20 CSR 2220-2.200 - Sterile Compounding
PUBLISHER'S NOTE: The secretary of state has determined that publication of the entire text of the material that is incorporated by reference as a portion of this rule would be unduly cumbersome or expensive. This material as incorporated by reference in this rule shall be maintained by the agency at its headquarters and shall be made available to the public for inspection and copying at no more than the actual cost of reproduction. This note applies only to the reference material. The entire text of the rule is printed here.
(1) Definitions.
(A) Aseptic processing: The technique
involving procedures designed to preclude contamination of drugs, packaging,
equipment, or supplies by microorganisms during processing.
(B) Batch: Compounding of multiple sterile
preparation units in a single discrete process, by the same individuals,
carried out during one (1) limited time period.
(C) Beyond-Use date: A date after which a
compounded preparation should not be used and is determined from the date the
preparation is compounded. Because compounded preparations are intended for
administration immediately or following short-term storage, their beyond-use
dates must be assigned based on criteria different from those applied to
assigning expiration dates to manufactured drug products.
(D) Biological safety cabinet: Containment
unit suitable for the preparation of low to moderate risk agents where there is
a need for protection of the preparation, personnel, and environment, according
to National Sanitation Foundation (NSF) International standards.
(E) Buffer area: An ISO Class 7 or better
area where the primary engineering control is physically located that is
constructed and used in a manner to minimize the introduction, generation, and
retention of particles inside the room and in which other relevant variables
(e.g., temperature, humidity, and pressure) are controlled as
necessary.
(F) Compounding: For the
purposes of this regulation, compounding is defined as in
20 CSR
2220-2.400(1). Compounded sterile
medications may include, but are not limited to:
1. Compounded biologics, diagnostics, drugs,
nutrients, and radiopharmaceuticals that must or are required to be sterile
when they are administered to patients, including, but not limited to, the
following dosage forms: bronchial and inhaled nasal preparations intended for
deposition in the lung(s), baths and soaks for live organs and tissues,
epidural and intrathecal solutions, bladder/wound solutions, injectables,
implantable devices and dosage forms, inhalation solutions, intravenous
solutions, irrigation solutions, ophthalmic preparations, parenteral nutrition
solutions, and repackaged sterile preparations. Nasal sprays and irrigations
intended for deposit in the nasal passages may be prepared as nonsterile
compounds;
2. An FDA approved
manufactured sterile product that is either prepared according to the
manufacturers' approved labeling/recommendations or prepared differently than
published in such labeling; and
3.
Assembling point-of-care assembled systems.
(G) Compounding aseptic containment isolator
(CACI): A restricted access barrier system (RABS) that is designed for
compounding sterile hazardous drugs and designed to provide worker protection
from exposure to undesirable levels of airborne drugs throughout the
compounding and material transfer processes and to provide an aseptic
environment for Compounded Sterile Preparation (CSPs).
(H) Compounding aseptic isolator (CAI): A
RABS specifically designed for compounding sterile non-hazardous pharmaceutical
ingredients or CSPs and designed to maintain an aseptic compounding environment
within the isolator throughout the compounding and material transfer
processes.
(I) Controlled area: For
purposes of these regulations, a controlled area is a separate room designated
for preparing sterile preparations or an area designated for preparing sterile
preparations that is separated from other activities/operations by a line of
demarcation that clearly separates the area from other operations.
(J) Critical area: Any area in the controlled
area where preparations or containers are exposed to the environment.
(K) Critical site: Any surface, pathway, or
opening (e.g., vial septa, injection ports, beakers, needle hubs) that provides
a direct pathway between a compounded sterile preparation or other ingredient
used to compound a sterile preparation and the air, environment or moisture, or
that poses a risk of touch contamination.
(L) CSP: Compounded sterile
preparation.
(M) Cytotoxic drugs: A
pharmaceutical product that has the capability of direct toxic action on living
tissue that can result in severe leukopenia and thrombocytopenia, depression of
the immune system, and the alteration of a host's inflammatory response
system.
(N) Emergency dispensing: Is
a situation where a Risk Level 3 preparation is necessary for immediate
administration of the preparation and no alternative product or preparation is
available and the prescriber is informed that the preparation is being
dispensed prior to appropriate testing. Documentation of the dispensing of the
preparation, the prescriber's approval for dispensing prior to the receipt of
test results and the need for the emergency must appear within the prescription
record. A separate authorization from the prescriber is required for each
emergency dispensing.
(O)
High-Efficiency Particulate Air (HEPA) filter: A filter composed of pleats of
filter medium separated by rigid sheets of corrugated paper or aluminum foil
that direct the flow of air forced through the filter in a uniform parallel
flow. HEPA filters remove ninety-nine point ninety-seven percent (99.97%) of
all particles three-tenths (0.3) microns or larger. When HEPA filters are used
as a component of a horizontal- or vertical-laminar-airflow workbench, an
environment can be created consistent with standards for an ISO Class 5
environment.
(P) In-use time/date:
The time/date before which a conventionally manufactured product or a CSP must
be used after it has been opened or needle-punctured.
