Sas 3

Course Code: PHA 069: Pharmaceutical Manufacturing
(with Regulatory Pharmacy, Quality Assurance, and cGMP)

SAS #3: Transfer of Technology
Name:______________________________________________________________ Class number: _______
Section: ____________ Schedule:________________________________________ Date:________________
Lesson title: Transfer of Technology Materials:

• Technologies applied in the manufacture of liquid dosage forms 1. Pen, Paper, SAS
and disperse systems 2. Remington: The Science and
• Technologies applied in the manufacture of solid and semi-solid Practice of Pharmacy, 21st Edition
dosage forms
• Technologies applied in the manufacture of parenterals and Reference/s:
novel dosage forms 1. PICS – Guide to Manufacturing
Lesson Objectives: Practice for Medicinal Products
1. Explain the different mixing mechanisms that may be done Part I (May 1 2021 edition)
in the manufacture of liquid dosage forms;
2. Identify the equipment used in the manufacture of
pharmaceutical liquid and solid dosage
f orm s, aerosols and parenterals.
3. Compare the typical manufacturing operations of Liquid, solid
dosage forms, and aerosols.
Productivity Tip: “Dreading a particular task only delays it further and increases the to-do pile. Because you
can’t avoid that tedious report forever, get on with it as soon as you are able. The sooner you start working,
the sooner you can get it over with.”
A. LESSON PREVIEW/REVIEW
1) Introduction (5 mins)
The goal of technology transfer activities is to transfer product and process knowledge between
development and manufacturing, and within or between manufacturing sites to achieve product
realization. This knowledge forms the basis for the manufacturing process, control strategy, process
validation approach and ongoing continual improvement (ICH Q10).
Robustness is the ability of a process to demonstrate acceptable quality and performance, while
tolerating variability in inputs. It is a function of formulation and process design. Experimentation in
manufacturing is limited vs research and development but the state of robustness can be determined via
proactive process monitoring.
2) Activity 1: What I Know Chart, part 1 (5 mins)

Introductions: In this chart, reflect on what you know now. Answer only the first column, “What I Know”.
What I Know Questions: What I Learned (Activity 4)

1. Give 2 samples of liquid dosage
forms in your house.
2. What is meant by solid dosage
forms?
3. Can aerosols be medicated?
This document is the property of PHINMA EDUCATION

B. MAIN LESSON
1) Activity 2: Content Notes (120 mins)
TECHNOLOGY TRANSFER
Technology transfer is the process by which the manufacturing process and analytical method are
transferred from one manufacturing unit to another unit or from Research and Development (R&D) to
manufacturing unit.
Transfer of technology requires a documented, planned approach using trained and knowledgeable
personnel working within a quality system, with documentation of data covering all aspects of
development, production and quality control.
Technology transfer from R&D to manufacturing site is critical because of the scale-up of the product
from pilot batch to large-scale commercial batch. A typical technology transfer process can be divided into
production part, quality control part and documentation part.
Importance of Technology Transfer

To elucidate necessary information to transfer technology from R&D to actual manufacturing by sorting
out various information obtained during R&D.
To elucidate necessary information to transfer technology of existing products between various
manufacturing places.
To exemplify specific procedures and points of concern for the two types of technology transfer in the
above to contribute to smooth technology transfer. This is applicable to the technology transfer through
R&D and production of drug (chemically synthesized drug substances and drug products) and the
technology transfer related to post-marketing changes in manufacturing places.
Technology Transfer Team PEP-QQ

o The technology transfer team consists of the following members and their responsibilities are given
below:
Process Technologist
Central focus for transfer activities.
Collates documentation from donor site
Performs initial assessment of transferred project for Feasibility, Compatibility with site capabilities
and Establishes resource requirements.
Quality Assurance (QA) Representative

Reviews documentation to determine compliance with marketing authorization (MA).
Reviews analytical methods with QC to determine capability, equipment training requirements.
Initiates conversion of donor site documentation into local systems or format.
Initiates or confirms regulatory requirements, e.g., change to manufacturing license; variations to
MA if process changes needed, etc.
Production Representative
Reviews process instructions (with process technologist) to confirm capacity and capability.
Considers any safety implications, e.g., solvents; toxic; sanitizing materials.

Considers impact on local standard operating procedures (SOPs).

Considers training requirements of supervisors or operators.
Engineering Representative
Reviews (with production representative) equipment requirement.
Initiates required engineering modifications, change or part purchase.
Reviews preventative maintenance and calibration impact, e.g., use of more aggressive ingredients;
more temperature sensitive process,and modifies accordingly.
Quality Control (QC) Representative

Reviews analytical requirement.
Availability with instruments.
Responsible for analytical method transfer for drug substance and drug product.
Technology Transfer Guidelines for Pharmaceuticals

Production: Technology Transfer
Receiving unit and sending unit both should develop the product transfer protocol jointly to transfer
the product related information. Information should be transferred according to the technical
expertness of the staff and the manufacturing site capabilities to run the process smoothly.
Raw Materials:
The material used for manufacturing on receiving unit should have consistency with the material used
at the sanding unit. The properties of the raw material those can alter the quality of the product should
be identified.
Active Pharmaceutical Ingredients (API):

Sending unit should provide the drug master file (DMF) and other related information of the active
materials. It may include the following information:
Flowchart of the manufacturing process of the drug material
Physical properties including bulk and tap density
Moisture content including water activity
Bioburden, endotoxin and sterility as required
Solubility and pH of solution
Particle size distribution and its dissolution profile
Manufacturer and the supply chain of the material
Other information like heat, light and moisture sensitivity
Excipients:
Excipients also have the considerable effect on the final product so their detailed information should
also be provided by the sending unit to receiving unit. It may include the following information:
Viscosity of material
Flowchart of the manufacturing process of the drug material
Physical properties including bulk and tap density
Moisture content range
Melting range

Bioburden, endotoxin and sterility as required

Ion strength of material
Solubility and pH of solution
Specific gravity
Particle size distribution and its dissolution profile
Manufacturer and the supply chain of the material
Compliance with Transmissible Spongiform Encephalopathy (TSE) and Bovine Spongiform
Encephalopathy (BSE) requirements
Material Safety Data Sheet (MSDS) and heat, light and moisture sensitivity
In-process Materials:
Sending unit should provide the detailed information of manufacturing process, physical description,
specification and in-process controls.
Finished Products:
History of the development of the product should also be provided for the further development or process
optimization after the successful technology transfer.
Information regarding the environment, health and safety should also be provided to the receiving unit.
It should also include the information on product quality review, validation, stability and environmental
conditions for manufacturing.
Generally, trial batches are taken at the receiving unit to test the manufacturing parameters and
capability of the manufacturing process before running the validation batch.
Packing Process:
All the information regarding the packing should be transferred as the manufacturing process.
It includes the specification of foils or containers and closures, and other related information as design
labeling, artwork and drawings.
Cleaning Process:
To prevent the contamination in the pharmaceutical products, it is essential the follow the adequate
cleaning procedure. It can minimize the risk of cross- contamination during manufacturing.
Receiving unit should validate the cleaning procedure and sending unit should provide the required
information such as existing cleaning procedure, the solubility of all materials, therapeutic dose,
the toxicity of the API, cleaning agents and recovery studies.
Manufacturing Facility:
Sending unit should provide the information related to the facility design.
Premises:
o It should include the layout of facility, buildings, utility services, fire risk,
health and safety requirements for operators and environmental issues.
Equipment:
o A list of required equipment with their make and models should be
provided by the sending unto. It should include the manuals, drawings and
cleaning, operating and maintenance procedures.
o Installation Qualification (IQ), Operational Qualification (OQ) and
Performance Qualification (PQ) of the equipment should be done by the
receiving unit.

