Aristopharma plant training

View with images and charts In-Plant Training Programme In Aristopharma Ltd. (Manufacturer Of Pharmaceutical Products) Introduction Plant training for the professionals is now essential to know in details the application mode of modern scientific and management issues aiming to familiar them correctly.

This training is the bridge between the theories and principles with their practices, in other words between the institution and commercial organization.

For gathering complete knowledge about pharmaceutical aspect of microbiology there is no alternative for in-plant or industrial training program. This training is conducted by the pharmaceutical industries in our country. By this training, each microbiology student can achieve vast experience many of which is almost new to us; can correlate the theoretical knowledge with the practical experience. Thus we can develop ourself completely for microbiology related job in pharmaceutical company. To take part in such type of training program we have been selected THE ARISTOPHARMA LTD. This ensures manufacturing and marketing of essential medicines with highest quality by following cGMP, GLP and ISO2000 by all modern technologies. The main dosage form manufacturing by the respective company are solid such as tablet, capsule and dry syrup. Semisolid such as ointments, creams and liquid such as suspension and syrup. Sterile products include ophthalmic, injectable product, MDI and lyophilized product. Special microbiological precautions have to maintain in sterile and liquid section. In order to GMP, every procedure and equipment has its own Standard Operating Procedure (SOP).

Policies of Aristopharma Ltd. ”Quality the Unit We Count” To maintain and improve status of an integrated healthcare company through  acquisition of state of arts skills and facilities and enhance competency of human resources through appropriate relevant training program.  To adhere strictly with WHO cGMP regulations in respect to manufacturing, Quality assurance, Marketing and distribution of medicinal products and to keep compliance of regulatory specifications of local authority.  To practice and continually improve Quality Management System (QMS) in it’s totally to consistency meet customers needs in the global context.  To review and upgrade “Quality Audit Programme” to match with regulatory requirements.

The Journey of Aristopharma Ltd. 1986 The journey started through the formation of a proprietorship firm under the dynamic guidance of Mr. M. A. Hassan, present Chairman & Managing Director of the company. It was a modest start with the introduction of a few products in oral liquid & tablet form.

1990 The new manufacturing unit was commissioned at Shampur-Kadamtali with highly sophisticated and advanced facilities.

1998 Production line was diversified with the addition of cream and ointment in the portfolio.

2000 Company starts its international operation – Vietnam being the first country to export.

2001 Export starts to Sri Lanka 2002 Sterile Products Block is commissioned & Ophthalmic Products are introduced in the market.As the first Pharmaceutical Company in Bangladesh, ARISTOPHARMA exports to Hong Kong – one of the most developed markets of Asia.

2003 The diversification rolls on - parenteral dosage form is introduced.

2004 Company touches another landmark in international operation - export starts to Singapore.

Export of highly sophisticated Ophthalmic Products starts to Hong Kong. Export also strarts to another country - Macau.

2005 Company crosses the continental boundary export start to Ukraine of East Europe.

2006 Export starts to Mauritius of Africa. Became No. 1 in Ophthalmic market in Bangladesh.

Enters the top 10 chart of Bangladesh Pharmaceutical Market.

2009 Agreement is signed with APC, Australia to set up its 3rd plant at Gacha, Gazipur for Europe/American Market. Export starts to United Arab Emirates of Middle East and Nigeria of Africa.

2010 Export starts to Pakistan. The new expansion building of factory starts operation with the facilities for inhalers, lyophilized injections, pre-filled injections, suppositories etc.

2012 New plant is under construction in Gazipur (Gacha). Manufacturing of insulin, suppository,amino acid will be started this year.And the journey continues...

SOLID DEPARTMENT (TABLET) Drug substances are most frequently administered orally by means of solid dosage forms, such as tablets and capsules. Solid dosage forms are some of the least expensive, most popular and convenient methods for drug delivery. Here we would focus different aspects of tablet making procedure and the equipment involved in it.

Total Units in Solid Department

Manufacturing area

Granulation unit

Packaging area

Compression unit

Coating unit

Capsule filling unit

Contents of a tablet 1. Active Ingredients 2. Filler/Diluents 3. Disintegrant 4. Binder 5. Lubricant 6. Glidant

Excipients

7. Antiadherent 8. Flavourings 9. Colourings •

Filler/Diluents - to increase the size (bulk) of the tablet. It is necessary as, sometimes,

the active ingredient used is in very small quantity and thus would be too small to handle the tablet.

