ASHP Guidelines On Compounding Sterile Preparations

ASHP REPORT Compoundng sterile preparations
ASHP REPORT
ASHP Guidelines on Compounding

Sterile Preparations
Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm. 2014; 71:145-66
Purpose for sterile compounding may not Many health care settings also
The compounding of medications know that inaccurate or contami- use CSPs prepared by compounding
is a fundamental part of pharmacy nated products are dispensed.10-13 pharmacies. Although these guide-
practice. All compounding person- These guidelines are intended lines may be useful in assessing the
nel, mainly pharmacists and phar- to help compounding person- quality of CSPs prepared by com-
macy technicians, are responsible for nel prepare CSPs of high quality pounding pharmacies, more informa-
compounding and dispensing sterile and reduce the potential for harm tion on the topic of outsourcing sterile
products and preparations of correct to patients and consequences for compounding services is available in
ingredient identity, purity (freedom compounding personnel. The rec- the ASHP Guidelines on Outsourcing
from physical contaminants, such as ommendations in these guidelines Sterile Compounding Services.16
precipitates,1 and chemical contami- are based on published data, when Finally, while these guidelines are
nants), strength (including stability2 available; on expert opinion and generally applicable to all personnel
and compatibility), and sterility and procedures used in similar indus- who prepare CSPs and all facilities
for dispensing them in appropriate tries; and on applicable regulations in which CSPs are prepared, phar-
containers that are labeled accurately and standards. These guidelines macists and other health care profes-
and appropriately for the end user. In are a revision of the 2000 ASHP sionals responsible for the prepara-
contemporary health care organiza- Guidelines on Quality Assurance of tion, selection, and use of CSPs are
tions, patients receive compounded Pharmacy-Prepared Sterile Prod- urged to use professional judgment
sterile preparations (CSPs) that are ucts,14 with the goals of providing in interpreting and applying these
stored for extended periods before more current recommendations and guidelines to their specific circum-
use. It has long been recognized that harmonizing the ASHP guidelines stances. Users of these guidelines are
extended storage of CSPs may allow with United States Pharmacopeia cautioned that the information pro-
for the growth of a pathological bio- (USP) chapter 797, Pharmaceutical vided is current as of publication and
burden of microorganisms3 and that Compounding—Sterile Prepara- are urged to consult current editions
patient morbidity and mortality can tions.15 To help achieve that harmo- of original sources (e.g., laws, regula-
result from contaminated or incor- nization, these guidelines employ tions, and applicable standards, in-
rectly compounded sterile prepara- the definitions and terminology of cluding USP compendial standards)
tions.4-9 When quality monitoring is USP chapter 797 rather than those to ensure patient safety as well as
inadequate, personnel responsible of the previous guidelines. legal and regulatory compliance.
Approved by the ASHP Board of Directors on June 2, 2013. Caryn D. Bing, M.S., FASHP; E. Clyde Buchanan, M.S., FASHP; Ryan
Developed through the ASHP Council on Pharmacy Practice. These A. Forrey, Pharm.D., M.S.; Eric S. Kastango, M.B.A., FASHP; Lee B.
guidelines supersede the ASHP Guidelines on Quality Assurance for Murdaugh, Ph.D.; Daryl McCollum, Pharm.D.; Luci A. Power, M.S.;
Pharmacy-Prepared Sterile Products dated April 27, 2000. Philip J. Schneider, M.S., FASHP; and James T. Wagner.
Patricia C. Kienle, M.P.A., FASHP, is gratefully acknowledged for The bibliographic citation for this document is as follows: Ameri-
leading the development of and drafting substantial portions of these can Society of Health-System Pharmacists. ASHP Guidelines on
guidelines. Linda F. McElhiney, Pharm.D.; Richard B. Osteen, D.Ph.; Compounding Sterile Preparations. Am J Health-Syst Pharm. 2014;
Ed Troell, M.B.A.; Fred Massoomi, Pharm.D., FASHP; Kathleen 71:145-66.
Sheehy, M.B.A.; and Angela T. Cassano, Pharm.D., BCPS, are also
gratefully acknowledged for their contributions to these guidelines. Copyright © 2014, American Society of Health-System Pharma-
ASHP gratefully acknowledges the following individuals for cists, Inc. All rights reserved. 1079-2082/14/0102-0145$06.00.
reviewing these guidelines (review does not imply endorsement): DOI 10.2146/sp140001
Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 145

Legal and Regulatory for a specific patient. Some states references to the chapter, some do
Considerations have specific regulations dealing with not mention the chapter, and some
Significant legal and regulatory CSPs for office use. Some pharmacies have additional regulations.21 The
changes have taken place since pub- whose primary purpose is preparing National Association of Boards of
lication of the previous ASHP guide- CSPs for hospitals and other facili- Pharmacy supports the incorpora-
lines (Figure 1). ties may be registered with the FDA tion of compounding regulations
At the time of its publication, as manufacturers and must adhere into state pharmacy practice legisla-
section 503A of the U.S. Food and to federal good manufacturing prac- tion by including such wording in the
Drug Administration Modernization tices. Some state boards of pharmacy association’s Model Rules and Model
Act (FDAMA) served to define the permit one pharmacy to compound State Pharmacy Act.22 State boards of
limits of legitimate compounding.18 for another pharmacy under central pharmacy should be consulted to de-

When section 503A of FDAMA was fill regulations. Most pharmacies termine the current status of sterile
ruled unconstitutional in 2001, the compound only pursuant to a pre- compounding regulations, as there
delineation between compound- scriber’s prescription and follow state are significant differences in regula-
ing and manufacturing reverted to regulations regarding compounding. tion among states.
earlier regulations based on the Fed- On January 1, 2004, USP chapter
eral Food, Drug, and Cosmetics Act.19 797, Pharmaceutical Compounding— Accreditation Considerations
Under those regulations, compound- Sterile Preparations,15 became of- The Centers for Medicare and
ing is considered part of the practice ficial, replacing USP chapter 1206, Medicaid Services (CMS) Hospital
of pharmacy and, in most states, is Sterile Drug Products for Home Conditions of Participation and In-
governed by state law and regula- Use.20 The change from a chapter terpretive Guidelines, the Joint Com-
tion. Manufacturing is regulated by numbered above 1000 to a chapter mission, the American Osteopathic
the federal government through the below 1000 marked a change from Association’s Healthcare Facilities
auspices of the Food and Drug Ad- an advisory standard to an enforce- Accreditation Program, and DNV
ministration (FDA). In most cases, able one. USP chapter 797 has since Healthcare’s National Integrated
extemporaneously compounded been revised.15 Some state regula- Accreditation for Healthcare Or-
preparations must be prepared pur- tions require full compliance with ganizations all include statements
suant to a prescriber’s prescription USP chapter 797, some have indirect concerning safe practices for storage
Figure 1. Evolution of Sterile Compounding Standards, 1970–2010. Adapted from The ASHP Discussion Guide on USP Chapter <797> for
Compounding Sterile Preparations.17 NCCLVP, National Coordinating Committee on Large Volume Parenterals; CSPs, compounded sterile
preparations; USP, United State Pharmacopeia; TAB, technical assistance bulletin; FDAMA, Food and Drug Administration Modernization
Act; PCAB, Pharmacy Compounding Accreditation Board.
2002— 2008—USP
FDAMA 2004—USP Chapter 797
1990—4 deaths, section Chapter 797 revisions become
1971—Deadly 2 cases of 1991 and 1995— 1997— 503A becomes official
nationwide blindness from ASHP national FDAMA ruled official 2006—PCAB
nosocomial contaminated compounding signed unconsti- established
infection CSPs surveys into law tutional
outbreak
1970 1980 1990 1995 2000 2005 2010
1975−80— 2002—ASHP national

NCCLVP publishes compounding survey 2012—
recommendations 1992—FDA 1993—ASHP 2000—USP Contaminated
Compliance TABs on Quality Sterile CSPs injure
Guide, USP Assurance for Compounding 2000—ASHP 271 and cause
Expert 2010—ASHP
Dispensing Pharmacy- Guidelines on 21 deaths in 16
Committee Guidelines on
Practices for Prepared Sterile Quality states
formed Outsourcing
Sterile Drug Products and on Assurance for Sterile
Products Pharmacy- Pharmacy- Compounding
Intended for Prepared Prepared Sterile Services
Home Use Ophthalmic Products published
published Products published
published
146 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

and preparation of sterile com- Infection Control in Healthcare Fa- all sizes may be captured). The uni-
pounds.23-26 Clinics, long-term care cilities,48 and Protect Patients Against directional (horizontal or vertical)
facilities, home care organizations, Preventable Harm from Improper Use HEPA-filtered air must provide suffi-
rehabilitation facilities, and physician of Single-dose/Single-use Vials,49 all cient velocity to sweep particles away
offices (all of which come under the from the Centers for Disease Con- from the direct compounding area
purview of USP chapter 79715) may trol and Prevention (CDC), serve and maintain unidirectional flow
all be subject to specific additional as the backbone for most infection during preparation of CSPs. (More
governance of sterile compounding prevention practices in the United information about HEPA filtration
practices, depending on the agencies States. Safe infusion, injection, and and first-air concepts can be found in
regulating or accrediting the facility. medication vial practices have been the ASHP publications Compounding
In addition, organizations preparing addressed by CMS50 and the Asso- Sterile Preparations,53 Basics of Aseptic

hazardous drugs27,28 should comply ciation for Professionals in Infection Compounding Technique,54 Getting
with National Institute for Occupa- Control and Epidemiology,51 and Started in Aseptic Compounding,55 and
tional Safety and Health (NIOSH) the Association of periOperative Compounding Sterile Preparations:
recommendations to ensure that Registered Nurses has recommended ASHP Video Guide to USP <797>.56)
compounding personnel are operat- practices for medication safety in PEC devices include laminar
ing in a safe environment.29,30 perioperative settings.52 airflow workbenches (LAFWs), bio-
logical safety cabinets (BSCs), com-
Other Compounding-Related Physical Facilities and Equipment pounding aseptic isolators (CAIs),
Guidelines and compounding aseptic contain-
ASHP provides several guidelines Design and Functionality ment isolators (CACIs) (Table 1).
for safe compounding practices28,31,32 Requirements Properly designed, unidirectional
and a discussion guide on USP chap- Facility requirements are intended airflow CAIs function in a similar
ter 79717 and has recognized USP to establish a safe environment for manner as LAFWs, but the direct
chapter 797 as a relevant practice compounding CSPs. The Interna- compounding area does not interact
standard in the ASHP Guidelines: tional Organization for Standardiza- with room air because it is within a
Minimum Standard for Pharmacies tion (ISO) air cleanliness classification closed system, with the air sweeping
in Hospitals.33 Other professional of the compounding environment is particles away from the compound-
organizations also provide guidance a critical measure that is affected by ing site. Smoke tests of PECs assist
on specific aspects of compounding. facility design. a facility in verifying unidirectional
Standards for prescribing, prepara- Primary Engineering Controls airflow and lack of turbulence and
tion, administration, and monitoring (PECs). A PEC is a device or room reverse flows.
of parenteral nutrition are available that provides an ISO Class 5 envi- CAIs or CACIs located outside of
through the American Society for ronment for compounding CSPs. an ISO Class 7 environment must be
Parenteral and Enteral Nutrition.34,35 PECs all rely on a special type of coupled with documentation from
The Institute for Safe Medication high-efficiency particle air (HEPA) the manufacturer that the device will
Practices provides recommendations filter that is ≥99.99% efficient in meet or exceed USP chapter 797 stan-
for preventing medication errors, removing particles as small as 0.3 dards under these conditions and be
including those involving CSPs.36,37 microns in size (the most penetrat- dynamically tested on site to USP 797
The Infusion Nurses Society offers ing particle size [MPPS], which refers and CETA requirements. If the CACI
standards, professional development, to the largest-sized particle that may used for hazardous drug preparation
and resources for all aspects of infu- escape the filter, although particles of is located outside the buffer area (see
sion care.38 The Controlled Environ-
ment Testing Association (CETA)
provides numerous CETA Applica-
tion Guides (CAGs) for the proper Table 1.
use, cleaning, and certification of Primary Engineering Controls (PECs)
primary engineering controls (PECs)
and buffer areas (generally referred Used to Prepare Used to Prepare
to as “cleanrooms”).39-45 Guidelines PEC Device Non-Hazardous CSPs Hazardous CSPs
for Hand Hygiene in Healthcare Set- Conventional Laminar airflow Class II biological safety cabinet
tings,46 Guidelines for Prevention of workbench (LAFW) (BSC)
Intravascular Catheter-Related Infec- Isolators Compounding aseptic Compounding aseptic
isolator (CAI) containment isolator (CACI)
tions,47 Guidelines for Environmental

