pilot plant is a small system which is operated to find out about the behavior of a process before using it on a large industrial scale. so, this presentation tries to illustrate its objective and significance to understand the methodologies of various pharmaceutical dosage forms.

1. Presented by: Omkar Tambekar
SMT.KISHORITAI BOYAR COLLEGE OF PHARMACY
Kamptee, nagpur
PILOT PLANT SCALE - UP

2. Pilot plant:- It is the part of the pharmaceutical industry wherea 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 dataobtained from the
pilot plant model.
pre-commercial production system that employs new production technology
and/or produces small volumes of new technology-based products
Pilot plants tend to be smaller compared to demonstration plants.
Definitions

3. Objective and significance
1 . To try the process on a model of proposed plant before
committing large sum of money on a production unit.
2. Examination of the formula to determine it’s ability to
withstand batch-scale and process modification.
3.Evaluation and Validation for process and equipments
4. Examination of formulae.
5. Review of range of relevant processing equipments. production
rate adjustment.
6. Idea about physical space required.
7. Appropriate records and reports to support GMP.
8. Identification of critical features to maintain quality.

4. 9 . To identify the critical features of the process
10.Guidelines for production and process controls.
1 1 . To provide master manufacturing formula withinstructions for
manufacturing procedure.
1 2 . To avoid the scale-up problems.

5. STEPS INVOLVE IN SCALE-UP
1. Define product economics based on projected market size and
competitive selling and provide guidance for allowable manufacturing costs.
2. Conduct laboratory studies and scale-up planning at the same time.
3. Define a key rate-controlling steps in the proposed process
4. Conduct preliminary larger-than-laboratory studies with equipment to be
used in rate-controlling step to aid in plant design
5. Design and construct a pilot plant including provisions for process and
environmental controls.
6. Evaluate pilot plant results (product and process) including process
economics

6. USE OF PILOT PLANT
1. Evaluating the results of laboratory studies
2. Producing small quantities of product for sensory, chemical,
microbiological evaluations
3. Providing data that can be used in making a decision on whether or not
to proceed to a full-scale production process
4. Use for shelf- life and stability studies
5. Design and construct study of full size plant

7. REPORTING RESPONSIBILITIES
Reporting Responsibility
R&D group (with separate staff)
The formulator who developed the product can take into the
production and can provide support even after transition into
production has been completed

8. 1. Scientist with experience in pilot plant operations as well as in
actual production area.
2. To understand the intent of the formulator.
3. To understand the perspective of the production
4. Personnel should have engeering knowledge for its principles
5. The candidate must have a professional license.
6. Should have analytical skills
7. Personnel should have knowledge of computer as well as
electronics
Personnel Requirement

9. Space Requirements
1. Administration and information process
2. Physical testing area
3. Std. equipment floor space
4. 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.

10. 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 for equipment needed for manufacture
Intermediate sized and full scale production equipment is essential
Equipments used should be made portable where ever possible.
Space for cleaning of the equipment should be also provided.

11. Storage Area
It should have two areas divided as approved and unapproved area for
active ingredient as well as excipient.
Also different areas are allotted for the storage of in process, bulk and
packaged products
Review of the formula
Carefull review of every aspects of formulation is imp.
The final product manufactured on the small-scale laboratory equipment
should be understood.
The product to stresses of different types and degrees can more readily be
predicted, or recognized.

12. Raw materials
responsibility of the pilot-plant is the approval & validation of the active
ingredient & excipients raw materials.
Equipments
The most economical and the simplest & efficient equipments are used
The size of the equipment should be appropriate w.r.t the batches,
otherwise it will not scaleup.
Production Rates
The future market trends are depend over the production rates.

13. PROCESS EVALUATION PARAMETER
1. Drying temp. and drying rate
2. mixing and its speed/time
3. addition of granulating agents, solvents, solutions of drugs etc.
4. heating & cooling rates
5. filter size
6. screen size
The knowledge of theeffects of various process parameters as few
mentioned above form the basis for process optimization and validation.

14. Master Manufacturing Procedures
The three important aspects
1. weight sheets
2. process directions
3. Mfg.. Process
Product stability and uniformity
physical as well as chemical stability of the products.
each pilot batch representing the final formulation
manufacturing procedure should be studied for stability & carried out in
finished packages as well.

