Innopharma Module: Tablet and Capsule Manufacturing

Innopharma Module Overview

• This module offers insight into Tablet and Capsule manufacturing and packaging processes
• The online course is designed to be informative, engaging, and easy to use, and includes an assessment
• The module reviews drug discovery, development, clinical trials, pharmaceutical dosage forms, solid dose, biopharmaceutical drug manufacturing, and a basic process map

Drug Discovery and Approval

• Section two examines new drugs and the sources used to create compounds
• Initial animal tests serve as toxicology studies
• Four trial development phases determine the potential drug's effects on humans and its suitability as medicine
• New drug development means identifying or creating a compound that serves a specific use
• Biotechnology, exemplified by the Human Genome Project, is significant in current drug research initiatives
• Discovering a new drug is difficult, costly, and time consuming
• Computer-assisted drug design techniques display the 3-D structure of a biological target and design an interacting molecule
• Researchers use libraries containing numerous molecules, screened against in-vitro biological targets
• Biotechnology advances provide researchers with new biological targets like cell membrane channels and complex biological proteins
• Compounds undergo testing to ensure they are both effective and safe
• Many compounds fail to make it through testing

Toxicology

• Toxicology studies are performed on animals before a compound can be used in humans
• Commonly used mammalian species include rats, rabbits, and guinea pigs
• Specific strains of purpose-bred animals can be used depending on the type of drug being tested
• Tests on male and female animals are conducted to study reproductive toxicology
• Clinical trials commence only when animal studies suggest the drug is safe and shows some efficacy
• Clinical trials must adhere to Good Clinical Practices which dictates trials should be agreed upon with regulatory authorities

Trial Development Phases

• Medicine development involves four trial phases
• Phase I trials are typically performed on healthy, young, male volunteers in groups of 10-80
• Safety is the main concern during Phase I to assess how the drug is Absorbed, Distributed, Metabolised, and Excreted (ADME) by the body
• The ADME process is also known as pharmacokinetics
• Drug effects, or pharmacodynamics, confirm a safe dose for Phase II trials
• Phase II trials examine the effects of the drug on the body while focusing on factors related to the disease in 100-200 patients
• Phase II may involve some healthy volunteers as well
• At Phase II close, dose-ranging studies confirm the maximum tolerated dose is safe and somewhat effective
• Phase III trials involve larger patient numbers who have a particular disease, and are usually conducted as randomised, comparative, double-blinded studies.
• Active drugs already well established for the disease under investigation may be used
• Typically several thousand patients are exposed to the investigational drug in Phase III, reinforcing efficacy and safety
• Phase III improves the determination of the appropriate dose range
• Cost-effectiveness is sometimes analysed during Phase III trials, while regulatory authorities may require multiple Phase III trials
• Infrequent adverse events may only be detected after extensive use
• Phase IV trials are randomised and controlled, being undertaken after the registration of the new medicine
• Phase IV answers important questions, helping to determine the clinical position of the drug in terms of use, cost-effectiveness, and safety profile

Regulators

• Regulators study evidence of new drugs chemistry, manufacturing, animal toxicology, and clinical studies
• Regulators also evaluate drug methodological quality, efficacy, and safety. This is known as 'the first three hurdles'
• New medicines must have the correct benefit to harm ratio in order to be registered to a controlled patient group
• After medicine approval, a Marketing Authorisation (MA) is given for the relevant country
• The MA holder decides where to manufacture the new drug and obtain the relevant license

Solid Dose Manufacturing

• Section three examines the differences between solid dose and biopharmaceutical manufacturing, focusing on solid dose pharmaceuticals
• The Active Pharmaceutical Ingredient or API for a solid dose pharmaceutical is usually manufactured in bulk
• The active ingredient is commonly a powder
• Tablets cannot consist solely of the API
• Pharmaceutical manufacturing raw materials are classified as either Active Pharmaceutical ingredients or as Pharmaceutical Excipient ingredients (Excipients)
• Tablet formulation is a list of all ingredients as a percentage of the weight
• The correct raw material weight is calculated to manufacture a batch and dispensed in a controlled environment where correct labeling is important to prevent errors
• API manufacture has many steps from simple chemical synthesis, to complex synthesis
• APIs move to drug product manufacturing once manufactured and tested
• Solid dose manufacturing can be a Basic Manufacturing Process e.g. direct compression tablets or a complex one involving ten process steps: mixing, granulation, drying, milling, blending, compression, seal coating, sorting and printing
• Most products contain one API, however some products contain 2 APIs
• The second API (referred to as an Atypical API) supports the action of the main API

