PILOT PLANT
SCALE- UP TECHNIQUE
By
SUNILBOREDDY
Contents
Definition
Objectives
Steps in scale-up
General considerations
GMP considerations
Advantages and Disadvantages
Scale up of liquid dosage forms.
Scale up of semisolid dosage forms.
Contract manufacturing.
References
Definitions
Plant:- It is a place were the 5 Ms like money, material, man,
method and machine are
manufacturing of the products.
brought
together
for
the
Pilot Plant:- It is 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.
Objective
To try the process on a model of proposed plant before
committing large sum of money on a production unit.
Examination of the formula to determine its ability to
withstand Batch-scale and process modification.
Evaluation and Validation for process and equipments
Objective
To identify the critical features of the process
Guidelines for production and process controls.
To provide master manufacturing formula with
instructions for manufacturing procedure.
To avoid the scale-up problems.
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 the same time
Define key rate-controlling steps in the proposed process
Conduct preliminary larger-than-laboratory studies with equipment
to be used in rate-controlling step to aid in plant design
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
Evaluate pilot plant results (product and process) including process
Economics to make any corrections and a decision on whether or not
to proceed with a full scale plant development
Why conduct Pilot Plant
Studies?
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.
It is usually not possible to predict the effects of a many-
fold increase in scale.
It is not possible to design a large scale processing plant
from laboratory data alone with any degree of success.
A pilot plant can be used for
Evaluating the results of laboratory studies and making
product and process corrections and improvements.
Producing small quantities of product for sensory,
chemical, microbiological evaluations, limited market
testing or furnishing samples to potential customers,
shelf-life and storage stability studies.
Providing 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
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
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 well as scale up also
involves engineering principles.
3. Space Requirements
Administration
and information
processing
Physical
testing area
Standard
equipment
floor space
Storage
area
Administration and information process:
Adequate office and desk space should be provided for
both scientist and technicians.
The space should be adjacent to the working area.
Physical testing area:-
This area should provide permanent bench top space for
routinely used physical- testing equipment.
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.
Storage Area
It should have two areas divided
as approved and unapproved
area for active ingredient as well
as excipient.
Different areas should provided
for the storage of the in-process
materials, finished bulk products
from the pilot-plant & materials
from the experimental scale-up
batches made in the production.
Storage area for the packing
material should also be provided.
4. Review of the formula:
A thorough review of the each aspect of formulation
is important.
The purpose of each ingredient and its 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.
5. Raw materials:One purpose/responsibility of the pilot-plant is the
approval & validation of the active ingredient &
excipients raw materials.
Why?
Raw materials used in the small scale production cannot
necessarily be the representative for the large scale
production
6. Equipment:The most economical and 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.
If the equipment is too small the process developed
will not scale up,
Whereas if equipment is too big then the wastage of
the expensive active ingredients.
7. Production Rates:The immediate as well as the future market
trends/requirements are considered while determining the
production rates.
8. Process Evaluation:-
Drying temp.
And drying time
Screen size
(solids)
Filters size
(liquids)
Order of mixing of
components
PARAMETERS
Heating and cooling
Rates
Mixing
speed
Mixing
time
Rate of addition of
granulating agents,
solvents,
solutions of drug etc.
Why to carry out process evaluation????
The knowledge of the effects of various process
parameters as few mentioned above form the basis for
process optimization and validation.
9. Master Manufacturing Procedures:The three important aspects
Weight sheet
Processing
directions
Manufacturing
procedure
Master Manufacturing Procedures
The weight sheet should clearly identify the chemicals
required In a batch. To prevent confusion the names and
identifying nos. for the ingredients should be used on batch
records.
The process directions should be precise and explicit.
A manufacturing procedure should be written by the actual
operator.
Various specifications like addition rates, mixing time,
mixing speed, heating, and cooling rates, temperature,
storing of the finished product samples should be mentioned
in the batch record directions.
10. Product stability and uniformity:The primary objective of the pilot plant is the physical as
well as 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.
GMP
CONSIDERATION
Equipment
qualification
Process validation
Regularly schedule preventative maintenance
Regularly process review & revalidation
Relevant written standard operating procedures
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
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.
Scale up of liquid orals
Liquid orals
The physical form of a drug product that is pourable
displays Newtonian or pseudo plastic flow behavior 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.
Steps of liquid manufacturing process
Planning of material requirements:
Liquid preparation:
Filling and Packing:
Quality assurance:
Critical aspects of liquid manufacturing
Physical Plant:
Heating, ventilation and air controlling system:
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.
Formulation aspects of
oral liquids
Suspensions:
Purpose
Agent
Facilitating the connection
between API and vehicle
-wetting agents
Salt formation ingredients
Protecting the API
- Buffering-systems, polymers,
antioxidants
Maintaining the suspension
appearance
Colorings, suspending agent,
flocculating agent.
Masking the unpleasant
taste/smell
Sweeteners, flavorings
Formulation aspects of
oral liquids
Emulsions:
Purpose
Agent
Particle Size
Solid particles, Droplet
particles
Protecting the API
Buffering-systems,
antioxidants, polymers
Maintaining the appearance
Colorings, Emulsifying
agents, Penetration
enhancers, gelling agents
Taste/smell masking
Sweetners, flavorings
Formulation aspects of oral
liquids
Solutions:
Protecting the API
Buffers, antioxidants,
preservatives
Maintaining the
appearance
Colorings, stabilizers, cosolvents, antimicrobial
preservatives
Taste/smell masking
Sweeteners, flavorings.
