Facility for making tablets

ABSTRACT

Tablet is the conventional and widely used oral solid dosage form. Tablet facility is though simple then than sterile facility, tablet facility has different hygiene zone areas for exposed products, products closed in a container and separate gowning area. This paper describes the detailed facility design for the coated and uncoated tablet with a block diagram, equipments used, its supplier and specification as per the need. It also includes the packaging line, utility system like HVAC, Water system and CIP system and its design. It has area wise movement for personnel and material through separate air lock with its layout and all the manufacturing areas has have fresh air from HVAC to avoid cross contamination. Ultimately this facility is meets the current good manufacturing practice cGMP and is in compiled with other governing codes, laws and regulations. and Finally, the facility is now ready to manufacture the tablet.

INTRODUCTION:

Pharmaceutical market comprises of wide variety varieties of dosage forms and tablet is one of the oldest dosage forms that is being has been used since many decades in the pharmaceutical industry. Global pharmaceutical market is mainly dominated by tablets because it has wide variety varieties of advantages like, :

1. Highest dose precision and lowest content variability
2. Relatively low cost as compare to other dosage form
3. Provides ease of manufacturing
4. Pleasant appearance to the patients
5. Ease in packaging and shipping
6. Enable self administration
7. Organoleptic properties like bad odor, taste and color can be masked by transforming drugs into tablet form.
8. Can be available in modified dosage form as extended, sustained and intermediate release etc.
9. Chemically, mechanically and microbiologically stable.
10. Special environmental specifications are not required in the tablet manufacturing like class 100, class 10,000.

The facility that we are going to discuss in this term paper is mainly dedicated to manufacturing of uncoated as well as coated tablets. This facility is capable of producing 500,000 tablets by wet granulation method. The facility is designed by taking consideration of cGMP and GEP. The facility mainly includes administrative office, manufacturing areas, QA and QC departments, warehouse for raw material and finished dosage form, utilities like HVAC, water system and other functions like cafeteria, rest room, and the gowning room.

Let’s start with brief process description of tablet manufacturing. Tablet manufacturing process includes the following steps:

1. Weighing of raw material
2. Sizing
3. Blending or Mixing
4. Granulation
5. Drying (In wet granulation)
6. Milling
7. Blending
8. Compression
9. Coating

Note: The bold or dark block in the figure indicates that process or steps like blending, compression and coating required in process quality control test (IPQC). These tests are carried out during manufacturing process to assure that the ongoing blend or material meets its pre specified specification as specified in master batch record.

EQUIPMENTS USED IN TABLET MANUFACTURING

WEIGHING EQUIPMENT:-

For drums and bins:-

After arrival of raw material in the facility, raw material is checked for its weight as per the ordered. For this operation we have selected CAS BW- 150 platform scale weighing equipment.

SPECIFICATIONS:

• Manufacturer: Central California scale sells and service
• Model number: CAS BW-150
• Type: Platform scale
• Capacity: 150* 0.1 lb
• Description: The display can be placed on a pole, a wall or a counter. It has various features like 1″ LCD display, switchable option between LB and Kg, powered by AC adapter and/or 6″C” batteries.

For production:-

Weighing is the first step involved in the manufacturing of the tablet. It is very important to weigh accurately active ingredient and other required excipients. For this step, we have selected Rice Lack IQ 2100 stainless steel bench scale manufactured by central California scale sells and service.

SPECIFICATIONS:

• Manufacturer: Central California scale sells and service
• Model number: IQ plus 2100 SL Digital Bench Scale
• Type: Bench scale
• Description: The display is large, bold 0.8″ light emitting diode (LED) display. It is constructed by stainless steel (SS 304). The display unit is available in decimal, lb, kg, oz and grams.

MILLING:-

Milling is the next unit operation and one of the most important unit operation after weighing of raw materials. As the raw materials are vary in the size so milling of raw materials is the necessary step in the tablet manufacturing. Besides that milling of raw materials has specific reasons like,

• To achieve uniform size of granules
• To achieve better flow property
• To provide proper particle size distribution
• To avoid powder segregation due to identical size of granules
• Milling enhance the surface area of particle and hence provide better rate of dissolution
• To improve content uniformity of tablet

For our facility we have selected FAS08 type of fitzmill made by FITZPATRICK, IL, USA

Principle of Working: – The fitzmil is working on the principle of the Impact or Cutting. So the material is feed fed by a hopper and it is then impacted by continuously rotating blade and then it is screened from the screen located at the bottom part of the mill.

