USP <797>

Pharmaceutical
Compounding-Sterile
Preparations
Mary Baker, Pharm.D., MBA
August 15, 2007
 United States Pharmacopeia
(USP)
 Volunteers with extensive science expertise from
clinical practice, academia, and industry
 Standards for medications, health care
technologies and related practices
 Chapters >1000 are informational; <1000 are
enforceable; undergo continuous revision
 Basis for Joint Commission and state pharmacy
board inspections
 2005-10 USP SCC1
♦ Dr. Sam Augustine ♦ Mr. Eric Kastango
♦ Dr. Mary Baker ♦ Dr. Dave Newton2
♦ Dr. Jim Cooper ♦ Mr. Keith St. John
♦ Dr. Don Filibeck ♦ Dr. Laura Thoma
♦ Mr. Larry Griffin ♦ Mr. Larry Trissel3
♦ Mr. Ken Hughes ♦ Mr. Jim Wagner
-------------------------------------------------------------
1
Dr. Claudia C. Okeke, cco@usp.org, is USP staff liaison to the SCC
2
Chairman
3
Vice Chairman
 Why is USP <797> Needed?
 Deaths in the 60s and 70s due to
contaminated injectables
 Series of ASHP recommendations in the
80s and 90s did not impact practice
 Cost
 Perceived lack of value; ‘not a problem here’
 Injury and death due to contamination
continues
 Publicized on television and in newspapers
 <797> is not just about non-sterility
 <797> very concerned with correct identities
and amounts of ingredients, e.g.,
♦ Deaths of 3 premature babies in 1990 in Philadelphia from
KCl that should not have been in their IVs (NY Times, Section 1,
p. 22, June 24, 1990)

♦ Death of baby after year 2001 from sterile IV CaHPO4

precipitate (DWN consulted)
♦ Death of 2 yr old girl in 2006 from sterile 23.4% instead of
0.9% NaCl inj. (The Plain Dealer, Nov.15, 2006; a Cleveland, OH newspaper)
♦ Deaths of 3 patients in Portland, OR and Yakima, WA in
2007 from 10 X colchicine inj. after weighing error at
compounding pharmacy in Texas (Sarah Skidmore, AP 4-27-2007)
♦ Deaths from mix-ups of heparin and insulin (ISMP Med. Safety
Alert 5-3-2007 Vol. 12, Issue 9)
 <797> Public Information Summary –1
(from USP Staff Officers, June 23, 2007)
♦ SCC meeting q 2 wks by phone since March,
2007
♦ Revision nearly complete based on thorough
review and consideration of more than 500
comments during May-August, 2006 regarding
[In-Process] proposed revision.
♦ SCC aware of delicate balance of practicality
issues to compounding practitioners and
protecting public health
 <797> Public Information Summary –2

♦ A 2007 Roundtable meeting on compounding aseptic

isolators, CAIs, at USP, isolator vendors, experts, and
FDA and NIOSH representatives helped SCC better
understand the design, performance, and other aspects
of the effective use of CAIs for preparing CSPs.
♦ Several sections completed and approved by
SCC are undergoing editorial review at USP
scheduled for USP 31-NF 26 in November 2007.
Plan to post on www.usp.org this summer when
finalized.
 <797> Public Information Summary –3

♦ Disinfectants and Cleaning, and Environmental

Monitoring sections currently in progress, as are
two appendices – hope to include these in
Supplement 1 of USP 31-NF 26, and post on
website.
♦ Two external expert advisory panels reported to
SCC on radiopharmaceuticals, and disinfectants
and cleaning.
 <797> Public Information Summary –4

♦ When revised chapter is posted on www.usp.org

USP plans a major educational and
communications effort to help healthcare
professionals and organizations understand and
implement the new responsibilities,
requirements, and standards associated with
sterile compounding.
Manuscript Reviewers’ Comments

