Introduction, scope, and history

of sterile products
Certain pharmaceutical agents, particularly peptides, proteins, and many chemotherapeutic agents, can
be administered only by injection (with or without a needle), because they are inactivated in the
gastrointestinal tract when given by mouth.

human insulin became the first biotechnology drug

Most biotechnology drug products are administered only by the parenteral route

Here is a definition of sterile dosage forms: A product introduced in a manner that circumvents the
body’s most protective barriers, the skin and mucous membranes, and, therefore, must be “essentially
free” of biological contamination.

Parenteral (the author prefers the term “sterile”) products must be exceptionally pure and free from
physical, chemical, and biological contaminants (microorganisms, endotoxins, particles).

As stated already, not all sterile dosage forms are administered by injection. Sterile products that are not
parenteral or injectable products include the following:
-Topical ophthalmic medications
-Topical wound healing medications
-Solutions for irrigation
-Sterile devices (e.g., syringes, administration sets, and implantable systems)
Sterile drug products are relatively unstable and are generally highly potent drugs

Action Level—An established microbial or airborne particle level that, when exceeded, should trigger
appropriate investigation and corrective action based on the investigation.
Air Lock—A small area with interlocked doors, constructed to maintain air pressure control between adjoining
rooms. Used to stage and disinfect large equipment prior to transfer from lesser-controlled room to
higher-controlled room.
Alert Level—An established microbial or airborne particle level giving early warning of potential drift from
normal operating conditions, and which triggers appropriate scrutiny and follow-up to address the potential
problem. Alert levels are always lower than action levels.
Ampule—A final container that is totally glass in which the open end after filling a product is sealed by heat. Also
referred as ampul, ampoule, carpule (French).
Antimicrobial Preservative—Solutes such as phenol, meta-cresol, benzyl alcohol, and the parabens that
prevent the growth of microorganisms. Must be present in multiple dose parenterals.
Antioxidants—Solutes that minimize or prevent drug oxidation. Examples include sodium bisulfite, ascorbic
acid, and butylated hydroxyanisole.
Aseptic—Lack of disease-producing microorganisms. Not the same as sterile.
Aseptic Processing—Manufacturing drug products without terminal sterilization. The drug product is sterile
filtered, then aseptically filled into the final package and aseptically sealed.
Autoclave—A system that sterilizes by superheating steam under pressure. The boiling point of water, when
pressure is raised 15 psig above atmospheric pressure, is increased to 121 ◦ C (250◦ F). This is the most
common means of terminally sterilizing parenteral products.
Barrier—A system having a physical partition between the sterile area (ISO 5) and the nonsterile surrounding
area. A barrier is differentiated from an isolator in that the barrier can exchange air from the fill zone to the
surrounding sanitized area where personnel are located, whereas an isolator cannot exchange air from the fill
zone to the sterilized surrounding area where personnel are located.
Bioburden—Total number of microorganisms detected in or on an article prior to a sterilization treatment. Also
called microbial load.
Biological Indicator—A population of microorganisms inoculated onto a suitable medium (e.g., solution,
container, closure, paper strip) and placed within an appropriate sterilizer load location to determine the
sterilization cycle efficacy of a physical or chemical process. The specific microorganisms are the most
resistant to the particular sterilization process.
Bubble Point—Used in filter integrity testing; the pressure where a gas will pass through a wetted membrane
filter. Each filter porosity and type has a given bubble point.
Buffers—Solutes used to minimize changes in pH, important for many drugs to maintain stability and/or
solubility.
Chelating Agents—Solutes that complex metal ions in solution, preventing such metals from forming insoluble
complexes or catalyzing oxidation reactions. Example: ethylenediaminetetraacetic acid (EDTA)
Class X—A Federal Standard for clean room classes. Whatever X is, for example, 100, means that there are no
more than X particles per cubic foot ≥ 0.5 m.
Clean Room—A room designed, maintained, and controlled to prevent particle and microbiological
contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air
cleanliness classification.
Colony Forming Unit (CFU)—A microbiological term that describes the formation of a single macroscopic
colony after the introduction of one or more microorganisms to microbiological growth media.
Coring—The gouging out of a piece of rubber material caused by improper usage of a needle penetrating a
rubber closure.
Critical Area—An area designed to maintain sterility of sterile materials.
Critical Surfaces—Surfaces that may come into contact with or directly affect a sterilized product or its
containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation,
