Innopharma

Tablet and Cap

Section 1 – Introduction
1.01: Introduction
This Innopharma module is an overview of Tablet and Capsule manufacturing and
packaging processes. The online learning environment is designed to be informative,
engaging and above all, simple to use. A short assessment follows.

1.02: Module Objectives

This module reviews the following:
• The basic steps and activities in drug discovery, development and clinical trials.
• Different pharmaceutical dosage forms.
• Processes for solid dose and Biopharmaceutical drug manufacturing.
• A basic Process Map identifying the inputs, outputs and processes.

Section 2 – Drug discovery and approval

2.01: Introduction
In this section, new drugs, and the sources used to create a compound are examined.
Initial tests are conducted on animals as a toxicology study. The four phases of trial
development determine the effects that this potential drug can have on human patients,
and whether it is fit to be manufactured as a medicine.

2.02: Drug discovery

• New drug development identifies or creates a compound for a specific use.
• Biotechnology is important in current drug research initiatives such as the Human Genome Project
however, discovering a new drug is difficult, costly and time consuming.
• Computer-assisted drug design techniques are used to show the 3-D structure of a particular biological
target and to design a molecule that interacts with it.
• Drug researchers also have access to libraries containing large numbers of molecules, which are
screened against multiple in-vitro biological targets.

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• Recent advances in biotechnology have provided researchers with new biological targets such as cell
membrane channels and complex biological proteins.
• New compounds undergo testing to ensure that they work and are safe. However only a small number
make it through this testing.

2.03: Toxicology
• Toxicology studies in animals are conducted before a compound can be used in humans.
• Usually three mammalian species are tested; such as rats, rabbits and guinea pigs.
• Depending on the type of drug being tested, specific strains of purpose-bred animals are also used.
• Reproductive toxicology tests on male and female animals are conducted.
• When animal studies suggest that the drug is safe for human testing and that the drug candidate has
some efficacy, clinical trials begin.
• Clinical trials must be conducted according to Good Clinical Practices, which define strict conditions
for the duration of the trial, as agreed with the regulatory authorities.

2.04: The Four Phases of Trial Development

• There are four phases of trials in the development of a new medicine.
• Phase I trials are typically conducted in healthy young male volunteers in groups of between 10 and 80.
• Safety is the overriding factor, and this phase of the trial is designed to assess how the drug is
Absorbed, Distributed, Metabolised and Excreted (ADME) by the body.
• This process is known as pharmacokinetics.
• The effects of the drugs (or pharmacodynamics) confirm what constitutes a safe dose for phase II trials.
• Phase II trials examine the effect the drug has on the body, (pharmacodynamics), focusing on factors
linked to the disease, which the drug is being developed to treat. These studies are usually conducted
in 100-200 patients with the disease, however, some healthy volunteers may be involved. At the close of
Phase II, dose ranging studies confirm that the maximum tolerated dose is safe and somewhat effective.
• Phase III trials involve larger numbers of patients with a particular disease or condition, and are usually
conducted as randomised, comparative and double-blinded studies.
• The comparator is either a placebo or an active drug already well established as treatment for the
disease under investigation.
• Typically, several thousand patients are exposed to the investigational drug in Phase III, which reinforces
efficacy and safety to better determine the appropriate dose range.
• The cost-effectiveness of a drug is sometimes analysed during Phase III. Several Phase III trials are
sometimes required by the different regulatory authorities.
• Uncommon adverse events may not be detected until extensive use.
• Phase IV trials are usually randomised controlled and undertaken after the new medicine has been
registered. They answer important questions which help determine the drug’s clinical position such as
its position use, cost-effectiveness, and safety profile.

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• Phase IV trials may be large studies involving thousands of patients for several years and allow broader,
more realistic patient groups to be studied.
• Once the Phase I to III programme is complete the sponsor compiles all the relevant data in a Common
Technical Dossier (CTD), which is assessed by the relevant regulatory authority.

2.05: Regulators
• The regulators examine the evidence relating to the chemistry and manufacturing of the new drug, the
animal toxicology, and the clinical studies. The methodological quality, the efficacy and safety of the
drug is evaluated. This is known as ‘the first three hurdles’.
• A new medicine must have an acceptable benefit: harm ratio in a well-defined patient group to allow it
to be registered.
• Once the medicine has been approved, a Marketing Authorisation (MA) is issued for the relevant
country.
• The MA holder must decide where to manufacture the new drug and obtain the relevant licence.

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Section 3 – Solid dose manufacturing
3.01: Introduction
This section will examine the key differences between solid dose and biopharmaceutical
manufacturing and look at the manufacturing of solid dose pharmaceuticals.

