Report on Solid Department of ARISTOPHARMA LTD
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. Total Units in Solid Department
Manufacturing area
Granulation unit
Packaging area
Compression unit
Coating unit
Capsule filling unit
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
Disintegrant:
Binder: Glidant: Lubricant: Antiadherent:
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. Disintegrants help the tablet to break down into small fragments, when it is ingested. This helps the medicine to dissolve and be taken up by the body so that it can act more quickly. Disintegrants may include potato or cocoa butter. A binder, such as glucose or sucrose, is added to hold the tablet together after it has been compressed, stopping it from breaking down into its separate ingredients. The glidant helps to keep the powder making up the tablet flowing as the tablet is being made, stopping it from forming lumps. Lubricants ensure that the tablet has a smooth surface and that the powder does not stick to the equipment used to make the tablet. The antiadherent also stops the powder from sticking to the equipment as the tablet is being made.
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 Weighing of active ingredient as well as excipients ↓ Dry mixing ↓ Wet mixing (in case of wet granulation) by addition of de-mineralized (DM) water or Maize starch paste in Rapid Mixer Granulator (RMG) for a certain time period specified in the Batch Production Record (BPR) ↓ Initial Phase drying in Fluid Bed Dryer (FBD) ↓ Milling in the Multimill ↓ Partial drying in FBD ↓ Milling in the Multimill ↓ Terminal/Final drying in the FBD ↓ Sieving in the Vibratory Sifter according to the required particle/granule size ↓ Measurement of Loss on Drying (LOD) ↓ Granules of desired size ready for blending.
Dry granulation Weighing of drugs and excipients Dry mixing of drugs and diluents Slugging or pre-compression Milling and sieving Lubrication Discharge for compression
•
Condition for manufacturing of Granules:
Relative Humidity: Not more than 55%. Temperature: Below 250C.
MIXING & BLENDING:
A powder blend should be as uniform as possible to assure the proper amount of medication in each dosages unit. The blending of solid particles is affected by the shape, density, size and size range of the particles, and surface effects such as absorbed liquid film, electrostatic charges and Van der Waals forces. Small particles are difficult to blend because they exhibit poor fluidity. However, more important than actual particle size is particle size range. All drugs and chemicals should be reduced to approximately the same size prior to weighing and mixing. MACHINERY: Tablet Processing unit: 1 Name of the machines 1.Planetary mixer-60 kg, Gansons, India. 2.FBD-1-10 kg, Alliance Eng. Co. 3.Multi mill-1 4.Double cone Blender 5.Tablet oscillating Granulator 6.Paste Kettle
India
Purpose To mix the active ingredient and binder to form granules. To Dry granules. To reduce the size of granules. To mix uniformly all the excipients. To reduce the size of granules. Preparation of slurry
Tablet Processing unit: 2 Name of the machines
Purpose
1.RMG– 160 kg, Saral ENG. Company 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 lubricating agents.
granules
with
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 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 ↓
Direct Compression Milling & Screening of active ingredient/s & the excipients ↓ Mixing of the active ingredient/s along with excipients including lubricants & disintegrants ↓ Transfer of mixer in the hopper of tablet press machine by hand or auto powder loader ↓ Rising of upper punch & dropping of lower
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
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: Coating Sugar coating
Film coating
Aqueous coating
Enteric coating
Organic coating
1. Sugar Coating:In suitable sugar- coating equipment, the tablet cores are successively treated with aqueous sucrose
solutions which, depending on the stage of the coating reached, may contain other functional ingredients e.g. fillers, colors etc. The build up of coating material is due to transference of coating medium from one tablet to another. Typically a single liquid application will be made which will be allowed to spread over the entire tablet bed utilizing the mixing capability of the particular equipment. At this point, drying, usually in the form of heated air will be used t o dry the application. The whole cycle will then be successively repeated. Stages Of Sugar Coating1. Sealing 2. 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 Organic Aqueous
Inlet 750c 60/650c
Outlet 650c 50/550c
→ 200 kg coating machine containing spray guns. → 110 kg coating machine containing spray guns → 100,70, 20 kg coating machine containing spray guns 3. Enteric coating There are two steps for enteric coating → Sub-coating: Sub coating is performed by using HPMC as polymer with either organic or aqueous solution. This process performs for 5 hours. → Enteric coating: Enteric coating is performed by using eudragit L-100 or L-50 over the sub coating. This is done for 15 hours. Machines used for both Film & Enteric Coating: Name of the Machine
CAPACITY
NR-COTA (FC) TC-TC9. NR INDS. THAILAND. ECO COTA TC-TC2 F D & C Pvt. LTD. PAKISTAN SUGAR COATING PAN, BANGLADESH & INDIA. RAMA COTA (EC) TC-TC-1 RAMA PROD. COM. LTD. N R COTA 2 TC TC-11, NR INDS. THAILAND
90-110 KG. Max:100 KG Max:70 KG Max:20 KG Max:200 KG
FIGURE: Sugar coating and Film coating machines.