SPECIFICATIONS:-

• Manufacturer:- Fitzpatrick, IL, USA
• Model Name:- FAS08
• Type:- Fitzmill
• Capacity:- 500 kg/hour
• Particle Size:- Able to produce 0.2 to 0.5 micron
• Motor Rating:- 15 HP
• Number of Blades:- 16
• RPM:- 4800
• Construction Material:- SS 316 and polished internal surface for ease of operation
• Other Important Features:-

1. Compact cGMP design
2. Spray nozzle provided for internal cleaning
3. Metered and gravity feed system available
4. Containment system for product is also available
5. Inbuilt pneumatic conveyor for raw material transfer
6. Output available for discharge valve

BLENDING:-

Blending is the next unit operation during tablet manufacturing which is followed by milling and shifting. As we know all single tablet contains active ingredients as well as excipients in wide ranges. So ,it is necessary that each tablet has appropriate and same amount of active ingredients and excipients and having with identical physical properties.

So, blending is carried out in manufacturing process to,

• To achieve homogenous mixture of active pharmaceutical ingredients and excipients
• To provide identical physical properties to each tablet
• To achieve proper flow of granules from hopper

For our facility we choose VB-500 blender (V- shaped) made by Unique Mixers and Furnaces, Mumbai, India.

Principle of working: – The V- shaped blender is best blender available in the market because it provides efficient mixing of ingredients. The V- blenders working on the principle of the bulk transport that means the material within the shell continuously collected at the bottom of the blender and then divided into 2 parts which provides uniform mixing of the API and excipients. In addition to that there is no blind spot during the blending. Our V- blender has following cGMP specification which is available in an ideal blender.

SPECIFICATIONS:-

• Manufacturer:- Unique Mixtures & Furnaces
• Model Name:- VB-500
• Type:- V-Blenders
• Capacity: – Working Capacity – 500 kg. and Total Capacity – 800 kg.
• Motor Rating:- 7.5 HP
• Construction Material: – SS 316 and Teflon coated on internal surface to improve flowability and hence reduce power requirement.
• Other important features:-

1. Intensifiers for delumping
2. Also offer vaccum application for material removal
3. Provides jacketed assembly for heating and cooling
4. Manually operated butterfly shaped material discharge valve
5. Easy to clean and maintained

DRYING AND GRANULATION6:-

These two unit operations are carried out in the same equipment in our facility as our fluid bed granulator can perform both activities in the same equipment. Both unit operations are necessary in the pharmaceutical industry as it exhibit their own importance in the manufacturing of tablets. Drying is carried out for following purpose in the pharmaceutical industry like,

• To reduce bulk and weight and hence reduces the cost of transportation and storage.
• To reduce the moisture level of product and hence reduces the chances of microbial contamination.
• Drying reduces the moisture and hence reduces the stickiness of ingredients and hence enhances the flow of ingredients from the hopper.

Granulation is the “HEART” of the tablet manufacturing process because granulation exhibit its own importance in the tablet manufacturing process like,

• Granulation enhance the compressibility of the powder material
• Granules have better flow property than powders
• Granulation does not allow formation of cake into the container.
• Granulation provides better content uniformity of API in to each tablet.
• Granulation enhances the resistance of API toward the atmospheric oxygen and moisture.

For our facility we have selected FL-300 fluidized bed granulator by Liaoyang Zhonglian Pharmaceutical Co. Ltd.

Principle of Working:- This equipment is working on the fluidized bed system as the flowing air suspend the particles in the assembly and the fluidized air(previously heated) absorbs the moisture from the surface of the particles and hence drying occurs. The granulation process is also follows the same manner of working principle.

