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+ PILOT PLANT SCALE UP TECHNIQUES
FACILITATED BY : DR. MANJULA TALLURIDEPT. OF PHARMACEUTICS PRESENTED BY: ANANTHA LAKSHMI IST YEAR M.PHARM PHARMCEUTICS
Introduction and definition
Introduction to Pilot Plant Pilot plant is defined as part of the pharmaceutical industry where a lab scale
formula is transformed into a viable product by development of liable and practical procedure for manufacture that effects the orderly transition from laboratory to routine processing in a full scale production facility.
Introduction to Scale Up Plant The art for designing of prototype using the data obtained from the pilot plant
model. It is a place were the 5 M’s like money, material, man, method and machine are
brought together for the manufacturing of the products
+
Pilot Scale and Scale-Up
Pilot Scale
Scale-Up
R & D
Large Scale Production
+What Do Pilot Scale and Scale-Up Mean ?
INTERMEDIATEBATCH SCALE
MANUFACTURES DRUG PRODUCT BY A PROCEDURE
FULLY REPRESRNTATIVE OF AND SIMULATORY TO THAT OF MANUFACTURING SCALE
PILOT SCALE SCALE-UP
NEXT TO PILOT SCALE
PROCESS OF INCREASING THE BATCH SIZE (MIXING) /PROCEDURE FOR APPLYING
THE SAME PROCESS TO DIFFERENT OUTPUT VOLUMES
(TABLETTING)
+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
Reduces the risk associated with the construction of full scale plant. Less capital is required.
+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 FOR 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 customers
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
+Why Pilot plant needed…………
8
Needed to make supplies for bench studies,
product characterization, purity animal studies
toxicology pharmacokinetics, ADME efficacy
clinical studies
+Regulations for Scale -Up
9
Code of Federal Regulations Title 21 Part 210 and 211 - Good Manufacturing Practices for Drugs Part 600 - 680 Processing of Biological materials Part 820 - Quality System Regulations for Medical Devices
Subpart C: Design Controls
Why Scale-Up needed……
A well defined process
A perfect product in laboratory and pilot
plant
But May fail in QA
Tests
Because process
are scale dependen
t
Processes behave
differently on a small scale and
a large scale
Scale up is
necessary to
determine the effect of scale
on product quality
OBJECTIVES OF SCALE UP….
To provide master manufacturing forumla
To identify the critical features of the process
Evaluation and Validation
Guidelines for production and process control
Review of the processing equipment
To produce physically and chemically stable therapeutic dosage
+CLOSE EXAMINATION OF FORMULA TO DETERMINE…
Physical space required and the layout related functions
Market requirement
Cost factor
Compatibility of the equipment with the formulation
Process Modification
Its ability to withstand batch scale
+SCALE UP EFFORTS IN PILOT PLANT….
Production and Process controls are evaluated, validated and finalized
Product reprocessing procedures are developed and validated
Appropriate records and reports are issued to support cGMP
+
PILOT PLANT DESIGN
+Pilot Plant Design…
Formulation and Process Development
Technology evaluation , Scale-Up and Transfer
Clinical Supply Manufacture
Attributes Required..
cGMP Complian
ce
A flexible highly trained
staff
Equipment to
support multiple dosage
form develop
ment
Equipment at
multiple scales
based on similarly operating principles to those
in productio
n (Interme
diate sized and Full scale equipme
nt)
Portable equipme
nt
Multipurpose rooms
Restricted
access , regulated personnel flow and material
flow
Low maintenance and
operating costs
+
PILOT PLANT OPERATION
+
Organizational
Aspects
Validation
Training
Engineering
Support
Maintenance
and calibration
Material control
Inventory ,Orders
and Labeling
Process and
Manufacturing
Activities
QA & QC
Organizational Aspects…
Validation……
Design Specification
s
Installation Qualification
Operational Qualification
Performance Qualification
Compliance with cGMP and FDA
Standards
+Training…..
Compliance with cGMP
Safety and Environmental Responsibilities
Compliance with SOP’s
Technical Skills and Knowledge
+Engineering Support….
Design, Construction, Commissioning and
validation of the pilot plant facility
Co-ordination ,Scheduling , Direction of ongoing
operations
+MAINTENANCE….
To meet cGMP Norms
To ensure Data Integrity and Equipment Reliability
+CALIBRATION…
Compliance with cGMP
Maintaining the
integrity of data during developme
nt
Well trained and expert
staff
+MATERIAL CONTROL…
CO
MPU
TER
IZED
S
YS
TEM
Material Control
Inventory
Orders (FIFO)
Labeling (GMP-GLP)
+Process And Manufacturing Activities..