Materials Usage

• API, diluents, disintegrants, binders, glidants, wetting agents, lubricants and film coats are materials used in tablet formulations
• APIs provide patients with desired results and benefits, but the other components are also important
• Diluents, known as fillers, bulk out the formulation to provide an effective dosage such as lactose, dicalcium phosphate, microcrystalline cellulose, and mannitol
• Formulations consist of brittle, plastic and ductile substances, resulting in a mixture that compresses well
• In direct compression formulations, diluents have to be free flowing, dense and within a narrow particle-size distribution.
• Spray-dried lactose is often used, as it flows well due to its spherical particle shape
• Spray-dried lactose also has good tableting properties due to its ductile behavior
• In wet granulation products, these things are less critical
• Material from different suppliers has different physical properties, even if the chemical composition is the same.
• Diluents compress through fragmentation or deformation
• With ductile materials, part of the deformation is elastic, so the material returns to its original shape as tablet punches return to their position
• Fast press speed means rapid release of elastic energy, weakening the tablet and causing lamination or capping
• Disintegrants are included to encourage disintegration of the tablet in the stomach by swelling up to many times their original size on contact with water, causing disruption
• Common disintegrants include Sodium, Starch, Glycollate, Croscarmellose Sodium and Cross-linked Povidone
• Effervescent disintegrants release carbon dioxide causing typically sodium bicarbonate and citric acid
• During compression, binders assist adhesion of the formulation and are added during granulation as dry powders or in a slurry solution
• Common examples of binders in wet granulation include: Hydroxypropylmethyl Cellulose, Pregelatinised Starch, Povidone

Mixing and Solid Dose Products and Their Production

• Dry binders can achieve high degrees of deformation, such as microcrystalline cellulose via direct compression
• Glidants such as Silicon Dioxide and Calcium Silicate reduce inter-particle friction assisting the flow
• Lubricants like magnesium stearate are added to facilitate tablet ejection from the die and prevent sticking as it is the most effective lubricant used
• Magnesium stearate has a sheet-like structure which helps increase their relative coverage on the granules.
• Magnesium stearate is hydrophobic and incompressible
• Over mixing or too much magnesium stearate may transfer these properties onto the granules, adversely impacting tablet mechanical strength and disintegration
• Magnesium Stearate materials are only mixed for a short time to avoid full homogeneity
• Solid dose products will include at least one mixing process with the active drug to ensure homogeneity
• Cohesive and Adhesive forces play a significant role during mixing
• Cohesion is the attraction of powder particles to each other by intermolecular forces and is important in mixing and segregation
• Mixing cohesive materials is harder than non-cohesive
• Adhesion is the attraction of particles to surfaces of process equipment
• Individual particles in an agitated bed are dilated via Shear, Diffusive, or Convective
• Mixing processes need to suit the batch size, or the batch will either slide over the surface instead of blending, or there will not be enough space for blending

