SOLID DEPARTMENT OF PHARMACUTICALS COMPANY

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 well-known 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.

Mission

• The course will begin by examining the finished dosage unit and
•  Will identify, in general terms, all unit operations required to get the unit into its finished form. Examples of these unit operations include blending, granulating, compressing, branding, and coating for tablets, as well as blending and filling for capsules.
•  Once unit operations have been identified and defined, product characteristics will be examined to determine the type of equipment utilized in each of these operations.
• The specific types of equipment for each unit operation will also be discussed. For example, a discussion of granulation will include information on different types of granulators and typical challenges encountered during scale-up.
• Process monitoring techniques will also be discussed. The course will review many known techniques for process monitoring with particular emphasis on their utilization in scale-up and technology transfer.
• The course will also cover the final dosage unit and analyze the necessary steps in the packaging operation to get from the finished tablet or capsule to the final filled and sealed container.
• Topics for discussion will include packaging equipment for tablet/capsule counting, capping, security seals and bands, labeling, cartooning, and blister packaging.
• The course will conclude with a discussion on technology transfer, how to get the product from the R&D laboratory to full-scale manufacturing, and how to transfer a marketed product from one facility to another. A competency test will be administered upon course completion.

Tablet Manufacturing

INTRODUCTION of Tablet

Tablets are solid preparations each containing a single dose of one or more active substances and usually obtained by compressing uniform volumes of particles.
As well as the ‘active’ ingredient (the medicine which actually causes the change in the body that you want), the tablet contains a number of other ingredients which ensure that the tablet is easy to use and of a high quality. These ingredients have been chosen because they do not affect the body and will not cause you any harm.

A typical tablet contains:

TABLET EXCIPIENTS

Filler or diluent	A filler, such as sucrose or lactose, 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.
Disintegrant:	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.
Binder:	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.
Glidant:	The glidant helps to keep the powder making up the tablet flowing as the tablet is being made, stopping it from forming lumps.
Lubricant:	Lubricants ensure that the tablet has a smooth surface and that the powder does not stick to the equipment used to make the tablet.
Antiadherent:	The antiadherent also stops the powder from sticking to the equipment as the tablet is being made.
Flavour:	Flavouring agents help to make the tablet taste better.
Colourant:	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.

Several categories of tablets for oral use may be distinguished:

• uncoated tablets;
• coated tablets;
• effervescent tablets;
• soluble tablets;
• dispersible tablets;
• orodispersible tablets;
• gastro-resistant tablets;
• modified-release tablets;
• Tablets for use in the mouth.

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

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. 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.

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.

Wet granulation:

This is the most widely used and most general method of tablet preparation. Its popularity is due to the greater probability that the granulation will meet all physical requirements for the compression of both tablets

Dry granulation:

This process is applied for those drugs which are sensitive to moisture. This process is also used for water sensitive powder that needs granule formation before compression.

FLOW CHART OF GRANULATION PROCESS

Wet granulation

Dry 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.

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	Purpose
1.Planetary mixer-60 kg, Gansons, India.	To mix the active ingredient and binder to form granules.
2.FBD-1-10 kg, Alliance Eng. Co.     India	To Dry granules.
3.Multi mill-1	To reduce the size of granules.
4.Double cone Blender	To mix uniformly all the excipients.
5.Tablet oscillating Granulator	To reduce the size of granules.
6.Paste Kettle	Preparation of slurry

Tablet Processing unit: 2

Name of the machines	Purpose
1.RMG– 160 kg, Saral ENG. Company LTD.	To mix the active ingredient and binder to form granules.
	To Dry granules.
2.Y- cone and Double cone blenders.	To mix the processed granules with lubricating agents.

 

Rapid mixing granulator(RMG)	Fluid bed dryer
multi milleer	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

Direct 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

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

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),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 Pre-compression 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

Models available in 16 Stn. /20 Stn./23 Stn. Tablet Compression Machine Design as per cGMP Standards Suitable for Medium Batch Size Optional Force Feeder and AC Frequency Drive for Turret Drive Available in D & B Tooling Safe and simple to operate and easy to maintain.

Common Problems that arise during Compression:

• Capping
• Chipping
• Sticking
• Weight variation
• Mottling
• Hardness problem
• Lamination

TABLET Coating:

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 film-coated 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:

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 Coating-

1. Sealing
2.  Subcoating

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

FIGURE: Sugar coating and Film coating machines.

