Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Solutions
Suspensions
Emulsions
Dry Powders
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Suspensions
Very difficult to formulate and produce
Excellent stability: ships without
caking/settling
Critical rheological properties:
syringeability: from container to syringe
injectability: from syringe to vein
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Suspensions
Two basic methods:
Sterile vehicle & powder aseptic
combination;
Sterile solutions are combined first and
in situ crystallization
Shanghai Jiao Tong University
3. Formulation of parenteral products
Solutions
Manufacture:
Dissolving drugs and excipients
Adjusting the pH
Sterile filtering
remove particulates and microorganisms
prefiltrate in large-scale production to prevent
clogging
select suitable filter material to avoid absorption loss
Aseptic filling
Fill volume should be greater than the exact labeled
dose
Autoclaving
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Suspensions
Components
Active ingredients
aqueous vehicle
surfactant for wetting
Preservatives
buffers
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Emulsions
Rarely used as parenteral products
Excellent stability requirement;
Particle size<1um, homodispersity;
Very limited selection of stabilizers &
emulsifiers;
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Emulsions
w/o, allergy test, SB
o/w, sustained-release, depot, IM
o/w, nutrient emulsion, IV
o/w type, use triglycerides as central
core, phospholipid as emulsifier, to
provide essential fatty acids and calories
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Freeze-drying
Advantages
Avoid damage to heat-sensitive drugs
High specific surface are facilitating complete
rehydration
Improvement in filling accuracy
Disadvantages:
Protective agents needed
Stability changing, crystalline/amorphous
High-cost and complicated
Shanghai Jiao Tong University
Process of freeze-drying
Freezing
Primary drying
Secondary drying
Capping
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Dry Powders
Purpose: To overcome the intrinsic
instability of the drug, be reconstituted
before use.
Production Method:
Freeze-drying
Aseptic crystallization and dry powder
filling
Spray-drying
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Freeze-drying: Under low pressure, under the
triple point of water, water was removed by
sublimation.
sublimation : ice
vapor directly
Triple point of water : three phases coexisting
in equilibrium
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Aseptic crystallization
The drug is dissolved in a suitable solvent
Sterile filtered
A second solvent is then added
Crystallization and precipitation of the drug
Collected and washed
Dried by vacuum drying
Milled and blended
Filled into vials
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Limitations of aseptic crystallization
Batch-to batch variance
Hard to maintain asepsis
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Spray-drying
A solution of drug is sterile filtered
An aerosol of small droplets of liquid is created by
an atomizer
Solvent evaporates quickly by contacting with a
stream of hot sterile gas
Drug is collected as a powder in the form of
uniform hollow spheres
Filled into vials
Fill weight uniformity
Shanghai Jiao Tong University
3. Formulation of parenteral products
Parenteral Dosage Forms
Limitations of spray-drying
Sterile filtration of very large volumes of air
Constructing and maintaining a spray dryer
that can be readily sterilized
Aseptic transfer of powder from the spray
dryer to the powder-filling line
precise control of the drying conditions to
prevent overheating of the product
Shanghai Jiao Tong University
4. Packaging
Small volume parenterals (SVPs)
Ampoules
Shanghai Jiao Tong University
4. Packaging
Container components for parenteral
products must be considered an integral
part of the product because they can
dramatically affect product stability,
potency, toxicity, and safety.
Shanghai Jiao Tong University
4. Packaging
Small volume parenterals (SVPs)
Ampoules
heat sealed after filling
Glass vials sealed with rubber stoppers
Plastic ampoules (blow-fill-seal)
Pre-filled syringes
Needle-free injection
Shanghai Jiao Tong University
4. Packaging
Small volume parenterals (SVPs)
Glass vials sealed with rubber stoppers
Shanghai Jiao Tong University
4. Packaging
Small volume parenterals (SVPs)
Pre-filled syringes
reducing the degree of manipulation required
facilitating administration in an emergency situation
Shanghai Jiao Tong University
4. Packaging
Large volume parenterals (LVPs)
Glass bottles sealed with rubber stoppers
Plastic bags
Shanghai Jiao Tong University
4. Packaging
Small volume parenterals (SVPs)
Plastic ampoules (blow-fill-seal)
Shanghai Jiao Tong University
4. Packaging
Small volume parenterals (SVPs)
Needle-free injection
Shanghai Jiao Tong University
4. Packaging
Single-dose container
A hermetic container holding a quantity of
sterile drug intended for parenteral
administration as a single dose; when opened,
it cannot be resealed with assurance that
sterility has been maintained.
Multi-dose container
A hermetic container that permits withdrawal
of successive portions of the contents without
changing the strength, quality, or purity of the
remaining portion.
Shanghai Jiao Tong University
Shanghai Jiao Tong University
5. Stability
6. Sterilization methods
90% to 95% activity of medicament
Other considerations
Adsorption of preservative to a rubber closure
Sterilization means destruction of all living
organisms and their spores or their
complete removal from the preparation.