(Q) ISO Class 5: An area with less than three
thousand five hundred twenty (3,520) particles (0.5 µm and larger in
size) per cubic meter.
(R) ISO Class
7: An area with less than three hundred fifty-two thousand (352,000) particles
(0.5 µm and larger in size) per cubic meter.
(S) Multiple-dose container: A multiple unit
container for articles or compounded sterile preparations that contains more
than one (1) dose of medication and usually contains an antimicrobial
preservative.
(T) Parenteral: A
sterile preparation of drugs for injection through one (1) or more layers of
skin.
(U) Point-of-care assembled
system: A closed system device that creates a physical barrier between
diluents, fluids, or other drug components and is designed to be activated by
the end user by allowing the components to mix prior to
administration.
(V) Primary
engineering control (PEC): A system that provides an ISO 5 environment for the
exposure of critical sites when compounding sterile preparations. PECs include,
but may not be limited to, horizontal/vertical laminar airflow hoods,
biological safety cabinets, and a RABS such as compounding aseptic isolators
(CAIs), or compounding aseptic containment isolators (CACIs).
(W) Process validation or simulation:
Microbiological simulation of an aseptic process with growth medium processed
in a manner similar to the processing of the preparation and with the same
container or closure system.
(X)
Quality assurance: For purposes of these regulations, quality assurance is the
set of activities used to ensure that the processes used in the preparation of
sterile drug preparations lead to preparations that meet predetermined
standards of quality.
(Y) Quality
control: For the purposes of these regulations, quality control is the set of
testing activities used to determine that the ingredients, components, and
final sterile preparations prepared meet predetermined requirements with
respect to identity, purity, nonpyrogenicity, and sterility.
(Z) Restricted access barrier system (RABS):
A primary engineering control that is comprised of a closed system made up of
four (4) solid walls, an air-handling system, and transfer and interaction
devices. The walls are constructed so as to provide surfaces that are cleanable
with coving between wall junctures. The air-handling system provides HEPA
filtration of inlet air. Transfer of materials is accomplished through air
locks, glove rings, or ports. Transfers are designed to minimize the entry of
contamination. Manipulations can take place through either glove ports or half
suits. Examples of a RABS may include, but is not limited to, a CAI or CACI.
(AA) Repackaging: The subdivision
or transfer of a compounded preparation from one (1) container or device to a
different container or device.
(BB)
Single-dose/single-unit container/vial: A container/vial of medication intended
for administration that is meant for use in a single patient for a single case,
procedure, or injection.
(CC)
Sterilization: A validated process used to render a preparation free of viable
organisms.
(DD) Temperatures:
1. Frozen means temperatures between
twenty-five degrees below zero and ten degrees below zero Celsius (-25 and
-10°C) (thirteen degrees below zero and fourteen degrees Fahrenheit (-13
and 14°F));
2. Refrigerated
means temperatures between two and eight degrees Celsius (2 and 8°C)
(thirty-six and forty-six degrees Fahrenheit (36 and 46°F)); and
3. Controlled room temperature means a
temperature maintained thermostatically that encompasses the usual and
customary working environment 20° to 25° Celsius (68° to 78°
F). Excursions between 15° and 30° Celsius (59° to 86° F) as
commonly experienced in pharmacies and other facilities shall be deemed
compliant.
(EE) USP:
The United States Pharmacopeia and the National Formulary
(USP-NF) as adopted and published by the United States Pharmacopeial
Convention, effective May 2013. Copies of the USP-NF are published by, and
available from, USP, 12601 Twinbrook Parkway, Rockville, MD 20852-1790 or
online at http://www.usp.org/. The
USP-NF is incorporated herein by reference. This rule does not include any
later amendments or additions to the USP-NF.
(FF) Validation: Documented evidence
providing a high degree of assurance that specific processes will consistently
produce a preparation meeting predetermined specifications and quality
attributes.
(GG) Definitions of
sterile compounded preparations by risk level:
1. Risk Level 1: Applies to compounded
sterile preparations that exhibit characteristics A., B., or C., stated below.