3.02: Active Pharmaceutical Ingredient (API)

• The Active Pharmaceutical Ingredient or API for a solid dose pharmaceutical is typically BULK
manufactured.
• The active ingredient is usually powder format.
• It is not possible to make a tablet consisting of only the API.
• Pharmaceutical manufacturing raw materials are classified into two groups:

Active Pharmaceutical ingredients Pharmaceutical Excipient ingredients (Excipients)

The tablet formulation is a list of all the ingredients expressed as a percentage of the weight.

3.03: Dispensing and Weighing

• The correct weight of raw materials is calculated to manufacture a batch and dispensed in a controlled
environment. Correct labelling prevents errors.
• The manufacture of the API comprises of many different processes, from simple chemical synthesis, to
extremely complex synthesis.
• Once the API is manufactured and tested, it is usually moved to a location for the drug product
manufacturing process.

3.04: Drug Product Manufacturing

Solid dose manufacturing can be a Basic Manufacturing Process e.g. direct compression tablets or it can
be a Complex Manufacturing Process involving ten process steps including: mixing, granulation, drying,
milling, blending, compression, seal coating, sugar coating, sorting and printing.
Most products contain one API, however some products contain 2 API’s for example:

Paracetamol and Codeine Paracetamol, diphenhydramine Paracetamol, diphenhydramine

The second API (referred to as an Atypical API) supports the action of the main API.

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Section 4 – Solid dose manufacturing processes I
4.01: Introduction
This module will look at the manufacturing processes involved in solid dose
manufacturing.

4.02: Materials, mixing, and blending

• Mixing and weighing are important stages of pharmaceutical manufacturing processes.
• The typical materials used in tablet formulations are as follows: the API, diluents, disintegrants, binders,
glidants, wetting agents, lubricants and film coats.
• APIs provide the desired benefit to patients, but the other components are also important.
• Diluents, also known as Fillers, are used to bulk out the formulation to provide a suitable dosage form.

These include:

Lactose Dicalcium Phosphate Microcrystalline

Anhydrous Cellulose Mannitol Sucrose

• Ideal formulations consist of brittle, plastic and ductile materials, resulting in a mixture which
compresses well. In direct compression formulations, the diluents also have to be free flowing, dense
and within a narrow particle-size distribution.
• Spray-dried lactose is often used, as it flows very well due to its spherical particle shape.
• It also possesses good tableting properties due to its ductile behaviour.
• For wet granulation products, these properties are less critical.
• Material from different suppliers often has different physical properties, even if the chemical
composition is the same. These differences can be difficult to test, predict, and can impart different
properties.
• Diluents typically compress by either fragmentation or by deformation. When ductile materials deform,
a small part of the deformation is elastic which means that the material tends to return to its original
shape when the tablet punches return to their original position during compression. Too fast a press
speed can result in rapid release of elastic energy, weakening the tablet, potentially causing lamination
or capping.
• Disintegrants are included in the formulation to aid the disintegration of the tablet in the stomach.
• They act 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 work by releasing carbon dioxide following reaction between, typically
sodium bicarbonate and citric acid.
• Binders assist adhesion of the formulation during compression. They are usually added during
granulation as dry powders or in a slurry solution.
• Common examples of binders in wet granulation are:

Hydroxypropylmethyl Cellulose Pregelatinised Starch Povidone (known as Polyvinylpyrrolidone or PVP)

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• In direct compression, dry binders with a very high degree of deformation properties are used, such as
microcrystalline cellulose.
• Glidants, such as Silicon Dioxide and Calcium Silicate reduce inter-particle friction assisting the flow.
• A lubricant is added to facilitate ejection of the tablet from the die and prevent sticking.
• Magnesium Stearate, is the most effective lubricant used.
• It has a sheet-like structure and increases their relative coverage on the granules.
• Magnesium stearate is hydrophobic and incompressible.
• Excessive amounts or over mixing can transfer these properties onto the granules, adversely impacting
tablet mechanical strength and disintegration.
• Therefore materials such as Magnesium Stearate is mixed for a short period of time, but not mixed to
full homogeneity.

4.03: The mixing process

• All solid dose products will include at least one mixing process with the active drug substance being
tested 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 of cohesive materials is more difficult than non-cohesive.
• Adhesion is the attraction of particles to surfaces of process equipment.
• The three mechanisms by which individual particles in an agitated bed are dilated and dispersed are:

Shear Diffusive Convective

• For mixing processes the size of the blending vessel must suit the batch size.
• If the batch is too small, then it slides over the surface rather than blending.
• If the batch is too large, then there may be insufficient space for adequate blending.
• Shear mixing occurs when a slip plane is formed in the powder bed and the bulk of the powder on either
side of the plane moves as a body.
• Diffusive mixing occurs when an interchange of particles takes place across an interface, usually a slip
plane, within the mix.
• Convective mixing involves the movement of groups of particles from one place in the powder bed to
another.