Quality Control: Analytical Method Transfer

o The analytical method has its own importance because the manufactured product shall be
tested by the developed analytical method and accuracy in the analytical method can save time.
o Receiving unit should implement the method of analysis for the finished product, raw materials,
packing materials and cleaning residues before the starting of the process validation.
o Analytical method transfer protocol should be prepared including responsibilities of both sanding
unit and receiving unit, the specification of product, acceptance criteria, interpretation of results,
report formats, reference standards and deviations during analysis. Training should be provided
to the analysts and should be documented in training record.
Documentation
o Every step followed during the technology transfer process should be documented and
a summary report should be prepared to contain the conclusion of the technology transfer.
o Discrepancies found during the process should be listed and should be resolved by taking the
appropriate action.
o Following documents should be prepared during the successful tech transfer:
Technology transfer protocol
Facility qualification protocol and report
Equipment qualification protocol and report
Process validation protocol and report
Cleaning validation protocol and report
Standard Operating Procedures (SOP) for Technology Transfer

Objective:
o To lay down the procedure that the required information, data and technology about the product,
processing and analysis is transferred and available at the site so that quality and integrity are
maintained.
Scope:
o This SOP shall be applicable to the new products which are transferred from R&D or all other
product from one site to another site or from contract giver.
Responsibility:
o R&D Head / Head QA & QC / GM-Production / Unit Head / Contract Giver.
• Accountability:
o Head- QA & QC
Procedure:
o Ensure the new product proposal is approved by QA.
o Manufacturing license for a commercial production or test license for registration batches for the
proposed product shall be obtained from local FDA.
o Technology transfer documents shall be received from R&D or contract giver.
o Analytical method transfer shall be carried out by using approved protocol given by R&D or
contract giver.
Upon completion of analytical method transfer, data shall be compiled; report shall be
prepared and sent to R&D or contract giver for review.
Method transfer shall be accepted if results are meeting the acceptance criteria.
The same method shall be used during the routine testing performed subsequently.
o Technology transfer document shall include:

Analytical method for API (Active Pharmaceutical Ingredient(s)) inclusive of critical tests
like assay, related substances and residual solvents.
In-process analytical methods.
Finished product analytical method inclusive of critical tests like assay, dissolution,
related substances and dissolution profile.
Master formula record or process instructions.
o Based on the technology transfer documents and analytical method transfer, the following
documents shall be prepared and approved:
Batch manufacturing record
Validation protocol
Batch packaging record
Specification for API, excipients, in-process and finished product.
o For site variation, the existing method/formula as used in the license shall be adopted. Separate
technology transfer is not required in case of site transfer products as the same process of
manufacturing is adopted on the basis of existing MFR provided by R&D (contract
manufacturing department), any difficulty or deviation observed from the process, the
specification shall be handled by coordinating with R&D.
o For new products launched at any facility by R&D, analytical method transfer shall be routed
through a product-specific protocol.
o In case if any change in approved formula, prior approval from contract giver shall be taken.
o The confirmation batches, registration batches shall be manufactured under the technical
guidance of R&D or contract giver as per approved validation protocol or batch manufacturing
record.
o Necessary training shall be provided to the concerned people.
o In case of any deviation from the approved protocol or BMR, deviation control procedure shall
be followed.
Abbreviations:
o SOP: Standard Operating Procedure
o QA: Quality Assurance
o QC: Quality Control
o R&D: Research and Development
o FDA: Food and Drug Administration
o API: Active Pharmaceutical Ingredient
o MFR: Master Formula Record
o BMR: Batch Manufacturing Record

TECHNOLOGIES APPLIED IN THE MANUFACTURE OF LIQUID DOSAGE

MANUFACTURE OF SOLUTIONS
For both small- and large-scale manufacture of solutions the only equipment necessary is suitable
mixing vessels, a means of agitation and a nitration system to ensure clarity of the final solution.
During manufacture, the solute is simply added to the solvent in a mixing vessel and stirring
is continued until dissolution is complete. If the solute is more soluble at elevated temperatures it may
be advantageous to apply heat to the vessel, particularly if the dissolution rate is normally slow.
Care must be taken, however, should any volatile or thermolabile materials be present. Size reduction
of solid materials to increase their surface areas should also speed up the process of solution.
FUNDAMENTALS OF FLUID MIXING

o Mixing is defined a process that tends to result in a randomization of dissimilar particles within
a system.
o Generally, fluids may be classified as:
Newtonian – have a constant viscosity that doesn’t change, no matter the pressure
being applied to the fluid. This also means they don’t compress.
Non-Newtonian – the opposite of Newtonian; if enough force is applied to these fluids,
their viscosity will change. These fluids are broken up into two categories:
Dilatants, which get thicker when force is applied
Pseudoplastics, which get thinner under the same circumstances.
Rheopectic - Rheopectic is very similar to dilatant in that when shear is applied,
viscosity increases. The difference here, is that viscosity increase is time-
dependent. For example: Gypsum paste, cream
Thixotropic - Fluids with thixotropic properties decrease in viscosity when shear
is applied. This is a time dependent property as well. For example: Paint,
cosmetics, glue
MIXING MECHANISMS
o Bulk Transport
The movement of a relatively large portion of the material being mixed from one location
in the system to another.
This is a simple circulation of material in a mixer but does not necessarily result in
efficient mixing.
For bulk transport to be effective, rearrangement or permutations of various portions of
the material should be done. It is usually accomplished by the means of paddles,
revolving blades or other devices within the mixer arranged so as to move adjacent
volumes of the fluid in different directions.
o Turbulent Mixing
The phenomenon of turbulent mixing is a direct result of turbulent fluid flow, which is
characterized by random fluctuation of the fluid velocity at any given point within the
system.
Highly effective, mixing is due to turbulent flow which results in random fluctuation of the
fluid velocity at any given point within the system.

o Laminar Mixing
Streamline or laminar flow is frequently encountered when highly viscous fluids are
being processed.
Mixing of two dissimilar liquids through laminar flow, i.e., applied shear stretches the
interface between them.
Suitable for liquids which require moderate mixing.
o Molecular Diffusion
The primary mechanism responsible for mixing at the molecular level is diffusion
resulting from the thermal motion of molecules.
When it occurs in conjunction with laminar flow, molecular diffusion tends to reduce the
sharp discontinuities at the interfaces between the fluid layers, and if allowed to proceed
for sufficient time, results in complete mixing.
This process can be described quantitatively in terms of Fick’s first law of diffusion.
o Scale and integrity of segregation

The quality of mixtures must ultimately be judged upon the basis of some measure of the
random distribution of their components. Such an evaluation depends on the selection of
a quantitative method of expressing the quality of randomness or "goodness of mixing ".
MIXING EQUIPMENT
BATCH MIXING – when the material is to be mixed is limited in volume to that which may be conveniently
contained in a suitable mixer, batch mixing is not usually feasible.
A system for batch mixing commonly consists of two primary components:

Tank or other container suitable to hold the material being mixed
A means of supplying energy to the system to bring about reasonably rapid mixing. Power may
be supplied to the fluid mass by means of:
Impellers
o The distinction between impeller types is often made based on type of flow pattern they
produce, or on the basis of the shape and pitch of the blades. Three basic types of flow
may be produced: radial, axial, and tangential. These may occur singly or in various
combinations.
o Propellers characteristically produce flow parallel to their axes of rotation whereas
turbines may produce either axial or tangential flow, or a combination of these.
o Propellers - It consists of number of blades, generally 3
bladed design is most common for liquids. Blades may be
right or left-handed depending upon the slant of their
blades.
Advantages of propellers:
Used when high mixing capacity is required
Effective for liquids which have maximum viscosity
of 2.0pascals.sec or slurry up to 10% solids of fine mesh size.
Effective gas-liquid dispersion is possible at
laboratory scale.
Disadvantages of propellers:

Propellers are not normally effective with liquids of viscosity greater

than 5pascal.second, such as glycerin, castor oil, etc.
o Turbines - consists of a circular disc to which several short blades are attached,
blades may be straight or curved. The diameter of the turbine ranges from 30-50%
of the diameter of the vessel. Turbines rotate at a lower speed than the
propellers (50-200rpm).
Advantages of turbines:
Turbines give greater shearing forces than propellers through
the pumping rate is less. Therefore suitable for emulsification.
Effective for high viscous solutions with a wide range of
viscosities up to 7.0 Pascal. Second.
In low viscous materials of large volumes turbine create strong currents which spread
throughout the tank destroying stagnant pockets.
They can handle slurries with 60% solids.
Turbines are suitable for liquids of large volume and high viscosity, if the tank is baffled.
Paddles - Consists of a central hub with long flat blades attached to it vertically. Two blades or four
blades are common. Sometimes the blades are pitched and may be dished or hemispherical in
shape and have a large surface area in relation to the tank in which they are used. Paddles rotate at
a low speed of 100rpm.
• Paddles are used in the manufacture of antacid
suspensions, agar and pectin related purgatives,
antidiarrheal mixtures such as bismuth-kaolin.
Advantage of paddles:
Vortex formation is not possible with paddle impellers
because of low-speed mixing.
Disadvantage of paddles:
Mixing of the suspension is poor therefore baffled tanks are required.
Airjets
• Subsurface jets of air, or less commonly of some other gas, are effective mixing devices for certain
liquids.
• Of necessity and for obvious reasons, the liquids must be of:
• Low viscosity
• Non-foaming
• Unreactive with the gas employed
• Reasonably non-volatile
• The jets are usually arranged so that the buoyancy of the bubbles lifts liquid from the bottom to
the top of the mixing vessel. This is often accomplished with the aid of draft tubes.
• The overall circulation in the mixing vessel brings fluid from all parts of the tank to the region of the jet
itself.
Fluid jets
• When liquids are to be pumped into a tank for mixing, the power required for pumping often can be
used to accomplish the mixing operation, either partially or completely. In such a case, the fluids are