•

Disintegrant - helps 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 quickly for it to act swiftly.

•

Binder - to hold the tablet together after it has been compressed, stopping it from breaking down into its separate ingredients.

•

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

•

Glidant- to help to keep the powder, used to make a tablet, flowing as the tablet and stopping it from forming lumps.

•

Antiadherent- to stop the powder from sticking to the equipment as the tablet is being made.

•

Flavourings - to make the tablets smell and taste better.

•

Colourings - to distinguish one tablet from another.

Process of tablet making Dispensing Granulation Blending Powder compression Coating Blistering Secondary Packaging 

• • • •

Several categories of tablets for oral use may be distinguished as: Uncoated tablets Coated tablets Effervescent tablets Soluble tablets

• • • • •

Dispersible tablets Orodispersible tablets Gastro-resistant tablets Modified-release tablets Tablets for use in the mouth

Granulation Granulation is the process in which the powder particles of raw materials are made to form larger particles in order to facilitate compression for the production of tablet.

The purposes of granulation are: -

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.

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 Difference between Wet and Dry Granlation

Wet granulation

Dry granulation

Weighing of active ingredient as well as Weighing of drugs and excipients; then excipients and sieving it sieving them. ↓ Dry mixing Dry mixing of drugs and diluents

↓ Wet mixing (addition of wet binder) ↓

Initial phase drying in Fluid Bed Dryer Slugging or pre-compression (FBD) ↓

Milling and sieving

Milling in the Multimill ↓

Lubrication

Partial drying in FBD ↓

Discharge for compression

Milling in the Multimill ↓ Terminal/Final drying in the FBD ↓ Sieving in the Vibratory Sifter according to the required particle/granule size ↓ Check moisture content and dry accordingly.

Add lubricant. ↓ Granules of desired size ready for blending.

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 & size range of the particles, and surface effects such as absorbed liquid film, electrostatic charges & 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 & chemicals should be reduced to approximately the same size prior to weighing & 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. India 3.Multi mill-1 4.Double cone Blender 5.Tablet oscillating Granulator 6.Paste Kettle Pam Glatt Fluid Bed Processor 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 Preparation of granules

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.

Fig: Rapid mixing granulator (RMG)

Fig: Fluid bed dryer

Fig: Multi Miller

Fig: Double cone blender

Features Specifications: Rapid Mixer Granulator: 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 is the reduction of the bulk size of a tablet due to high pressure. In the compression of active pharmaceutical ingredients, overall control is essential to ensure high quality.

Flow chart of 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:            

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), and 37(1)} Automatic tablet compression machine: New Se Jong Model 37 Station Rotary Tablet Press. Machine Features: 1) Unit has the capacity to deliver 54,000 to 216,000 tablets per hour.

2) Maximum Tablet Diameter: 16mm, Maximum Tablet Thickness: 8.5 mm, Filling Depth: 4.5 to 10mm, 8.5 to 14mm, 12.5 to 18mm (3) Lubrication System: Automatic lubrication by cycle pump, Lubricating interval and amount can be reset (4) Feeding System: Mechanical feeder as standard, open feeder is available as an option, Stainless Steel hopper with sight port.

(5) Tooling: ‘B’ Type.

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: 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

Film coating

Aqueous coating

Enteric coating

Organic coating

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.

Stages of Sugar Coating1. Sealing 2. Subcoating 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

750c 60/650c

Organic Aqueous

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 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.

Name of the Machine

CAPACITY

NR-COTA (FC) TC-TC9. NR INDS. 90-110 KG. THAILAND. ECO COTA TC-TC2 F D & C Pvt. LTD. Max:100 KG PAKISTAN SUGAR COATING PAN, Max:70 KG BANGLADESH&INDIA. RAMA COTA (EC) TC-TC-1 RAMA Max:20 KG PROD. COM. LTD. N R COTA 2 TC TC-11, NR INDS. Max:200 KG THAILAND  Condition required during Coating:  

Relative Humidity: Not more than 50%.

Temperature: Below 250C.

Common problem 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)

Solution: -

Modify core formulation to include more hydrophilic ingredients

-

Increase core porosity

-

Using 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.

Solution: -

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

Solution: -

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

Solution: -

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.