Layout of the pilot plant
Equipments
Mixer
Homogenizer
Filteration assembly
Bottling assembly
Filtration assembly
General flow chart
Raw Materials
Measured and
weighed
Mixing
Distilled water
Filling
Packing
Finished products storage
Quality Assurance
Quality assurance
Dissolution of drugs in solution
Potency of drugs in suspension
Temperature uniformity in emulsions
Microbiological control
Product uniformity
Final volume
Stability
Scale-up of semisolid dosage
forms
Semisolid dosage forms
In
general, semisolid dosage forms are complex
formulations having complex structural elements.
Often they are composed of two phases (oil and water),
one of which is a continuous (external) phase, and the
other of which is a dispersed (internal) phase.
The active ingredient is often dissolved in one phase,
although occasionally the drug is not fully soluble in the
system and is dispersed in one or both phases, thus
creating a three-phase system.
Semisolid dosage forms
The physical properties of the dosage form depend
upon various factors, including the size of the
dispersed particles, the interfacial tension between the
phases, the partition coefficient of the active
ingredient between the phases, and the product
rheology.
These factors combine to determine the release
characteristics of the drug, as well as other
characteristics, such as viscosity.
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
The effect that SUPAC changes may have on the stability
of the drug product should be evaluated. For general
guidance on conducting stability studies, see the FDA
Guideline for Submitting Documentation for the Stability
of Human Drugs and Biologics.
General stability consideration
For SUPAC submissions, the following points should
also be considered:
1. In most cases, except those involving scale-up,
stability data from pilot scale batches will be
acceptable to support the proposed change.
2. Where stability data show a trend towards potency
loss or degradant increase under accelerated
conditions, it is recommended that historical
accelerated stability data from a representative
prechange batch be submitted for comparison.
General stability consideration
It is also recommended that under these circumstances, all
available long-term data on test batches from ongoing
studies be provided in the supplement.
Submission of historical accelerated and available long-
term data would facilitate review and approval of the
supplement.
General stability consideration
3. A commitment should be included to conduct longterm stability studies through the expiration dating
period, according to the approved protocol, on either
the first or first three (see section III-VI for details)
production batches, and to report the results in
subsequent annual reports.
The Role of In Vitro Release
Testing
The key parameter for any drug product is its efficacy
as demonstrated in controlled clinical trials.
The time and expense associated with such trials
make them unsuitable as routine quality control
methods.
Therefore, in vitro surrogate tests are often used to
assure that product quality and performance are
maintained over time and in the presence of change.
The Role of In Vitro Release
Testing
A variety of physical and chemical tests commonly
performed on semisolid products and their components
(e.g., solubility, particle size and crystalline form of the
active component, viscosity, and homogeneity of the
product) have historically provided reasonable evidence
of consistent performance.
More recently, in vitro release testing has shown
promise as a means to comprehensively assure
consistent delivery of the active component(s) from
semisolid products.
The Role of In Vitro Release
Testing
An in vitro release rate can reflect the combined effect of
several physical and chemical parameters, including
solubility and particle size of the active ingredient and
rheological properties of the dosage form. In most cases,
in vitro release rate is a useful test to assess product
sameness between prechange and postchange products.
The Role of In Vitro Release
Testing
However, there may be instances where it is not suitable
for this purpose. In such cases, other physical and
chemical tests to be used as measures of sameness should
be proposed and discussed with the Agency.
With any test, the metrics and statistical approaches to
documentation of sameness in quality attributes should
be considered
The Role of In Vitro Release
Testing
The evidence available at this time for the in vitro-in
vivo correlation of release tests for semisolid dosage
forms is not as convincing as that for in vitro
dissolution as a surrogate for in vivo bioavailability of
solid oral dosage forms.
Therefore, the Centers current position concerning in
vitro release testing is as follows:
The Role of In Vitro Release
Testing
1. In vitro release testing is a useful test to assess
product sameness under certain scale-up and
postapproval changes for semisolid products.
2. The development and validation of an in vitro release
test are not required for approval of an NDA, ANDA
or AADA nor is the in vitro release test required as a
routine batch-to-batch quality control test.
The Role of In Vitro Release
Testing
3. In vitro release testing, alone, is not a surrogate
test for in vivo bioavailability or bioequivalence.
4. The in vitro release rate should not be used for
comparing
different
formulations
across
manufacturers.
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
Limits of contract
manufacturing
The Contract Manufacturing Procurement business scenario
has the following limitations:
Once a schedule line in the ERP purchase order is changed, the
date and quantity data originally requested are lost. Even if the
information is stored in SAP SNC, it is not possible to send this
information to the CM.
The Contract Manufacturing Procurement business scenario is
based on functions introduced in SAP ERP 6.0. For lower
releases, you need to develop a customer modification.
Limits of contract
manufacturing
No data import control functions are provided for messages
sent from the CM to SAP SNC.
The bill of material (BOM) is not available in SAP SNC.
New purchase order items cannot be created in SAP SNC.
Product substitution is not supported.
Scheduling agreements for the subcontracted material are not
allowed.
Limits of contract
manufacturing
A supplier should be able to update the component
consumption in SAP SNC until a good receipt has been
posted in the customer ERP back-end system.
The subcontracting scenario of the Rosetta Network Order
Management Program as described in the PIPs* 7B5 (Notify
of Manufacturing Work Order), 7B6 (Notify of
Manufacturing Work Order Reply), and 7B1 (Work In
Process Notification) is not included in the scope of SAP
SCM*.
* PIP- Partner Interface Process
* SCM- Supply Chain Management
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. 3rd Edition. Varghese publication house.
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