Transcript INDUSTRIAL PREPARATION OF PARENTERAL PRODUCTS

INDUSTRIAL PREPARATION
OF PARENTERAL PRODUCTS
INJECTIONS
• Injections are sterile, pyrogen-free solutions or dispersions
(emulsions or suspensions) of one or more active
ingredients in a suitable vehicle.
• Whenever possible, an injection should be prepared using
an aqueous vehicle. If necessary, suitable non-aqueous
solvents are indicated in the individual monographs.
Injections that are dispersions should remain sufficiently
stable so that, after shaking, a homogeneous dose can be
withdrawn.
• The use of single-dose injections is to be preferred and is
essential when the preparation is intended for administration
by routes where, for medical reasons, an antimicrobial
preservative is not acceptable, e.g. intracisternal, intrathecal
• Single-dose preparations
• Single-dose preparations should contain a sufficient quantity of the
injection readily to permit the withdrawal and administration of the
volume specified on the label.
• Multidose preparations
• Multidose preparations should contain a suitable antimicrobial
preservative in appropriate concentrations, except in cases where the
preparations themselves have adequate antimicrobial properties. The
containers should be equipped to ensure adequate protection of the
contents after partial withdrawal. In order to minimize the risk of
contamination resulting from multiple penetrations of the closure,
the contents of a multidose preparation should normally not exceed
30 ml.
Preparation of Parenteral Solutions
• 1-Aqueous parenteral solutions:
• The main steps in the manufacture of aqueous parenteral solutions are as
follows:
• ■The formulation components (including the therapeutic agent) are
dissolved in water for injection in the main mixing vessel within the
manufacturing area.
• ■If the active ingredient is thermostable, the formulation is filled into the
final containers and sealed. Sterilisation is then performed using moist-heat
sterilisation. Unless the preparation is a multidose product, the inclusion of
a preservative is unnecessary.
• ■If the active ingredient is thermolabile, the product is sterilised using
filtration and collected into a second mixing vessel, from which filling into
the final container is performed. In some cases it may be possible to fill the
product into the final container immediately after filtration, obviating the
need for a second mixing vessel. In this case preservatives are normally
included.
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• 2- Oil-based parenteral solutions:
• Moist-heat sterilisation cannot be used to sterilise oil-based solutions and
therefore the manufacturing procedure must accommodate this limitation.
The main steps involved in the manufacture of oil-based parenteral
solutions are as follows:
• ■ Sterilisation of the oil-based vehicle (containing the various soluble
excipients) within the mixing vessel in the aseptic manufacturing area
(performed using dry-heat sterilisation). If the therapeutic agent is stable
under the conditions of dry-heat sterilisation, the drug may be incorporated
(dissolved) at this stage. This product is then ready for filling into the final
container (which is then sealed). Alternatively the product may be
manufactured and terminally sterilised using dry-heat sterilisation.
• ■If the therapeutic agent is not stable under the above sterilisation
conditions, sterile drug should be dissolved sterile oil-based vehicle using
normal mixing facilities. This product is then ready for filling into the final
container, which is subsequently sealed.
PREPARATION OF PARENTERAL
SUSPENSION
• 1- Aqueous parenteral suspensions:
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As suspensions contain drug that has been dispersed in the chosen vehicle, filtration
cannot be performed to render the product sterile. Therefore, sterile drug must be
added to the chosen vehicle and suitably dispersed under aseptic conditions.
Typically, the main steps in the manufacture of aqueous parenteral suspensions are:
■dissolution of the formulation excipients in an aqueous (or hydroalcoholic)
vehicle within the main vessel
■sterilisation of the vehicle by filtration and collection into a second vehicle, under
aseptic conditions
■dispersal of the (sterile) therapeutic agent into the sterile vehicle. If required the
particle size of the disperse phase may be reduced by, for example, passage through
a ball mill(whose contents and packing material are both sterile)
■the formulation may then be filled into the final container, followed by sealing
■drug suspensions are often physically unstable if exposed to moist-heat
sterilisation; however, if the suspension is stable under these conditions, then the
formulation may be manufactured and filled into the final container, followed by
terminal sterilisation
• 2- oil-based parenteral suspensions
• The manufacture of oil-based suspensions combines the
manufacturing considerations of both oil-based solutions and
aqueous suspensions and includes:
• ■sterilisation of the oil-based vehicle (containing the various
soluble excipients) within the mixing vessel in the aseptic
manufacturing suite (performed using dry-heat sterilisation)
• ■mixing of the sterile therapeutic agent into the sterile vehicle,
prior to filling into and sealing the final container
• ■if the formulation can physically and chemically withstand
the conditions for dry-heat sterilisation, the product may be
manufactured and filled in the final container. This may then
be sterilised using dry heat.
• Advantages of Parental suspension:
• 1- It is better for the therapeutic use of drugs that
are insoluble in conventional solvents.
• 2- In this dosage from there is increased
resistance to hydrolysis & oxidation as drug is
present in the solid from.
• 3- Formulation of controlled released drug is
possible in this dosage form.