pumped through nozzles arranged to permit good circulation of material throughout the tank.
• Fluid jets behave somewhat like propellers in that they generate turbulent flow in the direction of their
axes. They do not in themselves, however, generate tangential flow, as do propellers.
Baffles
• Bulk transport is important in mixing and is particularly desirable in the initial stages, when segregation
may be present on a large scale.
• For bulk fluid flow to be most effective, an intermingling must occur between materials from
remote regions in the mixer. To accomplish this, it is necessary to install auxiliary devices (Baffles,
plates) for directing the flow. Baffle placement depends on the type of agitator used.
CONTINOUS MIXING
• The process of continuous mixing produces an uninterrupted supply of freshly mixed material and
is often desirable when very large volumes of material are to be handled.
• It can be accomplished in two ways:
• In a tube or pipe through which the material flows and in which there is very little back flow or recirculation
• In a chamber in which a considerable amount of holdup and recirculation occur.
MIXER SELECTION
• The first and most important consideration in any mixing problem is equipment selection. Factors
that must be taken into consideration include:
• The physical properties of the materials to be mixed, such as density, viscosity, and miscibility.
• Economic considerations regarding processing, e.g., time required for mixing and the power
expenditure.
• Cost of equipment and maintenance.
Monophase Systems
• The viscous character and density of the fluid(s) to be mixed determine to a large extent the type of flow
that can be produced and also, therefore, the nature of the mixing mechanisms involved.
• Fluids of relatively low viscosity are best mixed by methods that generate a high degree of turbulence
(air jets, fluid jets, and the various high-speed impellers).
• A viscosity of approximately 10 poise may be considered as a practical upper limit for the application
of these devices.
• Thick creams, ointments, and pastes are of such high viscosity that it is difficult if not impossible to
generate turbulence within their bulk and laminar mixing, and molecular diffusion must be relied upon.
• Mixing of such fluids may be done with a turbine of flat blade design.
• A characteristic feature of such impellers is the relative insensitivity of their power consumption to density
and/or viscosity.
Polyphase Systems
• The mixing of systems composed of several liquid or solid phases primarily involves the subdivision
or deaggregation of one or more of the phases present. The processes of homogenization, suspension
formation, and emulsification may be considered forms of mixing.
• When mixing of two immiscible liquids:
• One phase should be subdivided into globules
• Then distributed throughout the bulk of the fluid

• The process usually occurs by stages during which the large globules are successively broken
down into smaller ones.
• Two primary forces come into play here: the interfacial tension of the globules in the surrounding liquid,
and forces of shear within the fluid mass. The former tends to resist the distortion of globule shape
necessary for fragmentation into smaller globules.
PROCESSING EQUIPMENT FOR EMULSIONS

The preparation of emulsions requires a certain amount of energy to form the interface between the two
phases, and additional work must be done to stir the system to overcome resistance to flow.
In addition, heat often is supplied to the system to melt waxy solids and/or reduce viscosity.
Consequently, the preparation of emulsions on a large scale requires considerable amounts of energy
for heating and mixing.
Careful consideration of these processes has led to the development of low energy emulsification
equipment that uses an appropriate emulsification temperature and selective heating of the ingredients.
The following are the equipment used for the manufacture of emulsions:
Agitators
o Ordinary agitation or shaking may be used to prepare the emulsion.
o Under certain conditions, intermittent shaking is considerably more effective than ordinary
continuous shaking.
o Continuous shaking tends to break up not only the phase to be dispersed but also the
dispersion medium, thus impairing the ease of emulsification.
o Laboratory shaking devices may be used for small-scale production.
Mechanical Mixers
o Emulsions may be prepared by using one of several mixers that are available.
o Propeller and impeller type mixers
Have a propeller attached to a shaft driven by an electric motor are convenient and
portable and can be used for both stirring and emulsification.
This type operates best in mixtures that have low viscosity, that is, mixtures with
a viscosity of glycerin or less.
They are also useful for preparing emulsions.
o Turbine mixer
It has a number of blades that may be straight or curved, with or without a pitch,
mounted on a shaft. The turbine tends to give a greater shear than propellers.
The turbines can be used for both low-viscosity mixtures and medium-viscosity
liquids.
o Production sized mixers include high-powered propeller, shaft stirrers immersed in a tank,
or self-contained units with propeller and paddle systems. The latter usually are constructed
so that the contents of the tank either may be heated or cooled during the production
process. Baffles often are built into a tank to increase mixing efficiency.
Colloid Mills
o The principle of operation of the colloid mill is the passage of the mixed phases of an
emulsion formula between a stator and a high-speed rotor revolving at speeds of 2,000 to
18,000 rpm.
o The emulsion mixture, in passing between the rotor and stator, is subjected to a tremendous
shearing action that effects a fine dispersion of uniform size.

• Colloid mills are used frequently for the comminution of solids and for the preparation of suspensions,
especially suspensions containing solids that are not wetted by the dispersion medium.
Homogenizers
• A homogenizer comprises an adjustable valve stem (core) and a fixed outer valve wall, which can have
various geometries with externally adjustable gap sizes.
• Homogenizers may be used in one of two ways:
• The ingredients in the emulsion are mixed and then passed through the homogenizer to produce the
final product.
• A coarse emulsion is prepared in some other way and then passed through a homogenizer for
the purpose of decreasing the particle size and obtaining a greater degree of uniformity and stability.
• Homogenizers have been used most frequently with liquid emulsions, but now they may be used with
suspensions, as the metal surfaces are formed from wear-resistant alloys that will resist the wear of
solid particles contained in suspensions.
Ultrasonic Devices
• The preparation of emulsions using ultrasonic vibrations also is possible.
• An oscillator of high frequency (100–500 kHz) is connected to two electrodes between which is placed
a piezoelectric quartz plate. The quartz plate and electrodes are immersed in an oil bath and, when the
oscillator is operating, high-frequency waves flow through the fluid.
• Emulsification is accomplished by simply immersing a tube containing the emulsion ingredients
into this oil bath.
• The method has not been proven to be practical for large-scale production of emulsions, but evaluations
are underway.
Microfluidizers
• Microfluidizers have been used to produce very fine particles.
• The process subjects the emulsion to an extremely high velocity through micro-channels into an
interaction chamber; as a result, particles are subjected to shear, turbulence, impact, and cavitation.
Two advantages of this type of equipment are:
• Lack of contamination in the final product
• Ease of production scale up
PRINCIPLES OF PHARMACEUTICAL PROCESSING OF SOLID DOSAGE FORMS

A. MIXING
o Mixing Mechanisms
Convective Mixing
This mechanism may be regarded as analogous to bulk transport
Depending on the type of mixer employed, convective mixing can occur by an
inversion of the powder bed, by means of blades or paddles, revolving screw or by
any other method of moving relatively large mass of material from one part of the
powder bed to another.
Shear Mixing
As a result of forces within the particulate mass, slip planes are set-up.
Depending on the flow characteristics of the powder, these can occur singly or in

such a way as to give rise to laminar flow.

When shear occurs between regions of different composition and parallel to their
interface, it reduces the scale of segregation by thinning the dissimilar layers.
Shear occurring is direction normal to the interface of such layers is also effective
since it to reduces the scale of segregation.
Diffusive Mixing
Mixing by ‘diffusion’ is said to occur when random motion of particles within the
powder bed causes them to change position relative to one another.
Diffusive mixing occurs at the interfaces of dissimilar regions that are undergoing
shear and therefore results from shear mixing.
It may also be produced by any form of agitation that results in common use.
o Mixing Equipment
Batch Mixing
Twin shell blender
o A type of mixer that takes the form of a cylinder that has been cut in half,
at approximately a 45-degree angle with its long axis and then rejoined to
form a ‘V’ shape.
o This is rotated so that the material is alternately collected in the bottom of the
V and then split into two portions when the V is inverted.
o This is quite effective because the bulk transport and the shear which occur
in tumbling mixers generally are accentuated by this design.
Ribbon blender
o It consists of horizontal cylindrical tank usually opening at the top and fitted
with helical blades.
o The blades are mounted on the shaft through the long axis of the tank and
are often of both and left-hand twist.
Helical flight mixer
o In here, the powders are lifted by a centrally located vertical screw and
allowed to cascade to the bottom of the tank.
Continuous Mixing
Continuous mixing processes are somewhat analogous with the fluid mixing.
Metered quantities of powders or granules are passed through a device that reduces
both the scale and intensity of segregation, usually by impact or a shearing action.
The output of this mixing process is then transferred directly to a capsule filling or
tablet machine.
Mixer Selection
Measures of Mixing Degree
Mixer selection and evaluation depend on the quantitative measure of the degree of mixing.
This is generally accomplished by the arbitrary choice of a statistical function that indicated
the uniformity of composition of the powder bed.
Power Requirements
Unlike fluids mixing, the requirements for power of a given solids mixing operation cannot be
readily predicted.
Minimum power required to operate the mixer for the time is necessary to reach a satisfactory
steady state.