15. GMP CONSIDERATION
1. Equipment qualification
2. Process validation
3. Regularly schedule preventative maintenance
4. Regularly process review & revalidation
5. Relevant written standard operating procedures
6. use of competent technically qualifiedpersonnel
7. Adequate provision for training of personnel
8. well-defined technology transfer system
9. Validated cleaning procedures.
10. orderly arrangement of equipment so as to ease material flow &
prevent cross- contamination

16. ADVANTAGES
Members of the production and quality control divisions can readily obs.
Supplies of excipients & drugs, cleared by the quality control division, can
be drawn from the more spacious areas provided to the production division.
Easy access to engineering department personnel is provided
DISADVANTAGES
Frequency of direct interaction of the formulator with the production personnel
in the manufacturing area will be reduced.
Problem in manufacturing will be directed towards it’s own pilot-plant
personnel's.

17. SCALE UP FOR LIQUID FORMULATIONS
Liquid dosage forms may be dispersed systems.
There are two or more phases, one phase is distributed in another.
These solutions mixed homogenously.
Steps of liquid manufacturing process
Planning of material requirements
Liquid preparation
Filling andPacking
Quality assurance

18. Physical plant
Heating,ventilation and air controlling system:
effect of long processing times at suboptimal temperatures should
considered in terms of consequences on the physical or chemical stability
ingredients as well as product.
FORMULATION ASPECTS
For suspensions
Facilitating the connection between API and vehicle- Wetting agents
Protecting the API- buffers, antioxidants, polymers
Maintaining the suspension appearance- colouring agent, suspending agents,
flocullating agents
Masking the unpleasant taste/smell- sweetners, flavouring agents

19. For Solutions:
Protecting the API- buffers, antioxidants, preservatives
Maintaining the appearance- coloring agents, stabilizers,
antimicrobials
Taste masking or smell- sweetners, flavouring agents
Equipments
Mixer
Homogenizer
Filteration assembly
Bottling assembly

20. Quality assurance
Dissolution of drugs in solution
Potency of drugs in suspension
Temperature uniformity in emulsions
Microbiological control
Product uniformity
Final volume
Stability

21. SCALE UP FOR SEMISOLIDS
semisolid dosage forms are complexformulations having complex structural
elements. They are composed of two phases (oil and water)
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.
Factors combine to determine the release characteristics of drugs.
1. Size of dispersed particle
2. Interfacial tension
3. Partition coefficient
4. Rheology
For Emulsions
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

22. TESTING
key parameter for any drug product is its efficacy
Time and expense associated with such trials make them unsuitable as
routine quality control methods.
In vitro testing are used for product quality and performance.
in vitro release rate can reflect the combined effect several physical
and chemical parameters, including
Solubility
particle size of the active ingredient
rheological properties of the dosage form.
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.

23. CONTRACT MANUFACTURING
Contract manufacturing is the outsourcing of part of the manufacturing process of a product to
a third-party.
Scopes of contract manufacturing;
Procurement business scenario outlined in documentation only concerns the customer side
(OED -The Office of Enterprise Development ).
Advantages:
Economies of scale
Focuses on selling activities
quality products
Saving cost
Easy entry in markets
Disadvantages:
Quality issues
Lack of control
Lack of flexibility
Delay in delievery
Outsource problem

24. SCALE UP FOR SOLID FORMULATIONS
Each stage considered carefully from experimental lab batch size to
intermediate and large scale production.
Same process, same equipment but different performance when amount
of material increased significantly.
May involve a major process change that utilizes techniques and
equipment that were either unavailable or unsuitable on a lab scale.
Stages of production of tablets:
1. Material handling 9. Slugging (dry granulation)
2. Dry blending
3. Granulation
4. Drying
5. Reduction of particle size
6. Blending
7. Dry blending
8. Direct compression

25. MATERIAL HANDLING
materials are scooped, dumped or poured by hand.
It may work well for small or intermediate scale productions.
For large scale productions, mechanical means is necessary.
DRY BLENDING
Use of binary cohesive-powder mixture in which finer particles adhere
preferentially on the surface of the coarse particles called an interactive
mixture.
blending of fine and coarse particles breaks down the agglomerates of
fine and coarse powders, and produces an electric charge by contact.