Condition required during Coating: • •
Relative Humidity: Not more than 50%. Temperature: Below 250C.
COMMON PROBLEMS ASSOCIATED WITH TABLET COATING: 1. Logo bridging
Cause: • • •
Surface characteristics of the product being coated Inadequate adhesion of film coating Inadequate design of logo (e.g. too detail/fine logo)
Remedy: • • • •
Modify core formulation to include more hydrophilic ingredients Increase core porosity 0Using formulation with increased adhesion property. Increase area within the debossing and modified angles.
2. Core erosion
Cause: • • • •
Inherent softness or high friability of core. Excessive pan speed in coating process. Spray rate too low. High sensitivity of core to moisture as coating is applied.
Remedy: • • •
Increase mechanical strength of core. Decrease pan speed. Increase spray rate.
3. Edge chipping/erosion
Cause: • • • • • •
Low mechanical strength of coating Excessive pan speed Low solid content in coating liquid Low spray rate Sharp edges on tablets Worn tablet punches
Remedy: • • • • •
Using formulation with increased mechanical strength Decreased pan speed Increase solid content in coating liquid Decrease spray rate Use modified punch design
4. Picking/sticking:
Cause: • • • • •
Spray rate too high Inadequate drying condition Pan speed too low Inadequate atomization of coating liquid Poor distribution of coating liquid
Remedy: • • • • •
Decrease spray rate Increase drying condition Increase pan speed Increase atomizing air pressure/volume Increase number of spray gun
5. Cracking
Cause: • • •
Low mechanical strength of coating, exacerbated by inadequate plasticization, excessive pigmentation. Core has significantly different thermal expansion characteristics than coating. Extended strain relaxation of core after compaction.
• • •
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.
Remedy:
6. Peeling
Cause: • •
Low mechanical strength of coating Poor adhesion of coating to tablet surface
Remedy: • •
Using ingredients of improved mechanical strength. Using ingredients with improved adhesion properties.
7. Orange peel/roughness
Cause: • • • •
Viscosity of coating liquid is too high Poor atomization of coating liquid Excessive drying condition Over wetting (causing coating too rub)
Remedy: • • • •
Decrease solid content of coating liquid Increase atomizing air pressure/volume Decrease inlet air temperature/flow rate Decrease spray rate
8. Twinning
Cause: • • •
Spray rate too high Pan speed too low Inappropriate tablet shape
Remedy: • • • •
Decrease spray rate Increase atomizing efficiency Increase pan speed Select new tablet shape that decrease chances of flat surfaces coming into contact during application of coating liquid. (e.g. avoid capsule shape tablet with thick side wall)
9. Tablet-to-tablet color variation
Cause:
• • • • •
Too little coating applied Inadequate mixing of tablet during coating Poor opacity (or hiding power) Solid content of coating liquid too high Insufficient number of spray gun
Remedy: • • • • •
Increase quantity of coating applied Increase pan speed/increase improve baffle system Reformulate coating with respect to colored ingredients or use an opacified white precoat. 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 ↓ Encapsulation ↓ For encapsulation of powder, Blending ↓ Slugging ↓ Granulation