Architecture, below), it must be lo- tion; it also serves as a way to further and relies on a defined airflow veloc-
cated in a segregated and dedicated segregate the buffer area from other, ity to divide the two areas, which are
area that maintains at least 0.01-inch less-clean areas of the facility. Water marked by a line of demarcation; this
water column negative pressure and sources, such as sinks or floor drains, type of facility may only be utilized
maintains, at a minimum, 12 air are not permitted in the buffer area for low- and medium-risk com-
changes per hour (ACPH). and should not be immediately ad- pounding. Demarcation lines should
Architecture. The sterile com- jacent to segregated compounding be indicated by colored tiles or other
pounding area includes a well-lit areas outside of a buffer area. A stor- elements integrated into the flooring
buffer area and ante area (both are age area outside the buffer and ante pattern but may be as simple as mark-
secondary engineering controls) and areas should provide adequate space ing on the floor.
an area for storage of sterile prod- for placement of sterile products and Facilities for preparation of radio-

ucts and supplies. A buffer area (or supplies. pharmaceuticals have some different
“cleanroom”) is defined as an area The sterile compounding area requirements. Refer to USP chapter
where a PEC is located and where (ante and buffer areas) may be con- 79715 and other relevant standards
activities such as preparation, com- structed of either hard- or soft-walled for specifics.
pounding, and staging of CSPs occur. enclosures, with the zones being Facilities without USP chapter
This area should provide adequate delineated by open or closed archi- 797-compliant ante areas and buffer
space for the PEC and may include tecture. Closed architecture is formed areas may prepare low-risk, non-
a limited amount of shelving and/ by walls and doors between the buf- hazardous CSPs in a PEC within a
or carts for staging of compounding fer and ante areas and is required for segregated compounding area. A
(not for storing stock). An ante area high-risk compounding (Table 2). segregated compounding area is an
provides space for hand washing, Open architecture has openings unclassified space (i.e., an area with
garbing, and product decontamina- between the buffer and ante areas no specific ISO classification) and
Table 2.
Facility Features Required for Specific Types of Compounding (Data from USP Chapter 79715 Except
as Noted)
Low-Risk
with ≤12-hour
Beyond-Use Date Low-Risk Medium-Risk High-Risk Hazardous
Feature (Non-Hazardous) (Non-Hazardous) (Non-Hazardous) (Non-Hazardous) Drugs
Architectural stylea Segregated Open or closed Open or closed Closed Closed
Buffer zone ISO N/A ISO Class 7 or better ISO Class 7 or better ISO Class 7 or better ISO Class 7
classification or better
Ante area ISO N/A ISO Class 8 (ISO ISO Class 8 (ISO ISO Class 8 (ISO ISO Class 7
classification Class 7 if opens Class 7 if opens Class 7 if opens or better
into negative into negative into a negative
pressure area) or pressure area) or pressure area)
better better or better
Minimum air
exchanges for
buffer areab N/A 30 30 30 30
Minimum air N/A 20 if ISO 8; 30 if 20 if ISO 8; 30 if 20 if ISO 8; 30 if 30
exchanges for ISO 7 ISO 7 ISO 7
ante areac
Pressure N/A Positive Positive Positive Negative
a
Architectural style (“open” and “closed”) is not defined in USP chapter 797, but the concept of physical separation of ante areas and buffer rooms is described in the
chapter. For the purposes of these guidelines, “closed architecture” indicates that the buffer and ante areas are separated by a door (i.e., are physically separate rooms) and
maintain a pressure differential of no less than 0.02-inch water column positive pressure. “Open architecture” indicates that the buffer and ante areas are in one room, not
separated by a door (i.e., not physically separated). Displacement airflow is used to separate open architecture spaces, with at least 40 feet per minute of airflow across the
entire plane of the opening. A segregated compounding area contains a PEC within a restricted space.
b
If an ISO Class 5 recirculating device is in place, a minimum of 15 air changes per hour (ACPH) is sufficient if the total ACPH is 30 between the device and the area
supply HEPA filters.
c
USP chapter 797 does not address the air changes in ISO Class 8 ante areas. The FDA Aseptic Processing Guide57 recommends a minimum of 20 ACPH to maintain ISO 8.
However, this is a minimum value intended for industry. Since ante areas for CSPs include ungowned personnel and other activities, a minimum of 30 ACPH is best practice
for ISO Class 8 ante areas and required for ISO 7 ante areas.

does not include ante or buffer areas. a minimum of 30 times per hour in pounding accuracy, if permitted by
It is required to be separated from buffer and ante areas, but may need state regulations.
activities that are not essential to the to be increased in high-traffic/high- Surfaces. Surfaces of any kind in
preparation of CSPs; not be located volume areas in order to maintain the buffer area and ante area must
adjacent to food preparation sites, the room’s specified ISO classifica- be smooth, impervious, and easy to
warehouses, or construction sites; tion (Table 2) under dynamic condi- clean, with no cracks or crevices that
and not have unsealed windows or tions. Facilities may incorporate the could trap dust or contaminants. All
doors that connect to the outdoors contribution of up to 15 air changes materials used in the facilities must
or high-traffic areas.15 This archi- per hour from a LAFW in the total air be non-shedding. Walls and ceilings
tecture type is most often seen in changes per hours in a nonhazardous must be made of either hard plastic
satellite pharmacies, small hospitals, buffer area. By design, these devices or epoxy-painted gypsum board.

procedural areas, or clinics. The filter room air as it passes through If ceiling tiles are used, they must
beyond-use dating for sterile prepa- the HEPA filter. be coated with hard polymer and
rations compounded in a segregated Airflow within the room should caulked both around the perim-
compounding area cannot exceed 12 be as steady as possible, having as eter and around each tile. Ceiling
hours (see Expiration and Beyond- few interruptions as possible. Within lights must be smooth, mounted
Use Dating). the PEC, it must be unidirectional,39 flush, and sealed. Floors should be
with as few interruptions in steady made of wide, heavy-duty sheet
Buffer Areas airflow as possible. PEC placement vinyl, rubber, or epoxy that is coved
Air Supply. A buffer area differs within the room should be well de- around the corners and rolled up
from an ordinary ventilated room by signed, with PECs placed where they onto the walls. Paint must be an
having the following: are least affected by opened doors, epoxy, acrylic, or other non-porous
HVAC systems, or personnel traffic. sealant type.
• Increased air supply. For non-hazardous preparations, Work surfaces should preferably
• HEPA filtration (the filtered air should positive pressure is required be- be stainless steel, but at a minimum
be introduced at the ceiling, with re- tween rooms physically divided by are required to be non-porous and
turns mounted low on the walls; ceiling- walls or doors (closed architecture easily sanitized. Carts and shelves,
mounted returns should not be used) style) and should be maintained at a ideally made of stainless steel wire,
including a terminal air filter (a filter at minimum of positive 0.02 inch wa- nonporous plastic, or rustproof met-
the end of the heating, ventilation, and ter column. If a room does not have al, should be easy to move and clean,
air conditioning [HVAC] ducting). physical barriers (i.e., has an open if necessary. Office equipment (e.g.,
• Room pressurization. architecture style) and relies on a computers and components [includ-
• A perforated plate or swirl supply air line of demarcation, the displace- ing washable keyboard and mouse],
diffuser (if an air diffuser is necessary); ment airflow concept requiring air telephones, printers) placed in the
high-induction supply air diffusers velocity of 40 feet per minute (0.2 buffer area must be easily cleanable
should not be used in buffer areas. meter per second) from the buffer and placed in such a manner that
area across the entire plane of line they have no material impact on the
Structural components must be of demarcation into the ante area is ISO air cleanliness classification of
coupled with HEPA filtration and required. Open architecture is not the area.
air exchanges in order to provide a permitted in areas used for high-risk
complete buffer area environment preparations. Renovations
and proper ISO classifications. Buffer When designing buffer areas, To meet requirements for sterile
areas must meet or exceed ISO Class facilities must consider workflow compounding, many facilities choose
7 air cleanliness standards. Ante areas patterns, such as how personnel to renovate existing space rather than
must at least meet ISO Class 8 stan- performing double-checks will af- construct new facilities. Whether
dards; ante areas opening into a neg- fect air quality. If supervisory per- designing a new area or retrofitting
ative pressure preparation area must sonnel are not located in the buffer one, the specific types (e.g., hazard-
meet ISO Class 7 standards. The area, movement in and out of the ous or nonhazardous) and risk levels
number of ACPH is based upon air/ buffer area is likely to increase air- of CSPs that will be prepared in the
room pressure, velocity or air han- flow interruption. Communication area should guide the facility design
dler capacity, HEPA flow restriction, devices should be used to minimize and construction. A plan for how
duct size, the amount of process- traffic between areas, and cameras operations will continue without in-
ing completed on a daily basis, and may be installed to supplement su- terruption should be devised prior to
temperature. ACPH must occur at pervision of staff or check com- construction.

Power and Other Utility These devices are most commonly the preparation of CSPs remains the
Interruptions used for parenteral nutrition prepa- responsibility of the pharmacist.
The facility’s emergency manage- ration, but may be used for cardio-
ment plan should include steps to plegia solutions, continuous renal re- Cleaning and Disinfecting
meet patient-care needs during time placement therapy, or other complex Cleaning with a germicidal deter-
of utility interruptions, including processes. ASHP Guidelines on the gent and water will remove visible
the need for CSPs. In some cases, Safe Use of Automated Compounding solids or soiling before disinfect-
immediate-use procedures may be Devices for the Preparation of Paren- ing. Disinfecting removes microbial
safely implemented to meet some teral Nutrition Admixtures32 should contamination. It is critical that an
needs. Methods to identify and safely be consulted for further details on appropriate germicidal detergent and
meet interim compounding needs or utilizing ACDs. Accuracy and preci- water be used to clean all surfaces of

address patient-care needs with non- sion testing for ACDs is required by the buffer and ante areas in addition
compounded alternatives should be USP chapter 79715 and incorporate to all of the PECs. Great care must be
developed, put into standard operat- gravimetric, volumetric, and chemi- exercised to avoid getting the HEPA
ing procedures (SOPs), inserviced to cal analyses. These analyses, as deter- filters wet during cleaning. Cleaning
staff, and tested as part of the organi- mined by facility protocol, must be with a germicidal detergent will leave
zation’s emergency planning process. monitored and recorded on a daily a residue that needs to be removed
basis, with evaluation for outliers oc- from work surfaces (e.g., counter and
Pharmacy Compounding Devices curring at least weekly. PEC surfaces). This residue is best re-
Pharmacy compounding devices Repeater pumps are devices used moved by using sterile 70% isopropyl
are utilized to increase efficiency to pump a preset volume of fluid in a alcohol (IPA).
while decreasing the potential for hu- consistent and reproducible manner. Appendix II of USP chapter 79715
man error. Devices that do not create They must be calibrated according to provides information on types of
their own ISO Class 5 environment manufacturer specifications, which products that can be used for clean-
must be located within an ISO Class may depend on the volume and fre- ing and disinfecting the ante and
5 PEC and adhere to applicable stan- quency of use. buffer areas, including floors, walls,
dards for accuracy and precision. All Robotic systems automate the and ceilings. Choice of cleaning and
compounding devices must be moni- compounding and labeling of par- disinfection products should be ap-
tored and validated for accuracy enteral doses in syringes and bags proved by the organization’s appro-
consistent with device manufacturer using an enclosed chamber that must priate authority (e.g., the Infection
specifications. create an ISO Class 5 air cleanliness Control Committee).
Automated Compounding Devic- environment or better. Policies and procedures must
es (ACDs) are utilized to accurately The proper use of ACDs, repeater be developed to ensure consistent
combine multiple drugs and solu- pumps, robotic systems, and other practices, including dilution of clean-
tions into a single delivery container. compounding equipment used in ing products. Table 3 describes the
minimum frequency for cleaning
surfaces used to compound low- and
medium-risk CSPs in the sterile com-
Table 3. pounding area.
Minimum Frequency for Cleaning of Specific Sites (Reprinted
with Permission from USP Chapter 79715) Environmental Monitoring
Environmental monitoring and
Site Minimum Frequency
related documentation must be com-
ISO Class 5 PEC Beginning of each shift pleted on a routine basis to ensure
Before each batch
adequate environmental and person-
Every 30 minutes when compounding
After spills
nel controls are in place to prevent
When surface contamination is known contamination of CSPs. Ensuring a
or suspected safe compounding environment re-
Counters and easily cleanable quires viable and nonviable airborne
work surfaces Daily particle testing, pressure differential
Floors Daily or displacement airflow measure-
Walls Monthly ment, temperature monitoring, and
Ceilings Monthly surface disinfection sampling and
Storage shelving Monthly assessment. Nonviable particles are

