Viva Preparation for Pharmaceutical Production Department
Responsibilities of Production officer/Executive:
☞ Management day-to-day production activity.
☞ Conduct and follow daily, weeklu & monthly production plan and implement accordingly.
☞ Maintain GMP in all operations of the section.
☞ Maintenance of control charts, receipt, Return, Usage and Reconciliation of Materials and proper storage and delivery of intermediate and finished bulks, maintaining good house-keeping.
☞ Utilize effiently manpower, machinery & materials to improve productivity.
☞ Ensure proper cleaning & safe operation of product manufacturing and packing machine, equipment d areas.
☞ Ensure in-process test during manufacturing of product.
☞ Prepare and update BMR (Batch Manufacturing Practice), BPR (Batch Packaging Record), SOP (Standard Operating Procedure), and other documents.
☞ Organize training on SOP, basic GMP and machine operation & cleaning.
10 Key responsibilities of a production executive
A Pharmaceutical Production Executive in the production department plays a vital role in overseeing the manufacturing process of pharmaceutical products. Their key responsibilities include:
1. Production Planning and Scheduling: Developing production plans based on demand forecasts, ensuring that manufacturing schedules are met while maintaining product quality and regulatory compliance.
2. Manufacturing Process Oversight: Supervising the entire production process, including the preparation of raw materials, formulation, mixing, packaging, and final product inspection.
3. Quality Control and Assurance:
Ensuring that all products are produced according to Good Manufacturing Practices (GMP) and meet the required quality standards. They may also collaborate with quality control teams for in-process testing and final product analysis.
4. Regulatory Compliance:
Ensuring that all manufacturing processes comply with relevant health authority regulations, such as the FDA or EMA, and maintaining accurate records for audits and inspections.
5. Inventory Management:
Managing the inventory of raw materials, in-process goods, and finished products to avoid shortages or excess stock, ensuring smooth production flow.
6. Team Supervision and Training:
Leading and supervising production teams, ensuring they are adequately trained on safety protocols, machinery operation, and GMP standards.
7. Equipment Maintenance:
Ensuring that production equipment is properly maintained and calibrated to prevent breakdowns and ensure continuous production.
8. Troubleshooting and Problem-Solving: Addressing any production issues, such as equipment failure or delays, and working with technical teams to resolve problems quickly to minimize downtime.
9. Cost Control:
Monitoring production costs, identifying areas for cost reduction, and optimizing resource use to meet financial objectives while maintaining product quality.
10. Reporting and Documentation:
Keeping detailed records of production activities, including batch records, material usage, production times, and any deviations, ensuring transparency and compliance with regulatory requirements.
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Dry granulated tablets are tablets made using the dry granulation method, which avoids the use of liquids in the granulation process—ideal for moisture- or heat-sensitive drugs. Some common examples include:
1. Aspirin tablets – especially when moisture sensitivity is a concern.
2. Metoprolol succinate – some formulations use dry granulation.
3. Hydrochlorothiazide tablets – often produced via dry granulation due to poor compressibility.
4. Propranolol hydrochloride tablets
5. Lisinopril tablets
6. Cimetidine tablets
7. Ranitidine tablets (older formulations)
These tablets are typically made using slugging or roller compaction, depending on the scale and formulation needs.
What is a BMR?
A Batch Manufacturing Record is a comprehensive document that records the complete manufacturing process of a specific batch of a pharmaceutical product. It ensures that every step of production is carried out as per the approved procedures and GMP (Good Manufacturing Practices).
Key Components of a BMR:
1. Product Details:
Product name, batch number, batch size, and manufacturing date.
2. Bill of Materials:
List of raw materials, their quantities, and batch/lot numbers used.
3. Equipment Details:
Equipment used along with cleaning and calibration status.
4. Manufacturing Steps:
Detailed step-by-step procedures followed during production (e.g., mixing, granulation, drying, compression, coating).
5. In-Process Checks:
Parameters monitored during production (e.g., pH, temperature, time) and in-process test results.
6. Personnel Signatures:
Signatures of responsible personnel at each critical step for accountability.
7. Deviations (if any):
Documentation of any deviations from the standard process and corrective actions taken.
8. Yield Calculations:
Reconciliation of input vs. output to check for yield compliance.
9. Packaging Details:
Packaging material used, printed components, and packaging operations.
10. Final Approval:
Reviewed and approved by Quality Assurance (QA) before product release.
Importance of BMR:
- Ensures GMP Compliance
- Maintains Traceability
- Supports Regulatory Audits
- Improves Product Quality and Safety
- Acts as Legal Evidence in case of complaints or recalls
What is a BPR?
A Batch Packaging Record is a documented proof of the entire packaging process of a specific batch of a pharmaceutical product. It ensures that packaging activities are performed according to the approved Standard Operating Procedures (SOPs) and Good Manufacturing Practices (GMP).
Key Components of a BPR:
1. Batch Details:
Product name, batch number, batch size, manufacturing and packaging dates.
2. Packaging Material Information:
List of packaging materials (blister packs, bottles, labels, cartons, leaflets), their codes, quantities, and batch/lot numbers.
3. Line Clearance Checklist:
Pre-checks to ensure that the packaging line is clean, free from previous product/materials, and ready for operation.
4. Packaging Instructions:
Detailed instructions on how the product should be packed (e.g., number of tablets per blister, blisters per carton, labeling details).
5. In-Process Checks:
Monitoring critical parameters like batch coding, label accuracy, sealing integrity, and count accuracy.
6. Personnel Details:
Names and signatures of operators, supervisors, and QA personnel involved in packaging.
7. Yield Calculation:
Comparison of the quantity of packed goods with the quantity of bulk product and materials used.
8. Rejected/Returned Materials:
Documentation of any rejected or unused packaging materials.
9. Deviation & Incident Records:
Notes on any deviations, errors, or incidents that occurred during packaging, along with corrective actions.
10. Final QA Approval:
Review and sign-off by the Quality Assurance team before batch release.
Importance of BPR:
Ensures correct and consistent packaging
Helps maintain product identity and traceability
Supports GMP compliance and audit readiness
Prevents mix-ups and labeling errors
Facilitates investigation in case of complaints or recalls
General USP Dissolution Acceptance Criteria:
| Stage | Number of Units tested | Acceptance Criteria |
|---|---|---|
| Stage 1 | 06 |
Stage 2
Measuring the viscosity of a drug (typically a liquid formulation) is important for ensuring proper flow, dosing, and administration. Here's a general overview of how viscosity is measured in pharmaceutical contexts:
1. Use of a Viscometer or Rheometer
These are the primary instruments used to measure viscosity.
a. Capillary Viscometer (Ostwald or Ubbelohde)
Best for Newtonian fluids (constant viscosity).
Principle: Measures the time it takes for a drug to flow through a thin capillary tube.
Common for low-viscosity liquids.
b. Rotational Viscometer
Suitable for both Newtonian and non-Newtonian fluids.
Principle: A spindle rotates in the drug sample, and resistance to rotation is measured.
Examples: Brookfield viscometer
Good for semi-solids and thicker formulations like creams, gels, or suspensions.
c. Cone and Plate Viscometer
Useful for small sample volumes and temperature control.
A cone rotates against a flat plate with a small drug sample between.
d. Rheometer
Provides more advanced rheological data, including shear thinning/thickening, yield stress, and viscoelastic properties.
Best for complex, non-Newtonian formulations.
What are the units of Hardness in tablets :
Kilogram (kg), Newton (N), Pound (lb), Kilopond (kp) and Strong-Cobb (SC)
What is Leak test in Packing
The test which is used to check the integrity of packed strips, blisters, Bottles and small sachets containing tablets, Capsules and Dry Powders is called leak test.
Leak test Apparatus is used to test the quality of the packaging process and to check that the seals enclosing the product are perfectly intact and no water should go inside the pack. It is designed to find the smallest holes or Puncture and imperfections in packed Products.
What is FMD in Packing
The FMD (Falsified Medicines Directive) is a legal framework introduced by the European Commission to improve the protection of Public health within the European Union. The directive applies since 2 January 2013 & the European Commission Delegated Regulation, (EU) 2016/161, supplements Directive 2001/83/EC with rules regarding safety features for the packaging of medicinal products for human use. The regulation was adopted in October 2015 to counteract to fake medicines include stricter record-keeping of wholesale distributors, pharmaceutical producers, an EU-wide quality mark to identify online pharmacies and mandatory safety features on packages.
Which indicator is used in Leak test Apparatus
In order to identify the leakage in Blister or stripes methylene blue colour is used and the solution in the desiccators required to be changed every day or whenever required.