4.04: Sampling
• The success of mixing exercises is usually determined by sampling.
• The sample size should reflect the size of the finished product with the number and position of samples
taking into account the batch size and the blending operation.
• Sampling from the bulk blend should be supplemented with samples throughout the compression run
to take into account possible demixing or segregation.
• High adhesion and cohesion can lead to bridging of the powder above the discharge orifice which can
disrupt or even stop powder flow.

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• High cohesion and shallow hopper wall angles can also lead to core or funnel flow, also known as
Rat-holing. This is when there are dead spots in the powder which are not in motion.
• The desired flow where all the powder is in motion is called mass flow.
• It is a function of the cohesion and adhesion properties of the powder, the hopper design and the
roughness or smoothness of the surface finish.
• Segregation in blends occurs as smaller or denser particles move down via inter-particulate voids to the
bottom of the blend. The relative size differences do not need to be large for segregation to occur.
• Segregation can adversely impact our processes as it.
• May not allow us to achieve a random mix.
• May alter the density of the powder throughout the compression run (the tablet dose is reliant on
tablet weight, which is reliant on fill volume).
• May lead to a migration of active ingredient which could affect the tablet assay.
• Segregation in blends can be minimised by:
• Trying to make constituent components.
• Particle size, density and shape as close as possible.
• Making particles less free flowing by reducing their particle size, or by making them rougher
granulation, which binds the different components together.
• Finally, raw materials and blends often compact upon storage or transport, forming agglomerates or
clumps which impact upon efficient blending and even distribution of the blend components.
• This can be mitigated by sieving or screening prior to dispensing to break down agglomerates or clumps.
• Clumping can also be avoided by reducing the residual moisture or solvent levels in the powder.

4.05: Blending
• Once the mix has been compiled, there are a number of blending options available: Bin Blender, Barrel
Blender, V Blender.
• The most important quality outcome of the blending is blend homogeneity, or uniformity after mixing.
• This is dependent on: Blender speed, (the intensity of the mixing action) and Blend time (the duration).
• On completion, the blend is typically discharged into an Intermediate Bulk Container, also known as an
IBC, to await compression.

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Section 5 – Solid dose manufacturing processes II
5.01: Introduction
This module examines the last stages of drug manufacturing from granulation through to
packaging.

5.02: Granulation
After the mixing process the next steps in drug manufacturing typically are:

Granulation Compaction Extrusion and Spheronisation

Tablet Compression Coating Packaging

• Granulation involves combining powders with one another to form larger, more manageable granules.
For example, granulated sugar is easier than powdered sugar to compress. It consists of small particles,
which flow, compress badly and have to be compressed slowly to make a tablet.
• After granulation, tabletting characteristics are improved relating to flow, compressibility and
uniformity.
• The granulation process can either be a dry granulation, where pressure is used to force the particles
together, or by wet granulation.

5.03: Wet Granulation

• Wet granulation uses a high shear granulator, consisting of a large stainless steel product bowl, a three
bladed impeller and chopper blades.
• Ungranulated material is first added to the product bowl from the product drums.
• The product bowl is raised into position.
• When in place, the dry ingredients are slowly mixed according to the batch record instructions.
• When sufficient mixing occurs, a binding solution is added.

5.04: Granule Formulation

• To continue the manufacturing process, granulation is required.
• Raw material properties that impact the process include particle size distribution, moisture content,
solubility in the binding solution, ability to absorb the binding solution and surface roughness.
• Granulation produces dense, flowable materials with a controlled particle size that improve content
uniformity, while providing control of hazardous or dusty materials.
• The agglomerates formed in the high shear granulator are generally 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 enable better binder distribution and granulation at low/moderate impeller speeds.
• Mixing continues until the granule size/density occurs according to the product parameters.

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• For certain products, the end point of the process is determined by indirect measurement of the
changes in torque on the main impeller shaft.
• Torque increases as the granules increase in size, as more power is needed to maintain a constant RPM.
• When a certain torque is reached, the granules have reached the required size.

5.05: Fluid Bed Granulator

A Fluid Bed granulates and dries granulation which has been prepared through other processes. The Fluid
Bed’s key components are the Control Panel, Inlet Air Plenum, Product Container, Expansion Chamber,
Explosion Chamber Inlet air Handler and the Exhaust system.

