This document discusses scale up techniques for sterile products like parenteral and ophthalmic products. It explains the importance of pilot plants in examining formulas and processing equipment before full scale production. Key aspects of scaling up parenteral products are formulation considerations like choice of solvents, solubilizers, buffers and sterilization methods. Proper facilities are required for different production stages from clean up to filling to ensure sterility. Formulation and quality control testing factors for ophthalmic products are also outlined. Maintaining sterile conditions is essential throughout the manufacturing process of these sterile dosage forms.

1. Seminor on
Scale Up Techniques In The Production Of Sterile
Products And Ophthalmic Products
DEPARTMENT OF PHAEMACEUTICS

2. INTRODUCTION
PILOT PTANT:
It is defined as a part of pharmaceutical industry where
a lab scale formula is transformed into a product by the
development of procedure for manufacturing.
R & D Production
SCALE UP:
It is defined as the art of designing of prototype using
the data obtained from the pilot plant.

3. Importance of Pilot Plant:
Examination of formulae.
 Review of range of relevant processing equipments.
 The specification of the raw materials.
 Production rates.
The physical space required.
 Appropriate records and reports to support GMP.

4. SCALE UP OF PARENTRAL PRODUCTS
para: outside
enteron: intestine (i.e. beside the intestine)
These are the preparations which are given other than oral routes.
Injections:
These are
 Sterile,
 Pyrogen free preparations intended to be administered
parenterally (outside alimentary tract).

5. Scale-up for parenterals

6. Formulation aspects
 Solvent:
solvent used for parenteral production is water for injection.
WFI is prepared by distillation or reverse osmosis. Sterile water for
injection is used as a vehicle for reconstitution of sterile solid products
before administration and is terminally sterilized by autoclaving
Water miscible vehicles:
Ethyl alcohol, PEG, PG
Non aqueous vehicles:
Fixed oils

7. Solubilizing agents used in sterile products include:
1. co-solvents: glycerine, ethanol, sorbitol, etc.
2. Surface active agents: polysorbate 80, polysorbate 20, lecithin.
3. Complexing agents: cyclodextrins etc
They act by reducing the dielectric constant properties of the solvent
system, thereby reducing the electrical, conductance capabilities of the
solvent and thus increase the solubility.
Solubilizers:
They are used to enhance and maintain the aqueous solubility of
poorly water-soluble drugs.

8.  Antimicrobial agents:
 Added for fungistatic or bacteriostat action or concentration
 Used to prevent the multiplication of micro-organisms
 Ex..
• Benzyl alcohol
• Benzethonium chloride
• Methyl paraben
 Preservatives:
• Multidose containers must have preservatives unless prohibited by
monograph.
• Large volume parenteral must not contain preservative becoz it may be
dangerous to human body if it contain in high doses.

9.  Buffers:
They are used to maintain the pH level of a solution in the range that
provides either maximum stability of the drug against hydrolytic
degradation or maximum or optimal solubility of the drug in solution.
Exampies:Acetic acid , benzoic acid, citric acid, lactic acid
 Antioxidants:
Antioxidants function by reacting prefentially with molecular oxygen and
minimizing or terminating the free radical auto-oxidation reaction.
Examples: phenol (0.065-0.5%), m-cresol (0.16-0.3%) etc.
 Chelating agents:
 Used to form the complex with the metallic ions present in the
formulation so that the ions will not interfere during mfg. of
formulation.
 They form a complex which gets dissolved in the solvents.
 Examples:
 Disodium edetate , Disodium calcium edetate

10.  Stabilizers:
 As parenterals are available in solution form they are most prone to
unstabilize
 Used to stabilize the formulation
 Maintain stable
 Examples:
 Creatinine , Glycerin
 Tonicity- adjusting agents:
 Used to reduce the pain of injection.
 Buffers may acts as tonicity contributor as well as stabilizers for the
pH.
 Isotonicity depends on permeability of a living semipermaeable
membrane
• Hypotonic : swelling of cells (enlargement)
• Hypertonic: shrinking of cells (reduction)
 Example:
 Glycerin ,Lactose , Mannitol

12. Instrumentation
 Mixer
 Homogenizer
 Filteration assembly
 Filling machinery

13. Mixer/Homogenizer

14. Bottling/Filling machinery

15. Sterilization and Depyrogenation
 Steam sterilization
 Dry-heat sterilization and depyrogenation
 Gas and vapour sterilization
 Radiation sterilization
 Sterilization by filteration

16. LAY OUT OF PARENTERAL MANUFACTURING AREA

17.  Clean- up area:
 Non aseptic area
 Free from dust ,fibres & micro-organisms
 Constructed in such a way that should withstand moisture, steam &
detergent
 Ceiling & walls are coated with material to prevent accumulation of
dust & micro-organisms
 Exhaust fans are fitted to remove heat & humidity
 The area should be kept clean so that to avoid contamination to aseptic
area
 The containers & closures are washed & dried in this area.

