Unit 1: Pilot Plant Scale Up Techniques

Pilot plant scale-up is a crucial phase in the development of new products and processes. It involves transitioning from laboratory-scale experiments to larger, pilot-scale operations before full-scale production. This
step is essential for several reasons:
1. Process Optimization: Pilot plants allow for the optimization of processes on a larger scale, identifying any potential issues that may not have been apparent during laboratory experiments.
2. Data Collection: They provide valuable data on process parameters, which can be used to design and scale up to full production. This includes information on reaction kinetics, heat and mass transfer, and
equipment performance.
3. Cost Efficiency: By identifying and addressing potential problems early, pilot plants help avoid costly mistakes during full-scale production. They also allow for the testing of different process configurations
and conditions to find the most cost-effective solution.
4. Regulatory Compliance: Pilot plants can be used to produce samples for regulatory approval, ensuring that the final product meets all necessary standards and requirements.
5. Training and Development: They provide a platform for training personnel and developing standard operating procedures (SOPs) that will be used in full-scale production.
Overall, pilot plant scale-up is a critical step in the journey from concept to commercialization, ensuring that new products and processes are viable, efficient, and safe for large-scale production.

1
Definitions
• Plant: A place where the 5 M’s (money, material, man, method and
machine) are bought together for the manufacturing of the products.

• Pilot plant: The part of the pharmaceutical industry where a lab scale
formula is transformed into a viable product by development of liable and
practical procedure of manufacture.

• Scale-up: The art for designing of prototype using the data obtained from
the pilot plant model.

R&D Production
Pilot Plant
2
Pilot plan scale up

Commercial
manufacturing
Pilot plant & scale
up study

Laboratory

3
Why conduct pilot plant studies ?

• It is usually not possible to predict the effects of a many-fold increase

in scale.

• A pilot plant allows investigation of a product and process on an

intermediate scale before large amounts of money are committed to full-
scale production.

4
Pilot plant can be used for
• Evaluation of the results of laboratory studies
• Product and process corrections & improvements.
• Determination of possible salable by-products and waste which requiring treatment before
discharge.

• Obtaining data that can be used in making a decision on whether or not to proceed to a
full- scale production process; and in the case of a positive decision, designing and
constructing a full-size plant or modifying an existing plant.
• Production of small quantities of product for

 sensory, chemical, microbiological evaluations,

 limited market testing,
 furnishing samples to potential customers,
 shelf-live and storage stability studies 5
  Examination of formulae

 Production rate adjustment

Significance /  Idea about physical space required
importance of
 Appropriate record & reports to supports GMP
pilot plant
 Review of range of relevant
processing equipments
 Identification of critical features to
maintain quality
6
Objectives of pilot plant
• Find mistakes on small scale and make profit on large scale.

• To produce physically and chemically stable therapeutic dosage forms.

• Review of the processing equipment.

• Guidelines for productions and process control.

• Evaluation and validation for process and equipment.

• To identify the critical features of the process.

• To provide master manufacturing formula.

7
Steps in scale - up
1) Define product economics (based on projected market size, competitive
selling) & provide guidance for allowable manufacturing costs.

2) Conduct laboratory studies & scale – up planning at the same time.

3) Define key rate – controlling steps in the proposed process.

4) Conduct preliminary studies larger than laboratory studies with

the equipment to be used in rate-controlling step to aid in plant
design.
5) Design and construct a pilot plant (including provisions for process &
nvironmental
6) Evaluate pilot
controls,
plantcleaning
results (product
& sanitizing
& process)
systems,
including
packaging
process
&
waste
economics to make any corrections and to make a decision on whether or not to
proceed
andling systems, meeting regulatory agency requirements).
with a full scale plant development.
8
General considerations
1) Reporting Responsibility
2) Personnel Requirements
3) Space Requirements
4) Review of Formula
5) Raw materials
6) Equipment
7) Production rates
8) Process Evaluation
9) Preparation of Master Manufacturing Procedures
10) Product Stability and Uniformity
11) GMP Considerations

9
General considerations
1) Reporting responsibility

• R & D group with separate staffing

• The formulator who developed the product can

take into the production and can provide support

even after transition into production has been
completed

10
General considerations
2) Personnel requirement
• Scientists with experience in pilot plant operations as well as in actual

production area are the most preferable. As they have to understand the
intent of the formulator as well as understand the perspective of the
production personnel.
• The group should have some personnel with
engineering knowledge as scale up also involves
engineering principles.

