Aristopharma Pharmaceuticals

ARISTOPHARMA PHARMACEUTICALS LIMITED: An Overview INTRODUCTION ARISTOPHARMA is a leading Pharmaceutical company since 1990. ARISTOPHARMA achieved ISO-9001:2000 certificate in 2005. ARISTOPHARMA is committed to ensure better life through quality medicine.

Location: ARISTOPHARMA LTD, Shampur-Kadamtali Dhaka, Bangladesh.

Our training program had been scheduled 1st september to 7th October, 2009.

Solid Department General Introduction Solid dosage forms are some of the least expensive, most popular and convenient methods for drug delivery. They can be produced in a non-sterile environment and the technology is wellknown after more than 100 years of development. Since most pharmaceuticals are produced in solid dosage forms, it is important that the unit operations for their production be thoroughly understood. This course focuses on the fundamentals of each discrete processing step (unit operation) required for the manufacture and packaging of tablets and capsules, the most common of solid dosage forms.

Total Units in Solid Department

Manufacturing area

Granulation unit

Compression unit

Packaging area

Coating unit

Capsule filling unit

Tablet Manufacturing 1. Introduction of Tablet DEFINITION: A tablet is a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. The excipients include binders, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to ensure that the tablet breaks up in the digestive tract; sweeteners or flavours to mask the taste of bad-tasting active ingredients; and pigments to make uncoated tablets visually attractive. A polymer coating is usually applied to hide the taste of the tablet's components, to make the tablet smoother and easier to swallow, and to make it more resistant to the environment, extending its shelf life.

A TYPICAL TABLET CONTAINS:

TABLET EXCIPIENTS

Filler or diluent

Disintegrant:

Binder:

Glidant:

Lubricant:

Antiadherent:

Flavour: Colourant:

A filler, such as sucrose,lactose,mannitol and dextrose is included to increase the size of the tablet.

This is necessary as often the amount of 'active' is so tiny that the tablet would be too small to handle without it.

Disintegrants help the tablet to break down into small fragments, when it is ingested. This helps the medicine to dissolve and be taken up by the body so that it can act more quickly. Disintegrants may include potato or cocoa butter.

A binder, such as glucose or sucrose, is added to hold the tablet together after it has been compressed, stopping it from breaking down into its separate ingredients.

The glidant helps to keep the powder making up the tablet flowing as the tablet is being made, stopping it from forming lumps.

Lubricants ensure that the tablet has a smooth surface and that the powder does not stick to the equipment used to make the tablet.

The antiadherent also stops the powder from sticking to the equipment as the tablet is being made.

Flavouring agents help to make the tablet taste better.

Colours are added to help you to recognize your tablet and to make it easier to take your medicine correctly.

Tablets are usually right, circular solid cylinders, the end surfaces of which are flat or convex and the edges of which may be beveled. They may have break-marks and may bear a symbol or other markings. Tablets may be coated.

1.4.SEVERAL CATEGORIES DISTINGUISHED: • uncoated tablets; • coated tablets; • effervescent tablets; • soluble tablets; • dispersible tablets; • orodispersible tablets;

OF

TABLETS

FOR

ORAL USE MAY

BE

• • •

gastro-resistant tablets; modified-release tablets; Tablets for use in the mouth.

2.PRODUCTION OF TABLET In tablet production there are several steps involved which are following:      

Dispensing and Granulation.

Blending Powder compression Coating Blistering.

Secondary Packaging.

GRANULATION UNIT DEFINITION Granulation may be defined as a size enlargement process which converts small particles into physically stronger and larger agglomerates in order to facilitate compression for the production of tablet. All the materials are received from the dispensing unit and granulation is performed. For suitable granulation, it is required to have 30-40% powder and 60-70% granules and also 1-5% moisture in compressing particles.

PURPOSES OF GRANULATION -To produce tablets of appropriate size.

- To prevent segregation of the constituents in the powder mix.

-To improve the flow properties of the powder mix.

-To improve compression nature of powder.

Types of granules Two types of granules are produced in the four-granulation units of the industry, which include; • Granules with active ingredient/s • Placebo granules without any active ingredient/s for moisture sensitive active/s or drug/s Granulation Processes which are performed in the Aristopharma plant are following: • Wet Granulation.

• Dry Granulation.

• Direct compression Wet granulation: Wet granulation is a process of using a liquid binder or adhesive to the powder mixture.

The amount of liquid can be properly managed, and over wetting will cause the granules to be too hard and under wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvents.

Dry granulation This process is used when the product needed to be granulated may be sensitive to moisture and heat. Dry granulation can be conducted on a press using slugging tooling or on a roller compactor commonly referred to as a chilsonator. Dry granulation equipment offers a wide range of pressure and roll types to attain proper densification. However, the process may require repeated compaction steps to attain the proper granule end point.

Direct compression This method is used when a group of ingredients can be blended and placed in a tablet press to make a tablet without any of the ingredients having to be changed. This is not very common because many tablets have active pharmaceutical ingredients which will not allow for direct compression due to their concentration or the excipients used in formulation are not conducive to direct compression.

FLOW CHART OF GRANULATION PROCESS Wet granulation Weighing of active ingredient as well as excipients ↓ Dry mixing ↓ Wet mixing (in case of wet granulation) by addition of de-mineralized (DM) water or Maize starch paste in Rapid Mixer Granulator (RMG) for a certain time period specified in the Batch Production Record (BPR) ↓ Initial Phase drying in Fluid Bed Dryer (FBD) ↓ Milling in the Multimill ↓ Partial drying in FBD ↓ Milling in the Multimill ↓ Terminal/Final drying in the FBD ↓ Sieving in the Vibratory Sifter according to the required particle/granule size ↓ Measurement of Loss on Drying (LOD) ↓ Granules of desired size ready for blending.

Dry granulation Weighing of drugs and excipients Dry mixing of drugs and diluents Slugging or pre-compression Milling and sieving Lubrication Discharge for compression

 Condition for manufacturing of Granules:  

Relative Humidity: Not more than 55%.

Temperature: Below 250C.

MIXING & BLENDING

A powder blend should be as uniform as possible to assure the proper amount of medication in each dosages unit. The blending of solid particles is affected by the shape, density, size and size range of the particles, and surface effects such as absorbed liquid film, electrostatic charges and Van der Waals forces. Small particles are difficult to blend because they exhibit poor fluidity. However, more important than actual particle size is particle size range. All drugs and chemicals should be reduced to approximately the same size prior to weighing and mixing.

MACHINERY: Tablet Processing unit: 1 Name of the machines 1.Planetary mixer-60 kg, Gansons, India.

2.FBD-1-10 kg, Alliance Eng. Co. 3.Multi mill-1 4.Double cone Blender 5.Tablet oscillating Granulator 6.Paste Kettle

India

Purpose To mix the active ingredient and binder to form granules.

To Dry granules.

To reduce the size of granules.

To mix uniformly all the excipients.

To reduce the size of granules.

Preparation of slurry

Tablet Processing unit: 2

Name of the machines Purpose 1.RMG– 160 kg, Saral ENG. Company To mix the active ingredient and binder to LTD. form granules.

To Dry granules.

2.Y- cone and Double cone blenders.

To mix the processed granules with lubricating agents.

Rapid mixing granulator(RMG)

multi milleer

Fluid bed dryer

Double cone blender

FEATURES SPECIFICATIONS: RAPID MIXER GRANULATOR Rapid Mixer Granulator has been specially designed to meet the special needs of tablet manufacturing industry. The machines we offer are in compliance with GMP standards and are known to deliver long time performance. The seal housing and drive shaft is flushed with cleaning water, which is then drained away from the machine, through built in drain tubes.

Technical Specifications : • Standard Processing Duration • Dry Mixing approx 3 - 5 Minutes • Wet Mixing approx 5 - 10 minutes • Wet Granulation approx 5 - 10 minutes • Discharge approx 1-15 minutes Unique features : • RMG Improved Processing • Uniform distribution of all formulation ingredients • Reduced mixing and granulation time • Useful working capacity of up to 80% to 40% of bowl volume

• • • • • • • • • •

Uniform granules by gentle processing Widely applicable Easy scale up & Scale down between machine sizes Bowl shape design to have no dead spaces Homogeneous binder distribution Enclosed moving parts Ensured safety Air purge sealing for main shaft and Chopper shaft.

