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Pilot Plant Scale Up
Pilot Plant Scale Up
SCALE- UP TECHNIQUE
SUNEEL KUMAR PANDEY
RAVI KESHARI
M.PHARM(PHARMACEUTICS)
PSIT, (KANPUR)
Contents
Definition
Objectives
Steps in scale-up
General considerations
GMP considerations
Advantages and Disadvantages
References
Definitions
Plant:- It is a place were the 5 Ms like money,
material, man, method and machine are brought
together for the manufacturing of the products.
Pilot Plant:- It is the part of the pharmaceutical
industry where a lab scale formula is transformed
into a viable[practical] product by development of
liable
[accountable]
and
practical procedure
of
manufacture.
Scale-up:- The art for designing of prototype[model]
using the data obtained from the pilot plant model.
Introduction
What is Pilot plant :
Defined as a part of the pharmaceutical industry where a lab
scale formula is transformed into a viable product by the
development of liable practical procedure for manufacture.
R & D Production
Pilot Plant
Scale-up :
The art of designing of prototype using the data
obtained from the pilot plant model.
Objective
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula with instructions
for manufacturing procedure.
To identify the critical features of the process.
To avoid the scale-up problems.
STEPS IN SCALE UP
Steps in Scale-Up
Define product economics based on projected market
size and competitive selling and provide guidance for
allowable manufacturing costs
Conduct laboratory studies and scale-up planning at
Design and construct a pilot plant including provisions for process and
environmental controls, cleaning and sanitizing systems, packaging and
waste handling systems, and meeting regulatory agency requirements
General considerations
1.
Reporting Responsibility
R&D
group with
separate
staffing
3.
Space Requirements
Administration
and information
processing
Physical
testing
area
Standard
equipment
floor space
Storage
area
Physical testing area: The second required area is 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. (e.g,balance ,
ph meter , and viscometer)
Standard pilot-plant equipment floor space: Discreet pilot plant space, where the equipment needed for
manufacturing all types of dosage form is located.
Intermediate sized and full scale production equipment is
essential in evaluating the effects of scale-up of research
formulations and processes
Equipments used should be made portable where ever possible.
So that after use it can be stored in the small store room.
Space for cleaning of the equipment should be also provided.
Utilization of this area is most efficient when it is sub divided in
to areas for solid dosage forms, semi solid dosage forms , liquid
preparation and sterile products
7. Production Rates:
8. Process Evaluation:-
Drying temp.
And drying time
Screen size
(solids)
Filters size
(liquids)
Order of mixing of
components
PARAMETERS
Mixing
speed
Mixing
time
Rate of addition of
granulating agents,
solvents,
solutions of drug etc.
Weight sheet
Processing
directions or
sample
direction
Manufacturing
process
10. Product stability and uniformity: The primary objective of the pilot plant is the
physical as well as chemical stability of the
products.
Advantages
Members of the production and quality
control divisions can readily observe scale
up runs.
Supplies of excipients & drugs, cleared by
the quality control division, can be drawn
from the more spacious areas provided to
the production division.
Access to engineering department
personnel is provided for equipment
installation, maintenance and repair.
Disadvantages
The frequency of direct interaction of the
formulator with the production personnel
in the manufacturing area will be
reduced.
Any problem in manufacturing will be
directed towards its own pilot-plant
personnel's.
Dry Blending
Powders to be used for encapsulation or to be granulated must
be well blended to ensure good drug distribution.
Inadequate blending at this stage could result in discrete
portion of the batch being either high or low in potency.
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.
V cone blender
Ribbon blender
Granulation
The most common reasons given to justify granulating are:
1.To impart good flow properties to the material,
2.To increase the apparent density of the powders,
3.To change the particle size distribution,
4.Uniform dispersion of active ingredient.
Traditionally, wet granulation has been carried out using,
.Sigma blade mixer,
.Heavy-duty planetary mixer.
Planetary mixer
10/4/16
Dept. of Pharmaceutics
52
Binders:
Drying
The most common conventional method of drying a
granulation continues to be the circulating hot air oven, which
is heated by either steam or electricity.
The important factor to consider as part of scale-up of an oven
drying operation are airflow, air temperature, and the depth of
the granulation on the trays.
If the granulation bed is too deep or too dense, the drying
process will be inefficient, and if soluble dyes are involved,
migration of the dye to the surface of the granules.
Drying times at specified temperatures and airflow rates must
be established for each product, and for each particular oven
load.
Hammer mill
Blending
Type of blending equipment often differs from that using in
laboratory.
In any blending operation, both segregation and mixing
occur simultaneously are 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.
