This document discusses manufacturing considerations for ophthalmic dosage forms. It begins by defining ophthalmic preparations and listing their key requirements like sterility, tonicity, and avoidance of particulates. It then covers the manufacturing environment, personnel requirements, equipment needs, raw materials, and process analytical technology (PAT). Specific manufacturing operations for ophthalmic preparations in glass and plastic containers are outlined, including areas, equipment, and processing steps for water management, container preparation, solution preparation, filling/capping, sterilization, inspection, and packaging. Common ophthalmic dosage forms and their advantages and disadvantages are also briefly mentioned.

1. OPHTHALMIC DOSAGE FORMs

2. CONTENTS ….
1. INTRODUCTION
1 Definition
2 Types of ophthalmic dosage forms
2. MANUFACTURING CONSIDERATION
1 Environment
2 Personnel requirements
3 Equipments
4 Raw material
5 PAT (process analytical technology)
3. MANUFACTURING OPERATION
1 Area requirement
2 Equipments as per schedule M
3 Process flow chart
4 Simpler flow diagram showing arrangement of different area
5 Manufacturing operation of ophthalmic preparations
6 Packaging
4. OPHTHALMIC PREPARATION CHARACTERISTICS
5. QUALITY CONTROL TESTS
6. DOCUMENTATION
7. REFERENCES

3. 1. INTRODUCTION
1. DEFINITION:
“ophthalmic preparation are sterile
Product that are intended to be applied to the eyelids or placed
in the space between the eyelids and the eyeball.
Ophthalmic preparation are similar to parenteral dosage
forms in their requirement for:
1.Sterility
2.Tonicity (osmotic pressure)
3.Preservation
4.Tissue compatibility
5.Particulate matter
6.Avoidance of pyrogens (not as critical as other parenteral
products)
7.Suitable packaging

4. DOSAGE FORMS ADVANTAGES DISADVANTAGES
1. Solutions -convenience -rapid corneal elimination.
-loss of drug by drainage.
No sustained action
2. Suspensions -patient compliance
-best of drug with slow dissolution
-drug properties decide performance.
-loss of both solution & suspended
solid.
3. Emulsions -prolonged release of drug from
vehicle.
-enhanced pulsed entry.
-patient non compliance.
-Blurred vision
-possible oil entrapment.
4. Ointments -Flexibility in drug choice
-improved drug stability
-increased tissue contact time.
-inhibition of dilution by tears.
-sticking of eyelids.
-poor patient compliance
-blurred vision
-no true sustained effect.
5. Gels -comfortable
-less blurred vision than ointment.
-no rate control on diffusion.
-matted eyelids after use.
6.Erodible inserts -effective
-flexiblility in drug type & dissolution
rate
-need only be introduced into eye & not
removed.
--patient discomfort
-requires patient insertion
-occasional product.
7. Non-erodible inserts -controlled rate of release
-prolonged delivery
-flexibility for type of drug selected.
-sustained release
-patient discomfort
-irritation to eye
-tissue fibrosis
TYPES/CLASSES OF OPHTHALMIC DOSAGE FORMS :

5. 2. Manufacturing considerations in design of
ophthalmic production facility:
Because the official compendia require all topically
administered ophthalmic medication to be sterile, the manufacturer
of such medication must consider all the current concepts in the
manufacture of sterile pharmaceuticals in designing a manufacturing
procedure for sterile ophthalmic pharmaceutical products.
The manufacture of sterile ophthalmic pharmaceutical products
requires special attention to:
1. Environment 2. Personnel Requirements
3. Equipments 4. Raw Material
5. PAT (Process Analytical Technology)

6. 1 ENVIRONMENT:
Current U.S. std. for GMP provide for the use of specially
designed environmentally controlled areas for the manufacturing
of sterile large & small volume injections and ophthalmic for
terminal sterilization.
Grade Types of Operations for Terminally Sterilized Products
A Filling of products
C Placement of filling and sealing machines,
preparation of solutions
D blowing (pre-forming) operations of plastic
containers & closers.

