1. Liquid pharmaceuticals encountered in pilot plants can be solutions, suspensions, or emulsions. The pilot plant process aims to facilitate the transition of formulations from the laboratory to full-scale production. 2. Key steps in the pilot plant process for liquid orals include reviewing the formula, evaluating raw materials and equipment, setting production rates, optimizing the manufacturing process, and ensuring compliance with good manufacturing practices. 3. Stability testing of the liquid formulations evaluates physical and chemical stability over time to confirm the appropriate preservation and packaging.

1. LIQUID DOSAGE FORMS
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2. LIQUIDS ORALS
Liquid pharmaceuticals encountered in the pilot
plant are defined as non sterile solutions, suspensions
or emulsions. Scale of each of these present a different
set of processing concerns that must be considered
Liquid orals are the liquid dosage formulations
containing one (or) more active ingredients with (or)
without additives dissolved in a suitable vehicle, meant
for oral administration
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3. • The physical form of a drug product that is pourable
displays Newtonian or pseudoplastic flow behaviour
and comforts to it’s container at room temperature.
• Liquid dosage forms may be dispersed systems or
solutions.
• In dispersed systems there are two or more phases,
where one phase is distributed in another.
• A solution refers two or more substances mixed
homogeneously.
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4. TYPES OF ORAL LIQUIDS
SOLUTIONS
EMULSION
SUSPENSION
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5. OBJECTIVE
A formula is transformed into a viable robust product using
reliable and practical method of manufacture that effects the
orderly transition from lab to routine processing in a full-scale
production
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6. STEPSINVOLVEDIN PILOTPLANTFOR LIQUID
ORAL
• Reporting responsibility
• Personal requirements
• Space requirements
• Review of the formula
• Raw materials
• Relevant processing equipments
• Production rates
• Process evaluation
• GMP consideration
• Transfer of analytic method to quality assurance
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7. 7
Raw materials Weighing &
Measuring
Mixing Distilled
water
Filling
Packing Finished
Product
storage
Quality
Assurance
Pilot Plant Scale-Up
Techniques for
liquid orals

8. General Consideration:
I. Reportingresponsibilities:
• The goal of pilot plant scale is to facilitate the
transfer of a product from the laboratory in to
production.
• The formulators continue to provide support to the
production even after the transition in to production
has been completed.
• There must be good relation between pilot plant and
other departments. 8

9. II. Personnelrequirements:
Have good theoretic knowledge
of pharmaceutics.
Practical experience in liquid orals
manufacturing industry.
Chemical, physical, biochemical
and medical properties of drugs.
Have the knowledge of computer,
electronics. 9

10. III. Space requirements:
• Administration and information processing area
• Physical testing area
• Standard pilot plant equipment floor space
• Storage area
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11. Administration and information
processing area
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12. Physical testing area
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13. Standard pilot plant equipment floor
space
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14. Storage area
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15. IV Reviewof formula:
• A thorough review of each and every steps of
formulation is important
• The purpose of each ingredient and its
contribution to the final product should be
studied
• If any modification in formula, it should be done
as soon as possible in phase III trials to allow
time to generate meaningful long term stability
in a support of a proposed new drug application
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16. V. Rawmaterials:
• One responsibility of pilot plant function is the approval and
validation of the active ingredient and excipients raw materials
used in the pharmaceutical products.
• The quality of the active ingredients needs to be verified.
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17. Formulationconsideration:
 Solvents
 Preservatives
 Antioxidants
 Solubilizers
 Organoleptic agents etc.
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18. SOLVENTS
• Water
• Alcohol
• Glycerol
• Polyethylene glycol
• Propylene glycol.
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19. Water
• Compared to ordinary drinking water , purified water USP is
more free of solid impurities.
• When evaporated to dryness, it must not yield greater than
0.001% of residue.
• Purified water is obtained by distillation, ion-exchange
treatment, reverse osmosis and other relevant method
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20. PRESERVATIVES
• Preservatives are added to prevent the microbial growth
• Preservative are necessary due to chances of microbial
growth
• Raw material, processing containers & equipments, the
manufacturing environment, operators, packing
materials & the user.
• Phenol, chlorocresol, benzoic acid, etc.
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21. • Antioxidants: ascorbic acid, sodium thiosulphate, sodium
metabisulphate.
• Solubilizers: co-solvents and surface active agents
• Organoleptic agents etc: colour, flavor, sweetening agents
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22. VI. Relevantprocessingequipment:
• Almost all formulation development work is carried out on small,
relatively simple laboratory equipment.
• The equipment that is most economical, the simplest, the most
efficient should be selected
• Liquid pharmaceutical processing tanks, kettles, pipes, mills, filter
housings, and so forth are most frequently fabricated from stainless
steel.
• Of the three types commonly used in the industry (304, 308, and
316), type 316 is most often used because it is the least reactive.
• Ease of cleaning should be considered, if multiple products are to
be manufacture in the same equipment.
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23. Stagesof operations:
1.Tankselection
• Material of the tank must not be
additive to the product
• The shape and size of equipment
must be selected according to the
batch size
• The tanks are usually constructed of
polished stainless steel of different
grades
• Teflon and glass lined tank.
• Adequate clean-up procedures
developed. 23

24. 2.Mixing
• Simple mixing is essential to increase
flow of liquids.
• If the liquid is of high viscosity, high
electrical stirrer may be used.
• Addition of ingredients in proper order
have vital important.
• At high viscosity the chance of air
entrapment. 24