Auto / Manual Controls Hydraulic/ Pneumatic lifting of main shaft for cleaning

TABLET COMPRESSION

Compression of powder means reduction in bulk volume of a material as a result of displacement of the gaseous phase. Compression is used for the manufacturing of tablet.

In the compression of active pharmaceutical ingredients, overall control is essential to ensure high quality. Haphazard operations cannot be permitted in the compaction of substances that may be used to save life or to restore or promote health.

Adherence to the practices, complementing the various control tests carried out from the beginning at dispensing to the end of the production cycle with compaction, will contribute substantially to the production of consistently uniform batches of high-quality active pharmaceutical ingredient FLOW CHART OF TABLET COMPRESSION

General Compression Granules (previously made) ↓ Transfer of granules in the Hooper of tablet press machine by hand or auto powder/granules loader ↓ Rising of upper punch & dropping of lower punch ↓ Filling of die cavity through feed frame ↓ Removal of extra granules by scrape off plate ↓ Coming down of upper punch for ↓ compression to produce tablet ↓ Raising of both upper & lower punches to certain extent ↓ Ejection of tablet with the help of take out plate ↓ Conventional Uncoated Tablets of desired shape and size

Tablet-machine parts:

Direct Compression Milling & Screening of active ingredient/s & the excipients ↓ Mixing of the active ingredient/s along with excipients including lubricants & disintegrants ↓ Transfer of mixer in the hopper of tablet press machine by hand or auto powder loader ↓ Rising of upper punch & dropping of lower punch ↓ Filling of die cavity through feed frame ↓ Removal of extra granules by scrape off plate ↓ Coming down of upper punch for compression to produce tablet ↓ Raising of both upper & lower punches to certain extent ↓ Ejection of tablet with the help of take out plate ↓ Conventional Uncoated Tablets of desired shape and size

           

Hopper Main compression roller Feed frame Compression station Feed paddles Ejection cam Draw down cam Take off blade Weight controller fills station Ejection station Pre-compression roller Take off chute.

Machines used in the Tablet Press unit for Compression: # B-tooling machine → Die 30 mm & punch 19 mm (35 punches) # D-tooling machine → Die 38 mm & punch 25 mm (27,35 punches) There are 08 compression machines: # 1 automatic machine 30 station. (Sejong) # Press machines {Station: -16, 23(1), 27(1),35(3),37(1)} Automatic tablet compression machine 1. New Se Jong Model 37 Station Rotary Tablet Press. Machine (1) Unit has the capacity to deliver 54,000 to 216,000 tablets per hour. Maximum Tablet Diameter: 16mm, Maximum Tablet Thickness: 8.5 mm, Filling Depth: 4.5 to 10mm, 8.5 to 14mm, 12.5 to 18mm, Upper Punch Insert: 1 - 6mm, Maximum Pre-Pressure: 2 tons, Maximum Main Pressure: 8 tons, Die Size: 30.162 x 22.225mm.

(2) This is a high speed rotary tablet press, which is constructed of steel channel and aluminum bar, with exterior cover constructed of 304 Stainless Steel. Door is constructed of clear acrylic plate with cylinder supporter, Turret: FCD55. All contact parts are Stainless Steel. Machine Dimensions: 44” wide x 54” deep x 76” high, (without hopper), 82” high with hopper.

(3) Driving System: 5 HP motor, 1/19 ½ Speed Reducer, Rotation Speed of Turret: 25 - 75 RPM, Variable Speed Pulley (SAKAI) or AC frequency variation speed controller (Inverter), Clutch and Brake System.

(4) Turntable: Pitch Circle Diameter: 420 mm, 30 die holes, 30 holes each for upper and lower punches, Pre-compression roller, adjustable by index handle, Main compression roller, adjustable by index handle.:

(5) Lubrication System :Automatic lubrication by cycle pump, Lubricating interval and amount can be reset, Pump Motor: 0.9 Kw. (6) Compression Force Buffering System: Hydraulic Cylinder buffers on both of Precompression and Main compression stations, powered by hydraulic pump, adjustable by a push button controller on the panel, Pump Motor: 0.2 Kw. (7) Feeding System: Mechanical feeder as standard, open feeder is available as an option, Stainless Steel hopper with sight port.

(8) Tooling: IPT ‘B’ Type.

(9) Electric Control System: Index Handles, Hydraulic Pressure Indicator, Voltmeter, Ampere Meter, Digital Tachometer, Digital Product Counter, On - Off Switches, Function Selectors, Safety Lamps, Hydraulic Power Adjusting Buttons, Emergency Stop Button, Jog Drive Button, Alarm Buzzer. Comes with all controls and standard features needed to operate properly including a tool box and manual. If required, installation and training are available for an additional cost. The MRC 36 Tablet Press will come with standard instruction manual, installation qualifications and operation qualifications (IQOQ). Comes with a 1 year warranty. Delivery time: approximately 8 - 10 weeks from receipt of order and a 60% dep Semi Automatic Rotary Tableting Press GMP Common Problems that arise during Compression: Common Problems that generally arise during compression are-

• • • • • • •

Capping Chipping Sticking Weight variation Mottling Hardness problem Lamination

TABLET COATING DEFINITION Coated tablets are tablets covered with one or more layers of mixtures of various substances such as natural or synthetic resins, gums, gelatin, inactive and insoluble fillers, sugars, plasticizers, polyols, waxes, coloring matter authorized by the competent authority and sometimes flavoring substances and active substances. The substances used as coatings are usually applied as a solution or suspension in conditions in which evaporation of the vehicle occurs. When the coating is a very thin polymeric coating, the tablets are known as filmcoated tablets.

Coated tablets have a smooth surface which is often colored and may be polished;a broken section, when examined under a lens, shows a core surrounded by one or more continuous layers with a different texture.

Classification of Coating: Mainly three types of coating are performed in the solid section. They are as follows: Coating Sugar coating

Aqueous coating

Film coating

Enteric coating

Organic coating

1. Sugar Coating:In suitable sugar- coating equipment, the tablet cores are successively treated with aqueous sucrose solutions which, depending on the stage of the coating reached, may contain other functional ingredients e.g. fillers, colors etc. The build up of coating material is due to transference of coating medium from one tablet to another. Typically a single liquid application will be made which will be allowed to spread over the entire tablet bed utilizing the mixing capability of the particular equipment. At this point, drying, usually in the form of heated air will be used t o dry the application. The whole cycle will then be successively

repeated.

Stages Of Sugar Coating1. Sealing 2. Sub-coating 2. Film coating: In film coating two polymers are highly used. One is HPMC and another is Eudragit-L100 and L-50 (liquid). In aqueous solution water is used as solvent but in organic solution – methanol, methylene chloride and PEG 6000 are used. The distance between spray gun and tablet bed, incase of organic solvent is 3-4 inch and incase of aqueous solvents is 8 inch. Pan rotation is within 3-15/hr. it varies from product to product. Air pressure is maintained to 1.5-4 kg.

Steam temperature: Coating Inlet Outlet Organic 750c 650c Aqueous 60/650c 50/550c → 200 kg coating machine containing spray guns. → 110 kg coating machine containing spray guns → 100,70, 20 kg coating machine containing spray guns 3.Enteric coating: There are two steps for enteric coating → Sub-coating: Sub coating is performed by using HPMC as polymer with either organic or aqueous solution. This process performs for 5 hours. → Enteric coating: Enteric coating is performed by using eudragit L-100 or L-50 over the sub coating. This is done for 15 hours.

Machines used for both Film & Enteric Coating: Name of the Machine

CAPACITY

NR-COTA (FC) TC-TC9. NR INDS. THAILAND. ECO COTA TC-TC2 F D & C Pvt. LTD. PAKISTAN SUGAR COATING PAN, BANGLADESH & INDIA. RAMA COTA (EC) TC-TC-1 RAMA PROD. COM. LTD. N R COTA 2 TC TC-11, NR INDS. THAILAND

90-110 KG. Max:100 KG Max:70 KG Max:20 KG Max:200 KG

FIGURE: Sugar coating and Film coating machines. 

