1. PILOT PLANT SCALE UP FOR
LIQUID ORALS
DR VINOD M. THAKARE
NAGPUR COLLEGE OF PHARMACY
WANADONGARI, HINGNA ROAD,
NAGPUR
2. CONTENTS
• INTRODUCTION
• STEPS OF LIQUID MANUFACTURING PROCESS
• CRITICAL ASPECT OF LIQUID ORAL
• FORMULATION ASPECTS OF LIQUID ORAL
• LAYOUT OF PILOT PLANT FOR LIQUID ORAL
• EQUIPMENT'S
• STAGES OF OPERATION
• QUALITY ASSURANCE
• REFERENCES
3. LIQUID ORALS
• THE PHYSICAL FORM OF A DRUG PRODUCT THAT IS POURABLE
DISPLAYS NEWTONIAN OR PSEUDO PLASTIC FLOW BEHAVIOR AND
CONFORMS 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.
• SOLUTION REFERS TWO OR MORE SUBSTANCE MIXED
HOMOGENEOUSLY.
4. STEPS OF LIQUID MANUFACTURING PROCESS
• PLANNING OF MATERIAL REQUIREMENTS
• LIQUID PREPARATION
• FILLING AND PACKING
• QUALITY ASSURANCE
5. CRITICALASPECTS OF LIQUID MANUFACTURING
• PHYSICAL PLANT
• HEATING, VENTILATION AND AIR CONTROLLING SYSTEM:
THE EFFECT OF LONG PROCESSING TIMES AT SUBOPTIMAL
TEMPERATURES SHOULD BE CONSIDERED IN TERMS OF
CONSEQUENCES ON THE PHYSICAL OR CHEMICAL STABILITY
OF INGREDIENTS AS WELLAS PRODUCT.
6. FORMULATION ASPECTS OF ORAL LIQUIDS
SUSPENSIONS:
Purpose Agents
Facilitating the connection
between API and vehicle
- Wetting agents
Salt formation ingredients
Protecting the API - Buffering-systems,
polymers, antioxidants
Maintaining the suspension
appearance
- Colorings, suspending
agent, flocculating agent.
Protecting the API - Sweeteners, flavorings
7. FORMULATION ASPECTS OF ORAL LIQUIDS
EMULSION:
Purpose Agent
Particle Size Solid particles, droplet
particle
Protecting the API Buffering-systems,
antioxidants, polymers
Maintaining the appearance Colorings, emulsifying
agents, penetration
enhancers, gelling agents
Taste/smell masking Sweeteners, flavorings
8. FORMULATION ASPECTS OF ORAL LIQUIDS
SOLUTIONS:
Protecting the API Buffers, antioxidants,
preservatives
Maintaining the
appearance
Coloring, stabilizers, co-
solvents, antimicrobial
preservatives
Taste/smell masking Sweeteners, flavorings.
12. STAGES OF OPERATION
1. TANK SELECTION
• MATERIAL OF THE TANK MUST NOT BE ADDICTIVE TO THE
PRODUCT,
• THE SHAPE AND SIZE OF EQUIPMENT MUST BE SELECTED
ACCORDING TO BATCHES SIZE.
• THE TANKS ARE USUALLY CONSTRUCTED OF POLISHED
STAINLESS STEEL OF DIFFERENT GRADES.
• TEFLON AND GLASS LINED TANK.
• ADEQUATE CLEAN-UP PROCEDURE DEVELOPED.
13. 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 IMPORTANCE.
• AT HIGH VISCOSITY THE CHANCE OF AIR ENTRAPMENT.
• AIR ENTRAPMENT MINIMIZE:-
‾ BY REDUCING AGITATOR SPEED.
‾ BY CARING OUT THE MIXING PROCEDURE IN ENCLOSED TANK UNDER VACUUM.
‾ THE ALTERNATIVE PROCEDURE TO THE ALL IS VERSATOR.
15. 3. DISPERSION
• SUSPENSION AND EMULSION 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.
HOMOGENIZER COLLOIDAL MILL
16. 4. FILTRATION AND 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.
17. 5. TRANSFER AND FILLING
• FILLING IS IMPORTANT PARAMETER IN THE TRANSFER OF
LIQUID FROM TANK TO TANK AND INTO CONTAINERS.
• NEW BATCHES SHOULD NOT BE STARTED UNTIL THE PREVIOUS
BATCHES ARE COMPLETELY FILLED AND THE TANKS EMPTIED.
• BINS AND PIPING.
• METHODS FOR FILLING OF LIQUID:-
‾ 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
18. 6. CONTAINERS AND CLOSURES
• GLASS
• PLASTIC
• IT IS MORE IMPORTANT TO STORE THE FINAL PRODUCT IN
CONTAINER UNTIL ITS EXPIRATION.
• MOST ORAL LIQUID ARE PACKED IN EITHER AMBER OR FLINT
GLASS CONTAINERS WITH PLASTIC OR METAL CAPS.
19. 7. PRODUCTION RATES
• 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.
20. 8. PROCESS EVALUATION
• ITEMS THAT SHOULD BE EXAMINED INCLUDE THE
FOLLOWING-
• MIXING SPEED
• MIXING TIME
• RATE OF ADDITION OF SOLVENTS, SOLUTION OF DRUG,
SLURRIES, ETC.
• HEATING AND COOLING RATES
• FILTER SIZES
• FILLING
21. 9. PREPARATION OF MANUFACTURING PROCEDURE
• THE PROCESSING DIRECTIONS SHOULD BE PRECISE AND
EXPLICIT.
• THE BATCH RECORD SHOULD INCLUDE ADDITION RATE,
MIXING TIME, MIXING SPEED, HEATING AND COOLING RATES
AND TEMPERATURE SHOULD BE GIVEN.
• FINISHED PRODUCT SPECIFICATION AND RELEASE
SPECIFICATION ARE SET; THEY SHOULD BE TAKE INTO
CONSIDERATION.
22. 10. GMP CONSIDERATIONS
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 EQUIPMENT
23. 11. TRANSFER OF ANALYTIC METHOD OF 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.
24. QUALITY ASSURANCE
• DISSOLUTION OF DRUGS IN THE SOLUTION
• POTENCY OF DRUGS IN SUSPENSION
• TEMPERATURE UNIFORMITY IN EMULSIONS
• MICROBIOLOGICAL CONTROL
• PRODUCT UNIFORMITY
• FINAL VOLUME
• STABILITY
