Transcript Hazardous Drug Handling: Risks and Regulation

Hazardous Drugs:
Risks and
Regulations
Christine Roussel, PharmD, BCOP
Clinical Manager, Doylestown Hospital
Pharmacist Consultant, Medisca Network
Conflict Disclosure
Dr. Roussel has no conflicts of
interest and has not received
compensation for this program
Index Cards
 Please take one index card
 On one side, write down your
biggest safe handling challenge /
concern
 On the other side, write down one
thing you changed during the last
year that positively affected how
your institution handles hazardous
medications
PSHP Pharmacist Learning Objectives
 Examine data related to Hazardous Drug
contamination in the work place and its effects on
healthcare workers
 Review the current Safe Handling Standards,
Recommendations and Regulations from USP,
NIOSH, OSHA, ASHP and ONS.
 Categorize hazardous drugs and design a
process for handling them in a specific
facility
 Identify and Communicate to others, risks
related to handling hazardous drugs
PSHP Technician Learning Objectives
 Examine data related to Hazardous Drug
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contamination in the work place and its effects on
healthcare workers
Review the current Safe Handling Standards,
Recommendations and Regulations from USP,
NIOSH, OSHA, ASHP and ONS.
Locate and Interpret safe handling resources,
both internal and external documents
Assess work situations for safety
Communicate to others, risks related to handling
hazardous drugs
Growing Concern
12% of US workers are
employed by healthcare
U.S.:
1.5 million new
cases of
cancers/year
World Wide:
11 Million new
cases of cancer
/ year
8 million U.S. healthcare
workers potentially exposed to
hazardous drugs each year
Expected to
rise to 16
million new
cases / year by
2020
Increase in use
of hazardous
drugs to treat
non-malignant
diseases
OSHA, American Cancer Society (ACS), World Health Organization (WHO)
Question:
True or False:
Hazardous drugs and their metabolites
have been detected in the urine of exposed
healthcare workers, including staff not
directly involved in compounding or
administration.
Question:
True or False:
Chromosomal Aberrations and Other types of
Genetic Damage have been documented as
being increased in Healthcare Workers
working with antineoplastics compared
Healthcare Workers not involved in
compounding or administering
antineoplastics.
National Institute for Occupational
Safety and Health (NIOSH)
Alert 2004
Patient’s RISK vs. BENEFIT
“Although
the potential
therapeutic benefits of
compounded sterile
hazardous drug
preparations generally
outweigh the risks
of their adverse effects
in ill patients, exposed
healthcare workers risk
similar adverse effects
with no therapeutic
benefit.” USP 797
Hazardous Drug Characteristics
 CARCINOGENICITY
 GENOTOXICITY
 TERATOGENICITY
 REPRODUCTIVE TOXICITY
 ORGAN TOXICITY AT LOW DOSES
 INVESTIGATION
 STRONG STRUCTURAL AND TOXICOLOGY
SIMILIARITIES TO DRUGS CURRENTLY
CONSIDERED HAZARDOUS
Hazardous Drugs: “It’s not just oncology”
Rheumatology
cyclophosphamide, azathioprine, rituximab,
abetacept, tacrolimus, methotrexate
Transplant
cyclosporine, tacrolimus, sirolimus,
mycophenolate
Infectious Disease
ganciclovir
OB/GYN
methotrexate, estrogen, tamoxifene
Emergency room
methotrexate
Urology
mitomycin, BCG, valrubicin, testosterone
Operating Room
Formaldehyde, mitomycin,
Ophthalmology
mitomycin
Community Pharmacy
All of the oral agents listed + more
Inpatient Hospital
All oral, IV and IM agents + more
NIOSH’s New List for 2014
Group 1: Antineoplastic Drugs
identified by ASHP/AHFS as drugs used for the treatment of cancer.
Group 2 : Non-antineoplastic Drugs
Meet NIOSH criteria for a hazardous drug
and are used for diseases other than cancer.
This group will include some drugs that have
secondary reproductive toxicity.
Group 3: Reproductive Hazards
Poses a risk to pregnant and lactating
women
Mena and women actively trying to conceive
Hormone Disruptors
Monoclonal Antibodies
Exposure Risk
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CONSIDERATIONS
Large Protein Molecules,
skin absorption considered
unlikely
Concern for inhalation of
powder for reconstitution
Ingestion (hand to mouth)
considered less of risk due
to digestion
Considered Toxic For
Pregnancy / Reproductive
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CONCERN
Formation of neutralizing
antibiotics:
Loss of clinical response
Cross Reactivity with
endogenous proteins
Provoking cytokine release
Toxicity
Short Term
Long Term
 Skin reactions
 Reproductive Issues
 Ocular reactions
 Chronic Cough
 Allergic Asthma
 End-organ damage
 Flu-like symptoms
 Leukemia
 Headache
 Lymphoma
 Dizziness
 Myelodysplastic syndrome
 Increased infections
(MDS)
 Bladder and Liver Cancer
Opportunities for Exposure
 Manufacturing
 Packaging
 Transport
 Receipt
 Preparation
 Administration
 Research
 Disposal
 Room Cleaning / Sanitation
Routes of Exposure
• Dermal Contact
• Direct Contacts with the drugs and packaging
• Touching contaminated surfaces (Indirect)
• Inhalation
• Breathing contaminated air (aerosols and vapors)
• Spill Clean-up
• Ingestion
• Hand to Mouth Contact
• Ie. Eating , Drinking, Gum Chewing
• Injection
• Finger sticks
• Vial breakage
Who is at Risk of Exposure?