METHODS
DRY BLENDING
WET
GRANULATION
WEIGHING
SIZING
BLENDING
LUBRICATION
COMPRESSION
COATING
WEIGHING
SIZING
GRANULATION
DRYING
BLENDING
LUBRICATION
COMPRESSION
DRY
GRANULATION
WEIGHING
SIZING
BLENDING
COMPACTION
MILLING
LUBRICATION
COMPRESSION
Dry Compaction
Granulation by dry compaction can also be achieved by passing
powders between two rollers that compact the material at
pressure of up to 10 tons per linear inch.
Materials of very low density require roller compaction to
achieve a bulk density sufficient to allow encapsulation or
compression.
One of the best examples of this process is the densification of
aluminum hydroxide.
Pilot plant personnel should determine whether the final drug
blend or the active ingredient could be more efficiently
processed in this manner than by conventional processing in
order to produce a granulation with the required tabletting or
encapsulation properties.
Compression
The ultimate test of a tablet formulation and granulation
process is whether the granulation can be compressed on a
high-speed tablet press.
During compression, the tablet press performs the following
functions:
1.Filling of empty die cavity with granulation.
2.Precompression of granulation (optional).
3.Compression of granules.
4.Ejection of the tablet from the die cavity and take-off of
compressed tablet.
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 a high
press speeds.
For high-speed machines, induced die feed systems is necessary.
These are available with a variety of feed paddles and with variable
speed capabilities.
So that optimum feed for every granulation can be obtained.
DOUBLE ROTARY
MACHINE
Tablet Coating
Sugar coating is carried out in conventional coating pans, has undergone
many changes because of new developments in coating technology and
changes in safety and environmental regulations.
The conventional sugar coating pan has given way to perforated pans or
fluidized-bed coating columns.
The development of new polymeric materials has resulted in a change
from aqueous sugar coating and more recently, to aqueous film coating.
The tablets must be sufficiently hard to withstand the tumbling to which
they are subjected in either the coating pan or the coating column.
Some tablet core materials are naturally hydrophobic, and in these cases,
film coating with an aqueous system may require special formulation of
the tablet core and/or the coating solution.
A film coating solution may have been found to work well with a
particular tablet in small lab coating pan but may be totally unacceptable
on a production scale.
This is because of increased pressure & abrasion to which tablets are
subjected when batch size is large & different in temperature and
humidity to which tablets are exposed while coating and drying process.
Opaquing agents :
Titanium dioxide may be included to render the shell opaque.
Opaque capsules may be employed to provide protection against light or
to conceal the contents.
Preservatives :
When preservatives are employed, parabens are often selected.
2)
Shell manufacture :
I. Dipping :
. Pairs of the stainless steel pins are dipped into the dipping
solution to simultaneously form the caps and bodies.
. The pins are at ambient temperature; whereas the dipping
solution is maintained at a temperature of about 500C in a
heated, jacketed dipping pan.
. The length of time to cast the film has been reported to be
about 12 sec.
II. Rotation :
. After dipping, pins are elevated and rotated 2-1/2 times until
they are facing upward.
. This rotation helps to distribute the gelatin over the pins
uniformly and to avoid the formation of a bead at the capsule
ends.
III. Drying :
V. Trimming :
. The stripped cap and body portions are delivered to collects in which
they are firmly held.
. As the collects rotate, knives are brought against the shells to trim
them to the required length.
VI. Joining :
. The cap and body portions are aligned concentrically in channels and
the two portions are slowly pushed together.
3)
Sorting :
1.37
0.95
0.68
0.50
0.37
0.30
1.096
0.760
0.544
0.400
0.296
0.240
6) Sealing :
. Capsules are sealed and somewhat reshaped in the Etaseal process.
. This thermal welding process forms an indented ring around the waist
of the capsule where the cap overlaps the body.
7) Storage :
. Finished capsules normally contain an equilibrium moisture content
of 13-16%.
. To maintain a relative humidity of 40-60% when handling and storing
capsules.
ZANASI AUTOMATIC
CAPSULE FILLING MACHINE
In this both system, the scale-up process involve bulk density, powder
flow, compressibility, and lubricant distribution.
Overly lubricated granules are responsible for delaying capsule
disintegration and dissolution.
II.
Formulation :
C. Accogel process:
. In general, this is another rotary process involving
A measuring roll,
A die roll, and
A sealing roll.
. As the measuring roll and die rolls rotate, the measured doses
are transferred to the gelatin-linked pockets of the die roll.
. The continued rotation of the filled die converges with the
rotating sealing roll where a second gelatin sheet is applied
to form the other half of the capsule.
. Pressure developed between the die roll and sealing roll seals
and cuts out the capsules.
4. Bubble method:
. The Globex Mark II capsulator produces truly seamless, one-piece
soft gelatin capsules by a bubble method.