particles that do not contain a liv- Records of data collected through air displacement velocities must be
ing organism, such as particles shed the monitoring program must be maintained. If closed architecture is
from paper or dust. Viable particles maintained as part of the overall used, a pressure differential between
are living organisms, such as bacteria quality assurance program of the general, ante, and buffer areas must
or fungal spores, that require nonvi- facility. The data should be reviewed be monitored. A facility with open
able particles to travel. Monitoring of by management personnel or their architecture design must monitor
humidity,39,44 sound,39 and lighting39 designees and by the facility’s Infec- the differential airflow across the
may also be considered by facilities to tion Control Committee to ensure opening between ante and buffer
enhance the environmental monitor- that the findings of the reports are areas.
ing program. addressed. Table 4 provides an over- A pressure gauge or velocity meter
Each element of the monitor- view of environmental monitoring must be in place to monitor airflow

ing program must be included in a requirements. between relevant areas. Pressure be-
sampling plan with sample locations, Temperature Monitoring. Any tween ISO Class 7 positive-pressure
methods of collection, sampling controlled temperature area used areas and the general area must be at
frequency, and other specifics de- for compounding sterile prepa- least 5 Pa (0.02-inch water column).
pending on the type of monitoring rations or for storage of sterile Negative pressure areas should have
being performed. The environmen- products or CSPs must be moni- no less than 2.5 Pa (0.01-inch water
tal monitoring sampling frequency tored at least once daily and results column) negative pressure to adja-
must occur at a minimum as listed documented in a log. The facilities cent positive pressure. A monitored
below, with possible additional times should maintain a comfortable pressure indicator must be installed
based on the type of testing: room temperature (20 °C [68 °F] to ensure proper pressurization. If
or cooler) for properly garbed com- differential airflow is used as a mea-
• At the commissioning and certification pounding personnel. If facilities use sure, the velocity must be at least
of new facilities and equipment. continuous temperature recording 0.2 meter per second (40 feet per
• Every six months during routine re- devices, they must be monitored minute).
certification of equipment and facilities. and documented once daily to en- Results of pressure differential
• After any facility or equipment main- sure they are functioning properly. and/or velocity of air displacement
tenance, including construction or Controlled temperature ranges are must be reviewed and documented
remodeling of adjacent departments or listed in Table 5. each shift (at least daily) or by a con-
work on shared air handlers. Pressure Differential or Air Dis- tinuous device with alarms.
• At any point when problems are identi- placement. Since positive- and/or Nonviable Airborne Particle Test-
fied with products, preparations, or em- negative-pressure rooms are required ing Program. Determination of the
ployee technique or if a CSP is suspected for sterile compounding, the ap- ISO classification of an area or device
to be the source of a patient infection. propriate differential pressure or is dependent on nonviable particle
Table 4.
Environmental Monitoring Requirements (Adapted from USP Chapter 79715)
Parameter Monitored By Frequency
Temperature Compounding personnel or facilities Documented daily (at a minimum)
management staff (if electronic
monitoring is centralized)
Pressure differential or Compounding personnel Documented each shift (preferably), daily
velocity across line of (at a minimum)
demarcation Qualified certifier At least every 6 months
Nonviable particles Qualified certifier At least every 6 months
Surface sampling Compounding or laboratory personnel Periodically, as defined by compounding and
infection control personnel, at least every 6
months or after significant changes in procedures
or cleaning practices
Electronic device sample of Compounding personnel or qualified At least every 6 months
viable particles certifier

testing (“certification”), which must overall compounding recertification Sample data must be reviewed as
be completed by qualified person- process. The method of testing must a means of evaluating control of the
nel complying with the Certification be impaction via an electronic air compounding environment. Results
Guide for Sterile Compounding sampling device, as settling plates above recommended action levels
Facilities (CAG-003-2006).39 PECs alone are not considered an accept- (see Table 7) should prompt reevalu-
such as LAFWs, BSCs, CAIs, and able method. ation of work practices, cleaning
CACIs must be certified every 6 Sampling plans should be detailed procedures, and HEPA filtration.
months and whenever the device is and include all high-traffic loca- Any microbial growth that results
relocated or serviced. Both primary tions within the compounding area from viable environment sampling
(LAFWs, BSCs, CAIs, and CACIs) and any sites prone to contamina- must be identified to the genus level
and secondary engineering controls tion. Turbulence caused by airflow by microbiology personnel. If any

(buffer areas and ante areas) must disruption, such as within an ISO highly pathogenic organisms (e.g.,
be checked for total particle counts Class 5 LAFW or doorways, should gram-negative rods or yeasts) are
every 6 months according to the be included in the testing plan, along identified, infection control special-
manufacturer’s specifications or with areas where garbing, cleaning, ists should immediately be consulted
CETA recommendation and when labeling, and staging occur. In segre- to assist in formulating a response to
a device or room is relocated or al- gated compounding areas, sampling the situation.
tered. Thresholds for each ISO class should include locations within the Surface Disinfection Sampling
are presented in Table 6. ISO Class 5 PEC and other areas in and Assessment. Touch contamina-
Viable Airborne Particle Testing close proximity to the PEC. tion originating from contaminated
Program. Classified space (PECs and Viable particle testing must be work surfaces must be minimized
buffer and ante areas) must undergo performed using a general micro- and prevented if possible. Surface
routine viable particle testing. The biological growth medium, such as sampling provides facilities with a
testing plan should include the re- sterile nutrient agar. In facilities snapshot of the effectiveness of their
quired sample locations, method of that compound high-risk prepara- disinfection procedures (including
collection, frequency, the volume of tions, testing must also be done technique and cleaning products)
air to be tested, and the time of day with a medium that supports fun- and must be part of the overall qual-
testing will occur. Testing must occur gal growth, such as malt extract. ity assurance plan. Using a sterile
every 6 months in all compounding The growth medium should be nutrient agar contact plate for flat
areas (PECs, buffer areas, ante areas, incubated (outside of the sterile surfaces or swabs for equipment and
and areas adjacent to segregated preparation area) according to the other non-flat surfaces, sampling
compounding areas) as part of the manufacturer’s recommendations. must be performed in all ISO clas-
sified areas on a periodic basis, at a
minimum every 6 months, or when
significant procedural or cleaning
Table 5. changes are implemented. A specific
Controlled Temperatures (Data from USP General Notices and plan detailing the location of each
Requirements58) sample must be devised so that the
same locations are repeated with
Storage Condition Centigrade Fahrenheit
each testing session. Contact plates
Room temperature 20 to 25 °C 68 to 77 °F require pressing a plate directly to
Cold temperature (refrigerated) 2 to 8 °C 36 to 46 °F the surface being tested, while swab-
Freezer (frozen) −25 to −10 °C –13 to 14 °F
bing requires swabbing an area,
Table 6.
Particle Limits for Sterile Compounding Areas (Adapted from USP Chapter 79715)
Primary Engineering Buffer Area and Ante-Area Ante-Area Opening
Controls Opening into a Negative Only into a Positive
(LAFW, BSC, CAI, CACI) Pressure Room Pressure Room
ISO Class 5 7 8
Limit on number of ≥0.5 micron
particles/m3 of air 3,520 352,000 3,520,000

submersing the swab in the correct Expiration and Beyond-Use Processes such as thin-layer
amount of diluent, and then swab- Dating chromatography (TLC) and high-
bing onto or into a sterile nutrient A manufacturer’s expiration date performance liquid chromatographic
agar surface. Agar plates will leave is the date assigned pursuant to man- (HPLC) assays are the most reliable
a residue on contact surfaces that ufacturer testing. The drug product means of determining the stability
must be cleaned with sterile water is guaranteed by the manufacturer to of a product and should be used in
and disinfected with sterile 70% be safe and effective up to the listed place of theoretical predictions of
IPA. date when products are stored as de- stability when published literature
Results must be reported in colony- scribed in the product labeling. is not available. The use of commer-
forming units (CFUs) per plate. A beyond-use date (BUD) is the cial reference laboratories that offer
Reevaluation of work practices and date or time after which administra- qualitative and quantitative testing

cleaning procedures should occur if tion of a CSP shall not be initiated. As may serve as a key resource for end-
the CFU count exceeds the suggested described in previous ASHP guide- product testing.
action levels (Table 8). Investigation lines14 and in USP chapter 797,15 the
into the source of contamination BUD is determined from the date or Risk-Level Classification
should be undertaken, the sources time the preparation is compounded, In these guidelines, as in previous
eliminated, and the area cleaned and its chemical stability, and the sterility ASHP guidelines14 and USP chapter
re-sampled. limits described later in these guide- 797,15 CSPs are stratified by poten-
Environmental monitoring and lines. Both the stability of the compo- tial risk of microbial contamination
quality assurance programs and nents and the sterility limits described into three primary categories: low-,
documentation may be completed by above must be taken into consider- medium-, and high-risk CSPs, with
a limited number of personnel in any ation when determining BUDs, and an additional category for CSPs
given facility, but the actions of all the BUD must be the shorter of the intended for immediate use15 and
compounding personnel may affect sterility dating or chemical stability a sub-category for low-risk CSPs
these two critical elements of com- dating. Information regarding stabil- intended for use within 12 hours.15
pliance. All compounding personnel ity dating procedures and defaults The potential risk is based on the
should be familiar with all facility can be found in USP chapter 795, danger of exposing multiple patients
policies and procedures specific to Pharmaceutical Compounding— to microbial bioburden and based on
CSPs, even if the procedures are not Non-Sterile Preparations,59 and other microbial growth factors influenced
typically their responsibility. published literature sources.60,61 by product storage time, tempera-
ture and product ability to support
microbial growth, surface and time
Table 7.
exposure of critical sites, and micro-
Viable Environmental Monitoring Recommended Action Levels
bial bioburden in the environment.
for Microbial Contamination (Adapted from USP Chapter 79715)
Compounding personnel must de-
termine the appropriate risk level
Recommended Action and the appropriate BUD for use
Levels for Microbial Contamination
ISO Classification (CFUs/m3)a based upon chemical stability and
5 1b
the potential for microbial, physical,
7 10 or chemical contamination during
8 or above 100 compounding. In making a risk-
CFUs/m3, colony-forming units per cubic meter.
a level determination, compounding
Samples from ISO Class 5 environments should normally yield no microbiological contaminants.
b
personnel must evaluate where the
Table 8.
Recommended Action Levels for Personnel Testing (Adapted from USP Chapter 79715)a
PEC Buffer Area Ante Area
Viable airborne particle testing action levels for contamination
(CFUs per cubic meter [1000 L] of air per plate) >1 >10 >100
Surface sample contamination (CFUs per plate) >3 >5 >100
Glove fingertip sampling >3 N/A N/A
a
CFUs = colony-forming units.