11
General considerations
2) Personnel requirement

 The qualifications required for a position in a pilot plant organization:

• a blend of good theoretic knowledge of phamaceutics and some practical

experience in the pharmaceutical industry.

• the ability to communicate well, both in speaking and in writing.

• Pharmaceutically trained scientists contribute fundamental strength to the

function in their ability to assimilate the complex inter relationship between
pharmaceutical processes and the potential impact on chemical, physical,
biochemical, and medical attributes of dosage forms.
12
General considerations
2) Personnel requirement

• The number of people in a pilot plant group depends on the number

of products being supported and on the level of support required.

• An experienced scientist with a knowledgeable technician should

be able to handle one or two major projects simultaneously
depending on their complexity, while at the same time providing
technical support for an additional group of marketed products.

13
General considerations
3) Space requirements
3a) Administration 3b) Physical testing
and area
information

3c) Standard pilot plant

3d) Storage area
equipment floor space

14
General considerations
3) Space requirements
3a) Administration and information processing
• Adequate office and desk space should be provided for both scientist
and technicians.
• The space should be adjacent to the working area.

• There is the link between research, operations, and other disciplines,

members of the group frequently meet with people from other departments

should have an area available where three to four people can meet and
discuss subjects of mutual concern.
15
General considerations
3) Space requirements
3a) Administration and information processing

• There should also be space for a computer terminal

for convenient data entry and retrieval as well as archives for

stability data protocols and historical files.

16
General considerations
3) Space requirements
3b) Physical testing area

• An adequate working area

in which samples can be laid out and

examined and where physical tests on
these samples can be performed.

• This area should provide permanent

bench top space for routinely used
physical testing equipment.

17
General considerations
3) Space requirements
3c) Standard pilot-plant equipment floor space

is discrete plant space where equipment needed for manufacturing all types of
pharmaceutical dosage forms is located.

• The equipment should be available in a variety of sizes known to be representative

of production capability.

• Intermediate-sized and full-scale production equipment is essential in evaluating the

effects of scale-up of research formulations and processes.

• Utilization of the area is most efficient when it is subdivided into areas for solid
dosage forms, semisolid products, liquid preparations, and sterile products.
18
General considerations
3) Space requirements
3c) Standard pilot-plant equipment floor space
• Further subdivision of the areas should allow multiple operations to be conducted
simultaneously without raising GMP concerns.

• Because the utilization of pilot plant equipment is sporadic and dependent on project as
segments, equipment should be made portable, where possible.
• The provision of adequate
space for cleaning of pilot o stored in a relatively small area & brought
plant equipment should be out into suitable work areas for use.
there. o relieve some of the congestion often found in
• While some equipment can be pilot plant operations
cleaned in place, most o provides more working space around
equipment is better handled in a equipment that is in use.
dedicated cleaning area. 19
General considerations
3) Space requirements
3d) Storage area
• Approved area
• 2 areas: for active ingredient as well
• Unapproved area as excipient.

• Different areas should

provided for the storage
of
o in- process materials, scale-up batches made in the
o finish production
ed o packaging material
bulk
prod 20

ucts
from
the
pilot-
plant,
o mater
ials
from
the
exper
iment
al
General considerations
4) Review of formula

• Athorough review of the each aspect of formulation is important.

• The purpose of each ingredient and it’s contribution to the final product
manufactured on the small-scale laboratory equipment should be understood.

• Then the effect of scale-up using equipment that may subject the product to
stresses of different types and degrees can more readily be predicted, or
recognized.