1.       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.

1. 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.

 

1. 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

 

1. 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

 

1. 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.

 

1. 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.

 

1. 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

1. 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)

1. 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.

Capsule preparation

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
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Encapsulation
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For encapsulation of powder,

Blending
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Slugging
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Granulation
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Sieving
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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
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Filling of powder
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Rejoining of caps of the shells
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Encapsulation
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Sorting of Capsules
¯
Polishing of Capsule

Machinery:

Machine name	Machine specification	Manufacturer	Origin
Semi automatic Capsule filling machine	Capacity: 15000-17000/hr Capsule  fill	P+am pharmaceuticals	India
Automatic Capsule filling machine	Capacity: 30000/hr Capsule fill	Hanli	Korea
Automatic Capsule filling machine	Capacity:90000/hr Capsule fill	Se jong	Korea
S.S.Drum -Blender	Capacity: 200 kg	Gansons	India.
Charge Vat	Capacity: 50 kg	Myth	Bangladesh
Capsule polishing machine		P+am pharmaceuticals	India
Hand fill machine	Capacity:8000/hr	Pharmachem	India

Figure: Capsule filling machine.

• Dry Syrup

Dry syrup at Aristo Pharma Ltd is manufactured in a method namely,

• Direct Mixing,

1. 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

1.   Machines used in the Dry Syrup Manufacturing unit:

 

Name of the Machine	Function
Double cone Blender	Blending/Mixing
FITZ Mill	Crushing/ Milling
Dust Collector	Removal of dust
Bottle Filling Machine	Filling of Dry Syrup
Bottle Sealing Machine	Sealing of Dry Syrup Bottle

 

1. Condition for manufacturing Dry Syrup:

         Relative Humidity: Not more than 45%.
         Temperature: Below 25⁰
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	Machine specification	No. of Machine	Manufactured by	Origin
Automatic Blister Pack machine	Capacity: 80000/hr	1	Buchon	Korea
Automatic Blister Pack machine	Capacity: 72000/hr	1	Buchon	Korea
Automatic Blister Pack machine	Capacity: 60000/hr	1	Buchon	Korea
Automatic Blister Pack machine	Capacity: 90000/hr	1	Hoong-A	Korea
Automatic Blister Pack machine	Capacity: 82000/hr	1	Hoong-A	Korea
Automatic Blister Pack machine	Capacity: 60000/hr	2	Elmapack	India.
Strip Packing machine	Capacity: 120000/hr	1	Gansons	India.

Primary Packaging Materials

Materials	Sources
Polyvinyl Chloride [PVC], (PVC/PVC) Polyvinylidine chloride [PVDC], Aluminium  Foil	korea India, Korea, Bangladesh

Different parts of a blister pack machine:

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:

• Blister packaging:

We observed the blister packaging of Napa tab. (Paracetamol)

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

Feeding  problem – Chute channel Gate transfer Spiral Brush

 

• Strip packaging:

We observed the strip packaging of ……….. (………..)

• In-process check:

1. Observation no.
2. Leak test
3. Room condition

1. Temperature & humidity
2. Segregation of bulk materials/finished packs
3. Product identity
4. line, display board
   1. Aluminum foil leaving in machine and stock
   2. Number of individual strips/blisters checked
   3. Number of finished products checked
   4. Quality and identity of components complient slip/labels/cartons/leaflets/outer labels/outer box/ spoon
   5. Identity and appearance of product in packs
   6. Quantity: No./volume/weight
   7. Overprinting/embossing: batch no./MFD/Exp date/MRP
   8. Label/carton with product name, batch no., Mfg date, price. Exp date

 

1. 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

Aristopharma is now manufacturing defferent types of sterile dosges form including ophthalmic eye drop,eye ointment,eye cream, nasal drop ,ear drop,as well as IV and IM injection .Recently they are going to launch their MDI and lyophilized product.They have a future plan for manufacturing of Insulin and aminoacid product.