preparation is being made, the num- assignment unclear, guidelines for Low-Risk CSPs
ber of components or the number the more stringent risk level should This category encompasses simple
of aseptic breaches needed to com- prevail. For examples and a compari- admixtures involving closed-system
pound the preparation, and the com- son of the risk levels, requirements, transfer, measuring, and mixing of
plexity of the compounding process. and BUDs to be used in risk-level three or fewer commercially manu-
When circumstances make risk-level determination, see Table 9. factured sterile products (including
Table 9.
CSP Risk Levels and Beyond-Use Dates (BUDs) (Adapted from USP Chapter 79715)a

BUDs of CSP Stored at
Aseptic
Risk Compounding Garbing Technique Room Frozen
Category Location Required Required Examples Temperature Refrigerated (≤10 °C)
Low-risk ISO Class 5 PEC, Yes Yes Reconstitution of a 48 hours 14 days 45 days
ISO Class 7 single-dose vial, single
buffer area, ISO preparation of a small
Class 8b ante volume parenteral,
area single large volume IV
replacement fluids with no
more than 3 components
Low-risk with ISO Class 5 PEC Yes Yes Same as low-risk examples, 12 hours 12 hours N/A
<12-hour segregated non-hazardous
BUD from other preparations only
operations
Medium-risk ISO Class 5 PEC, Yes Yes Batched syringes, total 30 hours 9 days 45 days
ISO Class 7 parenteral nutrition,
buffer area, ISO ophthalmic preparations
Class 8b ante made from sterile
area products, pooled
admixtures, batch-
compounded preparations
without bateriostatic
additives, preparations
made using automated
compounders or other
automated devices,
elastomeric pumps
High-risk ISO Class 5 PEC, Yes Yes CSPs prepared from bulk, 24 hours 3 days 45 days
ISO Class 7 nonsterile components
buffer area, ISO or in final containers
Class 7 ante which are not sterile;
area preparations that must be
terminally sterilized before
administration
Immediate- Medication No Yes Emergent use preparations 1 hour N/A N/A
use preparation such as epidurals
areas should prepared by anesthesia
be clean, for immediate injection
uncluttered, or infusion, diagnostics,
and functionally any non-hazardous
separatec preparations that might
cause harm due to delays
in administration
a
ISO = International Organization for Standardization, PEC = primary engineering control, IV = intravenous.
b
Ante area must be ISO 7 if it opens into a negative pressure buffer area.
c
Source: The Joint Commission. MM.05.01.07, EP2.24

the infusion solution). Low-risk tiple patients (i.e., batching of syring- level of less than 10-6 or a probabil-
compounding conditions must in- es or large volumes), or one patient on ity of 1 nonsterile unit per 1 million
clude all of the following: multiple occasions (e.g., preparation sterilized units.57 For CSPs that are
for use over several days).49 heat-labile and cannot be processed
• CSPs are compounded using aseptic • More than three commercially available as above, sterilization using an alter-
technique within an ISO Class 5 PEC sterile products are used to produce the native method, such as a sterilizing
(e.g., LAFW, BSC, CAI, or CACI) that compound. grade 0.22 micron filter, must be
is located within an ISO Class 7 buffer • More complex compounding processes done. Filtration only achieves a ste-
area with an ISO Class 8 ante area. (e.g., total parenteral nutrition). rility assurance level of 10-3, which is
• Each container, including the final con- only 1 nonsterile unit per one thou-
All requirements for low-risk sand filtrated units. All filters used

tainer, may not be entered more than
twice to prepare the CSP. compounding regarding location and to sterilize CSPs must undergo filter
• Compounding is limited to aseptic aseptic technique must be followed. integrity (bubble-point) testing.
manipulations of disinfected containers
High-Risk CSPs Immediate-Use CSPs
using sterile needles and syringes.
High-risk CSPs are those The immediate-use category
Low-Risk CSPs for Use Within 12 should be reserved for emergent use
Hours. Under limited circumstances, • Prepared from nonsterile ingredients, or situations in which adhering to
sterile compounding may occur in a including manufactured products low-risk compounding procedures
segregated compounding area (such not intended for sterile routes of would add additional risk due to de-
as a satellite pharmacy or dedicated administration; lays in patient care. Examples of such
sterile compounding space) in which • Compounded using a nonsterile device situations may include cardiopulmo-
the ISO Class 5 PEC is not located prior to terminal sterilization; nary resuscitation, diagnostic proce-
within an ISO Class 7 buffer area. • Containing nonsterile water that are dures, or short-stability medications
A segregated compounding area is stored for more than 6 hours before that must be prepared immediately
a designated space, either a demar- sterilization; before administration outside health
cated area or room, in which com- • Exposed to conditions worse than ISO care facilities (e.g., in home infusion
pounding is restricted to preparing Class 5 air quality for longer than 1 or emergency care at the accident site
low-risk, nonhazardous CSPs with a hour, if they contain or are compound- or in an ambulance). Immediate-use
beyond-use time of no more than 12 ed from sterile contents of commercially CSPs do not need to be compounded
hours from the time of preparation. manufactured products or CSPs within an ISO Class 5 environment and
All other requirements for low-risk out antimicrobial preservatives; garbing and gowning are not re-
CSPs must be followed, with the • Containing bulk ingredients whose quired, as long as all of the following
exception that the ISO Class 5 PEC chemical purity and content strength are criteria are met:
is not required to be located within not verified by labeling and documenta-
an ISO Class 7 buffer area. The PEC tion from suppliers or by direct determi- • Hand hygiene per CDC
must be separate from other op- nation; or recommendations46;
erations, including sinks and other • Prepared by compounding person- • Aseptic technique is followed;
water sources or drains, and away nel who are improperly garbed or • No hazardous drugs are used;
from unsealed windows or doors gloved. • Only simple transfer of no more than
that connect to high traffic areas, three sterile, non-hazardous drugs in
construction, warehouses, or food Presterilization procedures for the manufacturer’s original containers
preparation areas. Distinct labeling high-risk level CSPs, such as weigh- are involved in the compounding, and
for conveying short BUDs should be ing and mixing, shall be completed no more than two entries into any one
considered. in no worse than an ISO Class 8 container occur;
environment. • No more than 1 hour elapses from

Medium-Risk CSPs CSPs in this category must be the time compounding commences
This category encompasses prepa- terminally sterilized before admin- to the time administration to the pa-
rations requiring more complex istration to patients. Terminal steril- tient begins (although best practice
compounding processes, including ization is defined by the FDA as the dictates that there are no interven-
application of a lethal process (e.g., ing steps between compounding and
• Multiple doses of sterile products com- steam under pressure or autoclaving) administration);
bined or pooled to prepare a product to sealed containers for the purpose • No batching or storage of CSPs occurs;

that will be administered either to mul- of achieving a sterility assurance and

• The preparation is labeled with patient (but not activated) by pharmacy staff dose vial for purposes of determining
identification, names and amounts of within an ISO Class 5 environment. BUDs. Manufacturer’s information
all ingredients, name or initials of pre- Activation of the devices should be for each PBP contains recommended
parer, and exact 1-hour BUD and time. completed at the point of care just BUDs, which are usually between 4
prior to administration. and 8 hours.
If CSPs prepared for immediate Multiple-dose vials may be reused
use are not administered within 1 Ampuls, Single-Dose, and or saved up to the manufacturer’s
hour, they must be properly discard- Multiple-Dose Containers recommended BUD, if they are
ed. All medications must be labeled Ampuls may not be reused or not opened in a direct patient-care
to meet regulatory and accreditation saved at any time during the com- area and if facility policy does not
standards and in accordance with pounding process. To minimize require a shorter period.66 If there is

facility policy. particulate contamination, 5 micron no manufacturer recommendation,
filter straws or filter needles must be multiple-dose vials may be reused or
Point-of-Care Activation Systems used when withdrawing contents of saved up to a maximum of 28 days
Point-of-care (POC) activation ampuls. Refer to the drug labeling for or for a shorter period dictated by
systems (i.e., vial/bag systems) create manufacturer’s recommendations facility policy. Table 11 illustrates the
a physical barrier between compo- concerning filtration. dating for these products based on
nents (fluid and medication) that can The environmental conditions in environmental conditions.
be activated to allow the components which drug vials are entered deter- The person who first punctures a
to mix. These devices are designed to mine the BUD for the CSP. Single- multiple-dose container intended for
create a closed system by which the dose vials are intended to be used re-use must note the BUD and other
end user activates the components to prepare single doses; however, in information required by facility
just prior to the administration of the times of critical need, contents from policy (e.g., his or her initials) on the
medication. BUDs for these products unopened single-dose/single-use vi- vial or attached label. A label indicat-
are based on the individual manufac- als may be repackaged for multiple ing “use by” clarifies that the date is
turer’s recommendations for labeling patients.49 This repackaging should the BUD rather than the opening
and dating. Table 10 provides a sum- only be performed by qualified date. If a vial lacks a BUD, it should
mary of manufacturer-recommended health care personnel in accordance not be used and should be properly
BUDs for POC systems at time of with the procedures described in discarded.
publication. To decrease potential these guidelines and in USP chapter
for contamination and errors, POC 797.15 Batch Compounding and Sterility
systems that will be attached and Pharmacy bulk packages (PBPs), Testing
stored for longer than 1 hour prior a type of vial containing many single Use of CSPs stored for extended
to activation should be assembled doses,65 must be considered a single- periods of time is guided by the
Table 10.
Beyond-Use Date (BUD) at Room Temperature for Point-of-Care Activated Devices Assembled in ISO
Class 5 Environmenta
Device Company BUDb Applicable Products
ADD-Vantage62 Hospira 30 days from date diluent removed
from overwrap
Mini-Bag Plus63 Baxter 15 days from date diluent removed 50 and 100 mL bags
from overwrap
Mini-Bag Plus63 Baxter 30 days from date diluent removed 100 mL containers docked with the following
from overwrap drugs: cefazolin 1 g, cefuroxime (Zinacef ) 750
mg, ceftriaxone (Rocephin) 1 g, aztreonam
(Azactam) 1 g, piperacillin and tazobactam
(Zosyn) 3.375 g
addEASE64 B. Braun 70 days When connected to 50 mL and 100 mL bags
56 days When connected to Excel 250 mL bags
a
Information is current as of January 2011. The manufacturer’s package insert should always be checked for the most current recommendation for dating.
b
BUD for assembled but not activated system.

