, pyrogen and unacceptable
particulate matter.
Parenteral products are radically different from other
dosage form in terms of standards of purity and safety.
Type of dosage form of sterile product:
1. Ophthalmic
2. Injectable
3. Powder for injection(Vial)
2/10/2015 71

Category of different parenteral processing area:
2/10/2015 72
Area Clean room standard
Filling point 100 class A
Filling room 1000 class B
Vial washing & sterilization room 10,000 class C
Filling room corridor 10,000 class C
Dress change room 10,0000 class D

Clean room classification according to EUGGMP:
2/10/2015 73
Class Particle count at
rest m³
Particle count
operation m³
Microbial
growth
(cfu)
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

Equipment used in Sterile Section
Process Name of Equipment Capacity
Vial washing Ambico Wash Machine(India) 1000-1200/hr.
Dry Heat Sterilization Hot air Oven (India) 40 Trays
Steam Heat Sterilization Autoclave (India) 40 Trays
Dry Heat Sterilization Ampoules Dry Heat sterilizer (Pakistan) 30 Trays
Vial Filling & sealing Automatic Vial filling & Sealing
Machine
30-40 vials/min
Solution Processing Solution Processing SS vessel (Germany) 500L for SVPL
Veterinary solution
processing
SS Vessel for Veterinary solution
(Germany)
100-500L
2/10/2015 74

Generally the products are manufactured by two ways:
Aseptically Sterilized: Products which must be processed
under aseptic conditions.
Terminally Sterilized: Products which can be sterilized in
their final container
2/10/2015 75

Flowchart showing the manufacturing of Parental
Product:
Aseptic
dispensing
Mixing in the
100L/500L
manufacturing vessel
Filtration is done
using 1.2µm and
0.2µm cartridge.
Filling in Filling
and sealing
Machine
Autoclave at 121°C
for 30 minutes in the
autoclave
Packaging
2/10/2015 76

2/10/2015 77

Quality Assurance is a wide ranging concept which covers
all matters which individually or collectively influence the
quality of a product.
Quality Assurance Department
Quality
Control
Documentation
In Process
Control
Microbiology
2/10/2015 78

Function of Quality assurance:
1. Calibration and validation of testing equipment.
2. Sampling of incoming Raw materials, In process
Analysis, Finished Product & Packaging Materials
Analysis.
3. Working Environmental Analysis.
4. Review of Stability Date and Shelf Life of Products.
5. Review of Product Design (Label & Formula).
6. Review of batch production and quality control records
and release of products.
7. Physical Inspection at random before release of a batch
of Finished Product.
2/10/2015 79

In-process control for dosage form checked by QA
department:
Tablets
a) Dispensing : Room condition –Temperature and RH should be within
limit.
b) Granulation: Uniformity of the granules as well as granule size.
c) Drying: LOD (Loss on drying).
d) Compression: Room condition, appearance of tablets , Average weight,
uniformity of weight, hardness, thickness and diameter of the tablet.
Friability of the tablet as well the disintegration time is also checked.
e) Coating: Absence of bridging, filling, sticking, color variation
2/10/2015 80

department:
Capsules
Room condition, appearance of shell, average weight, uniformity
of weight, disintegration time.
Liquid dosage forms, Ointment, creams, gels
a) Appearance, odor, color and pH
b) Filling: Fill weight; fill volume, sealing, presence of foreign
materials.
2/10/2015 81

department:
Powder for suspension
a) Bulk Appearance, odor, color
b)Filling: Room condition, fill weight, reconstituted
volume, sealing of cap.
Packaging
Blistering, PP infusion bags : Leak test
2/10/2015 82

Various test involved in raw materials analysis:
1. Identification
2. Solubility
3. Appearance of the solution
4. pH
5. Melting point limit
6. Loss on drying
7. Bulk destiny
8. IR spectroscopy
9. UV spectroscopy
10. HPLC
11. Water content
12. Potency determination
13. Microbiological test
2/10/2015 83

Apparatus used in QA Department:
TABLET
HARDNESS
TESTER
ANALYTICAL
BALANCE
FRIABILITY
TESTER
2/10/2015 84

Apparatus used in QA Department:
LOD MECHINE LEAK TESTER DISINTEGRATION TESTER
2/10/2015 85

Quality control refers to the process of striving to produce
a perfect product by a series of measures to prevent or
eliminate errors in production.
Functions:
Quality control department has functions in the following
areas:
Documentations.
Raw materials.
Finished products.
Packaging materials
2/10/2015 86

Equipment used in Quality Control Department:
Equipment Use
HPLC (High-
performance liquid
chromatography )
Analytical Test:
 Identification
 Qualification
 Separation
Atomic absorption
spectrophotometer
To identify and measure minerals.
IR Spectrophotometer Material identification & purity tests
UV-Visible
Spectrophotometer
Determination of impurities in
organic molecules
Gas Chromatography A wide range analytical test
2/10/2015 87