 Pharmacists
 Environmental Services
 Pharmacy Technicians
 Patients Family
 Oncology Nurses
Members
 Laboratory Staff
 Other Hospital Staff
 Patient Care Technicians
 Physicians
HD Risk as a permutation of 5 factors
Drug Characteristics
Dosage Form
Packaging
Type of handling / exposure
Quantity and Frequency of activity
Hazardous Drugs:
Every Move You Make, Every
Step You Take
External Drug Vial Contamination
Antineoplastic
2005
2010
5 – Fluorouracil
7%
98%
Cisplatin
100%
100%
Cyclophosphamide
89%
85%
Ifosfamide
100%
96%
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Manufacturers need to improve decontamination procedures
Workers need to protect themselves
Regardless of shrink wrap, plastic containers or boxes
5-FU vial contamination on a single vial quantified as over 0.6 mg (ASHP)
Connor et al, 2005, AJHP 2010; 67: 428-29
Hazardous Drugs on Work Surfaces (U.S.)
Author, Year
Incidence of Contamination
McDevitt et al, 1993
18% pharmacy surfaces + for CP
14% nursing surfaces + for CP
3/73 air samples + for CP
Connor et al, 1999
75% of pharmacy surfaces
65% of administration area
Connor et al, 2002
Almost 100% of surface samples contaminated
with at least one drug
Harrison et al, 2006
8% (28/342) Surfaces + 5-FU
95% (324/342) Surfaces + CP
Connor et al, 2010
60% (86/143 surfaces) + for HD
32% surfaces + for >1 HD
Sessink et al, 2013
83% Pharmacy Surfaces
Moretti et al, 2015
*Italy*
100% Surface Wipe samples + for CP
100% dermal pads + for CP
Common Locations of Contamination
 High levels of
contamination :
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Working surface of BSC
Surfaces inside the
compounding isolator
Leading edge (airfoil) of BSC
Floor in front of BSC
 Lower levels of
contamination :
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Floor in pharmacy
Countertops
Storage bins and trays
Storage shelves
Inside and outside passthrough windows
Waste containers
Keyboards
Door handles
Shoes of pharmacy
employees
Employee telephones
Antineoplastic Drug Contamination on
the Hands of Hospital Employees - 2014
 Employees of 5 hospitals
and 1 cancer center tested
based on convenience in
work day
 42 / 115 hospital staff hands
+ for Cyclophosphamide
(excluding Housekeeping
and Environmental)
Hands Contaminated with
Cyclophosphamide
 Employees with Contact during
work day (28%):
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Pharmacist, pharmacy
technicians
nurses, LPNs
 Employees without drug
Contact in work day:
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Hon, et al. Ann. Occup. Hyg., 2014, 1-10
oncologists, volunteer, dietician,
unit clerk
Greater % of + employees
Greater amount of drug detected
Analysis of Healthcare Workers Urine
Medication
+ / total
samples
%
Cytoxan
18/48
38%
Ifosfamide
10/48
21%
•Samples taken from nurses,
pharmacists and pharmacy
technicians, even those who do not
compound
•Ifosfamide last prepared 3 weeks
prior to first urine collection
Wick et al, 2003
• 17 / 20 studies positive
for biomarkers of
exposure in healthcare
workers urine
•
Included over 650 nurses and
pharmacist in 10 different
countries
•
15/20 studies included
cyclophophamide and
ifosfamide, but others have been
evaluated: methotrexate,
doxorubicin, epirrubicin,
paclitaxel, cytarabine and
gemcitabine
Suspiro, Prista, 2011
Monitoring for Hazardous Drugs in the
Operating Room 2003
Workplace
Contamination
Workers Hands
and Forearms
Urine Drug
Excretion
Genotoxic
Damage
Why are we concerned about exposure in
healthcare workers?
Based on long term side effects in treated
patients, it became obvious that there are risks
for the occupational exposed
Patients receive concentrated doses of a limited
number of agents for a defined period of time.