Solution: -

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

Solution: -

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)

Solution: -

Decrease solid content of coating liquid

-

Increase atomizing air pressure/volume

-

Decrease inlet air temperature/flow rate

8. Twinning Cause: -

Spray rate too high

-

Pan speed too low

-

Inappropriate tablet shape

Solution: -

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)



SOLID DEPARTMENT (CAPSULE)

Capsules are solid dosage forms in which the drug substance is enclosed in either a hard or soft soluble shell of a suitable form of gelatin, 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, coloring matter and flavoring substances may be added In this pharmaceutical industry encapsulation, sealing and polishing of capsules of hard gelatin shell are done during manufacturing, as the industry does not manufacture any capsule shell and has to be brought separately. The active is filled in the empty the hard gelatin capsule shell in the form of powder and pellets.

There are 6 different sizes of empty hard gelatin capsule shells used in AristopharmaLtd. 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: Blend Pellets with NPS ↓ Encapsulation ↓ For encapsulation of powder, Blending ↓ Slugging

↓ Granulation ↓ Sieving ↓ Encapsulation Encapsulation Process by Manual Capsule Filling Machine by Hand: 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 Capsul Machinery: Machine name

Machine specification Semi automatic Capsule Capacity: 15000filling machine 17000/hr Capsule fill Automatic Capsule Capacity: 30000/hr filling machine Capsule fill Automatic Capsule Capacity:90000/hr filling machine Capsule fill S.S.Drum -Blender Capacity: 200 kg Charge Vat Capacity: 50 kg Cap. polishing machine Hand fill machine Capacity:8000/hr

Manufacturer

Origin

P+am pharmaceuticals

India

Hanli

Korea

Se jong

Korea

Gansons Myth P+am pharmaceuticals Pharmachem

India.

Bangladesh India India

SOLID DEPARTMENT (DRY SYRUP) Dry syrup, in Aristopharma, is manufactured by dry mixing method.

Dry mixing procedure flow chart 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 Condition for manufacturing Dry Syrup 

Relative Humidity: Not more than 45%.

Temperature: Below 250 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



Packaging

Packaging can be described as a coordinated system 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.

Purpose of packaging     

To increase the acceptability of the drug Physical protection and barrier protection to increase the stability of the drug To minimize the transport/shipping hazards To improve patients’ compliance Containment or agglomeration. Liquids, powders, and granular materials need containment.  Information transmission and marketing  To improve the pharmaceutical elegance by the use of special color or contrasting printing At Aristopharma, two types of blister, PVC- Aluminium Blister and Aluminium Blistercombination are used.

Packaging can be divided into two categories mainly; primary packaging and secondary packaging.

Primary packaging is the material that first envelops the product and holds it.

Secondary packaging is outside the primary packaging, perhaps used to group primary packages together.

There is also tertiary packaging which is used for bulk handling, warehouse storage and transport shipping.

Primary Packaging Materials Materials 1. Polyvinyl Chloride [PVC], (PVC/PVC) 2. Polyvinylidine chloride [PVDC] 3. Aluminium Foil

Thickness 250-300 μm 250 μm 20 μm (top) 130 μm (Bottom)

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.

Korea

Major Steps of blister packaging: PVC sheet Heating plate Foil softens by hot plate at temp. 125-145°C

Passed through desired dies plate which is keptcold& air pressure is applied to make pocket for small time & desired shape is resulted (air pressure 6-8 bar)

Tablets or capsules are filled into the pockets

Pressed by two plates simultaneously (upper plate temp. 160-180°C for PVC & lower plate is cold)

Passed through cutter

Desired blister pack

Major steps of strip packaging: Tablets or capsules in hopper

Tablets/capsules in vibrating disc

Enter through tode channel

Tablets or capsules enter between two alu roll strips

Hot roller having particular dies shape Pressing

Poly-coated alu rolls (coated with plastic materials) come from two sides

Strip packaging Trouble shooting       

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

 Emboss problem  Heat exchanger  Feeding problem – o Chute channel o Gate transfer o Spiral o Brush In-process check:  Observation no.  Leakage test (at 400 mm Hg )  Room condition o Temperature & humidity o Segregation of bulk materials/finished packs o Product identity o Line, display board  Aluminum foil leaving in machine and stock  Number of individual strips/blisters checked  Number of finished products checked  Quality and identity of components compliant slip/labels/cartons/leaflets/outer labels/outer box/ spoon  Identity and appearance of product in packs  Quantity: No./volume/weight  Overprinting/embossing: batch no./MFD/Exp date/MRP  Label/carton with product name, Batch no, Mfg date, price, and Exp date.



