PILOT PLANT SCALE UP TECHNIQUES
Contents of
this chapter
• General considerations – including significance of
personnel requirements, space requirements, raw materials
• Pilot plant scale up considerations for solids, liquid
orals, semi solids and relevant documentation
• SUPAC guidelines
• Introduction to platform technology
Pilot Plant
Scale Up
• In every emerging pharmaceutical industry or an already
existing one, there is always a need to have an intermediate batch scale
representing procedures and simulating that used for commercial manufacturing
• This is achieved by determining the ability of formula to
withstand batch-scale and process modification
R & D à PILOT SCALE à SCALE UP à
LARGE SCALE MANUFACTURE
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.”
Why conduct
Pilot Plant Studies?
• A pilot plant investigates 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 complex food
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-live and storage stability studies
• Determining possible salable by-products or waste stream
requiring treatment before discharge
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
Considerations
in pilot plant development
• Kind and size – depends on goals; evaluating product and
process; producing samples of product for evaluation; market testing or
furnishing to potential customer
• Location: near R&D facility? At an existing plant?
Close liaison between R&D and pilot plant staff is essential
• Labor requirements and costs: engineering staff, skilled
operations and maintenance staff
• Pilot plant costs may exceed those of usual plant
production costs. The pilot plant may be used for training personnel for a
full- scale plant
Scale-up: - The art for designing of prototype using the
data obtained from the pilot plant model
• Pilot plant scale-up techniques involve reproducible
manufacture of an experimental formulation on high-speed production equipment,
in a cost effective manner
• It is a part of the pharmaceutical industry where the same
processes used during Research and Development (R&D) of dosage forms are
applied to different output volumes; usually greater than that obtained during
R&D
PILOT SCALE
â
INTERMEDIATE BATCH
SCALE
â
Representative and
simulates Manufacturing scale
SCALE UP
â
NEXT TO PILOT SCALE
â
Process of increasing
the batch size/ procedure for applying the same process to different output volumes
Objective
of scale up
“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
• To identify the critical features of the process.
• To provide master manufacturing formula.
Pilot plant
scale up must include:
• Close examination of the formula to determine its ability
to withstand batch scale process modification
• Compatibility of the equipment with the formulation
• Cost factor
• Availability of raw materials meeting the specifications
required to produce the product
• Market requirement
• Physical space required and the layout of the related functions
Pilot Plant
Design
A pilot plant design should support three key strategic
Objectives:
1. Formulation and
process development
2. Clinical supply
manufacture
3. Technology evaluation,
scale up and transfer
Attributes playing a key role in achieving the above
objectives are:
• cGMP Compliance
• A flexible highly trained staff
• Equipment to support multiple dosage form development
• Equipment at multiple scales based on similar operating
principles to those in production
General
considerations
1. Personnel Requirements:
Personnel should have –-
• Scientists with experience in pilot plant operations as well
as in actual production area (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
2. Space Requirements
Administrative and information processing
Physical testing area
Standard equipment floor space
Storage area
2a. Administrative
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
2b. Physical testing
area
• This area should provide permanent bench top space for routinely
used physical- testing equipment
2c. Standard
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.
• Equipment’s 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
2d. Storage area
• Two separate areas for approved and unapproved active
ingredient as well as excipients
• Separate areas 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, packing material
3. Review of the
formula
• A thorough review of the each aspect of formulation
• The purpose of each ingredient and its contribution to the
final product manufactured on the small-scale laboratory equipment
• 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.
4. 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
5. Relevant
Processing 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
6. Production Rates
• It can be determined by the immediate future market
requirements
• Equipment and the process should be chosen on the basis of
production of a batch at a frequency that takes into consideration:
1. Product loss in the equipment during manufacture
2. The time required to clean the equipment between batches
3. The number of batches that will need to be tested for release
7. Process Evaluation
• It is the basis of process validation
• Documentation of process is to be done
• Process is validated only if there are no changes in the formula,
quality of the ingredients, or the equipment configuration
• Revalidation needs to be done to ensure that changes have
not taken place
8. Preparation of Master Manufacturing Procedures
Manufacturing directions
Sampling directions
In process QC
Final product QC
Helps in better understanding by the technician and
compliance
9. 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
10. GMP
considerations
GMP items that should be a part of scale up are –
✓ 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
11. Transfer of
Analytic methods to Quality Assurance
• During scale up the analytical test methods developed in research
should be transferred to the QA dept.
• QA staff to review process to make sure proper analytic equipment’s
are available and personnel are trained
• They should review the assay procedures and the that obtained during validation studies to verify that the there are no changes in the analytical procedure
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