ORAL LIQUID

Dr. Kiran Dudhat

CONTENTS:
Classification
Departmental Layout of Liquid Manufacture
Quantitative Lay out of oral liquid mfg
Specific Requirements For Oral Liquids
Equipments Used In Liquid Manufacturing
SOP of Processing Steps
Batch Manufacturing Records (BMR)
Batch Packaging Records (BPR)
Batch Production In-process Control Records
Validation
Innovations
References
Classification
Oral liquid
dosage forms

Monophasic Biphasic

e.g:-Simple solutions
Draughts Suspensions Emulsions
Drops (solid in liquid) (liquid in liquid)
Linctuses
Syrups
Elixirs
Advantages:-
✓Immediately available for absorption
✓Easy administration
✓Easy to color, flavor, sweeten
✓Easy to change the dose

Disadvantages:-
✓Bulky than tablets or capsules so difficult to carry.
✓Less stable than solid dosage form.
✓Patients have no accurate measuring device.
✓Accidental breakage of container results in complete
loss
✓ Moisture sensitive drugs cannot be formulated.
 QUANTITATIVE LAYOUT

e.g. manufacturing of liquid syrup

Suppose,Plant Capacity:-1,00,000boottles/day
For preparing:-1,00,000boottles(each containing 50ml of
liquid syrup)
So,total syrup Quantity:-5000 L
Raw material Quantity:-
Drugs:-10 Kg
Std granulated sugar:-2750 Kg
Other excipients:-1000 Kg
Purified water
QUANTITATIVE LAYOUT OF LIQUID PREPARATION

WASHING AREA
WASHING
EMPTY 10sq.M
EQUIPMENT
BOTTLE STORAGE
STORAGE AREA
AREA Temp:-25˚C

C O R R I D O R
If hygroscopic
Temp:-<25˚C
OFFICE
If sterile area
WASHING 10sq.M Temp:-18˚C
I.P.Q.C.
FILLING & SEALING 10sq.M

SEMI FINISHED STORE Humidity:-<40%

LABELING 20sq.M If hygroscopic
Humidity> 40%
MEDICINE PREPERATION AREA
PACKAGING 20sq.M 30sq.M

FINISHED PRODUCT RAW MATERIAL LIQUID &

syrup
GOWNING ROOM
STORAGE AREA API & SOLVENT
CHANGE ROOM EXCIPIENT
OFFICE 30sq.M
F.P.Q.C 10sq.M DISTILLATION
UNIT
EXCISE DUTY
 SS Tank Steam G.jacketed Colloid mill Filtration
100-10,000 L SS Tank 120-12000 L 14”1000 L

Inspection Filling & Sealing Washing

Distillation
40-60bootles/M 60-80bottles\M 80-240bottles/M
50-2500 L

Labelling
Pkg conveyor cartoning
250labels/M
 Preparation of continous phase

WATER PRESERVATIVES

OTHER
HELPING CONTINUOUS SURFACTANTS
AGENTS PHASE

MIXING

AQUEOUS SOLUTION
Preparation of dispersed phase

• Grinded solid
For drug
Suspension

• Oil solubilised
For drug
Emulsions
Continous Dispersed Finished
phase phase product
SPECIFIC REQUIREMENTS FOR MANUFACTURING
OF ORAL LIQUIDS AS PER GMP

Building and equipment

Purified water

Manufacturing
1) Building and Equipments:-
layout and design of the manufacturing area:-minimize the
risk of cross cotamination and mix ups.
Manufacturing area:-double door airlock facility.
Drainage:-adequate size, adequate traps & prevent back flow.
Production area:-cleaned and sanitized.
Equipment design:- prevent accumulation of residual microbial
growth or cross-contamination.
 Closures and droppers:-suitable devices equipped
with high pressure air, water and steam jets.
furniture:- smooth, washable and made up of stainless
steel.
2) Purified water
Chemical and microbiological quality of purified water.
Microbiological evaluation:-not exceed 100 CFU/ml (as
per Appendix 12.5 of IP 1996).
Avoid the risk of microbial proliferation.
After any chemical sanitization of the water system, a
flushing shall be done to ensure that the sanitizing agent
has been effectively removed.
3) Manufacturing:-
Manufacturing personnel:- wear non-fibre
shedding clothing to prevent contamination of the
product.
Maintain the homogeneity of emulsion.
Primary packaging area:- shall have an air supply
which is filtered through 5 µ filters.
Temperature of the area:-not exceed 300C.
When the bulk product is not immediately packed,
the maximum period of storage and storage
conditions shall be specified in the master formula.
LIST OF EQUIPMENTS AS PER SCHEDULE M

1. Mixing & storage tanks [jacketed kettle /

SS tank (steam, gas or electrically heated)]
2. Portable mixer
3. Colloid mill or suitable emulsifier /
homogenizers or any other suitable
equipment.
4. Suitable filtration equipment or filter press.
5. Semi automatic / automatic bottle filling
machine
6. Pilfer proof cap sealing machine
7. Water still or deionizer
8. Clarity testing inspection table
 Mixing & Storage Tanks

✓Manufactured from SS 304/SS 316 & is Argon welded.

