industry point of view

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PCE – MIP 202T: Scale up and
Technology Transfer
Pilot Plant Design & Scale Up: Introduction
Submitted by: Guided by:
Bhautik M ladani, Dr. Mahalaxmi Rathnanand,
190617002, Associate Professor,
M.Pharm IP Department of Pharmaceutics,
MCOPS – MAHE. MCOPS – MAHE.

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 Definition:
 A pilot plant is a pre-commercial production system that employs new
production technology or produces small volumes of new technology-based
products and it is used for design of full-scale production system and
commercial products.
 In other words a part of the pharmaceutical industry where a lab scale process
is transformed into a viable product by the Development of liable practical
procedure for manufacture of dosage forms.
 Objective:
 To develop and formulate physically and chemically stable therapeutic dosage
forms by optimizing various parameters.
 To create a guidelines for production and process control.
 Raw materials handling and its specifications requirements
 To identify the critical steps involved in the process.
 To develop a master manufacturing formula.
 Pilot plant studies may be developed to establish the identical examination of
the formula to withstand batch scale.

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Rationale for Pilot Plant:
 A pilot plant allows investigation of a productand process onan intermediate
scale before large amounts are committed to full-scale production.
 It is usually notpossible 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.
 GENERAL CONSIDERATIONS:
A.PERSONNEL REQUIREMENTS :
 A successful pilot plant organization frequently include scientists with
experience in bothareas (pilot plant operations as well as in actual production
area).
 Type and level of education within the group is important. Pharmaceutically
trained scientist have ability to understand the complex interrelationships
between pharmaceutical processes and the potential impact on chemical,
physical, biochemical and medical attributes of dosage forms.
 It is also important that the group should possess the ability to communicate
well as well as some engineering capability since the scale up of many of the
processes involves engineering principles and also knowledgeable in both
electronics and computers.

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 The number of people in a pilot plant group depends on the number of
products being supported and on the level of support required.
 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
B.SPACE REQUIREMENTS :
A pilot plant has following four types of spacerequirements:
1. Administration and Information Processing
2. Physical Testing Area
3. Standard Pilot Plant Equipment Floor Space
4. Storage Area
1. Administration and Information Processing:
 Documentation is extremely important and therefore adequate office and desk
space must be provided for both the scientists and technicians.
 This group is the link between research, operations, and other disciplines,
members of this group frequently meet with the personnel from other
departments.

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2. PhysicalTesting Area:
 The Second area required is an adequate working area in which the 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.
3. Standard Pilot Plant Equipment FloorSpace:
 A thorough review of each aspect of the formulation is important.
 The purposeof each ingredient and its contribution to the final manufactured
product on the small-scale laboratory equipment should be understood.
 As a result of this, the effects of scale up using equipment that may subject
the product to stresses of different types and degrees would be more readily
predicted, or recognized when they actually occur.
4. Storage Area:
 The fourth area is the storage space. Separate Provisions should be made for
the storage of active ingredients and excipients.
 These should further be segregated into approved and unapproved areas
according to GMPs.
 There should be generous storage areas for in process materials, finished bulk
products from the pilot plant, and material from experimental scale up
batches.

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 There should be controlled environment space allocated for storage of
stability samples.
 Finally, there should be space for the storage of packing materials.
C. Review of the formula:

 Thorough review of each aspect of the formulation is important.
 The purposeof each ingredient and its contribution to the final manufactured
product on the small-scale laboratory equipment should be understood.
 As a result of this, the effects of scale up using equipment that may subject
the product to stresses of different types and degrees would be more readily
predicted, or recognized when they actually occur.
 The need to modify the formulation during the scale up is not unusual, and
this should bedoneas early as possiblein the phaseIII trials to allow sufficient
time for the generation of meaningful long-term stability data in supportof a
proposed new drug application (NDA).
D. Raw Materials:

 Approval and validation of the active and excipient raw materials used in the
pharmaceutical products is necessary because the raw materials used during
the small-scale formulation trials may not be representative of the large
volume shipments of materials which would be used during the large-scale
production.