SPECIFICATIONS:-

• Manufacturer: – Liaoyang Zhonglian Pharmaceutical Co. Ltd
• Model Name:- FL -300 Fluidized Bed Granulator
• Type:- Fluidized Bed Granulator
• Capacity: – 150 kg/hr to 550 kg/hr.
• Other Important Feature:-

1. Made from SS 316
2. Compatible with cGMP
3. Air Volume: – 7000 m3 / hr.
4. Air Pressure:- 950 mmH2O
5. Temperature Range:- Room Temperature- 120 degree Celsius
6. Material Recovery:- 99%
7. Noise: – Less than 75 db.
8. Motor Power:- 30 kw
9. Dimension:- 2.8m x1.9m x3.8 m

COMPRESSION:-

After granulation and mixing with other raw material, the final powder blend is carried out for next step that is compression. This step includes compression of material into its final dosage form tablet. For compression tablet press is used in industry. There are wide range of tablet press are available in market ranging from single press to double rotary press.

Here we have selected ACCURA PRESS IV- 75 tablet press for compression stage in our facility.

Double Rotary Tablet Press India, Double rotary tablet press manufacturers, Double rotary tablet press suppliers, Double rotary tablet press exporter, Double rotary tablet press exporters Double rotary tablet pressing machine exporter, Double rotary tablet pressing machine exporters, Double rotary tablet pressing machine India

SPECIFICATION:-

• Manufacture: Fluidpack
• Machine name: Accura press IV-75
• Type: Double rotary press
• Output: 108,000 to 540,000 tablets per hour
• Technical specification:

Salient Features:

1. Acura press is high speed rotary tablet press suitable for large batch production having higher tablet output.
2. Acura press is designed as per GMP standards having square design.
3. Acura press also has pre-compression facility.
4. Acura press has specially designed dust extractor that can be attached to dust extractor away from machine.
5. There is excellent bottom driven force feeding system for material feeding in Acura press and gravity type feeding provided optionally if wanted.
6. Acura press has front control at outside of the machine with SEIKP dials by which we can handle all tablet parameters fine tuned during manufacturing from outside tableting zone.
7. Acura press has box type detachable control panel with a electrical control on the top.
8. Acura press has hydraulic power pack with purpose of pressure loading and overload release.

COATING:-

After compression, tablets are subjected coating operation as per need. Coating of tablet is done for many reasons like for masking bitter taste of tablet, improve appearance of tablet and sometimes for delayed or modified release action for tablets.

For the coating purpose, we have selected VHL-60L Hi-Coater which is fully perforated tablet coating system by Vector Corporation.

SPECIFICATION:

• Manufacturer: Vector corporation
• Model Name: VHL-60L
• Type: Fully Perforated Hi-coater
• Volume Min/Max: 156-625 Kg
• Working Capacity: 500 kg
• Pan diameter: 1524 mm (60″)
• Spray Guns: 6
• Special features:

1. VHL-60L is designed and suitable for aqueous and solvent film coating processes. It also can be organized for optional sugar processing.
2. It is efficient, economical and designed for flexibility.
3. It has anti marking coating pans which has abrasion resistant perforations. Mirror-smooth finish and removable anti-slide baffles for cleaning.
4. It has anti bearding spray gun having no drip design with needle valve, precise control of atomization, pattern air for improved coating uniformity. The spray bar can be also easily removable for calibration.
5. It is designed for clean in place having streamline exhaust plenum for easy lifting and cleaning. It has continuous weld pan housing means have no seals and cracks.
6. The control system is easy to use with automatic and manual modes.

PACKAGING LINE: –

In the final stage of manufacturing the packaging is the most important unit operation and it should have appropriate number of automation so as to achieve speed as well as efficiency in the packaging. The packaging should involve primary, secondary and tertiary packaging and should also follow the cGMP guideline. The ideal packaging should involve unscramble, tablet counter, cotton inserter, capper, bottle sealer and labeler. Today wide range of packaging option available like blister package, bottle package, strip package but in the United States the bottle package is dominant one so here we have selected bottle package to be compatible with current pharmaceutical market.

We have selected TBU automatic packaging line made by Janetrustar Equipment Co. Ltd.