Condition required during Coating: • •

Relative Humidity: Not more than 50%.

Temperature: Below 250C.

COMMON PROBLEMS ASSOCIATED WITH TABLET COATING: 1. Logo bridging

Cause:  Surface characteristics of the product being coated  Inadequate adhesion of film coating  Inadequate design of logo (e.g. too detail/fine logo) Remedy:    

Modify core formulation to include more hydrophilic ingredients Increase core porosity 0Using formulation with increased adhesion property.

Increase area within the debossing and modified angles.

2. Core erosion

Cause:    

Inherent softness or high friability of core.

Excessive pan speed in coating process.

Spray rate too low.

High sensitivity of core to moisture as coating is applied.

Remedy:  Increase mechanical strength of core.  Decrease pan speed.  Increase spray rate.

3. Edge chipping/erosion

Cause:      

Low mechanical strength of coating Excessive pan speed Low solid content in coating liquid Low spray rate Sharp edges on tablets Worn tablet punches

Remedy:     

Using formulation with increased mechanical strength Decreased pan speed Increase solid content in coating liquid Decrease spray rate Use modified punch design

4. Picking/sticking:

Cause:

    

Spray rate too high Inadequate drying condition Pan speed too low Inadequate atomization of coating liquid Poor distribution of coating liquid

Remedy:     

Decrease spray rate Increase drying condition Increase pan speed Increase atomizing air pressure/volume Increase number of spray gun

5. Cracking: Cause:  Low mechanical strength of coating, exacerbated by inadequate plasticization, excessive pigmentation.  Core has significantly different thermal expansion characteristics than coating.  Extended strain relaxation of core after compaction.

Remedy:  Selecting formulation with increased mechanical strength and elasticity properties.  Avoid use of mineral type fillers (e.g. CaCO3, CaSO4, MgCO3 etc.)  Extend holding period of tablets prior to submitting them to coating process.

6. Peeling

Cause:  

Low mechanical strength of coating Poor adhesion of coating to tablet surface

Remedy:  Using ingredients of improved mechanical strength.  Using ingredients with improved adhesion properties.

7. Orange peel/roughness

Cause:  Viscosity of coating liquid is too high  Poor atomization of coating liquid  Excessive drying condition  Over wetting (causing coating too rub) Remedy:    

Decrease solid content of coating liquid Increase atomizing air pressure/volume Decrease inlet air temperature/flow rate Decrease spray rate

8. Twinning

Cause:  Spray rate too high  Pan speed too low  Inappropriate tablet shape Remedy:    

Decrease spray rate Increase atomizing efficiency Increase pan speed Select new tablet shape that decrease chances of flat surfaces coming into contact during application of coating liquid. (e.g. avoid capsule shape tablet with thick side wall) 9. Tablet-to-tablet color variation

Cause:     

Too little coating applied Inadequate mixing of tablet during coating Poor opacity (or hiding power) Solid content of coating liquid too high Insufficient number of spray gun

Remedy:

 Increase quantity of coating applied  Increase pan speed/increase improve baffle system  Reformulate coating with respect to colored ingredients or use an opacified white pre-coat.  Decrease solid contents of coating liquid.  Increase number of spray gun.

Number of tablet being produced in ARISTOPHARMA. CAPSULE PREPARATION Trade name A-MYCIN ARISTO GOLD CALBON D ALFA-E XPA GLUCOMET

Generic name Erythromycin Multivitamin (AZ) Calcium+Vitamin D3 Vitamin E Paracetamol Metformi

Strength 250mg, 500mg 500mg+200IU 200mg 500mg 500mg, 850mg

2. Capsule DEFINITION Capsules are solid preparations with hard or soft shells of various shapes and capacities, usually containing a single dose of active substance(s). They are intended for oral administration.

The capsule shells are made of gelatin or other substances, the consistency of which may be adjusted by the addition of substances such as glycerol or sorbitol. Excipients such as surface-active agents, opaque fillers, antimicrobial preservatives, sweeteners, colouring matter authorised by the competent authority and flavouring substances may be added. The capsules may bear surface markings.

The contents of capsules may be solid, liquid or of a paste-like consistency. They consist of one or more active substances with or without excipients such as solvents, diluents, lubricants and disintegrating agents. The contents do not cause deterioration of the shell. The shell, however, is attacked by the digestive fluids and the contents are released.

Several categories of capsules may be distinguished:

• hard capsules; •

soft capsules;

•

gastro-resistant capsules;

•

modified-release capsules;

•

cachets.

In this pharmaceutical industry filling (encapsulation), sealing and polishing (if required) of capsules of hard gelatin shell are done during manufacturing, as the industry does not manufacture any capsule shell.

The active is filled in the empty the hard gelatin capsule shell in the form of Powder  Pellets There are 6 different sizes of empty hard gelatin capsule shells used in Aristopharma Ltd. for general production, which include Capsule shell size 0  Capsule shell size 00  Capsule shell size 1  Capsule shell size 2

  

Capsule shell size 3 Capsule shell size 4

# Encapsulation Process by Automatic Capsule Filling Machine: For encapsulation of pellets the following procedure is done with the help of Automatic Capsule Filling Machine in the capsule filling units of Aristo Pharma Ltd.; Blend Pellets with NPS ↓ Encapsulation ↓ For encapsulation of powder, Blending ↓

Slugging ↓ Granulation ↓ Sieving ↓ Encapsulation 

Encapsulation Process by Manual Capsule Filling Machine by Hand: For encapsulation of powder the following procedure is done with the help of Manual Capsule Filling Machine by hand in the capsule filling units of the industry:

Loading of capsule in the loading plate ↓ Removal of caps of the shells ↓ Filling of powder ↓ Rejoining of caps of the shells ↓ Encapsulation ↓ Sorting of Capsules ↓ Polishing of Capsule Machinery: Machine name

Machine Manufacturer specification automatic Capacity: 15000- P+am filling 17000/hr Capsule fill pharmaceuticals

Origin

Semi Capsule machine Automatic Capsule filling machine Automatic Capsule filling machine S.S.Drum -Blender Charge Vat Capsule polishing machine Hand fill machine

India

Capacity: 30000/hr Capsule fill Capacity:90000/hr Capsule fill Capacity: 200 kg Capacity: 50 kg Capacity:8000/hr

Hanli

Korea

Se jong

Korea

Gansons Myth P+am pharmaceuticals Pharmachem

India.

Bangladesh India India

.

Figure: Capsule filling machine.

Number of tablet being produced in ARISTOPHARMA. Trade name OMEP AZ ARISTOMOX REUMACAP TRAMACAP

Generic name Omeprazole Azithromycin Amoxacillin Indomethacin Tramadol

Strength 20mg, 40mg 250mg, 500mg 250mg, 500mg 25mg 50mg

DRY SYRUP Dry syrup at Aristo Pharma Ltd is manufactured in a method namely,  Direct Mixing, 

Flow chart for Direct Mixing for the manufacturing of Dry Syrup: Crushing the sucrose in FITZ mill at 3000 rpm ↓ Transfer of half portion of sucrose from step-1 into a double cone blender by passing through a 20 mesh screen ↓ Transfer of all other excipients in the blender to blend for 30 minute ↓ Transfer the mix from the double cone blender by Passing through a 20 mash screen 

Machines used in the Dry Syrup Manufacturing unit:

Name of the Machine

Function

Double cone Blender FITZ Mill Dust Collector Bottle Filling Machine Bottle Sealing Machine 

Blending/Mixing Crushing/ Milling Removal of dust Filling of Dry Syrup Sealing of Dry Syrup Bottle

Condition for manufacturing Dry Syrup: • •

Relative Humidity: Not more than 45%.

Temperature: Below 250

Number of tablet being produced in ARISTOPHARMA: Trade name AFIX AXIM STAFOXIN

Generic name Cefixime Cefuroxime Flucloxacillin

Strength 100mg/5ml 125mg/5ml 125mg/5ml

PACKAGING AREA Packing can be defined as an economical means of providing, presentation, protection, identification/information, containment, convenience, and compliance for a product during storage, carriage, display and use until such time as the product is used or administered.