CAPSULE
POLISHING
MACHINE
AUTO MATIC
CAPSULE
ARRANGEMNT
ORAL LIQUIDS:
Liquid orals
The physical form of a drug product that is pourable
displays Newtonian or pseudoplastic flow behaviour and
conforms to its 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.
Raw Materials
Mixing
Distilled water
Filling
Packing
Quality Assurance
Agent
-wetting agents
Salt formation ingredients
- Buffering-systems, polymers,
antioxidants
Sweeteners, flavorings
Emulsions:
Purpose
Agent
Particle Size
Buffering-systems,
antioxidants, polymers
Colorings, Emulsifying
agents, Penetration
enhancers, gelling agents
Sweetners, flavorings
Taste/smell masking
Solutions:
Buffers, antioxidants,
preservatives
Maintaining the
appearance
Colorings, stabilizers,
cosolvents, antimicrobial
preservatives
Taste/smell masking
Sweetners, flavorings.
Equipments
Mixer
Homogenizer
Filtration assembly
Bottling assembly
Filtration assembly
Quality assurance
Dissolution of drugs in solution
Potency of drugs in suspension
Temperature uniformity in emulsions
Microbiological control
Product uniformity
Final volume
Stability
Critical manufacturing
parameters
For a true solution, the order in which solutes are added
to the solvent is usually unimportant.
The same cannot be said for dispersed formulations,
however, because dispersed matter can distribute
differently depending on to which phase a particulate
substance is added.
In a typical manufacturing process, the critical points are
generally the initial separation of a one-phase system
into two phases and the point at which the active
ingredient is added.
Critical manufacturing
parameters
Because the solubility of each added ingredient is
important for determining whether a mixture is visually
a single homogeneous phase, such data, possibly
supported by optical microscopy, should usually be
available for review.
This is particularly important for solutes added to the
formulation at a concentration near or exceeding that of
their solubility at any temperature to which the product
may be exposed.
Critical manufacturing
parameters
Variations in the manufacturing procedure that occur after
either of these events are likely to be critical to the
characteristics of the finished product.
This is especially true of any process intended to increase
the degree of dispersion through reducing droplet or
particle size (e.g., homogenization).
Aging of the finished bulk formulation prior to
packaging is critical and should be specifically addressed
in process validation studies.
General stability consideration
3.
Contract manufacturing
Definition of contract
manufacturing
Production of goods by one firm, under the label or brand of another firm.
Contract
manufacturers provide such
service to
several
(even competing) firms based on their
own or
the customers' designs, formulas, and/or specifications. Also called private
label manufacturing.
Contract manufacturing
Contract manufacturing is a process that established a working
agreement between two companies.
As part of the agreement, one company will custom produce parts or
other materials on behalf of their client.
In most cases, the manufacturer will also handle the ordering and
shipment processes for the client.
As a result, the client does not have to maintain manufacturing facilities,
purchase raw materials, or hire labour in order to produce the finished
goods.
Contract manufacturing.
The basic working model used by contract manufacturers translates
well into many different industries.
Since the process is essentially outsourcing production to a partner
who will privately brand the end product, there are a number of
different business ventures that can make use of a contract
manufacturing arrangement.
There are a number of examples of pharmaceutical contract
manufacturing currently functioning today, as well as similar
arrangements
in
food
manufacturing,
the
creation
of computer components and other forms of electronic contract
manufacturing.
Contract manufacturing
Even industries like personal care and hygiene products, automotive
parts, and medical supplies are often created under the terms of a
contract manufacture agreement.
In order to secure contract manufacturing jobs, the contract manufacturer
usually initiates discussions with the potential client.
The task is to convince the prospective customer that the manufacturer
can use their facilities to produce quality goods that will meet or exceed
the expectations of the customer.
Contract manufacturing
At the same time, the manufacturer will demonstrate how the
overall unit cost of production to the customer will be less than
any current production strategies in use, thus increasing the
amount of profit that will be earned from each unit sold
There are several advantages to a contract manufacturing
arrangement.
For the manufacturer, there is the guarantee of steady work.
Having contracts in place that commit to certain levels of
production for one, two and even five year periods makes it much
easier to forecast the future financial stability of the company.
Contract manufacturing
For the client, there is no need to purchase or rent
production facilities, buy equipment, purchase raw
materials, or hire and train employees to produce the
goods.
There are also no headaches from dealing with
employees who fail to report to work, equipment
that breaks down, or any of the other minor details
that any manufacturing company must face daily.
Contract manufacturing
All the client has to do is generate sales, forward orders to the
manufacturer, and keep accurate records of all income and expenses
associated with the business venture.