Healthcare workers are exposed to small doses
of a broad range of hazardous medications over
decades
Secondary Malignancies in Chemotherapy Treated
Cancer PATIENTS
 A new cancer that occurs in
a patient after treatment
with chemotherapy or
radiation for a different
cancer
 May occur in months to
years after treatment
 Considered side effect /
caused by the initial cancer
treatment
 Easily treated:
 skin cancers (basal cell or
squamous cell carcinoma)
 Extremely serious:
 Acute Leukemia (patient will
die without immediate
hospitalization and very
strong chemotherapy)
 Other cancers:
 Non-Hodgkin’s Lymphoma
 Myelodysplastic Syndrome
(aka pre-leukemia)
Example of Risk to the Patients
Breast Cancer Treatment
 Secondary Cancers
with doxorubcin based
treatment
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10 years – 3.8%
15 years – 7%
 Secondary Cancers
 With radiation - 3.4%
 Chemo only – 4.7%
Hodgkin’s Disease
 Secondary Cancers
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20 years – 10 %
30 years – 26 %
 6.5 times the normal
person’s risk or dying
from another cancer
 Chemo while < 21 yo
– 14 fold increase in
death from secondary
cancer
Drugs Associated with Secondary Cancers in Patients
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Alkeran
Bleomycin
Carboplatin
Cisplatin
Cyclophosphamide
Daunorubicin
Dexamethasone
Doxorubicin
Epirubicin
Etoposide
 Fluorouracil (5-FU)
 Ifosphamide
 Lenolidomide
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(revlimid)
Mitoxantrone
Procarbazine
(Matulane)
Taxol
Taxotere
Temodar
Vinblastine
Vincristine
Chemotherapy does not discriminate
EXPOSURE - EFFECT PATHWAY
External
Dose
Workplace
Exposure
Internal
Dose
Blood and
urine studies
Biologic
Effective
Dose
DNA adducts
Early
Biologic
Effects
Chromosome
abnormalities,
SCEs,
Micronucleui
Altered
Structure
Function
Cancer,
Reproductive
Toxicity
Committee on Biological Markers in Environmental Health Research, of the National Research Council (USA) 1987
How Does the Malignancy Risk relate to
Healthcare Workers?
Incidence is related to:
Cumulative dose
Dose Intensity
Individuals innate DNA repair capacity
Therapy induced Myelodysplastic syndrome (t-MDS) and
therapy induced Acute Myelogenous Leukemia (t-AML)
related to specific mutations
Can this data be extrapolated to Healthcare worker
Exposure?
Chromosomal Damage in Healthcare Workers Exposed to
Antineoplastic
Total
Chromosome
Changes
per 200 cells
Matched
Controls =
HCW with No
Exposure
HCW with High
Exposure
( > 153 handling
events/6 weeks)
P Value
Chromosome 5 and 7
0.13 (0.40)
0.47 (0.80)
0.02
Chromosome 5
0.04 (0.21)
0.29 (0.59)
0.01
• Peripheral blood samples from 107 HCW
• A chromosomal aberration is a missing, extra, or irregular portion of
chromosomal DNA
• Chromosomes 5 and 7 are associated with t-MDS and t-AML induced
by alkylators
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JOEM 2010; Vol 52; 10: 1028-1034
(SD)
https://en.wikipedia.org/wiki/Micronucleus
Genotoxicity Biomarkers in Healthcare Workers
Type of Study
Definition
+ Studies
Chromosomal
Aberrations
numerical and structural aberrations , ie
strand breaks, DNA cross linking, base
substitution
21/29
Sister Chromatid
Exchanges
symmetrical exchange of DNA replication products
between two identical sister chromatids, not
resulting in any alteration in chromosomal number
or structure , maybe related to DNA repair
6/6
Micronuclei
Nuclear material in cytoplasm after mitosis
occurring from replication of damaged
chromosomes
12/22
Comet Assay
Gel electrophoresis method for DNA
damage
10/13
HPRT mutation
test
Mutations in this gene (which codes for
2/2
enzyme hypoxanthine-guanine
phosphoribosyltransferase that plays a role in the
purine salvage) associated with resistance to
6-Thioguanine
Compliance with Glove Usage
Nurses
Micronuclei
Chromosomal
Abnormalities
< 100 % Compliance
29
9.5 (+/- 5.2)
2.6 (+/- 2.6)
100 % Compliance
33
4.3 (+/- 3.7)
0.9 (+/-1.9)
For both markers of genetic damage there were
statistically significant difference between staff with 100%
compliance and staff non-complaint with recommended
personal protective equipment
1992 Harris and Connor, Journal of Occupational Medicine and Toxicology
Relationship of cancer occurrence in HCW
exposures to antineoplastic HDs (NIOSH)
Cancer mortality study of HCWs in 24 states [Petralia et al. 1999]
 Nurses: 30% ↑ mortality due to liver cancer and myeloid
leukemia among nurses
 Pharmacists: two-fold ↑ of mortality from myeloid leukemia
in pharmacists
Occupation and Leukemia Study in two mid-western U.S.
states (Blair et al. 2001)
 Nursing and healthcare workers: ↑ in Leukemia
Danish Female Pharmacy Technicians: ↑ risk of nonmelanoma skin cancer and non-Hodgkin’s lymphomas [Hansen
and Olsen 1994].
Cancer incidence in registered nurses
 56,213 Female RNs - professional regulatory body
compared to Canadian cancer registries.
 Worked in cancer center or oncology nursing unit:
↑ risk of breast cancer (RR = 1.83; CI = 1.03 - 3.23)
 RNs with highest weighted durations of exposure to
antineoplastic drugs:
↑ risk of rectal cancer (RR = 1.87, CI = 1.07 - 3.29)
 No statistically significant increased risks of leukemia,
other cancers
Cancer Risk Assessment
 Mathematical Analysis based on:
 Patient Exposure to CP and Secondary Cancers
 Healthcare worker Urinary Excretion Data
 Rodent Models to test Acute and Chronic Exposures and
Secondary Cancers
 Healthcare worker with CP exposure conservative
estimates – additional 1.4 to 10 cases of cancer per 1
million workers per year.