IPC Checks during Oral liquid filling & sealing:
☞ Appearance
☞ pH
☞ Viscosity
☞ Leakage test
☞ Volume check
☞ Check sealing of the bottle
☞ Machine speed
IPC checks,during Injectable Product filling & sealing:
☞ Room condtion (Air particle, Temperature, Humidity)
☞ Appearnace
☞ Average Weight
☞ Uniformity Weight
☞ Clarity
☞ Leakage test
☞ Volume check
IPC checks during Tableting:
☞ Room condition (RH & Temperature)
☞ Machine speed (RPM & TPM)
☞, Compression pressure
☞, Appearnace of Tableta
☞ Thickenn of tablets
☞, Hardness of tablets
☞ Friability of tablets
☞, Diameter of tablets
☞ Average weight
☞ Uniformity weight
☞, RSD
☞ Disintegration time
☞ Moisture content
IPC check during coating
☞ Appearnace
☞ Room condition
☞ Speed & time
☞ Disintegration time
☞ % Weight gain
☞ Moisture content
What are the classifications of clean rooms
Generally clean rooms are classified in to the following types as per different guidelines:
1) WHO 2002: Grade A, Grade B, Grade C, Grade D
2) EU GMP: Grade A, Grade B, Grade C, Grade D
3) Schedule M: Grade A, Grade B, Grade C, Grade D
4) US-FDA (US 209E): Class 1, Class 10, Class 100, Class 1000, Class 10000, Class 100,000
5) ISO 14644-1: ISO-1, OSO-2, ISO-3, ISO-4, ISO-5, ISO-6, ISO-7, ISO-8, ISO-9
Grade A & B Corresponds with clsss 100 & ISO-5
Grade C Correseponds with Class 10000 & ISO-7
Grade D corresponds with class Class 100000 & ISO 8
How to increase solubility of a poorly soluble drug?
Increasing the solubility of poorly soluble drugs is a common challenge in pharmaceutical development. Here are several strategies to improve solubility:
1. Physical Modifications
Particle Size Reduction: Micronization or nanonization increases surface area (e.g., via jet milling or high-pressure homogenization).
Solid Dispersions: Drug is dispersed in a carrier matrix (e.g., PEG, PVP) to enhance solubility.
Amorphous Form: Converting a crystalline drug to its amorphous form can improve solubility.
2. Chemical Modifications
Salt Formation: Converting the drug into a more soluble salt form.
Prodrugs: Chemically modifying the drug to improve solubility, then converting it back in the body.
Co-crystals: Forming crystals with other molecules (co-formers) to enhance solubility.
3. Use of Solubilizers and Excipients
Surfactants: Such as Tween 80, sodium lauryl sulfate to improve wetting and solubilization.
Cyclodextrins: Form inclusion complexes that enhance aqueous solubility.
Lipid-Based Formulations: Use of oils or emulsions (e.g., SEDDS, SMEDDS) for lipophilic drugs.
4. pH Adjustment
Solubility can depend on pH; adjusting the pH of the formulation medium can improve solubility of ionizable drugs.
5. Complexation
Use of agents like cyclodextrins or polymers that form complexes with the drug.
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What is Tablet Bed Temperature?
The temperature of the warm rotating tablets during the tablet coating process is known as tablet bed temperature.
What Is Atomization?
The division of coating suspension into fine mist by the use of air pressure is known as Automation.
How To Calculate Compression Machine Capacity?
Formula: Number of punches × rpm × Feeding system number × 60
How to Measure the Capacity of a Compression Machine hopper?
Measured in liters not in kilograms because we can easily find out the amount of powder or granules to be added to the hopper by utilizing the bulk density with the help of the following formula
Formula= The volume of the hopper (Liters) × Bulk density of the product
Bulk Density
Definition: The mass of a powder divided by its volume when loosely filled into a container without any external force or compaction.
Formula:
Bulk Density = Mass of Powder/Bulk Volume
Usage: Indicates how the powder flows or fills a container.
2. Tapped Density
Definition: The mass of a powder divided by its volume after being mechanically tapped or vibrated until the volume becomes constant.
Formula:
Tapped Density} = Mass of Powder/Tapped Volume
Usage: Useful for determining compressibility, flow properties, and formulation development.
How To Check End Point In Wet Granulation.
The endpoint is observed during the kneading stage of wet granulation & it is a very critical stage because in this stage the granule formation is observed to stop or continue the kneading process.
Enlist Granulation Defects
☞ Overwetting
☞ Underwetting.
☞ Over Drying
☞ Under Drying
☞ Assay Issue
☞ Segregation
Stages of Tablet Compression?
The tablet compression cycle is completed in four stages,
☞ Filling
☞ Weighing
☞ Compression
☞ Ejection
Parts of A Compression machine:
The name of the most important compression machine parts are given below
☞ Feeder
☞ Turret
☞ Upper Punches
☞ Lower Punches
☞ Dies
☞ Cams
☞ Pre Compression Rollers
☞Main Compression Rollers
☞ Tail over Die
☞ Discharging Chute
☞ HMI
☞ Lubrication Pump
☞ Hopper
What is double Disintegration?
For better disintegration & dissolution profile, the specific ratio of disintegrants is used intragranular & remaining is used in final blending this effect is known as double Disintegration.
What are Lubricants?
The excipients which are used to reduce friction between product & machine parts are known as lubricants. Ex. Magnesium stearate
What Is Recommended Blending Time For lubricant?
The optimum blending time of powders or granules with lubricants is 3 to 5 minutes.
What Is The Effect of Lubricant on Disintegration?
The higher concentration of lubricant or higher blending time with hydrophobic lubricants may prolong the disintegration time.
Effect of Lubricant on Dissolution?
The higher concentration of lubricant or higher blending time with hydrophobic lubricants results in a low dissolution profile.
Effect of lubricant on tablet Capping?
A higher concentration of lubricant or high blending time with lubricants may result in an increased tendency of tablet capping.
What are Glidants?
The materials which are used to promote flow by reducing inter-particle friction are known as Glidants.The most commonly used Glidants are,
☞ Talc
☞ Aerosil
What is another name for Aerosil?
Aerosil is a brand name & it contains colloidal silicon dioxide also known as fumed silica.
What is blending?
Blending refers to the uniform mixing of different powdered ingredients before or during the granulation process. This ensures that the final granules have consistent properties (like drug content, flowability, and compressibility).
Difference between lubricants & Glidants?
The class of excipients which is used to reduce friction between product & machine parts to prevent sticking & picking is known as lubricant.
The class of excipients which is used to promote flow by reducing inter-particle friction is known as Glidants.
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Bulk Powder
Powder mixture is packed into a suitable bulk container to facilitate dosing.
Example: Antibacterial powder, antifungal powder
Divided powder
Divided powders are similar formulations to bulk powders but individual doses are separately wrapped.
Granules
Granules are prepared aggregates of powdered materials to form a larger particle (0.2-4 mm).
Advantages of granules
☞, More flow properties
☞ Segragation could be avoided by granulation
☞ more stable against humidity & temperature and less likely to make cake or harden upon standing.
☞ Granules are mire easily qetted by liquids than light and fluffy powder and are more preferable for dry products.
Granulation
Granulation is the process in which powder particles are made to adhere to form larger particles called granules. Pharmaceutical granules typically have a size range between 0.2 to 4 mm, depending on theur subsequent uae.
Reason for granulation
Main three reasons:
☞ To prevent segregation of constituents in powder mix.
☞ To improve flow properties of mixture
☞ To improve compression characteristics of the mixture.
Particle bonding mechanisms in granulation
There are five primary bonding nechanisms between particles:
1. Adhesion and cohesion forces in the immobile liquid films between individual primary powder particles.
2. Interfacial forces in mobile liquid films within the granules.
⇨ Pendular state
⇨ Capillary state
⇨ Funicular stare
⇨ Droplet
3. The formation solid bridges after solvent evaporation.
4. Attractive forces between solid particles.
5. Mechanical interlocking.
Mechanism of granule formation
1. Nucleation
2. Transiition
3. Ball growth
The four possible mechanisms of ball growths:
1. Coalesecene
2. Breakage
3. Abrasion transfer
4. Layering
Granulation properties
a) Particle size and shape
b) Surface area
c) Density: Dense particles are generally less cohesive than less dense particles of the same size and shape.
d) Strength d friability
e) Flow properties: There are many types of forces to affect flow property of a solid. Such as: Frictional forces, Surface tension forces, Mechanical forces, Electrostatic forces & Cohesive or van der waals forces.
f) Compressibility: The compressibility is commonly known as Carr's Index. The higher the compressibility, the poorer the flowability.
g) Moisture content
h) Granules porosiry
Calculation of Compresibility:
% Compressibility = [100 × (Packed density - Untapped Density)÷ Packed Density]
Calculation of Carr's Index
Carr's Index = [(Tapped density - Poured density)/Tapped density] × 100
Calculation of Hausner ratio
Hausner ratio = Tapped density/ Poured density
% of Compressibility ➤ 1-10 ➤ Excellent
% of compressibility ➤ >38 ➤ Very very poor
% of Carr's index ➤ 5-15 ➤ Excellent
% of Carr's index ➤ > 40 ➤ Extremely poor
% of Hausner ratio ➤ 1.00 -1.11 ➤ Excellent
% of Hausner ratio ➤ > 1.60 ➤ Very very poor
Hausner ratio
| Hausner ratio | Type of flow |
|---|---|
| Less than 1.25 | Good flow |
| 1.25 – 1.50 | Moderate flow |
| More than 1.5 | Poor flow |
Common methods for determining powder flowability
a) Angle of repose
b) Hausner ratio
c) Shear strength determination
d) Hopper flow rate measurements
e) Angle of spatula
Angle of repose ➤ 25°-30° ➤ Excellent
Angle of repose ➤ >66° ➤ Very very poor
Methods of preparation of granules
1. Wet granulation
2. Dry granulation
3. Direct compression
Wet granulation
Wwt granulation is a process of dry mixing, wet mixing and particle size enlargement and is a process of particle attachment. This method is popular due to the granulation meets all the qualities required for a good tablet.
