| (ii) The primary engineering control device shall be
certified and maintain ISO Class 5 for exposure of critical sites
and shall be located in a segregated compounding area restricted to
sterile compounding activities that minimizes the risk of contamination
of the compounded sterile preparation;
(iii) The segregated compounding area shall not be
in a location that has unsealed windows or doors that connect to the
outdoors or high traffic flow, or that is adjacent to construction
sites, warehouses, or food preparation.
(iv) For a low-risk level preparation compounded as
described in clauses (i) - (iii) of this subparagraph, administration
of such compounded sterile preparations must commence within 12 hours
of preparation or as recommended in the manufacturers' package insert,
whichever is less. However, the administration of sterile radiopharmaceuticals,
with documented testing of chemical stability, may be administered
beyond 12 hours of preparation.
(C) Medium-risk level compounded sterile preparations.
(i) Medium-Risk Conditions. Medium-risk level compounded
sterile preparations, are those compounded aseptically under low-risk
conditions and one or more of the following conditions exists:
(I) Multiple individual or small doses of sterile products
are combined or pooled to prepare a compounded sterile preparation
that will be administered either to multiple patients or to one patient
on multiple occasions;
(II) The compounding process includes complex aseptic
manipulations other than the single-volume transfer;
(III) The compounding process requires unusually long
duration, such as that required to complete the dissolution or homogenous
mixing (e.g., reconstitution of intravenous immunoglobulin or other
intravenous protein products);
(IV) The compounded sterile preparations do not contain
broad spectrum bacteriostatic substances and they are administered
over several days (e.g., an externally worn infusion device); or
(V) For a medium-risk level preparation, in the absence
of passing a sterility test the storage periods cannot exceed the
following time periods: before administration, the compounded sterile
preparations are properly stored and are exposed for not more than
30 hours at controlled room temperature, for not more than 9 days
at a cold temperature, and for 45 days in solid frozen state between
minus 25 degrees Celsius and minus 10 degrees Celsius.
(ii) Examples of medium-risk compounding. Examples
of medium-risk compounding include the following:
(I) Compounding of total parenteral nutrition fluids
using a manual or automated device during which there are multiple
injections, detachments, and attachments of nutrient source products
to the device or machine to deliver all nutritional components to
a final sterile container;
(II) Filling of reservoirs of injection and infusion
devices with more than three sterile drug products and evacuations
of air from those reservoirs before the filled device is dispensed;
(III) Filling of reservoirs of injection and infusion
devices with volumes of sterile drug solutions that will be administered
over several days at ambient temperatures between 25 and 40 degrees
Celsius (77 and 104 degrees Fahrenheit); and
(IV) Transfer of volumes from multiple ampules or vials
into a single, final sterile container or product.
(D) High-risk level compounded sterile preparations.
(i) High-risk Conditions. High-risk level compounded
sterile preparations are those compounded under any of the following
conditions:
(I) Non-sterile ingredients, including manufactured
products not intended for sterile routes of administration (e.g.,
oral) are incorporated or a non-sterile device is employed before
terminal sterilization.
(II) Any of the following are exposed to air quality
worse than ISO Class 5 for more than 1 hour:
(-a-) sterile contents of commercially manufactured
products;
(-b-) CSPs that lack effective antimicrobial preservatives;
and
(-c-) sterile surfaces of devices and containers for
the preparation, transfer, sterilization, and packaging of CSPs;
(III) Compounding personnel are improperly garbed and
gloved;
(IV) Non-sterile water-containing preparations are
exposed no more than 6 hours before being sterilized;
(V) It is assumed, and not verified by examination
of labeling and documentation from suppliers or by direct determination,
that the chemical purity and content strength of ingredients meet
their original or compendial specifications in unopened or in opened
packages of bulk ingredients;
(VI) For a sterilized high-risk level preparation,
in the absence of passing a sterility test, the storage periods cannot
exceed the following time periods: before administration, the compounded
sterile preparations are properly stored and are exposed for not more
than 24 hours at controlled room temperature, for not more than 3
days at a cold temperature, and for 45 days in solid frozen state
between minus 25 degrees Celsius and minus 10 degrees Celsius; or
(VII) All non-sterile measuring, mixing, and purifying
devices are rinsed thoroughly with pyrogen-free or depyrogenated sterile
water, and then thoroughly drained or dried immediately before use
for high-risk compounding. All high-risk compounded sterile solutions
subjected to terminal sterilization are prefiltered by passing through
a filter with a nominal pore size not larger than 1.2 micron preceding
or during filling into their final containers to remove particulate
matter. Sterilization of high-risk level compounded sterile preparations
by filtration shall be performed with a sterile 0.2 micrometer or
0.22 micrometer nominal pore size filter entirely within an ISO Class
5 or superior air quality environment.
(ii) Examples of high-risk compounding. Examples of
high-risk compounding include the following.
(I) Dissolving non-sterile bulk drug powders to make
solutions, which will be terminally sterilized;
(II) Exposing the sterile ingredients and components
used to prepare and package compounded sterile preparations to room
air quality worse than ISO Class 5 for more than one hour;
(III) Measuring and mixing sterile ingredients in non-sterile
devices before sterilization is performed; and
(IV) Assuming, without appropriate evidence or direct
determination, that packages of bulk ingredients contain at least
95% by weight of their active chemical moiety and have not been contaminated
or adulterated between uses.
(3) Immediate Use Compounded Sterile Preparations.
For the purpose of emergency or immediate patient care, such situations
may include cardiopulmonary resuscitation, emergency room treatment,
preparation of diagnostic agents, or critical therapy where the preparation
of the compounded sterile preparation under low-risk level conditions
would subject the patient to additional risk due to delays in therapy.
Compounded sterile preparations are exempted from the requirements
described in this paragraph for low-risk level compounded sterile
preparations when all of the following criteria are met:
(A) Only simple aseptic measuring and transfer manipulations
are performed with not more than three sterile non-hazardous commercial
drug and diagnostic radiopharmaceutical drug products, including an
infusion or diluent solution, from the manufacturers' original containers
and not more than two entries into any one container or package of
sterile infusion solution or administration container/device;
(B) Unless required for the preparation, the compounding
procedure occurs continuously without delays or interruptions and
does not exceed 1 hour;
(C) During preparation, aseptic technique is followed
and, if not immediately administered, the finished compounded sterile
preparation is under continuous supervision to minimize the potential
for contact with nonsterile surfaces, introduction of particulate
matter of biological fluids, mix-ups with other compounded sterile
preparations, and direct contact with outside surfaces;
(D) Administration begins not later than one hour following
the completion of preparing the compounded sterile preparation;
(E) When the compounded sterile preparations is not
administered by the person who prepared it, or its administration
is not witnessed by the person who prepared it, the compounded sterile
preparation shall bear a label listing patient identification information
such as name and identification number(s), the names and amounts of
all ingredients, the name or initials of the person who prepared the
compounded sterile preparation, and the exact 1-hour beyond-use time
and date;
(F) If administration has not begun within one hour
following the completion of preparing the compounded sterile preparation,
the compounded sterile preparation is promptly and safely discarded.
Immediate use compounded sterile preparations shall not be stored
for later use; and
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