21
General considerations
5) Raw materials

• Raw materials used in the small scale production

cannot necessarily be the representative for the large
scale production

therefore

One purpose/responsibility of the pilot-

plant is the approval &validation of the
active ingredient & excipients raw
materials.
22
General considerations
6) Equipments

• The most economical, the simplest & efficient equipment which are capable of
producing product within the proposed specifications are used.

• The size of the equipment should be such that the experimental trials run should
be relevant to the production sized batches.

too small too big

the process the wastage of the expensive

developed will active ingredients.
not scale up
23
General considerations
7) Production rates

• While determining the production rates

The immediate as well as the future market trends/

requirements are considered

24
General considerations
8) Process evaluation parameters

Rate of addition of granulating agents,

solvents, solution of drugs etc.
Order of mixing of
Screen size (for solids)
components
Process evaluation
Filter size (for liquids) parameters Mixing speed

Heating & cooling rate Mixing time

Drying temperature,
Drying time
25
General considerations
8) Process evaluation parameters
• The knowledge of the effects of various
process parameters (as few mentioned above)

Form the basis for process optimization &

validation

• The process validation

confirms that
the selected manufacturing procedure assure the
quality of the product at various critical stages
in the process & finished form.
26
General considerations
9) Master manufacturing procedures
3 aspects

a) Weighing sheets b) c) Manufacturing

Processing procedure
directions
Clearly identify the
chemicals required Precise
Written by the
in a batch & actual operator
explicit
27
General considerations
9) Master manufacturing procedures
3 aspects

a) Weighing sheets b) c) Manufacturing

Processing procedure
directions
Clearly identify the
chemicals required Precise
Written by the
in a batch & actual operator
explicit
28
General considerations
10) Product stability & uniformity

• The primary objective of the pilot plant is the physical & chemical stability
of the products.

• Hence, each pilot batch representing the final formulation and

manufacturing procedure should be studied for stability.

• Stability studies should be carried out in finished packages as well.

29
GMP consideration
• Equipment qualification
• Process validation
• Regularly schedule preventative maintenance
• Regularly process review & revalidation
• Relevant written standard operating procedures (SOPs)
• The use of competent technically qualified personnel
• Adequate provision for training of personnel
• A well-defined technology transfer system
• Validated cleaning procedures.
• An orderly arrangement of equipment so as to ease material flow &
prevent cross- contamination
30
31
Pilot plant scale-up for solid dosage
forms (Tablets)
• The primary responsibility of the pilot plant staff is to ensure that the newly
formulated tablets developed by product development personnel will prove to be
efficiently, economically, and consistently reproducible on a production scale.

• The design and construction of the pharmaceutical pilot plant for tablet
development should incorporate features necessary to facilitate maintenance and
cleanliness.

• If possible, it should be located on the ground floor to expedite the delivery and
shipment of supplies.

32
Pilot plant scale-up for solid dosage
forms (Tablets)
• Features for prevention of extraneous and microbiological contamination in
the pilot plant design:

1. Fluorescent lighting fixtures should be the ceiling flush type.

2. The various operating areas should have floor drains to simplify cleaning.
3. The area should be air-conditioned and humidity controlled.
4. High -density concrete floors should be installed.
5. The walls in the processing and packaging areas should be enamel cement
finish on concrete.
6. Equipment in the pharmaceutical pilot plant should be similar to that used by
production division- manufacture of tablets.
33
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets

1) Material handling
2) Dry blending
3) Granulation
4) Drying
5) Reduction ofparticle size
6) Special Granulation techniques
a) Dry blending
b) Direct compression
c) Slugging (dry granulation)

34
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
1) Material handling

• In the laboratory, materials are simply scooped or poured by hand, but in

intermediate- or large-scale operations, handling of this materials often become
necessary.
• If a system is used to transfer materials for more than one product steps must be
taken to prevent cross contamination.
• Any material handling system must deliver the accurate amount of the
ingredient to the destination.
• The type of system selected also depends on the characteristics of the materials.
• More sophisticated methods of handling materials such as vacuum loading
systems, metering pumps, screw feed system can be used.
• There is no or minimal loss of material.
35
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
2) Dry blending