After compression of tablets and coating [if required], the tablets are packed either in blister pack or in the strip.  Purpose of packaging: • • • • •

To increase the acceptability of the drug To increase the stability of the drug To minimize the transport/shipping hazards To improve patients compliance To improve the pharmaceutical elegance by use of special color or contrasting printing

At Aristopharma Limited, two types of combination is used depending on the upper & lower layers as well as product requirement. They are; • PVC-Aluminium Blister • Aluminium -Aluminium Blister Besides blister packaging, at Aristo Pharmaceuticals Limited, other packaging includes;    

Striping Filling of tablets &capsules in bottles Labeling of bottles Secondary Packaging (Both on-line & off-line)

 

Packaging of Ampoules Packaging of Vial

Packaging machineries: Machine Name Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Strip Packing machine

Machine specification Capacity: 80000/hr Capacity: 72000/hr Capacity: 60000/hr Capacity: 90000/hr Capacity: 82000/hr Capacity: 60000/hr Capacity: 120000/hr

No. of Manufactured Machine by 1 Buchon

Origin

1

Buchon

Korea

1

Buchon

Korea

1

Hoong-A

Korea

1

Hoong-A

Korea

2

Elmapack

India.

1

Gansons

India.

fig: Aluminium foil Primary Packaging Materials Materials 1. Polyvinyl (PVC/PVC)

Sources Chloride

[PVC],

2. Polyvinylidine chloride [PVDC], 3. Aluminium Foil

Different parts of a blister pack machine:

 korea  India,  Korea, Bangladesh

Korea

Different parts of a blister pack machine and their functions are giver in the following table: Parts of blister machine

Function

1. Base grid

Draws the base material, which may be PVC, PVDC, ALUMINIUM FOIL.

2. Forming Station

Forms blister in the base material either by hydraulic pressure or by air pressure and temperature

3. Hopper

Tablets are kept in the hopper

4. Chute and Sprial Feeder

Regulate the vibration so that table can move and fall in the feeding channel

5. Feeding Channel

Feed the blister with tablet

6. Deduster

Collects dust by creating vacuum

7. Scanner

Scan the empty blister

8. Sealing station

Seal the blister pack

9. Cooling station

Cool the blister pack

10. Marking station

Marks the empty blister

11. Code embosser

Emboss code number

12. Slitting station

Slit the blister pack

13. Web clump

Draws the blister

14. Punching Station

Cut the blister and slit down

15. Timer

Regulate the passage of blisters

16. Detector

Detect the empty packet

17. Rejector

Rejects the empty blister packet

18. Conveyer belt

Convey the pack for further processing.

Steps of Blister packing: ďƒ˜ Blister packaging: We observed the blister packaging of Napa tab. (Paracetamol)

PVC sheet

Foil soften by hot plate Temp. 125-145°C

Heating plate

Passed through desired dies plate which is kept cold & air pressure is applied to make pocket for small time & desired shape is resulted (air pressure 6-8 bar) with Pressed by twoAlu-alu plates foil simultaneously properly labeled (upper plate temp. 160-180°C for PVC & lower plate is cold

Tablets or capsules are filled into the pockets

Passed through cutter

Desired blister pack

 Trouble shooting:.         

Preheating problem – malleability Forming problem Sealing problem Slitting problem – perforation Loading problem Air pressure Scanner problem Emboss problem Heat exchanger

 Feeding problem –  channel  transfer  

Chute Gate Spiral Brush

 Strip packaging: We observed the strip packaging of ……….………..

Tablets or capsules in hopper

Pressing Strip packaging

Tablets/capsules in vibrating disc

Hot roller having particular dies shape

Enter through tode channel

Tablets or capsules Poly-coated alu rollstwo (coated enter between alu with plastic materials) come roll strips from two sides

 1.

2.

3.

In-process check: Observation no.

Leak test Room condition a) Temperature & humidity b) Segregation of bulk materials/finished packs c) Product identity d) line, display board 5. Aluminum foil leaving in machine and stock 6. Number of individual strips/blisters checked 7. Number of finished products checked 8. Quality and identity of components complient slip/labels/cartons/leaflets/outer labels/outer box/ spoon 9. Identity and appearance of product in packs 10. Quantity: No./volume/weight 11. Overprinting/embossing: batch no./MFD/Exp date/MRP 12. Label/carton with product name, batch no., Mfg date, price. Exp date  Secondary Packaging (Both on-line & off-line): Secondary packaging includes-

•

•

Unit Cartooning with -Container -Leaflet -Spoon/dropper (in case of liquid) -Security seal/Hologrammed Seal Master Cartooning with - Unit cartoons

Sterile Department Commonly the small volume parenteral or injectable products are filled in 

Ampoules Vials

Generally the products are manufactured by two ways:

→ Aseptically Sterilized → Terminally Sterilize Injectable Products in Ampoule: Injectable Products are dispensed in ampoules following the procedure given belowAmpoule De-boxing ↓ Ampoule washing ↓ Sterilization (in case of aseptically filled ampoules) ↓ Ampoule filling (under laminar air flow) ↓ Ampoule Sealing ↓ Terminal Sterilization ↓ Ampoule Inspection ↓ Sealed Ampoules 

Ampoule Washing: Sequence of “wash” by Ampoule Washing Machine:

DM water (inner-outer) → Compressed air spray → Distilled water → WFI Ampoule Filling & Sealing (under laminar air flow): Ampoule on the filling belt ↓ N2 flush → Filling → N2 flush → Sealing by flame → Ejection (O2: LPG-1: 10) 

Ampoule Inspection: • • •

The white zone detects visually the black particles, The black zone detects the white particles.

The volume is measured visually by taking 4 ampoules at a time in hand



Different Sterilization Techniques & their uses:

Sterilization Technique

Temperature ( 0C)

Exposure Time (hrs)

Pressure (Bar)

Uses

180

3

1.1

Vials

2.5 1

1.1 1.1

0.5

1.1

Dry Heat Sterilization 220 (DHS) 250 Steam Sterilization 121 /Autoclave

Ampoules, Gloves, Filters, Gourmets

Equipment Sound protector, Mask, Surgical gloves, Cap, Apron, Electric Balance.

Accessories - Dust collector.

- SS Vat charge.

- SS Jug. - SS funnel.

- Perforated tray.

Specialized location The processes are done in fully aseptic area.

Production process flow Manufacturing of injectable preparations require a clean room which should have the following standard Class

Cfu/m3

100 1000 10,000 1,00,000

<1 NMT 10 NMT 100

Category of different vial processing area Area Filling point Filling room Vial washing & sterilization room Filling room corridor Fabrics change room

Particle of micron/ft3 NMT 100 NMT 1000 NMT 10,000 NMT 1,00,000

Clean room standard 100 1,000 10,000 10,000 10,000

Preparations of vial involves the following steps: Vial Sorting Vial Washing Vial Sterilization Vial cooling Powder filling

0.5 Particle micron /ft3 0 NMT 7 NMT 70 NMT 700

of

5

Rubber capping Alu-sealing Labeling Blistering Packaging Category of different ampoule processing area Area Filling point Filling room Mixing room Filling room corridor Fabrics change room

Clean room standard 100 1,000 10,000 10,000 10,000

ď ą

Zonal Classification of Clean Rooms & Respective Air pressure:

Zone

Class

Under Laminar Airflow Filling zone Sealing zone Filtration room Change Rooms Ampoule cooling room Ampoule storing room

A A B B C C D

of Environmental Air pressure Cleanliness (Pascal) NLT 40 40 40 30 15-30 20 10

Machinery Machine Name Semi automatic bottle filling machine Semi automatic cap closer machine

Manufacturer Mig pen Machine CO MP-VS-OL

Origin Taiwan Taiwan

Semi automatic infusion cap sealing machine

Mig pen Machine CO

Taiwan

Ampoule filling & Sealing machine Automatic Steam Sterilizer Dry heat sterilizer Dry heat sterilizer Charging vessel

Mig Pen Machine CO Sturdy industries Ltd Indo-German Myth indries Kothari

Taiwan Taiwan India Bangladesh India

142 mm filtration unit 293 mm filter unit Washing Machine

Satorius Satorius Chung MachineryCO

Germany Germany Taiwan

Number of tablet being produced in ARISTOPHARMA. Trade name APROCIN ERDON OVEL ARISTOPHEN