chemical stability of components rogen) testing prior to dispensing available, default guidance can be
and the sterility limits of the CSP de- or administration. Sterility testing, found in USP chapter 85.68
fined above. If medium-risk batches as outlined in USP chapter 71, must For high-risk preparations, batch-
are prepared and assigned a BUD be completed prior to dispensing or es of 25 or fewer CSPs do not require
within those limits, no sterility test- administration. 67 USP Membrane sterility testing.15 However, facilities
ing is required. However, if those Filtration, USP Direct Inoculation should consider sterility testing of
limits are exceeded, each batch must of the Culture Medium, or another such CSPs as part of their quality as-
be tested for sterility according to the testing method that produces veri- surance plans to ensure that proper
requirements of USP chapter 71.67 fication results statistically compa- procedures are being followed.
Facilities that wish to store CSPs rable with those methods may be
for periods longer than those de- utilized.67 Outsourced CSPs

scribed above must complete sterility If sterility testing results are not Outsourcing the preparation of
testing for each batch to determine received prior to dispensing, pro- CSPs to pharmacies that specialize
the extended BUD. Each batch of any cedures must be in place for daily in sterile compounding provides an
risk-level CSP intended for storage observation of the sterility test speci- option for facilities that cannot or do
outside the limits described above mens, immediate recall of dispensed not wish to prepare all or some types
must be tested for sterility, according CSPs, and notification of patients of CSPs (e.g., radiopharmaceuticals,
to the requirements of USP chapter and their physicians if microbial high-risk CSPs, parenteral nutrition)
71, Sterility Tests.67 The results must or fungal growth is observed. An in their own facility. Facilities con-
be evaluated along with stability data investigation into the root cause of sidering outsourcing compounding
to establish the extended BUD. The contamination must occur if sterility should consult the ASHP Guidelines
policies and procedures of the indi- testing is positive. on Outsourcing Sterile Compounding
vidual facility must outline the pro- All high-risk CSPs prepared in Services.16 The decision to use CSPs
cesses used to determine extended batches of more than 25 units, with prepared by outside compounding
BUDs. the exception of inhalation or oph- pharmacies should be reviewed and
Batches of high-risk CSPs pre- thalmic preparations, must be tested approved by hospital leadership,23,70
pared as multiple-dose vials intended to ensure that they do not contain and such use should only occur in
for administration to multiple pa- excessive bacterial endotoxins, as de- accordance with written policies and
tients, batches of high-risk CSPs scribed in USP chapter 85, Bacterial procedures.
exposed for more than 12 hours to Endotoxins Test,68 and USP chapter
temperatures of 2 to 8 °C (36 to 46 °F) 151, Pyrogen Test.69 Endotoxin limits Administration of CSPs
or for more than 6 hours to tempera- (reported in USP endotoxin units/ USP chapter 797 does not include
tures above 8 °C (46 °F) before ster- hour/kg or units/hour/m2), if estab- any specifications for administration
ilization, or batches of more than 25 lished, are included in the official or timing during this crucial pe-
identical, single-dose, high-risk CSPs monograph for the product or may riod of the drug delivery cycle. CDC
must undergo sterilization and mi- be found in other formula sources. provides the most comprehensive
crobial and bacterial endotoxin (py- If specific endotoxin limits are not guidance regarding administration
Table 11.
Beyond-Use Dates for Ampuls, Single-Dose, and Multiple-Dose Containers (Adapted from USP Chapter
79715)
Opened and Maintained Opened Outside an ISO Class 5
within an ISO Class 5 Environment or Taken from ISO Class 5
Container Environment Conditions to Less Clean Air
Ampuls One time use; cannot be stored One time use; cannot be stored
Single-dose vials One time use, cannot be stored; contents One time use; cannot be stored
of unopened vial may be repackaged
in times of critical need49
Pharmacy bulk packages 6 hoursa Not intended for use outside ISO 5
environment
Multiple-dose vials 28 daysa 28 daysa
Unless otherwise specified by manufacturer.
a

of intravenous medications, includ- bining different agents in a prepa- to hand hygiene and garbing and
ing administration times, frequency ration may affect bioavailability, should not be used within the sterile
of infusion set changes, use of filters, compatibility (visual and chemi- compounding area.
and prevention of catheter-related cal), pH, and concentration effects. Hand hygiene must be per-
infections.38,47 Factors that influence stability (e.g., formed prior to and after gowning
temperature, pH, sorption, pho- and includes
Personnel tolysis, and chemical degradation)
must be carefully evaluated and sup- • Washing hands, under the fingernails,
Personnel Responsibilities ported by references or appropriate wrists, and up to the elbow for 30 sec-
The term compounding personnel testing. onds with a facility-approved agent.
refers to any individual involved in Compounding personnel must

• Drying hands and arms with nonshed-
compounding sterile preparations, understand and demonstrate com- ding disposable towels or an electronic
regardless of profession. Compound- petency in aseptic technique and hand dryer.
ing personnel are responsible for en- for the products and systems used • Sanitizing hands with application of
suring that CSPs are accurately iden- in CSP preparation, such as needles, a waterless, alcohol-based hand rub
tified, measured, diluted, and mixed syringes, administration sets, fluid (ABHR) with persistent activity prior to
and are correctly purified, sterilized, containers, and compounding de- donning sterile gloves.
packaged, sealed, labeled, stored, vices. Aseptic principles and tech-
dispensed, distributed, and disposed niques are explained in depth in Garbing occurs in the ante area
of if not used. Emphasis should be Compounding Sterile Preparations53 and should be sequenced as follows
on the need to maintain quality stan- and demonstrated in Basics of Aseptic (from “dirtiest” to “cleanest”):
dards for the control of processes, Compounding Technique,54 Getting
components, and environments and Started in Aseptic Compounding,55 • Don shoe covers, hair and beard covers,
for the skill and knowledge of per- and Compounding Sterile Prepara- and a mask.
sonnel who prepare CSPs. tions: ASHP’s Video Guide to Chapter • Perform hand hygiene.
Accurate identification and in- <797>.56 Personnel must understand • Don gown, fastened securely at the neck
spection of quality and purity of the types of PECs, HEPA filtration, and wrists.
non-sterile chemicals or non-sterile and airflow concepts that are critical • Sanitize hands using an ABHR and al-
ingredients are necessary for the in- to sterile compounding. low hands to dry.
tegrity of the finished preparations. Policies should be developed in • Enter the buffer area (if facility layout
Upon arrival from the manufacturer conjunction with employee health dictates, this step may occur after the
and subsequently after opening, bulk or infection control personnel to set following two steps).
packages should be inspected for thresholds for health status fitness • Don sterile powder-free gloves.
breaks in the package or closure in- for compounding personnel. Com- • Sanitize the gloves with application
tegrity and for proper appearance, pounding personnel with weeping of 70% sterile IPA and allow gloves to
color, odor, and texture. sores, rashes, conjunctivitis, or respi- dry.
If nonsterile ingredients are not ratory infections must not partici-
official USP or National Formulary pate in compounding processes until Studies support the use of sterile
products, compounding person- these conditions resolve. rather than nonsterile gloves in the
nel must require a Certificate of Hygiene and Garbing. Proper reduction of initial bioburden. 71
Analysis from the manufacturer to preparation for sterile, nonhazard- Furthermore, nonsterile gloves run
accompany the products.59 Once a ous drug compounding must include the risk of cross-contamination from
product is received from the manu- effective hand hygiene and garbing hands touching multiple gloves as
facturer, the date of receipt must be procedures. To minimize the number they are removed from a stock box or
clearly marked on each package. If a of particles introduced into the ster- container. Gloves must be inspected
manufacturer’s expiration date is not ile compounding area and to mini- by personnel on a routine basis dur-
provided, chemicals should be given mize the risk of bacteria, all outer ing the compounding process to
a three-year BUD from the time of jackets and sweaters, visible jew- check for tears or holes. The gloves
opening unless inspection or test- elry, and cosmetics must be removed should be disinfected with sterile
ing deems the product within drug prior to initiating the handwashing 70% IPA throughout the compound-
monograph specification (if avail- and garbing processes. Personal ing process and each time contami-
able) to be used for a longer time.59 electronic devices (e.g., cell phones, nated items are touched.
Compounding personnel must MP3 players) and any associated at- When high-risk compounding
have an understanding of how com- tachments must be removed prior operations prior to terminal steriliza-

tion occur, personnel must glove and When used for sterile compound- pounding accuracy processes are in
garb as stated above. ing, items in plastic or foil overwrap place, and (when applicable) steril-
When exiting the compounding should remain in the overwrap until ity and endotoxin testing. Finished
area during a work shift, gowns that introduced into the ISO Class 5 preparation evaluation is the respon-
are not soiled may be removed and PEC, at which point they should be sibility of compounding personnel
retained in the ante area and re-worn opened immediately before placing and should be performed during
during the same work shift. All other in the PEC and the overwrap im- the compounding process and when
garb, including gloves, must be re- mediately discarded.75 Items stored the preparation leaves the storage
moved and replaced, and proper hand in the buffer area but not in an over- area. Visual inspection should assess
hygiene must be completed before wrap must be decontaminated again particulate matter, coring, cloudi-
re-entering the compounding area. prior to entering the PEC, as items ness, leaks, and container and closure

When CAIs are utilized, compound- may be stored in a buffer area for an integrity.
ing personnel must glove and garb extended period of time and may be- Compounding accuracy checks
as above, unless the manufacturer of come contaminated by dust or other must comply with federal and state
the isolator provides written docu- particles. dispensing regulations and include
mentation based on environmental accuracy of the product or prepara-
testing that any or all of the com- Packaging and Labeling tion and the labeling. Prescription
ponents of personnel hygiene and Packaging and subsequent label- orders, compounding procedures,
garbing are not required based on the ing are critical to patient safety. Pack- records, and materials used to prepare
PECs of the facility where the device aging must be appropriate to pre- the compounds should be evaluated.
is located. serve both sterility and stability until A process should be implemented
Proper garb should always be used the BUD. Proper labeling requires an to confirm that the compounding
with CACIs, because personnel will understanding of compounding risk process and end-preparation testing
be handling hazardous materials. Vi- levels and how to determine BUDs are properly done. Checking proce-
als may be contaminated, even upon based on both stability and sterility. dures should follow facility policy
delivery,72-74 and the garb is needed Labels for single compounded and procedures and may be accom-
to protect compounding personnel preparations must, at a minimum, plished via cameras or other devices,
from unexpected drug residue and include the following: by video recordings, or by keeping
from inadvertent spills. the used additive containers and
Compounding Areas. Compound- • Names of active ingredients, syringes with the final product until
ing personnel must understand the • Amounts or concentrations of active checked. The check ideally should be
purposes of and relationships be- ingredients, performed by someone other than
tween ante, buffer, segregated, and • BUD and time, the compounder to decrease confir-
storage areas. A systematic process of • Storage requirements, and mation bias. Accuracy can be further
entering and exiting the various areas • Identification of responsible com- verified by weighing when applicable
is necessary to minimize contami- pounding personnel. and practical. When using an ACD,
nation. Food, drinks, and gum are specific gravity values must be in-
prohibited in all of these areas. Since Labels for batch-prepared CSPs dependently confirmed after being
shedding from paper and labels pro- must also include entered to ensure proper volumes are
vides a source of nonviable particles, delivered during the compounding
only paper products essential to the • Control or lot number, process.
compounding process should be al- • Appropriate auxiliary labeling (includ-
lowed in the buffer area. Corrugated ing precautions), and Storage of CSPs
cardboard packaging must be elimi- • Device-specific instructions (when Temperatures of areas used for
nated from buffer areas and should appropriate). storage on patient-care and proce-
be eliminated from ante areas, with dural units, including room temper-
all products and components such Federal and state regulations and ature and in refrigerators, freezers,
as needles, syringes, and tubing re- accreditation requirements may and warmers, must be monitored
moved from their outer cardboard necessitate additional label informa- and recorded daily. On at least a
packaging and decontaminated by tion before the CSP is dispensed to a monthly basis, compounding per-
wiping the individual packages (if specific patient. sonnel or designated pharmacy per-
not in an overwrap) with a suitable Verification of compounding sonnel should evaluate storage areas
disinfectant (e.g., 70% IPA) prior to accuracy and sterility incorporates for appropriate secure conditions,
entering the buffer area. physical inspection, ensuring com- separation of drugs and food, and

proper use and disposal of single- leakage or accidental exposure dur- Health Administration (OSHA) re-
and multiple-dose vials. ing transport, and they should not quires that employers and employees
be delivered using a pneumatic tube be made aware of the hazards of all
Control and Oversight of IV device due to the risk of contamina- chemicals used in the workplace,
Solutions tion to the environment if breakage including drugs. 76 Compounding
Some facilities delegate storage occurs. Cleaning protocols for pneu- personnel of reproductive capabil-
and distribution of parenteral so- matic tube systems are inadequate ity shall confirm in writing that they
lutions to materials management. for hazardous drug contamination understand the risks of handling
Since the products are prescription throughout the system. hazardous drugs.15 Personnel at high
drugs, the pharmacy must maintain Transport may occur outside of risk of exposure to hazardous drugs
oversight, including selection of ap- the compounding facility to other should be enrolled in a medical sur-