Specifications:-

• Manufacturer: – Janetrustar Equipment Co. Ltd.
• Model Name:- TBU automatic packaging line
• Type:- Bottle packaging line
• Capacity:- 100 bottle/ minute
• Other Important Features:-

1. Two producing line
2. Double conveying system
3. High speed packaging so suitable with other equipments
4. Counter is applicable for wide variety of tablets like coated, uncoated, soft and hard capsules.
5. The capper is suitable with different shape of cap like round, flat and square so it can use for any bottle design.
6. Pressure sensitive label is also part of this packaging line which is ideal for pharmaceutical facility.

Intermediate Bulk Container (IBC):-

Plastic Hopper Bins is the ideal Intermediate Bulk Container for the Pharmaceutical Industry. Its unique hopper bottom design is ideal for free flowing dry granular materials. We do not need to stock replacement parts as it has 3 piece molded design. The top cover of the container has the tamper evident capabilities and it protects contents from moisture, contamination. Its unique sloped bottom is ideal for the granules, pellets and small component parts. It has center flow discharge area which is fitted with an efficient, optimally designed proprietary slide gate to increase discharge efficiencies. It has smoothed, seamless sloped interior allows quick and easy release of content.

There is also some dimensional specification provided in the table which indicates the height, width and length of the intermediate bulk container.

Lay Out of Facility:-

Here, we have designed two layer facilities in which production operations are carried out on first floor and general administrative, other utilities are located on second floor.

The weighing area, blending, sizing, granulation, compression, coating, packaging, storage of raw material and finished products, gowning room, receiving and shipping area are located on the first floor of the facility. Administrative area, QA unit, utilities like HVAC system and water system are located on second level of facility.

Material Flow Diagram:-

In any facility, it is very important to maintain proper flow of material during manufacturing. The proper flow of the material will help to reduce chances of mix up and provide ease of performing operations. Ideally one way material flow is good but it also increases cost of the facility as it requires more space. Two way flow can be use but it requires proper air control to prevent cross contamination. Also the design of material flow is done with consideration of weighing, mixing, compression, packaging, coating, granulation etc operation.

Personnel Flow Diagram:

The layout must also allow for sufficient room for personnel flows in compliance with the applicable building codes. Personnel flows should be designed to prevent contamination to products and materials and to ensure personnel safety. Personnel flow diagrams should be generated and used to facilitate the evaluation of the potential impact of personnel flows on processes as well as raw materials.

UTILITIES

It is essential to supply and have control on utilities like air, temperature, pressure, humidity, water etc. in the facility. There are mainly three utilities that we have included in our facility.

1. HVAC System (Heating, vacuum and air conditioning)
2. Purified Water System
3. CIP System (Clean In Place)

HVAC System:-

HVAC (Heating, ventilation and Air conditioning) maintain the environment by controlling the temperature, relative humidity, air movement, air quality. The quality of product depends on the manufacturing environment like Light, Temperature, Humidity, Air, Microbial contamination, Particulate contaminate, Uncontrolled environment can lead to product degradation.

Heating ventilation and air conditioning is one of the most important systems which needs high amount of piping and controlled specs. In our tablet manufacturing area we should follow class 100,000 specification and as per that specification we have to build our HVAC system. HVAC is the combination of heating, ventilation and air conditioning so ultimately it required maintaining the desired room temperature in the facility. HVAC system mainly comprises,

• Ventilation
• Filtration of Air
• Heating
• Cooling
• Humidification of Air
• Dehumidification of Air for cooling purpose

HVAC is critical part of our facility as our working condition should follow the USP requirement. USP guideline suggests that the ideal range for room temperature 59 to 86 F and Relative Humidity should be 30 to 50 % RH. So we have to design our HVAC as per those requirements.

We have selected Arizon Company for designing our HVAC system and the model name is MaCraft Air Handling Unit, which has following specifications.

• Manufacturer:- Arizon Company
• Model Name:- MaCraft Air Handling Unit
• Capacity: – Can work on 0 CFM to 200,000 CFM volume of air.
• Some Important Features:-

1. Provided reverse panel construction for smooth air
2. Very less chances of leaking
3. Structure is fully steel base
4. Internal floor plan which retains water
5. High quality paint finish to avoid corrosion and hence less chances of contamination in the product.
6. Availability of access panel for removal of coils and fan wheels.