Examples: Calcium tablet, Paracetamol Tablet
Advantages of Wet granulation
☞ Cost effectiveness
☞ Stability: More stable for moisture and heat sensitive materials
☞ Faster dissolution
☞ Leass wear & tear of punches
☞ Simplified validation
Limitation of wet granulation
☞ Expensive process
☞ Loss of materials during various stage of processing
☞ Stability concerns for moisture sensitive or thermo labile drugs
☞ Multiple procesding stepts add complexity andmaje validation and control difficulty.
☞ Time consuming process
Steps of wet granulation
Requisition of raw materials
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Weighing/Dispensing
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Crushing & sieving of all ingredients
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Dry mixing in Rapid mixer Granulator
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Addiyion of binder solution or granulating solvent
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Wet mixing
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Co-milling
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Drying in FBD
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Dry-Milling/Size reduction
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Lubrication/blending
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Compression of tablet
Equipment of Wet granulation
A. Low-shear granulators
a) Mechanical agitator granulators
i) Ribbon blender
ii) Planetary mixer
iii) Orbiting screq mixer
iv) Sigma blade mixer
v) Zig-zag mixer-agglomerator
b) Rotating shape granulators
B) Medium-shear granulator: Fluid bed granulator
C) High-shear granulators
Fluid bed Granulator
Fluidization is the operation by which fine fluids are transformed into a fluid like state through contact with a gas. At certain gas velocity the fluid will support the particles giving them free mobility without entrapment. Fluid bed granulation is a process by which granules are produced in single equipment by spraying a binder solution onto a fluidized powder bed. The material processed by fluid bed granulation are finer, free flowing and homogenous.
The following three versions of fluidized bed granulation are most widely used:
☞ Top-spray method
☞ Bottom-spray method
☞ Tangential spray method
High Shear Granulator
High shear granulator is equally known as Rapid Mixer Granulator. It is,designed to achieve excellent mixing and consistent granules at lower operating cost along with higher productivity. Better mixing and closed control of granule size leads to faster tableting speeds with improved quality and least rejections. It has been widly used for blending and granulation, which can be acvompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification & agglomeration are achieved through shear and compaction force exerted by the impeller.. Most of the high-shear granulator consists of a mixing bowl, impeller, chopper, discharge pot.
Dry granulation
In dry granulation process, the powder mixture is compressed without the use of heat and solvent. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain granules. This method is especially applicable to materials that cannot be prepared by wet granulation method due to their sensitivity to moisture or to the elevated temperature required for drying.
Examples: Aspirin tablet, montelukast tablet, Magnesium hydroxide etc.
Methods of Dry granulation
Formation of granules using dry granulation process is generally achieved either by slughing technique or roller compaction.
Slughing technique
This process involves compression of primary powder particles into large flat tablets or pallets using a tablet press or more usually, a large heavy-dury rotary press. This process is often known as slugging. The compaction made in the process being termed as a 'slug'. The resultant compact is then milled using a hammer mill or other conventional milling equipment. The milled slugs are passed through a screen of desired mesh for sizing. Lubricants is added in the usual manner and the granules compressed into tablets.
Roller compaction
Roller compaction also referred to as ribbon blending is a relatively simple, more efficient and inexpensive form of dry granulation. It is a process where formulation ingredients are continuously passed between two counter-rotating rollers where it is densified and consolidated into a sheet of solid mass. Depending on the type rollers used, the feed material may be compacted into dense ribbon-like materials known as flakes (smooth rolls) or dense briquettes (almond or stick-shaped) if the roller have grooved or etched surfaces. The compacted materials are further milled, sized, lubricated and compressed into tablets.
Differences between dry granulation and wet granulation
| Dry Granulation | Wet granulation |
|---|---|
| No solvent us used. | Suitable solvnt is used. |
| Production cost is less. | Production cost is high. |
| Very simple process. | It is complex process. |
| Little chance of contamination | As water is used, contamination may be required |
| Required when producing tablets from highly moisture and heat sensitive compounds. | Required to avoid the destruction of active components in the powder. |
| Requires finely powdered conpound and tablet pressers or roll compactors | Requires powder particles, a granulating fluid and a shieve. |
Extrusion-Spheronization
It is a multiple step process capable of making uniform sized spherical particles. It is primarily used as a method to product multi-particulates for controlled release application. It is applicable to both immediate and controoled release dosage form.
Spray drying Granulation
It is a unique granulation technique that directly converts liquids into dry powder in a single step. This method removes moisture instantly and converts pump able liquids into a dry powder.
Advanced Wet Granulation Techniques
☞ Steam Granulation Technique
☞ Thermoplastic Granulation
☞ Moisture Activated dry Granulation
☞ Moisture distribution
☞ Moist Granulation Technique
☞ Foam Granulation
☞ Thermal Adhesion Granulation Process
☞ Freeze Granulation Technology
☞ Reverse wet granulation
☞The TOPO Vacuum granulation
Fluidized bed dryier
Systems in which the solid particles are partially suspended in an upward moving gas stream. In this drier hot air is passed at high pressure through a perforated bottom of the container containing granules to be dried. The granular are lifted from the bottom suspended in the stream of air. This condition is called fluidized state. The hot gas is surrounding every granule to conpletely dry them.
What is SMF and how it works :
When the product is under drying in FBD, the product loss often occurs due to a puncture or broken filter bag. Solid flow monitor (SFM ) or broken bag detector (BBD) provides good detection of filled filter bag failure or tear in FBD, thus prevent product loss. SFM or BBD located in the exhaust duct of FBD.
What is NFD & how it works :
Non Fill Detection is an system incorporated into the machine which enables the machine to automatically detect and reject those strips or Blisters that have missing tablets or capsules in cavity. This arrangement involves a sensing system, a control system consisting of a Programmable Logic Controller (PLC) and an HMI (Human Machine Interface), and an electro pneumatically activated auto-rejection system. Both the Strip & blister Packing Machine as well as the NFD system are designed and built by us at our works and are therefore fully integrated with each other.
Tablet Ingredients
1. Diluent
Diluents are fillers used to make required bulk of the tablet when the drug dosage itself is inadequate to produce the bulk. Secondary reason is to provide better tablet properties such as improve cohesion, to permit use of direct compression manufacturing or to promote flow.
Examples:
☞ Microcrystalline cellulose-Avicel (PH 101 & PH 102)
☞ Lactose anhydrous and spray dried lactose
☞ Directly compreseed starch
☞ Hydrolyzed starch
☞ Dibasic calcium phosphate dehydrate
☞ Mannitol
☞ Sorbitol
☞ Dextrose
Fillers
Fillers fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, the fillers make it possible for the final product to have the proper volume for patient handling.
Examples:
☞ Lactose
☞ Sucrose
☞ Glucose
☞ Mannitol
☞ Sorbitol
☞ Calcium carbonate
☞ Magnesium stearate
Binders
Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength and give volume to low active dose tablets.
Classification of binders:
A) Sugars: Sucrose, Liquid glucose
B)
Disintegrants
Disintegrants are agents added to tablet formulation to promote the breakup of the tablet into smaller fragments in an aqueous environmemt, thereby increasing the available surface area and promoting a more rapid release of the drug substance.
Superdisintegrants
Superdisintegrants swell the tablet up to ten fold within 30 seconds compare to conventional disintegrants when contact with water. Three major group of compunds that have been developed as superdisintegrands are:
1) Modified starches
2) Cross-linked polyvinylpyrrolidone
3) Modified cellulose
Lubricants
Lubricants are the agents that act by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection.
There are two major types of lubricants:
1. Water Insoluble lubricants
Water insoluble lubricants are most effective and used at reduced concentration than water soluble lubricants. Since these lubricants function by coating, thrir effectivenesd is related with their surface area, extent of partucle size reduction, time, procedure of addition and length of mixing.