• Dry blending process uses a binary cohesive-powder

mixture which contains two different sizes.
• It is well known that finer particles adhere preferentially
on the surface of the coarse particles.
• This type mixture has been called an interactive
mixture.
• The blending of fine and coarse particles breaks down
the agglomerates of fine and coarse powders, and
produces an electric charge by contact and collision
between particles.
36
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
2) Dry blending
• Powders to be used for encapsulation are to be granulated & must be well
blended

• Inadequate blending at this stage to ensure good drug

distribution
could result in

discrete portion of the batch being either high or low

in potency.

37
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
2) Dry blending

• Steps should also be taken to ensure that all the ingredients are free of lumps
and agglomerates.

• For these reasons, screening and/or milling of the ingredients usually makes
the process more reliable and reproducible.
 Improper blending cause following
 Scale- up considerations:
issues:
• Time of blending
• Content variation (no content uniformity)
• Size of blender
• Flow problems
• Blender loading
• Non-reproducible compression
38
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
2) Dry blending

 Equipments used:

• V-Blender
• Double cone Blender
• Ribbon Blender
• Slant cone Blender
• Bin Blender
• Orbiting Screw Blenders vertical & horizontal high intensity mixers

39
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
2) Dry blending

Slant Cone Blender Bin Blender

Double Cone Blender Ribbon Blender 40

Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation

‘‘process whereby small particles are gathered into larger, permanent masses in
which the original particles can still be identified’’

 Granulation

• impart good flow properties to the material,

• increase the apparent density of the powders,
• change the particle size distribution,
• uniform dispersion of active ingredient.

41
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation
 Wet granulation utilize some form of liquid to bind the primary particles
• Equipment Used: o Sigma blade mixer
o Heavy duty planetary mixer
• Efficient and reproducible process

• In wet-granulation process, binders promote size enlargement to produce granules

and thus improve flowability of the blend during the manufacturing process.

• Natural Polymers: Starch, Pregelatinized Starch

• Synthetic polymers: PVP, Methyl cellulose, HPMC

42
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation
 Wet granulation

Sigma Blade Mixer Planetary Mixer

43
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation

44
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation
 Wet granulation
“Multifunctional processors”

capable of performing all functions required to

prepare a finished granulation, such as dry
blending, wet granulation, drying, sizing and
lubrication in a continuous process in a single
equipment.

45
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation
 Dry granulation (slugging)
• There are a number of drug substances which are moisture sensitive

can not be directly compressed.

• A dry powder blend that cannot be directly
compressed because of poor flow or compression
properties.
• Equipment: Roller compactor

46
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation
 Fluidized bed granulation a process by which granules are produced in single
equipment by spraying a binder solution onto a
fluidized powder bed.

finer, free flowing & homogenous

material
• Equipment: Fluidized bed granulator

• The system involves the heating of air and then directing it through
the material to be processed .
• Later the same air exists through the voids of the product.
47
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation

 Scale- up considerations:

• Process air temperature

(Selected to achieve desired product temperature)
(Adjusted with process air volume)

• Process air volume

(Produce fluidization pattern)
(Delivers heat to the product)

48
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
3) Granulation

 Application of granulation:

‣ to reduce dust
‣ to densify the material
‣ to facilitate metering or volumetric dispensing
‣ to enhance the flow rates & rates uniformity

49
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
4) Drying
• The most common conventional method a granulation continues to be the
of drying circulating hot air oven, which is
heated by either steam or
electricity.
• If granulation bed is too deep or too dense

the drying process will be inefficient

• If soluble dyes are involved migration of the dye to the surface of the granules

50
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
4) Drying

 Scale- up considerations:

• Air flow
• Air temperature
• Depth of the granulation bed

51
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
4) Drying
 Tray dryer
• Parameters to be considered for scale up are :
1. Air flow
2. Air temperature
3. Depth of the granulation on the trays
4. Monitoring of the drying process by the use of moisture and
temperature probes
5. Drying rates at specified temperatures and air flow rates for
each product

52
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
4) Drying
 Fluidized bed dryer

• Parameters to be considered for

scale up are

1. Optimum Load
2. Air Flow Rate
3. Inlet Air Temperature
4.Humidity of the Incoming Air

53
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
5) Reduction of particle size

‣ Flowability
‣ Compressibility Compression factors
‣ Uniformity of tablet weight
‣ Content uniformity affected by particle size
‣ Tablet color uniformity distribution
‣ Tablet hardness

• First step in this process is to determine the particle size distribution of

granulation using a series of “stacked” sieves of decreasing mesh openings.
54
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
5) Reduction of particle size

• Equipments used for particle size reduction of dried granulation:

‣ Oscillating granulator
‣ Hammer mill
‣ Mechanical sieving device
‣ Screening device

55
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
5) Reduction of particle size
• As part of the scale-up of a milling or sieving operation, the lubricants and glidants,
which in the laboratory are usually added directly to the final blend, are usually
added to the dried granulation during the sizing operation.

• In Lab : Added to the final blend

• Scale Up : Added to the dry granulation during size reduction

• This is done because additives like magnesium stearate, agglomerate when added in
large quantities to the granulation in a blender.

• Over mixing or under mixing should be avoided.

56
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
5) Reduction of particle size

Hammer Mill
Mechanical Sieving

Oscillating Granulator
57
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
5) Reduction of particle size

• Control factors:

‣ Speed of mill
‣ Rate of material feed
‣ Equipment type

58
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
6) Blending
• Type of blending equipment often differs from that using in laboratory.

• In any blending operation, both segregation and mixing occur simultaneously as a

function of particle size, shape, hardness, and density, and of the dynamics of the
mixing action.

• Particle abrasion is more likely to occur when high-shear mixers with spiral screws or
blades are used.

• When a low dose active ingredient is to be blended it may be sandwiched between two
portions of directly compressible excipients to avoid loss to the surface of the blender.59
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
6) Blending
 Scale- up considerations:

1. Blender loads  Control factors:

2. Blender size
3. Mixing speeds 1. Blender loads
4. Mixing times 2. Mixing speeds
5. Bulk density of the raw material (must be 3. Mixing times
considered in selecting blender and in 4. Design
determining optimum blender load)
6. Characteristics of the material
60
 Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
6) Blending
 Characteristic of material
• Fragile particles or agglomerates more readily abbraided more fines

• When high-shear mixing More particle Improper mixing,

with spiral screws or abbraision Flow problems,
blades are used Filling problems,
Content uniformity problems
• Tumble blenders: for prolonged mixing
• Excessive granulation: poor content unifor mity, poor lubrication & improper color
dispersion.
• Bulk density of raw materials considered in selection of the blender & determining
optimum blender load. 61
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
7) Compression
 Functions of a tablet press:

• Filling of empty die cavity with granulation.

• Pre compression of granulation (optional).
• Compression of granules.
• Ejection of the tablet from the die cavity and take- off of compressed tablet.

 Potential problems such as sticking to the punch surface, tablet hardness, capping,
and weight variation detected.

62
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
7) Compression
Control factors while selecting the speed of the press:

1. Granulation feed rate.

2. Delivery system should not change particle size distribution.
3. System should not cause segregation of coarse & fine
particles, nor it should induce static charges.

• The die feed system must be able to fill the die cavities adequately in the short period
of time that the die is passing under the feed frame.
• The smaller the tablet, the more difficult it is to get a uniform fill at high press speeds.
63
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
7) Compression
• Slowing down the press speed or using reduce capping in a formulation
larger compression rollers
• High level of lubricant or over blending ‣ result in a soft tablet
‣ decrease in wettability of the powder
‣ an extension of the dissolution time

• Binding to die walls can also be overcome by designing the die to be 0.001 to
0.005 inch wider at the upper portion
than at the center in order to relieve
pressure during ejection.