LIQUID SECTION

The liquid department in Aristopharma Ltd. is divided into four sections. They are: 

Liquid



Cream,ointment& gel



Topical



suppository

General working procedure of liquid Receive monthly product schedule ↓ Analysis the monthly product schedule ↓ BMR &BPR prepared ↓ QA approval Sent BMR, BPR to RM &PM ↓ Receive the materials ↓ Processing ↓ Filling ↓ Packaging ↓ Transferring to finished goods Procedure of a liquid formation

↓

Active ingradient ↓ Suspending agent (guargum) ↓ Solvent (purified water) ↓ Sweeting agent (aspartame,saccharineetc) ↓ Buffering agent (citric acid, sodium citrate etc ) ↓ Preservatives (sodium benzoate, methyl paraphene) ↓ Co-solvent (propylene glycol) ↓

Coloring agent ↓ Flavouring agent ↓ Viscosity enhancer (glycerine) Suspension preparation Steps 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 Condition For Manufacturing Of Oral Liquids: -

Relative Humidity: Not more than 55%.

-

Temperature: Below 30oc



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 30oc Cream, Ointment & Gel

Cream, ointment and gel fall into topical product. Semi sterile condition is maintained here.

Cream is made of two ways; firstly water in oil; secondly, oil in water.

In ointment, no water is used, only oil.

In gel, both water and oil is used.

General process for manufacturing of cream Water Phase

Oil Phase

Water phase to Oil phase in a steam jacketed vessel

Blending by mechanical stirrer

Filling

Sealin g

General process for manufacturing ointments

Oil phase-I Oil PhaseII

Oil phase-I to Oil phase-II in a steam jacket vessel.

Addition of active ingredien ts

Blending by mechanic al stirrer

Fillin g

Machinery Machine Name

Specification and Origin

Vacuum Emulsifying Mixer

China

Auto tube filling and sealing machine

China

Automatic tube filling machine

Precitechindustries,india

Automatic tube filling machine

Pharmachemmachinaries,india

Colloid mill

Cadmach ,India

Charging vessel

Mythindustries,Bangladesh

Sealig

High speed emulsifier

India

Vacuum homogeniger

China

Transfer pump

U.S.A

Automatic labeling machine

Korea

Automatic liquid filling, Cap Sealing and India labeling machine Machine Name Specification and Origin Vacuum Emulsifying Mixer

China

Auto tube filling and sealing machine

China

Automatic tube filling machine

Precitechindustries,india

Automatic tube filling machine

Pharmachemmachinaries,india

Colloid mill

Cadmach ,India

Charging vessel

Mythindustries,Bangladesh

High speed emulsifier

India

Vacuum homogeniger

China

Transfer pump

U.S.A

Automatic labeling machine

Korea

Automatic liquid filling, Cap Sealing and labeling machine

India

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SUPPOSITORY

A suppository is a drug delivery system that is inserted intotherectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository), where it dissolves.

They are used to deliver both systemically-acting and locally-acting medications. The general principle is that the suppository is inserted as a solid, and will dissolve inside the body to deliver the medicine pseudo received by the many blood vessels that follow the larger intestine.

Condition:

Temperature- 45-50oC Base- Carnauba Wax STERILE DEPARTMENT Aristopharma is a leading pharmaceutical company in Bangladesh and leading to produce ophthalmic product in Bangladesh. Aristopharma is now manufacturing different types of sterile dosages form including ophthalmic eye drop, eye ointment, eye cream, nasal drop, ear drop as well as IV and IM injection and recently included lyophilized product. Recently they have launched their MDI and Insulin product. They have a future plan for manufacturing of amino acid product,hormone& anti cancer product.

Doses forms in Sterile Department        

Liquid injection (suspension) Eye drop Eye ointment Dry vial Lyophilized vial Pre-filled syringe Lyophilized injection Insulin

Generally the products are manufactured by two ways: -

Aseptically Sterilized Terminally Sterilized

Injectable Products in Ampoule Injectable products are dispensed in ampoules in the following procedure: Ampoule 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 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 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 Dry Heat Sterilization 220 (DHS) 250

3

1.1

Vials

2.5 1

1.1 1.1

Steam Sterilization 121 /Autoclave

0.5

1.1

Ampoules, Gloves, Filters, Gourmets

Manufacturing of injectable preparations require a clean room which should have the following standard: Class