Water System:

In pharmaceutical industry water is primary raw material in most of process so it is the important pharmaceutical solvent. As per the USP and European Pharmacopeia there are different grade of water as per need like Purified water, WFI, sterile WFI and more. In oral solid dose facility purified water is required so there is need of purified water system and main concern is for its storage and distribution because in “USP water is Drug.”

The purified water system is three step processes

1. Pretreatment: The technologies like ion exchange, filtration, adsorption, Reverse osmosis are used it is generally used to remove the contaminants which can damage the membrane.
2. Purification
3. Storage and distribution

The difficulty in producing Purified water is Feed water source because of geographical and seasonal change due to this there is no Standard purification process. Purified water must meets the chemical specification, USP has the action guideline of <1OOCFU/mL and over it is not accepted. Piping system defect may lead to contamination of incoming water.

In the facility, the purified water generation plant is provided by Puretech Company which will design, install the system.

Clean In Place (CIP) System:-

Once any manufacturing operation finished, it is essential or important to wash or clean the equipments in which the operation has been carried out. Cleaning or washing is mainly done to prevent cross contamination of new batch from previously done batch. So the cleaning system must be able to clean equipment at one level that there must not be any particle of the previous batch that may be carried out in next batch.

CIP is one of the most important systems in the pharmaceutical industry because it maintains the cleanability of equipment, container as well as other supported utilities. In addition to the cleaning it also maintains the sanitization and hygienic condition of the equipment and other utilities. The ideal CIP should has capability to attach each equipment and hence remove the extra work of disassembling all equipment. Also, the ideal CIP has characteristics to clean one area without disturbing the other area. Modern CIP system should not only save the money but should also save the cleaning solution and the man-power.

For our facility we have selected GEA CIP System made by GEA Process Engineering Inc.

Our modern CIP system has following specification.

SPECIFICATION:-

• Manufacturer: – GEA Process Engineering Inc.
• Model Name:- GEA- CIP
• Type:- Matrix
• Capacity:- As per our criteria and can accommodate 8 tanks
• Flow Velocity:- 3 m/s
• Flow Rate:- Flow rate is up to 140 m³/h and 10 Bar
• No. of Tanks:- up to 8 tanks
• Other Important features:-

1. cGMP compatible
2. Do not require to disassemble all equipment because we can attach it directly to the equipment.
3. Can perform cleaning of single equipment without disturbing other processes in the plant.
4. Efficient in term of cleaning
5. Use relatively low amount of cleaning solution hence saves resources.

OTHER SUPPORTED AREAS:-

Supported Areas have their own importance in the pharmaceutical facilities. Various supported areas are included in the pharmaceutical facility like,

• Administrative Offices
• Quality Assurance Department
• Quality Control Department and Laboratories
• Gowning Area
• Warehouse
• Cafeteria
• Parking Lot

The listed supported areas are having following importance.

1. Administrative Offices: – The administrative offices include personal offices for management, board of directors, project managers, managing directors and chief executive officers. The administration also comprises the conference room for board of director’s and upper level management’s meeting.
2. Quality Assurance Department: – Quality Assurance Department is one of the major supported areas in the pharmaceutical facility. Quality Assurance provides big role in the sampling of raw materials, in processing material and also final product. The personnel from the quality assurance carried out samples and transfer to the quality control, where the samples are checked for their quality, purity, identity and strength.
3. Quality Control Department and Laboratories: – Quality Control Department and Laboratories are the most important supported area and comprises large area of the facility. Quality Control Department is responsible for the quality testing of the raw material before releasing, in process samples and final product. Quality control Department carried out quality testing in the laboratories as well as they also inspect the manufacturing site to assure the quality in the ongoing processes. So ultimately Quality Control Department built the quality within the product.
4. Gowning Area: – Gowning area is located in the entrance of the facility. After entering in the facility the operators has to go to gowning area to change the casual dressings and then have to wear the gowns provided by the manufacturer. The operators have to wear the mask, cap and also shoes provided by the manufacturer.

The gowning process should be follow,

• To protect the personnel from hazards
• To protect the product from personnel as the human being is the major source of contamination in the pharmaceutical industry.