propriate products, package sizes, facilities or directly to patients. In veillance program. In many larger
and forms; safe and secure storage; these situations, compounding per- facilities, the employee’s health de-
and temperature control. IV solu- sonnel must ensure physical integrity, partment will determine who should
tions that contain medications (e.g., sterility, and stability are maintained be enrolled. Specific guidance about
potassium chloride, heparin, dopa- during transit. Proper packaging must surveillance for health care workers
mine, dextran, mannitol) or high- be chosen to prevent contamination, exposed to hazardous drugs is avail-
risk agents (e.g., sterile water, so- leaks, damage, and temperature varia- able from NIOSH,77 as is a list of
dium chloride greater than 0.9%, and tions and to protect the end recipients drugs NIOSH considers hazardous.27
parenteral nutrition components) and transporting personnel from The risks of occupational exposure to
should be stored in and distributed harm. Handling and exposure in- hazardous drugs and their potential
by the pharmacy. structions should be legibly displayed effects on compounding personnel
on the outside of shipping contain- should be conveyed to employees
Transporting CSPs ers. BUDs, storage instructions, and during employee orientation and in
All personnel involved in the han- disposal instructions for out-of-date an ongoing manner through con-
dling, transport, or storage of CSPs, preparations must be available to tinuing education and monitoring
whether they are compounding recipients, and recipients must be at least annually. Training and com-
personnel or not, must be properly able to properly store CSPs (e.g., in a petency programs should be pro-
trained to complete these tasks, and refrigerator or freezer, if necessary). vided in addition to competencies
the performance of all person- for compounding of non-hazardous
nel, including contractors, must be Redispensing CSPs sterile drugs, with details of differen-
monitored for compliance with facil- If facility policy allows redispens- tiating the garbing, storage, prepara-
ity policies. Transportation methods ing of CSPs, the process must only be tion, and disposal procedures for
for CSPs should be evaluated, as done by compounding personnel to hazardous drugs. USP chapter 797
some forms of transportation, such ensure continued sterility, purity, and requires that training, at a mini-
as pneumatic tube systems, may stability. Facilities must determine mum, include
adversely affect stability or integrity. how to track original preparation and
Pneumatic tube delivery may require thaw dates (if applicable) and be able • Safe aseptic manipulation practices.
additional padding around contain- to detect product tampering. There • Negative pressure techniques when
ers to ensure that heat and light must be policies and procedures in compounding.
exposure and impact are minimized. place to provide assurance of proper • Proper utilization of a BSC or CACI.
Some preparations may degrade if storage conditions for each product or • Correct use of closed-system transfer
shaken, and therefore personnel, preparation (e.g., refrigeration, pro- devices (CSTDs), if used.
including pharmacy and nursing tection from light, package integrity) • Containment, cleanup, and disposal
personnel, should be aware of which before redispensing. CSPs must not be procedures for breakages and spills.
preparations may not be delivered redispensed if package integrity has • Treatment of personnel contact and
via a pneumatic tube device. been compromised, including tem- inhalation exposure.15
Hazardous drug transport must perature variations.
incorporate measures to maintain OSHA requires more general
CSP integrity while minimizing the Personnel Responsibilities for training on chemical label elements
risk of drug residue exposure to Handling, Preparation, and and safety data sheet (SDS) format.76
patients, personnel, and the environ- Disposal of Cytotoxic and Other When training or evaluating compe-
ment. These preparations should al- Hazardous Agents tency, facilities may choose products
ways be delivered in a bag to prevent The Occupational Safety and to objectively evaluate hazardous

drug compounding technique. These • Direct contact contamination of critical Manufacturer’s guidelines for BUDs
products utilize dyes or fluorescence sites is minimized by utilizing aseptic should be followed for radiophar-
to determine personnel technique compounding. maceutical multiple-dose vials that
and assess for spills or hazardous • Multiple-dose vials are labeled with are compounded with technetium-
drug exposures. the name of one patient and a BUD 99m and exposed to ISO Class 5
Definitions of hazardous drugs and storage temperature range based conditions with no direct contact
and proper handling of hazardous on manufacturer recommendations contamination.
drugs, including receiving, distribu- or published literature. Single-dose
tion, stocking, inventorying, prepa- extracts are not to be stored for subse- Personnel Compounding
ration, transport, and disposal, are quent use after entry. Competency
all concepts discussed in detail in the Touch contamination remains the

ASHP Guidelines on Handling Haz- Nuclear pharmacies are regulated primary cause of microbial contami-
ardous Drugs.28 by the Nuclear Regulatory Com- nation in sterile compounding.71,80
mission as well as other applicable For this reason, personnel training
Personnel Responsibilities for pharmacy laws and regulations. USP and assessment of competency are
Specialty Preparations chapter 823, Radiopharmaceuticals of utmost importance to ensure the
Specialty preparations (e.g., al- for Positron Emission Tomography,79 lowest possible risk for contamina-
lergen extracts, radiopharmaceuti- provides the standards for produc- tion due to human error. For low-
cals, and evolving technology and tion facilities. Once the components and medium-risk operations, train-
therapeutics such as biologics and for use in positron emission tomog- ing and competency assessment are
nanotechnology) provide specific raphy are released as finished prepa- required initially upon hire or upon
treatments for patients and require rations, handling, manipulation, and transfer to compounding responsi-
specialized procedures to be fol- use are considered compounding bilities, and again at least every 12
lowed. Although compounding of by USP chapter 79715 and for the months for all staff involved in the
intradermal or subcutaneous injec- purposes of these guidelines. Low- compounding of sterile products.
tions of allergen extracts would risk-level radiopharmaceuticals are High-risk operations require more
ideally occur under conditions for those compounded from sterile com- frequent assessments, and staff
similar risk-level CSPs, they may not ponents with a volume of less than must be evaluated upon hire or
necessarily be subject to the same 100 mL for a single-dose injection transfer and again at least every six
personnel, environmental, and stor- or no more than 30 mL taken from months.
age requirements as for other CSPs a multiple-dose container.15 These As part of the training competency
of a similar risk level, as long as the radiopharmaceutical preparations assessment, a written test that evalu-
following criteria outlined by USP must be compounded in an ISO ates knowledge about proper com-
chapter 797,15 in conjunction with Class 5 PEC within an ISO Class 8 pounding SOPs, aseptic technique,
the American Academy of Otolaryn- environment. cleaning and garbing, environmental
gic Allergy and the Joint Council of Non-radiopharmaceuticals com- monitoring, calculations, risk levels
Allergy Asthma, and Immunology,78 pounded in nuclear pharmacies and BUDs, and quality assurance
are met: must be compounded under full principles must be successfully com-
USP 797 compliant conditions. The pleted. Thresholds for passing the
• Compounding process involves simple radiopharmaceutical exemption in written examination should be set by
transfer using sterile components and USP chapter 79715 does not apply to the facility. While written tests assess
allergen products. non-radiopharmaceuticals. knowledge, hands-on observation
• All allergen extracts contain effective The concept of limiting radiation of daily duties assesses for proper
preservatives to prevent microbial exposure to a level that is as low as technique. Personnel should be able
growth. reasonably achievable (ALARA) to demonstrate at least the following
• All hand hygiene, garbing, and gloving must be adhered to for handling, in a hands-on, witnessed assessment,
procedures for low-risk compounding, compounding, and visual inspec- as applicable to their compounding
with the exception of donning shoe cov- tion of products. Technetium-99m/ responsibilities:
ers, must be followed. molybdenum-99 generator system
• Ampul necks and vial stoppers are operations and storage must occur • Proper hand hygiene technique (see
disinfected by wiping with sufficient within an ISO Class 8 environment Appendix III of USP chapter 79715 for a
amounts of sterile 70% IPA to ensure and must further comply with all sample assessment form).
that the critical sites remain wet for 10 manufacturer’s recommendations • Proper gloving and garbing technique,
seconds and are allowed to dry. and federal and state regulations. including successful glove fingertip test

(see Appendix III of USP chapter 79715 should take place under conditions contamination limits can be found
for a sample assessment form). that reflect realistic workflow, such as in Table 6. Patterns of failures (per-
• Proper aseptic technique, including the end of a shift, to simulate a worst- sonnel, media, or facility) must be
successful media-fill test (see Appendix case scenario environment for com- evaluated as part of the facility’s
IV of USP chapter 79715 for a sample pounding sterile preparations. Once quality assurance plan. Qualified
assessment form). started, the test should be completed microbiology personnel and the fa-
• Proper cleaning and disinfecting pro- without interruption. Fluid culture cility’s infection control practitioner
cedures, including successful surface media are available commercially for should be consulted.
sampling test (see Appendix V of USP low- and medium-risk evaluations.
chapter 79715 for a sample assessment High-risk assessments may utilize Growth Media Requirements
form and Appendix II for information nonsterile nutrient medium in a Sterile nutrient agar for media-fill

about cleaning products). powder form, which may be diluted testing, plates for fingertip testing,
• Competency in the compounding of and sterilized by filter methods. Fin- and surface testing materials are
hazardous drugs. ished tests should be incubated per available from multiple vendors. USP
• Competency in the compounding of al- manufacturer’s recommendations. If chapters 797 and 1116 provide speci-
lergen extracts. incubators are in the pharmacy, they fications and requirements.15,81 The
• Competency in the compounding of must be placed outside the sterile media-fill testing growth media and
radiopharmaceuticals. compounding area. Ideally, the facil- viable airborne particle plates should
• Competency in the use of sterile devices, ity’s microbiology services should utilize a Soybean-Casein Digest me-
such as filter needles, injection port incubate and read the tests, provid- dium, which may also be sold as Tryp-
adapters, sterile fluid transfer devices, ing an independent evaluation by tic Soy Agar/Broth. The agar plates
and CSTDs. qualified individuals. Turbidity in the for glove fingertip testing and surface
• Competency in the use of pharmacy culture media signifies failure of the testing should utilize general nutrient
compounding devices. media-fill testing and requires retest- agar with neutralizing agents such as
• Ability to fill pump reservoirs. ing of compounding personnel. Per- lecithin and polysorbate 80.
• Competency to perform end-product sonnel who fail these tests will require
testing and sterilization. re-training and may not compound SOP Development
sterile preparations until tests have SOPs are documents containing
USP chapter 79715 requires spe- been repeated with successful results. detailed, step-by-step instructions on
cific assessments to be completed how to perform a task or procedure
using sterile nutrient agar growth Glove Fingertip Testing so that all personnel consistently
media to test for potential contami- Three sets of glove fingertip evalu- perform the task or procedure in
nation. Personnel-specific examples ations must be completed with no the same manner. SOPs are part of
of this type of testing include growth prior to personnel being a good quality assurance program
media-fill testing of aseptic tech- allowed to compound sterile prepa- within the pharmacy. They provide
nique and glove fingertip testing of rations. This initial testing involves assurance that:
compounding personnel. compounding personnel completing
all necessary hand hygiene and garb- • Equipment and facilities are properly
Media-Fill Testing ing procedures (with the exception of maintained in good working order.
As described in USP chapter 797, applying sterile 70% IPA to gloves). • Personnel are properly educated,

the media-fill component of person- Immediately upon completion of trained, and evaluated.
nel assessment provides an objective these procedures, the glove finger- • Supplies are received, stored, and dis-

evaluation of aseptic technique.15 tip and thumb samples from each posed of properly and meet compendial
Media-fill tests should be custom- hand are placed on sterile nutrient standards.
ized to mimic the most challenging agar plates. The samples should be • All tasks and procedures are performed

preparations compounded by per- incubated (such as by the facility’s uniformly and documented.
sonnel on a regular basis in a specific microbiology personnel) according
facility. Testing should occur at least to manufacturer standards. This test There are several components that
every 12 months for personnel who must be successfully completed three should be included in an SOP:
compound low- and medium-risk times initially, then at least every 12
preparations, while testing at least ev- months. Personnel compounding • Title—should clearly identify the task.
ery 6 months is required for person- high-risk products must success- • SOP number—an internal department
nel involved in compounding high- fully complete the test at least every number assigned by the organization to
risk preparations. The actual testing 6 months. Suggested thresholds for identify it.