7. Grade Types of Operations for Aseptic Preparations
A Aseptic preparation and filling
B Background room conditions for activities
requiring Grade A
C Preparation of Solution to be filtered
D Handling of components after washing
Note :
 Grade A and B correspond to with class 100
 Grade C correspond to with class 10000
 Grade D correspond to with class 100000
(Class 100 : NMT 100 particles /ft3 of air of diameter of 0.5 µm or
larger)

8. • Class 10,000: area contains NMT 10,000 particles of
0.5 microns and even larger per cubic feet of air
• The areas where the containers and closures are
not exposed to the environment and in which the
processes of filling and capping are not undertaken
• Can be achieved by conventional air conditioning.

9. • Class 100:
• Area contains NMT 100 particles of 0.5 microns and
larger per cubic feet of air.
• areas where the containers and closures are
exposed to the environment and areas associated
with filling and capping processes are required to
meet the requirements of class 100.
• This class 100 condition can be achieved by laminar
air flow.

10. Monitoring and evaluation of production
environment
• Particle count: Number of particles in as ample of
air by particle measuring systems – measures only
dust particles not viable forms.
• Slit to agar sampler
• Rodac plates- consists of nutrient agar with convex
surface .
• The plate is rolled on the surface to be tested where
MO sticks to the surface of agar plate
• Plates are incubated during which MO starts
growing

11. a)Walls,ceiling&floors
Constructed of material →hard, non flaking , smooth &
unaffected by surface cleaning agents & disinfectants.
For that epoxy or vinyl ceiling coat for finishing avoids holes on
surface.
b)Alllights&windows
Should be flush mounted in walls & ceilings for ease of
cleaning&disinfection
c)U.V.lamps
May be provided in recessed , flush mounted fixtures to
maintainsurfacedisinfection
d)Separateentrance
For both personnel & equipments (specially designed air
locks maintained at negative pressure relative to aseptic
manufacturing area & at positive pressure relative to non-
environmentally controlled area.

12. 2 PERSONNEL REQUIREMENTS
Physically fit
No. of workers should kept to a minimum- to
minimize human derived particulate matter which
includes the epidermal cells, hair.
Training of personal
Sterile uniform
Personal hygiene:-
All employees should be in good health,
Subjected to Physical examination,
Understood their responsibilities to report
own illness like cold, a sore throat, or
other infection.
• conditions maintained in the working area. RH – 40
to 60 % and temp between 20-250c

13. Traffic control
• Traffic includes
• Supply of materials
• Entry and exit of the workers in the production area
• Traffic should be strictly controlled in aseptic rooms
• Prescribed procedure should be followed for every
person who enters aseptic areas
• They should change their clothes, cover their faces with
masks, wear hand gloves, head covers or caps and
shoes
• Once a person enters the aseptic area, he or she cannot
leave until completion of MFG cycle
• Entry of unauthorized persons in this area should be
restricted

14. General cleaning
• Cleaning schedule should be developed and
followed on a daily or monthly basis based on
sterility requirements .
• General cleaning and surface disinfection
• Sanitization is carried out using disinfectants or UV
radiation before starting the production
• Cleaning and sanitization carried out in two ways
• A. By spraying a suitable liquid disinfectant over all
the surfaces in aseptic areas/ by wiping surfaces
with liquid disinfectant

15. • Surface disinfection is achieved by use of germicidal
UV lamps
• Irradiation of UV light rays is done to decrease the
population of bacteria in aseptic areas.
• Direct irradiation is carried out only when the room
is vacant.

16. Cleaning of air
• Greatest source of contamination is air entering
aseptic area as air contains most of the bacteria
• Conventional systems/ class 10,000
• Consists of two air conditioners fixed at ceiling and
at the bench level respectively
• This area is responsible for the control of dust
particles, humidity and temperature
• Before entering the air is dehumidified, cooled and
filtered
• This filtered air is allowed to enter at a velocity of
800ft/min

17. • Laminar flow systems
• Used for cleaning air in aseptic rooms
• To remove bacteria/ dust particles
• Clean air obtained by use of HEPA filters

18. 3 EQUIPMENTS :
sterile – because of direct contact with the ingredients
during formulation
All tanks , valves , pipings →best available grade of corrosion-
resistant stainless steel.(S.S. type 304 or 316) is preferable.
All the product contact surface should be finished either
mechanically or by electro polishing to provide a surface as free as
possible from scratches or defects.
For the equipment that will reside in aseptic filling areas such as
filling & capping machine, care should be taken in their design to
yield equipment as free as possible from particle generating
mechanisms.