✓The tank will be mounted on 4 legs with castors for
movements.
✓Available from 50-10,000 litres.
SS Tank with Stirrer / Manufacturing
vessel

✓ With SS steam jacketed &

insulation with SS cladding.

✓ Different type of stirrer (paddle/

anchor/propeller) available.

✓ Electric heating also possible

for small scale.

✓ Capacity:-100 ltrs to 10,000ltrs

 Jacketed kettle / SS Tank
(steam, gas or electrically heated)
Liquid blender
 Colloid mill
• Superfine grinding
and simultaneous
emulsifying, dispersing, and
homogenizing within one
process.
• Clearance between rotor &
Crude mixture inlet
stator: 0.001inch
• Rotor speed: 2800 rpm
• Continuous and
Clearance recalculating method of
ROTER
operation possible
Homogenized • Jacket is provided for
liquid heating or cooling application

Drive shaft
 Homogenizer

Outlet Homogenized
Spring liquid

Valve cover

Valve seating

Crude mixture inlet

 Ultrasonifier

Outlet

inlet

Orifice

Vibrating blade
Filter press

Standard filter press

Plate & frame filter press

 Used for sugar syrup filtration, liquor

clarification, and has application were
solids are recovered.
Zero Holdup Filter press

✓ For high value liquids

✓ Give crystal clear filteration
Multicolumn distillation unit
Liquid Syrup Manufacturing Plant
✓Capacity up to 20,000 ltrs

PLANTS CONSISTS OF : - •Zero Holdup Filtration Unit.

•Sugar Dissolving Vessel. •Inline Homogeniser.
•Manufacturing Vessel. •Inter connecting vessel / Sugar
•Holding Vessel. Suction Pipeline
•Online Sugar Syrup Pre Filter
•Vacuum System for Transfer of Sugar & Sugar Syrup
Automatic Syrup Preparation Plant
Bottle washing machine
Bottle filling machine
ROTARY PISTON FILLING CUM SEALING
MACHINE
Automatic single / Multi head ROPP
cap sealing machine
Bottle inspection Machine
Automatic high speed labeling
machine
Bottle trimming & cartooning
machine
Packing conveyor belt
CGMP Model Complete untouched process

✓Capacity:-500ltrs-1500ltrs
SOP
 SOP FOR LIQUID MIXING/
STORAGE TANK
1. Ensure that tank is closed & having cleaned
status label, where “use before date” has not lapsed.
2. Ensure that the bottom valve of the tank is closed.
3. Open the top lid of the mixing tank / storage tank
provided for loading the material.
4. Transfer the purified water & required material as per
BMR of the particular product of the particular batch.
5. Close the lid of the mixing tank / storage tank.
6. Run the stirrer for the time duration mentioned in the
respective manufacturing record. Speed of the stirrer
can be increased or decreased using speed adjustment
knob as per required.
7. After completion of mixing, switch off the stirrer.
8. Affix the status label.
 SOP FOR FILTRATION
(FILTER PRESS)
1. Check the equipment is clean and ready for use.
2. 25 liter of syrup to be filtered is taken in a tank and 1 kg
Hyflosupercel (filter aid) is suspended in it. This slurry is
pumped into the chamber and the air displaced from the top.
3. This top outlet is closed when syrup starts coming out.
4. The syrup is filtered out and is removed from the bottom
outlet of the chamber and should be re - circulated until the
out coming filtrate is clear.
5. The main compound tank is then connected to the filter
press pump and the valve opened.
6. The out coming filtrate is collected into storage tank, which
is previously cleaned.
7. This tank is then suitably labeled.
LIQUID PACKAGING AREA