↓ Sieving ↓ Encapsulation Encapsulation Process by Manual Capsule Filling Machine by Hand: For encapsulation of powder the following procedure is done with the help of Manual Capsule Filling Machine by hand in the capsule filling units of the industry: Loading of capsule in the loading plate ↓ Removal of caps of the shells ↓ Filling of powder ↓ Rejoining of caps of the shells ↓ Encapsulation ↓ Sorting of Capsules ↓ Polishing of Capsule Machinery: Machine name Semi automatic Capsule filling machine Automatic Capsule filling machine Automatic Capsule filling machine S.S.Drum -Blender Charge Vat Capsule polishing machine Hand fill machine
Machine specification Capacity: 1500017000/hr Capsule fill Capacity: 30000/hr Capsule fill Capacity:90000/hr Capsule fill Capacity: 200 kg Capacity: 50 kg
Manufacturer P+am pharmaceuticals
Origin India
Hanli
Korea
Se jong
Korea
Gansons Myth P+am pharmaceuticals
India. Bangladesh India
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,
Flow chart for Direct Mixing for the manufacturing of Dry Syrup: Crushing the sucrose in FITZ mill at 3000 rpm ↓ Transfer of half portion of sucrose from step-1 into a double cone blender by passing through a 20 mesh screen ↓ Transfer of all other excipients in the blender to blend for 30 minute ↓ Transfer the mix from the double cone blender by Passing through a 20 mash screen
Machines used in the Dry Syrup Manufacturing unit:
Name of the Machine
Function
Double cone Blender FITZ Mill Dust Collector Bottle Filling Machine Bottle Sealing Machine
Blending/Mixing Crushing/ Milling Removal of dust Filling of Dry Syrup Sealing of Dry Syrup Bottle
Condition for manufacturing Dry Syrup: •
Relative Humidity: Not more than 45%.
• Temperature: Below 250 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. o
Purpose of packaging: • • • • •
To increase the acceptability of the drug To increase the stability of the drug To minimize the transport/shipping hazards To improve patients compliance To improve the pharmaceutical elegance by use of special color or Contrasting printing
At Aristopharma Limited, two types of combination is used depending on the upper & lower layers as well as product requirement. They are;
• •
PVC-Aluminium Blister Aluminium -Aluminium Blister Besides blister packaging, at Aristo Pharmaceuticals Limited, other packaging includes;
• • • • • •
Striping Filling of tablets &capsules in bottles Labeling of bottles Secondary Packaging (Both on-line & off-line) Packaging of Ampoules Packaging of Vial
Packaging machineries: Machine Name Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Automatic Blister Pack machine Strip Packing machine
Machine specification Capacity: 80000/hr Capacity: 72000/hr Capacity: 60000/hr Capacity: 90000/hr Capacity: 82000/hr Capacity: 60000/hr Capacity: 120000/hr
No. of Manufactured by Machine 1 Buchon
Origin
1
Buchon
Korea
1
Buchon
Korea
1
Hoong-A
Korea
1
Hoong-A
Korea
2
Elmapack
India.
1
Gansons
India.
Korea
Primary Packaging Materials Materials
Sources
1. Polyvinyl Chloride [PVC], (PVC/PVC)
korea
2. Polyvinylidine chloride [PVDC],
India,
3. Aluminium Foil
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)
PVC sheet
Heating plate
Foil soften by hot plate Temp. 125-145°C
Passed through desired dies plate which is kept cold & air pressure is applied to make pocket for small time & desired shape is resulted (air pressure 6-8 bar)
Alu-alu foil with Pressed by two plates simultaneously properly labeled (upper plate temp. 160-180°C for PVC & lower plate is cold
Passed through cutter
Tablets or capsules are filled into the pockets
Desired blister pack
Trouble shooting:.
Preheating problem – malleability Forming problem Sealing problem Slitting problem – perforation Loading problem Air pressure Scanner problem Emboss problem Heat exchanger
Feeding problem – channel transfer
Chute Gate Spiral Brush
Strip packaging: We observed the strip packaging of ……….. (………..)