Cfu/m3

Particle of 0.5 micron/ft3

Particle of 5 micron /ft3

100 1000 10,000

<1 NMT 10 NMT 100

NMT 100 NMT 1000 NMT 10,000

0 NMT 7 NMT 70

1,00,000

NMT 1,00,000

NMT 700

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

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

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

Injectable products (powder or solution) in Via The following steps are following to dispense injectable products in vial: Vial Sorting

Vial Washing

Vial Sterilization

Vial cooling

Powder filling

Rubber capping

Packaging

Blistering

Labeling

Alu- sealing

Machinery Machine Name

Manufacturer

Bung washing machine Automatic eye filling,plugging,overcapping machine Semi automatic cap closer machine Ampoule filling & Sealing machine

Origin

drop Ming Pen Machine CO

India Taiwan

MP-VS-OL Ming Pen Machine CO

Taiwan China

Automatic Steam Sterilizer Vial filling,stoppering,sealing machine Dry heat sterilizer Dry heat sterilizer Charging vessel 142 mm filtration unit 293 mm filter unit Washing Machine

Sturdy industries Ltd Indo-German Myth indries Kothari Satorius Satorius Chung Machinery CO

Taiwan China India Bangladesh India Germany Germany Taiwan

Lyophilization Lyophilization is used to increase the shelf life of products, such as vaccines and other injectables. It is done by removing the water from the material and sealing the material in a vial. The material is easily stored, shipped, and later reconstituted to its original form for injection. Generally, IV,IM-fluids and products used for parenteral routs are lyophilized prior to sealing.

The lyophilizer unit is composed of a large air-tight cylindrical reservoir, equipped with shelves to hold the trays of products to be freeze-dried. Access is through a large door, strong enough to resist the high pressure created when air is withdrawn from the freeze-drying unit to produce a vacuum needed for the process of sublimation.

Procedure flow chart Shelf-precooling  Precooling  Condenser cooling  Chamber cooling  Primary Drying  Pressure rise test  Secondary Drying  Pressure rise test  Vacuum break Stoppering  Shelf cooling  Cycle end COMPOSITION The lyophilizer unit is composed of a large air-tight cylindrical reservoir, equipped with shelves to hold the trays of products to be freeze-dried. Access is through a large door, strong enough to resist the high pressure created when air is withdrawn from the freeze-drying unit

to produce a vacuum needed for the process of sublimation. 

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 - Plant room 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 Function of engineering department a. Power production. b. Effluent treatment. c. Water treatment. d. Air conditioning system (HVAC).

Water treatment plant in APL. Earth water

Supply

Vertical pump

Heat Exchanger

Sand bag-Gravel filter

Distillation tank

Overhead tank Condenser Chlorination

Distillation unit

Pre-filtration

D.M water storage tank

Raw or City water Tank Activated carbon filter 2.5 mic. Filter 0.2mic.filter D.M Water plant

2.5mic.filter 0.2 mic.filter Mixed bed Exchanger Anaionic Exchanger Cationic Exchanger

Gas Generator: There are three (3) gas generators. One is Gauscor generator. It produces 952 KW electricity.

Other two are Banglacaterpillar and produce 1800 KW electricity(1030KW+770KW).

Diesel Generator: Model: SDMO There are two diesel generators. Produce 500 KVA electricity per diesel generator.

PDB: From PDB, get 100 KW electricity.

Effluent treatment plant in APL. Waste water PIT-1 PIT-2 Equalization tank (6-7 hr) Second equalization tank (12 hrs) (lime, Alam) (reduce BOD,COD, odor) Primary clarifier Sludge reactor Secondary reactor Treated water tank Filtering (activated carbon filter) (To QC) Drain off HVAC system HVAC (Heating,Ventilation& Air conditioning) refers to technology of indoor or automotive environmental comfort. HVAC system design is a major subdiscipline of mechanical engineering based on the principles of thermodynamics, fluid mechanics, and heat transfer.

QUALITY ASSURANCE

Quality assurance is a wide ranging concept which covers all matters that individually or collectively influence the quality of a product. It also helps to prepare the standard operating procedures (SOP) related to the control of quality.

It is the sum total of the 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 (GMP) plus other factors outside the scope of ISO guidelines.

The function of Quality Assurance starts from raw materials and continues up to released products. The function of Quality Assurance in a pharmaceutical is given below.

In ARISTOPHARMA LTD. the Quality Assurance Division (QA) performs it function through the following sections: - Quality Control (QC) Department - Quality Compliance Department - Product Development and - Validation.