The general concept of contract manufacturing is not limited to the
production of goods. Services such as telecommunications, Internet
access, and cellular services can also be supplied by a central vendor
and private branded for other customers who wish to sell those
services.
Doing so allows the customer to establish a buy rate from the
vendor, then resell the services at a profit to their own client base
Scopes of contract
manufacturing
The
scope
of
the Contract
Manufacturing
Procurement business scenario outlined in this
documentation only concerns the customer side (OED
-The Office of Enterprise Development ).
This business scenario does not cover how an ERP
(Enterprise Relationship Management) system
on the supplier's side (that is, the contract manufacturer's
side) receives messages sent by the customer, and how it
deals with the additional information (for example,
components) submitted with these messages.
Scopes of contract
manufacturing
Mappings are only provided for A2A communication (between
the OED's ERP system and SAP* SNC*) from IDoc to XML
and vice versa.
This business scenario does not cover the tracking of the
manufacturing process (production phases) that takes place at
the contract manufacturer's site - it does not take into account
the current production phase at the contract manufacturer' site.
Consequently, the OED planner cannot predict the supply
situation of finished goods.
* SAP- Supply Network Planning
* SNC- Supply Network Collaboration
Injectables
The majority of the parenteral solutions are
solutions requiring a variety of tankage,
piping and ancillary equipment for liquid
mixing, filteration, transfer and related
activities.
The majority of the equipments are
composed of 300 series austenitic stainless
steel, with tantalum or glass lined vessels
employed for preparation of formulations
sensitive to iron and other metal ions.
The vessels can be equipped with external
jackets for heating and/or cooling and
various types of agitators, depending upon
the mixing requirements of the individual
formulation.
Facility Design
To provide the control of microbial, pyrogen
and particles controls over the production
environment are essential.
Warehousing:
All samples should be aseptically taken,
which mandates unidirectional airflow and
full operator gowning.
These measures reduce the potential for
contamination ingress into materials that are
yet to receive any processing at any site.
Preparation Area:
The materials utilized for the production of
the sterile products move toward the
preparation area through a series of
progressively cleaner environments.
First the materials are passed through class 100,000 i.e. grade D
environment for presterilization.
Production area
Compounding area:
The manufacture of parenterals is carried
out in class 10,000 (Grade C) controlled
environments in which class 100
unidirectional flow hoods are utilized to
provide greater environmental control
during material addition.
These areas are designed to minimize the
microbial, pyrogen, and particulate
contamination to the formulation prior to
sterilization.
Formulation aspects
Solvent:
The most widely used solvent used for
parenteral production is water for injection.
WFI is prepared by by distillation or
reverse osmosis. Sterile water for injection
is used as a vehicle for reconstitution of
sterile solid products before administration
and is terminally sterilized by autoclaving
Solubilizers:
They are used to enhance and maintain
the aqueous solubility of poorly watersoluble drugs.
Buffers:
They are used to maintain the pH level of
a solution in the range that provides either
maximum stability of the drug against
hydrolytic degradation or maximum or
optimal solubility of the drug in solution.
Antioxidants:
Antioxidants function by reacting
prefentially with molecular oxygen and
minimizing or terminating the free the free
radical auto-oxidation reaction. Examples
phenol (0.065-0.5%), m-cresol (0.16-0.3%)
etc.
Instrumentation
Mixer
Homogenizer
Filteration assembly
Filling machinery
Mixer/Homogenizer
Filtration assembly
Bottling/Filling machinery
Sterilization and
Depyrogenation
Steam sterilization
Dry-heat sterilization and depyrogenation
Gas and vapour sterilization
Radiation sterilization
Sterilization by filteration
Particulate matter
Pyrogen test
Stability test
Liquid orals
The physical form of a drug product that is
pourable displays Newtonian or pseudoplastic
flow behaviour and conforms to its 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.
Technology Transfer:
Reference
The theory & practice of industrial pharmacy by Leon Lachman, Herbert
A. Lieberman, Joseph L. kenig, 3rd edition, published by Varghese
Publishing house.
Lachman L. The Theory and practice of industrial pharmacy. 3 rd Edition.
Varghese publication house.
www.google.com
References
1. The theory and practice of industrial pharmacy. Leon
Lachman, Herbert A. Lieberman, Joseph L. Kanig. Third
edition. Varghese publishing house. Page no. 681-703.
2. Pharmaceutical dosage forms: Tablets. Volume 3. second
edition. Leon Lachman, Herbert A. Lieberman, Joseph B.
Schwartz. Page no. 303-365.
3. Pharmaceutical process scale up edited by Michael Levin.
4. Modern pharmaceutics. Edited by Gilbert S. Banker &
Christopher T. Rhodes. 4th edition.
5. www.google.com
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