20 pp & 12 authors

May 2006 >1000 pp & ~ 500 [com/tor]mentors

May 2006 – Jan. 2007

 Sterile vs Nonsterile
Compounding
 Sterile compounding requires
 Cleaner facilities
 Specific personnel training and testing in
aseptic technique
 Air quality standards
 Knowledge of solutions sterilization and
stability
 Main Sections of <797>
 Risk levels
 Automated compounders for TPN
 Equipment
 Verification of compounding accuracy and
sterilization
 Main Sections of <797>
(continued)
 Personnel responsibilities and training
 Environmental quality
 Storage
 Finished product checks
 Beyond-use dating
 Risk Levels
 Low, Medium and High
 Probability of contaminating a product with
microbes, chemicals or other matter
 People are a major source of
contamination
 Applies to final mixed or filled product
 Pharmacist responsible for determining
risk level at his/her institution
 Dressing Properly
 Shoe covers
 Head and facial hair covers
 Face masks
 Sterile gloves
 Non-shedding gowns
 No makeup
 No long fingernails or artificial nails
Employee hand hygiene and garbing
 Hair net
 Beard cover and face
mask
 Gown
 Gloves
 Shoe covers
Personnel Cleansing and Garbing
 Clarify garbing process by emphasizing the
“dirtiest to cleanest” order
 Discussion of personal garments, cosmetics,
jewelry, fingernails (natural and artificial)
 Don garb that covers non-hand areas first,
followed by proper hand hygiene, then donning
gowns and sterile gloves
 Frequent disinfection of sterile gloves with 70%
IPA
 Evidence-based science
 An Intervention to Decrease Catheter-Related Bloodstream
Infections in the ICU. N Engl J Med 2006;355:2725-32.
 An evidence-based intervention resulted in a large and
sustained reduction (up to 66%) in rates of catheter-related
bloodstream infection that was maintained throughout the 18-
month study period.
 The average infection rate fell from 7.7 percent to 1.4 percent
after 18 months. 'More than half the hospitals (103) in this study
were able to report that they had ZERO infections after
implementing the program,'
 Consistent and vigilant work practices were key factor:
 Assuring that participants wash their hands before the
procedure.
 Assuring full barrier protection -- a sterile bed sheet rather
than just keeping the insertion site sterile,
 Staff wear sterile gloves, gowns, hats and masks.
 Cleansing the skin surface with chlorhexidine.
 Compounding Personnel

 A human person in a cleanroom is considered a broad

spectrum particle generator enclosed by inefficient
mechanical filters which may also be sources of particles
 The human body harbors an average of 150-200 different
classes of bacteria
 Hands have an average of 100,000 organisms / sq mm
 The body sheds 5 grams of skin fragments each day along
with shedding 1 layer of skin every 5 days (size range 10 to
300 micron – 1000th of a mm)
 “Our greatest asset and biggest liability!”
 “But I was just talking”

* Photo courtesy of Francis P. Mitrano, MS, RPh, Director of Pharmacy,

Beth Israel Deaconess Medical Center, Boston, MA, November, 2005.
 Hair and Jewelry DO Matter!*

covered hair at 1 hr – head shake

uncovered hair – head shake

* Blood agar cultures courtesy of Francis P. Mitrano, MS, RPh, Director of

Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, November, 2005.
 Low Risk Level
 Aseptic manipulations entirely within ISO
Class 5 (Class 100) or better air quality in
a ISO Class 8 (Class 100,000) cleanroom
using only sterile ingredients, products,
and devices
 Transfer, measuring and mixing with
closed or sealed packaging systems that
are performed promptly
 Low Risk Level (continued)
 Aseptically opening ampuls, penetrating
sterile stoppers on vials with sterile
needles and syringes and transferring
sterile liquids in sterile syringes to sterile
administration devices and packages of
other sterile products
 Low Risk Level (continued)
 Storage-Unless documented by sterile
test, no more than:
 48 hrs controlled room temperature
 14 days cold (refrigerated)
 45 days in a solid frozen state at –20 degrees
C or below
 Low Risk Examples
 Compounding piggybacks or hydration
fluids in a ISO 5 laminar flow hood located
in an ISO 8 cleanroom
 Dual Chamber parenteral nutrition
container with no more than 3 additives
 Low Risk Quality Assurance
Procedures
 Annual media fill
 Appropriate personnel garb
 Visual inspection
 Does not require chemical analysis or
pyrogen testing
 Medium Risk=Low Risk Plus…
 Multiple individual doses of sterile
products are combined or pooled to
prepare a product that will be given to
multiple patients or one patient multiple
times
 Complex manipulations
 Long duration of the compounding
process
 No bacteriostat and administered over
several days (implantable pumps)
 Medium Risk Storage
 Unless documented with sterility test, no
more than:
 30 hours at controlled room temperature
 7 days refrigerated
 45 days in solid frozen state at –20 degreed C
or colder
 Medium Risk Examples
 TPN using automated compounder where
all ingredients are sterile
 Filling device reservoirs with multiple
sterile drug products and evacuating air
 Batch preparation of syringes
Medium Risk Quality Assurance
Procedures
 More stringent media fill
 MD Anderson study (2002-2003)*
 Bare hands and nonsterile gloves with initial
disinfection with 70% isopropyl alcohol (IPA)
 539 evaluations over a 2 year period
 5.2% yielded microbial growth
 Inadvertent touch contamination principal
source