The section of Microbiology department is a part of quality control under the supervision of Quality Assurance Division in Aristopharma Ltd.

Quality Assurance (QA) Division

Quality Control (QC) Department

Quality Compliance Department

Product Development (PD)

Microbiology Department

The activities of QA at a Glance: 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 tag for raw & packaging material.

Attachment of respective

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

Validation

Investigation of product complaints, product recall returned product from market Figure: Flow chart of Quality Assurance activity 

Quality Control

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 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).

Function of Quality Control            

Raw Material Analysis In Process Analysis Finished Goods Analysis Packaging Material Analysis Calibration Laboratory Instrument Fixation of Expiration Date Process Validation Handling of Product Complain Investigation of Out of Specification Environmental Analysis Development of Test Procedure GMP Audit

Tests performed in Quality Control Department: Test requirements vary with product to product according to compendia. But the common tests are: Tests for starting materials:     

Appearance and odor Solubility Identity (complies/ not complies) Melting point Weight per ml  Loss on drying at 105°C (3 hrs)/ water content by KFR  Appearance of solution/Clarity & color of solution  Assay

• •

Spectrophotometric/Titrimetric/HPLC Microbial assay

Tests for tablets or capsules:           

Loss on drying at 105°(3 hrs)/ Moisture content by KFR Disintegration test Length/diameter Width Thickness of 20 tablets Friability test Dissolution test Uniformity of weight Appearance of tablets or capsules Average hardness for tablets Assay by titration/spectrophotometer/HPLC/AAS method ** AAS – Atomic absorption spectrophotometer used mainly for the assay vitamins or minerals.eg. Fe, Zn etc.

Tests for Liquid cream and ointment:        

Identification of active ingredient PH value Water per ml at 20±°C, gm.

Viscosity Sedimentation test Total solid Color content Alcohol content

In Process QC:      

Quantitative assay Disintegration test pH Viscosity test Weight / ml for liquids Weight variation tests



TESTS FOR PACKAGING MATERIALS

Packets

Cap

• • • • •

Printing error test, Length, width of secondary packing materials, Lock bottom test, Defection of gluing, Wide color variation

of

• • • • •

Color, Printing, Weight, Length, diameter Length from top to the cut mark.

Bottle

• Length, • Diameter of neck and body, • Weight, • Over flow capacity, Aluminum Foil • Thickness of Al foil, • Weight at gm / sq. inch, • Printing conditions.

Label • Conditions of color printing, • Quality of paper, • Checking of spelling and any types of error.

Tubes, Spoon and Dropper • Types of rubbers and droppers, • Measurement about quantity for spoon, • Class of glass for tubes.

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

Hot air oven

No. of Machine 1 7 1 1 1 1 2 1 1 1 1 1 1 2 1 3 2

Origin England Japan Japan Japan Japan Japan Germany China Taiwan Japan England Japan India Switzerland Korea Germany U.S.A

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

Tapped volumeter ERWEKA Centrifuge machine Titrator DL50

1 1 2 1 1 1

Japan Bangladesh Germany Germany China Bangladesh

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

Figure: HPLC machine and UV machine.

Tablet friability tester

Tap density test apparatus

Melting apparatus



point

Moisture analyzer

MICROBIOLOGY SECTION

Microbiology section is one of the vital sections 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 aureus. Salmonella species.

3. LAL test for injectable preparations.

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 persons 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.

Machineries used in Microbiology Section 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

Figure: Laminar Air Flow Bench.

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

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). 

Sterilization

Methods of sterilization:

Calibration is done first in each equipment.

Sometimes biological indicators are used as follows:

Microbiological tests 1. Microbial Limit Test: It is a quantitative test. In this test number of microbial colony forming unit per ml is counted.

For limit test dilution of sample is performed. This is done to reduce microbial load and to reduce inhibitory effect of antimicrobial compounds. Before inoculating in a culture media, diluted sample is treated with a neutralizing media (e.g. 1% meat peptone). Finally the sample is inoculated in media for bacteria (TSB) or for fungus (SDA).

To remove the viscosity nature of cream and ointment isopropyl myristate is used for dilution.

This test is done for both raw active, raw excipients and finished products. Normally USP or BP recommendation is followed. Presence of four bacteria is counted in this test:  Staphylococcus aureus  Pseudomonas aeruginosa  Salmonella  E. coli Among fungus: mold and yeast.