• 4- There is elimination of hepatic first pass effect
• Disadvantages of Parental suspension:
• 1- Difficulty in formulation: Parenteral suspensions limit the formulator
in selecting the ingredients, which are parenterally acceptable as
suspending agent, viscosity inducing agent, wetting agent, stabilizers
and preservative.
• 2- Difficulty in manufacturing: Special facilities are required to
maintain aseptic condition for manufacturing processes such as :
crystallization, particle size reduction, wetting, sterilization.
• 3- The stabilization of suspensions for the period between manufacture
& use present a number of problems. e.g. solids gradually settle & may
cake, causing difficulty in redispersion prior to use.
• 4- Maintenance of physical stability is very difficult in this dosage
form.
• 5- There may be chances of non‐uniformity of dose at the time of
administration.
• Parenteral suspensions are developed due to
following reasons:
• 1-The drugs, which are insoluble and are
difficult to be formulated as a solution.
• 2- For the drug which are more stable when
suspended than in solution form.
• 3- When there is a need to develop dosage
forms having retarded or controlled release of
drug.
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Ideal characteristics of parental suspension:
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1- The suspensions are manufactured and tested for microbial contamination. So as
to maintain its sterility during its storage & use.
2- It should be easily drawn into a syringe (Syringeability) and readily ejected from
the syringe (Injectability). The syringeability & injectability of a suspension are
closely related to viscosity & particle characteristics.
3- Particle size should be small & uniform.
4- Re‐ suspension of drug particles should occur easily with mild shaking.
5- The dispersed particles do not settle rapidly after shaking.
6- Re‐suspension should result in homogeneous mixing of drug particles in such a
manner that same concentration of drug can be removed repeatedly.
7- Cake formation shouldn’t occur during its shelf life.
8- The suspensions should maintain its stability and elegance during its shelf life.
9- It should be isotonic & non‐irritating.
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• Typical excipients used in
suspensions include following
• 1. Flocculating \ suspending agents.
• 2. Wetting agents.
• 3. Solvent systems
• 4. Preservatives
• 5. Antioxidants
• 6. Cheating agents
• 7. Buffering agents
• 8. Tonicity agents
parenteral
PREPARATION OF PARENTERAL
DRY POWDER
• Powder for injections are sterile solid substances
(including freeze dried material) which are distributed
in their final containers which, when shaken with the
prescribed volume of the appropriate sterile liquid,
rapidly form clear and practically particle-free
solutions
or
uniform
suspension.
PACKAGING AND LABELING
• Injections are filled either in:
• 1- Single dose containers: is a hermetic container
holding a quantity of sterile drug intended for
parenteral administration as a single dose, and
which when opened cannot be re-sealed with
assurance that stability has been maintained.
• 2-Multiple dose containers: A multiple dose
container that permits withdrawal of successive
portions of the contents without changing the
strength, quality, or purity of the remaining
portion.
• The Labels on containers of injections must state:
• 1- The name of the drug product;
• 2- A list of the active ingredients (if applicable, with the International
• Nonproprietary Names (INNs), showing the amount of each present, and a
statement of the net contents, e.g. number of dosage units, mass or volume;
• 3-The batch number assigned by the manufacturer;
• 4- The expiry date in an uncoded form;
• 5- Any special storage conditions or handling precautions that may be
necessary;
• 6- The directions for use, and any warnings and precautions that may
• be necessary;
• 7- The name and address of the manufacturer or the company or
• person responsible for placing the product on the market.
Finished product quality control test
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Leaker test
Pyrogen test
Particulate test
Sterility test.
Uniformity of weight.
Uniformity of content
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Leak test
• To detect incompletely sealed ampoules.
Principle
10% methylene blue or 0.1% FDC red one or red two.
Generally combined with autoclave.
• Disadvantage
• Leakage of 15 micron in diameter or smaller is not
detected.
• Vial and bottles are not subjected to this test.
LAL test
Limulus Amoebocyte Lysate test or bacterial Endotoxin test for the
validation of depyrogenation process.
• Reagent - LAL reagent (limulus Polyphemus)
• Reaction - In presence of Endotoxin a firm gel is formed within 60 min
when incubated at 370 C.
• o CHARACTERISTIC
• • Test tube scale.
• • Only pyrogen of gram negative bacteria detected.
• • Semi quantitative test.
• • Sensitivity in terms of Endotoxin unit.
• • In-vitro test.
• • Doesn‟t measure fever producing potential of Endotoxin.
• • Sensitivity varies with different microbial source of LAL.
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Pyrogen test- Fever response of rabbit
Sham test is performed to select the proper animals for the main tests.
Rabbit test - Qualitative fever response test.
Procedure
• Test solution is injected into the vein of rabbit. Temperature elevation is
seen for 3 hrs.
• Disadvantage
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Biological variation
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Expensive
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Laborious
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Dose dependent.
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Not for anti pyretic drug.
• Particulate test USP
• Visually inspected- all (WHITE AND BLACK )
• Any with visible particle is discarded.
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Large volume parenteral
50 particles of 10μm
5 particulates of 25 μm per ml
Particulate count is done by:
1. Light obscuration particle count test
2. Microscopic particle count test