 New data with 5 times greater daily urinary CP
excretion
 Extrapolation of data could yield an additional 7 to
50 additional cancer cases per million healthcare
workers each year.
Sessink, Cancer Risk Assessment 1995
Immunomodulators
Adalimumab (Humira ) & Etanercept (Enbrel)
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Lymphoma (3X more than the general populations) (median of
30 months) and other malignancies, some fatal, reported in
children, adolescents and adults taking TNF blockers
Tacrolimus (Prograf) & Cyclosporin (Sandimmune,
Neoral)
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at increased risk of developing lymphomas and other
malignancies, particularly of the skin The risk appears to be
related to the intensity and duration of immunosuppression
rather than to the use of any specific agent.
Post transplant lymphoproliferative disorder (PTLD) has been
reported in immunosuppressed organ transplant recipients.
Package Inserts: Adalimumab (Humira ) & Etanercept (Enbrel)
Tacrolimus (Prograf) & Cyclosporin (Sandimmune, Neoral)
Pharmaceutical Dust Exposure
 Water soluble can be absorbed across mucous
membranes
 Particles <0.02 microns
 Can remain suspended in air for several hours
 After using Compressed air to clean canisters,
> hour passed before the small particles
produced were reduced to the pre-cleaning level
Lactose Concentrations Pharmacy Air Samples
Lactose used as a marker for API, found in air and on surfaces throughout the pharmacy;
Lactose was only present in 77 of 200 tablets sampled
Fent 2014
Pharmaceutical Drug
Dust Exposures
Specific Drug Exposure
 Methotrexate – air samples tested positive during
and after hand filling a prescription for MTX (OEL
0.03 ug/m3)
 Lisinopril – air samples exceeded the manufacturer
recommended Occupational Exposure Limit (OEL 1
ug/m3)
 Levothyroxine – air samples when cleaning and
refilling canisters (OEL < 1ug/m3)
Safe Practices for Automated Dispensing
Machines
 Use partially enclosed, HEPA filtered hoods for counting
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hazardous medications
Consider use of hood when refilling canisters
Clean machines with HEPA filtered vaccum and change
filter often per manufacturer guidelines
Do not use compressed air to clean canisters
Wear nitrile gloves when handling pharmaceuticals
Clean pharmacy surfaces with alcohol based cleaner
every 2-4 hours
Wash hands before eating, drinking or using tobacco
products
So now that we know the risks what
can we do to minimize HD exposure
to “as low as reasonably achievable”
(ALARA)
• S T A N D A R D S , R E C O M M E N D A T I O NS
AND REGULATIONS
• USP <797> VS <USP 800>
• CURRENT LEGISLATION
• ENVIRONMENTAL CONTROLS
Current Compliance
Pharmacy Purchasing and Product Magazine 2014 Data
55.6%
61.2%
42.3%
Store Hazardous Drugs in a Negative Pressure Room such as a
hazardous drug compounding room
Employees who handle, dispose or compounding hazardous CSP’s
successfully complete a hazardous CSP Competency Assessment
prior to working with hazardous CSPs and annually thereafter.
Written confirmation by each compounding employee of
reproductive age (male or female) that they understand the risk of
handling hazardous CSPs.
USP 797 on Hazardous Drug Compounding
Patient
Safety
Hazardous
Drug Safety
USP <797> and <795> vs USP <800>
 Should, Shall and Must
 USP = Federally enforceable STANDRADS
USP 797
USP 800
Safety for patients
•Safety for Healthcare Worker
Harmonization of
USP Chapters
expected in 2015
Storage
Compounding
•Additive on top of USP 797 and 795
•Receiving
•Storage is more detailed
•Compounding
•Administration* New
•Monitoring
USP 797 vs PURPOSED USP 800
Receiving (New in 800)
HDs MUST be Unpacked in neutral or negative pressure
NOT in Positive Pressure or Sterile Compounding Areas
HD Storage
MUST store hazardous drugs separately
USP 797 = SHOULD --> USP 800 = MUST:
negative pressure
12 Air Changes per Hour
externally vented
COMPOUNDING
USP < 797 >
USP < 800 >
Shall (MUST) compound hazardous drugs within a primary engineering
control in an ISO 7 room (note separate room!)*
“SHOULD optimally be” negative MUST be negative pressure
pressure
MUST be externally vented
“SHOULD” be externally vented
30 Air Changes per Hour *
EXEMPTION CHANGE***
USP < 797 >
Low Volume Exception For
the Negative Pressure
Requirement Is Being
Eliminated
“In facilities that prepare a
low volume of hazardous
drugs, the use of two tiers
of containment (e.g.,
CSTD within a BSC or
CACI that is located in a
non-negative pressure
room) is acceptible.”
