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PILOT PLANT SCALE UP

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 Contents of this chapter
• General considerations – including significance of

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materials

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• Pilot plant scale up considerations for solids, liquid orals,

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semi solids and relevant documentation
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• SUPAC guidelines
• Introduction to platform technology

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 Pilot Plant Scale Up

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© Ramaiah
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• In every emerging pharmaceutical industry or an already

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existing one, there is always a need to have an intermediate

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batch scale representing procedures and simulating that used

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• This is achieved by determining the ability of formula to

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withstand batch-scale and process modification

 R&D PILOT SCALE

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LARGE SCALE SCALE UP

MANUFACTURE
 What is Pilot plant ??

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“Defined as a part of the pharmaceutical industry where a lab

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scale formula is transformed into a viable product by the
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development of liable practical procedure for

manufacture.”
 Why conduct Pilot Plant Studies?

•A pilot plant investigates a product and process on an

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intermediate scale before large amounts of money are

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committed to full-scale production

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

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and process corrections and improvements

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•Producing small quantities of product for sensory, chemical,

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microbiological evaluations, limited market testing or furnishing
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samples to potential customers, shelf-live and storage stability
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studies
•Determining possible salable by-products or waste stream
requiring treatment before discharge
 A pilot plant can be used for

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Providing data that can be used in making a decision on whether

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or not to proceed to a full scale production process; and in the case
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of a positive decision, designing and constructing a full-size plant or

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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

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• Location: near R&D facility? At an existing plant? Close liaison

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between R&D and pilot plant staff is essential

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• Labor requirements and costs: engineering staff, skilled
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operations and maintenance staff

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• Pilot plant costs may exceed those of usual plant production

costs. The pilot plant may be used for training personnel for a
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Scale-up:- The art for designing of prototype using
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the data obtained from the pilot plant model

• Pilot plant scale-up techniques involve reproducible

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manufacture of an experimental formulation on high-speed

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production equipment, in a cost effective manner

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• It is a part of the pharmaceutical industry where the same
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processes used during Research and Development (R&D) of

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dosage forms are applied to different output volumes;

usually greater than that obtained during R&D
 PILOT SCALE SCALE UP

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INTERMEDIATE

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NEXT TO PILOT

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BATCH SCALE SCALE

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Process of increasing
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Representative and the batch size/

simulates procedure for applying
Manufacturing scale the same process to
different output
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© Ramaiah University of Applied Scienc
 Objective of scale up

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“Find mistakes on small scale and make profit

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on large scale.”

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 Objectives of scale up

• To produce physically and chemically stable therapeutic

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dosage forms

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• Review of the processing equipment

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• Guidelines for productions and process control
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• Evaluation and validation

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• 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

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• Compatibility of the equipment with the formulation

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• Cost factor

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• Availability of raw materials meeting the specifications
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required to produce the product

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• 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 :

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1. Formulation and process development

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2. Clinical supply manufacture

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3. Technology evaluation , scale up and transfer
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 Pilot Plant Design
Attributes playing a key role in achieving the above objectives
are :
• cGMP Compliance

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• A flexible highly trained staff

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• Equipment to support multiple dosage form development

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• Equipment at multiple scales based on similar operating
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principles to those in production

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 General considerations
1. Personnel Requirements : Personnel should have –-
• Scientists with experience in pilot plant operations as well as in
actual production area

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(to understand the intent of the formulator as well as understand

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the perspective of the production personnel

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• The group should have some personnel with engineering
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knowledge as well as scale up also involves engineering

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principles
 2. Space Requirements

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Space Requirements

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Administrative Standard

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© Ramaiah
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of Pharmacy © Ramaiah University of Applied Scienc es
2a . Administrative and Information processing

• Adequate office and desk space should be provided for both

scientist and technicians

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• The space should be adjacent to the working area

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 2b. Physical testing area

• This area should provide permanent bench top space for

routinely used physical- testing equipment

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© Ramaiah
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2c. Standard equipment floor space

• Discreet pilot plant space, where the equipment needed for

manufacturing all types of dosage form is located.

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• Intermediate – sized and full scale production equipment is

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essential in evaluating the effects of scale-up of research

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formulations and processes.

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• Equipments used should be made portable where ever
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possible so that after use it can be stored in the small store

room
• Space for cleaning of the equipment should be also provided
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 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,

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finished bulk products from the pilot-plant & materials from the

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experimental scale-up batches made in the production, packing

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 3. Review of the formula

• A thorough review of the each aspect of formulation

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• The purpose of each ingredient and it’s contribution to the final

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product manufactured on the small-scale laboratory equipment

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• Effect of scale-up using equipment that may subject the product
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to stresses of different types and degrees can more readily be

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predicted, or recognized.
4. Raw Materials
• One purpose/responsibility of the pilot-plant is the approval &
validation of the active ingredient & excipients raw materials.

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Why?

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• Raw materials used in the small scale production cannot
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necessarily be the representative for the large scale production

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5. Relevant Processing Equipment

• The most economical and the simplest & efficient equipment

which are capable of producing product within the proposed
specifications are used

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• The size of the equipment should be such that the

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experimental trials run should be relevant to the production

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sized batches
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• If the equipment is too small the process developed will not

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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

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production of a batch at a frequency that takes into

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consideration :

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1. Product loss in the equipment during manufacture
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2.The time required to clean the equipment between

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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

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• Process is validated only if there are no changes in the

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formula , quality of the ingredients , or the equipment

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• Revalidation needs to be done to ensure that changes have

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not take place

 7. Process Evaluation

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8. Preparation of Master Manufacturing Procedures

Manufacturing Sampling
directions directions

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In process QC Final product QC

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Helps in better understanding by the technician

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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

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and manufacturing procedure should be studied for

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stability

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• Stability studies should be carried out in finished packages
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as well
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10. GMP considerations
GMP items that should be a part of scale up are –

 Equipment qualification
 Process validation

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 Regularly schedule preventative maintenance

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 Regularly process review & revalidation

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 Relevant written standard operating procedures

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 The use of competent technically qualified personnel

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 Adequate provision for training of personnel
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 A well-defined technology transfer system

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 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

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• QA staff to review process to make sure proper analytic

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equipments are available and personnel are trained

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• They should review the assay procedures and the that

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obtained during validation studies to verify that the there are
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no changes in the analytical procedure

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Summary

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