All Risk Level 1 preparations shall be prepared with sterile equipment and
sterile ingredients and solutions in an ISO Class 5 environment. Risk Level 1
includes the following:
A. Preparations:
(I) Stored at controlled room temperature and
assigned a beyond-use date of forty-eight (48) hours or less; or
(II) Stored under refrigeration and assigned
a beyond-use date of seven (7) days or less; or
(III) Stored frozen and assigned a beyond-use
date of thirty (30) days or less;
B. Unpreserved sterile preparations prepared
for administration to one (1) patient or batch-prepared preparations containing
suitable preservatives prepared for administration to more than one (1) patient
with an assigned beyond-use date that does not exceed the beyond-use date
allowed under subparagraph (1)(GG)1.A. of this rule;
C. Preparations prepared by closed-system
aseptic transfer of sterile, nonpyrogenic, finished pharmaceuticals (e.g., from
vials or ampules) obtained from licensed manufacturers into sterile final
containers obtained from licensed manufacturers with an assigned beyond-use
date that does not exceed the beyond-use date allowed under subparagraph
(1)(GG)1.A. of this rule;
2. Risk Level 2: Sterile preparations exhibit
characteristic A., B., or C., stated below. All Risk Level 2 preparations shall
be prepared with sterile equipment and sterile ingredients in an ISO Class 5
environment and with closed-system transfer methods. Risk Level 2 includes the
following:
A. Preparations stored under
refrigeration and assigned a beyond-use date greater than seven (7) days, or
preparations stored frozen and assigned a beyond-use date greater than thirty
(30) days, or preparations stored at controlled room temperature and assigned a
beyond-use date greater than forty-eight (48) hours;
B. Batch-prepared preparations without
preservatives that are intended for use by more than one (1) patient;
C. Preparations compounded by complex or
numerous manipulations of sterile ingredients obtained from licensed
manufacturers in a sterile container or reservoir obtained from a licensed
manufacturer by using closed-system aseptic transfer (e.g., automated
compounder);
3. Risk Level
3: Sterile preparations exhibit either characteristic A. or B.:
A. Preparations compounded from nonsterile
ingredients or compounded with nonsterile components, containers, or equipment
before terminal sterilization;
B.
Preparations prepared by combining multiple ingredients (sterile or nonsterile)
by using an open-system transfer or open reservoir before terminal
sterilization.
(2) Policy and Procedure Manual/Reference
Manuals.
(A) A manual, outlining policies and
procedures encompassing all aspects of Risk Level 1, 2, and 3 compounding
performed, shall be available for inspection at the pharmacy. The manual shall
be reviewed on an annual basis. The pharmacy shall have current reference
materials related to sterile preparations.
(3) Personnel Education, Training, and
Evaluation.
(A) Risk Level 1: All pharmacy
personnel preparing sterile preparations must receive suitable didactic and
experiential training in aseptic technique and procedures and shall be skilled
and trained to accurately and competently perform the duties assigned.
Additional training must be provided if the risk level of sterile activity
conducted by the individual changes or if there is a change in compounding
methods performed. To ensure competency, individuals preparing sterile
preparations must successfully pass an Aseptic Technique Skill Assessment that
complies with section (10) of this rule. The pharmacy shall establish policies
and procedures for staff training and assessment.
(B) Risk Level 2: In addition to Risk Level 1
requirements, personnel training must include assessment of competency in all
Risk Level 2 procedures via process simulation.
(C) Risk Level 3: In addition to Risk Level 1
and 2 requirements, operators have specific education, training, and experience
to prepare Risk Level 3 preparations. The pharmacist knows principles of good
compounding practice for risk level preparations, including-
1. Aseptic processing;
2. Quality assurance of environmental,
component, and end-preparation testing;
3. Sterilization; and
4. Selection and use of containers,
equipment, and closures.
(4) Storage and Handling in the Pharmacy.
(A) Risk Level 1 and 2: Solutions, drugs,
supplies, and compounding equipment must be stored and maintained in a manner
that will maintain the chemical and microbiological stability of CSPs.
Refrigeration, freezer and, if applicable, incubator temperatures shall be
documented daily. Other storage areas shall be inspected regularly to ensure
that temperature and lighting meet requirements. Drugs and supplies shall be
shelved above the floor. Removal of drugs and supplies from boxes shall be done
outside the controlled and buffer areas. Removal of used supplies from the
controlled area shall be done at least daily. Preparation recall procedures
must comply with section (21) of this rule and must permit retrieving affected
preparations from specific involved patients.
(B) Risk Level 3: In addition to Risk Level 1
and 2 requirements, the pharmacy must establish procedures for procurement,
identification, storage, handling, testing, and recall of components and
finished preparations. Finished Risk Level 3 preparations awaiting test results
must be quarantined under minimal risk for contamination in a manner that will
maintain chemical and microbiological stability.
(5) Facilities and Equipment. The pharmacy
shall establish and follow proper controls to ensure environmental quality,
prevent environmental contamination, and maintain air quality in all ISO
classified areas.
(A) Risk Level 1: Risk Level
1 preparations must be prepared in a PEC located in a controlled area that
meets the requirements of this rule. A sink with hot and cold water must be
near, but not in, the controlled area. The controlled area and inside equipment
must be cleaned and disinfected as provided in section (17) of this rule.
Activities within the critical area shall be kept to a minimum to maintain the
ISO classified environment. Primary engineering controls shall meet the
requirements of section (6) of this rule; prefilters must be visually inspected
on a regularly scheduled basis and replaced according to manufacturer's
specifications. Pumps utilized in the compounding process shall be recalibrated
and documented according to manufacturer procedures.
(B) Risk Level 2: In addition to all Risk
Level 1 requirements, Risk Level 2 preparations must be prepared in a PEC
located in a buffer area or prepared in a RABS located within a controlled
area. Applicable environmental monitoring of air and surfaces must be
conducted. Risk Level 2 preparations shall at a minimum remain a Risk Level 2
for the life of the preparation.