B. MILLING
A mill consists of three basic parts:
o Feed chute – delivers the material
o Grinding mechanism – consists of a rotor and stator
o Discharge chute
The principle of operation depends on direct pressure, impact form a sharp blow, attrition or cutting. In
most mills, the grinding effect is a combination of these actions.
o Types of Mills
1. Hammer Mill
The hammer mill is an impact mill using a high-speed rotor (up to 10000 rpm) to which a
number of swinging hammers are fixed.
The material is fed at the top or center, thrown out centrifugally and ground y impact of hammer
or against the plates around the casing.
Particles fine enough to pass through the screen are discharged almost as fast as they are
formed.
The hammer mill can be used for almost any type of reduction, making it popular in the
pharmaceutical industry.
It is used to mill dry materials, wet filter-press cakes, ointments and slurries.
2. Ball Mill
The ball mill consists of a horizontally rotating hollow vessel of cylindric shape with the length
slightly greater than its diameter.
The mill is partially filled with balls of steel or pebbles, which act as the grinding medium.
If pebbles are used, it is known to be as the pebble mill.
If rods or bars are used, it is known to be as the rod mill.
Rod mill – useful with sticky material that would hold the balls together, but because the rods
are heavier, the rods causes them to pull apart.
Tube mill – modified ball mill in which the length is about four times than the ball mill. This
grinds more finely than the ball mill.
Ball milling is a combination of impact and attrition.
3. Fluid-Energy Mill
In the fluid-energy mill or micronizer, the material is suspended and conveyed at high velocity
by air or steam, which is passed through nozzles at 100-150 psi. The violent turbulence of the
air and steam reduces the particle size chiefly by interparticular attrition.
The fluid-energy mills can reduce the particle to 1-20 microns. However, the feed should be
premilled to approximately 20-100 mesh size to facilitate milling.
In selecting fluid-energy mills for production, the cost of fluid-energy source and dust collection
equipment must be considered in addition to the cost of the mill.
4. Cutting Mill
Cutting mills are used for tough, fibrous materials and provide a successive cutting or shearing
action rather than attrition or impact.
Disc mill – consists of two vertical discs, each may rotate in opposite directions with adjustable
clearance. The disc may be provided with cutting faces, teeth or convolutions.

The material is premilled to approximately 40-mesh size and is usually suspended in a stream
of air or liquid when fed to the mill.
5. Roller Mill
Roller mill consists of two to five smooth rollers operating at different speeds; thus, size
reduction is effected by a combination of compression and shearing action.
6. Colloid Mill
Colloid mill consists of a high-speed rotor and a startor with conical milling surfaces between
which is an adjustable clearance ranging from 0.002-0.03 inches.
The colloid mill is usually used to process suspensions and emulsion and is not used to process
dry materials.

Selection of a Mill
The choice of mill to be used is based on:
o Product specification (size range, particle size distribution, shape, moisture content, physical and
chemical properties)
o Capacity of the mill and production rate requirements
o Versatility of operations (wet and dry milling, rapid change of speed and screen, safety features)
o Dust control (loss of costly drugs, health hazards, contamination of the plant)
o Sanitation (ease of cleaning, sterilization)
o Auxiliary equipment (cooling system, dust collectors, forced feeding, stage reduction)
o Batch or continuous operation
o Economic factors (cost, power consumption, space occupied, labor cost)
C. DRYING
Drying is defined as the removal of a liquid from a material by the application of heat, and is
accomplished by the transfer of liquid from a surface into an unsaturated vapour phase.
Drying is most commonly used in pharmaceutical manufacturing as a unit process in the preparation of
granules, which can be dispensed in bulk or converted into tablets or capsules.
Drying can also be used to reduce bulk and weight thereby lowering the cost of transportation and
storage.
Classification of Dryers
1. Static-bed dryers
These are systems in which there is no relative movement among the solid particles being
dried, although there may be bulk motion of the entire drying mass.
In here, only a fraction of the total number of particles is directly exposed to heat sources.
A. Tray and truck dryers
These dryers are most commonly used in pharmaceutical plant operations.
Tray dryers – sometimes called shelf, cabinet or compartment dryers which
consist of a cabinet in which the material to be dried is spread on tiers of
trays.
Truck dryers – one of which trays are loaded on trucks (racks with wheels), which
can be rolled into and out of the drying cabinet.
Truck dryers are more preferred than tray dryers because it offers greater
convenience in loading and unloading.
B. Tunnel and conveyor dryers
Tunnel dryers – adaptations of the truck dryer for continuous drying. The
trucks are moved progressively through the drying tunnel by a moving chain.
The operation is said to be semicontinuous because each truck requires
individual loading and unloading before and after the drying cycle.
Conveyor dryers – improved over tunnel dryers because they are truly
continuous.
In here, the individual trucks of the tunnel are replaced with an endless belt or
screen that carries the wet materialt through the drying tunnel thus provides an
uninterrupted loading and unoading and more suitable for handling large volumes
of materials.

2. Moving-bed dryers
These are systems in which the drying particles are partially separated so that they flow over each
other. Motion may be induced by either gravity or mechanical agitation.
The resultant separation of the particles and continuous exposure of new surfaces allow more
rapid heat and mass transfer that can occur in static beds.
A. Turbo-tray dryers
o Turbo-tray dryer is a continuous shelf, moving-bed dryer. It consists of series of rotating
annular trays arranged in a vertical stack that rotate slowly at 0.1- 1.0rpm.
o This offers a faster rate of drying than tunnel dryers because the dryer continuously
exposes new surfaces to the air.
B. Pan dryers
O Pan dryers are moving-bed dryers of the indirect type that may operate under
atmospheric pressure or vacuum and is generally used to dry small batches of pastes
and slurries.
3. Fluidized-bed dryers
These are systems in which the solid particles are partially suspended in an upward-moving gas
stream.
The particles are lifted and then fall back in random manner so that the resultant mixture of solid
and gas acts like a boiling liquid.
The gas-solid contact is excellent and results in better heat and mass transfer than in static moving
beds.
Types:
o Vertical
o Horizontal
4. Pneumatic dryers
These are systems in which the drying particles are entrained and conveyed in a high- velocity
gas stream.
Pneumatic systems are not channelling or short-circuiting the gas flow path through the bed of
particles. Each particle is completely surrounded by an envelope of drying gas. The resultant
heat and mass transfer are extremely rapid thus, drying times are short.
Spray dryers
o Spray dryers differs from most other dryers in that they can handle only fluid materials
such as solutions, slurries and thin pastes.
o In here, fluid is dispersed as fine droplets into a moving stream of hot gas, where they
evaporate rapidly before reaching the wall of the drying chamber.
o The product dries into a fine powder, which is carried by the gas current and gravity
flow into a collection system.
o Parts of spray dryer:
Feed delivery system
Atomizer
Heated air supply
Drying chamber
Solid-gas separator

Flash dryers
o In flash drying, the moistened solid mass is suspended in a finely divided state in a
high velocity, high temperature stream.
o The drying process is referred to as flash drying, because the drying time is extremely
short.
o The drying air temperature can drop from 1300°F to 600°F in two seconds and to
350°F in only four seconds.
5. Specialized drying methods

A. Freeze dryers
o The material to be dried is first frozen and then subjected under a high vacuum to
heat (supplied by conduction or radiation, or by both) so that the frozen liquid sublimes
leaving only the solid, dried components of the original liquid.
o Such materials as blood serum, plasma, antibiotics, hormones, bacterial cultures,
vaccines, and many foodstuffs are dehydrated by freeze drying, also referred to as
lyophilisation, gelsiccation or drying by sublimation.
o Freeze dryers are composed of four basic components
a chamber for vacuum drying
vacuum source
heat source
vapor-removal system
B. Microwave dryers
o The application of microwave energy to the drying of solids represents a radical departure
from conventional means of drying.
o Instead of applying heat externally to a material, energy in the form of microwaves is
converted into internal heat by interaction with the material itself. This permits extremely
rapid heat transfer throughout the material, which in turn can lead to rapid drying.
EQUIPMENT USED IN TABLET MANUFACTURE

A. Single-Punch Machines
o The simplest tableting machines available are those having the single-punch design.
o Compression is accomplished on a single-punch machine.
Steps:
The feed shoe filled with the granulation is positioned

over the die cavity, which then fills.
The feed shoe retracts and scrapes all excess
granulation away from the die cavity.
The upper punch lowers to compress the granulation
within the die cavity.

The upper punch retracts, and the lower punch rises

to eject the tablet.
As the feed shoe returns to fill the die cavity, it
pushes the compressed tablet from the die platform.
B. Rotary Tablet Machines

For increased production, rotary machines offer
great advantages.
A head carrying a number of sets of punches and
dies revolves continuously while the tablet
granulation runs from the hopper, through a feed
frame and into the dies placed in a large, steel plate
revolving under it.
This method promotes a uniform fill of the die and
therefore an accurate weight for the tablet.
On most rotary machine models there is an excess
pressure release that cushions each compression
and relieves the machine of all shocks and undue
strain.
The punches and dies can be removed readily for
inspection, cleaning, and inserting different sets to
produce a great variety of sizes and shapes.
C. High-speed Rotary Tablet Machines

The rotary tablet machine has evolved gradually into models capable of compressing tablets at high
production rates.
Rotary machines with dual compression points are referred to as double rotary machines, and those
with one compression point, single rotary.
The main difficulty in rapid machine operation is ensuring adequate filling of the dies. With rapid filling,
dwell time of the die cavity beneath the feed frame is insufficient to ensure the requirements
of uniform flow and packing of the dies.
D. Multi-layer Rotary Tablet Machines

The rotary tablet machines also have been developed into models capable of producing
multiple-layer tablets; the machines are able to make 1-, 2-, or 3-layer tablets (Versa Press,
Stokes/Pennwalt).
Incompatible drugs can be formed into a single tablet by separating the layers containing them with
a layer of inert material. It has permitted the formulation of time-delay medication and offers a wide
variety of possibilities in developing color combinations that give the products identity.
Other multiple-compression presses can receive previously compressed tablets and compress
another granulation around the preformed tablet. An example of a press with this capability is the
Manesty Drycota (Thomas/Manesty). Pressurecoated tablets can be used to separate incompatible
drug substances and also to give an enteric coating to the core tablets.