Generic name Ciprofloxacin Diclofenac Sodium Levofloxacin Chloramphenicol

ARISTOMOL CORTISOL

Timolol Prednisolone acetate

Strength 0.3% 0.1% 0.5% Eye drop 0.5% Ointment 1% 0.5% 1%

Liquid preparation •

Liquid

Oral liquid preparations include-

• •

Oral Syrup Suspension

GENERAL MANUFACTURING PROCESS OF ORAL LIQUIDS: The general manufacturing of oral liquids in the liquid section of Aristopharma Ltd is briefly described below with a flowchart; Weighing of active ingredient/s along with excipients ↓ Mixing of excipients with certain amount of demineralized (DM) water as specified in the Batch Production Record (BPR) by the aid of a mechanical stirrer ↓ Addition of active ingredient/s ↓ Passing through a pump to the storage vessel to the ↓ Transfer of the solution to the filling vessel through 0.5µ Cartridge filter. ↓ Filling, Flushing of Nitrogen (N2) & Sealing of Bottles (glass or pet) containing oral liquids 

Machines used in the Oral Liquid Manufacturing unit:

Name of the Machine

Function

Capacity

Steam Jacketed Vessel Charge Vessel Storage Vessel Cartridge Filter Bottle Filling & Sealing Machine

Mixing Manufacturing Storage Filtration Filling & Sealing of Oral Liquid Bottles

1000 Liter 2000 Liter 2000 Liter 2500 bottles /hour



Condition for manufacturing of Oral Liquids: • •

Relative Humidity: Not more than 55%.

Temperature: Below 300

In the packaging unit, filled & sealed bottles are sequentially→ Labeled → Packed with an insert in the intermediate carton → Finally packed in master carton.

Steps involved in Suspension Preparation: Dispersion of suspending agent Transfer to compounding vessel containing sucrose solution Addition of drugs & other ingredient Mixing with continuous stirring Adjustment of final volume with purified water Filling & sealing

Packaging

CREAM / OINTMENT The topical preparations include the manufacturing of ointments and creams. Semi-sterile condition is maintained as eye and ear preparations are available. As the bases used in topical semisolid preparations are susceptible to microbial attack entry is strictly maintained as of the sterile zone, which must be highly appreciated. General flow charts of cream and ointment preparations are shown below.

General process of manufacturing Creams:

Water Phase

Oil Phase Sieving

Water phase to Oil phase in a Steam Jacketed Vessel

Blending by Mechanical Stirrer

Filling

Sealing

ď ą

General process of manufacturing Ointments: Oil Phase-I

Oil Phase-II

Oil phase-I to Oil phase-II in a Steam Jacketed Vessel

Addition of Active Ingredient/s

Blending by Mechanical Stirrer

Filling

Sealing

Machinery: Machine Name Automatic tube filling machine Automatic tube filling machine Collioid mill Charging vessel

Specification and Origin Precitech industries,india Pharmachem machinaries,india Cadmach ,India Mythindustries,Bangladesh

High speed emulsifier

India

Homogeniger

India

Transfer pump

U.S.A

Automatic labeling machine

Korea

Automatic liquid filling ,Cap Sealing and labeling machind

India

Cephalosporin Facility According to cGMP regulations separate facility for cephalosporin is required to prevent cross contamination with other penicillin products or non beta-lactum products. Unintended exposure with Cephalosporin products may cause health concern to patients sensitive to Cephalosporin. â&#x20AC;˘ Fully separated, well established and isolated manufacturing area only for Cephalosporin. â&#x20AC;˘ Highly sophisticated HVAC system and AHU are used to condition, monitor and supply clean air to the working zone. â&#x20AC;˘ Production floors and wall are covered with epoxy resin.

• • • • •

A complete set up of machineries required for tablets and capsule productions is established only for Cephalosporins.

More precautions are maintained in each and every steps during production, filling, Sealing and packaging to prevent cross contamination.

Officers and the workers are trained specially to work more carefully in order to minimize cross contaminations.

Well furnished change rooms are maintained each floor of the production areas.

Samples during various steps of manufacturing are collected by QC officers all the times for proper manufacturing.

QUALITY ASSURANCE Quality Assurance is a wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It is the sum total organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide.

of the

The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that : • medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and Good Laboratory Practice; • production and control operations are clearly specified and Good Manufacturing Practice adopted; • managerial responsibilities are clearly specified; • arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; • all necessary controls on intermediate products, and any other in process controls and validations are carried out; • the finished product is correctly processed and checked, according to the defined procedures; •

medicinal products are not sold or supplied before an authorized person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of medicinal products;

• satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; • there is a procedure for self-inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality

assurance system.

The chain of Quality Assurance (QA) activity stretches from the product design and product development stage up to the end users. It embraces all functions concerned with the attainment of quality during manufacturing and also other factors that influence the quality of a product during it’s shelf life.

Quality According to ISO8402 quality is defined as” Total of features and characteristics of a product or service that bears on its ability to satisfy a given need’’.

QUALITY ASSURANCE

QUALITY CONTROL

QUALITY COMPLIANCE

QUALITY CONTROL Quality control activity is an organization has to be carried out in an integrated manner at all levels from top to bottom, each level taking responsibility for quality in its sphere of activity, and only then, continuous improvement in an organization can happen and improve its competitive position. This brings us to Total Quality Control (TQC).

The impact of Total Quality Maintenance (TQM) - Better employee relation.

- Improved operating procedures.

- Greater customer satisfaction.

- Increased financial performance.

Quality Management The holder of a manufacturing authorization must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company's suppliers and by the distributors.

To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance Incorporating Good Manufacturing Practice and thus Quality Control. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and

suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the manufacturing authorization and for the authorized person(s).

To put in simple words, it is organization wide commitments to do things right and strive, for continuous improvement in the performance.

In ARISTOPHARMA LTD. the Quality Assurance Department (Q.A) performs it function through the following sections: - Quality Control Department (QC).

- Microbiology Section.

- Product Development and Validation.

- Quality Compliance Department.

Flow chart for Quality Assurance activity: Receiving of Raw & packaging Materials by visual inspection

Attachment of quarantine Tag of yellow color

Sampling of raw & packaging Materials for QC analysis Release / rejection

Attachment of respective tag for raw & packaging material.

Dispensing of raw & packaging Material Checking of cleanliness, Approval of equipment &area of manufacturing In process checking of Some parameters during Compression, filling etc.

Sampling of in process Product to Q.C.

In process checking of Packing operation

Transfer of finished product For distribution after Collecting the retention sample

Investigation of product complaints, product recall returned product from market QUALITY COMPLIANCE Monitoring cGMP to ensure that products and consistently produced and controlled to the quality standard appropriate to the product specification.

Major duties and responsibilities: - Inspection and reporting that manufacturing operations are running as per SOP. - IPC of the bulk products.

- IPC of the finished products - Checking general cleanliness - Checking that manufacturing instructions and packing instructions of followed properly.

- Analysis of product, raw materials and water - Identification constraints of existing manufacturing and testing operations in compliance with cGMP and find out the possible solution - Prepare the compliance related reports/inquires - Generation or revision of SOP - Coordinating and participating in cGMP, GLP and other training programs that focus on the elements of the compliance program thus striving to ensure that all appropriate employees are knowledgeable of WHO, cGMP standard, local and other regulatory norms.

Documentation: - The site quality policy manual - Reports on general cleanliness - Training records - Stability study records - IPC records - Instrument requisition record - SOR/Protocol record - Training materials - Maintains the follows of reports - Minutes of meeting - Inter-departmental correspondence - ISO/cGMP audit circular files - The modification the record of MI, PI,CI. - The customer complain handling documents Instrumental facilities: This department is very new in this factory. Yet it has not developed its own laboratory. Now it uses the test facilities from the QC department.