Example: In case liquid product 200/ml is the limit but no pathogenic strain is allowed.

In case of cream and ointment 200 cfu/gm is the limit but presence of pseudomonas and staphylococcus cause the product fail.

1. Microbiological Assay or Bioassay: This test is done to check potency and to check the amount of ingredients. In Aristpharma Ltd. antibiotic assay is associated with following antibiotics:  Azithromycin  Polymyxin

 Neomycin  Tobramycin Example : in case of neomycin this test is performed with Bacillus pumilis. Then incubation period is allowed for 18 to 24 hours. Normally media which is specific for that antibody is used.

Microbial assay is also done for vitamin products.

Bioassay

Agar diffusion

Turbidimetric assay

MIC test

MBC test

2. Preservative Efficacy Test: The basic principle of a preservative test is to inoculate separate container of the product with known concentrations of a variety of test organisms, then removed samples from each container over a period of time and determine the proportion of the inoculums that has survived.

This test is done for liquid finished product. Example: eye drop, cream, ointment. This test detects the amount of preservatives (excess or low).

Microorganisms which are used for this test are:  Staphylococcus aureus  E. Coli  Pseudomonas aerogenosa  Candida albicans  Aspergillusniger

105-106 organisms/ml are used as inocula. Incubation condition is allowed for 28 days.

When preservative remain in excess amount then all microorganisms will be killed. When count become too much then it indicates low amount of preservatives.

4. Sterility test : This test is done for both ophthalmic drop and injectable products. Conditions of testing area are maintained as same as filling area.

For inject able products two parameters are observed:1.sterility and 2.endotoxin For ophthalmic products only sterility is observed. Two methods used  Direct inoculation

 Indirect inoculation Direct Inoculation: Products which are water insoluble (e.g. ointment and cream) are directly inoculated in to media. Before transfer in to media inhibitory effect of antimicrobial agent is reduced. This is done in two ways: 

Dilution (1/10)



Chemical inactivation (β-lactamase)

As neutralizing media 1% meat peptone treatment is allowed. Then final inoculation into media is performed (TSB or SDA) B. Indirect method (Filtration): First filtered with membrane filter (0.22µ) Treated with neutralizing media (1% meat peptone) Then filter is cut in to two pieces Each piece is inoculated in different media specific for bacteria and fungus.

For anaerobic bacteria fluid thyoglycolate medium is used( incubate at 30-350C). For aerobic bacteria and fungi tryptone soya broth is used(incubate at 30-350for bacteria and 20250C for fungus).

5.Endotoxin Test or Pyrogen Test: This test is done for injectable products. Endotoxins are lipopolysaccharide of gram negative bacteria. The hemolymph (blood) of the Atlantic coast horseshoe crab, Limulus polyphemus, contains white blood cells called amoebocytes, which have large amounts of a protein (lysate) that causes clotting. In the presence of endotoxin, amoebocytes in the crab hemolymph lyse and liberate their clotting protein. The resulting gel-clot (precipitate) is a positive test for the presence of endotoxin. The degree of the reaction is measured using a spectrophotometer.

Test sample and same volume of reagent is mixed.

Incubation condition is 370c for 1 hour

Formation of gel clot indicate presence of pyrogen

No gel formation absence of pyrogen.

indicate

6. Settle Test: Air sampler is used for settle test. Particle count is done by this method.

Another method is TSAor SDA media which is exposed for 4 hour in room atmosphere.

7. Water Test: R2A agar is used for viable count. This media is used to cure injured bacteria. 

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

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

Ware House

Warehouse is the place or store where raw materials and packaging materials are kept in specified conditions before they are used in production. In the factory of Aristopharma Ltd, the warehouse is situated near the main gate and in the ground floor to ensure the ease of receiving materials and keeping them.

The main function of Ware House: 1) Receiving 2) Storing 3) Dispensing GRN: GRN means Goods Receiving Note.

KISS: KISS means Keep in Simple System.

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.

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: CiclisonideMicronised , Clavulanate Potassium blend , Esomeprazole Magnesium , Nystatin, Tiotropium Bromide.

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

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

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

FIFO The term FIFO stands for First In First Out. FEFO The term FEFO stands for First Expire First Out. Dispensing Dispensing means the materials are supplied to the production areas bymweighing 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.

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.