Tablets or capsules in hopper
Tablets/capsules in vibrating disc
Hot roller having particular dies shape
Pressing
Strip packaging •
In-process check:
Enter through tode channel
Tablets or capsules enter between two alu roll strips
Poly-coated alu rolls (coated with plastic materials) come from two sides
1. Observation no. 2. Leak test 3. Room condition a) Temperature & humidity b) Segregation of bulk materials/finished packs c) Product identity d) line, display board 5. Aluminum foil leaving in machine and stock 6. Number of individual strips/blisters checked 7. Number of finished products checked 8. Quality and identity of components complient slip/labels/cartons/leaflets/outer labels/outer box/ spoon 9. Identity and appearance of product in packs 10. Quantity: No./volume/weight 11. Overprinting/embossing: batch no./MFD/Exp date/MRP 12. Label/carton with product name, batch no., Mfg date, price. Exp date
Secondary Packaging (Both on-line & off-line): Secondary packaging includes-
•
•
Unit Cartooning with -Container -Leaflet -Spoon/dropper (in case of liquid) -Security seal/Hologrammed Seal Master Cartooning with - Unit cartoons
Sterile Department
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
Injectable Products in Ampoule: Injectable Products are dispensed in ampoules following the procedure given belowAmpoule De-boxing ↓ Ampoule washing ↓ Sterilization (in case of aseptically filled ampoules) ↓ Ampoule filling (under laminar air flow) ↓ Ampoule Sealing ↓ Terminal Sterilization ↓ Ampoule Inspection ↓ Sealed Ampoules
•
Ampoule Washing: Sequence of “wash” by Ampoule Washing Machine:
DM water (inner-outer) → Compressed air spray → Distilled water → WFI •
Ampoule Filling & Sealing (under laminar air flow): Ampoule on the filling belt ↓ N2 flush → Filling → N2 flush → Sealing by flame → Ejection (O2: LPG-1: 10)
•
Ampoule Inspection: o o o
•
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 (DHS)
Steam /Autoclave
Sterilization
180
3
1.1
220
2.5
1.1
250
1
1.1
0.5
1.1
Sterilization 121
Vials
Ampoules, Gloves, Filters, Gourmets
Equipment Sound protector, Mask, Surgical gloves, Cap, Apron, Electric Balance. Accessories • • • • •
Dust collector. SS Vat charge. SS Jug. SS funnel. Perforated tray.
Specialized location The processes are done in fully aseptic area. Production process flow Manufacturing of injectable preparations require a clean room which should have the following standard Class
Cfu/m3
Particle of micron/ft3
100 1000 10,000 1,00,000
<1 NMT 10 NMT 100
NMT 100 NMT 1000 NMT 10,000 NMT 1,00,000
o
0.5 Particle micron /ft3
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
0 NMT 7 NMT 70 NMT 700
of
5
o
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 ď ś Category of different ampoule processing area: Area Filling point Filling room Mixing room Filling room corridor Fabrics change room
Clean room standard 100 1,000 10,000 10,000 10,000
ď ś Zonal Classification of Clean Rooms & Respective Air pressure: Zone
Class
Under Laminar Airflow Filling zone Sealing zone Filtration room
A A B B
of Environmental Cleanliness
Air pressure (Pascal) NLT 40 40 40 30
Change Rooms Ampoule cooling room Ampoule storing room
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C C D
15-30 20 10
Machinery
Machine Name Semi automatic bottle filling machine Semi automatic cap closer machine
Manufacturer Ming pen Machine CO MP-VS-OL
Origin Taiwan Taiwan
Semi automatic infusion cap sealing machine
Ming pen Machine CO
Taiwan
Ampoule filling & Sealing machine Automatic Steam Sterilizer Dry heat sterilizer Dry heat sterilizer Charging vessel 142 mm filtration unit 293 mm filter unit
Ming Pen Machine CO Sturdy industries Ltd Indo-German Myth indries Kothari Satorius Satorius
Taiwan Taiwan India Bangladesh India Germany Germany
Washing Machine lyophilized Meter dose inhelar
Chung MachineryCO
Taiwan
Fig:Ramaco MDI filling ,sealing machine
Fig: Lyophilization prosses.