Solid Dosage Form - Mixing and Sampling

• Shear mixing forms a slip plane in the powder bed, shifting the bulk of the powder
• Diffusive mixing interchanges particles across an interface within the mix
• Convective mixing shifts groups of particles around
• The success of mixing exercises is determined by sampling
• Sample size should reflect the end product size, taking account of the batch size and blending operation
• Supplementing bulk blend sampling with compression run samples accounts for demixing or segregation
• High adhesion and cohesion leads to bridging of the powder above the discharge orifice, disrupting powder flow
• High cohesion and shallow hopper wall angles create core or tunnel flow, also known as Rat-holing where there are dead spots of powder
• Desired flow with all powder in motion is called mass flow
• Mass flow a function of cohesion and adhesion properties of the powder, hopper design, and the surface finish
• Segregation happens when smaller or denser particles move down through inter-particulate voids to the blend bottom, so similar size differences may cause segregation
• Segregation may stop achievement of random mix
• Segregation may alter the density of powder throughout the compression run needed for tablet weight, which depends on the fill volume
• Segregation causes a migration of active ingredients which affects the tablet assay
• Segregation can be minimised by trying to make consistent components with close particles and sizes
• Reduce free-flowing particles by lowering size or making rougher granulation which binds components together
• Materials can compact on storage/transport, forming clumps that impact efficient blending
• Sieving or screening breaks down clumps
• Avoid clumping by reducing the residual moisture or solvent levels in the powder

Blending Options and Solid Dosage Manufacturing

• Blending has several options once the mix is compiled such as bin, barrel, or V blenders
• A important quality outcome is blended homogeneity
• Blended homogeneity depends on blender speed (the mixing intensity) and blend time (the duration)
• If completed effectively, the blend is discharged into an IBC to await compression
• Processing steps after mixing are compressing, compacting, tablet compression, coating, extrusion/ spheronisation, and packaging
• Granulation forms larger, manageable granules by combining powders. For example, granulated sugar is easier than powdered sugar, which flows, compresses badly, and must be compressed slowly to make tablets
• Tabletting characteristics improve after granulation
• The granulation process is dry or wet
• Dry granulation needs pressure to force the particles together
• Wet granulation uses high shear granulator which has a three bladed impeller, chopper blades, and stainless steel product bowl
• Product drums first adds ungranulated material to the product bowl
• Once dry ingredients are mixed according to batch instructions, a binding solution is slowly added

Solid Dosage Manufacturing Formulation and Its Processes

• Granulating requires certain material properties such as particle size distribution, moisture content, solubility, ability to absorb binding solution, and surface roughness
• Granulation creates dense, flowable materials with controlled particle size to improve content uniformity and provides control of hazardous or dusty materials
• the agglomerates, that are made in high shear granulators, are harder and denser than in the fluid bed agglomeration process.
• A good granule is spherical, with a narrow particle size distribution, flows easily and remains stable
• Choppers improves binder distribution and granulation at low/moderate impeller speeds
• Mixing continues until the granule size/density conforms to the product parameters
• Endpoint is determined by indirectly measuring torque change
• Torque increases as the increases granules in size, needing more power to maintain RPM
• Once a torque is reached, the granules are at the proper size

Fluid Bed Granulator And Its Processes

• The fluid bed granulates and dries previously prepared granulation
• The Fluid Bed’s main kit are the control panel, air plenum, product container, explosion chamber, exhaust system
• Product from storage can be agglomerated and require delumping; comminutors break up the materials into uniform sizes
• Once the material is sufficiently delumped, it is placed in the fluid bed through drum lift
• The product container secures where the material remains while the bed is idle with the expansion chamber
• Air releases to exit as a filter to retain the product
• Application area allows decelerated product to retain momentum
• The explosion chamber is designed to explode outwards if something goes wrong
• The airflow draws in and maintains vacuum through the airflow which is critical to keep variables uniform
• Correct airflow is one of the major factors of affect filtration with a fixed position
• The separate and fluidise space allows more separate as airflow increases
• Binder is added to dry power and atomises with the air and creates droplets
• Then drying starts after correct amount the liquid is added
• Then heated air mixes and sampling
• Lab analyzes moisture levels that will lead to the next process
• Comil is used when additional milling is needed
• In dry granulation granules are formed and formed to be sensitive and resistive
• The Compactor eliminates segregation and ensures uniformity reducing waste and cross contamination
• It improves material and controls properties, while it decreases waste
• Harder granular particles are used for resistance and the the rates influence dissolution, digestion, and tablets
• Powder particles consolidate when mechanically pressured using two rolls to produced compressed material
• It then delivered to a upper feed with flow measurements and even the flow
• Vertical Feed pre-treats the material and the arrangement allows compaction at usually 130Kn force
• The product is then fed for minor milling
• Then it decreases the compact with impact and assures consistent results
• Knide-edge and impact help the assembly The screens ensure and blade ensures sizing Tests make sure right sample and size are used