18.  Preparation area:
 The ingredients are mixed & preparation is prepared for filling
 Not essential that the area is aseptic
 Strict precaution is taken to prevent contamination from outside
 Cabinets & counters: SS
 Ceiling & walls : sealed & painted
 Aseptic area:
 Filtration & filling into final containers & sealing is done
 The entry of outside person is strictly prohibited
 To maintain sterility, special trained persons are only allowed to enter & work
 Person who worked should wear sterile cloths
 Should be subjected for physical examination to ensure the fitness
 Minimum movement should be there in this area
 Ceiling & walls & floors : sealed & painted or treated with aseptic solution and
there should not be any toxic effect of this treatment

19.  Cabinets & counters: SS
 Mechanical equipments : SS
 AIR:
• Free from fibres, dust & micro organisms
• HEPA filters are used which removes particles upto 0.3
micron
• Fitted in laminar air flow system, in which air is free
from dust & micro organisms flows with uniform
velocity
• Air supplied is under positive pressure which prevents
particulate contamination from sweeping
• UV lamps are fitted to maintain sterility

20.  Quarantine area:
 After filling, sealing & sterilization the products or batch
is kept in this area
 The random samples are chosen and given for analysis to
QC dept.
 The batch is send to packing after issuing satisfactory
reports of analysis from QC
 If any problem is observed in above analysis the decision
is to be taken for reprocessing or others..

21.  Finishing and packaging area:
 After proper label, the product is given for packing
 Packing is done to protect the product from external
environment
 The ideal Packing is that which protects the product during
transportation, storage, shipping & handling.
 The labeled container should be packed in cardboard or
plastic containers
 Ampoules should be packed in partitioned boxes.

22. Opthalmic Solutions
Ophthalmic preparations are sterile product that are
intended to be applied to the eyelids or placed in the
space between eyelids or placed in the space
between the eye lids and the eyeball

23. Ideal property for ophthalmic preparation
 Sterility. (Avoidance of pyrogens )
 Preservation.
 Tissue compatibility.
 Suitable packaging.
 Must be isotonic with lacrymical fluids.
 should have P H approx 7.4.
 viscosity.

24. Types of ophthalmic dosage forms
1)Solutions-
ADVANTAGES DISADVANTAGES
convenience - rapid corneal elimination.
- loss of drug by drainage.
- No sustained action
2) Suspensions-
ADVANTAGES DISADVANTAGES
- patient compliance loss of both solution
- slow dissolution & suspended solid.

26. FORMULATION
(1) Vehicles:
There are two types of vehicles which are:
 Aqueous vehicles:-
e.g. Water is used as vehicle because water is tolerated well by the
body
 Non-aqueous vehicles:-
e.g. Oils and Alcohols, such as, fixed oils, almond oil, ethyl alcohol,
propylene glycol.

27. Adjuvants
Thickening agents
- methyl cellulose.
- carboxy methyl cellulose.
- polyvinyl alcohol.
- polyethylene glycol.
Buffers
-- Boric acid.
-- Sodium acid phosphate.
-- Sodium citrate.

28.  Anti-oxidants.
They are added to provide protection from Oxidation.
e.g Sodium metabisulphite - Sodium thiosulphate -
Thiourea . - ascorbic acid.
 Wetting agents.
e.g. Polysorbate 20 Polysorbate 80

29.  Tonicity Adjusting Agents.
Commonly used tonicity adjusting agents are Nacl ,
Kcl , buffer salts, dextrose,glycerin , propylene glycol
and mannitol .
 Preservatives.
- Benzalkonium chloride
- Phenylmercuric acetate
- Phenylemercuric nitrate

30. VARIOUS FACTORS AFFECTING STABILITY OF
FORMULATIONS
 Temperature.
 pH.
 Excipients.
 Oxidation.
 Light.
 packaging.

31. Manufacturing considerations
 Manufacturing Environment:
The environment should be sterile and particle-free
through: -
Laminar-flow should be used throughout the
manufacturing area.
 Relative humidity controlled to between 40 and 60%.
 Walls, ceilings and floors should be constructed of
materials that are hard, non flaking, smooth and non-
affected by surface cleaners or disinfectants.

34.  MANUFACTURING OPERATION
1) 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 .

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

44. PACKAGING
 Plastic containers → ease of use.
→ little breakage.
→ less spoilage.
 Large volume intraocular solutions of 250ml
&500ml have been packaged in glass.
 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 FDA.

45.  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

46. 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.

47. Documentation:
1. Master formula records.
2. Batch formula records.
3. Equipment & containers records.
4. Filtration & filling records.
5. Batch Packaging & Labeling Records.

48. REFERENCES:
 Remington-The science and practice of pharmacy 21 st edition
volume I.
 Controlled drug delivery by N.K.Jain, Page No.(82,85,86,92,94-
96)
 Indian pharmacopoeia , 2007 . vol – 1.
 Controlled drug delivery by Roop K.Khar & S.P.Vyas, Page
No.(384-397,399,403)
 Modern pharmaceutics edited by Gilbert S. Banker.
 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.html.