• Author(s)—the name of the person or nutrition, hazardous drugs, epidural, Specific quality assurance mea-
persons who write the SOP so that prob- patient-controlled analgesia, or oph- sures, pursuant to each risk level
lems and revisions can be addressed. thalmics), formulas, assigning BUDs, compounded in a facility, include
• Date effective—date when the SOP is handling, and packaging. routine cleaning and disinfection
implemented into the compounding • Safety—injuries, hazardous spills, and and air quality testing, visual con-
routine. accidental exposures. firmation of proper garbing pro-
• Authorization signature—person or • Quality assurance—inspection of CSPs, cedures, review of all orders and
committee that approves the SOP. testing of CSPs, BUDs, delivery and preparations to ensure accuracy of
• Responsibility—person- or persons-in- storage of final CSPs, patient monitor- compounded products, and visual
charge who are responsible for making ing, adverse event reporting, and per- inspection of final CSPs to confirm
sure that the SOP is performed properly. the absence of particulate matter or

sonnel and environmental monitoring.
• Purpose of the procedure—brief expla- • Administration—record keeping and leakage.
nation of why the SOP is necessary or management. A critical part of any quality assur-
being implemented. ance program is proper documenta-
• Equipment and supplies required—list All significant procedures per- tion, corrective action, and follow-
of equipment and supplies needed to formed in a pharmacy should be up. Institutions must determine how
perform the SOP. covered by SOPs and documenta- results will be reported and evaluat-
• Procedure—detailed step-by-step expla- tion. These procedures should be ed, including development of action
nation that can be easily followed by dif- routinely reviewed and modified for limits and thresholds. Thresholds
ferent individuals with the same results. improvements at least annually. and follow-up mechanisms must be
The instructions should be concise to in place prior to initiating a quality
minimize any required interpretation. Quality Assurance Program assurance program or immediately
• References—references should be listed The purpose of a quality assur- after collecting initial benchmark
to support the implementation and use ance program is to provide a mecha- data. Responsible persons for com-
of the SOP. nism for monitoring, evaluating, pleting these tasks should be iden-
• Documentation form—easily accessible correcting, and improving activities tified and trained, if necessary, in
written record or log that demonstrates and processes. A quality assurance the proper execution of the quality
that the SOP is being performed rou- program should review and analyze assurance plan. Results of monitor-
tinely and properly. objective data and use these data ing and measurements should be
• Revision—documentation of the date to develop action plans. Facilities reported within and outside of the
that an SOP has been reviewed and the should actively work to correct prob- department responsible for com-
name of the reviewer. lems detected and improve activities pounding practices to committees
and processes as needed. Any plan such as Infection Control and Qual-
USP chapter 79715 lists and rec- designed to correct problems should ity Improvement.
ommends SOPs and should be include follow-up parameters to If corrective action is needed, the
reviewed to guide the pharmacy make certain actions were taken and problem should be resolved as soon
department in developing, writing, were effective. as possible. Assessment of problems
and implementing SOPs. There Activities and processes that are with compounding errors, evident
should be SOPs written to address identified based on their high fre- contamination during preparation,
tasks or procedures in the following quency, high risk, or problem-prone quarantine, or patterns of personnel
general categories: nature should have specific moni- or environmental monitoring out-
toring and evaluation criteria as- side the established parameters re-
• Pe r s o n n e l — t r a i n i n g , e d u c a t i o n , signed for objective and measurable quire formal follow-up. A root cause
skills, competency evaluations, and assessment. The quality assurance analysis, including participation by
responsibilities. program should encompass any and other facility experts such as infec-
• Facilities—access, cleaning, mainte- all activities that are included in pre- tion control personnel, should be
nance, use, monitoring, and testing. vious sections of this document as completed.82 For situations needing
• Equipment—calibration, maintenance, elements which should be assessed more time for corrective measures,
cleaning, certification, verification, and use. and documented. This includes, but an action plan should be developed
• Supplies—ordering, storing, certifica- is not limited to and followed. Indicators and effec-
tion, inspection, and disposal. tiveness of the quality assurance pro-
• Compounding procedures—preparation • Personnel training and assessment, gram should be reassessed annually.
of various sterile compounded medi- • Environmental monitoring, and New technologies, procedures,
cations (e.g., batches, total parenteral • Equipment calibration and maintenance. and policies should be incorpo-

rated on an as-needed basis. A failure Sterile Products. Am J Health-Syst Pharm. and Surveyor Guidance, Revision 10;
2000; 57:1150–69. 2012.
mode and effects analysis of new 15. Pharmaceutical compounding—sterile 27. National Institute for Occupational
techniques can serve as a valuable preparations (general information chap- Safety and Health [NIOSH]. NIOSH List
proactive assessment of the ease and ter 797). In: The United States Pharma- of Antineoplastic and Other Hazard-
copeia, 36th rev., and The national for- ous Drugs in Healthcare Settings 2012.
value prior to introduction into the mulary, 31 ed. Rockville, MD: The United www.cdc.gov/niosh/docs/2012-150/
compounding process.83 States Pharmacopeial Convention; 2013: (accessed 2012 Dec 28).
361–98. 28. American Society of Health-System
References 16. American Society of Health-System Pharmacists. ASHP guidelines on han-
1. Hasegawa GR. Caring about stability and Pharmacists. ASHP guidelines on out- dling hazardous drugs. Am J Health-Syst
compatibility. Am J Hosp Pharm. 1994; sourcing sterile compounding services. Pharm. 2006; 63:1172–93.
51:1533–4. [editorial] Am J Health-Syst Pharm. 2010; 67:757– 29. National Institute for Occupational Safe-
2. Stability considerations in dispensing 65. ty and Health [NIOSH]. NIOSH alert:

practice (general information chapter 17. ASHP Discussion Guide on USP Chap- preventing occupational exposure to an-
1191). In: The United States pharma- ter <797>; 2008. www.ashp.org/s_ashp/ tineoplastic and other hazardous drugs in
copeia, 34th rev., and The national docs/files/DiscGuide797-2008.pdf health care settings; 2004. www.cdc.gov/
formulary, 29th ed. Rockville, MD: The (accessed 2012 Dec 28). niosh/docs/2004-165/#g (accessed 2012
United States Pharmacopeial Conven- 18. Food and Drug Administration Modern- Dec 28).
tion; 2011:742–5. ization Act of 1997, Pub. L. No. 105-115, 30. National Institute for Occupational Safe-
3. Guynn JB Jr, Poretz DM, Duma RJ. 111 Stat. 2296. www.fda.gov/Regulatory ty and Health [NIOSH]. Personal protec-
Growth of various bacteria in a variety Information/Legislation/FederalFood tive equipment for health care workers
of intravenous fluids. Am J Hosp Pharm. DrugandCosmeticActFDCAct/Significant who work with hazardous drugs (NIOSH
1973; 30:321–5. AmendmentstotheFDCAct/FDAMA/ document 2009-16). www.cdc.gov/niosh/
4. Selenic D, Dodson DR, Jensen B, et al. En- default.htm (accessed 2012 Dec 28). docs/wp-solutions/2009-106/ (accessed
terobacter cloacae bloodstream infection 19. Office of Regulatory Policy and Office of 2012 Dec 20).
in pediatric patients traced to a hospital Compliance, Center for Drug Evaluation 31. American Society of Hospital Pharma-
pharmacy. Am J Health-Syst Pharm. 2003; and Research (CDER), Food and Drug Ad- cists. ASHP technical assistance bulletin
60:1440–6. ministration. Guidance for FDA staff and on pharmacy-prepared ophthalmic prod-
5. Hughes CF, Grant AF, Lick BD, et al. industry. Compliance policy guides manual. ucts. Am J Hosp Pharm. 1993; 50:1462–3.
Cardioplegic solution: a contamination Sec. 460.200. Pharmacy compounding. 32. American Society of Health-System
crisis. J Thorac Cardiovasc Surg. 1986; www.fda.gov/ICECI/ComplianceManuals/ Pharmacists. ASHP guidelines on the safe
91:296–302. Compl iancePoli cyGuidanceManu al / use of automated compounding devices
6. Dugleaux G, Coutour XL, Hecquard C, ucm074398.htm (accessed 2012 Dec 28). for the preparation of parenteral nutri-
et al. Septicemia caused by contaminated 20. Sterile drug products for home use (gen- tion admixtures. Am J Health-Syst Pharm.
parenteral nutrition pouches: the refrig- eral information chapter 1206). In: The 2000; 57:1343–8.
erator as an unusual cause. J Parenter United States pharmacopeia, 23rd rev., 33. American Society of Health-System
Enteral Nutr. 1991; 15:474–5. and The national formulary, 19th ed. Pharmacists. ASHP guidelines: minimum
7. Sachs GS. Microbial contamination of Rockville, MD: The United State Pharma- standard for pharmacies in hospitals. Am
parenteral nutrition—How could it hap- copeial Convention; 1995:2130–43. J Health-Syst Pharm. 2013; 70:1619–30.
pen? J Parenter Enteral Nutr. 2011; 35:432. 21. Douglas K, Kastango E, Cantor P. State 34. ASPEN Task Force for the Revision of
8. Traynor K. Meningitis outbreak chal- regulations impact USP <797> compli- Safe Practices for Parenteral Nutrition:
lenges hospital pharmacies. Am J Health- ance. Pharm Purch Prod. 2012; 9:S18–S21. Mirtallo J, Canada T, Johnson D, et al.
Syst Pharm. 2012; 69:2024–6. 22. National Association of Boards of Phar- Safe Practices for Parenteral Nutrition.
9. Pierce LR, Gaines A, Varricchio R, et macy. Model State Pharmacy Act and J Parenter Enteral Nutr. 2004; 28(6):S39–
al. Hemolysis and renal failure associ- Model Rules of the National Association S70.
ated with use of sterile water for injec- of Boards of Pharmacy. www.nabp.net/ 35. Bankhead R, Boullata J, Brantley S, et al.
tion to dilute 25% human albumin publications/model-act/ (accessed 2012 Enteral nutrition practice recommen-
solution. Am J Health-Syst Pharm. 1998; Dec 28). dations. J Parenter Enteral Nutr. 2009;
55:1057,1062,1070. 23. CMS Hospital Conditions of Participation 33:122–67.
10. Flynn EA, Pearson RE, Barker KN. Obser- and Interpretative Guidelines, Centers for 36. Institute for Safe Medication Practices
vational study of accuracy in compound- Medicare and Medicaid Services (CMS), [ISMP]. 2004 ISMP medication safety
ing i.v. admixtures at five hospitals. Am J Department of Health and Human Ser- self assessment for hospitals. Huntington
Health-Syst Pharm. 1997; 54:904–12. vices. State Operations Manual Appendix A— Valley, PA: ISMP; 2004. www.ismp.org/
11. Morris AM, Schneider PJ, Pedersen CA, Survey Protocol, Regulations and Interpretive selfassessments/Hospital/2004
et al. National survey of quality assurance Guidelines for Hospitals, Rev 78 (12-22-11). Hospsm.pdf (accessed 2012 Dec 28).
activities for pharmacy-compounded Washington, DC: Government Printing Of- 37. Institute for Safe Medication Prac-
sterile preparations. Am J Health-Syst fice; 2011. www.cms.gov/Regulations-and- tices [ISMP]. Proceedings from the
Pharm. 2003; 60:2567–76. Guidance/Guidance/Manuals/downloads/ ISMP Sterile Preparation Compounding
12. Santell JP, Kamalich RF. National survey som107ap_a_hospitals.pdf (accessed 2012 Safety Summit: Guidelines for SAFE
of quality assurance activities for phar- Dec 28). Preparation of Sterile Compounds; 2012.
macy-prepared sterile products in hospi- 24. Comprehensive accreditation manual w w w. i s m p . o r g / t o o l s / g u i d e l i n e s /
tals and home infusion facilities—1995. for hospitals: the official handbook. IVSummit/IVCGuidelines.pdf (accessed
Am J Health-Syst Pharm. 1996; 53:2591– Oakbrook Terrace, IL: The Joint Com- 2012 Dec 28).
605. mission; 2012. 38. Infusion Nurses Society. Infusion nursing
13. Kastango ES, Douglass K. Improving the 25. American Osteopathic Association. standards of practice. J Infus Nurs. 2011;
management, operations and cost effec- Healthcare Facilities Accreditation Pro- 34(1S):S1–S110.
tiveness of sterile-product compounding. gram, 2009 Accreditation Requirements 39. Controlled Environment Testing As-
Int J Pharm Compd. 1999; 3:253–8. for Healthcare Facilities; 2009. sociation [CETA]. CETA certification
14. American Society of Health-System 26. DNV Healthcare. National Integrated guide for sterile compounding facilities
Pharmacists. ASHP Guidelines on Qual- Accreditation for Healthcare Organiza- (CAG-003-2006) (revised January 31,
ity Assurance for Pharmacy-Prepared tions (NIAHO), Interpretive Guidelines 2012). www.cetainternational.org/

r e f e r e n c e / C AG - 0 0 3 - 2 0 0 6 v 1 1 . p d f injectionsafety/CDCposition-SingleUse 63. Personal communication from Baxter.