26. GRANULATION
rapid breakdown of agglomerates is important to maximize the available
surface area and aid in solution of the active drug.
small particles are gathered into larger, permanent masses in which the
original particles can still be identified
Granulation methods are of two types
1. Wet methods.
2. Dry methods.
Granulation mechanism: wetting, nucleation, coalescence or growth,
consolidation, and attrition or breakage. Initial wetting of the feed powder
and existing granules by the binding fluid is strongly influenced by spray
rate or fluid distribution as well as feed formulation properties, in
comparison with mechanical mixing
Binders use in granulation:
Natural Polymers: Starch, Pregelatinized Starch
Synthetic polymers: PVP, Methyl cellulose, HPMC

27. DRYING
involves circulating hot air oven, which is heated by either steam or
electricity.
considerations for drying operation are:
1. Airflow
2. Air temperature
3. The depth of the granulation on the trays
4. Fluidized bed dryers are an attractive alternative to the circulating hot
air ovens.
Factor considered as part of scale up drying are
optimum loads, rate of airflow, inlet air temperature and humidity

28. REDUCTION OF SIZE PARTICLES
The size and shape of powders influences flow and compaction properties.
Larger, more spherical particles will typically flow more easily.
Smaller particles dissolve more quickly and lead to higher suspension
viscosities.
Smaller droplet sizes and higher surface charge (zeta potential) will typically
improve suspension and emulsion stability.
Powder or droplets in the range of 2-5µm aerosolize better and will penetrate
into lungs deeper than larger sizes.
Factors for particle size;
Flowability hardness lamination and capping
Feeder clearance ejection force punching
Electrostatic effects lubrication levels cost
Die fill disintegration environmental conditions
Weight control dissolution
Compressibility friability

29. BLENDING
Based on two objectives;
1) To achieve blend uniformity 2) to distribute the lubricant.
To achieve homogeneity of all components prior to the final blend of the
lubricant
To introduce the proper particle profile within a range; between 40 – 180
mesh for most oral solid dosages.
DIRECT COMPRESSION
tablets are compressed directly from powder mixture of API and suitable
excipients.

30. Advantages of direct compression;
1. efficient and economical process
2. Reduced processing time, reduced labor costs
3. fewer manufacturing steps
4. less number of equipments are required
5. less process validation
6. reduced consumption of power.
7. Elimination of heat and moisture
8. Particle size uniformity
9. Prime particle dissolution.
10. Chemical stability problems for API and excipient would be avoided.
11. Provides stability against the effect of aging which affects the dissolution
rates

31. Disadvantages of direct compression;
1. Capping, lamination, splitting, or layering of tablets is sometimes related
to air entrapment during direct compression.
2. Due to air entrapment splits or layers forms in the tablet.
3. greater sophistication in blending and compression equipments are req.
4. Direct compression equipments are expensive.
Aspects for direct compression;
Order of addition of components to the blender
Mixing speed: can be varied with the original direction as necessary
Mixing time: excessive mixing may fracture the fragile excipients and ruin
their compressibility
Use of auxiliary dispersion material within the mixer

32. SLUGGING
This process involves compression of primary powder particles into large
flat tablets or pallets using a tablet press or, more usually, a large heavy-
duty rotary press. The resultant compact is then milled using a hammer
mill or other conventional milling equipment. The milled slugs are passed
through a screen of desired mesh for sizing. Lubricant is added in the usual
manner, and the granules compressed into tablets.
Slugging results in considerable dust production which poses a problem for
good containment and reduction of cross-contamination. Other main
shortcomings of slugging include batch processing, low throughput (30–50
kg/hr), poor process control, frequent maintenance changeovers and poor
economy of scale. The method is being replaced by the more modern, and
better, roller compaction process.