64
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
7) Compression
 Double Rotary Press 65
Single Rotary Press
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
7) Compression
 Different types of punches

66
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
8) Tablet coating
 There are mainly 3 types of coating:
i. Sugar Coating
ii. Film Coating
iii. Enteric Coating

 Scale up considerations:
• The tablet loading of the coating pan
• Spray rate of the coating solution
• Quantity of solution required
• Volume of air used during coating

67
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
8) Tablet coating

 Equipments Used
• The standard coating pan
• The perforated coating pan
• Accela cota system
• Hi-coater system
• Dria coater
• Glatt coater
• Fluidized bed (air suspension) coater

68
Pilot plant scale-up for solid dosage
forms (Tablets)
Unit operations involved in production of tablets
8) Tablet coating

Accela Coata

Coating Pans

Dria Coater Fluidized Bed Coating

69
Pilot plant scale-up for solid dosage
forms (Capsules)
 To produce capsules on high-speed equipment, the powder blend must have,
• uniform particle size distribution
• bulk density
• formation of compact of the right size and of sufficient cohesiveness to be filled into
capsule shells.

 Equipments :-
• Zanasi or Mertalli – Dosator(hollow tube)
• Hoflinger – Karg – Tamping pins
Weight variation problem can be encountered with these two methods.

• Overly lubricated granules – delaying disintegration.

70
Pilot plant scale-up for solid dosage
forms (Capsules)
 Humidity affect moisture content granulation
of on the empty gelatin capsules

 At high humidity capsule swells,

make separation of the capsule parts,
difficult to interfere with the transport of the capsule through the
process.

 At low humidity capsule brittle,

increased static
charge,
interfere with the encapsulation operation.
 Empty gelatin capsules have a recommended storage condition of 15-25 ºC
temperature & humidity 35-65 % RH.
71
72
Pilot plant scale-up for liquid orals
• The physical form of a drug product that is pourable displays Newtonian or
pseudoplastic flow behavior and conforms to it’s container at room
temperature.

• Liquid dosage forms may be dispersed systems or solutions.

• In dispersed systems there are two or more phases, where one phase is
distributed in another.

• A solution refers two or more substances mixed homogeneously.

73
Pilot plant scale-up for liquid orals
 Steps of liquid manufacturing process

Planning of material requirements

Liquid preparation

Filing & packing

Quality assurance

74
Pilot plant scale-up for liquid orals
 Critical aspects of liquid manufacturing

 Physical Plant:

• Heating, ventilation and air controlling system (HVAC)

• The effect of long processing times at suboptimal

temperatures should be considered in terms of
consequences on the physical or chemical stability of
ingredients as well as product.

75
Pilot plant scale-up for liquid orals
 Solutions
 Formulation aspects:
Purpose Agents
• Buffers
1) Protecting the API • Antioxidants
• Preservatives
2) Maintaining the appearance • Colorings
• Stabilizers
• Co-solvents
• Antimicrobial preservatives
3) Unpleasant taste or smell • Sweeteners
masking • Flavorings
76
Pilot plant scale-up for liquid orals
 Solutions
 Parameters to be considered are –

1. Tank size ( diameter )

2. Impeller type
3. Impeller diameter
4. Rotational speed of the impeller
5. Number of impellers
6. Number of baffles

77
Pilot plant scale-up for liquid orals
 Solutions
 Parameters to be considered are –

7) Mixing capability of impeller

8) Clearance between Impeller Blades and wall of the mixing tank
9) Height of the filled volume in the tank

10) Filtration equipment (should not remove active or adjuvant ingredients)

11) Transfer system

12) Passivation of stainless steel (SS) (pretreating the SS with acetic acid or nitric
acid solution to remove the surface alkalinity of the SS)
78
Pilot plant scale-up for liquid orals
 Suspensions
 Formulation aspects:
Purpose Agents
1) Facilitating the connection • Wetting agents
between API & vehicle • Salt formation agents
• Buffers
2) Protecting the API • Antioxidants
• Polymers
• Suspending agent
3) Maintaining the suspension
• Flocculating agent
appearance
• Colorings
4) Unpleasant taste or smell • Sweeteners
masking • Flavorings 79
Pilot plant scale-up for liquid orals
 Suspensions
 Parameters to be considered are –