(C)
Risk Level 3: In addition to Risk Level 1 and 2 requirements, Risk Level 3
preparations must be prepared in a PEC located in a buffer area or prepared in
a RABS located within a controlled area. All non-sterile equipment that is to
come in contact with the sterilized final preparation must be sterilized before
introduction in the buffer area or into the RABS.
(D) Automated compounding devices shall be
calibrated according to manufacturer procedures for content, volume, weight,
and accuracy prior to initial use and prior to compounding each day the device
is in use or more frequently as recommended by manufacturer guidelines.
Calibration results shall be reviewed by a pharmacist to ensure compliance. The
identity of the reviewing pharmacist and the review date shall be documented in
the pharmacy's records.
(E) All PECs
and ISO classified areas shall be certified to ensure compliance with the
requirements of this rule prior to beginning sterile compounding activities and
every six (6) months thereafter. Certification shall be conducted by competent
staff/vendors using recognized and appropriate certification and testing
equipment. Certification results shall be reviewed by a pharmacist once
received. The pharmacist's identity and date of review must be documented in
the pharmacy's records. Deficiencies or failures shall be investigated and
corrected prior to further compounding which may include recertification of the
PEC/ISO classified area.
1. The PEC and ISO
classified areas must be recertified when- 1) any changes or major service
occurs that may affect airflow or environmental conditions or 2) the PEC or
room is relocated or the physical structure of the ISO classified area has been
altered.
2. Corrections may include,
but are not limited to, changes in the use of the affected PEC or ISO
classified area or initiating a recall.
(F) Pressure differential: If the sterile
compounding area is equipped with a device to monitor pressure differential
between ISO classified air spaces, pressure differential results must be
recorded and documented each day that the pharmacy is open for pharmacy
activities. Alternatively, a continuous monitoring system may be used to record
pressure differential results if the system maintains ongoing documentation of
pressure recordings or maintains pressure alerts that are reviewed
daily.
(6) Primary
Engineering Controls (PECs).
(A) PECs must be
properly used, operated, and maintained and must be located out of traffic
patterns and away from conditions that could adversely affect their operation
or disrupt intended airflow patterns (e.g., ventilation systems or
cross-drafts).
(B) PECs shall
maintain ISO Class 5 or better conditions during dynamic operating conditions
and while compounding sterile preparations, including, when transferring
ingredients into and out of the PEC and during exposure of critical
sites.
(C) PECs shall provide
unidirectional (laminar flow) HEPA air at a velocity sufficient to prevent
airborne particles from contacting critical sites.
(D) The recovery time to achieve ISO Class 5
air quality in any PEC shall be identified in the pharmacy's policies and
procedures. Procedures must be developed to ensure adequate recovery time is
allowed before or during compounding operations and after material
transfer.
(7) Controlled
Areas. The controlled area shall be designed, maintained, and controlled to
allow effective cleaning and disinfection and to minimize the risk of
contamination and the introduction, generation, and retention of particles
inside the PEC.
(A) Controlled areas must be
clean and well-lit and shall be free of insects, rodents, and/or other vermin.
Trash shall be disposed of in a timely and sanitary manner and at least daily.
Tacky mats or similar articles are prohibited in the controlled area or any ISO
classified environment.
(B) Traffic
flow in or around the controlled area shall be minimized and controlled. Food
items, chewing gum, eating, drinking, and smoking are prohibited in the
area.
(C) Non-essential objects that
shed particles shall not be brought into the controlled area, including, but
not limited to, pencils, cardboard cartons, paper towels, and cotton items
(e.g., gauze pads). Furniture, carts, supplies, and equipment shall be removed
from shipping cartons/containers and properly cleaned and disinfected with
sterile alcohol or an equivalently effective non-residue generating
disinfectant before entering any ISO classified area. No shipping or other
external cartons may be taken into the controlled area or an ISO classified
area.
(D) Only supplies essential
for compounding shall be stored in the controlled area. Supplies or other
non-essential equipment shall not be stored in or on the
PEC.
(8) Garbing and Hand
Hygiene. Individuals engaged in, or assisting with, CSPs shall be trained and
demonstrate competence in proper personal garbing, gloving, and hand hygiene.
Competence must be documented and assessed through direct visual observation as
part of the aseptic technique skill assessment required by this rule.
(A) Risk Level 1: Low-particulate and
non-shedding gowns, hair covers, gloves, face masks, and, if applicable, beard
covers must be worn during compounding and cleaning. All head and facial hair
must be covered. During sterile preparation, gloves shall be disinfected before
use and frequently thereafter with a suitable agent and changed when integrity
is compromised. All personnel in the controlled area must be appropriately
garbed as required by this section.
(B) Risk Level 2 and Risk Level 3: In
addition to Risk Level 1 requirements, shoe covers and sterile gloves must be
worn while compounding and cleaning, including, over RABS gloves. All personnel
in the controlled or buffer area must garb as required by this
section.
(9) Aseptic
Technique and Preparation. Appropriate quality control methods shall be
maintained over compounding methods at all times to ensure proper aseptic
technique.