19. • Advancement in technology – specialized
equipments that can be cleaned in their positions
itself – clean – in – place concept.
• CIP and SIP equipments
• Sequence of treatments for CIP systems
• Chlorinated water rinse filtered air blow->
detergent wash-> filtered air blow-> Chlorinated
water rinse-> filtered air blow-> WFI rinse-> filtered
air blow.

20. • Sterilization of equipments :
• Materials which can with stand high temps
rendered sterile by dry heat sterilization at a temp
of 170 c or above for an hour/ 140 c for 3 hrs.
• Which cannot with stand high temps sterilized by
moist heat sterilization by use of autoclave at 121 c
15 psig for 20 mins / 130 c 27 psig for 3 mins
• Before MHS equipment thoroughly rinsed with 80c
pyrogen free water.

21. • Equipments which are sensitive to autoclaving
temps gas sterilization by ethylene oxide.
• Equipments which are exclusively employed in the
sterile area such as bottles, filling machinery,
sterilizing membranes, stoppering equipment,
tanks, utensils, vent filters must be sterilized just
before sterile operation.

22. 4 RAW MATERIAL :
Highest quality, sterile
Specifications laid down by regulatory authorities strictly
followed
Care on particle size. Eye sensitive to particle size >25 microns

23. In most sterile dosage form largest proportion is of
“water” which is main source of contamination.
For the preparation intended for parenteral
administration ,U.S.P. xxii requires the use of
→ WFI
→ SWFI
→ BWFI
All of above are produced by distillation or reverse
osmosis & kept in circulation at relatively high
temperature up to 800c, or alternatively its disposal
at every 24 hrs, in all S.S. equipment of highest
attainable , corrosion resistant quality

24. 5 PAT (PROCESS ANALYTICAL TECHNOLOGY)
The product manufacturing & quality control is
governed by the c GMP regulation.
For better output ,PAT is to be followed.
“System for designing ,analyzing &
controlling manufacturing through timely
measurements (during process) of critical quality
& performance attribute of raw & in process
material & process with a goal of ensuring final
product quality. ”

25. 3. MANUFACTURING OPERATION
A. AREA REQUIREMENT
Minimum of 10 m2 → for ancillary area
Minimum of 25 m2 → for basic installation
Manufacturing & filling shall be carried out in air –conditioned areas
under aseptic condition
The rooms shall be further dehumidified as considered necessary if
preparation containing antibiotics are manufactured.

26. B. LIST OF EQUIPMETNS AS PER
SCHEDULE M
For Ophthalmic solutions & suspensions
1. Jacketed kettle/stainless steel tanks(steam gases electrically
heated)
2. Mixing & storage tanks of stainless steel/planetary mixer
3. Sintered glass funnel , Seitz filter or filter candle(preferably
cartridge & membrane filter)
4. Liquid filling equipments (semi automatic & automatic filling
machine)
For Ophthalmic Ointments
1. Colloid mill/ointment mill
2. Tube filling & crimping equipment(semi automatic &
automatic filling machine)
3. Tube cleaning equipments (air jet type)
4. Tube washing & drying equipments

27. EQUIPMETNS
1. Thermostatically controlled Hot air oven. (preferably
double ended)
2. Autoclave (preferably ventilator autoclave)
3. Air conditioning & dehumidification arrangement
4. Laminar air flow units.
5. Automatic vial washing machine
6. Vial drying oven
7. Distillation unit
8. Packaging & labeling
9. Inspection machine

28. Multicolumn distillation unit
It consist of specially designed columns
which make optimum use of the
principles of inter stage heat exchange
(Multi effect distillation method) to
produce pure pyrogen free sterile
distilled water for injectables as per
IP/BP specification.

29. Mixing & Storage Tanks

30. 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.