Metered-Dose Inhaler (MDI) Section A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is inhaled by the patient. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for the treatment of asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as (cromoglicate or nedocromil)

Auto tube filling & sealing machine A metered-dose inhaler consists of three major components;  the canister which is produced in aluminium or stainless steel by means of deep drawing, where the formulation resides;  the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation;  and an actuator (or mouthpiece) which allows the patient to operate the device and directs the aerosol into the patient's lungs.

The formulation itself is made up of the drug, a liquefied gas propellant and, in many cases, stabilising excipients.

The actuator contains the mating discharge nozzle and generally includes a dust cap to prevent contamination.

To use the inhaler the patient presses down on the top of the canister, with their thumb supporting the lower portion of the actuator. Actuation of the device releases a single metered dose of the formulation which contains the medication either dissolved or suspended in the propellant. Breakup of the volatile propellant into droplets, followed by rapid evaporation of these droplets, results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled.

However, The MDI section is new one in Aristopharma Ltd. Pre requirement of MDI solution: • • • • • • • •

be a liquefied gas have appropriate solvent properties have very low toxicity have appropriate density be chemically stable be compatible with a wide range of medicines be acceptable to patients (taste and smell) be non-flammable

Canister

Actuator

Condition of different parts in MDI: Room Pass room Dispensing room Store room Can-vulve store room Filling machine Can cleaning room

Class D A,C C C

Humidity <50 >35 25-55 25-55

A C

35 25-55

Pressure 5-20 Pa

<25oC <250C

Filling process

Machinary : Machinaries Pamsol filling machine Weight checking machine Auto tube filling &sealing machine Blank tube machine emulsifiere

Origin Switzerland china china

Capacity 18/min

china china

2500/hour

Closer view of filling process:

ď ą

PRODUCT DEVELOPMENT

Temperature <250C <250C <250C <250C

2400/hour

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 performs 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

No. of Machine 1 1 1 2

Source India India.

India Japan

1

Japan

1 2

China Germany

2 1 1

U.S.A Japan Bagladesh

Humidity chamber Disintigrator tester Friability tester Electronic balance Double cone mixture Planetary mixture Wet granulator Moisture analyzer Drying oven

2 1 1 1 1 1 1 1 1

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.

Validation In recent years, the term validation has become familiar in connection with pharmaceutical processes. Validation is a component of cGMP (current good manufacturing practice). According to Food and Drug Administration, the process validation may be defined as “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics”.

In other words, validation of a process is the demonstration that controlling the critical steps of a process results in products of repeatable attributes or causes a reproducible event.

Purpose of Validation: The purpose of validation is to ensure consistent product quality. A new product or an old product manufactured using a modified process or facility cannot be solid until the ‘process’ has been adequately validated.

Types of Validation: Validation may be divided into four types: a) Prospective validation b) Retrospective validation c) Concurrent validation d) Revalidation Prospective validation: This is where the validation programme is designed before the equipment or facility is used, or before the product manufactured by the process being validated is distributed. This type of validation is employed when producing the data on initial full-scale production batches

required in order obtaining a regulatory authorization for marketing and manufacture of that product.

Retrospective validation: This is achieved by reviewing historical manufacturing and testing data of products or possesses.

Concurrent validation: This is ongoing prospective validation or ongoing review and evaluation of historical data.

Revalidation: Revalidation involves repeating all or part of the validation if, for example, a process or facility is modified.

So, 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.

Conclusion ARISTOPHARMA LTD. -‘Manufacturer of Pharmaceutical Product’s is well known for constructive endeavor to innovation that is usually the result of very extensive product testing and market research in Bangladesh. Its chemical division is almost a saturated one having all types of dosage forms including tablet, capsule, syrup, suspension, cream, ointment, gel and ophthalmic product. We are very proud to take our training in such a leading industry To speak the truth it’s the ‘in plant training’ which visualizes our four years academic course in a month only. It helps us to understand the complicated steps of tablet coating, methods of granulation, physics of compression, preparation of suppositories, liquid filling, microbiological testing and such difficult topics which we just learn by heart in our academic session in the department. So we can’t but thank Aristopharma Limited as we all assume the knowledge we gathered from this training will of course be the assets for our future life.

The extraordinary faces of Aristopharma are- here everything is systematic and the good affiliation between the colleagues and boss-subordinates-workers. They are very helpful to each other as well as to the trainees. We have got an immense support from all the members of Aristopharma Limited.

However, today Aristopharma Limited has not only attained the apex of its development for the dedication of its employees, proper management, proper application of science and technology and for the standard of products but also has succeeded in attaining a good position in the world market.