Formulation and Process
Management Studies
Technology Evaluation ,
Scale-Up and Transfer
Clinical Supply Manufacture
+QUALITY ASSURANCE….
Auditing pilot plant
Auditing and approval of component suppliers
Reviewing, approval and maintaining batch records for clinical supplies
Sampling and release of raw materials and components required for clinical supplies
Release of clinical supplies
Maintaining and distributing facility and operating procedures (SOPs)
Review and approval of validation and engineering documentation
+QUALITY CONTROL….
Release Testing of finished product
Physical, Chemical and Microbiological testing of finished clinical products, components required for clinical supplies
Testing for validation and revalidation programs
QC in-process testing during development, Scale-Up and Technology transfer activities
+
REQUIREMENTS
+Requirements for pilot plant and Scale-Up…. Personnel Requirements
Space Requirements
Administration and Information Process
Physical Testing Area
Standard Pilot-plant Equipment Floor Space
Storage Area
Review of Formula
Process Evaluation
Preparation of Master Manufacturing Procedures
Product Stability and Uniformity
GMP Considerations
+GENERAL CONSIDERATIONS
REPORTING RESPONSIBILITIES
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
+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.
Space Requirement
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.
+
This area should provide permanent bench top space for routinely used physical- testing equipment.
Physical testing area
+
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 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.
Standard pilot-plant equipment floor space
+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.
+
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.
Review of the formula
+
One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipients raw materials.
Raw materials used in the small scale production cannot necessarily be the representative for the large scale production
Why?
Raw materials
+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.
+
The immediate as well as the future market trends/requirements are considered while determining the production rates.
Production Rates
+
PARAMETERS
Order of mixing of components
Mixing speed
Mixing time
Rate of addition of granulating agents, solvents,solutions of drug etc.
Heating and coolingRates
Filters size (liquids)
Screen size(solids)
Drying temp.And drying time
Process Evaluation
+
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.
+Master manufacturing procedures
The three important aspects are
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 no’s 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.
+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 Considerations….
A checklist of GMP items that should be part of scale-up or new product or processes introduction includes the following:
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
+Transfer of Analytical Methods
During scale up of new product, the analytic test methods developed in research must be transferred to QA Department.
In early transfer processes, the QA staff should review the processes to make sure that the proper analytic instrumentation is available and personal all trained to perform test.
If requires ASSAY method can be reformatted and re written using technology and procedures consistent with current QA laboratory practice.
To complete transfer, research personal should review the assay procedure and the data obtained during the validation studies, verify the analytical methods have not been altered in a way that might affect the reliability precision or accuracy of the tests.
+Types of organizational structures responsible for pilot operations:
A) Research pharmacist responsible for initial scale-up and initial production runs.
B) Pharmaceutical pilot plant controlled by Pharmaceutical Research.
C) Pharmaceutical pilot plant controlled by production division.
A) Research pharmacist responsible for initial scale-up and initial production runs
Department of pharmaceutical research
Technical director of production
Manager of solid dosage form research
Manager of tablet and capsule production
Pharmaceutical research staff
Section head
operators
+Technical director of productionDirector of
pharmaceutical research and development
Manager of solid dosage form research
Manager of pilot development
Manager of tablet and capsule production
Pharmaceutical research staff
Pharmacists and engineers
Section head in charge of tablet production
Operators
B) Pilot plant controlled by pharmaceutical research
+C) Pharmaceutical pilot plant controlled by production division
Director of Pharmaceutical research
Technical director of production
Manager of solid dosage form research
Manager of tablet and capsule production
Pharmaceutical Research staff
Section head of pilot department
operators operators
Section head in charge of tablet production
+Educational backgrounds of pilot plant personnel
They should possess the knowledge of physicochemical factors which could adversely affect bioavailability of drug component from the tablet dosage form.
An individual with graduate training in industrial pharmacy is well qualified for such a responsibility.
Industrial pharmacy core curriculum and electives usually include the following courses:
Product formulation, mfg. pharmacy, industrial pharmacy, biopharmaceutics, homogeneous system, ph. engineering, evaluation of pharmaceutical dosage form, regulatory aspects, principles of QA.
+
Mechanical and chemical engineers would be advantageous in the selection of new equipment offerings and in the organization of most economical sequences of unit operations.
In addition good communication skills both oral and written are essential, because these individuals must frequently interact with members of the pharmaceutical research and production divisions.
Whatever the technological trend, once the goals are defined, the best combination of trained personnel can be determined for the pilot plant.
+Advantages…..
Members of the production and quality control divisions can readily observe scale up runs
+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 it’s own pilot-plant
personnel's.
+Liquid-Liquid Extraction pilot plant setup
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