2. Water soluble lubricants:
Water soluble lubricants are used when a tablet is completely soluble or when unique disintegrantion and dissolution characteristics are required. Tablet containing soluble lubricants shows higher dissolution rate than tablet with insoluble lubricants.
Glidants
Glidants are added to the formulation to improve the flow properties of the material which is to be fed into the die cavity and aid in particle rearrangememt within the die during the early stages of compression.
Antiadherents
Some materials have strong adhesive properties towards the metal of punches and dies or the tablet formulation containing excessive moisture which has tendency to result in picking and sticking problem. Therefore antiadherents are added, which prevent sticking to punches and die walls.
Preservatives
Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation.
Dissolution retardants
Dissolution retardants are incorporated into tablet formulation only when controoled release of drug is required.
Dissolution enhancers
Dissolution enhancers enhance the dissolution rate of active pharmaceutical ingredients. They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent.
Antioxidants
Antioxidants are added in tablet formulation to peotect drug from undergoing oxidation. Antioxidants undergo undergo oxidation in place of drug or they blocj the oxidation reaction or they act as synergists to other antioxidants.
Adsorbents
Adsorbents are capable of retaining large quantities of liquids without becoming wet. This property of adsorbent allows many oils, fluid extracts and eutectic melts to be incorporated into tablets. Adsorbents are the agents that can retain large quantities of liquids. Therefore, liquids like vitamin E can be incorporated into tablets by addition of adsorbents.
Buffers
Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability.
Wetting agents
Wetting agents are added to tablet formulation to aid water uptake during disintegration and assist drug dissolution. Wetting agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution.
Chelating agents
Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments.
Tablet compression machine
Basic components of tablet compression machine:
☞ Hopper: used to hold the matetial to be compressed.
☞ Dies: define the shape and size of the tablet.
☞ Punches: used for compressing the materials withing the dies.
☞ Cam Crack: guiding the movement of the punches
☞ Feeding mechanism: A feeding mechanism for moving the materials from hopper into the dies.
Dwell time/Dual time compression
Dwell time is that time where the punch head remains in contacts with the compression roller or total of compression force applied during the formation of tablets.
Tapered die
A tapered die allows entrapped air in the powder to exhaust as the upper punch enters the die at the beginning of the compression cycle. The resulting air pressure from the upper punch entering the die is about one-third of that for a die without a taper.
Types of Tableting machine
1) Single punch/single station/eccentric presses compression machine (Those with the single set of tooling)
2) Multi punch machine/Rotary tablet machine/High speed rotary tablet mechine/Multi layer rotary tablet machine (Those with the several stations of tooling)
Compression machine Tooling
Tooling: Tooling is the setup of dies and punches for compression of tablets on the machine is called tooling.
There are four types of tooling in compression machine, such as:
1. D tooling
2. DB tooling
3. B tooling
4. BB tooling
There are two size of Punch Barrel Diameter:
1) 25.40 mm
2) 19.05 mm
There are three size of die outer diameter:
1) 38.10 mm
2) 30.16 mm
3) 24.00 mm
There are 4 size of tablet:
1) 25 mm
2) 19 mm
3) 16 mm
4) 13 mm
| Type of Tooling | Punch Barrel Diameter (mm) | Die outer Diameter (mm) | Punch length (mm) | Maximum tablet size (mm) |
|---|---|---|---|---|
| D tooling | 25.40 mm | 38.10 mm | 133.60 mm | 25 mm |
| DB tooling | 19.05 mm | 30.16 mm | 133.60 mm | 19 mm |
| B tooling | 25.40 mm | 30.16 mm | 133.60 mm | 16 mm |
| BB tooling | 19.05 mm | 24.00 mm | 133.60 mm | 13 mm |
What is the work of Pre-compression Rollers in Compression Machine?
These are the very first rollers in rotary tablet press. Basically, these rollers apply a small amount of force on the upper and lower punches.
This gives the initial compression force. The aim of this process is to remove air that could be in the die or powder particles.
43. What is the work of Main compression Rollers in Compression Machine?
Main compression rollers exert a predetermined amount of force (final compression force) for the formation of tablets. The compression force at this stage is higher than the pre-compression force.
It is important that the rollers remain stable with no vibration during the entire process. This is to ensure consistency of the tablets’ thickness and size.
Tableting Problems & Remedies
1. Capping:
Capping is the partial or complete separation of the top or bottom crowns of a tablet from the main body of the tablet.
Causes:
☞ Large amount of fines in the granulation.
☞ Too dry or very low moisture content.
☞ Insufficient amount of binder or improper binder
2. Lamination:
Lamination is the separation of tablet into two or more distinct layer.
Causes:
☞ Oily or waxy materials in ganules.
☞ Too much of hydrophobic lubricant.
3. Chipping:
Chipping is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling.
Causes:
☞ Sticking on punch face.
☞ Too dry granules
☞ Too much binding causes chipping at bottom.
4. Cracking
Small fine crackes observed on the upper & lower central surface of tablets or very rarely on the side wall are refer to as cracks.
Causes:
☞ Large size of granules
☞ Too dry granules.
☞ Tablets expand
☞ Granulation too cold.
5. Sticking
In sticking, the tablet material i.e. the granules adhere to the die wall and there by the lower punch cannot move freely.
Causes:
☞ Granules not dried properly
☞ Too little or improper lubrication
☞ Too much binder
☞ Hygroscopic granular material
☞ Oily or waxy materials
☞ Too soft or weak granules.
6. Filming
Filming is a slow form of sticking and largely due to excess mousture in the granulation.
Causes: Improperly drued or improperly lubricated granules.
7. Picking
In picking a small surface of the tablet material is removed by the punxhes and adheres to the surface of punxhed therefore the resulting in this problem tablets show a pitted surface instead of smooth surface.
Causes:
☞ Excessive moisture in granules
☞ Too little or improper lubrication
☞ Low melting point substances
☞ Too warm granules when compressing
☞ Too much amount of binder
8. Binding
Binding in the die, is the term used when the tablets adhere, seize or tear in the due. A filn is formed in the die and ehection of tablet is hindered. With excesdive binding, the tablet sides are cracked and it may crumble apart.
Causes:
☞ Too moist granules and extrudes around lower punch.
☞ Insufficient or improper lubricant.
☞ Too coarse granules.
☞ Too hard granules for the lubricant to be effective.
☞ Granular matetials very abrasive and cutting into dies.
☞ Granular material too warm, sticks to the die.
9. Mottling
Mottling is the term used to describe an unequal distribution of color on a tablet, with light or dark spots standing out in an otherwise uniform surface.
Causes:
☞ A coloured drug used along with colourless or white-coloured excipients.
☞ A dye migrates to the surface of granulation while drying.
☞ Improperly mixed dye, especially during direct compression.
☞ Improper mixing of a coloured binder solution.
10. Double Impression
Double impression involves only those punches which have a monogram or other engraving on them. It is due to free rotation of punches which have some engraving or monogram on the punxh faces. During ite free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in 'Double impression'.
Causes:
☞ Free rotation of either upper punch or lower punch during ejection of a tablet.
11. Weight variation
12. Hardness variation
13. Pitted surface:
The pitted surface results due to the improper ratio of granules an fine powder.
Causes:
☞ The presence of granules which are nonguniform in size and lack of the fine powder necessary fill the voids.
14. Drug instability
Tablet coating
Tablet coating is the application of a coating material to the exterior of a tablet with the intention of conferring benefits and properties to the dosage form over the uncoated variety.
Principle of Coating process
The basic principle of tablet coating involves the application of coating solution to a moving bed of tablets with the concurrent use of heated air to facilitate evaporation of the solvent. The distribution of coating is achieved by the movement of the tablets either perpendicular (coating pan) or vertical (air suspension).
Purpose of tablet coating
☞ To mask bitter taste and unpleasant odor of some drugs.
☞ To provide physical and chemical protection for the drug.
☞ To protect the drug from the gastric environment of the stomach with an acid resistant enteric coating.
☞ To protect the drug from the external environment in order to improve stability.
☞ To control the release of the drug from the tablet.
Critical parameter for tablet Coating
☞ Pan speed
☞ Spray rate
☞ Inlet temperature
☞ Exhaust temperature
☞ Gun-to-bed distance
☞ Atomizing air pressure
☞ Bed temperature
Types of Tablet Coating
1) Film coating
2) Sugar coating
3) Compressed/Press coating
Film Coating
Film coating process, which involves the deposition of a membrane, consisting of polymer, plasticizer, colorant and possibly other additives on to the surface of a pharmaceutical dosage form, especially a tablet or a granule.
Reasons for film coating
☞ To improve product appearance, to mask odor and taste and to aid swallowing.
☞ To protect the active ingredient against heat, light and moisture
☞ To create modified relapse form.
☞ To separate incompatible active ingredients, present in a repeat.
☞ To aid identification and hence decrease the risk of confusion especially when patients have to take several preparations.