The gowning room should have large mirror and also have images of ideal gowning so personnel can emulate the standard gowning procedure. Vertical blower should be installed at the exit of the gowning room to blow out any particulate or contaminants from the gowns.

• Raw material storage
• Release Raw material
• In-process material
• Packaging material
• Finished product.

Warehouse has proper design to store each and every material which described above. The warehouse has proper design for proper flow of the material.

Warehouse has proper design to follow FIFO (First in First Out) so there is no duplication of the raw material, and finished product. Proper shelves and proper space should require accommodating all different kind of materials. The warehouse also comprises material receipt process, sampling area, storage and control of material and support function. The warehouse also has enough amounts of conveyors, other bulk handling equipments and pallets.

Safety is also another issue while designing the facility so during designing of facility we have to make consideration of the safety that include environmental requirements, compliance to the building and personnel safety.

CONCLUSION

In a nutshell the facility we have design is ready to manufacture the tablet and has the capacity of 500,000 tablets per hour. The tablet compressing machine which we are going to used is ACCURA PRESS IV- 75 and is capable of producing 5,00,000 tablet per hour. The facility is designed with class 100,000 area for exposed as well as closed product with separate growing area. Cross contamination is minimized by indicating and specifying of material flow and personnel flow and circulating clean air with HVAC system. All the equipment used for facility is within the specification provided by us and it meets the regulatory requirements .The design facility is meets all the cGMP issue and is in complying other governing code and regulation.

ABBREVIATIONS:

CGMP-Current good manufacturing Practice
FDA-Food and drug administration
USP-United State Pharmacopoeia
HVAC-Heating Ventilation and Air Conditioning
CIP-Clean In Place
GEP-Good Engineering Practice
QA- Quality Assurance
QC-quality Control
IPQC-In Process Quality Control
API- Active Pharmaceutical Ingredient
FIFO-First in First Out
RH- Relative Humidity
CFM-Cubic Feet per Minute
PW- Purified Water
WFI- Water for Injection
AHU-Air Handling Unit
IBC-Intermediate Bulk Container

REFERENCES:

1. Leon Lachman, Herbert A. Lieberman, Joseph L. Kanig, Third Edition, 1991, “The Theory and Practice of Industrial pharmacy”, At Varghese Publishing House, Hind Rajasthan Building, Dadar Bombay 400 014.
2. http://cas.centralcarolinascale.com/BW.htm, CAS BW-150 platform scale, as of 11/12/09.
3. http://bench.centralcarolinascale.com/RLWS-IQ-2100-Bench-Scale.htm, Rick Lack IQ 2100 SL Bench Scale, as of 11/12/09.
4. http://www.fitzmill.com/pharmaceutical/size_reduction/models_styles/models_scale_up/models_scale_up_pharm_sr.html, Fitzmill, as of 11/14/09.
5. http://www.uniquemixer.com/products_blender_v.htm, VB – 500 V- Blender, as of 11/14/09.
6. http://www.tradevv.com/chinasuppliers/EddieD/products-detail/china-FL-Fluideized-Granulator-and-Dryer-1d930.html, FL Fluidized Granulator and Dryer, as of 11/ 17/09.
7. http://www.pharmalabmachinery.com/accura_pressIV.htm, Accura tablet press IV, as of 11/ 23/09.
8. http://www.vectorcorporation.com/products/hicoater_prod.asp, Hi-Coater, as of 11/20/09.
9. http://www.ecvv.com/product/922291.html, Automatic Bottle Filling Line, as of 11/17/09.
10. http://www.snydernet.com/_pdf/_dry_handling/Flowmaster-EZ-Box-Revised-2007.pdf, Intermediate bulk container, as of 11/25/09.
11. http://www.snydernet.com/_pdf/_ibc/_product-sheets/Buyers%20Guide%202008%20Rev..pdf, Intermediate bulk container, as of 11/25/09.
12. http://www.niroinc.com/gea_liquid_processing/cleaning_in_place_sip.asp, CIP system, as of 11/29/09.
13. http://www.johnson-marcraft.com/custom_air_handling.html, MaCraft Air Handling Unit, as of 11/23/09.
14. http://www.puretech-process.com/pdfs/genesys.pdf, Genesys, as of 11/29/09.