Commonly the small volume parenteral or injectable products are filled in-

• Ampoules
• Vials

Generally the products are manufactured by two ways:

• Aseptically Sterilized
• Terminally Sterilized

 

1. Injectable Products in Ampoule:

 

Injectable Products are dispensed in ampoules following the procedure given below- 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 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
Dry Heat Sterilization (DHS)	180	3	1.1	Vials
	220	2.5	1.1
	250	1	1.1
Steam Sterilization /Autoclave	121	0.5	1.1	Ampoules, Gloves, Filters, Gourmets

v  Equipment

Sound protector,  Mask, Surgical gloves, Cap, Apron, Electric Balance.
v  Accessories

      Dust collector.
      SS Vat charge.
      SS Jug.
      SS funnel.
      Perforated tray.

1. Specialized location

The processes are done in fully aseptic area.

1. Production process flow

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	<1	NMT 100	0
1000	NMT 10	NMT 1000	NMT 7
10,000	NMT 100	NMT 10,000	NMT 70
1,00,000		NMT 1,00,000	NMT 700

 

 

o   Category of different vial processing area

 

Area	Clean room standard
Filling point	100
Filling room	1,000
Vial washing & sterilization room	10,000
Filling room corridor	10,000
Fabrics change room	10,000

 

 

 

 

 

 

A preparation of vial involves the following steps:

 

Vial Sorting

Vial Washing

 

Vial Sterilization

 

Vial cooling

 

Powder filling

 

Rubber capping

 

Alu-sealing

 

Labeling

 

Blistering

Packaging

v  Category of different ampoule processing area:

 

Area	Clean room standard
Filling point	100
Filling room	1,000
Mixing room	10,000
Filling room corridor	10,000
Fabrics change room	10,000

 

1. Zonal Classification of Clean Rooms & Respective Air pressure:

 

Zone	Class of Environmental Cleanliness	Air pressure (Pascal)
Under Laminar Airflow	A	NLT 40
Filling zone	A	40
Sealing zone	B	40
Filtration room	B	30
Change Rooms	C	15-30
Ampoule cooling room	C	20
Ampoule storing room	D	10

 

·         Machinery

Machine Name	Manufacturer	Origin
Semi automatic bottle filling machine	Ming pen Machine CO	Taiwan
Semi automatic cap closer machine	MP-VS-OL	Taiwan
Semi automatic infusion cap sealing machine	Ming pen Machine CO	Taiwan
Ampoule filling & Sealing machine	Ming Pen Machine CO	Taiwan
Automatic Steam Sterilizer	Sturdy industries Ltd	Taiwan
Dry heat sterilizer	Indo-German	India
Dry heat sterilizer	Myth indries	Bangladesh
Charging vessel	Kothari	India
142 mm filtration unit	Satorius	Germany
293 mm filter unit	Satorius	Germany
Washing Machine	Chung MachineryCO	Taiwan
lyophilized
Meter dose inhelar

Fig:Ramaco MDI filling ,sealing machine

Fig:  Lyophilization process.

Liquid preparation

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 0.5m Cartridge filter.
¯
Filling, Flushing of Nitrogen (N₂)
& Sealing of Bottles (glass or pet) containing oral liquids

1. Machines used in the Oral Liquid Manufacturing unit:

Name of the Machine	Function	Capacity
Steam Jacketed Vessel	Mixing	1000 Liter
Charge Vessel	Manufacturing	2000 Liter
Storage Vessel	Storage	2000 Liter
Cartridge Filter	Filtration	–
Bottle Filling & Sealing Machine	Filling & Sealing of Oral Liquid Bottles	2500 bottles /hour

 

1. 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

 

Packagin

      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:                                             Sealing

 

• General Process of manufacturing Ointments:

	Oil Phase-I			Oil Phase-II

 

 

·         Machinery

Machine Name	Specification and Origin
Automatic tube filling machine	Precitech industries,india
Automatic tube filling machine	Pharmachem machinaries,india
Collioid mill	Cadmach ,India
Charging vessel	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.