E. Instrumented Tablet Presses

Compressional and ejectional forces involved in tablet compression can be studied by attaching strain
gauges to the punches and other press components involved in compression.
Instrumentation permits a study of the compaction characteristics of granulations, their
flowabilities, and the effect of formulation additives, such as lubricants, as well as differences in tablet
press design.
Instrumentation has led to the development of on-line, automatic, electromechanical tablet weight-
control systems capable of continuously monitoring the weights of tablets as they are produced.
EQUIPMENT USED IN CAPSULE MANUFACTURE
A. Filling Equipment for Hard Gelatin Capsules

1. Eli Lilly/Parke-Davis
Each of these capsule filling machines requires an individual operator and may achieve a daily
output of up to 200,000 capsules.
Process:
The empty capsules are fed from the storage hopper and through the rectifying unit into the two-
piece filling ring (3A and 3B).
Rectification is based on dimensional differences between the outside diameters of the cap and
body portions of the capsule.
As the ring (3A and 3B) is rotated, a vacuum is applied on its underside.
These vacuum seats the bodies into the lower half of the ring, while the caps are retained in the
upper portion.
The two pieces of the ring are separated, and the cap-containing portion is placed aside.
The body-containing portion of the ring is placed on a variable speed turntable and is
mechanically rotated under the powder hopper which contains an auger for the forced delivery of
the powder.
After one (or more) complete rotations of the ring, the powder hopper is removed, and the two
segments of the ring (3A and 3B) are rejoined.
The intact ring is positioned in front of the peg ring and the closing plate is pivoted to a
position approximately 180 degrees.
Pneumatic pressure is applied to the peg ring which forces the capsule body into the cap, and the
closing plate holds the caps in position.
2. Farmatic
The machines feature continuous motion with dosator-type powder feeding units, and are totally
enclosed for dust and noise control. Adjustable vacuum is used for separating the capsules after
rectification, and any defective or unopened capsules are automatically rejected.
3. Hofliger and Karg
The Hofliger and Karg (H & K) line consists basically of four machines—Models GKF'- 303,
GKF-602, GKF-1500, and GKF-2500; the numbers represent the approximate output of filled
capsules per minute.
All Hofliger and Karg machines are completely automatic and require only compressed air and a
power for operation.
4. Macofar
The Macofar fine of capsule filling equipment consists of three models: MT-12, MT-13/1, and MT-
13/2.
All units are based upon a similar method of rectification and filling. The empty capsules are

rectified into bushings in a central plate. Separation of cap from body is accomplished
by vacuum, and the body-carrying bushings are positioned under the dosator unit.
5. mG2
Five models of continuous-motion filling machines are currently offered by mG2.
All mG2 models either run or can be fitted with attachments to allow them to run with powders,
granules, or pellets. Models G37N and G38 can be supplied with auxiliary equipment to provide for
presorting of the empty capsules, automatic sampling of filled capsules, and an inspection unit, based
upon weight, for filled capsules.
6. Osaka
The Osaka filling machine is a high-capacity, continuous-motion machine recently introduced in
the United States.
The powder-filling principle utilized is unique in that vibration is used to move the powder from the powder
hopper to powder shoes and from the powder shoes into the capsule bodies.
The unit is totally enclosed, with external access to the capsule and powder hoppers.
7. Perry
Perry utilizes the well-established ACCOFIL method of powder dose control, which is unique in
capsule filling.
The machine is a continuous-motion rotary machine with a rated output of up to about 60,000 capsules
per hour; it fills powder mixtures only.
8. Zanasi
The line of Zanasi equipment currently available includes nine different units in four model lines.
With suitable change parts, all may be capable of handling powders, pellets, or tablets. Some models
may be purchased with attachments to allow the insertion of smaller capsules, and some may be
capable of paste or liquid filling.
B. Equipment used for Soft-gel capsule
1. Rotary-die Machine
The rotary-die machine is a self-contained unit capable of
continuously and automatically producing finished
capsules from a supply of gelatin mass and filling
material, which may be any liquid, semiliquid, or paste
that will not dissolve gelatin.
Two continuous gelatin ribbons, which the machine
forms, are brought into convergence between a pair of
revolving dies and an injection wedge.
Accurate filling under pressure and sealing of the capsule
wall occur as dual and coincident operations; each is
delicately timed against the other.
2. Norton Capsule Machine

This machine produces capsules completely automatically by leading two films of gelatin between
a set of vertical dies.
These dies as they close, open, and close are in effect a continual vertical plate forming row after

row of pockets across the gelatin film.

These are filled with medicament and, as they progress through the dies, are sealed, shaped,
and cut out of the film as capsules, which drop into a cooled solvent bath.
3. Accogel capsule Machine

The Accogel, or Stern machine, uses a system of rotary dies but is unique in that it is the only
machine that successfully can fill dry powder into a soft gelatin capsule.
It is extremely versatile, not only producing capsules with dry powder but also
encapsulating liquids and combinations of liquids and powders.
The capsules can be made in a variety of colors, shapes, and sizes.
PHARMACEUTICAL PROCESSING OF SEMISOLID DOSAGE FORMS

MIXING OF SEMI-SOLIDS
The problems that arise during the mixing of semisolids (ointments and pastes) stem from the fact that,
unlike powders and liquids, semisolids will not flow easily.
Material that finds its way to 'dead' spots will remain there. For this reason, suitable mixers must have
rotating elements with narrow clearances between themselves and the mixing vessel wall and they
must produce a high degree of shear mixing, as diffusion and
convection cannot occur.
Mixers Used for Semi-solids

1. Planetary Mixers
This type of mixer is commonly found in the domestic
kitchen (e.g. Kenwood-type mixers) and larger
machines which operate on the same principle are
used in industry.
The mixing blade is set off-centre and is carried on
a rotating arm. It therefore travels round the
circumference of the mixing bowl while simultaneously
rotating around its own axis.
This is therefore a double rotation similar to that of a
spinning planet rotating around the sun - hence the
name.
2. Sigma-blade mixer
Planetary mixers are also sometimes used to mix
powders, particularly if a wet mass for granulation is
required.
This robust mixer will deal with stiff pastes and

ointments and depends for its action on the close
intermeshing of the two blades which resemble the
Greek letter ∑ in shape.
It is very difficult using primary mixers to completely
disperse powder particles in a semisolid base so

that they are invisible to the eye.

The mix is usually subjected to the further action of a roller mill or colloid mill, to 'rub out' these
particles by the intense shear generated by rollers or cones set with a very small clearance
between them.
EQUIPMENT USED IN MANUFACTURE OF SUPPOSITORY

1. Rotary molding machine
Consists of chrome-plated brass molds that are installed radially in the cooling turntable.
In here, the prepared mass is fed into a filling hopper where it is continuously mixed and
maintained at constant temperature. The suppository mold is lubricated by brushing or spraying
and then filled to slight excess. After the mass solidifies, the excess material is scraped off and
collected for re-use. The solidified suppositories are moved to the ejecting station where the mold
is opened and the suppositories are pushed out by steel rods.
2. Sarong SpA Semiautomatic Equipment

This machine is used for in-package molding of suppositories.
It involves the automated filling of molds or preformed shells by a volumetric dosing pump that meters
the melt from a jacketed kettle or mixing tank directly into the molds or shells.
The fully jacketed piston-type dosing pump (1) meters the suppository melt in the jacketed tank
(2) into preformed shells that pass directly beneath injection nozzles. The strips of filled preformed
shells continue into a cooling chamber (3) prior to sealing and cartoning.
EQUIPMENTS USED IN THE MANUFACTURE OF PARENTERALS

The following equipment as per Schedule-M are recommended:
o Manufacturing Area
Storage equipment for ampoules, vials and closures
Washing and drying equipment
Dust-proof storage cabinet
Water still
Mixing and preparation tanks or other containers
Mixing equipment (if necessary)
Filtering Equipment
Hot air sterilizer
Aseptic filling and sealing rooms

Benches for filling and sealing
Bacteriological filters
Filling and sealing unit under laminar flow work station
o General Room
Inspection table
Leak testing table