Observation:

We have observed various tests carried out by compliance personnel. The tests are as follows — - Hardness - Weight variation - Average weight - Friability test - Disintegration - Thickness - LOD - Leak test - Sanitation reports - Microbial count test We observed these tests during the production of the following products— - Aristogold Tablet - Xpa-C Tablet - Aprocin Tablet

QUALITY CONTROL DEPARTMENT Organogram of the section Director (Production) Manager (QA) Deputy Manager/Asst. Manager (QC) Senior officer Officer Lab Assistant The Q.C department has to perform the following major responsibilities Raw materials analyses to issue passed, reject or quarantine advice for each batch of raw material.  Assessment of the intermediate products for further processing  Assessment of bulk products for their release, reprocess, reject etc.  In- process quality control (IPC).

 Control of laboratory reagents.  Analysis of complaint samples. 

Maintaining batch wise full quality control test records with signature of the persons who perform the tests.

 Preserves retention sample for exp. date + 1 year.

Availability of written procedures/instructions/ forms for routine works Batch analysis test  Appearance.  Identification.  Average weight.  Uniformity of weight.  Disintegration time.  Melting point.  Resistance to rupture.

Manufacturing instruction  Sample identification.  Raw material sampling information.  GRIR from warehouse.  Batch analysis data sheet.  For active material, all of the containers are sampled.  For excipient, sampling done by √n+ 1 rule, where n = total number of container.  For sterile products, sampling done aseptically before filling and sealing.  Forms for routine work  Sampling intimation form.  Batch analysis report.  Batch analysis data sheet.

Routine activities  Samples raw materials, packaging material and finished products.  Monitors the products at a fixed interval of time after releasing it.  Stores retention sample from each batch.  Stores batch wise full quality control record.  Assess the packed products to release.  Handles complains with greatest care.

Extent of implementation of the WHO’s cGMP and Regulatory Norms



Procedures shall be prepared and documented in consistent with the requirements of ISO 9001:



2000 WHO- cGLP standard and the quality policy set by the top management.



Procedure shall identify the person (s) who are responsible to perform activities according to approved document.



Procedure shall be identified as’ master procedure’.



All personnel will be trained on procedures that affect their activities.



Controlled copies of master procedure shall be distributed according to the distribution list of each master procedure.

MACHINERY Machine Name Refractometer LEICA MARK-2 HPLC (High Performance Liquid Chromatography) Atomic Absorption Spectrophotometer(Shimadju) Pharmaspac1700 Spectrophotometer(Shimadju) UV-1610PC. Spectrophotometer(Shimadju) Moisture analyzer Shaker Magnetic stirrer Hardness tester Polarimeter AA5-SERIES Digital Viscometer Brookfield Fourier Transformed infrared spectrophotometer Ultrasonic bath Friability test apparatus Karl Fischer Titrator Refrigerator Simens Dissolution Machine (Electro lab.)

Hot air oven Hanna PH Meter Water bath Disintegration tester(Electro lab.)

Tapped volumeter ERWEKA Centrifuge machine Titrator DL50 Melting point apparatus(Buchi B-540) Osmo meter(3320)AIIC

No. of Machine 1 2 1 1 1 2

Origin England Japan Japan Japan Japan Germany

1 1 1 1 1 1 1 2 1 2 2 1 1 2 1 1

China Taiwan Japan England Japan

1

India Switzerland Korea Germany U.S.A Japan Bangladesh Germany Germany China Bangladesh

Figure: HPLC machine and UV machine.

Equipment: PH meter, Electric balance, Bulk density apparatus, Sieve shaker, Centrifuger, Ultrasonic bath, Digital tablet hardness tester, Digital friability tester, Griffin melting point apparatus.

Accessories: Spatula, Spoon, Filter paper, Micro-syringe, Micro filter syringe, Mortar- paste Gloves, Mask etc.

Specialized locations: All the analysis processes were done in the area of quality control section (which is reachable for all types of analysis except microbial analysis). Sophisticated machines like FTIR, HPLC, Atomic Absorption Spectrophotometer etc are kept in two controlled AC room.

Category, Type and Number of materials/ Products being analyzed: Number of finished products of SPL is about 450. So all the active ingredients, excipients packaging materials etc is required for the products as well as the finished products are analyzed in this section. The products are of different type like solid, semisolid, cream, ointment etc.

Some common reagents and glassware management: Most of the reagents that are required for analysis are available at any time. Different types of glassware like test tube, conical flask, Volumetric flask, burette, pipette etc are available. To ensure the smoothness of the job, every analyst uses his/her personal glassware. For easy access, there is a chart which consists the name of reagent and container no. So anyone can get the desired reagent bottle very easily.

Some of the reagents: Karl-Fischer reagent, Bromocresol green, Crystal violet, Îą-Naphthol benzene, Methanol, Methyl orange/ red, Phenolphthalein, Chloroform, Starch, Na-acetale buffer, Potassium iodide, Acetic acid. Iodine solution, Acetonitrile, 2- Butanol, Citric acid, Cyclohexane, Hexane, Ether, Dithiozone etc.

Some of the glass wares:

Conical flask, Burette, Pipette, Volumetric flask, Beaker, Graduated cylinder, Separating funnel. Glass bottles, Round bottom flask, Desicator etc.

Particulars of in –Process check(IPC):  Physical appearance.  Weight variation of tablet.  Disintegration time (DT).  Friability, hardness, thickness of the tablet.  Mottling problem.  Volume checks in liquid filling.  Physical parameter of cartons.  Printing, batch no, Mfg. date, exp. date, price etc.

Document review: After analysis of the raw material/ product by the analyst, every document is checked/reviewed by Q.C manager or any other responsible person.

Preparation of approved vendor list and storage guide for materials: The QC department approves the vendor list of product by analysis and stores it in a specific area. The vendor list consists of different vendor’s name for a single material to avoid crisis.

It also prepares the storage guide for materials are to be stored in controlled room (temperature and relative humidity is maintained), some are in AC room. On the other hand some are stable in normal room condition.

Handling of product complaint: If there is any complain for the product is found then the Q.C department handles it very sincerely and take the corrective action as soon as possible. For this complain management, the QC department stores the retention sample for exp. Date+1 year of time.

An outline of the minimum requirement at working place in the context of safety Control of chemicals: • Proper care should be taken about all the harmful chemicals that are toxic.

Personnel protection: • Proper care should be taken where necessary i.e. eye, hand, head, foot, respiratory track etc.

•

Googols, mask, gloves etc can be used.

•

Pipette filler should be used to draw reagents from the container.

•

Mask should be used during working with gas or in production floor.

•

One-piece cover all should be used in parenteral production area.

Safe use of instruments: • Proper care should be taken to ensure that the instruments are working properly.

•

Those should be regularly inspected and calibrated.

•

Sophisticated machines should be kept in a controlled room as per requirement.

Fire precaution: • Proper care should be taken to prevent fire or explosion.

•

Enough fire fighting equipments should be available.

•

Fire fighting equipments should be used by the trained persons.

•

Emergency exit process should be practiced at least once in a month.

Safe working environment: • Care should be taken to reduce the chances of slips, trips and falls.

•

Working area should be kept clean for all the time.

•

Smoking

•

Smoking inside the factory must be strictly prohibited.

MICROBIOLOGY SECTION Microbiology section is one of the vital section of any pharmaceutical to ensure quality product. The microbiology section of QC department in Aristopharma Ltd is a well-decorated and segregated area that evaluates microbial load and particulate matter of both raw materials and finished product particularly sterile products. It includes the following test1. Microbiological assay of raw materials and finished products 2. Limit test of liquid preparations for the pathogenic organisms like Pseudomonas aerogenosa, Escherichia Coli, Staphylococcus aureous. Salmonella species.

3. LAL test for injectable preparations.

Availability of written procedures  SOP for sterility testing of ampoule, vial and ophthalmic products.  SOP for microbial limit test.  SOP for microbial examination of raw materials.  SOP for detection and measuring the penicillin contamination in drug and equipment.  SOP for microbiological monitoring in sterile production environment  SOP for identification of bacteria by gram staining method.  SOP for microbiological monitoring of water.  SOP for cleaning and sanitation of area and utensils.  SOP for antimicrobial preservative effectiveness test.  SOP for safety test of different raw materials and formulated products.  SOP for determination of particle size and crystallinity.  SOP for calibration of the microscopic scale.