Major advantages of film coating
☞ Substantial reduction in quantity of coating applied
☞ Faster processing times
☞ Improvement in process efficiency and output
☞ A simplified procesa that facilitates automation.
Types of Film coating
1. Based on solvent:
A) Aqueous based coating
B) Organic solvent based coating
C) Dry coating:
i) Electrostatic dry coating
ii) Magnetically assisted Impaction
2. Based on Coat:
A) Based on drugbdelivery system:
i) Immediate release film coating
ii) Modified release film coating:
a) Sustained release film coating
b) Enteric coating
B) Based on type of derivative:
i) Cellulose derivatives
ii) Methacrylate based
iii) Polyvinyl acetate phthalate
Enteric film coating:
Enteric film coating is a special type of coating, which intended to make the tablet to pass through the stomach intact to disintegrate and release their drug content for absorption along the intestines.
Purpose of enteric film coating:
☞ To protect acid-liable drugs from the gastric fluid. Such as enzymes and certain antibiotics.
☞ To prevent gastric distress or nausea due to irritation from a drug such ax Sodium salicylate.
☞ To deliver drug intended for local action in the intestine.
☞ To deliver drugs that is optimally absorbed in the small intestine.
☞ To provide a delayed-release component for repeat action tablets.
☞ To protect the tablet from heat and moisture sensitivity.
Enteric film coating agents:
☞ Cellulose acetate phthalate (CAP)
☞ Acrylate Polymers
☞ Hydroxypropyl methylcellulose phthalate (HPMCP)
☞ Polyvinyl acetate phthalate (PVAP)
Raw materiala used in filn coating formulations:
1. Polymer
2. Plasticizer
3. Colourant
4.Solvent/Vehicle
Polymer used in immediate release film coating formulations:
Sugar Coating
Sugar coating may be considered the traditional method of coating tablets. It involves the successive application of sucrose-based solutions to tablet cores in suitable coating equipment.
Stages involves in the production of sugar-coated tablets:
a) Sealing of the tablet cores
b) Sub coating
c) Smoothing (or grossing)
d) Colouring
e) Polishing
f) Printing
Sealing
Seal coating involves the application of specialized polymer-based coating directly to the tablet core.
Sealants that are commonly used include:
☞ Shellac
☞ Zein/zinc oxide
☞ Cellulose Acetate phthalate
☞ Hydroxy propyl methyl cellulose
☞ Hydroxypropyl cellulose
☞ Polyvinyl Acetate phthalate
☞ Oxalic acid
☞ Propylene glycol
☞ Polyethylene glycol
☞ Methylene chloride
Sub coating
Sub coating is a critical operation that can have a marked effect on ultimate tablet quality. This stage is where the tablet is smoothed and colour may be added. In sub coating following fillers and film former may be used to improve the structural integrity of the coating.
High level fillers:
☞ Calcium.carbonate
☞ Talc
☞ Cocoa powder
☞ Calcium sulphate
☞ Kaolin
☞ Titanium dioxide
Auxiliary film former:
☞ Acacia
☞ Gelatin
☞ Cellulose derivatives
Smoothing/grossing
The smoothing or grossing invloves filling out and smoothing irregular features or areas of the tablet. Smoothing usually can be accomplished by applying sucrose-based solution with or without additional components such as starch and calcium carbonate. The smoothing coating may simply consists of 60-70% sucrose syrup that is often coloured with titanium dioxide to achive the desired level of whiteness.
Coloring
This is one of the most important steps in the sugar-coating process as it has immediate visual impact that is associated with overall quality. It involves the multiple application of syrup solutions (60-70% sugar solids) containing the requisite colouring materials necessary to achieve the desured shade.
Sugar-coating colourants may be subdivided into two groups:
a) Water-soluble dyes: FD&C Yellow #5, FD&C Blue #2
b) Water-indoluble pigments
⇨ Inorganic pigments: Titanium dioxide
⇨ Certified lakes: Aluminium lakes
Sugar coating problems
1. Chipping
2. Cracking
3. Non drying coating
4. Twinning
5. Uneven color
6. Blooming & sweating
7. Marbling
Causes of chipping of sugar coating:
☞ Less or absence of polymer
☞ Excessive use of insoluble fillers/pigments.
Causes of Cracking of sugar coating:
☞ Exapansion of tablet core during/after coating by moisture absorption/stress relaxation
Causes of Non-drying of sugar coating:
☞ Excess level of invert sugar present.
Causes of Twinning of sugar coating:
☞ Flat surface/high edge walls.
Causes of uneven color of sugar coating:
☞ Poor distribution of coating liquid
☞ Color migration due to under drying or too rapid drying.
☞ Uneven surface of sub-coat layer.
Causes of Blooming & Sweating of sugar coating:
☞ Residual moisture in finished coated tablets.
Causes of Marbling of sugar coating:
☞ Uneven coating surface.
Compression Coating
Compression coating method involves the compression of coating materials around a preformed core tablet using conventional or specially designed tablet compression machine and it doesn't require use of any special solvent for coating purpose. Hence it is also known as press coating or solvent-less coating technique or dry coating technique. By composition, compression coated tablet has two parts: internal core and sorrounding coat.
Conventional Coating Pan
The Conventional Coating Pan is simple unit, which employs the principle of rolling a batch of tablets in an oval shape pan, spraying the coating solution on it and passing hot air across the tablet bed. An exhaust blower may be used to carry away the excess fumes generated during the coating and drying process.
Improvements in conventional pan are pellegrini system which has a baffled pan and diffuser which improves the drying efficiency and can be suitable for sugar coating process.
The immersion sword system which includes a metal sword that will immerse in the tablet bed and during drying process it will introduce drying air which flows through perforated metal sword then upwards towards bed.
The immersion tube system which includes a tube that will immerse in the tablet bed and this tube has a spray nozzle that delivers both the hot air and coating solution. This is suitable for both sugar coating and film coating.
Differences between Sugar coating & Film coating
| Features | Sugar Coating | Film Coating |
|---|---|---|
| Appearance | Rounded with high degree of polish | Retains contour of original core usually not as shiny as sugar coat types |
| Weight increase due to coating materials | 30-50% | 2-3% |
| Logo or break lines | Not possible | Possible |
| Process stages | Multistage process | Usually single stage |
| Functioned coating | Not usually possible apart from enteric coating | Easily adaptable for controlled release |
| Drying time | Long | Short |
Types of Capsules
1. Hard gelating capsule: Omeprazole capsule
2.Soft gelatin capsule: Vitamin E capsule
Physical specification of empty hard gelatin capsules
| SI. No. | Capsule Size | Outer diameter (mm) | Height (mm) | Actual volume (ml) | Fill weights (mg) |
|---|---|---|---|---|---|
| 1. | 000 | 9.91 | 26.10 | 1.36 | 960 |
| 2. | 00 | 8.53 | 23.30 | 0.95 | 665 |
| 3. | 0 | 7.65 | 21.70 | 0.67 | 475 |
| 4. | 1 | 6.91 | 19.40 | 0.48 | 350 |
| 5. | 2 | 6.35 | 18.00 | 0.37 | 260 |
| 6. | 3 | 5.82 | 15.90 | 0.27 | 210 |
| 7. | 4 | 5.31 | 14.30 | 0.20 | 145 |
| 8. | 5 | 4.91 | 11.10 | 0.13 | 90 |
Gelatin
Gelatin is a heterogenous product obtained by the partial irreversible hydrolysis of collagen derived from the skin, while connective tissue and hide portion, frozen pork & bones of animals.
Common defects in Hard Gelatin Capsules
1. Lumpy or misshapen capsule
2. Improper rectification
3. Failure to separate
4. Dented capsule
5. Telescoping
6. Popping
7. Brittleness
Telescoping
This defects occurs when the cap and body misalign and the capsule body splits and a portion of it covers the cap.
Microencapsulation
Microencapsulation is a process by which solids, liquids or even gases may be enclosed in microscopic particles by formation of thin coatings of wall material around the substance. A capsule with a size range of about 200 micron is termed as mucrocapsule.
Process of Microencapsulation
1. Air suspension
2. Pan coating
3. Spray drying d Spray congealing
Pan coating
With respect to microencapsulation, solid particles greater than 600 micro in size are generally considered essential for effective coating, and the process has been extendively employed for the preparation of controlled-release beds.
Difference between Hard gelating & Soft gelatin
Types of gelatin
Type-A: Derived from acid treated precursor that exhibits an isoelectric point at pH 9. It is mainly manufactured from pork skin.
Type-B: Derived from alkali treated precursor that exhibits an isoelectric point at pH 4.7. It is manufactured mainly from animal bones.