1) Addition and dispersion of suspending agents (Lab scale – sprinkling method

& Production scale – vibrating feed system)
2) Hydration/Wetting of suspending agent
3) Time and temperature required for hydration of suspending agent
4) Mixing speeds (High speed leads to air entrapment)
5) Selection of the equipment according to batch size
6) Versator (to avoid air entrapment)
7) Mesh size (the one which is chosen must be capable of removing the unwanted foreign
particulates but should not filter out any of the active ingredients . Such a sieve can
only
be selected based on production batch size trials) 80
Pilot plant scale-up for liquid orals
 Suspensions

81
Pilot plant scale-up for liquid orals
 Emulsions
 Formulation aspects:
Purpose Agents
• Solid particles
1) Particle size
• Droplet particles
• Buffers
2) Protecting the API • Antioxidants
• Polymers
• Emulsifying agents
• Penetration enhancers
3) Maintaining the appearance
• Gelling agents
• Colorings
• Sweeteners
4) Unpleasant taste or smell masking
• Flavorings 82
Pilot plant scale-up for liquid orals
 Emulsions

 Parameters to be considered are-

1) Temperature
2) Mixing equipment
3) Homogenizing equipment
4) Inprocess or final product filters
5) Screens , pumps and filling equipment
6) Phase volumes
7) Phase viscosities
8) Phase densities
83
84
 Pilot plant scale-up for semisolid
dosage forms
• Pastes, gels, ointments and creams are closely related to suspensions, liquids and
emulsion except that they are products with higher viscosities.
 The following parameters are to be considered during the scale up of
semisolid products :
1) Mixing equipment (should effectively move semisolid mass from outside walls to the
center and from bottom to top of the kettle)
2) Motors (used to drive mixing system and must be sized to handle the product at its
most viscous stage.)
3) Working temperature range (critical to the quality of the final product)
4) Mixing speed
5) Component homogenization
6) Heating and cooling process
7) Addition of active ingredients 8) Product transfer 85
Pilot plant scale-up for semisolid
dosage forms
 The following parameters are to be considered during the scale up of
semisolid products :

9) Shear during handling and transfer from manufacturing to holding tank to filling lines
10) Transfer pumps (must be able to move viscous material without applying
excessive shear and without incorporating air)
11) While choosing the size and type of pump ,
• Product viscosity
• Pumping rate
• Product compactibility with the pump surface
• Pumping pressure required should be considered

86
Pilot plant scale-up for semisolid
dosage forms
 Suppositories

 The manufacturing of suppositories on a laboratory scale

usually involves the following steps:

• the preparation of a molten mass

• the dispersion of drug in the molten base
• casting of suppositories in a suitable mold
• cooling of the mold
• opened & remove the suppositories
• More no. of molds & large size Pan for melting of drug & base.

87
Pilot plant scale-up for semisolid
dosage forms
 Suppositories
• The manufacturing and packaging processes for suppositories have recently been
simplified to a one stage operation.

• This new technology eliminates many of the troublesome molding, cooling &
unmolding steps of the older technology.

• The basic improvement of the newer processing equipment is that the molten
suppository mass is filled into formed PVC or foil shells, which serve both as the mold
and finished package.

• Such a process eliminates many of the problems encountered during the removal of the
suppository from the two-piece molds in which they were formed on the older
equipment.
88
Pilot plant scale-up for semisolid
dosage forms
 Suppositories

• The extra work and equipment required to complete the off-line packing
operation of wrapping or blistering are also eliminated.

• The manufacture of suppositories using modern equipment can be

divided into several operations involving first the manufacture of the
molten suppository mass and then the molding and packaging of the
suppository.

89