and sterility is maintained throughout processing.
D-Value—Time in minutes (or dose for radiation sterilization) of exposure at a given temperature that causes a
one-log or 90% reduction in the population of specific microorganisms.
Disinfection—Process by which surface bioburden is reduced to a safe level or eliminated. Some disinfection
agents are effective only against vegetative microorganisms.
Endotoxin—Extracellular pyrogenic compounds.
HEPA—High Efficiency Particulate Air filters, capable of removing 99.97% of all particles 0.3 and higher.
(continued)
4 STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY
Table 1-1 Glossary of Terms Related to Parenteral Drug Technology (Continued)
Isolator—A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality that provides
uncompromised, continuous isolation of its interior from the external environment. Isolators can be closed or
open.
Closed—exclude external contamination from the isolator’s interior by accomplishing material transfer
via aseptic connection to auxiliary equipment, rather than by use of openings to the surrounding
environment.
Open—allow for continuous or semicontinuous ingress and/or egress of materials during operations through
one or more openings. Openings are engineered, using continuous overpressure, to exclude the entry of
external contamination into the isolator.
Laminar Flow—An airflow moving in a single direction and in parallel layers at constant velocity from the
beginning to the end of a straight line vector.
Lyophilization—The removal of water or other solvent from a frozen solution through a process of sublimation
(solid conversion to a vapor) caused by combination of temperature and pressure differentials. Also called
freeze-drying.
Media Fill—Microbiological evaluation of an aseptic process by the use of growth media processed in a manner
similar to the processing of the product and with the same container/closure system being used.
Micron ()—One millionth of a meter. Also referred to as micrometer (m).
Needle Gauge—Either the internal (ID) or external (OD) diameter of a needle. The larger the gauge the smaller
the diameters. For example, a 21-G needle has an ID of 510 and an OD of 800 . A 24-G needle has an ID
of 300 and an OD of 550 . An 18-G needle has an ID of 840 and OD of 1,250 .
Nominal Rating—The size of particles, which are retained at certain percentages. A 0.2 nominal membrane
filter indicates that a certain percentage of particles 0.2 and higher are retained on the filter.
Overkill Sterilization Process—A process that is sufficient to provide at least a 12-log reduction of a microbial
population having a minimum D-value of 1 minute.
Parenteral—Literally, to avoid the gastrointestinal tract. Practically, the administration of a drug product that is
not given by mouth, skin, nose, or rectal/vaginal. Parenteral conveys the requirement for freedom from
microbiological contamination (sterile), freedom from pyrogens, and freedom from foreign particulate matter.
Pyrogen—Fever producing substances originating from microbial growth and death.
Reverse Osmosis—A process used to produce water for injection whereby pressure is used to force water
through a semipermeable membrane where the solute content (ions, microbes, foreign matter) of the solution
is retained on the filter while the solvent (pure water) passes through.
Sterile—The complete lack of living (viable) microbial life.
Sterility—An acceptably high level of probability that a product processed in an aseptic system does not contain
viable microorganisms.
Sterility Assurance Level—The probability of microbial contamination. A SAL of 10-6 means that there is a
probability of one in one million that an article is contaminated. Also called probability of nonsterility or sterility
confidence level.
Surface Active Agents—Solutes that locate at the surface of water and air, water and oil, and/or water and
solid to reduce the interfacial tension at the surface and enable substances to come together in a stable way.
Examples include polysorbate 80 and sodium lauryl sulfate.
Terminal Sterilization—A process used to produce sterility in a final product contained in its final packaging
system.
Tonicity Agents—Solutes used to render a solution isotonic, meaning similar in osmotic pressure to the osmotic
pressure of biological cells. Sodium chloride and mannitol are examples of tonicity agents.
ULPA—Ultra-Low Penetration Air filter with minimum 0.3 m particle retaining efficiency of 99.999%.
Validation—The scientific study of a process to prove that the process is doing what it is supposed to do and
that the process is under control. Establishing documented evidence that provides a high degree of assurance
that a specific process will consistently produce a product meeting its predetermined specifications and quality
attributes.
Worst Case—A set of conditions encompassing upper and lower processing limits and circumstances, including
those within standard operating procedures that pose the greatest chance of process or product failure

fever reactions after injections were microbial in origin. these microbial derivatives were nonliving,
nonproteinaceous, and could not be eliminated by sterilization methods.