*Trissel LA et al AJHP 2005: 62: 285-288

 Medium Risk Quality Assurance
Procedures
 Follow up study MD Anderson
 Group A-previous study
 Group B-non-sterile chemo gloves with initial and
repeated disinfection with IPA
 Group C-sterile gloves with initial and repeated
disinfection with IPA
 Contamination rate: B=0.96%; C=0.34%
 Statistically significant differences between A
and B and A and C
 Those who worked regularly in sterile
preparation had the worst record
 Trissel et al AJHP 2007; 64: 837-41
 High Risk
 Nonsterile ingredients or devices used
before sterilization
 Air quality inferior to ISO Class 5
 Nonsterile exposure for 6 hrs before
sterilized
 Storage-no more than 24 hours controlled
room temperature, 3 days refrigerated or
45 days in solid frozen state at –20 deg C
 High Risk Examples
 Nonsterile bulk and nutrient powders that
will be sterilized (morphine, glutamine)
 Sterile ingredients in nonsterile containers
 Bladder irrigations made from bulk powder
 With low and medium risk, start out sterile
and maintain sterility; with high risk a
nonsterile component needs to be made
sterile.
 High Risk Quality Assurance
Procedures
 Semi-annual media fill testing
 Sterilization procedures must be validated
 Beyond Use Dating
 Microbiologic as well as chemical data
 BUD is shorter of the two
 Valid scientific data
 Differs from the expiration date which
applies to manufactured drug products
 Parenteral Nutrition

 All compounders are medium risk

 Verifying accuracy of compounders
 Calibration and weigh mode
 Maintenance and documentation
 Cleaning!
 Outsourcing
 Another pharmacy prepares the admixture
 All compounding or certain preparations
 Waste, cost, expiration issue
 You are still responsible for the product
given to the patient
 Quality records
 Proposed Immediate Use CSPs
♦ Begin administration within 1 hour of
compounding. ≤3 non-hazardous sterile
products
♦ No direct contact contamination
♦ Exempt from <797> personnel and
environmental standards
♦ Potentially great health hazard to patients
if contaminated, esp. multi-day infusions
 Multi-Dose & Single-Dose Vials
 Definitions in the General Notices and Requirements
USP29—NF24
 Emphasizes storage once opened or needle-punctured
based on:
 Air quality of the environment
 Type of container involved
 Multiple-dose container intended for multiple entries has
a 28 day beyond-use date from date and time of entry
unless otherwise specified by the manufacturer
 Selection of 28 days based on the antimicrobial
preservative effectiveness test General Chapter <51>
Antimicrobial Preservative Testing
 Multi-Dose & Single-Dose Vials
 Opened or needle-punctured single-dose containers such
as ampuls, bags, bottles, syringes, and vials of sterile
products and CSPs shall be used in ONE hour if opened in
worse than ISO Class 5 air quality.
 Remaining content must be discarded.
 Single-dose vials exposed to ISO Class 5 or cleaner air
quality may be used up to SIX hours after needle puncture.
 Opened single-dose ampuls shall not be stored for anytime
period.
 The concern is PATIENT RISK!
 As early 1970, Michael Cohen of ISMP was raising the red
flags on MDVs.
 Calculated Microbial Growth
 Review of the Media Selection and Incubation
Conditions for the Compendial Sterility and Microbial
Limit Tests. Anthony M. Cundell , Ph. D.,* USP Expert
Committee on Analytical Microbiology. USP Pharmacopeial
Forum 28(6) Stimuli to the Revision Process:
 Things to Take Home
 USP <797> is more than building a new
facility. What can you do now vs several
years from now?
 Training and documentation is key
 Leadership from pharmacists and
technicians-don’t rely on one person
 Consistent work practices-nights,
weekends and holidays
 Passing the ‘loved one’ test