5.06: Fluid Bed Granulation Process

• Overly moist product or product from storage may have become agglomerated and require delumping.
• A comminutor breaks up the material into clumps or agglomerates within a more uniform size range.
• Once sufficiently delumped, the product is then charged into the fluid bed using a drum lift or more
commonly via a dust-reducing vacuum charging system.
• The Product Container is the area where the material will remain when the bed is idle.
• The Expansion Chamber allows the product bed to expand and maintain fluidisation.
• This is the application area for the granulating solution and the deceleration zone, which allows the
product to lose momentum before being re-circulated into the bed.
• Filters allow for air to exit the fluid bed while retaining the product.
• The explosion chamber is designed so that if an explosion occurs it will explode upwards and outwards.
• The exhaust system draws the airflow creating a vacuum inside to maintain fluidisation.
• Product movement is critical in this process, and when combined with other variables such as
temperatures and humidity, will result in a consistent particle size and uniform granulation.
• Inlet airflow is one of the main factors that affect fluidisation.
• At low airflow, the material exists as a fixed or packed bed.
• As the airflow increases passes through the bed via void spaces, the particles seperate and fluidise.
• During the process, a binder solution is added to the dry powder, which mixes with atomising air in
the spray gun assembly, and different tip sizes, creating droplets, forming liquid bridges between the
particles.
• Once the correct amount of binder has been added, the drying process begins.
• Heated air is fed to the product to evaporate moisture.
• Continuous mixing in the Fluid Bed means that efficient and thorough drying can be accomplished
• Samples are taken within the product bed and measured to verify drying uniformity.
• A moisture analyzer determines moisture content based on prescribed weighing-drying methods.
• Upon completion the material is discharged to the next process.
• If additional milling is required, a COMIL can be used to achieve a desired granule size range.

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5.07: Roller Compaction
• In the dry granulation process, granules are formed without using a liquid solution.
• Dry granulation is used when the product is sensitive to moisture and heat.
• Forming granules without moisture requires compacting and densifying using a roller compactor.
• Roll Compaction eliminates segregation and produces uniformity for enhanced control.
• It improves material flow properties, controls bulk density, particle hardness, and dust, which decreases
waste and cross contamination.
• Harder particles are used to resist breakdown, while softer particles facilitate further processing.
• It improves solution dispersion rates which affect the digestion of tablets/capsules.
• Granular product is easier wetted in liquid than fine powders due to surface tension and agglomeration.
• Compaction is the consolidation of powder particles by exerting a mechanical pressure on two rolls, one
fixed and one floating, to produce a densified sheet of material.
• Feed material is delivered to the upper feed hopper of the compactor from the floor hopper via a flex
screw conveyor.
• A feed screw meters the product from the hopper into the pre-compression stage producing an even
flow. Feed rates are critical.
• Pre-compression and de-aeration of the material is carried out by using a vertical feed screw.
The material is forced on to the rolls where compaction occurs.
• The twin screw feed arrangement allows for efficient compaction.
• The main compaction occurs between two counter rotating rolls.
• Maximum operating pressure is typically 130 kN total force.
• The product is then gravity fed to a FitzMill Comminutor for milling.

5.09: The Fitzmill Communitor

• This reduces the compact to the desired particle size by cutting it and causing it to pass
through a screen.
• It consists of the Feed Throat, Blade Assembly, Screen and Control Panel.
• The control panel controls blade operation.
• The Feed Throat controls the material feed angle, and assures consistent results.
• The Blade Assembly includes: impact (aggressive size reduction) or knife edge blade
(gentle granulation).
• Screens ensure proper sizing, which is achieved by varying the blade type, rotor speed, and screen size.

5.10: Sieve Analysis

• There are two different tests conducted in compaction to ensure product.
• In mesh analysis, mixed samples of product are tested to ensure proper granual size.
• The sieves have different size screens to separate varying sizes.
• Sieves are stacked starting with the 20 mesh, 60 mesh, 80 mesh, 100 mesh and pan.

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• The 100g sample is introduced to the sieve shaker which separates the varying particles.
• Each tiered sieve is then weighted to determine the amount of material remaining.
• Results are recorded.

5.11: Tablet Compression

A tablet press can produce up to 10,000 tablets per minute. In-process test equipment includes the
Hardness Tester, the Thickness Gauge, and the Tablet Balance. In-process sampling is conducted
throughout the run to indicate that content of the active is correct, and that the tablets are strong
enough for further processing.

5.12: Compression Process

The tablet making process consists of: the Filling Stage, the Metering Stage, the Compression Stage
and the Ejection Stage.
• The Filling Stage: the turret with its punches and dies rotates past the feeder.
• The feeder contains the granulation used to manufacture the tablet.
• Inside the feeder there is mixing paddles to ensure consistent flow.
• The mixing paddles rotate continuously and as the turret is rotating, the lower punches are pulled
down.
• This pulled down action under the feeder causes the granulation to be drawn into the die by the
vacuum.