Mainly 3 areas-
I. Bottle washing

II. Filling & capping area

III. Box filling area

OPERATION OF THE ROTARY BOTTLE
WASHING MACHINE
1.Before starting the operation clean the bottle
washing machine and tanks thoroughly with detergent
(1% soln.ofTeepol & fresh water to remove any trace
of the dirt.
2.Remove glass piece if present & check the water jet.
3.Fill the respective tanks with fresh DM water. Ensure
that stainless steel tray is properly cleaned before
loading the bottles.
4.Broken bottles are inspected and rejected before
sending for washing. The washing process is semi-
automatic.
5. Bottles to be washed are placed inverted on
empty nozzles and after the washing one cycle is
completed, unloading of the washed bottles in Aluminium
clean perforated tray in inverted position so that all the
water is drain out.
6. After completion of washing operations, bottles are to
be dried in oven at 1200C for 1hour.
OPERATION OF LIQUID FILLING MACHINE
To ensure that right quantity and right quality
material received on the line
Before starting liquid or suspension filling ensure that:
1.The bulk container are having released label for filling.
2.The filling machine is assured to determine
required volume.
3.Only washed bottles & caps are used.
4.Filled volume record is maintained as per proforma
prescribed.
5.Take care that suspension & emulsion is filled under
constant slow stirring operation and there is no air
trap in the suspension during filling operation.
Box filling area
✓ The sealed filled bottles are passed through the
conveyor belt & filled in the empty corrugated box
with labeling.
B.M.R. (Batch Manufacturing record)

M/s (Name & address of the company)

Name of the product…………………………………………

(Trade name, if any)…………………………………………
(MFR No.)…………………………………………………….
Batch No. …………………………Batch size……………..
Date of Expiry…………………………………………………
Date of commencement of manufacture……………………
Sr. Ingredient stan Q/C Label Quantity Quantity Remark
s as per d- report claim required actually s
No. order of ards used
no.
mixing
1. 2. 3. 4. 5. 6. 7. 8.

TOTAL

Raw materials initially weighed or measured by

(attach requisition / issue slip duly signed by stores personal)
Weights/Measures counter-checked by
I certify that all the equipments and machinery to be used have
been examined by me and have been found clean.
Sign.
Mixing
Equipment used
Specify order of mixing

Date Duration of mixing

pH of bulk solution

Adjusted pH (if needed of bulk solution)

Filtration
Machine used

Date Duration of filtration

Actual yield
Theoretical yield
Whether within limits
Q/C report of finished product
(Status No. & date and release order)
Date of release
Qty. released
Date of transfer of finished Product to warehouse

Production supervisor
Sign. Counter signed
(HOD Q.C.)
B.P.R. (BATCH PACKAGING RECORDS)

M/S (Name & address of company)

Product name
Generic name
Batch no. Batch size
Mfg. Date
Exp. Date
Container description
Precoding of labels / Printing packaging
Material examined and verified by
Precoded
1. Labels received
2. Carton received
 Labelled claim
Precautions taken
(Specify)
Result of bulk finished
Product analysis
(Status, report no. & date)

Dt Time Personnel responsible for

Filling Filling Chk. of Chk. of Chk. of Chk. of

Comm stopped empty filled labeled cartons
enced bottles bottles bottles

No. of refiltered and refilled bottles

 Total quantity packed
Date of completion

Reconciliation of labeling & Packaging materials

Labels cartons
Requisitioned / received
Used
Returned
Destroyed
Destroyed on (date)
Destroyed by
Packaging in charge
Sign.
Batch Production in-process Control records

M/s (Name & address of company)

Name of the product

Batch No.
Batch Size
Date of commencement of manufacture
1.Visual examination of empty washed and dried containers:
Date ……………………………………………………..
Name of the workers who examined the containers
…………………………………………………………….
Total no. of the container examined ..…………………
Number of container found defective …………………
Nature of defect …………………………………………

2.pH of the Bulk solution :

Date ………………………………………………………..
pH of bulk solution ……………………………………….
Adjusted pH………………………………………………..
(if needed to be adjusted)
3. Visual examination of the filled bottles:
Date ………………………………………………………………………
Name of the workers who examined the containers …………………
Total no. of bottles examined ………………………………………….
Number of bottles found defective …………………………………….
Nature of defects ………………………………………………………..

4. Net contents in containers:

Volume claimed on label .……………………………………………..

Date Time Volume found Date Time Volume found

Sign. Of Q/C personnel who is

Responsible and / or carried out the tests
 VALIDATION PROTOCOL
Validation studies are an essential part of GMP
& should be conducted in accordance with predefined
protocols.

Protocol means a document that gives details of:

1. Critical parts of manufacturing process
2. The parameters that should be measured
3. Their allowable range of variability
4. The manner in which the system will be tested

Why validate?
✓ To conform Manufacturing to cGMP regulations.
✓ To avoid the possibility of rejected or recalled batches.
✓ To ensure the product uniformity and quality.
❑Validation can be defined as a procedure that
demonstrates a process under standard conditions,
is capable of consistently producing a product that
meets the established product specifications.