(A) Risk Level 1: Sterile
preparations must be prepared in an ISO Class 5 environment. Personnel shall
scrub their hands and forearms a minimum of thirty (30) seconds and remove
debris from underneath fingernails under warm running water before donning the
required gloves. Eating, drinking, and smoking are prohibited in the controlled
area. Talking shall be minimized to reduce airborne particles. Ingredients
shall be determined to be stable, compatible, and appropriate for the
preparation to be prepared, according to manufacturer, USP, or scientific
references. Ingredients and containers shall be inspected for defects,
expiration, and integrity before use. Only materials essential for aseptic
compounding shall be placed in the PEC. Supplies, equipment, and the surfaces
of ampules and vials shall be disinfected before entering the PEC by wiping the
outer surface with sterile alcohol or an equivalently effective non-residue
generating disinfectant. Sterile components shall be arranged in the PEC to
allow a clear, uninterrupted path of HEPA-filtered air over critical sites.
Automated devices and equipment shall be cleaned, disinfected, and placed in
the PEC to enable laminar airflow. Aseptic technique shall be used to avoid
touch contamination of critical sites of containers and ingredients. Particles
shall be filtered from solutions, if applicable. Needle cores shall be avoided.
The pharmacist shall check before, during, and after preparation to verify the
identity and amount of ingredients before release.
(B) Risk Level 2: In addition to Risk Level 1
requirements, a file containing the formula, components, procedures, sample
label, and final evaluation shall be made for each preparation batch. A
separate work sheet and lot number for each batch shall be completed. When
combining multiple sterile preparations, a second verification of calculations
shall take place. The pharmacist shall verify data entered into any automatic
compounder before processing and check the end preparation for
accuracy.
(C) Risk Level 3: In
addition to Risk Level 1 and 2 requirements, nonsterile components must meet
compendial standards or must be verified by a pharmacist and a certificate of
analysis. Batch preparation files shall also include comparisons of actual with
anticipated yields, sterilization methods, and quarantine specifications.
Presterilized containers shall be used when feasible. Final containers must be
sterile and capable of maintaining preparation integrity throughout the shelf
life. Sterilization methods must be based on properties of the preparation, and
must be conducted in a method recognized by USP for the preparation and
confirmed through sterility testing using a testing method recognized by USP
for the preparation.
(D) Single-dose
vials/containers and pharmacy bulk vial/ containers exposed to ISO Class 5 or
cleaner air may be used in compounding until the assigned in-use time which
shall not exceed six (6) hours after initial needle puncture, unless otherwise
specified by the manufacturer. Opened single-dose ampules shall not be stored
for any time period. The in-use time must be placed on the vial/container. For
multiple-dose vials/containers with no antimicrobial preservative used in the
preparation of radiopharmaceuticals whose beyond-use dates are twenty-four (24)
hours or less, the in-use time shall not exceed twenty-four (24)
hours.
(E) Unless otherwise
specified by the manufacturer, multipledose vials/containers with an
antimicrobial preservative may be used in compounding until the assigned in-use
date which shall not exceed twenty-eight (28) days after initially entering or
opening the vial/container (e.g., needle-puncture). The in-use date must be
placed on the vial/container.
(10) Aseptic Technique Skill Assessment.
Individuals engaged in sterile compounding must take and successfully pass an
aseptic technique skill assessment to verify aseptic competency. The assessment
must include a direct visual observation of the individual's aseptic competency
during a process simulation that represents the most challenging or stressful
conditions encountered or performed by the person being evaluated. The
assessment must include media-fill testing for all risk levels performed.
Self-observation is not allowed.
(A) The
required visual observation shall assess:
1.
Proper aseptic technique, manipulations, and work practices, including, but not
limited to, avoiding touch contamination, proper use of first air, and if
applicable, sterilizing high risk CSPs;
2. Cleaning and disinfection;
3. Hand hygiene, gloving, and
garbing;
4. Identifying, weighing,
and measuring of ingredients;
5.
Maintaining sterility in ISO Class 5 areas;
6. Labeling and inspecting CSPs for
quality.
(B) Media-Fill
Testing. Pharmacies shall establish and follow policies and procedures for
media-fill testing. Media-fill testing shall comply with USP Chapter 797's
recommended procedures and methods and must be conducted using the most
challenging or stressful conditions/compounding actually encountered or
performed by the person being evaluated using the same container or closure. A
minimum of three (3) mediafill tests must be completed during initial
media-fill testing and one (1) media-fill test completed for ongoing
testing.
(C) Frequency: The required
Aseptic Technique Skill Assessment must be conducted prior to initial
compounding and every twelve (12) months thereafter for Risk Levels 1 and 2
compounding and every (6) months thereafter for Risk Level 3 compounding.
Additionally, an Aseptic Technique Skill Assessment must be conducted whenever
unacceptable techniques are observed or discovered, if the risk level of
sterile activity conducted by the individual changes, or if there is a change
in compounding methods performed.