25. Air entrapmentMinimize:-
• By reducing agitator speed
• By caring out the mixing procedure in enclosed tank under
vacuum
• The alternative procedure to the all is versator
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26. Versator
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27. 3. Dispersion
• Suspensions and emulsions
require considerably greater shear
forces
• Laboratory formulation is difficult
to duplicate at large scale
• Dispersion produced by colloidal
mill or an immersion homogenizer
• Variety of equipment should
evaluated for better results.
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Homogenizer
Colloidal mill

28. 4. Filtrationand clarification—
• Filtration procedure, requires careful evaluation to
ensure that pilot scale-ups will exhibit the same degree
of clarity as their laboratory counterparts.
• During the pilot run the clarity of the filtrate should be
checked periodically, in order to establish schedule for
changing pads, cake, or cartridges, depending on the type
of filtration employed.
• In filtration, filter pads are used which is made up of
asbestos and cellulose.
Selection of filtration depends on
• The product viscosity
• Volumes
• Rate requirement 28

29. 5. Transferand filling
• Filling – important parameter in the transfer of liquids from tank to
tank and into containers.
• New batches should not be started until the previous batches are
completely filled and the tanks are emptied.
• Bins and Piping
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30. Methods for filling of liquids:-
• The selection of equipment
depends on characteristic of
liquid such as, viscosity, type of
packaging, surface tension.
• Gravimetric (specific weight)
• Volumetric (specific volume)
• Constant volume filling
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Gravimetric Volumetric

31. Containers and closures:
• Glass
• Plastic
• It is more important to store the final product in
container until its expiration.
• Most oral liquids are packed in either amber or
flint glass containers with plastic or metal caps.
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32. VII. Productionrates:-
• The immediate and future market requirements -estimating
the production rates, selecting the type and the size of the
equipment needed.
• Determining the product loss in the equipment during
manufacture.
• The time required to clean the equipment between batches.
• The number of batches that will need to be tested for release.
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33. VIII. Processevaluation:-
Items that should be examined include the following-
• Mixing speed
• Mixing time
• Rate of addition of solvents, solutions of drug, slurries etc
• Heating and cooling rates
• Filter sizes
• Filling
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34. IX. Preparationof manufacturing
procedures:-
• The processing directions should be precise and explicit.
• The batch records should include addition rates, mixing
times, mixing speeds heating and cooling rates and
temperature should be given.
• Finished product specification and release specification
are set; they should be take into consideration.
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35. X. GMPconsiderations:-
A check list of GMP items
Equipment qualification
Process validation
Regular process review and revalidation
Relevant written SOP
Adequate provision for training of personnel
A well defined technology transfer system
An orderly arrangement of equipments 35

36. XI. Transferof analyticmethodto quality
assurance:-
• During the scale up new product the analytic test methods
transferred to the quality department.
• The quality assurance staff should review the process to make
sure that the proper analysis instrumentation is available and
that personnel are trained to perform tests.
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37. Viscosity-
• It is the internal resistance (or) friction to the
movement of molecules to “FLOW”.
• Agents which control viscosity
E.g. Polyvinylpyrrolidine, alginates, carbomers, and
various cellulose derivatives. .
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38. Purpose to control Viscosity -
1. Improve pour ability.
2. Improve acceptability.
3. Improve palatability.
Equipment used for this purpose
are as followed-
By OSTWALD VISCOMETER
(Or)
BY FALLING SPHERE VISCOMETER.
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OSTWALD VISCOMETER
FALLING SPHERE VISCOMETER

39. Preservativeevaluation
• Preservative evaluation – should be done in addition to
physical and chemical tests.
• Depending on the nature of the product and degree of
protection required the surface of the product can be
over lapped during filling or holding stages with carbon
dioxide or nitrogen.
• Bacteriological testing should be done, to know if the
concentration of preservative is to be increased in the
formulation
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40. Stabilitystudies:-
• Physical: Physical instability of liquid formulations involves the
formation of precipitates, less-soluble polymorphs, and adsorption
of the drug substances onto container surfaces, changes in product
appearance.
• Chemical: Chemical instability of liquid formulation is mainly due to
interaction between additives, oxidation or some due to interaction
with containers.
• Microbiological: It is the most favorable condition for the growth of
microorganism. So studies must me conducted for different
microbiological test. Different preservatives are used to make
product more stable.
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41. Type of changes:
• Contents: Viscosity, Texture, Color, Odour, pH
• Containers: a) Leakage, b) Corrosion, c) Stress d)
cracking
• Glass container
• Plastic or metal cap
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42. REFERENCES:
• Leon Lachman, Liberman & Joseph.L, The theory & practice of industrial
pharmacy. 3rd Ed., Vargese publishing house-1991, 466-75,681-84,703-706.
• James Swarbrick, encyclopedia of pharmaceutical technology Third Edition
volume 5.
• Herbert A. Lieberman, Martin M. Rieger and Gilbert S. Banker, pharmaceutical
dosage forms: Disperse system vol 1.
• Howard C. Ansel Introduction to pharmaceutical dosage forms, 4th edition.
• www.google.com
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43. The optimized conditions can be achieved
using a surfactant immersion fluid along with
the dark background and High intensity
lighting.used for the lyophilized vials
of biopharmaceuticals.
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