• Fully separated, well established and isolated manufacturing area only for Cephalosporin.
• Highly sophisticated HVAC system and AHU are used to condition, monitor and supply clean air to the working zone.
• 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 refers to a program for the systematic monitoring and evaluation of the various aspects of a project, service, or facility to ensure that standards of quality are being met.
It is important to realize also that quality is determined by the program sponsor. QA cannot absolutely guarantee the production of quality products, unfortunately, but makes this more likely.
Two key principles characterize QA: “fit for purpose” (the product should be suitable for the intended purpose) and “right first time” (mistakes should be eliminated). QA includes regulation of the quality of raw materials, assemblies, products and components; services related to production; and management, production and inspection processes.
It is important to realize also that quality is determined by the intended users, clients or customers, not by society in general: it is not the same as ‘expensive’ or ‘high quality’. Even goods with low prices can be considered quality items if they meet a market need. QA is more than just testing the quality of aspects of a product, service or facility, it analyzes the quality to make sure it conforms to specific requirements and comply with established plans.
The department is headed by Mr. Tushar Kanti Pal
Steps for Quality Assurance Process involve:

• Test previous article
• Plan to improve
• Design to include improvements and requirements
• Manufacture with improvements
• Review new item and improvements
• Test new item

The process for Quality Assurance is very rigorous and requires a lot of testing and planning. The team or firm has to comply with previous requirements, implement new requirements and improve the old item. Other than following requirements, the team or firm has to comply with consumers needs.

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.

In AristoPharma LTD, Quality Assurance supervises Quality Control, Quality Compliance, and Product Development.
QUALITY CONTROL:

Quality control is a process by which entities review the quality of all factors involved in production. It 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.
A total quality control system involves:

Responsibilities of QC department:

• 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 Ön+ 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.

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.

• Includes: Moisture analyzer, mechanical shaker, magnetic stirrer, hardness tester, polarimeter, digital viscometer, ultrasonic bath, friability tester, Karl Fischer Titrator, Dissolution Machines, Disintegration tester, Hot air oven, water bath, Centrifuge machine, osmometer, melting point apparatus, 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, a-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.

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.

QUALITY COMPLIANCE:

Quality compliance monitors cGMP to ensure that products and consistently produced and controlled to the quality standard appropriate to the product specification. It has two major functions:

• Performing non – analytical functions
• To make sure all the conditions are ensured

Customer related targets:

• Product must not return for quality
• On time delivery
• Reduce customer complaint

In house targets:

• Sales growth
• Productivity

Material control:
Evaluations are done on the basis of the ratio, 30:50:20

·         If the total mark for the product is above 80, it is accepted

·         If the mark is 70-80, the supplier is told to improve quality

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

PRODUCT DEVELOPMENT:

It is a combination of all the sectors in the pharma industry, sometimes termed as “A Factory Inside a Factory”, which emphasizes on:

• Formulation development: the product development department develops a formulation and manufactures the product on a laboratory scale.
• Analytical Method Development: 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.
Thiey 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.

Working flow sheet of PD&V department for new product development:

 

Machineries:

Name		No. of  Machine	Source
Tablet compression machine		1	India
Fluid bed dryer		1	India.
Multimill		1	India
HPLC (High Performance Liquid Chromatography)		2	Japan
UV-1610PC. Spectrophotometer(Shimadzu)		1	Japan
Magnetic stirrer		1	China
Dissolution Machine (Electro lab.)		2	Germany
Hot air oven		2	U.S.A
Hanna PH Meter		1	Japan
Water bath		1	Bangladesh
Humidity chamber		2	U.S.A
Disintegrator tester		1	Germany
Friability tester	1		Germany
Electronic balance	1		Japan
Double cone mixture	1		Germany
Planetary mixture	1		U.S.A
Wet granulator	1		India
Moisture analyzer	1		U.S.A
Drying oven	1		Germany

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 test-

1. 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	Origin
Eyela autoclave	Japan
Incubator for fungus	India
Laminar air flow(2)	Indian, Taiwan
hot air oven	Germany
Royco (air borne particle counter)	U.S.A
Climet (liquid borne particle counter)	U.S.A
Mark 102 (air sampler)	Germany
Pyrogen tester	Denmark
Sterility tester	Germany
Microscope	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

• In microbiological section generally assays the liquid and semisolid preparations such as  suspension. Syrup, cream, ointment and gel are analyzed for microbial load.
• 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.

1. 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.
• 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.

 

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.

Boiler machine

Name: Cochran
Country: Scotland.
Capacity: 300 Kg per hour.

ETP plant:

Chiller

There are three chillers.
Model: LS
Country: Korea
Capacity: 250 Kg per hour.

Mechanism of chiller:

Lithium-Bromide heated

 

Produce vapour

 

Suck distilled water

 

Produce cool water

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

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).
WARE HOUSE

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.

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 Sodiumn 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.

FEFO

The term FEFO stands for First Expire 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 Ön+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.