Labelling and packing benches

Storage of equipment including cold storage and refrigerators if necessary
* Schedule M – is a part of the Drug and Cosmetic Act of 1940. It is a part of quality assurance which ensures
that the products are consistently manufactured and controlled to the quality standards appropriate for their
intended use. It is a requirement of factory premises, plant and equipment for pharmaceutical product.
* M-1 – requirement of factory premises for manufacturing of homeopathic preparations
* M-1 – requirement of factory premises for manufacturing of cosmetics
* M-3 – requirement of factory premises for manufacturing of medical devices
EQUIPMENTS:
Sterile Garment Cabinet
o Stainless steel
o Ensures a clean storage space by making use of UV disinfectant and heating through IR lamps.
o These cabinets may be designed in horizontal air flow system and clean air through HEPA filters.
Cooler or Cold Storage
o Used to prolong the life of the products and preventing the products from deterioration
o It provides the assurance that products are kept in a cool and temperature controlled environment.
High Efficiency Particulate Air (HEPA) Filters
o HEPA filters can remove at least 99.97% of airborne particles 0.3micrometer in diameter.
o HEPA filters are composed of a mat randomly arranged fibres (Poly-vinylidene fluoride -PVDF)
o Smaller pollutants and particles are mainly trapped by one of the following mechanisms:
Interception
Impaction
Diffusion
Laminar Flow Hoods
o Clean air work benches are specially designed to ensure the aseptic preparation of sterile products.
o Introduction of personnel, equipment, and material into the work area provides sources of particulate
matter which may contaminate the product.
o Very small particles are not heavy enough to settle due only to the force of gravity, but instead are
carried and directed by air currents. And if there is turbulent air, particles may be driven into product.
o Laminar air flow velocity satisfactorily sweeps the area yet does not create unacceptable turbulence.
Sterilization in Place (SIP) System
o For in-line sterilization of various processing equipments.
o Handling various biological solutions and mixtures requires cleaning and sterilizing these equipments
from time to time as they are susceptible to contamination.
o Proper SIP integration with pharmaceutical equipment is very important for the overall success of the
operation
Filters in Filtration Sterilization
o Millipore’s Airvent filters
Constructed with Polytetrafluoroethylene (PFTE) membrane
These filters have been qualified to withstand at least 40 SIP cycles at 135 C for 30 minutes.
o Millipore’s Durapore filters

Constructed with a Polyvinylidene difluoride (PVDF) membrane

These filters have been qualified to withstand 5 to 30 SIP cycles at 135 C for 30 minutes
Other types of Sterile Filters
Filter Type Size Range (microns) Examples of what is removed by this filter type
Particle 10 to 200 Pollens

Particles
Some bacteria
Microfilter 0.1 to 10 All bacteria type
Yeast
Colloids
Ultrafilter 0.001 to 0.1 Most viruses
Large organic compounds (> 10 000 daltons)
Nanofilter Less than 0.001 Small organic compounds

Ions
Microfilters
Porosity of microfilters range from 0.1 m to 10 m
Used to remove all bacteria, yeast and colloidal forms
Ampule Washing Machine

o Water is sprayed onto the ampoules.
o Turned to an angle of 180 degree with their mouth downward to remove water.
o Finally the ampoules are filled with compressed air to remove residual water.
o Final rinsing is done with water for injection.
Vial Washing Machine

o It has several channels for washing of the vial.
o The vials travel through these channels and simultaneously purified water, air, water for injection,
are introduced through various nozzles and arranged in the washing machine.
o After washing completes the vial run through depyogenation zones and the ampoules /vials are made
to free from pyrogens.
Filling Machines
1. Syringe Filling Machine
Characteristics:
Barrier isolators
In-process check weighing
Filling: Rotary piston pumps; 0.2 to 29 ml
All types of syringe including glass, plastic can be filled
It can fill 300 to 600 syringes in a minute

2. Ampule Filling Machine

Features:
Accommodate a variety of ampoules in terms of shapes and size.
Has 'no ampoule no fill' capability
Check weight mechanism of the machine helps to maintain consistency in each batch.
Sealing is done either by laser sealing system or conventional gas flame.
Filling range of these machines is normally between 1ml to 20 ml
3. Vial Filling Machine

For filling vials and bottles with liquids, viscous material and suspensions and powders.
Process:
The machine comprises of an intake section which loads the vials.
Transferred through an intermittent transport section.
Liquid filling section which fills the vials with predetermined quantity.
Finally the filled and rubber stoppered vials are released and discharged.
Other filling approaches:

Driving Device Filling Mechanisms
Gravity (solids and liquids) Gravimetric, time pressure,
(oldest and most economical) fill by weight
Piston (liquids and gases) Rotary piston, rolling diaphragm pump
Rotary pump (liquids and gases) Rotary peristaltic
Auger screw or vibrator (solids) Vibratory, mechanical force
Sealing Equipment
o Blow-fill-seal (BFS) technology
Blow-fill-seal (BFS) technology is an automated process by which containers are formed, filled,
and sealed in a continuous operation.
This manufacturing technology includes economies in container closure processing and reduced
human intervention.
Blow-fill-seal (BFS) technology is also known as the form-fill-seal process
Most BFS machines operate using the following steps:

Extrusion
o An endless sterile plastic tube is continuously extruded from the melted granulate in the
filling cavity of the mould.
Blowing
o Final container is produced by sterile air pressure from Blow and Fill nozzle.
Filling
o After the container is formed inside the mould, sterile liquid product is introduced into
the container.
Sealing
o Final container is sealed in place by closing of the seal-mould form onto the container top.

Mould opening
o Upon completion of filling and sealing steps, the mould is separated, producing the
sterile filled and sealed container.
o SYFPAC ®LVP
SYFPAC is acronym for System for Filling Parenterals Aseptically into Containers of Plastic
Materials
It is specifically designed for containers which have a fill volume typically between 50-2500ml
for aseptic primary packaging of it.
Temperature of the liquid while filling should be typically between 4-30C.
o Vial Sealing
Jaw Type Crimper
Stainless steel jaws draw up the vial finish and crimp the aluminum seal skirt as
compression of the rubber occurs within the crimper head.
Spinning Rollers
The vial is raised, or the head is lowered causing the rubber to be compressed
against a sealing pressure block (or plunger). The rollers constrict to tuck the
metal of the cap skirt beneath the vial flange.
Rail Sealing
A semi-circular hardened stainless steel section (sealing rail assembly) with a
gradually decreasing angle (typically 45°to 15°) performs the crimping action as
the vial is compressed between spring loaded platens (pressure block and vial
rest).
The vial rotates and revolves around a turret with the cap skirt against the
crimping rail.
EQUIPMENTS USED IN THE MANUFACTURE OF NOVEL DOSAGE FORMS

FILM-COATING TECHNOLOGY
The majority of tablet coatings are purely cosmetic, to improve the appearance and aid identification for
branding and patient safety. These coatings should have minimal effect on the therapeutic efficacy of the
product, although certain colours have been associated with psychological response to medicines.
Almost all tablets are now coated and while the dominant technology is film coating other techniques are
available:
o Enrobing
Uses a process similar to soft gelatine capsule manufacture, where tablets and polymer (e.g.
gelatine) sheets are fed between die rollers that press the polymer around the tablet.
Requires specific equipment.
Can yield a capsule-like appearance with high gloss
o Gel dipping
Has been used for OTC (over-the-counter) products in particular as it permits a capsule-like
two-tone appearance and high gloss.
Relatively complex to manufacture as specialist equipment is required to hold, dip and dry the
tablets.

o Hot-melt coating
Used for pellet coating to provide taste masking or modified release. Low-melting waxes can
be sprayed using conventional equipment with heated lines to prevent the melted wax from
congealing in the equipment.
o Compression coating
Uses standard tableting materials to compress a coating around a core, on a special tablet
press.
It is mostly used to provide a modified release profile of some sort e.g. a fast-release
outer coat with a prolonged-release inner core
o Sugar coating
Uses inexpensive materials and a simple, solid coating pan to apply a subcoat, a
bulking layer, pigments and polish, followed by printing with identifying text
o Film coating
Pigments are suspended in a solution or dispersion containing polymer and plasticiser in
a solvent or continuous phase. This suspension is then sprayed onto tablets, typically
in a perforated, sidevented coating pan.
EQUIPMENTS UTILIZED IN FILM COATING
1. Standard Coating Pan

The conventional coating pan system consists of a spherical, hexagonal or pear-shaped pan that
rotates on an inclined axis. The rotational movement of the pan causes the substrates to tumble
and make multiple passes through the spray application zone. Heat is blown across the
surface of the tumbling tablets and exhaust air is withdrawn.
Disadvantages:
o Low drying efficiency since much of the drying
takes place on the surface of the bed of material
being coated.
o Poor mixing efficiency that results in dead spots
(regions of low product movement) in the product
bed.
o Health hazards for the operator and
increased risk of explosion in the case of organic
solvent-based film coating due to improper
balance between inlet and exhaust air which
causes solvent vapour to leak into the general
coating area.
Modifications of the standard coating pan:

o Immersion sword system
o Immersion tube system
o Baffled pan and diffuser (Pellegrini pan system)

