in-plant training report at ziska pharmaceuticals ltd

Assalamu alaikum

Welcome to Our Presentation on

By…

MD. Waliulah Wali Department of Pharmacy

Southeast University [email protected]

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



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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.


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


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.


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


HVAC system:


Spoiled Air

Back Filter Added with

natural air Pre-filter

Fine Filter Pass through Cold Water

Coil

Hepa Filter

Fresh Air

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HVAC system:


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

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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%.


HEPA Filter :


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.

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Water

Portable water

Purified Water

Water for Injection (WFI)

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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

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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)

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Distillation Column :


WFI storage tank:


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.


Process Flow Chart of Effluent Treatment Plant (ETP)


Raw sewage from

Cepha & Peni

Neutralization (conc. NaOH)

Sewage from

production

floor

Bar screen

chamber Equalization

Tank Sewage transfer pump

Primary clarifier Aerotor Biozone Secondary

clarifier Chlorination tank

(NaOCl dosing)

Clarified Water

Tank Treated sewage

pump

Multimedia

Filter

Carbon

filter

Discharge to

Public sewer or

recycle


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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


Generally three types of labels are used in ware house. They are-


Passed

Rejected

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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

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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.


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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

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The Tablet section performed the following steps to manufacture a complete tablet dosage form.


Dispensing Granulation Compression

Packaging

Coating

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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.


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2. Granulation

Granulation is the process where the granules are prepared from the powders.

Types:

A. Wet granulation

B. Dry granulation

C. Direct compression


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A. Wet granulation

Steps:


Weighing Granulating in rapid mixing

granulator(RMG)

Drying in fluid bed

dryer(FBD)

Multi Milling Screening Lubrication

(In Blender)

Compression

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Double cone blender FBD RMG 2/10/2015 43

Fluid Bed Processor

B. Dry granulation

Steps:


Requisition of raw materials

Weighing/Dispensing

Compression into slugs or roll compaction

Milling and screening of slugs

Lubrication/Blending

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C. Direct compression

Steps:


Weighing of the ingredients

Mixing & Sieving according to desired mesh size

Mixing with Lubricant

Compression Tablet is prepared

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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.


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TABLET COMPRESSION MACHINE(JAGUAR):


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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.


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


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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

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Coating Machine : Sejong


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.


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Blister packaging machine


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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

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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.


Types of capsules:

1.Hard gelatin capsule

(double piece)

2.Soft gelatin capsule

(single piece)


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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

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Capsule filling Machine: Automatic


HUASHILI NJP- 2000

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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


Capsule filling Machine: Manual


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


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


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


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

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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.


Filling & Sealing Machine: Pharmalab


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.



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).

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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)


Category of different parenteral processing area:


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:


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

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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


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

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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

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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.


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



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.



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


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


Apparatus used in QA Department:


TABLET HARDNESS

TESTER

ANALYTICAL BALANCE

FRIABILITY TESTER

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Apparatus used in QA Department:


LOD MECHINE LEAK TESTER DISINTEGRATION TESTER

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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


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

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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

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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.




UV-Visible Spectrophotometer

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Atomic-absorption Spectrometer

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http://elchem.kaist.ac.kr/vt/chem-ed/spec/atomic/graphics/aa.jpg



pH meter Melting Point Analyzer

Karl Fischer titrator

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Apparatus used in QC Department:


DISSOLUTION TESTER

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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.


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)


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.


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.

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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


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

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Diagrammatic Representation of packaging unit:


Packaging

Blister Packaging

Strip packaging

Bottle filling/ Lose

Packaging

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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

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Blister packaging machine:


Steps involved in strip packaging :


Formation of pocket of aluminum

Filling

Sealing

Cooling

Batch and expire number printing

Cutting of strip

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Strip packaging Machine:


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


http://ziskapharmabd.com

https://www.google.com.bd/image

The Theory and Practice of Industrial Pharmacy by Lachman.

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in-plant training report at ziska pharmaceuticals ltd

Education

plant training program

engineering department

days training areas

good training period

hr class c

pharmaceutical sector

production machineries

production area