2 Characteristics of sterile dosage forms

SEVEN PRIMARY CHARACTERISTICS OF STERILE DOSAGE FORMS
Table 2-1 Seven Basic Characteristics of Sterile Product Dosage Forms
1. Safety (freedom from adverse toxicological concerns)
2. Sterility (freedom from microbiological contamination)
3. Nonpyrogenic (freedom from pyrogenic—endotoxin—contamination)
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)

Pyrogens are fever-producing entities originating from a variety of sources, primarily microbial.
Because of the advent of the in-vitro test, Limulus Amebocyte Lysate (LAL), for the quantitative
detection of the most ubiquitous type of pyrogen called bacterial endotoxins, all marketed
injectable products must meet requirements for pyrogen (or endotoxin) limits.
Freedom from Pyrogenic Contamination, Depyrogenation methods include cleaning validation,
time limitations, validated depyrogenation cycles for glassware, validation of pyrogen/endotoxin
removal from rubber closures and other items that depend on rinsing techniques, validated
water systems, and use of endotoxinfree raw materials.
Freedom from Visible Particulate Matter Both ready-to-use solutions and reconstituted solutions are
to be free from any evidence of visible particulate matter and must meet compendial specifications for
numbers of subvisible particles no greater than certain sizes, those particle sizes being
for most compendia no greater or equal to 10 micro m and no greater or equal to 25micro m.

Stability, sterile dosage forms, product stability encompasses not only chemical and physical properties,
but also includes microbiological stability

Compatibility, For example, 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. What all this means is that the sterile
product must be shown to be compatible with diluents for reconstitution and diluents for infusion.
Furthermore, many infusions contain more than one drug, so obviously the two or more drugs in the
infusion system must be compatible.

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, that is, the solution is
hypotonic, the solvent from the injection will move across the cell membranes and could cause these cells
to burst. If the cells are red blood cells, this bursting effect is called hemolysis. Conversely, if the
formulation injected has an osmotic pressure greater than that of biological cells, that is, the solution is
hypertonic, the solvent or water from the cell interior will move outside the cell membranes and could
cause these cells to shrink, for example, crenation.

NOMENCLATURE AND DEFINITIONS

There are five general types of parenteral preparations listed in the USP:
[Drug] Injection: Liquid preparations that are drug substances or solutions thereof.
[Drug] for Injection: Dry solids that, upon the addition of suitable vehicles, yield solutions
conforming in all respects to the requirements of injections.
[Drug] Injectable Emulsion: Liquid preparations of drug substances dissolved or dispersed
in a suitable emulsion medium.
[Drug] Injectable Suspension: Liquid preparations of solids suspended in a suitable liquid
medium.
[Drug] for Injectable Suspension: Dry solids that, upon the addition of suitable vehicles,
yield preparations conforming in all respects to the requirements of Injectable Suspensions.

Definitions included in the USP are as follows:

Pharmacy Bulk Package: A pharmacy bulk package is a single product containing a sterile
drug injection, sterile drug for injection, or sterile drug injectable emulsion (i.e., suspensions
cannot be contained in pharmacy bulk packages. A pharmacy bulk package contains many
single doses of the active ingredient to be used for the preparation of admixtures for infusion, or, using a
sterile transfer device, for filling empty sterile syringes. The closure of the
bulk package shall be penetrated only once with a sterile device that will allow measured
dispensing of the contents.
Large- and Small-Volume Injections: The demarcation of volume differentiating a smallfrom large-
volume injection is 100 mL. Any product 100 mL or less is a small-volume
injection. The main purpose for differentiating large- from small-volume injections is the
method of sterilization. With perhaps a single exception for blood products, all large-volume
injections must be terminally sterilized while most small-volume injections are not terminally
sterilized.