Solid Dose Processing

• There are 2 tests to make sure product is working with the test
• Proper grams product make sure right analysis
• Different size screens help the seive
• Seives are stackable with mash and pans
• Introduces shaker which separate compounds
• Each section determine matter
• Tablet compression machines up to 10k tablets a minute test includes hardness and balance Important steps include fill and metering
• Filing and turrent punches help push
• The vacuum and padding mixes with pressure
• It is a high part which is metering and controls the output with the fill levels and cams
• Granules make it that length is variable by resulting is problems
• Then push excesses out to the sides Punch can be be shaped
• Cleanliness and designs also help The wheels help the roll in Air and the air gets pushed to the chamber
• It creates to release the press and makes it harder and by making it hard
• It has compression and that force is required

Weight Parameters and Thickness

• Limits have to be rejected and shut down
• The stage ejects
• All most important quality outcomes is weights
• Major limits helps thickness to be tested
• There also machines such as those that check the dust is out and are sampled and help ensure that is the case
• The mix film helps with coating
• Helps with shellac eudragit and makes it apply both by film and sugar
• Angle keep the mix going is important
• It regulated temperature for correct drying and prevents dust entering
• Heated pressure also needed
• The aim is it correct with the distance
• Coating is also important that will be dispersed

Film Coating Process

• Has stages

1. The blend will coat and moisture evaporates per layer
2. With increased evaporation the is less moisture
3. Is is very balanced or a problem occur Strict process make sure to watch Adjustments also help it is one

• Colour coating is another major need
• The correct angle should be sprayed Chips can be resolved with angle and rate
• Edge reduce means chips can get made
• Then mix if they are stuck with it means product or drying
• And balance the spray

Tablet Processing and Coatings

• If the erosion exist the speed can adjusted with hardness being resolved
• Peeling results
• Then reformulate more if needed
• If it’s also too thick it can be resolved with texture analysis
• There also a coating process which synchronize the mix
• It is important parts such as water color and solvent with plasticisers/polymers
• It is important to protect a certain product Coatings can helps if there is problems
• In general sugar coating
• Automation often help
• Low intensity mean it is not in depth enough
• In printing, product flows with levels
• Rollers and feed are helpful for pressure at a point
• Then stripping and and an angle and a stripper blade
• All products reviewed for printing and inspected
• It then verified verified and rejected
• It vacuums and released

Encapsulation Methods and Spheronization

• Extrusion and spheronisation follows these processes to achieve controlled properties
• Material mix fed into it to be moved with and it can then extrude
• Segmented, or pellets are made and fed to a spheroniser
• This processes makes rounded, spherical or spheroid products for controlled release
• Rounded results need the least material
• After the materials is thrown together the pellet makes ropes
• The mix collides and spheronises
• One more good outcome which is there is less by product
• Fines get removed with the batch
• They depend on formulation dependent
• Then capsule, weight and interfaces
• Capsules are made with materials and are edible in all colors of forms
• This process achieves all steps
• This includes orientations which the lever releases.
• As it beaks a direction is selected and suction helps make sure it the casing
• And the transfer is then put in the proper unit
• Suction helps it run on the right ring
• There two sections of parts which the vacuum that pushes
• The measure helps level the capsules
• Pistons and and areas level helps the form with is helped
• This causes for product to release
• Then the machine returns and it runs the same system and cycle
• Closing happens over and again without stop
• Vacuum continues with the loop
• Capsule weights are inspected
• Low factors and there is no good problems
• This can be seals and air or excessive damage
• More parts allow for filling
• And make more ribbons allow to go faster

Tablet Packaging and Conclusion

• Packing done within blisters
• Blisters made with certain metals and are sealed correctly
• Then we packed safely and prevent damage and are safe
• Each has a number
• Ensure a clear list of chain commands are good
• Include anti-fake and radio identifiers
• To ensure labels are right and safe
• And that GDP procedures follow that process
• The capsule follows the proper set practices
• To know this capsule and is all for training