Equipment Use
Conductivity Tester To test conductivity
Viscometer Viscosity determination
pH meter To determine pH
Dissolution Tester Dissolution testing
Melting Point Analyzer Identification
LOD Tester To determine moisture content
Weighing Balance Analytical weighing
Potentiometry titrator Potentiometric titration for ions
Karl Fischer titrator Moisture determination
2/10/2015 88

HPLC (High-performance liquid chromatography )
High-performance liquid chromatography (HPLC) is a
form of liquid chromatography to separate compounds
that are dissolved in solution & also used to ensure the
purity of raw materials.
2/10/2015 89

UV-Visible Spectrophotometer
2/10/2015 90

Atomic-absorption Spectrometer
2/10/2015 91

pH meter Melting Point
Analyzer
Karl Fischer titrator
2/10/2015 92

Apparatus used in QC Department:
DISSOLUTION
TESTER
2/10/2015 93

Microbiology laboratory is the part of quality control.
It has following responsibilities-
Microbial limit test (For bacteria and fungi).
Antibiotic assay.
Microbial content of environment.
2/10/2015 94

Instruments used in Microbiology
1. Incubator (Memmert)
2. Incubator (Gallenkamp)
3. Biological safety cabinet class 2
4. Shaking water bath
5. PH meter
6. Kinetic LAL analyzer
7. Dynamic pass box
8. Autoclave
9. Sterilizing oven
10. TOC (total organic carbon analyzer)
11. LPC (liquid particle counter)
2/10/2015 95

Activity of PD:
 Receive of raw materials for product development.
 Prepare lab batch.
 Develop and validation and rationale.
 Prepare final formulation & rationale.
 Prepare pilot batches.
 Perform initial studies.
 Put samples on storage conditions.
 Perform 01 month study.
Prepare content of shelf-life.
2/10/2015 96

Instruments used in this department:
 Disintegration Tester
 Suction Pump
 Drying Oven
 Refrigerator
 Hardness Tester
 Shaker
 IR Moisture Balance
 Analytical Balance
 Dissolution Tester
 Friability Tester
 PH Meter
 Melting Point Apparatus
 Hot plate Stirrer
 Karl Fischer titrator
 UV Visible Spectrophotometer
 HPLC
Product development department also use QC lab., production
department and SVP department for their test purposes.
2/10/2015 97

2/10/2015 98

Packaging is the process by which the pharmaceuticals products
are suitably packed, in such way that they should retained their
therapeutic effectiveness from the time of their packaging to
consume by the consumers and it also helps to withstand the
stress during transport.
Ziska Pharmaceuticals Ltd. has a well-established packaging
department.
There are mainly two types of packing materials:
1. Primary packing materials
2. Secondary packing materials
2/10/2015 99

Type of Material used for packaging:
Primary packing
materials
1. Alu Foil (Blister/Strip)
2. PVC/PVDC Film
3. Alu Bottom Foil
4. Bottle
5. P.P. Cap
6. Unit Carton
7. Vial
8. Ampule
9. Rubber stopper
Secondary packing
materials
1. Box/ Inner carton
2. Insert
3. Label
4. Flipoffseal
5. Plastic Spoon/ Dropper
6. Cup
7. Stopper
8. Master Carton
9. Shipper cartoon
10. Hologram sticker
11. Honey com
2/10/2015 100

Diagrammatic Representation of packaging unit:
Packaging
Blister
Packaging
Strip
packaging
Bottle filling/
Lose
Packaging
2/10/2015 101

Steps involved in blister packaging :
Forming of Pocket
(By air Pressure &
temperature)
Filling Station
(Channel/ Feeder /
dosage Cannel)
Sealing
(Temperature
Station)
Cooling
Rejection of
empty
Blister Pack
Collection
of Blister
Pack
Send for
Secondary
Packaging
2/10/2015 102

Blister packaging machine:
2/10/2015 103

Steps involved in strip packaging :
Formation of pocket of aluminum
Filling
Sealing
Cooling
Batch and expire number printing
Cutting of strip
2/10/2015 104

Strip packaging Machine:
2/10/2015 105

Every production biased company has a ware house. There
are two types of ware house. Finished product store is one
of them.
2/10/2015 106

http://ziskapharmabd.com
https://www.google.com.bd/image
The Theory and Practice of Industrial Pharmacy by
Lachman.
http://www.bdquery.com/details.php?c=1556
2/10/2015 107

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In-plant Training Report at Ziska Pharmaceuticals Ltd. by~ Waliullah

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