USP < 800 >
New Exemption for Not
having ISO 7 Buffer Room
“Allowance …for a Containment
Segregated Compounding Area
(C-SCA), a separate, negative
pressure room with at least 12 air
changes per hour (ACPH) for use
when compounding HDs. Lowand medium-risk HD CSP may be
prepared in a BSC or CACI
located in a C-SCA, provided the
BUD of the CSP does < 12 hours.”
USP 800 on Hazardous Drug Handling
Patient
Safety
Hazardous
Drug Safety
Standards, Recommendations and Regulations
OSHA Occupational Safety and Health Administration
• Federal Regulation
• Technical Manual on Controlling Occupational Exposure to Hazardous Drugs
(1999)
NIOSH National Institute for Occupational Safety and Health
• Maintain Hazardous Drug List, updated Q 2 Years
• 2014 version includes Tiered list of Hazardous Drugs
• Bulletin on Medical Surveillance - 2012
US Pharmacopoeia Chapter <800>
• Federally enforceable standard
• 2nd version available for public comment March 2015
NIOSH 2014
 Table 5
http://www.cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf
Recommendations
 Oncology Nursing Society: Safe Handling of
Hazardous Drugs, 2nd Edition. Polovich, et al. 2011
 ASHP Guidelines on handling Hazardous Drugs
2006
 Safe Handling of Oral Chemotherapeutic Agents in
Clinical Practice: Recommendations From an
International Pharmacy Panel 2011
 ISMP Oncology Safety Self Assessement
The Joint Commission is Interested
The Joint Commission ECNews;
March 2014:volume 7; issue3
Summary of State Bills on Hazardous Drugs
State
Bill Year
Comments
Washington
Senate Bill 55942011
Medical surveillance not
included.
Resources for retail
pharmacy
California
Assembly Bill 12022013
Only applies to
antineoplastics
North Carolina Carolina—House Bill
6642013
Follows NIOSH
Maryland
Currently in committee
Regulations proposed by
Maryland Occupational
Safety and Health 2013
Legislation
Washington OSHA
 “adopt standards consistent with the NIOSH alert
regardless of setting”
 Established Registry
 Adopted January 2012, Three Phase Implementation
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January 2015 – develop and Implement Plan
July 2015 – Complete Training
January 2016 – Install Ventilated Hoods
Washington State’s Hazardous Drugs
Control Program Mandatory Elements
 A written inventory of hazardous drugs in the workplace.
 A current hazard assessment for the hazardous drugs.
 Hazardous drugs policies and procedures that cover, but are
not limited to:
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Engineering controls (equipment use and maintenance).
Personal protective equipment (PPE).
Safe handling practices (receiving and storage, labeling, preparing,
administering, and disposing of hazardous drugs).
Cleaning, housekeeping, and waste handling.
Spill control.
Personnel issues (such as exposure of pregnant workers).
Training.
Proposed USP Chapter < 800 >
Environmental Controls
 Biologic Safety Cabinet (BSC) – Class II
 Compounding Aseptic Containment Isolator (CACI)
 Negative Pressure Room
 Appropriate Ventilation
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Direct drive fans
Exhaust to Outside
 Closed System Transfer Devices
 Surface Contamination Testing Q 6 Months
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Cyclophosphamide, 5-FU, Ifex, Taxanes, Platins
Evaporation of Hazardous Drugs
NEGATIVE PRESSURE IS A MUST
 Drugs known to vaporize at room
temperature
 Cyclophosphamide (Cytoxan)
 Ifosfamide (Ifex)
 Fluorouracil (5-FU)
 Nitrogen Mustard (Mustargen)
 Carmustine
 Thiotepa
 As temperature increase so does
evaporation
 Majority of antineoplastics have
not been evaluated
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Conner T, Shults M, Fraser M. Determination of the
vaporization of solutions of mutagenic antineoplastic agents
at 23 and 37°C using a desiccator technique. Hosp Pharm.
1999; 34(11): 85-92.
Opiolka S, Molter W, Goldschmidt R et al. Evaporation of
cytostatic drugs during preparation. GefahrstoffeReinhaltung der Luft. 1998; 58
CONCERNS:
 HEPA Filters can protect against particles > 2
microns
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HEPAs can not filter drug in gas form
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Poor technique, opening doors and changes
to air flow during compounding can
adversely effect intended air flow patterns in
BSC.
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BSC’s that are not vented to the outside.

BSC’s that are not in negative pressure
environments.
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In the absence of controlled system devices,
drug vapors are released during syringe and
vial manipulations.
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Opiolka M, et al. Umgang mit Zytostatika: Besteht ein
ausreichender Personenschutz bei der ZytostatikaZubereitung? Krankenhaus Technik. 1998; 56-58.