Polymers used in Nano-capsule
A) Natural polymers:
☞ Chitosan
☞ Gelatin
☞ Sodium alginate
☞ Albumin
B) Synthetic polymers:
☞, Poly lactide
☞ Polyglycoliders
☞ Poly glutamic acid
☞ Poly malic acid
☞ Polyacrylic acid
☞ Poly ethylene glycol
Solution
Suspension
Emulsion
Multi-emulsion
Micro-emulsion
Tincture
Syrup
Elixir
Colloid
Gargles
Mouthwash
Diference between Syrup & Elixir
Difference between Solution & Suapension
Difference between Suspension & Emulsion
Difference between Deflocculated & Flocculated Suspension
Difference between Suspension & Colloid
Suspending agents used in oral liquid preparations
☞ Alginates
☞ Methylcellulose
☞ Hydroxyethylcellulose
☞ Carboxymethylcellulose
☞ Sodium carboxy methylcellulose
☞ Microcrystalline cellulose
Buffering agents used in oral liquid
☞ Citric Acid
☞ Na Phosphate
☞ L-methionine
Preservatives used in oral liquid
☞ Benzalkonium chloride
☞ Benzoic acid
☞ Butyl paraben
☞ Methyl paraben
Surfactants used in oral liquid
☞ Polysorbate 80
☞ Pluronics
☞ Poloxamers
Antioxidants used in oral liquid
☞ Ascorbic acid derivatives such as ascorbic acid, erythorbic acid, Na ascorbate
☞ Thiol derivatives such as Thioglycerol, cysteine, acetylcysteine
☞ Tocopherols
☞ Butylated hydroxyanisole (BHA)
☞ Butyl hydroxytoluene (BHT)
☞ Sufurous acid salts such as Sodium sulfate, sodium bisulfite
Humectants used in oral liquid
Humectants absorb moisture and prevent degradation of API by moisture. Examples of humectants most commonly used in suspensions are propylene glycol and glycerol. Total quantity of humectants should be between 0-10% w/w. propylene glycol & glycerol can be used at concentration of 4% w/w.
Quality control tests for Oral liquid preparations
☞ Appearance
☞ Identification
☞ Taste & Odor
☞ pH
☞ Weight/ml
☞ Refractive Index
☞ Filled volume
☞ Viscosity
☞ Preservative contents
☞ Light stability
☞ Redispersibility
☞ Suspensibility
☞ Pourability
☞ Relative density
☞ Assay
☞ Microbial limit test
Semisolids
Semisolids are neither solid nor liquid. They are in between the two. They are not fluid at ordinary temperature like liquids; at the same time at normal temperature, they are not too hard and too rigid like solids.
Examples of Semisolid Preparation
Creams, Ointments, Gels, Pastes d Poutics
Ointment
Ointments are hydrophobic type of preparation and are mainly composed of hydrocarbons, mineral oils or petrolatum. As such they are more viscous, sticky and hard to wash using water
Examples:
Creams
Creams are semisolid preparations. They are used externally and usually contain one or more medicinal agents dissolved or duspersed in either a w/o or o/w emulsion base or in a water washable base.
Examples: Vanishing cream, cold cream, cetrimide cream etc.
Lotion
Lotions are similar to solutions but are thicker and tend to be more emollient in nature than solution. They are usually oil mixed with water and more often than not have less alcohol than solutions
Difference between ointment and cream
Difference between Cold cream & Vanishing cream
Difference between Paste & Ointment
Factors considered for the preparation of Parenteral Products:
☞ Volume of Injection
☞, Adjustment of pH
☞, Stabilizer
☞ Preservatives
☞ Adjustment of Specific gravity
☞ Adjustment of Isotonicity
☞ Vehicles
Additives used to formulation of Parenteral Products
To formulate parenteral products various additives must be added to active ingredients. These substances added to a ptoduct to enhance its stability are essential for every products. Such as:
⇨ Antibacterial agents
⇨ Antioxidants
⇨ Buffers
⇨ Tonicity agents
⇨ Cryoprotectants
⇨ Lyoprotectants
⇨ Solvents
Aqueous vehicles used for preparation of Parenteral products:
1) Water for Injections, USP
2) Sterile water for injection USP
3) Bacteriostatic Water for Injection USP
4) Sodium Chloride Injection USP
5) Bacteriostatic Sodium chloride Injections USP
6) Ringer's Injections USP(Soluyion of Nacl, Kcl and CaCl)
Differences between SVP and LVP
| Parameter | SVP | LVP |
|---|---|---|
| Volume | 100 ml or less | 101-1000 ml |
| Routes | IV, IM & SC | IV-LVP, Non IV-LVP |
| Dosage unit | Single or multiple Usp max size 30 ml | Single |
| Technique | Vein puncture | Venolysis |
| Needle | 1.5 Inch, 20-22 Gauge | 1.5 Inch, 18-19 Gauge |
| Preservative | Used | Not Used |
| Buffer | Used | Not Used |
| Formulation | Solution, Suspension, Emulsion | Solution, O/W nutrient emulsion |
| Isotonicity | Not essential | Must |
| Pyrogenicity | Not essential | Must |
| Use | As therapeutuc agent As disgnostic agent | As nutrient In detoxification Aid during surgery |
Classification of Parenteral Product According to Routes of Administration
1) Intra-cutaneous or Intra-dermal Injection
2) Sub-cutaneous or Hypodermic Injection
3) Intra-muscular Injection
4) Intravenous Injection
5) Intra-cardiac Injection
6) Intrathecal Injection
7) Intra-arterial Injection
8) Intraintestibal Injection
9) Peridural Injection
10) Intra-articular Injection
11) Intra-cerebral Injection
Ampoules
An ampoule is a small glass bottle which normally contains a liquid drug that is mainly used for injection. It is sealed glass containers with an elongated neck that must be broken.
Vials
A vial is a small glass vessel or bottle which normally contains a powder drug that is mainly used for injection.
Prefilled Syringes
A prefilled syringe is a single-dose product of drug to which a needly has been fixed by the container.
Blow Fill Seal Technology (BFS)
BFS is a manufacturing technique used used to produce small (0.1 ml to 99 ml) and large volume (100 ml to above) liquid filled containers. BFS is a speciali
ed packaging technology using in-line forming and sealing a polymeric material to a container of choice.
BFS Steps:
Step-1: Paeison extrusion
Step-2: Container moulding
Step-3: Container filling
Stwp-4: Container sealing
Isotonic Solution
An isotonic solution is when two solutions separated by a semipermeable membrane, habe equal concentrations of soluyes and water.
Examples: 0.9% Saline, 5% dextrose in water, 5% dextrose in 0.225% saline.
Hyotonic solution:
Examples: 0.45% saline, 0.225% Saline, 0.33% saline.
Hypertonic solution
Examples: 3% saline, 5% saline, 10% dextrose in water, 5% dextrosevin 0.9% saline, 5% dextrose in 0.45% saline, 5% dextrose in lactated Ringer's.
Lyophilization Technology
Lyophilization: Lyophilization or freeze drying is a process in a substance is first frozen and then the quantity of the the solvent is reduced, first by sublimation (primary drying stage) and the desorption (Secondary drying stsge) to values that will no longer support biological activity or chemical reactions.
Objectives of Lyophilization process
☞ To preserve the buological activity of a drug.
☞ To reduce the product weight for lower the transportation cost.
☞ To extent the shelf life or stability.
☞ To dry thermolabile materials
☞, To elimiate the need for refrigerated storage.
☞ To get accurate, sterile dosing into the final product container.
Processing of Lyophilization:
a) Freezing
b) Vacuum
c) Heat
d) Condensation
Freeze Drying process:
Freeze dryng process consists of three stages:
1) Freezing: Decrease the shelf temperature to –50%
2) Primary Dryng (Sublimation)
3) Secondary Drying (Desorption)
Form Fill Seal Technology (FFS)
Form Fill Seal Technology is an automated computer gerated technology to prepare sterile products. The reason behind FFS technology is to reduce the contamination during production in a closed sterile chamber of a mqchine.
Processing of FFS:
1) Pre-sterilization of machine; Carried out in 2 different phases:
i) Programmed in sequence
ii) H2O2 sterilization cycle
2) Production in sceptic chamber
3) Post-production cleaning.
Aseptic Processing
Asepyic processing is the processing of drug components, drug product containers and excipients in a manner that precludes microbial contamination of the final sealed product.
Chemical Names of Various Materials
| Name of the material | Chemical Name |
|---|---|
| Magnesium Silicate | Talc |
| Povidone | 1-Ethenyl-2-pyrrolidinone homopolymer |
| Stearic acid> | Octadecanoic acid |
| Glycine | Aminoethanouc acid |
| Borax | Sodium tetraborate decahydrate |
| Lime | Calcium oxide |
| Limestone | Calcium carbonate |
| Quartz | Silicon dioxide |
| Wood Alcohol | Methyl Alcohol |
Blistering
Blistering is the process of making blister or enclosing the tablets and capsules into performed plastic packing.