31. Jacketed kettle / SS Tank (steam, gas or
electrically heated)

32. Triple roller mill
• It’s used for grinding ointment,
pastes, paints, etc.
• Side scrappers moves up and
down with compression spring
and knob to secure appropriate
working pressure

33. ROTARY TUBE FILLING
MACHINE
• Rotary tube filling &
closing (crimping) machine
with coding device.
• Speed :- 30 to 80 TPM
• Another TWIN HEAD
machine also available in
market.

34. Vial filling machine
.
• Suitable for 2 ml to 30 ml vials
• Output Speed up to 120 VPM

35. Fully Automatic Labeling Machine SBSL-
120F
• Fully Automatic, User Friendly, Sticker (Self-Adhesive)
Labeling Machine Model SBSL-120F,
• Suitable to apply accurate Labels on Double Side (Front
& Back) of Flat/Oval/Square shaped products .

36. Manual Vial & Bottle Inspection machine
Out put Approx. 80 to 250 vials per
minute
No of
operator
six

37. Automatic Packaging Conveyor
•Conveyor belt is used as a PVC coated canvas belt /
endless rubberized belt.
•The Reduction Gear Box provides jerk less &
noiseless performance for long time.

38. STEAM STERILIZER or AUTOCLAVE
used for sterilizing
• Solutions in glass containers like ampoules,
vials, glass bottles etc.

39. C. PROCESS FLOW CHART

40. D. FLOW DIAGRAM SHOWING
ARRANGEMENT OF DIFFERENT AREA
OPHTHALMIC– MANUFACTURING PLANT LAYOUT

41. E. MANUFACTURING OPERATION OF
OPHTHALMIC PREPARATIONS
Divided in to two separate areas:-
1. Ophthalmic preparation in glass container.
2. Ophthalmic preparation in plastic container.

42. 1. OPHTHALMIC PREPARATIONS
IN GLASS CONTAINER
Different areas Equipments recommended
Water management area
(water treatment & storage)
1)De-ionised water treatment unit.
2)Distillation (multi column with heat
exchangers) unit.
3)Thermostatically controlled water storage
tank.
4)Stainless steel service lines for carrying
water into user areas.
Container & closure preparation
area
(washing & drying of vials , bottles &
closures)
1)Automatic rotary vial washing machine.
2)Automatic closures washing machine.
3)Storage equipment for vials, bottles and
closures.
4)Dryer / sterilizer (double ended).
5)Dust proof storage cabinets.

43. Different areas Equipments recommended
Solution preparation area
(preparation & filtration of solution)
1) Solution preparation and mixing
2) Stainless steel tanks and other
containers.
3) Portable stirrer.
4) Filtration equipment with
cartridge and membrane filters/
bacteriological filters.
5)Transfer pumps.
6)Stainless steel benches / stools.
Filling, capping and sealing area
(filing , capping , sealing of vials &
bottles)
1)Automatic vial/bottle filling,
sealing and capping machine
under laminar air flow work
station.
2)Gas lines (Nitrogen, Oxygen,
Carbon di-oxide) wherever
required.
3)Stainless steel benches/stools

44. Different areas Equipments recommended
Sterilization area 1)Steam sterilizer (preferably with computer
control for sterilization cycle along with
trolley sets for loading/unloading
containers before and after sterilization).
2)Hot Air sterilizer (preferably double ended).
3)Pressure leak test apparatus.
Quarantine area 1)Storage cabinets.
2)Raised platforms/steel racks
Visual inspection area 1)Visual inspection units (preferably
conveyor belt type and composite white
and black assembly supported with
illumination).
2)Stainless steel benches/stools.
Packaging area 1)Batch coding machine (preferably
automatic).
2)Labeling unit (preferably conveyor belt
type).
3)benches/stools.

45. 2. OPHTHALMIC PREPARATIONS
IN PLASTIC CONTAINER
FORM-FILL-SEAL TECHNOLOGY OR
BLOW-FILL-SEAL TECHNOLOGY
SIMPLE FILL-SEAL TECHNOLOGY
Form-Fill-Seal units are specially built automated
machines in which through one continuous operation,
container's are formed from thermoplastic granules, filled
and then sealed .
Fill-seal units are machines in which containers are
molded (preformed) in separate clean rooms by non
continuous operation then filling & sealing is carried out.

