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Sterile & Parenteral
Preparations
Overview of Sterile Preparation
Formulation
Introduction
 The objective of formulating and compounding sterile
preparations is to provide a dosage form of a labeled
drug, in the stated potency, that is safe to use.
 This section will explore the professional standards and
operating procedures that should be followed during
formulation and compounding.
 The components, containers, and closures also are
described, as well as the physiological and physical norms
of preparing formulations for parenteral and ophthalmic
use.
 Stability, incompatibility of drugs, sterilization methods,
labeling, documentation, and end preparation evaluation.
Sterile dosage forms include parenteral/injectable dosage
forms as well as other sterile products such as topical
ophthalmic products, irrigating solutions, wound-healing
products, and devices.
Ideally, a sterile dosage form is absolutely free of any form
of biological contamination, and, of course, is the final goal
of every single unit of sterile product released to the
marketplace, either commercial or clinical.
Parenteral (the author prefers the term “sterile”) products
must be exceptionally pure and free from physical,
chemical, and biological contaminants (microorganisms,
endotoxins, particles).
 Seven Basic Characteristics
Product Dosage Forms
of
Sterile
1. Safety (freedom from adverse toxicological concerns)
2. Sterility
(freedom
from
microbiological
contamination)
3. Nonpyrogenic (freedom from pyrogenic-endotoxincontamination)
4. Particle-free (freedom from visible particle
contamination)
5. Stability (chemical, physical, microbiological)
6. Compatibility (formulation, package, other diluents)
7. Tonicity (isotonic with biological fluids)
 SEVEN PRIMARY CHARACTERISTICS OF
STERILE DOSAGE FORMS:
1- Safety
 Any component of an injectable product must be proven
safe at the quantitative level.
 The safety considerations when selecting additives to
combine with the active ingredient to overcome one or
more problems related to drug solubility, stability, tonicity,
and controlled or sustained delivery.
 with a nonsterile dosage form, a excess of choice with respect to
additives safe to use for administration other than by injection.
 with sterile dosage forms, the requirement for safety prohibits the
use of many additives that could be effective
 The parenteral products pass the routine sterility test,
pyrogen and/or endotoxin test, as well as the chemical
analyses, and still cause unfavorable reactions when
injected.
 A safety test in animals is essential, particularly for
biological products.
 The FDA has published guidance for safety evaluation of
pharmaceutical ingredients that is periodically updated
2- Sterility
 The sterility is what defines/differentiates a sterile product.
The characteristic of sterility is achieved via:o valid sterilization procedures for all components during
manufacturing of the product,
o design and maintenance of clean rooms meeting all
requirements for preparing sterile products,
o validation of aseptic processes, training and application of
good aseptic practices,
o use of antimicrobial preservatives for multiple-dose.
o valid testing for sterility of the product and maintenance of
container/closure integrity.
3- Freedom from Pyrogenic Contamination
1. Pyrogens are fever-producing entities originating from a
variety of sources, primarily microbial.
2. In sufficient amounts following injections, pyrogens can
cause a variety of complications in the human body.
3. The pyrogen called bacterial endotoxins, all marketed
injectable products must meet requirements for pyrogen (or
endotoxin) limits.
4. To achieve freedom from pyrogenic contamination, like
achieving and maintaining product sterility,
1. Depyrogenation methods include:o cleaning
validation,
time
limitations,
validated
depyrogenation cycles for glassware, validated water
systems
o validation of pyrogen/endotoxin removal from rubber
closures and other items that depend on rinsing
techniques, and use of endotoxin free raw materials.
4. Freedom from Visible Particulate Matter
 The visible particulate matter involves product quality and
perhaps safety.
 The solutions and reconstituted solutions are to be free from any
evidence of visible particulate matter.
 Several factors contribute to the presence or absence of foreign
particulate matter.
valid cleaning methods of all equipment and packaging
materials,
valid solution filtration procedures,
adequate control of production and testing environments,
adequate training of personnel in manufacturing,
testing and using sterile product solutions.
5. Stability
All dosage forms have stability requirements.
 All dosage forms are required to be stable under
predetermined manufacturing, packaging, storage, and
usage conditions.
 Achieving and maintaining chemical and physical stability
starts with the active ingredient and how it is stored,
shipped, and handled.
 Stability challenges continue with the compounding,
mixing, filtration, filling, stoppering, and sealing of the
product.
 Many injectable drugs are so unstable in solution that they
must exist in the solid state so lyophilization processes.
 Maintaining stability in the final container/closure system,
while being stored, shipped, and worked prior to being
administered to people or animals.
 Sterile dosage forms also have one extra requirement
related to stability and that is maintaining sterility as a
function of stability.
 So, with sterile dosage forms, product stability includes
not only chemical and physical properties, but also
includes microbiological stability throughout the shelf-life
and usage of the product.
6. Compatibility
 Freeze-dried products are released by the manufacturer, but must
be manipulated by the user and/or health care professional prior
to administration.
 The product must be reconstituted by sterile dilution, withdrawn
into a syringe, and, often, then combined with another solution,
perhaps a large volume infusion fluid, for administration.
 The sterile product must be shown to be compatible with
diluents for reconstitution and diluents for infusion.
 Many infusions contain more than one drug, so obviously the
two or more drugs in the infusion system must be compatible.
 7. Isotonicity
 Osmotic pressure is a characteristic of semipermeable cell
membranes where osmotic pressure is the pressure where no
water migrates across the membrane.
 Osmosis is the phenomenon where solutes will diffuse from
regions of high concentration to regions of low concentration.
 So, if a formulation is injected that has an osmotic pressure less
than that of biological cells (hypotonic), the solvent will move
across the cell membranes and could cause these cells to rupture.
 Conversely, if the formulation injected has an osmotic pressure
greater than that of biological cells (hypertonic), the solvent will
move outside the cell membranes and cause these cells to shrink.
 Ideally, any injected formulation should be isotonic with
biological cells to avoid these potential problems of cells
bursting or shrinking.
o It is well known that 0.9% sodium chloride solution and
5% dextrose solution are isotonic with biological cells.
o Why the difference in isotonic concentrations between
these two common large-volume solutions?
• Dextrose is a nonelectrolyte that in solution exists as a single
entity; therefore, the osmotic pressure of a nonelectrolyte
solution is proportional to the concentration of the solute.
• Sodium chloride is an electrolyte in solution that dissociates into
two ionic species. Thus, the osmotic pressure dissociating into
two species would be at least twice that of a solution containing a
nonelectrolyte.