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 Even though all analytic specifications are met, these larger lots of active
ingredients may change in particle size, shape morphology, resulting in
different handling properties ordifferences in bulk density, static charges, rate
of solubility, flow properties.
 The Quality ofactive ingredients needs to be verified becausehaving alternate
suppliers is usually desirable because a single supplier leaves the company
vulnerable with respect to both supply and acquisition price.
E. RelevantProcessing Equipment:
 Most of the formulation development work is carried out on small, relatively
simple laboratory equipment and during the subsequent scale up, alternative
manufacturing equipment should be considered.
 The equipment should be most economical, simplest, the most efficient and
most capable of consistently producing product within the proposed
specifications should be evaluated.
 For feasibility studies, if a particular technology is not available in-house
small-scale trials can be carried out at the various equipment vendors
facilities. Then, when a decision has been made to use a particular process,
the selected pilot plant equipment should be acquired.
 When a reasonable process has been developed on the pilot plant equipment,
intermediate sized experimental batches should be run.
 Factors to be considered when several vendors are existing:
 Ease of Cleaning should be considered.
 The time required for cleaning and to change from one product to another
should also be determined.

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F. ProductionRates:
 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.
G. Process evaluation:
 Evaluation of process is critical and optimized its performance based on that
evaluation. various parameters should be examine include following:-
 Order of addition of components including adjustment of their amounts,
mixing speed, mixing time, rate of addition of granulating agent, heating and
cooling rate, filter size (Liquid),screen size (Solid),drying temperature, drying
time.
 Knowledge of effect of these important parameter on in process and finished
product quality is the bases for process optimization and validation.
 The purposeof process validation is to confirm that select the manufacturing
procedure, assurethe quality of the productat various stages in process and in
the finished form.
 This is accomplished by monitoring the within batch variation of measurable
parameter such as content uniformity, moisture content and compressibility
 This data indicate where the process is performing as intended and where the
problem areas may be found

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 The part of process such as milling, mixing, heating, cooling, drying,
sterilizing, compacting and filtering which cause some measurable change in
the state of the material being proceed.
 Such process data should be accumulated for a series of batches using a
particular equipment configuration and well documented.
 If the data shows that the process performs consistently at critical step to
producea productthat falls within release specification, then that process has
been elevated.
 The process remains validated only if there are no changes in the formula, the
quality of ingredients or equipment configuration.
 The change in any of this areas would have to be carefully evaluated and
determination would have to be made as to the need and extent of revalidation
required.
 The manufacturing process and the quality control information should be
review on an annual bases, and if deemed necessary, some revalidation study
should be carried out to ensure that the changes have not occurred.
 A validated process establishes a data base of cause and effect relationship
between critical step and in-process and end product specification.
 Therefore, the documentation obtained during process validation can often be
use predictively to shorten the time require to identify the factor in-process
that has “drifted” from normal.

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H. PREPARATION OF MASTER MANUFACTURING PROCEDURES:
It includes-
 The chemical weigh sheet. It should clearly identify the chemicals required in
a batch and present the quantities and the order in which they will be used .
 The sampling directions
 In-process and finished product specifications
 Manufacturing directions should be in a language understandable by the
operator termed as SOP’s .
 Batch Record Directions should include specifications for addition rates ,
mixing times , mixing speeds , heating and cooling rates , temperature .
 Proper documentation should be carried out.
I. 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 packaged as well.

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J. GMP Considerations:
A Checklist of the GMP items that should be a part of the scale up or new product
or process introduction includes:
• Equipment Qualification
• Process Validation
• Regularly scheduled preventative maintenance
• Regular Process review and 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 and prevent cross
contamination.
K. Transfer of Analytic Methods to Quality Assurance:
 During the scale up of a new product, the analytic test methods developed in
research must be transferred to the quality assurance department.

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 Early in the transfer process, the quality assurance staff should review the
process to make sure that the properanalytic instrumentation is available and
that personnel are trained to perform the tests. If required, the assay method
can bereformatted and re written using terminology and procedures consistent
with current quality assurance laboratory practice.
 To complete the transfer process, the research personnel should review the
assay procedure and the data obtained during the validation studies, to verify
that the analytic methods have not been altered in a way which might affect
the reliability, precision, or accuracy of the tests.
Reference:
 The Theory and Practice of Industrial Pharmacy : Leon Lachman , Herbert A
Lieberman , Joseph L Kanig : Section IV : Chapter 23 : Pilot Plant Scale-Up
Techniques : Page No . 681 – 710.
 Ramasubramaniya P, shibin raj C, nagarajan P, Sherly D, subramaniya L, and
solairaj p.(2014): pilot scale up techniques for solid dosage form- An
overview for tablet. World journal of pharmaceutical research. 3(8),925-931.
 http:/www.slideshare.net/sujitpatel11/pilot-plant-scale-up-techniques.
 http:/www.authorstream.com/presentation/manohar.kasturi-1355890-pilot-
plant-scale-up-study.

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 Onunkwo G.(2016). Leture on pilot plant scale up techniques. Personal
collection of Onunkwo, university of Nigeria, nskka, enugu state.

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