Physical stability
Shanghai Jiao Tong University
Shanghai Jiao Tong University
6. Sterilization methods
Steam
Dry heat
Filtration
Gas
Autoclave
6. Sterilization methods
Steam
Steam sterilization is conducted in an
autoclave and employs steam under
pressure.
This method is preferred to other
sterilization methods if the product and
container can withstand it.
Shanghai Jiao Tong University
6. Sterilization methods
Steam
The usual temperature and the
approximate length of time required is
121oC for 15 to 30 minutes, depending
on the penetration time of moist heat into
the load.
Shanghai Jiao Tong University
6. Sterilization methods
Dry heat
The transfer of energy from dry air to the
object that is sterilized. The transfer
occurs through conduction, convection
and radiation.
Shanghai Jiao Tong University
6. Sterilization methods
Dry heat
Less effective heat transfer than for
steam sterilization
Higher temperature and longer time are
required
160oC for more than 2 hours
Shanghai Jiao Tong University
6. Sterilization methods
Dry heat
Substances that are not effectively
sterilized by steam
Glassware and surgical instruments
Shanghai Jiao Tong University
6. Sterilization methods
Filtration
Sterilization by filtration depends on the
physical removal of microorganisms by
adsorption on the filter medium or by a
sieving mechanism.
For heat-sensitive solutions
Shanghai Jiao Tong University
6. Sterilization methods
Filtration
Depth filters
Membrane filters
(0.22 m)
Shanghai Jiao Tong University
6. Sterilization methods
Filtration
The filtration process might be affected
by adsorption.
The integrity of the filters has to be
proven
Avoid filters that cause particles
Test the filters so that they do not give
extractable
Shanghai Jiao Tong University
6. Sterilization methods
Gas
Ethylene oxide (ETO) is widely used as a
sterilant in hospitals and industry for items that
cannot be sterilized by steam.
It is often diluted with carbon dioxide, or
sometimes fluorocarbons, to overcome its
flammable and explosive nature.
Post treat procedure: to remove the residual
ETO and its byproducts
Shanghai Jiao Tong University
Shanghai Jiao Tong University
6. Sterilization methods
Validation of sterility
Regardless of the method,
pharmaceutical preparations required to
be sterile must undergo tests to confirm
the absence of microorganisms.
Shanghai Jiao Tong University
6. Sterilization methods
6. Sterilization methods
Validation of sterility
Validation of sterility
Biological indicator
F0 value
Biologic indicator
A characterized preparation of specific
microorganisms resistant to a particular
sterilization process.
Added to the product or strips of filter paper
Shanghai Jiao Tong University
6. Sterilization methods
Validation of sterility
F0 =D121(logN0-logNt)
D121 is the time required for a one-log
reduction in the microbial population
exposed to a temperature of 121oC
N0 is the initial microbial population
Nt is the final microbial population after
sterilization
Shanghai Jiao Tong University
7. Quality assurance
Core meaning: To build the quality into the product
Especially significant for parenteral products, sterility,
absence of pyrogens, freedom from extraneous
particles
Testing of raw materials, packaging components, and
final product
Written operating procedures, personnel training, record
keeping, and facility design and monitoring
Shanghai Jiao Tong University
7. Quality assurance
Regulatory and Compendial Requirements
GMP: Good Manufacturing Practice
Organization and personnel
Buildings and facilities
Control of drug components, packaging, and
materials
Production and process control
Equipment
Packaging and labeling control
Holding and distribution
Laboratory control
Records and reports
Shanghai Jiao Tong University
7. Quality assurance
Product testing and evaluation
Sterility testing
Pyrogen testing
Leaker testing
Clarity testing and particulate analysis
Shanghai Jiao Tong University
7. Quality assurance
Monitoring Programs
Process facilities
Production areas
Personnel
Environmental monitoring
Shanghai Jiao Tong University
7. Quality assurance
Product testing and evaluation
Sterility testing
Direct method : culture tube
Indirect method: membrane
Labeling
Shanghai Jiao Tong University
7. Quality assurance
Product testing and evaluation
Pyrogen test
Rabbit test
Limulus amebocyte lysate (LAL) test
Shanghai Jiao Tong University
7. Quality assurance
Product testing and evaluation
Leaker testing
For sealed ampoules
under vacuum, dying method
ordinary pressure, high-frequency spark
test
Shanghai Jiao Tong University
Shanghai Jiao Tong University
7. Quality assurance
Product testing and evaluation
Clarity testing and particulate analysis
Clarity: the state of quality of being clear or
transparent to the eyes
Particulate matter: extraneous, mobile, undissolved
substances unintentionally present in parenteral
7. Quality assurance
Product testing and evaluation
Labeling
The drug substance
Concentration/dose,
Handling/storage condition
Any special precautions.
solutions
Shanghai Jiao Tong University
Learning objectives
Concepts: Parenteral, WFI, GMP, LVP, SMP,
pyrogen, Freeze-drying (lyophilization) ,
Sterilization
Routes of parenteral administration
Functions of the added substances
Calculation of tonicity adjustment
Parenteral dosage forms
Sterilization methods