(D) Individuals who fail written tests;
visual observation of hand hygiene, garbing, or aseptic technique; or
media-fill tests must undergo immediate requalification through additional
training by competent compounding personnel. Individuals who fail visual
observation of hand hygiene, garbing, or aseptic technique; or media-fill tests
must pass a reevaluation in the deficient area before they can resume
compounding of sterile preparations. Individuals who fail media-fill testing
must pass three (3) successive media-fill tests prior to resuming sterile
compounding.
(E) If needed to
prevent interruptions in patient care during an emergency, a pharmacy may
accept aseptic technique skill assessment results from another pharmacy or
hospital in lieu of the required initial aseptic technique skill assessment,
provided-
1. A pharmacist verifies the aseptic
technique skill assessment to be accepted complies with the requirements under
subsections (10)(A)-(C) of this rule for an ongoing aseptic technique skill
assessment, at a minimum;
2. The
pharmacy maintains documentation of the other pharmacy or hospital's completed
aseptic technique skill assessment, including the dates and results of the
required training, visual observation, and media-fill testing. Additionally,
the receiving pharmacy must maintain a manual or electronic copy of the other
pharmacy's or hospital's policies and procedures on aseptic technique skill
assessment and mediafill testing for board licensees or registrants;
3. The board licensee or registrant has
received training on applicable pharmacy operational procedures as needed to
ensure proper compounding. The licensee or registrant must be skilled and
trained to accurately and competently perform the duties; and
4. Individuals may not assist with
compounding under the emergency allowance authorized by this subsection for
more than forty-five (45) days without an initial aseptic technique skill
assessment for the pharmacy.
(11) Record Keeping.
(A) Risk Level 1 and 2: The following must be
documented/ maintained:
1. Training and
competency evaluation of pharmacy personnel involved in sterile compounding,
including, the dates and results of the required aseptic technique training,
aseptic technique skill assessment, and media-fill testing;
2. Refrigerator, freezer and, if applicable,
incubator temperature logs;
3.
Certification dates and results for any PEC or ISO classified area;
4. Manufacturer manuals that are relied upon
to maintain compliance with this rule;
5. Other facility quality control logs, as
appropriate, including all maintenance, cleaning, and calibration
records;
6. If applicable, pressure
recordings including documentation of the review of continuous monitoring
system results as required by subsection (5)(F);
7. Any end-preparation testing records;
and
8. Single preparation and batch
preparation records.
(B)
Risk Level 3: In addition to Risk Level 1 and 2 requirements, record
requirements for Risk Level 3 preparations must include:
1. Preparation work sheet;
2. Sterilization records;
3. Quarantine records, if
applicable;
4. End-preparation
evaluation and testing records as required in section (14); and
5. Ingredient validation records as required
in section (14).
(C) All
records and reports shall be maintained either electronically or physically for
two (2) years and shall be readily retrievable and subject to inspection by the
board of pharmacy or its agents. At a minimum, records shall be physically or
electronically produced immediately or within two (2) hours of a request from
the board or the board's authorized designee.
(12) Labeling.
(A) Sterile preparations shall be labeled in
accordance with section
338.059, RSMo and with the
following supplemental information:
1.
Beyond-use date;
2. Storage
requirements if stored at other than controlled room temperature;
3. Any device specific
instructions;
4. Auxiliary labels,
when applicable; and
5. If
applicable, a designation indicating the preparation is
hazardous.
(13)
Beyond-Use Dating.
(A) Risk Level 1 and Risk
Level 2: All sterile preparations must bear a beyond-use date. Beyond-use dates
must be assigned based on current drug and microbiological stability
information and sterility considerations.
(B) Risk Level 3: In addition to all Risk
Level 1 requirements, there must be a reliable method for establishing all
beyond-use dates, including laboratory testing of preparation stability,
pyrogenicity, particulate contamination, and potency. Beyond-use dating not
specifically referenced in the products approved labeling or not established by
preparation specific instrumental analysis shall be limited to thirty (30)
days. There must be a reliable method for establishing all beyond-use dating.
Preparations assigned a beyond-use date of greater than thirty (30) days shall
have laboratory validation of preparation stability and
potency.
(14)
End-preparation Evaluation.
(A) Risk Level 1:
The final preparation must be inspected for clarity, container leaks,
integrity, and appropriate solution cloudiness or phase separation, solution
color, and solution volume. The pharmacist must verify that the preparation was
compounded accurately as to the ingredients, quantities, containers, and
reservoirs. Background light or other means for the visual inspection of
preparations for any particulate and/or foreign matter must be used as part of
the inspection process, provided an alternate means of inspection shall be used
if a visual inspection or exposure to the preparation may pose a health
hazard.
(B) Risk Level 2: All Risk
Level 1 requirements must be met.
(C) Risk Level 3: In addition to all Risk
Level 1 requirements, the process validation procedure shall be supplemented
with a program of end-preparation sterility testing according to a formal
sampling plan. Samples shall be statistically valid to ensure that batches are
sterile. A method for recalling batch preparations shall be established if
preparation testing results are unacceptable. A sample from each sterile
preparation/batch must be tested for sterility. A sample from each parenteral
sterile preparation/batch must also be tested for pyrogenicity. Risk Level 3
preparations must be quarantined and stored to maintain chemical and
microbiological stability pending results of end-preparation testing.