Class II, Type A2 Biologic Safety Cabinet
Must be External Exhausted through
canopy (aka Thimble)
70% Recirculation of Downflow air
within the BSC
(Risk of Vapor Recirculation)
30% Vented
More energy efficient because of less
exhaust
Air Curtain
The Baker Company 2014
Class II, Type B2 Biologic Safety Cabinet
Must be Hard ducted to Facilities
Exhaust System, BSC and HVAC
system must be integrated
100% Externally Exhausted
0% Recirculation
Less energy efficient secondary to
high tempered air loss
Considered the safest BSC for
hazardous drug compounding
The Baker Company 2014
Draft USP Chapter 800 Released 3/14
Hazardous Drug Storage Room and Potential
Integrated Design
Negative Pressure
Cleanroom
ISO 7
Positive Pressure
Cleanroom
ISO 7
_
HD Storage
and Receiving
unclassified
++
Anteroom
ISO 7
+
-
Unclassified Room Air
Hopefully USP 800 final version will better
define HD storage rooms, this
representation is my personal educated
guess.
Personal Protective Equipment
Hair Cover
•
•
Respirator
• Select respiratory protection based on risk assessment of HD: particles vs
vapors
• N-95 Respiratory Appropriate for Particles but not Volatiles
• Powered Air Purifying Respirators (PAPRs)
Shoe Covers
• greatest contamination is the floor directly in front of the BSC.
• Double shoe covers?
Gowns
•“Dispose after each use. Reuse increases chance of exposure. …. If no permeation
information is available … change after every 2 -3 hours.” [NIOSH]
•Manufacturers recommendations, or 2-3 hours [USP 800]
Gloves
•ASTM Rated: Material - Exposure time - Glove thickness
•Wear two pairs of gloves
•Change every 30 minutes
RESPIRATORY PROTECTION
• Select respiratory protection based on risk
•
•
•
•
•
assessment of HD: particles vs vapors
Surgical Masks only protect the product from the
compounder
NIOSH certified N-95 and N-100 masks
Full-face piece chemical cartridge-type respirator
also known as Powered Air Purifying Respirators
(PAPRs)
Respirators require fit testing prior to use
Filter cartridge compatibility with specific HDs
Decreasing Work Place
Contamination:
• CLOSED SYSTEM TRANSFER
DEVICES
• D E C O N T A M I N A TI O N
Where is the Hazardous Drugs Escaping From?
 Leakage Detected at IV
and Syringe
Connections
 Leakage greatest at
IV spike Connection
 Floors, toilets and
nurses’ shoes
were contaminated
Kromhout et al, 2000
“Chemoprotectant Spike”
CSTD Yield a Significant Reduction
in Surface Contamination
 Outpatient Cancer Center
 CSTD in 22 U.S. Hospitals
HD contamination:



Infusion chairs
offices
door handles
Post CTDS Implementation:
 ↓ contamination @ 60 days
 114 samples analyzed for CP,
IF, FU
 CSTD provide a significant
Reduction in surface
contamination
 no contamination detected
@ 1 year
Clark 2013
Sessink
2011
Urine Drug Sampling
Medication
Pre-CSTD
Post-CSTD
#positive
samples
%
Cyclophosphamide 18/48
38%
Ifosfamide
21%
10/48
Cyclophosphamide 0/49
0%
Ifosfamide
0%
0/49
 Samples taken from nurses, pharmacists and pharmacy
technicians, even those who do not compound
 Ifosfamide last prepared 3 weeks prior to first urine
collection
AJHP 2003:60: 2314-2320
CSTD Device Selection
Direct input from the compounding team
Product specific data
Look beyond a manufacturer’ provided lit.
visual indicators ie. titanium tetrachloride (a vapor) and fluorescein.
 head to head product comparisons data compiled from multiple studies.
Product specific environmental sampling studies
conducted in actual work environments should be a
major component of the decision making process.
Compliance with Devices is Important
 Uncontrolled trial in a active hospital
 Trialed one CSTD, then trialed a different CSTD.
 Decontamination products were employed in the hospital
 Wipe Studies Preformed by commercial company
 Both Products considered statistically equal
 Both resulted in undetectable levels of CP, FU, MTX
 Compliance with one system was poor
 System with full compliance lead to 70% lower levels
of exposure to the HDs analyzed for
Lepford 2010
Survey from Pharmacy Purchasing and Products Magazine April 2015
Q: Which of the statements is true with regards to
the role of Alcohol and HD contamination
A. Alcohol is an effective agent for decontamination
of hazardous drugs
B. Alcohol is not effective for decontamination of
hazardous drugs
C. Alcohol solubilize hazardous drugs and can spread
contamination
D. A and C
D. B and C
Decontamination
 Isopropyl for disinfecting a BSC will not deactivate any
hazardous drugs and may result in the spread of
contamination. (ASHP)
 Alkaline Soap – traditional soap and water will liberate
the chemicals from the surface and the water will wash
them away
 Sodium Hypochlorite (Bleach) is a strong oxidizer shown
to deactivate many hazardous drugs (MDMS)
Decontamination
 Sodium Hypochlorite
 Sodium Thiosulfate
 Surface Safe (2 step)
 Sodium Hypochlorite + Surfacant
 Sodium thiosulfate
 HD Clean (2 Step)
 Combination of 4 ammonium chloride compounds
 Neutralizer
 Magnesium oxide + Titanium dioxide
 Fast Act
 Baby Wipes?