35. SCALE UP FOR PARENTRALS
Formulation of parentrals;
1. Therapeutic agents
2. Vehicles – water aq. And non aq.
3. Additives – antimicrobials, antioxidants, buffers, bulking agents,
chelating agents protectants, solubilizers, surfactants, tonicity adjusters
General steps involved in it;
1. Cleaning
2. Preperation of bulk products
3. Filteration
4. Filling of product in ampoule or vials
5. Sealing
6. Sterilisation
7. Quality control test

36. LAYOUT OF PARENTRAL MANUFACTURING AREA
S
T
O
C
K
R
O
O
M
COMPOUNDING
AREA
CLEAN UP
AREA
ASEPTIC
AREA
STERILIZATION
QUARANTINE
AREA
QUARANTINE
AREA
STORAGE
AND
TRANSPORT

37. WORKING AREA
1. Incoming goods are stored in special areas for Quarantine
2. cold room is available for storage of temperature- sensitive
products.
3. Sampling and weighing of the raw material is performed in dedicated
sampling area and a central weighing suite.
4. route for final products is separated from the incoming goods; storage of
final products is done in designated areas in the warehouse while they
are awaiting shipment.
5. Several clothing and cleaning procedures in the controlledtransportzone
are ensure full quality compliance.
6. a technical area is located in between the reproduction zone and
the area for formulation development.
7. the water for injection equipment is located, aswellas the technical
installation of the lyophilizer.

38. CLEAN UP AREA
1 . N o n asepticarea
2 . Free from dust , fibers & micro-organisms
3. Withstand with moisture, steam & detergent
4. Prevent accumulation of dust & micro-organisms
5. Exhaust fans are fitted to remove heat & humidity
6. area should be kept clean sodium that to avoid contamination.
7. containers & closures are washed & dried in this area.

39. PREPARATION AREA
1. ingredients are mixed & preparation is prepare for filling.
2. NO essential that the area should be aseptic
3. precaution is taken to prevent contamination from outside
ASEPTIC AREA
1. Filtration & filling into final containers & sealing isdone
2 . T h e entry of outside person is strictly prohibited
3 . To maintain sterility, special trained persons are only allowed to enter
& work
4. Person who worked should wear sterilecloths
5. Should be subjected for physical examination toensure the fitness
6. Minimum movement should be there in this area
7. Ceiling & walls & floors : sealed & painted or treated with aseptic
solution and there should not be any toxic effect of this treatment

40. QUARANTINE AREA
1. After filling, sealing & sterilize the products is kept in this area
2 . T h e random samples are chosen and given foranalysis to QC dept.
3 . T h e batch is send to packing after issuing satisfactory reports of
analysis from QC
4 . I f any problem is observed in above analysis the decision is to be
taken for reprocessing or others..

41. FINISH AND PACKAGING AREA
1. After proper label, the product is given forpacking
2. Packing is done to protect the product from external environment
3. ideal Packing is that which protects the products during transportation,
storage, shipping & handling.
4. labeled container should be packed in cardboard or plastic containers
5. Ampoules should be packed in partitioned boxes.
CLASSES OF PARTICULAR AREAS
1. Clean up area – class 1,000,00 D
2. Preparation area – class 10,000 C
3. Aseptic area – class 100 and 1000 A & B
4. Quarantine area – class 1000 B
5. Finish and packaging area – class 10,000 C

42. QUALITY TESTING
1. Sterility test
2. Pyrogen Tests.
3. Leaker Tests.
4. Particulate matter test
Sterility tests
complete absence of all viable Micro-organism. The methods which are
used to perform sterility tests are
1. Direct transfer method.
2. membrane filtration method
Pyrogen Test
Basically there are test performed to detect the presence of pyrogens in
sterile parenteral products they are
1. Rabbit Test
2. LAL Test.

43. Rabbit test
1. involves the injection Sample solution which is to be tested into a
Rabbits (ear vein).
2. The Temperature sensing probe (Clinical Thermometer or similar probe)
into a rectum cavity of Rabbit at the depth of 7.5 cm the test solution
must be warmed at 37 degrees prior to injection.
3. Rectal temperature is recorded at 1,2,3 hour subsequent to injection.
4. Initially this test is performed on 3 Rabbits but if required results are not
obtained this test is repeated on 5 additional Rabbits with same sample
solution administer to initial 3 rabbits.
5. Prior to 1hr of injecting sample solutions the control temperatures of
rabbits are determined.
6. Use only those rabbits whose control temperature is no vary by more
than 1 degree Celsius.

44. LAL test
1. combination of 0.1 ml of test sample with LAL Reagent after incubation
for 1 hour at 37 degree Celsius the mixture is analyzed for the presence
of Gel clot.
2. The LAL Test is positive indicating that the presence of endotoxin.