1. Sterility testing: Sampling for the
sterility test shall occur promptly upon the completion of preparation. The
sterility test, including the sampling scheme, shall be conducted according to
a method recognized for the preparation by USP Chapter 71.
2. Pyrogen/Endotoxin testing: Sterile
parenteral preparations prepared from non-sterile drug components shall be
tested for pyrogen or endotoxin according to a method recognized by USP Chapter
151 for pyrogen testing and recognized by USP Chapter 85 for endotoxin
testing.
3. Potency: The pharmacy
shall have a procedure for a pre-release check of the potency of the active
ingredients in the compounded sterile preparation prepared from non-sterile
bulk active ingredients. The procedure shall include at least the following
verifications by a pharmacist:
A. The lot of
the active ingredients used for compounding have the necessary labeling,
potency, purity, certificate of analysis, and other relevant
qualities;
B. All weighings,
volumetric measurements, and additions of ingredients were carried out
properly;
C. The compounding or
control records include documentation that the fill volumes of all units
available for release were checked and were correct; and
D. The final potency is confirmed by
instrumental analysis for sterile preparations that have been assigned a
beyond-use date of more than thirty (30) days.
(D) Emergency Dispensing of a Risk Level 3
Sterile Preparation: When a compounded Risk Level 3 preparation must be
released prior to the completion of testing, the sterile preparation may be
dispensed pending test results. Emergency dispensing shall be defined as, and
comply with, subsection (1)(N) of this rule.
(15) Storage, Handling, and Transport.
Sterile preparations shall be packaged, stored, dispensed, and distributed in a
manner that will maintain the preparation's chemical and microbiological
stability until the assigned beyond-use date or until delivery to the patient
or intended recipient. The pharmacist-in-charge shall assure the environmental
control of all sterile compounded preparations shipped. Sterile preparations
shall be transported so as to be protected from excesses of temperatures and
light within appropriate packaging or delivery containers that maintain
necessary storage conditions to preserve the quality and integrity of sterile
preparations. The pharmacy shall follow written procedures that specify packing
techniques, configuration, and materials for groups of preparations with common
storage characteristics and for specific preparations where unique storage
conditions are required to retain adequate stability and preparation
quality.
(16) Point-of-Care
Assembled Systems. Assembly of point-of-care assembled systems shall be
considered Risk Level 1 compounding. Point-of-care assembled systems shall be
assigned a beyond-use date which may exceed the beyond-use date authorized for
Risk Level 1 preparations provided the date is assigned in accordance with the
manufacturer's recommendations or labeling.
(A) When dispensed, an assembled
non-activated system shall be labeled with beyond-use dates for both activated
and non-activated states. The compounding record must document both dates. The
beyond-use date of an assembled non-activated system shall be limited to a
maximum of fifteen (15) days unless the pharmacy has documentation from the
system's manufacturer that a longer date is acceptable.
(B) Point-of-care assembled systems shall be
assembled and stored in accordance with the manufacturer's labeling and
recommendations.
(17)
General Cleaning and Disinfection Requirements. Except as otherwise provided
herein, cleaning and disinfection of controlled and buffer areas, supplies, and
equipment shall be performed and conducted in accordance with USP Chapter 797
timeframes and procedures. Controlled areas that do not meet ISO air
classifications shall be cleaned and disinfected as required by USP Chapter 797
for segregated compounding areas. If compounding is done less frequently than
the cleaning and disinfection timeframes specified in USP Chapter 797, cleaning
and disinfection must occur before each compounding session begins.
(A) The pharmacy shall establish and follow
written policies and procedures governing all aspects of cleaning and
disinfection, including approved cleaning/disinfecting agents and materials,
schedules of use, and methods of application.
(B) Individuals shall be trained in proper
cleaning and disinfection procedures prior to performing such activities.
Training shall include direct visual observation of the individual's cleaning
and disinfecting process by qualified staff. The individual shall be annually
reassessed for competency through direct visual observation. Documentation of
the required training and training dates shall be maintained in the pharmacy's
records. Individuals who fail to demonstrate competency shall be reinstructed
and successfully reevaluated prior to any further cleaning or
disinfection.
(C) Cleaning and
disinfection activities shall be performed using approved cleaning/disinfection
agents and procedures described in the pharmacy's written policies and
procedures. Manufacturers' directions for minimum contact time shall be
followed.
(D) All cleaning tools
(e.g., wipes, sponges, and mop heads) must be low-lint and dedicated for use in
the controlled area and ISO classified areas.
(E) Primary engineering controls shall be
cleaned with a germicidal cleaning agent followed by sterile alcohol. Sterile
water for irrigation shall be used to dilute all agents used inside the PEC
that require dilution.
(F) At a
minimum, the critical area shall be cleaned and disinfected prior to
compounding, between batches, and whenever contamination is suspected using
sterile alcohol which is allowed to dry immediately prior to
compounding.