Perforated Coating Pan
Perforated coating pan consists of a perforated or partially perforated drum that rotates on its horizontal
axis in an enclosed housing.
The equipment was developed to maximize the interaction between the tablet bed and the drying air,
which it does by drawing the air through the tumbling product bed as opposed to supplying air to the bed
surface only.
Examples of perforated coating pans include:
Accela-cota (Thomas Engineering, USA)
Hi-coater (Freund-Vector Japan and USA)
Driacoater (Driam Metallprodukt GmbH, Germany)
Glatt perforated coating pan (Glatt., Switzerland, Germany and USA)
Huttlin Butterfly Pan, HBP (G S, Italy)
IDA Coating equipment (Dumoulin, France)

3. Fluidized Bed Equipment

The ﬂuidized bed equipment offers an alternative to pan coating and is particularly popular for coating
multiparticulate systems.
The equipment offers the potential advantage of being able to affect the most efficient drying of any
product that is possible in any existing coating equipment.
In a fluid bed system, the objects being coated are suspended in an upward stream of air, maximizing
the surface available for coating. The coating is applied by an atomizer, and this is dried by the fluidizing
air.
Types:
1. Top spray (granulation or conventional mode)
o Used predominately for taste and odour masking purposes, where drug release rates are
not critical since films produced by this method are not uniform in thickness. Additionally,
it is suitable for the application of hot-melt coatings
2. Bottom spray (Wurster)
o It is preferred for the application of rate-controlling polymers to a wide variety of multiparticulates.
The process is also suitable for drug layering when the drug dose is in the low-to-medium
range
3. Tangential spray (rotary granulator)
o It is suitable for the application of modified-release film coatings to a wide range of
multiparticulate products. The process is ideal for drug layering when the dose is medium to
high. It is also useful as a spheronizing process for producing spheroidal pellets from powders.

4. Spray Application System

While sugar coating operations can be accomplished using manual ladling procedures, success
of the film coating process rests on the availability of coating equipment with spray atomization system
which allows coating liquids to be applied in a much more controlled and reproducible manner.
There are basically two types of spray-atomization systems available:
Airless (Hydraulic) spray system
o In this type of system, the coating solution is pumped at high pressure (250 –3000 psig)
through a spray nozzle with a small orifice.
o Atomization of the liquid occurs as it expands rapidly on emerging from the nozzle.
o The degree of atomization achieved by this system depends on:
Fluid pressure
Orifice size
Viscosity of coating solution
Air-spray system
o The coating solution is pumped, under little or no pressure, to the nozzle and is
subsequently atomized by means of a blast of compressed air that makes contact with
the stream of liquid as it passes from the nozzle aperture.
o This system is typically more effective in small-scale coating processes and all those
involving aqueous-film coating operations.
o The degree of atomization achieved by this system depends on:
Fluid pressure
Fluid cap orifice
Viscosity of coating solution
Air pressure
Air cap design

MICROENCAPSULATION
o It is a modified form of film coating, differing only in the size of the particles to be coated and the
methods by which this is accomplished.
o Microencapsulation is a process or technique by which thin coatings can be applied reproducibly to
small particles of solids, droplets of liquids, or dispersions, thus forming microcapsules.
o A number of coating materials have been used successfully; examples of these include gelatin,
polyvinyl alcohol, ethylcellulose, cellulose acetate phthalate, and styrene maleic anhydride.
o The microcapsules may consist of a single particle or clusters of particles.
o The process provides answers for problems such as masking the taste of bitter drugs, a means of
formulating prolonged-action dosage forms, a means of separating incompatible materials, a
method of protecting chemicals against moisture or oxidation, and a means of modifying a
material’s physical characteristics for ease of handling in formulation and manufacture.
NANOPARTICLES/NANOCAPSULES/NANOSPHERES
Production of nanoparticles of soft materials is much more difficult and challenging than that of hard
materials because of the high stickiness of the former.
Technologies Utilized:
o Pearl/Ball Milling Technology for Production of Drug Nanocrystals
These mills consist of a milling container filled with fi ne milling pearls or larger sized balls. The
container can be static and the milling material is moved by a stirrer; alternatively, the complete
container is moved in a complex movement leading consequently to movement of the milling
pearls.
Products:
Rapamune coated tablet – more convenient formulation, introduced by Wyeth
Pharmaceuticals
Emend – introduced in 2003 by MSD, Sharp and Dohme Gmbh, is a capsule
composed of sucrose, microcrystalline cellulose, hyperlose, and sodium
dodecylsulfate
Nanoparticles/Nanoemulsions/Nanospheres Prepared by High - pressure

Homogenization
Using the piston gap homogenizer, the liquid is forced through a tiny homogenization gap.
Intralipid and Lipofundin are generally produced by this technology
Nanoparticles/Nanocapsules Obtained by Interfacial Polymerization

Nanoparticles/ nanocapsules can be obtained by fast polymerization of a monomer at the interface
between the organic and the aqueous phase of an emulsion.
Alkylcyanoacrylates have been proposed for the preparation of both oil - and water - containing
nanocapsules.
These monomers polymerize within a few seconds, initiated by hydroxyl ions from equilibrium
dissociation of water or by nucleophilic groups of any compound of the polymerization medium.

NOVEL TABLETING TECHNOLOGY
1. THREE-DIMENSIONAL PRINTING OF TABLETS

o It is called 3DP by Therics Corporation, the company to first apply this technology
to pharmaceuticals.
o The technology is quite similar to ink-jet printer technology. It was improved by engineers at
the Massachusetts Institute of Technology, and later at Therics.
o Powder is spread into a tray and binder droplets are precisely sprayed onto a substrate to
form virtually any shape or design. A piston holding the unit changes position for each pass
of the dispensing module, allowing for a build-up of the tablet. The process is repeated over
and over until the desired shape is obtained.
o To this date, there are no commercial tablets made from this technology.
2. WEB-COATED SYSTEMS
o Roche laboratories developed a system whereby sheets of a substrate were coated with drug and
binder solution.
o In here, a number of sheets were then laminated, or glued together to form a complex, multi-layered
sheet containing drug and various binder/excipient systems. The final laminate sheet was then
punched to produce many dosage forms.
o This system was quite flexible, and was capable of producing various types of controlled-release,
and combination products.
3. HOT-MELT EXTRUSION
o Hot-melt extrusion technology has been extensively used as a processing technique in the plastics
industry and is currently being investigated in the pharmaceutical arena as a novel tableting
method.
o The process involves the active, suitable polymeric carrier, and other excipients being mixed in the
molten state and then extruded through a die. The final product may take the form of a film, pipe,

tube, or granule, depending on the shape of the die.

o In addition to being anhydrous, this technology offers the advantage of tableting poorly
compressible materials and manufacturing sustained-release tablets.
PHARMACEUTICAL AEROSOLS
The packaging of therapeutically active ingredients in a pressurized system is not new to the
pharmaceutical industry.
According to present day usage, an aerosol or pressurized package is defined as “a system that depends
on the power of a compressed or liquefied gas to expel the contents from the container”.
To prepare and package pharmaceutical aerosols successfully, special knowledge, skills, and equipment
are required. As with other pharmaceutical products, these operations must be carried out under strict
supervision and adherence to rigid quality controls.
FILLING APPARATUS
Pressure Filling Apparatus

Pressure filling apparatus consists of a pressure burette capable of metering small volumes of
liquefied gas under pressure into an aerosol container.
Cold Filling Apparatus

Cold filling apparatus is somewhat simpler than the pressure filling apparatus. All that is needed
is an insulated box fitted with copper tubing that has been coiled to increase the area exposed
to cooling.
This system can be used with metered valves as well as with nonmetered valves; however, it should
not be used to fill hydrocarbon aerosols since an excessive amount of propellant escaping and
vaporizing may form an explosive mixture at the floor level.
Compressed Gas Filling Apparatus

Compressed gases can be handled easily in the laboratory without the use of elaborate
equipment.
Since the compressed gases are under high pressure, a pressure-reducing valve is required
LARGE SCALE EQUIPMENT
Concentrate Filler
This can range from a single-stage single hopper to a large straight-line multiple-head filler or a
rotary type multiple-head filler.
Production schedules dictate the type of filler required. Most of these fillers deliver a constant volume
of product and they can be set to give a complete fill in one or more operations.
Usually, only part of the product is added at each stage, assuring a more accurate fill
Valve Placer
The valve can be placed over the container either manually or automatically.
High-speed equipment utilizes the automatic valve placer. This orients the valve and places it in

position prior to the crimping operation.
Purger and Vacuum Crimper

Aerosols are packaged in both metallic and glass each requiring their own style of crimper.
Combination can and bottle cappers can be used for most laboratory procedures and operate
manually or on air pressure (about 80 pounds per square inch).
These are capable of producing more than 10 to 12 cans per minute.
Pressure Filler
These units are capable of adding the propellant either through the valve stem, body, and dip tube,
around the outside of the stem, or under the valve cup before crimping.
They are either single- or multiple-stage units arranged in a straight line or as a rotary unit.
To speed production, a positive pressure is used to force the liquid propellant into the
container.
Leak Test Tank

This consists of a large tank filled with water and containing heating units and a magnetized chain
so that the cans or pucks for glass, aluminum, and plastic containers are carried through and
submerged into the water.
The length of the tank is such that the temperature of the product before it emerges from the tank
is 130°F.