46. FORM-FILL-SEAL OR BLOW-FILL-SEAL
MACHINE

47. PACKAGING
Plastic containers → ease of use
→ little breakage
→ less spoilage
Large volume intraocular solutions of 250ml &500ml
have been packaged in glass, but even this parenteral
type products are beginning to be packaged in specially
fabricated polyethylene/polypropylene containers or
flexible bags.
Type 1 glass vials with appropriate stoppers are used
for intraocular ophthalmic products administered by
injection.
Different ophthalmic cap color coding are given by the
cooperative efforts of FDA , the ophthalmic industry &
academy of ophthalmology .

48. OPHTHALMIC CAP COLOR CODING
Color Pharmaceutical class
Yellow or blue Beta blockers
Gray Non steroidal
Pink Steroidal
Brown Anti infective
Orange Carbonic anhydrase inhibitors
Turquoise Prostaglandins
Red Mydriatics
Green Mitotic

49. 4. Ophthalmic preparation characteristics
1) Clarity:
Ophthalmic solutions by definition contain no
undissolved ingredients & are essentially free from
foreign particles.
But solution containing viscosity imparting polymers
diminish clarity. In these situation it may be important to
define both the visual clarity of the product & monitor its
stability.
The E.P. describes visual clarity & recommended
standards that can be used for clarity specifications.

50. 2) Stability:
The stability of a drug in an ophthalmic product depends
on a number of factors including the chemical nature of the
drug substance, product pH, method of preparation
(particularly temperature exposure), solution additives, &type
of packaging.
Pharmaceutical manufacturers conduct comprehensive
stability programs to assure the assigned expiration dating for
each product.
The stability of the preservative is also monitored by
chemical means or by actual challenge of the preservative
efficacy with appropriate test organisms.

51. 3) Sterility:
The important property of ophthalmic formulations
is that they must be sterile.
The USP-22 listed five methods of achieving sterility.
a) Steam sterilization at 1210c
b) Dry heat sterilization
c) Gas sterilization
d) Sterilization using ionizing radiation
e) Sterilization by filtration
The method chosen is often depends on resistance
of the active ingredient & the resultant product to
heat & to the type of packaging(i.e. container) used.

52. 4) pH adjustment & buffers:
The adjustment of ophthalmic solution pH by the
appropriate choice of a buffer is one of the most
important considerations.
Ideally, ophthalmic preparations should be
formulated at a pH equivalent to the tear fluid value of
7.4
5) Tonicity:
Tonicity refers to the osmotic pressure exerted by
salts in aqueous solution.
An ophthalmic solution is isotonic with another
solution when the magnitudes of the colligative
properties of the solutions are equal.

53. 5. QUALITY CONTROL SPECIFICATION
1) Raw material 2) packing material
- Description - Compatibility
- Moisture content - Stability
- Assay of ingredient
- Purity
3) In process Product
a) Mixing b) Filling
- Assay - weight variation
- Grittiness - content uniformity
- Viscosity
- Density
- pH

54. 4) Product Specification
a) Microbial specification
- limit for total microbial count
- Absence of specific microorganism as per pharmacopoeia
b) Chemical specification
- pH
- Content uniformity
- Chemical potency
c) Physical specification
- clarity
- Particle size
- Density
- Viscosity

55. Compendial requirements for semi-
solid product
• Semi-solid product must meet USP tests for,
1) Microbial content
2) Minimum fill
3) Packing
4) Storage
5) Labeling
• Ophthalmic ointment must meet to the,
- USP sterility tests
- Test for metal particles
• USP directs the ophthalmic ointment must be packed in collapsible tube
with narrow tip.