(18)
Environmental Sampling/Testing. The pharmacy shall establish and follow proper
controls to ensure environmental quality, prevent environmental contamination,
and maintain air quality in all ISO classified areas. Applicable environmental
monitoring of air and surfaces must be conducted. Air monitoring must be
conducted prior to initial compounding and every six (6) months thereafter.
Surface sampling/ monitoring must be conducted every six (6) months for Risk
Level 2 and every thirty (30) days for Risk Level 3 compounding.
(19) Cytotoxic Drugs.
(A) The following additional requirements are
necessary for those licensed pharmacies that prepare cytotoxic drugs to insure
the protection of the personnel involved:
1.
Cytotoxic drugs shall be compounded in a vertical flow, Class II biological
safety cabinet or a CACI. If used for other preparations, the cabinet must be
thoroughly cleaned;
2. Protective
apparel shall be worn by personnel compounding cytotoxic drugs which shall
include disposable masks, gloves, and gowns with tight cuffs;
3. Appropriate safety and containment
techniques for compounding cytotoxic drugs shall be used in conjunction with
the aseptic techniques required for preparing sterile preparations.
Chemotherapy preparations should be compounded using a closed system transfer
device;
4. Appropriate disposal
containers for used needles, syringes, and if applicable, cytotoxic waste from
the preparation of chemotherapy agents and infectious waste from patients'
homes. Disposal of cytotoxic waste shall comply with all applicable local,
state, and federal requirements;
5.
Written procedures for handling major and minor spills and generated waste of
cytotoxic agents must be developed and must be included in the policy and
procedure manual; and
6. Prepared
doses of cytotoxic drugs must be labeled with proper precautions inside and
outside, and shipped in a manner to minimize the risk of accidental rupture of
the primary container.
(20) Remedial Investigations. A remedial
investigation shall be required if any environmental monitoring sample
demonstrates a colony forming unit (CFU) count that exceeds USP Chapter 797
recommended action levels for the type of sampling. A remedial investigation
shall include resampling of all affected areas to ensure a suitable state of
microbial control. CSPs and any ingredients used within the compounding process
that are part of the remedial investigation shall be quarantined until the
results of the investigation are known. The pharmacy shall ensure that no
misbranded, contaminated, or adulterated CSP is administered or dispensed for
patient use.
(A) If an environmental
monitoring sample taken from an ISO-5 classified area exceeds USP 797 action
levels, the pharmacy must cease compounding in the affected ISO classified area
until resampling shows a suitable state of microbial control has been achieved
in the affected area. However, a pharmacy may continue to compound during the
remedial investigation if-
1. The affected ISO
classified area is cleaned and disinfected by using a germicidal cleaning agent
and a sporicidal agent followed by sterile alcohol;
2. The beyond-use date assigned to all
preparations is no greater than twelve (12) hours; and
3. The affected ISO classified area is
resampled under dynamic conditions. If the resampling exceeds USP Chapter 797
action levels, compounding must cease until resampling shows a suitable state
of microbial control has been achieved in the affected area, unless otherwise
authorized by the board or board's authorized designee to continue compounding
upon a showing the facility can be operated in a manner not to endanger the
public safety.
(B) If an
environmental monitoring sample taken from an ISO-7 classified buffer area
exceeds USP 797 action levels, the pharmacy must cease compounding in the
affected ISO classified buffer area until resampling shows a suitable state of
microbial control has been achieved in the affected area. However, a pharmacy
may continue to compound during the remedial investigation if-
1. The affected ISO classified area is
cleaned and disinfected by using a germicidal cleaning agent and a sporicidal
agent;
2. The beyond-use date
assigned to Risk Level 1 preparations is not greater than twenty-four (24)
hours or, for Risk level 2 and 3 preparations, no greater than twelve (12)
hours; and
3. The affected ISO
classified area is resampled under dynamic conditions. If two (2) consecutive
resamplings exceed USP 797 action levels, compounding must cease until
resampling shows a suitable state of microbial control has been achieved in the
affected area, unless otherwise authorized by the board or board's authorized
designee to continue compounding upon a showing the facility can be operated in
a manner not to endanger the public health or safety.
(C) The pharmacy shall notify the board in
writing within three (3) days of any environmental monitoring sample collected
as part of a remedial investigation that exceeds USP 797 action
levels.
(21) Recalls. A
recall must be initiated when a dispensed CSP is deemed to be misbranded,
adulterated, or non-sterile or if end-preparation testing results are out of
specification. The pharmacy shall notify the prescriber of the nature of the
recall, the problem(s) identified, and any recommended actions to ensure public
health and safety. In cases where the CSP has the potential to harm the
patient, the same notification shall be provided to all patients that received
the recalled CSP(s). Any recall initiated by a pharmacy shall be reported, in
writing, to the board within three (3) business days. The pharmacy shall
document their activities related to the recall.
Notes
State regulations are updated quarterly; we currently have two versions available. Below is a comparison between our most recent version and the prior quarterly release. More comparison features will be added as we have more versions to compare.
No prior version found.