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 0.5µ Cartridge filter. ↓ Filling, Flushing of Nitrogen (N2) & Sealing of Bottles (glass or pet) containing oral liquids
Machines used in the Oral Liquid Manufacturing unit:
Name of the Machine
Function
Capacity
Steam Jacketed Vessel Charge Vessel Storage Vessel Cartridge Filter Bottle Filling & Sealing Machine
Mixing Manufacturing Storage Filtration Filling & Sealing of Oral Liquid Bottles
1000 Liter 2000 Liter 2000 Liter 2500 bottles /hour
Condition for manufacturing of Oral Liquids: • •
Relative Humidity: Not more than 55%. Temperature: Below 300
In the packaging unit, filled & sealed bottles are sequentially→ Labeled → Packed with an insert in the intermediate carton → Finally packed in master carton. Steps involved in Suspension Preparation: Dispersion of suspending agent Transfer to compounding vessel containing sucrose solution Addition of drugs & other ingredient
Mixing with continuous stirring
Adjustment of final volume with purified water Filling & sealing
Packagin
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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.
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General Creams:
process
Water Phase
of
manufacturing
Oil Phase Sieving
Water phase to Oil phase in a Steam Jacketed Vessel
Blending by Mechanical Stirrer
Filling
Sealing
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General Process of manufacturing Ointments:
Oil Phase-I
Oil Phase-II
Oil phase-I to Oil phase-II in a Steam Jacketed Vessel
•
Machinery:
Machine Name Automatic tube filling machine Automatic tube filling machine Collioid mill Charging vessel
Specification and Origin Precitech industries,india Pharmachem machinaries,india Cadmach ,India Mythindustries,Bangladesh
High speed emulsifier
India
Homogeniger
India
Transfer pump
U.S.A
Automatic labeling machine
Korea
Automatic liquid filling ,Cap Sealing and labeling machind
India
CEPHALOSPORIN FACILITY According to cGMP regulations separate facility for cephalosporin is required to prevent cross contamination with other penicillin products or non beta-lactum products. Unintended exposure with Cephalosporin products may cause health concern to patients sensitive to Cephalosporin. • • • • • • •
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 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.
controls and
In AristoPharma LTD, Quality Assurance supervises Quality Control, Quality Compliance, and Product Development.
Flow chart for Quality Assurance activity:
Receiving of raw and packaging materials by visual inspection
Attachment of quarantine with a yellow tag
Sampling of raw and packaging materials for QC Analysis
Release/Rejection
Dispensing of raw and packaging materials
Checking of cleanliness, approval of equipment and area of manufacturing
In process checking
Transfer of finished product for distribution after collecting the retention sample
Investigation of product complaints, recalls, etc.
Attachment of respective tags for raw and packaging materials
Sampling of in-process product to Q.C
In process checking of packing operation
Organ gram of the Department: Director of Production
QA Manager
QC Manager
Senior Officer
Officer
Lab Assistant
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 perform the tests.
•
Preserves retention sample for exp. date + 1 year.
•
Availability of written procedures/instructions/ forms for routine works
Batch analysis test •
Appearance.
•
Identification.
•
Average weight.
•
Uniformity of weight.
•
Disintegration time.
•
Melting point.
•
Resistance to rupture.
Manufacturing instruction •
Sample identification.
•
Raw material sampling information.
•
GRIR from warehouse.
•
Batch analysis data sheet.
•
For active material, all of the containers are sampled.
•
For excipient, sampling done by √n+ 1 rule, where n = total number of container.
•
For sterile products, sampling done aseptically before filling and sealing.
•
Forms for routine work
•
Sampling intimation form.
•
Batch analysis report.
•
Batch analysis data sheet.
who
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. Quality of Raw Materials: The audit for the quality of raw materials is described in the following chart:
2, 5, 10g sample is taken from vendor and tested for quality
Specifications are available for all the raw materials, packaging materials finished materials, etc.
If approves, visit vendor to make sure GMP guidelines are followed
If approved, 3 batches of product is bought and tested
The Batches are received in the warehouse, and GRN is filled
Identification of sample via tests, according to the specifications
Sample is taken in a sample container with a suitable sampling label
Machineries in QC Department: HPLC Machines: Models: DGA-20A3 x 3; SPC-10A Manufacturer: SHIMADZU
Gas Chromatography Machines: Model: GC-2010 Manufacturer: SHIMADZU
UV Machines: Model: UV-1700 Manufacturer: SHIMADZU
Atomic absorption spectrometer: Model: AA-6800F Manufacturer: SHIMADZU
Total Carbon Analyzer Model: TOC-VCPH Manufacturer: SHIMADZU
Fume hood Models: ST1500ABP, ST1800ABP Manufacturer: LabGuard
Fourier-Transform Infra-Red Spectrophotometer Model: FTIR-8400S Manufacturer: SHIMADZU
Others 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, α-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.