Spill Clean Up Procedures
Liquid Spill
Powder/ Dry Spill
 Cover with absorbent
 Cover with absorbent
Towels
 Adorn PPE
 Alert Others of Spill
Towels
 Pour water over towels
to get powder into
solution
 Adorn PPE
 Alert Others of Spill
Respirators must be used when cleaning spills.
Disposal and Decontamination
 All disposable protective clothing as well as any
disposable materials used while handling oral
chemotherapeutic agents should be disposed of as
cytotoxic waste according to the local waste disposal
regulatory guidelines.
 All nondisposable materials exposed to
chemotherapeutic agents including counting trays,
tools, surfaces, etc should be washed or
decontaminated* thoroughly after use.
Administrative Controls
Administration Concerns
 No direct priming of chemotherapy
 Do not remove tubing from an IV containing
chemotherapy
 Be aware of surface contamination
 Wear appropriate PPE for administration
 Ensure excellent hand washing after removing PPE
 Communicate safe handling information
Employee Training and Competency
 Orientation Programs and Routine training courses
“didactic overview of hazardous drugs, including mutagenic,
teratogenic, and carcinogenic properties”.
Competency assessments
Spill Clean-up
Trained and competent to treat individuals accidentally exposed
Hazard Communication
 All risk personnel (including support staff) shall confirm in writing
that they understand the risks of working with hazardous
medications.
Custodial staff involved in cleaning activities and waste removal
should have appropriate training on how to protect themselves and
prevent contamination. This should be documented, initially and
annually thereafter.






Medical Surveillance
 “Workers who are potentially exposed to chemical
hazards should be monitored in a systematic
program of medical surveillance intended to prevent
occupational injury and disease.”- ASHP
 NIOSH 2012 Alert: Medical Surveillance for Health
Care Workers Exposed to Hazardous Drugs
considers this mandatory, but provides little detail
 OSHA has a very detailed section on this OSHA:
Controlling Occupational Exposure to Hazardous
Medications
 USP 800 comprehensive Medical Surveillance.
Monitoring Environmental Contamination
 OSHA - environmental surveillance is mandatory
 USP 797 – “recommended” initially and at least every 6
months.

Currently a strong recommendation due to lack of standardized
analysis and established acceptable levels.
 USP 800: “To ensure containment of HDs,
environmental wipe sampling to detect
uncontained HDs should be performed routinely
(e.g., initially as a benchmark and at least every 6
months, or more often as needed, to verify
containment).”
Environmental Monitoring is Not Hard
 Commercially Available Do-It-Yourself kits
 Identify the appropriate surfaces
 Read instructions and collect samples
 Mail samples to lab
 One wipe sample can be tested for presence of multiple drugs
 Electronic Reports provide comparisons with other facilities
 Use as a bench mark and then get Safer!!!!!
 ChemoGlo
 Tests for 5 drugs with option of one additional drug
 Bureau Veritas – Chemo Alert
 Can test for 45 compounds, customize panel of 9
Example Report for HD Surface Testing
Caring for Patients Receiving HDs
 Cyclophosphamide detected on:


linens, wash clothes
Test pads attached to RNs bodies
 Cyclophosphamide most
concentrated on RNs Hands:



Gloves had high incidence of
contamination
Hands were swabbed after RN removed
gloves
Skin contamination most frequently
detected after handling urine
Fransman 2005
Post-Administration Concerns
 Wear appropriate PPE when handling bodily fluids of
patient treated with chemotherapy (for at least 48 hours
and up to 7 days for some medications)
 Post Signs that “patient has received chemotherapy with
the last 48 hours”
 Minimize handling of HD contaminated urine
Body Waste Disposal – no current research
 Double flushing
 Bleach in the toilet – appearing more frequently
 Contaminated Body Waste Disposal Systems
Prolonged HD Body Fluid Clearance
Detected in Urine
Detected in Stool or
Bile
Cisplatin
At Least 5 Days
Doxorubicin
Up To 5 Days
Etoposide
At Least 5 Days
-
Gemcitabine
At Least 7 Days
-
Imatinib (Gleevec)
Up to 7 days
Up to 7 days
Methotrexate (oral)
Up To 5 Days
Up To 5 Days
ONS – Safe Handling of Hazardous Drugs, 2011
-
Up To 7 Days
Hazardous Drugs in Body Fluids
 Emesis * IV MTX enters emesis
 Seminal Fluid * cyclophosphamide in rats
 Effusions (pleural or peritoneal)
 PPE for administration = PPE for handling patient
body fluids (add splash shield where appropriate)
 High incidence of non-compliance related to PPE for
handling body fluids
Medical Surveillance
Per Proposed USP Chapter 800:
“The goal of medical surveillance is to minimize adverse health
effects in workers exposed to HDs.
“A medical surveillance program involves collecting and
interpreting data to detect changes in the health status of
working populations potentially exposed to hazardous
substances.
“Employers shall ensure that healthcare workers who are
exposed to HDs are routinely monitored as part of a medical
surveillance program.”