Activity 3: Skill-building Activities (7 mins + 3 mins checking)
I. Supply what is asked.
1. Give the meanings of the following abbreviations:
SOP: Standard Operating Procedures

QA: Quality Assurance
QC: Quality Control
R&D: Research & Development
FDA: Food & Drug Adminstration
API: Active Pharmaceutical Ingredient
MFR: Master Formula Record
BMR: Batch Manufacturing Record
II. MATCHING TYPE.
B 1. This member of the technology transfer team reviews the analytical A. QA representative
requirement and is responsible for analytical method transfer for drug
substance and drug product.
2. This member of the technology transfer team reviews the documentation
A
to determine compliance with marketing authorization (MA).
3. This member of the transfer team reviews equipment requirement B. QC representative
E
and reviews preventative maintenance and calibration impact.
4. This member of the transfer team performs initial assessment of
C transferred project for feasibility, compatibility with site
capabilities and establishes resource requirements.
5. This member of the transfer team reviews process instructions to C. Process
D
confirm capacity and capability. technologist
B 6. Reviews analytical requirement.
7. Initiates conversion of donor site documentation into local systems or D. Production
A
format. representative
C 8. Collates documentation from donor site
9. Performs initial assessment of transferred project for Feasibility, E. Engineering
C
Compatibility with site capabilities anD Establishes resource requirements. representative
D 10. Considers any safety implications, e.g., solvents; toxic; sanitizing materials.
D 11. Considers training requirements of supervisors or operators.
D 12. Considers impact on local standard operating procedures (SOPs).
B 13. Responsible for analytical method transfer for drug substance and drug
product.
A 14. Reviews analytical methods with QC to determine capability, equipment
training requirements.
15. Initiates or confirms regulatory requirements, e.g., change to
A
manufacturing license; variations to MA if process changes needed, etc.

Activity 4: What I Know Chart, part 2 (2 mins)
Instruction: To review what was learned from this lesson, please go back to Activity 1 and answer the
“What I learned” column. Notice and reflect on any changes in your answers from what you know
before answering your SAS and after answering your SAS.
Activity 5: Check for Understanding (10 mins)
BLOCK 1. MULTIPLE CHOICE.

1. Which among the following in not a type of non-Newtonian fluid?
A. Dilation C. Rheopectic E. Dilatant
B. Pseudoplastic D. Thixotropic
2. This equipment subjects the emulsion to an extremely high velocity through micro-channels in to an
interaction chamber; as a result, particles are subjected to shear, turbulence, impact, and cavitation.
A. Colloid mill C. Impeller type mixer E. Ultrasonic devices
B. Turbine mixer D. Microfluidizers
3. This equipment comprises an adjustable valve stem (core) and a fixed outer valve wall, which can have
various geometries with externally adjustable gap sizes and is most frequently used with liquid emulsions.
A. Homogenizers C. Microfluidizers E. Turbine mixer
B. Impellers D. Colloid mills
4. This equipment allows the passage of the mixed phases of an emulsion formula between a stator and high-
speed rotors and is used frequently for the comminution of solids and for the preparation of suspensions.
A. Agitators C. Turbine mixer E. Colloid mill
B. Propeller mixer D. Homogenizer
5. Which among the following is/are advantages of turbines?
I. Offers greater shearing forces than propellers
II. Can handle slurries with 60% solids
III. Suitable for liquids of large volume and high viscosity
A. I only
B. II only
C. I and II
D. II and III
E. I, II and III
6. Defined as a process that tends to result in a randomization of dissimilar particles within a system.
A. Mixing B. Blending C. Bulk Transport D. Newtonian E. Non-Newtonian
7. Have a constant viscosity that doesn’t change, no matter the pressure being applied to the fluid. This also
means they don’t compress.
A. Mixing B. Blending C. Bulk Transport D. Newtonian E. Non - Newtonian
8. Gets thicker when force is applied
A. Dilatant B. Mixing C. Pseudoplastics D. Thixotropic E. Rheopectic
9. Gets thinner when force is applied
A. Dilatant B. Mixing C. Pseudoplastics D. Thixotropic E. Rheopectic
10. If enough force is applied to these fluids, their viscosity will change.
A. Mixing B. Blending C. Bulk Transport D. Newtonian E. Non - Newtonian

C. LESSON WRAP-UP
Activity 6: Thinking about Learning (5 mins)
Work Tracker. You are done with this session! Let’s track your progress. Shade the session
number you just completed.
P1 P2
1 2 3 4 5 6 7 8 9 10
A. Think about your Learning. Tell me your thoughts! Does medication dosage form matter?
Explain.
---------------------------------------------------------------------------------------------------------
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FAQs
CC-APODS
1. What are the factors to consider when choosing a dosage form?
Condition of the patient, convenience, amount of drug required, potency, onset of action, and disease
state.
To know more about this. Click this link: https://www.youtube.com/watch?v=fx6rFbYCIAA
2. What is a drug?
Any chemical substance which can produce a biological response.
To know more about drug and dosage forms, click this link:
https://www.youtube.com/watch?v=egJDps1jY8o

KEY TO CORRECTIONS
Activity 3
Supply what is asked.
Give the meanings of the following abbreviations:
SOP: Standard Operating Procedure

QA: Quality Assurance
QC: Quality Control
R&D: Research and Development
FDA: Food and Drug Administration
API: Active Pharmaceutical Ingredient
MFR: Master Formula Record
BMR: Batch Manufacturing Record
MATCHING TYPE.
This member of the technology transfer team reviews the analytical A. QA representative
requirement and is responsible for analytical method transfer for drug
substance and drug product.
This member of the technology transfer team reviews the documentation to
determine compliance with marketing authorization (MA).
This member of the transfer team reviews equipment requirement and B. QC representative
reviews preventative maintenance and calibration impact.
This member of the transfer team performs initial assessment of
transferred project for feasibility, compatibility with site capabilities
and establishes resource requirements.
This member of the transfer team reviews process instructions to C. Process
confirm capacity and capability. technologist
Reviews analytical requirement.
Initiates conversion of donor site documentation into local systems or format. D. Production
Collates documentation from donor site representative
Performs initial assessment of transferred project for Feasibility, Compatibility E. Engineering
with site capabilities anD Establishes resource requirements. representative
Considers any safety implications, e.g., solvents; toxic; sanitizing materials.
Considers training requirements of supervisors or operators.
Considers impact on local standard operating procedures (SOPs).
Responsible for analytical method transfer for drug substance and drug
product.
Reviews analytical methods with QC to determine capability, equipment training
requirements.
Initiates or confirms regulatory requirements, e.g., change to manufacturing
license; variations to MA if process changes needed, etc.

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Course Code: PHA 069: Pharmaceutical Manufacturing

(with Regulatory Pharmacy, Quality Assurance, and cGMP)

Lesson title: Transfer of Technology Materials:

2) Activity 1: What I Know Chart, part 1 (5 mins)

What I Know Questions: What I Learned (Activity 4)

This document is the property of PHINMA EDUCATION

Importance of Technology Transfer

Technology Transfer Team PEP-QQ

Quality Assurance (QA) Representative

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Considers impact on local standard operating procedures (SOPs).

Quality Control (QC) Representative

Technology Transfer Guidelines for Pharmaceuticals

Active Pharmaceutical Ingredients (API):

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Bioburden, endotoxin and sterility as required

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Quality Control: Analytical Method Transfer

Standard Operating Procedures (SOP) for Technology Transfer

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This document is the property of PHINMA EDUCATION

TECHNOLOGIES APPLIED IN THE MANUFACTURE OF LIQUID DOSAGE

FUNDAMENTALS OF FLUID MIXING

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o Scale and integrity of segregation

A system for batch mixing commonly consists of two primary components:

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Propellers are not normally effective with liquids of viscosity greater

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PROCESSING EQUIPMENT FOR EMULSIONS

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PRINCIPLES OF PHARMACEUTICAL PROCESSING OF SOLID DOSAGE FORMS

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such a way as to give rise to laminar flow.

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This document is the property of PHINMA EDUCATION

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5. Specialized drying methods

EQUIPMENT USED IN TABLET MANUFACTURE

The feed shoe filled with the granulation is positioned

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The upper punch retracts, and the lower punch rises

B. Rotary Tablet Machines

C. High-speed Rotary Tablet Machines

D. Multi-layer Rotary Tablet Machines

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E. Instrumented Tablet Presses

EQUIPMENT USED IN CAPSULE MANUFACTURE

A. Filling Equipment for Hard Gelatin Capsules

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B. Equipment used for Soft-gel capsule

2. Norton Capsule Machine

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row of pockets across the gelatin film.