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Validates the product formulation.
Working flow sheet of PD&V department for new product development: Product Management Department (PMD)
PD makes the first 3 commercial batches
Prepares New Product Proposal Form, which only contains Generic name
Send to head office to approve price
Provided to the PD Department by the PMD
Send annexure to Drug Administration to get D.A.R. Number
PD prepares a recipe, which contains pharmacodynamics, pharmacokinetics, and a tentative formulation
Provide length/width/height for the packaging department
PD notifies commercial dept. for raw materials
Perform accelerated stress test
Commercial dept. acquires raw materials and QC analyzes them
If passes, PD dept. prepares a formulation and a subsequent dosage form
Check for any problems with the dosage form Prepare an improved formulation to overcome the problems
Make a larger batch, add color, and send to marketing office for acceptability
Validate the method for accuracy, precision, and linearity
If sufficient equipments are not available, modify the procedure Develop a method for analysis, according to that of BP/USP
Machineries: Name Tablet compression machine Fluid bed dryer Multimill HPLC (High Performance Liquid Chromatography) UV-1610PC. Spectrophotometer(Shimadzu)
No. of Machine 1 1 1 2
Source India India. India Japan
1
Japan
Magnetic stirrer Dissolution Machine lab.) Hot air oven Hanna PH Meter Water bath Humidity chamber Disintegrator tester Friability tester Electronic balance Double cone mixture Planetary mixture Wet granulator Moisture analyzer Drying oven
1 2
China Germany
2 1 1 2 1 1 1 1 1 1 1 1
U.S.A Japan Bangladesh U.S.A Germany Germany Japan Germany U.S.A India U.S.A Germany
(Electro
MICROBIOLOGY SECTION Microbiology section is one of the vital section of any pharmaceutical to ensure quality product. The microbiology section of QC department in Aristopharma Ltd is a well-decorated and segregated area that evaluates microbial load and particulate matter of both raw materials and finished product particularly sterile products. It includes the following test1. Microbiological assay of raw materials and finished products 2. Limit test of liquid preparations for the pathogenic organisms like Pseudomonas aerogenosa, Escherichia Coli, Staphylococcus aureous. Salmonella species. 3. LAL test for injectable preparations.
o
Availability of written procedures :
o
•
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.
o
Machinery:
Machine Name Eyela autoclave Incubator for fungus Laminar air flow(2) hot air oven Royco (air borne particle counter) Climet (liquid borne particle counter) Mark 102 (air sampler) Pyrogen tester Sterility tester Microscope
Origin Japan India Indian, Taiwan Germany U.S.A U.S.A Germany Denmark Germany China
Figure: Laminar Air Flow Bench. o
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. o
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.
o
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.
o
Reagents and glass ware management :
o
•
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. o
Bioassay:
Antibiotic media no 01 and antibiotic media no 11 are used for bioassay. o
Buffer solution : - Potassium dihydrogen orthophosphate. - Dipotassium hydrogen orthophosphate. - Disodium hydrogen orthophosphate.
o
Glass ware management :
Petridish, separating funnel, pipette, volumetric flask, test tube etc are to be used with extra care. Particulars of in-process check : •
Weight and volume check of product.
•
Cleanliness of production area.
•
Preparation of apparatus, media, buffer solution and saline water according to instruction.
•
Preparation of culture organism.
•
Preparation of assay plate.
•
Dilution of the standard stock solution up to desired concentration.
•
Preparation of test solution.
•
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). Diesel Generator: Model: There are two diesel generators. Produce 500 KVA electricity per diesel generator. PDB: From PDB, get 100 KW electricity. Figure Generators
SDMO
Water treatment plant in APL: Earth water Vertical pump
Supply 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 µ Filter 0.2 µ filter D.M Water plant
2.5µfilter
0.2 µfilter
Mixed bed Exchanger Anionic Exchanger Cationic Exchanger
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 Hydrochloride.
L-Arginine,
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.
Ciprofloxacin
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 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.