• The metering stage (dosing) is the most important part of the tablet-making process.
• During this stage the final tablet weight is determined volumetrically by the fill depth of the die cavity.
• Metering occurs while the dies are still under the feeder.
• The fill depth is controlled via the fill cam which is interchangeable dependent on the tablet’s weight.
• As the lower punches travel through the fill cam, granulation is drawn into the dies.
• If the press is running too fast, or the punch length is variable, the granules may not fully fill the space
created resulting in inconsistent tablet weight, hardness and friability properties.
• As the punches leave the fill cam, the lower punches travel up the ramp on the metering cam, pushing
out excess granulation which is then scraped from the die table and re-circulated.
• Punches can be shaped and embossed to give the tablet its identity.
• All punches and dies must be cleaned and polished prior to use to avoid Picking or Sticking.
• Picking or sticking may be caused by poor punch design, enclosed areas such as the number 8 or
letter B.
• During the Compression Stage, the upper and lower punches travel between two pairs of large wheels
called pressure rolls.
• The upper rolls are referred to as the Pre and Final Penetration Rolls.
• The lower rolls are referred to as the Pre and Main or Final Compression Rolls.
• The first pair of rolls gently forces the punches together in the die to remove excess air.

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• This prevents expansion during the tablet ejection phase from the tablet press, resulting in capping or
laminated tablets.
• Pre-compression also helps form a stronger tablet by increasing dwell time.
• The second pair forces the punches closer together in the die hard enough to form a tablet.
• The distance between the upper and lower punches determines the thickness and porosity of the
tablet.
• This determines how hard the tablet is and its disintegration time.
• A strain gauge attached to the compression rollers can be used to measure how much force is required
to make the tablet - this is known as the compaction force.
• Increasing force results in decreased tablet thickness, friability and increases hardness and dissolution/
disintegration time, while over-compression can also be a cause of capping.
• If the compaction force measured is outside the pre-set limits tablets are rejected by compressed air
blow or a mechanical reject gate.
• Multiple rejections usually indicate machine malfunction and require shut down.

• The ejection stage is the final part of the tablet-making process where the lower punch rises as it
travels along the ejection cam.
When the lower punch reaches the top of the ejection cam, the tablet will be pushed up and out of the die
when the tablet take off guides the tablet off the turret and outside the press.

5.13: Weight Parameters

The most important quality outcome of the compression process is uniform tablet weights.
Critical Parameters controlling tablet weight are:

Feeder speed (5 – 40 rpm) Die fill depth (up to 40mm) Press Speed (2,000 – 10,000 tablets per min)

The main Critical Parameter which affects the hardness and thickness of the tablets is Compaction Force
(10 -20 KN).
At line in-process controls take place during manufacturing where characteristics undergo physical testing
at regular intervals (usually every thirty minutes) during compression including:

Appearance Weight Thickness

Hardness Friability Disintegration

5.14: Tablet Weights

• Depending on tablet size, shape, material, and press configuration, a typical modern press can produce
between 250,000 to over 1,000,000 tablets an hour (3 – 16k tpm).
• There are also several pieces of ancillary compression equipment including:

Metal checker Deduster Automated sampling

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5.15: Film Coat Components
The enteric coating solution contains one of the following materials:

Shellac Eudragit HPMC

• The Enteric coat can be applied by sugar coating or Film coating techniques.
• Tablet coating takes place in a controlled atmosphere inside a fully perforated, rotating coating pan.
• Angled mixing baffles and air flow inside the drum provide consistent and effective tablet movement
for uniform coating.
• The air flow is regulated for temperature and volume to control drying rates while maintaining a slightly
negative drum pressure relative to the room to isolate the operator from product dust and overspray.
• As the drum rotates, the liquid spray coating is dried onto the tablets by heated air drawn through the
tablet bed by the slightly negative pressure.
• A Gun Arm Assembly permits easy access to each spray gun for adjustments, priming and cleaning.
• It is critical that the gun to bed distance is correct to ensure uniform coverage of the tablets.
• Using a pump delivery system, the liquid coating is applied to the bed through the guns at a specific
angle, rate and distance.

• The process of film formation can be viewed in three stages:

1) An atomised droplet is applied to the tablet and moisture evaporates at a rate that is dependent on
the air inlet temperature and humidity as well as the physical properties of the tablet and coat.
2) As evaporation of the excess moisture increases the polymer begins to coalesce and spread. If the
evaporation rate is too high the polymer chains have insufficient time to settle completely over the
tablet contact area and will produce a porous coat.
3) Conversely, if evaporation is too slow the surface layer will dry leaving a wetter layer underneath
causing twinning or sticking. Once the solvent is evaporated, a solid film is formed on the surface of
the tablet core. Once the desired amount of suspension and/or solution is applied and visual quality is
acceptable, the tablets are then discharged into product drums for further processing.