 SOP for preparation of different buffer and stock solutions.  SOP for microbiological monitoring of empty bottle.  SOP for microbiological monitoring of clean room including LAF station of microbiology lab.  SOP for working in LAF station.  SOP for disposal of expired media and biochemical.  SOP for entry, exit and downing procedure for the clean area.  SOP for media preparation and its quality control.  SOP for bacterial endotoxin test (BET).  SOP for calibration of bioindicator.  SOP for preservation and maintenance of laboratory control organisms.  SOP for Laboratory control numbering system.

Extent of implementation of the WHO’s cGMP and Regulatory Norms:  Procedures shall be prepared and documented in consistent with the requirements of ISO 9001: 2000 WHO- cGMP standard and the quality policy set by the top management.  Procedure shall identify the person (s) who are responsible to perform activities according to approved document.  Procedure shall be identified as’ master procedure’.  All personnel will be trained on procedures that affect their activities.  Controlled copies of master procedure shall be distributed according to the distribution list of each master procedure.

Machinery Machine Name Eyela autoclave Incubator for fungus Laminar air flow(2) hot air oven Royco (air borne particle counter) Climet (liquid borne particle counter) Mark 102 (air sampler) Pyrogen tester Sterility tester Microscope

Origin Japan India Indian, Taiwan Germany U.S.A U.S.A Germany Denmark Germany China

Figure: Laminar Air Flow Bench.

Equipment and Accessories Tungsten loop, Bunsen burner, Forcef, Volumetric flask, Test tube, Conical flask, Measuring cylinder. Glass petridish (9cm diameter), water bath, Microliter pipette, Electronic balance, LAF station.

Specialized locations - This section is completely separated from other sections.

- There is a class 100 clean room in this section.

- Different equipments are placed in different rooms.

Category, Type and Number of products being analyzed o In microbiological section generally assays the liquid and semisolid preparations such as suspension. Syrup, cream, ointment and gel are analyzed for microbial load. o The most important job of microbiological section is injectable product analysis.

Because these products are intended to inject through one or more layer of the body which reaches the blood directly.

Reagents and glass ware management  Caso agar. 

Macconkey agar.



Vogel gonson (selective media).



Catrimide.



Lactose broth.



Peptone buffer solution (PBF).

Sterility test Caso broth, Thioglycollate broth, Membrane filter, rinse fluid etc. are used to perform sterility test.

Bioassay Antibiotic media no 01 and antibiotic media no 11 are used for bioassay.

Buffer solution  Potassium dihydrogen orthophosphate.  Dipotassium hydrogen orthophosphate.  Disodium hydrogen orthophosphate.

Glass ware management Petridish, separating funnel, pipette, volumetric flask, test tube etc are to be used with extra care.

Particulars of in-process check  Weight and volume check of product.  Cleanliness of production area.  Preparation of apparatus, media, buffer solution and saline water according to instruction.  Preparation of culture organism.  Preparation of assay plate.  Dilution of the standard stock solution up to desired concentration.  Preparation of test solution.  Personal garment print.  Preparation of reagent for analysis.  Confirmation test for selective pathogens.  Ensure proper cleaning of specific areas.  Particulate matter counting in aseptic area.  Sterility test of Injectable.

PRODUCT DEVELOPMENT To launch a new product, the product development department develops a formulation and manufactures the product on a laboratory scale. The stability tests are performed on these new products. After passing the tests the product is manufactured commercially. Product development department prepares the manufacturing instruction, coating instruction (if necessary), packaging instruction, product specification and testing procedure file of the new product. PD develops the formulation on the basis of trial and error method.

This section also perform the following duties : •

Establishes specifications for all starting materials, excipients and finished products.

•

Establishes proper batch documentation system.

•

Identity problems and takes positive action, Concerning with previous marketed formulation

•

Evaluates the old and new products.

•

Validates the product formulation.

Availability of written procedures/instructions/ forms for routine works Written procedures, instructions, forms for routine works are developed by the PD&V Department and these are maintained.

Extent of implementation of the WHO’s cGMP and Regulatory Norms • Procedures shall be prepared and documented in consistent with the requirements of ISO 9001: 2000 WHO- cGLP standard and the quality policy set by the top management.

•

Procedure shall identify the person (s) who is responsible to perform activities according to approved document.

•

Procedure shall be identified as’ master procedure’.

•

All personnel will be trained on procedures that affect their activities.

•

Controlled copies of master procedure shall be distributed according to the distribution list of each master procedure.

Machinery : Name Tablet compression machine Fluid bed dryer Multimill HPLC (High Performance Liquid Chromatography) UV-1610PC. Spectrophotometer(Shimadju) Magnetic stirrer Dissolution Machine (Electro lab.)

Hot air oven Hanna PH Meter Water bath Humidity chamber Disintigrator tester Friability tester Electronic balance Double cone mixture Planetary mixture Wet granulator Moisture analyzer Drying oven

No. of Machine 1 1 1 2

Source India India.

India Japan

1

Japan

1 2

China Germany

2 1 1 2 1 1 1 1 1 1 1 1

U.S.A Japan Bagladesh U.S.A Germany Germany japan Germany U.S.A India U.S.A Germany

Equipment and Accessories Electric stirrer, Impulse sealer, Electric balances, Dust collector, SS Charge vat, Different size of sieve. Measuring cylinder, Measuring beaker, Surgical gloves etc.

Specialized locations - This place is separated from the production area.

- This department has a production laboratory that is well equipped.

- Retention sample stores.

Working flow sheet of PD&V department for new product development Product Management Department (PMD) Proposal form with product brief to PDV Requisition for trial sample to TSD Stability study accelerated Analytical method development Analytical method validation

Recommended by Manager, PMD

Formulation development

Pilot Trial in the laboratory Commercial production in production area.

Validation : Validation is defined as establishing document evidence, which provide a high degree of assurance that a specific process or system will consistently produce a result meeting its predetermined specification Validation normally required for processing, equipment’s services, production process, test procedure & computer system. The parameters, considered for the validation, are - Linearity - Accuracy (Recovering) - Precision (Reproducibility), etc.

ENGINEERING DEPARTMENT Engineering department is the service department, it is the heart of any pharmaceutical industry as it maintains and repairs all the electrical and mechanical devices of the factory. It is divided in to four sections - Store - Boiler and water treatment plant - Engineering workshop Store: Here the electrical and machinery parts are stored systemically. This section also deals with the purchase of any new parts with proper documentation.

Boiler and water treatment plant : This section supplies steam and DM water where needed in the factory.

Engineering workshop This section has various types of machine  Lathe machine  Drill machine  Shaper machine  Welding machine  Milling machine  Soldering machine  Grinding machine  Multimeter It also includes a special type of service area where the machines with trouble are repaired.

Engineering workshop maintains preventive and predictive breakdowns.

Plant room The plant room consists of an individual power substation. This section supplies electricity to the factory. It ensures the electricity supply during load shedding by using generators. The generators automatically supply electricity within 20 seconds after the PDB supply has failed.

It also supplies compressed air to the production area. It has the following machines

- Chiller - Diesel generator - Gas generator - Air compressor Water treatment plant in APL. Earth water Vertical pump Sand bag-Gravel filter

Supply Heat Exchanger Distillation tank

Overhead tank Condenser Chlorination

Distillation unit

Pre-filtration

D.M water storage tank

Raw or City water Tank

2.5mic.filter

Activated carbon filter

0.2 mic.filter

2.5 mic. Filter 0.2mic.filter D.M Water plant

Mixed bed Exchanger Anaionic Exchanger Cationic Exchanger

WARE HOUSE Involved departments: • Raw materials • Packaging materials store • Finished product store Availability of written procedures/instructions/Forms for routine works For raw materials stores:  Receives raw material according to the invoice/challan.  Takes GRIR from the Q.A department.  Updates the present status of raw materials.  Stores all raw materials according to the instruction.  Supplies raw materials according to the FIFO to the production floor.  Adjust present stock after dispensing the raw material.  Find out raw material that requires re-test.  Find out under safety stock.