❑Process and procedure should be established on the

basis of a validation study and undergo periodic re-
validation to ensure that they remain capable of
achieving the intended results.
 Process Variables
Process Equipme- Process Properties Monitoring
nts variables affected by output
variables

Mixing Kettle & Capacity of unit, Appearance Potency,

of Tank fitted Shape & position of liquid, Appearance
liquid with of agitation Viscosity of , pH,
agitator system, liquid. Viscosity,
Order of addition, Specific
gravity.
Rate of addition,
Fill volume,
Mixing speed of
agitator,
Temperature of
liquid,
Mixing time.
Process Equipment Process Properties Monitoring
variables affected by output
variables

Dispersing Homogenizer, Bore opening/ Particle Potency,

Colloid mill, clearance of rotor size of Particle
ultrasonic & stator/power solids, size
device setting, Viscosity of Distribution,
Pressure/rotor liquid. Viscosity,
speed/power Specific
consumption, gravity.
Feed rate,
Temperature,
Dispersion time,
Order of mixing.
 PRODUCT VALIDATION
Major test parameters used for final product testing
Appearance
pH
Viscosity
Specific gravity
Microbial count
Leakage test for filled bottle (By plastic vacuum
dessicator)
Check the cap sealing
Fill volume determination
Particulate matter testing
Water vapour permeability test
Stress test
Test parameters specific for suspension
• Sedimentation rate
• Resuspendibility
• Particle size & particle size distribution
• Zeta potential measurement
Type of emulsion determination by
• Dilution test
• Conductivity test
• Dye solubility test
• COCl2 filter paper
• Fluorescence test
• Direction of creaming
Test parameters specific for solution
• Clarity of solution
• Color of solution
 INNOVATIONS
NANOSUSPENSION
Increased dissolution
Increased physical stability
Improved biological activity
For targeted delivery
MICROEMULSION
Prepared by spontaneous emulsification.
Increased stability
Dose uniformity
Increased Oral bioavailability
Eg. Cyclosporine
61\73
Difference between emulsion and microemulsion
BAXA SYSTEMS
(www.baxa.com)
• Baxa systems for delivering
oral and other non-IV
medications without risking
wrong-route administration
support patients at every age
and stage of life. Exacta-Med
Oral Dispensers benefit
pediatric patients – and their
caregivers – by presenting
medications behind the taste
buds. The same device
provides adult and geriatric
populations an alternative to
solid unit-dose medications.
 New tretment for babies with Sickle cell
anemia
✓ Oral liquid Hydroxyurea can prevent some of the
complications generated by this disease.
✓ This can prevent the red blood cells from becoming
sickle cells.

Comar’s Liquid Dispensing Solutions

✓As an “Oral Syringe”,when used with Comar’s press-
in-Bottle-Adapter & bottles,drawing,measuring &
dispensing is highly accurate & clean.
MULTIPLE EMULSION
Taste masking
Adjuvant vaccines
Formulate parenteral preparation
More effective dosage form for prolonged action
Increased oral bioavailability
Eg. Nitrofurantoin & Griseofulvin

LIQUID OROS SYSTEM (L-OROS):

Prepared by using HGC or SGC.
Controlled release dosage form
Bioavailability-enhanced delivery systems
Used for hydrophobic drug
Enhanced bioavailability
Eg. Concerta®, Ditropan XL®, and Procardia XL®.
 MULTIPLE EMULSIONS

continuous phase
intermediate phase 1
intermediate phase 2
internal phase

example of w/o/w/o emulsions:

Water / silicon oil / water / silicon oil emulsion

DIFFERENT DESIGNS OF MULTIPLE
EMULSIONS
REFERENCES
How to practice GMP by P.P. Sharma.
Validation of Disperse System: Pharmaceutical Dosage Form:
Disperse Systems: Volume 3 (Part B).
Pharmaceutical Process Validation by Bernard T. Loftus and Robert
A. Nash.
SOP guidelines by D.H.Shah.
Drug and cosmetic act, 1940.
Indian drug September 2005: 42 (9): 557.
Remington,20thedition.
The Theory & Practice of Industrial pharmacy by Leon Lachman.
www.pharmaceuticalmachines.com
www.baxa.com
www.alza.com
www.drugdeliverytech.com
www.ravipharma.com
www.elmach.com
www.kotharipharma.com
www.cadmach.com
www.wintechpharma.com
THANK
YOU