• During the coating process, strict sampling criteria are followed to measure tablet weight and visual
quality throughout the run until the target weight is achieved.
• Common appearance issues can be resolved through small adjustments of the coating process variables
during the coating process.
• One common issue, Tablet-to-Tablet Colour Variation or Shading, occurs when the tablets receive an
insufficient amount of coating to achieve uniform coverage.
• To resolve shading the spray gun angle and distance must be correct and altered until the pan speed has
been increased, the spray rate decreased and the process rebalanced. The process will be slower, but
shading will be resolved.
• Another issue, chipping, can occur if a tablet lacks robustness or the process is too aggressive.
• To reduce or eliminate coating chips, an operator can decrease the pan speed or increase the spray rate.
• Chipping can also be a sign of sharp edges from worn tablet punches or inherent low tablet hardness/
friability.
• Picking and Sticking of tablets can be caused by poor distribution of coating liquid or inadequate drying.
• Increasing the pan speed or decreasing the spray rate by increasing air pressure/volume may resolve it.

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• Core erosion is a potential problem in soft or fast dissolving tablets.
• Decreasing the pan speed/increasing the spray rate may help, but mechanical core strength must be
improved.
• Cracking and peeling of tablets are caused by low mechanical strength of coating, poor adhesion to the
tablet surface and can also be the result of elastic recovery following compression.
• Reformulation may be required to improve mechanical strength.
• If the viscosity of the coating liquid is too high, or the liquid is poorly atomised, the tablets will have a
rough texture.

5.16: Tablet Coating

• Creating a film-coated product is a complex process that requires synchronizing many interrelated
factors between: the uncoated tablet core variables, the coating formulation variables, and the physical
coating.
• Film coating is used to apply both aqueous-based and/or functional enteric coating to the tablet
surface.

Common components of a film coat include:

• Solvents, which can be water or alcohol based.
• Colorants and opacifiers, such as titanium dioxide mask core colour and provide light protection.
• Plasticisers, e.g. polyethylene glycol (PEG), modify the properties of the polymer to assist coating
process.
• Polymers which form a clear, non-tacky, mechanically strong film.
• The most common example is Hydroxypropylmethylcellulose (or HPMC).
Tablets are coated for the following reasons:

Clearly identifies the product Visual attractiveness

Minimises breakage friability Assists swallow
Improves stability by protecting the drug Palatable
Coingestion Assists packing

Enteric coating is when drug products are treated to ensure they pass through the stomach and release
in the intestine. These coatings contain materials with solubility profiles dependent upon pH which
specifically target drug absorption in the gastrointestinal Tract. They protect the tablet from the acidity
of the stomach, or to protect the stomach from drug irritants.

5.17: Coating Process

• Sugar coating is often still used.
• It can be an automated or a manual operation with a pan and ladling on the solution.
• Sugar coating is popular as it is simple and the ingredients are cheap.
• It is a slow and labour intensive, while it does not allow tablet embossing it allows edible ink printing.

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5.19: Tablet Printing
• A tablet printing process includes: a product drum lift, a bulk hopper assembly, and a tablet printing
machine.
• Once charged with product, the bulk hopper delivers a steady flow of tablets via a vibratory feed
system to the inlet hopper. A hopper level sensor, which can be manually positioned, based on the type
of product and the speed of production controls the product level in the inlet hopper.
• The product is directed into carrier bar pockets and conveyed past rotating brushes custom designed to
maximise the carrier bar fill rate.
• The ramp feed angle can be adjusted to maximise the fill rate.
• The product moves through the print unit where it is engraved.
• When the ink well is filled with ink, the design roll must remain in motion to keep fresh ink in the logo
etchings, while rotation of an oscillating blade removes excess ink.
• After receiving the logo, the product is then conveyed through a drying section.
• If a tablet remains stuck to the offset roll, a metal stripper,(‘rake’), gently removes the tablet.
• The tablets are then inspected for print quality by the vision system.
• High speed cameras are used to capture high-resolution images of each pocket.
• If a pocket is present, then the system checks for the presence of a tablet.
• Once logo presence has been verified, the product surface and printed logo is quality checked to verify
that it is centred within a pre-set tolerance.
• The inspection results are updated and displayed on the operations screen of the control panel.
• If the overall yield drops below 99%, production management should be notified immediately.
• Non-conforming product is gravity discharged into the reject bin.
• Product that is determined to be acceptable is vacuum lifted out of the carrier bar pockets using soft,
silicone suction cups rotating around a synchronised product eject transfer drum.
• As the drum rotates, the accepted product is released into the discharge chute where it will exit the
machine and into a container where it awaits final approval.