Types of Blister packaging machine:
There are mainly three types of blister packaging machine:
1. Thermo form blistering machine: ALU-PVC mavhine
2. Cold form blistering machine: ALU-ALU machine
3. Thermo-cold complex blistering machine: ALU-Tropical machine
How to increase the hardness of tablet?
Hardness of tablets can be increased by adjusting of compression machine or adding some excipients. Such as:
☞ Proper rotation speed (RPM, TPM) of the feeder and turret.
☞ Proper setting of upper punch penetration and pre-compression
☞ Use colloidal silicon dioxide extra-granularly to improve flow rate of the API, will give higher hardness for Direct compression method.
☞ Use slugging process for dry granulation method.
☞ Some excipients that have the best compressibility properties available in the market may be added such as Avicel PH 200, Microlac.
☞ Use a mix of magnesium stearate (1% of total tablet weight) + Stearic acid (1%) + colloidal silicon dioxide (0.5%) as a lubricant mix.
☞ Use gelatin with starch paste will give excellent hardness for wet granulation method
☞ Use stronger binders as methylcellulose, hydroxypropyl cellulose for dry compression method.
☞ Use lactose and Microcrystalline cellulose 101 intragranularly provide highrr hardness for wet granulation.
☞ Optimize granules fine ratio.
How can you increase the dissolution rate of tcomplex
☞ The agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent may be used.
☞ Fructose, Povidone, Surfactants are usex as dissolution enhancer.
☞ There are many excipients that can enhance dissolution in tablet formulation. Excipients that are used for disintegrant (Croscarmellose sodium, Crosspovidone rtc), Wetting agents (Sorbitan esters, sodium lauryl sulfate, polysorbates etc), binder (povidone, hypromellise etc), inclusion complexe (cyclodextrins etc) and also filler (mycroctystalline cellulose, lactose etc) can enhance dissolution depend on characteristic active ingredient.
Type A cleaning:
☞ Use 0.5% Sodium lauryl sulfate solution
☞ Type A cleaning is applicable for:
⇨ Product to product changeover
⇨ Batch to Batch changeover of same product from higher strength to lower strength
⇨ Batch to Batch changeover of same product but change in colour/flavor.
⇨ After completion of five consecutive batches or completion of 120 hrs whichever is earlier.
⇨ After any major breakdown where product conact parts are contaminated.
⇨ After completion of preventive maintenance work if product parts are disturbed/contaminated.
Type B claning
Type B cleaning is applicable in the following condition:
⇨ Batch to Batch changeover of same product having same strength, same color and same flavor.
⇨ Batch to Batch changeover but lower strength to higher strength.
⇨ After completion of the batch.
⇨ After completion of five consecutive batches or completion of 120 hrs whichever is earlier.
⇨ After any minor breakdown where product conact parts are not disturbed or contaminated as applicable.
⇨ After completion of preventive maintenance work if product contact parts are not touched/disturbed/contaminated.
Advantage of Effective Production Planning:
☞ Reduce labor costs by eliminating wasted time and improving process flow.
☞ Reduce inventory costs by decreasing the need for safety stocks and excessive work-in-process inventories.
☞, Optimized equipment usage and increased capacity.
☞, Improves ongtime deliveries of products and services.
Advantages of Rectal route over oral route
☞ Drugs are not destroyed or inactivated by the pH or enzyme activity of the stomach or intestines.
☞ Drugs may be given without irritation to the stomach
☞ Avoid first pass metabolism after absorption through oral.
☞ It is an effective route in the treatment of patient with vomiting episodes.
☞ The route is convenient for adminitration of drugs to adult, pediatric patients who may be unable or unwilling to swallow medication.
Types of Airlock:
1) Cascade Airlock: Having higher pressure on one side and lower pressure on other side.
2) Bubble Airlock: Having higher pressure inside the airlock & lower pressure both outside.
3) Sink Airlock: Having lower pressure inside the airlock and higher pressure on both sides of airlock.
What type of parameters to be checked before & after dispensing?
☞ Room Condition (Temperature & RH)
☞ Appearance check of the materials
☞ Contamination during weighing
☞ Weighing of incorrect materials.
☞ Weighing of wrong materials.
☞ Weighing into an unclean container.
☞ Weigning into a wrong labeled container.
☞ Check release label.
☞ Check manufacturing test, retest and Expiry date.
Sanitation
Sanitation is the reduction of microbiological contamination. Examples: 70% IPA, Phenolics, Sodium hydroxide, Hydrogen peroxide.
Chapter: Calculation
Batch Size Calculation (In Kilograms)
Batch size in kilograms is the total standard weight of a final product in kilograms.
Example:
Suppose we have a tablet product having 200,000 tablets. Weight of an individual tablet is 300 mg. What will be the total batch size of the product in kilograms?
Solution
It’s simple unit rule calculation and the solution is as follow,
As we know
Weight of 1 tablet is = 300 mg
To calculate the weight of 200,000 tablets simply multiply 300 mg to the batch size of the product in the number of tablets which is 200,000.
So
300 mg×200,000=60,000,000 mg
Convert it in kilograms
So First Convert milligrams into grams as follow
As we know 1gram=1000 mg so divide the above value to 1000 to get value in grams
60,000,000 mg / 1000=60,000 gram
Now convert grams into kilograms.
As we know 1 kg =1000 gm so divide above value with 1000 to get kilograms as follow
60,000 gm/ 1000= 60 kg
Conclusion
The Required standard batch size of our product in kilograms is 60 kg
Hint
A simple rule to remember for weight conversion calculations is that when we have to convert Higher values to Lower values (Kg to mg) then use the multiplication rule.
Multiply kilograms to 1000 to get value in the gram and then again multiply by 1000 to get values in milligrams(kg×1000×1000).
When we have to convert lower values to Higher values (mg to kg) then use the
Division rule.
Divide milligrams to 1000 to get value in the gram and then again Divide by 1000 to get values in kilograms(mg÷1000÷1000).
Batch Size Calculation (In Numbers)
Batch size in Numbers is the total number of units of a final product.
Example
Suppose we have a tablet product having 60-kilograms weight and Weight of individual tablets is 200 mg. What will be the total batch size of the product in Numbers?
Solution
It is also a simple unit rule calculation and solution is as follows.
As we know Weight of 1 tablet is = 200 mg
To calculate the number of total tablets produced from 60 kg use following
Batch Size (In Number) = Batch Size in Milligrams ÷ Weight Of Tablet
So
First of all, convert 60 kilograms into milligrams as follow
60 kg×1000×1000=60,000,000 mg
Divide the value of milligrams by the weight of an individual tablet which is 200 mg in this case.
Or
Put values in the above formula as
60,000,0000/200 mg = 300,000 Tablets
Conclusion
The Required Standard batch size of our product in terms of numbers is 300,000 Tablets.
Tablet Weight calculation
This calculation is helpful when we have numbers of tablets and standard weight of the product in kilograms but we do not have weight of the tablet and we want to calculate the individual tablet weight.
Example
Suppose we have a tablet product having 80-kilograms standard weight and the total batch size in terms of numbers is 200,000 Tablets. What will be the weight of the individual tablet?
Solution
As we know
The standard weight of our product is 80 kilograms and the number of tablets is 200,000 Tablets.
To calculate the weight of individual tablet use following formula
Weight of Tab=Batch Size in mg ÷ Batch Size in numbers
So first we will convert kilograms into milligrams and then we will divide it with the number of tablets as
Weight of Tab= 80 kg ×1000×1000 / 200,000
Weight of Tablet = 400 mg
Conclusion
The Weight of an individual tablet is 400 mg.
Basic API Calculation
This basic calculation helps us to calculate the basic amount of API (Active material) required for specific batch size
Example
Calculate the amount of Metformin HCl required for a tablet formulation having 200,000 tablets and tablet strength is 500 mg/ tablet.
Solution
As we know
A single tablet contains 500 mg Metformin HCl so to calculate Metformin HCl for 200,000 tablets we will use the following formula
Amount of API=Tablet Strength × Batch Size in numbers
For the above example put values in formula as follow
Amount of API = 500 mg × 200,000 =100,000,000 mg
For kilograms divide it by 1000 × 1000 as follow
100,000,000 /1000×1000 = 100 kg
Conclusion
Amount of Metformin HCl required for 200,000 tablets having 500 mg potency is 100 kg
Density Calculation:
Density = Mass/Volume
Friabiliry Calculation
Friability =[(W1-W2)/W1]× 100
LOD Calculation
LOD =[(W1-W2)/W1)]× 100
Moisture content calculation
MC =[(W1-W2)/W2]× 100
Potency Calculation
Required Quantity = (Standard Potency/Potency)× 100
Chapter: Quality Control
Uniformity of Tablets
For uncoated tablets, film coated tablets & hard capsules containing at least 25 mg of drug substance and the drug substance is at least 25% of the dosage form, then variation in weight may be used as a measure of uniformity.