For packaging materials store:  Receives packaging materials according to the invoice/challan.  Takes GRIR from the Q.A. department  Inputs the batch number.  Store all the packaging materials according to the storage guide.  Updates the present status of packaging materials.  Dispense packaging materials according to the requisition from production area.  Adjust present stock after dispensing the packaging materials.  Find out under safety stock.

For finished products store:  Receives finished product according to the delivery token of production area.  Preserves the packaged product report of Q.A department.  Prepares transfer note.  Prepares VAT challan.  Dispense FP according to FRFO basis.  Updates the current stock of finished goods.  Find out under safety stock.

 Maintain the proper storage condition of finished product.

Extent of implementation the WHO’s cGMP and Regulatory Norms:  Procedures shall be prepared and documented in consistent with the requirements of ISO 9001: 2000 WHO-cGMP standard and the quality policy set by the top management.  Procedure shall identify the person(s) who are responsible to perform activities according to approved document.  Procedure shall be identified as “master procedure”  All personnel shall be trained on procedures that affect their activities.  Controlled copies of master procedure shall be distributed according to the distribution list of each master procedure.

Machinery and equipment Forklift and trolley are used for carrying the container to keep it on the desired rack.

The raw materials, which are stored in cold and dry place, ( 2-8)°C: Ciclisonide Micronised , Clavulanate Potassium blend ,Esomeprazole Magnesium ,Nystatin, Tiotropium Bromide.

The raw materials, which are stored in cool and dry place, ( 8-15)°C: Amoxicillin Sodium Sterile,Cefixime,Cefdinir,Cefradine L Arginine,Ciprofloxacin Hydrochloride.

The raw materials, which are stored in covered store,( 15-30)°C: Acyclovir,Acetic acid,Alluminium Hydroxide paste,Aminophylline.

The raw materials, which are stored in controlled temperature store,( 20-25)°C: Acetile Salicylic Acid,Abacavir Sulphate,Ascorbic Acid.

The packaging materials, which are stored in packaging storing room : Aluminum foil, PVC, Label, Direction slip, Dropper, Tube, Washer, Spoon, Container, Bottle, Carton.

The finished products which are stored in AC room : Aprocin, Aristobet-N, Aristophen, Erdon,etc.

The finished products which are stored in covered store : X pa-C, Lumeran,VC-250, Contine syrup Some common terms of Ware house: Sampling As the process of taking a small portion from a lot for test and analysis to show the quality of the whole lot. The purpose of sampling and subsequent testing is to provide an effective check on the quality of the product or substances being processed.

Sampling quantity Sampling quantity should be the double of one complete test.

Lot A batch or number of batches in a consignment.

Batch A quantity of the product or material which is processed in one run following manufacturing USP. Campaign A campaign means number of batches manufactured without any interruption or product change.

Handling The term handling means checking according to invoice/challan and other documents during receiving of the materials.

Preservation The term preservation means the materials are stored in different conditions according to its nature of stability i.e. to maintain a specific temperature and relative humidity.

Dispensing Dispensing means the materials are supplied to the production areas by weighing according to the proper document and release it from the RM Store.

Quarantine The term quarantine means the material is not ready for use and it is under test after received.

So a quarantine label is attached to the container.

FIFO The term FIFO stands for First In First Out. Re-test The term re-test means the samples are needed to be repeated analysis for identify vs previous documentation and it has been done either 3/6/12 months.

Materials sampling plan The materials sampling plan done on the basis of FIFO system i.e. first in first out. For active ingredients every container and for excipients â&#x2C6;&#x161;n+1 containers are sampled (where n = total number of containers) Routine activities - The executive receives RM according to the invoice/challan.

- Takes complain, if any problem is found.

- Takes GRIR form to the Q.A. department.

- Store all the RM according to the storage guide.

- Supplies RM on the FIFO basis to the production floor as per requirement.

- Adjust present stock after dispensing.

- Find out the raw materials.

Observation During our training period in the ware house and its related departments we observed the

following processes - How to develop production plan.

- How to maintain safe stock of inventory - How to supervise RM, PM and FP store - How to receive and dispense RM, PM - How to receive, store and dispense FP. Marketing The theme of ARISTOPHARMA’s Marketing is to care for its customers and this responsibility doesn’t lie only on the shoulder of Marketing Department rather all the company’s departments work together to serve the customers’ interests. And by the customers we don’t mean only the external customers, but also the internal customers i.e. our employees. Thus we always thrive to build and maintain an integrated marketing environment within the organization. However, the core marketing job is accomplished by six departments- Product Management, Sales, Distribution, Medical Services, Sales Training and Market Research.

Product Management Department (PMD): Product Management Department lies in the center of all marketing activities. A dedicated team with solid professional background comprising Pharmacists, MBAs, Biochemists and Medical Graduates work in this department. They formulate the strategies to uphold the market share of company’s products, select and introduce new products to keep the company growing and develop promotional materials for sales people to win in the market.

Sales Department: The sales department lies as an important part of marketing as they do the implementation part of all strategies. A large team of around 1200 highly skilled sales people work throughout the country to bring in success for the company. Team spirit remains as the key to success of the sales department in ARISTOPHARMA. Distribution Department: To make its quality products available at every corner of the country, ARISTOPHARMA has a strong distribution network comprising of 14 depots throughout the country. A dedicated team of around 450 people and a fleet of vehicles comprising delivery vans, three wheelers etc. are engaged in the timely distribution of products throughout the country.

Medical Services Department (MSD) In ARISTOPHARMA, we believe that our responsibility does not end only in manufacturing and marketing quality medicines but also extends to the total improvement of the healthcare sector of the country. To do this, ARISTOPHARMA has established an independent Clinical Research and Medical Services Department (CRMSD) for the first time in Bangladesh.

CRMSD comprised of medical graduates, assists in conducting Clinical Researches with our own medicines on our local people upon collaboration with different medical institutions. It also arranges seminars & symposia, publishes news letters & articles and provides other professional services to the doctors.

Sales Training Department: They organize training for sales people. Training is organized both in the entry level as well as for existing people to keep them updated with product knowledge, selling skills etc.

Market Research Team (MRT): The Market Research Team conducts prescription audit throughout the country to find out the prescription behavior of the doctors, which acts as the major input for formulating marketing strategies Conclusion

Today, at the age of globalization, it is a world without boundaries. With the aim to cope up with the challenges of globalization, ARISTOPHARMA started its export operation in 2000, Vietnam being the first destination. Today ARISTOPHARMA export to 9 countries of three continents namely Singapore, Sri Lanka, Myanmar, Vietnam, Bhutan, & Macau of Asia; Ukraine of East Europe & Mauritius of Africa. Apart from usual tablet, capsule, syrup, suspension or cream/ointment, it also exports sophisticated ophthalmic dosage forms to Hong Kong and Myanmar. It is the 1st pharmaceutical company in Bangladesh to export to a developed country like Hong Kong & 2nd company to export to Singapore.

Now ARISTOPHARMA is moving aggressively to increase its market share in the operating countries as well as to invade new countries. Some other African countries & countries of Middle East are under active search. ARISTOPHARMA is moving aggressively to increase its market share in the operating countries as well as to invade new countries. Some other African countries & countries of Middle East are under active search.

• • • • • • • • •

Singapore Hong Kong Sri Lanka Vietnam Myanmar Bhutan Macau Ukraine Mauritius

HUMAN RESOURCES

Skilled human resources are the key driving force of ARISTOPHARMA’s growth.Their success is based on selecting, developing & retaining talented and motivated human resources. They share both of their desire to excel & their commitment to improve the lives of the people.

The employees of ARISTOPHARMA believe in collaborative spirit. They appreciate that working together as a team multiplies the strength of the individuals involved as well as the impact of the results.

Skill acquisition & development of all staff is the key to a company’s growth, they believe.

Hence they are always on the lookout for identifying training needs of their employees in order to enable them to carry out the entrusted responsibilities. Training programs undertaken address not only skills relating to the specialty of the individuals concerned but also their leadership & management skills.

To date the total numbers of employees in ARISTOPHARMA is around 2600 and 60% of them are white collar employees. Among them are• • • • • • • • •

Pharmacists Chemists Biochemists Microbiologists Medical Graduates Engineers CMAs MBAs Other Graduates

It is their people who make them different from their competitors. The secret of their success lies in their people.