5.20: Extrusion
Extrusion and Spheronisation is explained using the following equipment:
• Twin Dome Granulator Extruder, Floor Scale, Extruder Control Panel, Twin Bowl Marumerizer®
Spheroniser, Spheroniser Control Panel, Parts Rack, Product Drums and Plate Lift.
• For controlled release applications, extrusion precedes spheronisation when spherical granules are
needed for subsequent pellet coating and encapsulation operations.
• The wet mix, which is typically prepared in a high shear granulator, is manually fed into the feed hopper.
• Twin screws transport the mix to the extrusion zone where it is wiped through the screen of the dome
die to produce, cylindrically extruded material of a controlled diameter.
• The extruded material bends under its own weight after leaving the dome die, and breaks off into
segments of irregular length.
• Once the specified weight of material has been extruded, the segments, also known as pellets, are
ready to be fed into the twin bowl Spheroniser.

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5.21: Spheronisation
• Spheronisation is the technique of converting extruded or irregularly formed particles into a rounded
or spheroid form.
• Spherical particles are needed for coating applications where a thin polymeric material is applied to the
surface of the sphere for controlled release properties.
• Rounded particles are better for coating because sharp edges tend to have less coating material at
the peak.
• The extruded material(pellets) are fed to the spinning friction plate and thrown against the
Marumerizer bowl forming twisting ropes.
• Collision of particles with the wall of the bowl, the friction plate, and with other particles, results in the
deformation of the pellets into spheres.
• Another benefit of spheronisation is the reduction in fines. Breaking off of sharp edges results in very
small particles called fines which can negatively affect the product flow.
• The spheroniser separates most of the fines from the batch. The remaining spherical shapes produce
fewer fines and help achieve more predictable fluid bed processing.
• The final particle shape is time and formulation dependent. Once the desired particle shape is achieved,
the discharge valves are opened and the batch is collected for subsequent coating and packaging
operations.

5.22: Capsule Filling

For end-product capsules, the process is slightly different to tabletting. A typical filling room includes:

CFS Unit Machine Control Interface Statistical Weight Control Capsule Filling Machine

• Capsule shells are generally made from Gelatine, HPMC and other cellulosics.
• Gelatine and HPMC are edible and readily soluble.
• Capsules are available in many different sizes and colours and can be filled with powders, granules,
small tablets, pellets, semi-solids or liquids, provided there is no interaction with the shell.

5.23: Encapsulation
Although referred to as a capsule filling machine, the machine performs a process called Encapsulation.
Complete encapsulation of capsules is achieved through the following stages:

Feeding /Orientation Transfer Opening and Separation Filling or Dosing Closing

Ejection
• The Feeding and Orientation Unit mainly consists of a capsule hopper, feed tubes having a vertical
motion, and an orienting drum employing twenty-four grooves centred with the upper feeding tubes.
• During the feeding phase, capsules are inserted and vertically deposited into the feeding tubes.
• Capsules are then oriented with their bodies downward to be pre-arranged for dosing.
• Capsules fall into the feeding tubes where they are randomly oriented.
• They are released by a Capsule Release Lever, and drop onto the Resting Blade held in position by
beaks.

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• As the beaks move upwards, the orienting blade pushes each capsule outward until horizontally
arranged.
• The capsule orientation occurs because the internal width of the gauged groove of the drum is larger
than the diameter of the body, but smaller than the diameter of the lid.
• Therefore the blade push makes the capsules rotate by 90 degrees and orients only its body outward,
pivoting upon its lid.
• The beaks of the feeding tubes go down again completing the rotation of the capsules.
• As the capsules are oriented with their bodies downward, suction keeps them in position as the static
pins ensure that each capsule is gently moved downward.
• Once the beaks complete their descent, the suction stops and the capsules are then released to fall into
the lower housings of the drum protected by the beaks.
• Vacuum will hold each capsule in position as the beaks begin their upward travel to complete the cycle.
• The Transfer Unit consists of a horizontal ring which turns in phase with the other units.
• The external cylindrical surface contains slots and suction holes for capsule transfer from the orienting
drum to the dosing unit.
• As the beaks begin their upward run, suction keeps the capsules in position until the in-phase rotation
aligns each capsule with a slot on the transfer ring.
• Once a capsule is in position, the suction becomes a blow while a simultaneous suction from the
transfer ring pulls the capsule into the slot.
• Capsules are then held in place on the ring for half a rotation until they are aligned vertically with the
capsule body bushings, housed in blocks on transversal shaft, and the capsule lid bushings on the dosing
unit turntable (lid plate).
• New suction from the bottom simultaneous with the end of the suction which held capsules to the ring
causes capsules to fall into the bushings.
• The diameter of the capsule lid through-hole bushing is larger than the diameter of the capsule body
bushing; therefore the lid remains in the upper bushing while the body falls into the lower bushing.
• Next, the transversal shafts move inward in order to align the bushings vertically with the dosators to
fill the bodies of the capsules with product.
• The Dosing Unit mainly consists of a dosing head with a number of dosators, a rotary container, a sector
container which controls the powder level and a powder hopper. The product formulation is very similar
to tablets, with the API, binders, lubricant and disintegrants.
• The dosators, which have already discharged the product into the capsules during the previous cycle,
lift and move down following an oblique trajectory until they reach the product layer inside the rotary
container; during this phase, the pistons are aligned with the lower edge of the dosators.
• Dosators are composed of a cylinder and an inner piston adjustable in height to form the “dosing
chamber” which deliver the quantity of product to be filled into capsules.
• Dosators continue their descent into the product layer whereas pistons remain in their position to form
the dosing chamber, whose volume values are established through a pre-set adjustment.
• Piston and dosator go down until they reach the bottom of the rotary container to allow for product
compression.
• If necessary, additional compression can be applied to the piston to form a slug.
• Dosators then lift again and pass over the rotary container to discharge product slugs into the capsule
bodies when they are vertically aligned with dosators.