56. 6. DOCUMENTATION
1. Master formula records
2. Batch formula records
3. Equipment & containers records
4. Filtration & filling records
5. Batch Packaging & Labeling Records
6. IPQC records

57. 1. Master formula records
• Name of the product________________________________________
• Name and Weight of API ____________________________________
• Name and Weight of Ingredient _______________________________
• Description of equipment ____________________________________
• Statement of theoretical yield_________________________________
• Process and packaging procedure_____________________________
• A description of container____________________________________
• closure and packaging material _______________________________
• In process control during processing ___________________________
• In process control during packaging____________________________
• Precaution to be taken______________________________________

58. Environmental control
Product_______________________________ lot no.__________________________
Room________________________________ date exposed_____________________
Media____________________
Date Time Incubation
Temp.
Humidity (in case of
hygroscopic substances)
Plate no Duration Location No. of colonies

59. 2. Batch Manufacturing Records
• Name of the company:-_______________________________________
• Address:-___________________________________________________
• Name of the product _________________________________________
• Active pharmaceutical ingredient ______________________________
• M F R No. __________________________________________________
• Batch No._____________________ Batch size ____________________
• Mfg. date _____________________Date of expiry_________________
• Requisition slip
Sr no Ingredients Item
code
Standards ATR no Label claim Qty
required
Qty
issued

60. 3. Equipment & containers records
• Description of containers _______________________________________
• Q/C report of container ________________________________________
• Date ________________________ Equipment used__________________
• Cleaning agent used ___________________________________________
• Cycle of washing: _____________________________________________
• Sign. Of officer_______________________________________________
If sterilized by dry heat or autoclave:
Articles Date Time when
oven started
Desired
temp.
attained
Temp. Time when
oven switched
off

61. 4. Filtration & filling records
• Equipments used for filtration ___________________________________
• Date__________________________ Time_________________________
• Result of test or analysis of solution_______________________________
• Equipment used for filling_______________________________________
• Date________________________________________________________
• Sign. Of officer_______________________________________________
Time Filling started Filling completed

62. 5.Batch Packaging & Labeling Records
• Product name_______________________ Batch no _______________________
• Strength___________________________ batch size ______________________
• Category___________________________ mfg date _______________________
• MFG no____________________________ exp date _______________________
• Batch Packaging & Labeling Records
• Description of packaging______________________________________________
• Pre-coding of labels & printed packaging materials,
• examined & verified by _______________________________________________
• No. of pre-coded ____________________________________________________
• (ii). Printed packaging material received __________________________________
• Result of bulk finished products ________________________________________
• Sign. Of officer _____________________________________________________
• Reconciliation of labeling and packaging material
• Quantity of material received___________________________________________
• Quantity of material destroyed__________________________________________
• Quantity of material used _____________________________________________
• Quantity of material returned___________________________________________
• Date of release____________________ quantity release____________________
• Signature of supervisor _______________

63. 6. IPQC records
• 1. Visual inspection:
• Description
________________________________________________________
• Total no of filled, sealed & sterilized containers rejected
__________________
• Nature of defects
____________________________________________________
• Name of worker who examined:
(i). ________________________________________________
(ii). _______________________________________________
(ii). _______________________________________________

64. FDA APPROVED DRUGS FOR OPHTHALMOLOGY
* Restasis (Cyclosporine Ophthalmic emulsion):
• In treatment of low tear production.
• * Lumigan(Bimatoplast Ophthalmic Solution): For the reduction of intra
ocular pressure in open-angle glaucoma.
• * Travatan(Travoplast Ophthalmic Solution)
• * Betaxon: For lowering intraocular pressure.
• * Quixin: For bacterial conjuctivitis.
• * Rescula: (Iso propyl) Ophthalmic Solution. In treatment of open-angle
glaucoma.
• * Alamast: Potassium Ophthalmic Solution.
• * ZADITOR:For the prevention of itching of eye.
• * Alrex: For the treatment of allegic conjuctivitis.
• * Cosopit: For the treatment of glaucoma.

65. 7. REFERENCES
• Remington-The science and practice of pharmacy 21st
edition volume I
• 1.Controlled drug delivery by N.K.Jain,
• Page No.(82,85,86,92,94-96)
• 2. Controlled drug delivery by Roop K.Khar & S.P.Vyas,
• Page No.(384-397,399,403)
• Modern pharmaceutics edited by Gilbert S. Banker volume
72
• Pharmaceutical dosage forms parenteral medications
volume 2 edited by Kenneth E. Avis, Leon Lachman
• Pharmaceutical dosage forms Disperse systems volume2
http:// www.optisgroup.com/TechnologyEyegate.htm
• www. Pharmamachine.com