(accessed 2012 Dec 28). Vial.html (accessed 2012 Dec 28). December 18, 2008.
40. Controlled Environment Testing As- 50. Centers for Medicare & Medicaid Ser- 64. Personal communication from B. Braun.
sociation [CETA]. Servicing hazard- vices [CMS]. Single use of single dose/ December 26, 2008.
ous drug compounding primary en- single use medications to prevent healthcare- 65. Injections (general information chapter
gineering controls (CAG-005-2007). associated infections. www.cms.gov/ 1). In: The United States pharmacopeia,
www.cetainternational.org/reference/ Medicare/Provider-Enrollment-and- 34th rev., and The national formulary,
CAG005-v15.pdf (accessed 2012 Dec 28). Certification/SurveyCertificationGenInfo/ 29th ed. Rockville, MD: The United
41. Controlled Environment Testing As- Policy-and-Memos-to-States-and-Regions- States Pharmacopeial Convention;
sociation [CETA]. Application guide Items/Survey-and-Cert-Letter-12-35.html 2011:33–8.
for the use of surface decontaminants (accessed 2012 Dec 28). 66. Centers for Disease Control and Preven-
in biosafety cabinets (CAG-004-2007). 51. Dolan SA, Felizardo G, Barnes S, et al. tion, National Center for Emerging and
www.cetainternational.org/reference/ APIC position paper: Safe injection, Zoonotic Infectious Diseases (NCEZID),
CAG0042007i.pdf (accessed 2012 Dec infusion, and medication vial practices Division of Healthcare Quality Promo-

28). in health care. Am J Infect Control. 2010; tion (DHQP). Safe Injection Practices to
42. Controlled Environment Testing As- 38:167–72. Prevent Transmission of Infections to Pa-
sociation [CETA]. Compounding iso- 52. Chapter 17. Recommended Practices tients. www.cdc.gov/injectionsafety/IP07_
lator testing guide (CAG-002-2006) for Medication Safety. In: Conner R, standardPrecaution.html (accessed 2013
(revised December 2008). Blanchard J, Burlingame B, et al. (eds). Jan 30).
www.cetainternational.org/reference/ Perioperative Standards and Recom- 67. Sterility tests (general information
CETACompoundingIsolatorTesting mended Practices. Denver, CO: Associa- chapter 71). In: The United States phar-
Guide2006.pdf (accessed 2012 Dec 28). tion of periOperative Registered Nurses macopeia, 34th rev., and The national
43. Controlled Environment Testing As- (AORN); 2012:251–300. formulary, 29th ed. Rockville, MD: The
sociation [CETA]. Application guide 53. Buchanan EC, Schneider PJ. Compound- United States Pharmacopeial Conven-
for the use of compounding isolators ing sterile preparations, 3rd ed. Bethesda, tion; 2011:65–70.
in compounding sterile preparations in MD: American Society of Health-System 68. Bacterial endotoxins test (general in-
healthcare facilities (CAG-001-2005) Pharmacists; 2009. formation chapter 85). In: The United
(revised December 2008). www.ceta 54. American Society of Health-System States pharmacopeia, 34th rev., and The
international.org/reference/Applications Pharmacists [ASHP]. Basics of aseptic national formulary, 29th ed. Rockville,
GuideBarrierIsolator-CAG-001-2005.pdf compounding technique. Bethesda, MD: MD: The United States Pharmacopeial
(accessed 2012 Dec 28). ASHP; 2006. Convention; 2011:78–82.
44. Controlled Environment Testing As- 55. Davis K, Sparks J. Getting started in 69. Pyrogen test (general information chapter
sociation [CETA]. CETA Certification aseptic compounding. Bethesda, MD: 151). In: The United States pharmacopeia,
Matrix for Sterile Compounding Fa- American Society of Health-System 34th rev., and The national formulary,
cilities (CAG-008-2010) (updated Janu- Pharmacists; 2008. 29th ed. Rockville, MD: The United States
ary 2012). www.cetainternational.org/ 56. Kienle PC. Compounding sterile prepa- Pharmacopeial Convention; 2011:115–7.
reference/CAG-008-2010v2.pdf (accessed rations: ASHP video guide to chapter 70. Oversight of Care, Treatment, and
2012 Dec 20). <797>. Bethesda, MD: American Society Services Provided through Contrac-
45. Controlled Environment Testing As- of Health-System Pharmacists; 2009. tual Agreement (Standard LD.04.03.09).
sociation [CETA]. CETA Certification 57. U.S. Department of Health and Human Comprehensive accreditation manual
Application Guide USP <797> Vi- Services, Food and Drug Administration, for hospitals: the official handbook. Oak-
able Environmental Sampling & Gown- Office of Regulatory Affairs. Guidance brook Terrace, IL: The Joint Commission;
ing Evaluation (CAG-009-2011v3). for industry: sterile drug products pro- 2012.
www.cetainternational.org/reference/ duced by aseptic processing—current 71. Trissel LA, Gentempo JA, Saenz LM, et
CAG-009v3.pdf (accessed 2012 Dec 28). good manufacturing practice. September al. Effect of two work practice changes
46. Centers for Disease Control and Preven- 2004. www.fda.gov/downloads/Drugs/ on the microbial contamination rates of
tion [CDC]. Guidelines for hand hygiene GuidanceComplianceRegulator y pharmacy-compounded sterile prepara-
in healthcare settings. MMWR. 2002; Information/Guidances/UCM070342. tions. Am J Health-Syst Pharm. 2007;
51(RR16):1–45. www.cdc.gov/mmwr/ pdf (accessed 2012 Dec 28). 64:837–41.
p r e v i e w / m mw r h t m l / r r 5 1 1 6 a 1 . h t m 58. General notices and requirements. In: 72. Sessink PJ, Boer KA, Scheefhals AP, et al.
(accessed 2012 Dec 28). The United States pharmacopeia, 34th Occupational exposure to antineoplas-
47. O’Grady NP, Alexander M, Burns LA, et rev., and The national formulary, 29th tic agents at several departments in a
al. 2011 Guidelines for the Prevention ed. Rockville, MD: The United States hospital: environmental contamination
of Intravascular Catheter-Related Infec- Pharmacopeial Convention; 2011:11– and excretion of cyclophosphamide and
tions. Centers for Disease Control and 12. ifosfamide in urine of exposed workers.
Prevention, 2012. www.cdc.gov/hicpac/ 59. Pharmaceutical compounding—non- Int Arch Occup Environ Health. 1992;
pdf/guidelines/bsi-guidelines-2011.pdf sterile preparations (general information 64:105–12.
(accessed 2012 Dec 28). chapter 795). In: The United States phar- 73. Kiffmeyer TK, Ing KG, Schoppe G. Ex-
48. Centers for Disease Control and Preven- macopeia, 34th rev., and The national ternal contamination of cytotoxic drug
tion [CDC]. Guidelines for Environ- formulary, 29th ed. Rockville, MD: The packing: safe handling and cleaning pro-
mental Infection Control in Healthcare United States Pharmacopeial Conven- cedures. J Oncol Pharm Pract. 2000; 6:13.
Facilities. MMWR. 2003; 52(RR10):1–42. tion; 2011:330–6. 74. Connor TH, Sessink PJ, Harrison BR
www.cdc.gov/mmwr/preview/mmwr 60. Trissel LA. Handbook on injectable et al. Surface contamination of chemo-
html/rr5210a1.htm (accessed 2012 Dec drugs. 17th ed. Bethesda, MD: American therapy drug vials and evaluation of new
28). Society of Health-System Pharmacists; vial-cleaning techniques: results of three
49. Centers for Disease Control and Preven- 2013. studies. Am J Health-Syst Pharm. 2005;
tion, National Center for Emerging and 61. Bing CD, Nowobilski-Vasilios A. Ex- 62:475–84.
Zoonotic Infectious Diseases (NCEZID), tended stability for parenteral drugs. 5th 75. Kastango ES, Wagner JT, Kastango KB, et
Division of Healthcare Quality Promotion ed. Bethesda, MD: American Society of al. Generation of particulate matter dur-
(DHQP). Protect Patients Against Prevent- Health-System Pharmacists; 2013:321. ing handling of needle and syringe pack-
able Harm from Improper Use of Single- 62. Personal communication from Hospira. aging. Am J Health-Syst Pharm. 2008;
Dose/Single-Use Vials. www.cdc.gov/ December 16, 2008. 65:1443–50.

76. OSHA Hazard Communication Stan-

dard (revised 2012). www.osha.gov/dsg/
hazcom/index.html (accessed 2012 Dec
28).
77. National Institute for Occupational
Safety and Health [NIOSH]. Medical
surveillance for healthcare workers ex-
posed to hazardous drugs. NIOSH Pub-
lication No. 2013-103; November 2012.
www.cdc.gov/niosh/docs/wp-solutions/
2013-103/ (accessed 2012 Dec 28).
78. Joint Council of Allergy, Asthma, and
Immunology. Allergen Immuno-
therapy Extract Preparation Guide-

lines. www.jcaai.org/file_ dep ot/
0-10000000/20000-30000/27387/
folder/62846/Allergen_Extract_
Preparation_Guidelines.pdf (accessed
2012 Dec 28).
79. Radiopharmaceuticals for positron
emission tomography—compounding
(general information chapter 823). In:
The United States pharmacopeia, 34th
rev., and The national formulary, 29th ed.
Rockville, MD: The United States Phar-
macopeial Convention 2011:385–9.
80. Thomas M, Sanborn MD, Couldry R.
I.V. admixture contamination rates: Tra-
ditional practice site versus a class 1000
cleanroom. Am J Health-Syst Pharm.
2005; 62:2386–92.
81. Microbiological evaluation of clean
rooms and other controlled environ-
ments (general information chapter
1116). In: The United States pharmaco-
peia, 34th rev., and The national formu-
lary, 29th ed. Rockville, MD: The United
States Pharmacopeial Convention; 2011:
633–41.
82. Agency for Healthcare Research and
Quality Patient Safety Network (AHRQ
PSNet). Patient safety primer: root cause
analysis. www.psnet.ahrq.gov/primer.
aspx?primerID=10 (accessed 2012 Dec
28).
83. DeRosier J, Stalhandske E, Bagian JP, et
al. Using health care failure mode and ef-
fects analysis: the VA National Center for
Patient Safety’s prospective risk analysis
system. Jt Comm J Qual Improv. 2002; 28:
248–67.

ASHP Guidelines On Compounding Sterile Preparations

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

ASHP Guidelines On Compounding Sterile Preparations

Uploaded by

Copyright:

Available Formats

ASHP REPORT Compoundng sterile preparations

ASHP Guidelines on Compounding

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 145

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

1970 1980 1990 1995 2000 2005 2010

1975−80— 2002—ASHP national

146 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 147

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

148 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 149

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

150 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 151

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

152 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 153

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

154 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 155

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

156 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 157

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

158 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 159

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

160 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 161

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

162 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 163

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

164 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

r e f e r e n c e / C AG - 0 0 3 - 2 0 0 6 v 1 1 . p d f injectionsafety/CDCposition-SingleUse 63. Personal communication from Baxter.

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

Am J Health-Syst Pharm—Vol 71 Jan 15, 2014 165

76. OSHA Hazard Communication Stan-

Downloaded from https://academic.oup.com/ajhp/article-abstract/71/2/145/5111112 by guest on 15 May 2019

166 Am J Health-Syst Pharm—Vol 71 Jan 15, 2014

You might also like