*According go USP: Active less than 25 mg or 25%
* According to IP: Active less than 10 mg or 10%
* According to BP: Active less than 2 mg or 2%
According to USP/BP/IP:
☞ 10 Tablets limit:
⇨ NMT 1 tablet deviate 85-115% & none outside 75-125% of the average value (RSD <
</= 6%)
⇨ If 2 or 3 individual tablet values are outside the limits 85-115% of the average value & none outside 75-125%, repeat for 20 tablets.
⇨ Complies when 30 tablets NMT 3 of the individual values are outside the limit 85-115% of the average value and none outside 75-125%.
Weight Variation of Tablet
According to BP:
| Average weight of tablets | Maximum percentage difference allowed |
|---|---|
| 80 mg or less | 10% |
| 80–250 mg | 7.5% |
| More than 324 mg | 5% |
According to USP:
| Average weight of tablets | Maximum percentage difference allowed |
|---|---|
| 130 mg or less | 10% |
| 130–324 mg | 7.5% |
| More than 324 mg | 5% |
According to IP:
| Average weight of tablets | Maximum percentage difference allowed |
|---|---|
| Less than 300 mg | 10% |
| 300 mg or more than 300 mg | 7.5% |
Friability
Calculation of Percentage of Friability: [(W<sub>1</sub> – W<sub>2</sub>)/W<sub>1</sub>]× 100
Where, W1 = Weight of tablets before testing
W2 =Weight of tablets after testing.
Friability Limit:
According to BP, Percentage of friability should not be more than 0.8%.
According to USP, Percentage of friability should not be more than 1%.
19. What are the Disintegration Time of tablets:
Dispersible Tablets 3 min ( 15- 25º C ) as per BP.
Soluble Tablets 3 min ( 15- 25º C ) as per BP.
Effervescent Tablets 1 tablet in 200 mL water for 5 min ( 15- 25º C )
as per BP
Uncoated Tablet 15 min as per BP & 30 min as per USP
Film Coated Tablet 30 min as per BP
Plain Coated Tablets DT in specific medium for 30 min as per USP
Sugar Coated Tablet 60 min as per BP
Enteric Coated Tablets DT in simulated gastric fluid (0.1 M HCl) for 1 hr and then in simulated intestinal fluid (Phosphate buffer 6.8 pH) until disintegrate as per USP. [2 hr as per BP.]
Buccal Tablets 4 hrs as per USP.
Chewable Tablets are not require to comply with test
20. What is Disintegration Time of capsules :
Gastro resistant capsule DT 2 hrs without disk in 0.1 M HCl and phosphate buffer pH 6.8 for further 60 min as per BP.
Hard and Soft gelatin capsule DT 30 min as per BP & USP.
Water Analysis
Purified Water
| Test Parameters | Accepatance Criteria | Method Reference |
|---|---|---|
| Description | Clear, colorless, Odorless liquid | USP 43 |
| pH | 5.00–7.00 | USP 43 |
| Conductivity | NMT 1.30 at 25°C and 1.10 at 20°C | USP 43 |
| TOC | NMT 500 ppb | USP 43 |
| Nitrates | NMT 0.2 ppm | BP 2023/Ph.Eur 11.0 |
| Total Viable Count (TVC) | NMT 100 CFU/mL | USP-43 |
Water for Injection
| Test Parameters | Accepatance Criteria | Method Reference |
|---|---|---|
| Description | Clear, colorless, Odorless liquid | USP 43 |
| pH | 5.00–7.00 | USP 43 |
| Conductivity | NMT 1.30 at 25°C and 1.10 at 20°C | USP 43 |
| TOC | NMT 500 ppb | USP 43 |
| Nitrates | NMT 0.2 ppm | BP 2022/Ph.Eur 10.0 |
| Total Viable Count (TVC) | NMT 10 CFU/100 mL | USP-43 |
| Bacterial Endotoxin Test | NMT 0.25 EU/mL | USP-43 |
Potable Water
| Test Parameters | Accepatance Criteria | Method Reference |
|---|---|---|
| Description | Clear, colorless, Odorless liquid | In house |
| pH | 6.50–8.50 | In house |
| Conductivity | NMT 250 uS/cm | In-house |
| Total Hardness | NMT 500 mg/L | In-house |
| Heavy metal | NMT 0.1 mg/L | In-house |
| Iron | NMT 0.3 mg/L | In-house |
| Arsenic | NMT 10 ppb | In-house |
| Free Chlorine | NMT 0.4 mg/L | In-house |
| Total Viable Count (TVC) | NMT 500 CFU/mL | USP-43 |
Effluent Treatment Plant Water (ETP Water)
| Test Parameters | Acceptance Criteria | Reference Method |
|---|---|---|
| Description | Visual Inspection | In-house |
| pH | 6.00 to 9.00 | ECR-2023 |
| Total Dissolved Solid (TDS) | NMT 2100.0 mg/L | ECR-2023 |
| Dissolve Oxygen (DO) | 4.5 to 8.0 mg/L | In-house |
| Chemical.Oxygen Demand (COD) | NMT 200 mg/L | ECR-2023 |
| Biological Oxygen Demand (BOD) | NMT 30 mg/L | ECR-2023 |
| Total Suspended Solid | NMT 100 mg/L | ECR-2023 |
Chapter: Quality Assurance
What is Hold time Study?
Hold Time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not degrade significantly during the hold time at a required temperature and Relative Humidity.
Hold time can be considered as the established time period for which materials (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications. Hold-time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not produce results outside the acceptance criteria during the hold time.
What is the difference between dedicated and non-dedicated equipments
Dedicated equipment: It is used solely for the production of a single product or product line. Concerns over cross-contamination with other products are markedly reduced. Dedicated equipment’s must be clearly identified with the restrictions of use in order to prevent potential errors during cleaning and preparation.
Non-dedicated equipment: Where the same piece of equipment is utilized for a range of products formulations. The prevent of cross-contamination between products becomes the main objective in the cleaning validation effort. Clearly, cleaning non-dedicated equipment’s represents a more significant obstacle to overcome.
Which instrument is used for the measuring of RPM
Techo meter is used for the measurement of RPM.
63. What is HACCP
HACCP : Hazard Analysis Critical Control Point
64. What is OHSAS
OHSAS : Occupational Health & Safety Assessment Series
10 Golden Rules of GMP
1. Get the Facility Design Right from the Start
A well-designed facility prevents cross-contamination, allows smooth workflow, and ensures hygienic operations.
2. Validate Processes and Systems
All manufacturing processes, cleaning, equipment, and systems must be validated to consistently produce quality products.
3. Write Good Procedures and Follow Them
Standard Operating Procedures (SOPs) must be clear, approved, and followed exactly to ensure consistent practices.
4. Identify Who Does What
Roles and responsibilities must be well-defined and understood by all team members involved in GMP processes.
5. Keep Good Records
Documentation is key — if it’s not recorded, it didn’t happen. Every step must be traceable through accurate records.
6. Train and Develop Staff
Personnel must be trained regularly on GMP principles, SOPs, and job-specific requirements to maintain compliance and competency.
7. Practice Good Hygiene
Employees must follow strict personal hygiene and gowning procedures to avoid contamination of products.
8. Maintain Cleanliness and Order
Work areas must be clean, organized, and free of clutter to ensure safe and efficient operations.
9. Prevent Cross-Contamination
Implement physical and procedural controls (e.g., airlocks, equipment cleaning, line clearance) to avoid mix-ups or contamination.
10. Perform Regular Self-Inspections
Conduct internal audits regularly to identify gaps and continuously improve GMP compliance.
What will happen if cGMP are not followed
☞ Poor quality of product / services
☞ Batch failure
☞Market complaints and product recalls
☞ Company’s reputation will be affected
☞ Business will be affected
☞ Regulatory action
☞ Injuries or accidents
☞ Equipment failures
| Dry Granulation | Wet granulation |
|---|---|
| No solvent us used. | Suitable solvnt is used. |
| Production cost is less. | Production cost is high. |
| Very simple process. | It is complex process. |
| Little chance of contamination | As water is used, contamination may be required |
| Required when producing tablets from highly moisture and heat sensitive compounds. | Required to avoid the destruction of active components in the powder. |
| Requires finely powdered conpound and tablet pressers or roll compactors | Requires powder particles, a granulating fluid and a shieve. |
| Dry Granulation | Wet granulation |
|---|---|
| No solvent us used. | Suitable solvnt is used. |
| Production cost is less. | Production cost is high. |
| Very simple process. | It is complex process. |
| Little chance of contamination | As water is used, contamination may be required |
| Required when producing tablets from highly moisture and heat sensitive compounds. | Required to avoid the destruction of active components in the powder. |
| Requires finely powdered conpound and tablet pressers or roll compactors | Requires powder particles, a granulating fluid and a shieve. |
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