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• Once the product has been filled, the dosators lift again and pass over the rotary container to start
again.
• In addition to the dosators, there are contrast closing shafts in the dosing head which correspond to the
closing shafts underneath. Their vertical motion is operated by cams during the rotation of the unit.
• When the filling phase is over, the transversal shafts move each block housing with the capsule body
outward until they align vertically with the capsule lid-housing contained in the turntable while the
contrast closing shafts descend near the lids.
• Subsequently, the closing shafts gradually push the bodies upward into the lids in order to eject the air
contained in the two halves of the capsules until they are completely closed.
• Finally, the contrast closing shafts travel up again as the closing shafts continue their upward run to
eject capsules from each bushing to transfer them to the exit ring where they are held in place by
vacuum until being discharged down the exit chute.
• Capsule weight is monitored throughout the manufacturing process by a combination of Manual In-
process Sampling, Automatic In-process Sampling or 100% Weight Verification.
• Inconsistency in the weight can result from large differences in the granule particle size, agglomeration
of granules, and insufficient level of granules in the hopper that fills the supply chamber, and poor flow
properties.
• Capsule leakage is another potential quality problem; this can be caused by either a leaking seal
between the two parts of the capsule, or by excessive vacuum during separation resulting in pinhole
leaks in the gelatine dome.
• Soft Gel Capsules consist of a soft, flexible gelatine shell containing a liquid fill.
• They are a highly specialised dosage form, mainly used for liquid fill formulations that allow for a high
accuracy of dose filling.
• In the manufacturing process a molten gelatine mixture is formed into two ribbons which pass through
lubricating rollers before passing over heated die rollers which form the capsule as they come together.
• As the capsule is forming the liquid fill is injected in between the rollers, the capsule is then fully sealed,
encapsulating the liquid fill.
• The sealed capsules are washed to remove the lubricant and dried.

5.24: Tablet Packaging

• Tablets are typically packaged in Blisters or Bottles.
• Blister packages consist of a PVC blister filled with tablets and foil sealed.
• Bottles are typically made from High Density Polyethylene (HDPE).
• They are filled using tablet counters and feature tamper proof seals.
• Packaging ensures the integrity of the product and its stability.

5.25: Packaging Lines

Packaging must include the following information:
• Identification and strength.
• Safe preparation of the medicine if required, such as reconstitution or dilution.

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• Safe use of the medicine, i.e. clearly worded instructions and pictograms. These should include
precautions, such as food/drug compatibilities and side effects.
• Storage and shelf-life of an in-use product.
• Appropriate disposal of any unused medicine and the packaging itself.
• Batch number.

Packaging plays a key role in ensuring supply-chain integrity of the medicine. These measures are:
• Pedigree and “Track-and-Trace” systems assuring “chain of custody”.
• Anti-counterfeiting measures.
• Counter-measures for illegal cross-border trading.
• Covert and overt certification, e.g. holograms, digital watermarks, microdot patterns and other printing
marks, radiofrequency identification (RFID) technologies.
• All labels, inserts, cartons or boxes must be checked before beginning the packaging operation to
ensure that they are the correct size, type and are free from damage.
• Tertiary packaging materials are usually large cardboard boxes or crates used for the shipment of the
product to the final destination.
• Good Distribution Practices, also known as GDP, must be implemented throughout the supply chain.

5.27: Conclusion
This concludes the Overview of Tablet and Capsule manufacturing and packaging processes training
module. An assessment follows.

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