Developmental and Reproductive Effects
NIOSH Meta Analysis
 Increased risk of miscarriage
 Increased risk of congenital malformations
 Increased risk of sub-fertility (Women and
Men)
 Concern for non-antineoplastic HDs, that exhibit
adverse reproductive effects in treated patients,
may also be problematic as occupational risks.
Connor, Lawson, Polovich, McDiarmid. Reproductive health risks associated with occupational exposures to antineoplastic drugs in health
care settings: a review of the evidence. Occup Environ Med. 2014 Sep;56(9):901-10.
Developmental and Reproductive Effects
American Journal of Obstetrics & Gynecology (Lawson 2012)
• Study of 7500 Oncology Nurses
• Spontaneous Abortion - Risk↑ by 2 fold
Journal of Occupational & Environmental Medicine (Valanis
1999)
• 7094 Pregnancies and 2976 pharmacy and nursing staff
• Spontaneous Abortion and Stillbirth – Risk↑ by 40–50%
• Paternal Exposure Associated with Risk
 Low birth weight – Risk↑ by 17-fold
 Congenital malformations – Risk↑ by 5-fold
Valanis et al. Occupational Exposure to antineoplastics: self reported miscarriages and stillbirths among nurses and pharmacist.
J Occupational Environ Med. 1999; 41:632-8.
Valanis et al. Occupational Exposure to antineoplastics: self reported infertility among nurses and pharmacist.
J Occupational Environ Med. 1997; 39:574-80.
HDs with known excretion into Breast Milk
 Arsenic trioxide
Meraptopurine
Methotrexate
Mitomycin
Mitoxantrone
Streptozocin
Tacrolimus
Tretinoin
Vincristine
 Cisplatin
 Cyclophosphamide
 Cyclosporin
 Doxorubicin
 Etoposide
 Exemestane
 Goserelin
 Imatinib
 Interferon
 Lomustine
 Megestrol acetate
Melissa McDiarmid, MD – Lsides AOHP
2014 National Conference
September 10-14, 2014
New Orleans, LA
Sutent –In rats, the
concentration in
breast milk found
to be 12x greater
than the
concentration in
blood
Developing fetus and newborns up to the age of
six months more sensitive to chemical toxicity
 Immature Detoxification and Excretion pathways
 Toxicants may be present in higher concentrations in the
blood for longer periods
 Fetus is often more susceptible than the mother to toxicants
 Placenta is poorly effective against lipophilic chemicals and
low-molecular-weight molecules
 “Exposure to chemicals and radiation in utero and early in
life can disproportionally increase the occurrence of
childhood cancer compared with exposures that occur later
in life”
Connor, Lawson, Polovich, McDiarmid. Reproductive health risks associated with
occupational exposures to antineoplastic drugs in health care settings: a review
of the evidence. Occup Environ Med. 2014 Sep;56(9):901-10.
http://www.nurseuncut.com.au/pregnancy-and-parentalleave-discrimination/
Alternative Duty
 NIOSH Proposal on Federal Register in 2015
 Pregnancy = Confidential Medical Information
 Hazard Communication
 Reproductive and Breastfeeding Risks
 Pre-conception – Pregnancy – Post-Partum
 Temporary Protective Reassignment
 Reassignment of Duties Within Same Job OR True Position
Reassignment Needed
 Identify specific Duties within a Job as Hazardous
 Explore options of Temporary Duty Transfer rather than
position re-assignment
 Discussions with affected Parties and Supervisors
Melissa McDiarmid, MD – Slides AOHP 2014 National Conference
September 10-14, 2014 New Orleans, LA
ORAL CHEMOTHERAPY
ORAL CHEMOTHERAPY
 1.5% of all Insured receive anti-cancer
treatment in a given year
 Of those patients 16% receive their chemotherapy
orally (2010 data).
 Of the 400 new anti-neoplastics in development,
25% are orally administered
 Currently no specific competency requirements for
individuals authorized to administer oral
chemotherapy vs. other oral medications
2013 Updated ASCO / ONS Chemotherapy Administration Standards
Non-Oncology Uses of Common Chemotherapy
 Cyclophosphamide
 Idiopathic Thrombocytopenia
 Multiple Sclerosis
 Rheumatoid arthritis
 Sarcoidosis
 Scleroderma
 Lupus
 Solid Organ Transplant
 Vasculitis
 Mercaptopurine
 Crohn’s Disease
 Ulcerative Colitis
 Inflammatory Bowel Disease
 Methotrexate
 Ectopic Pregnancy
 Crohn’s Disease
 Ulcerative Colitis
 Multiple Sclerosis
 Rheumatoid arthritis *
 Sarcoidosis
 Lupus
 Psoriasis *
* = FDA Approval
Non-Liquid Hazardous Drugs
 HDs in solid dosage forms pose a health risk to employees
 Pressed powder, uncoated tablets liberate dust particles



surface contamination
airborn drug dust directly inhaled by employees
Common medications include:
 cyclophosphamide, methotrexate, alkeran, 6mercaptopurine
 Dosage Form Risk

non-coated tablets > Coated tablets > Capsules
 Gel-caps or coated tablets are unlikely to produce dust unless broken in
handling, but still pose a risk for surface contamination
 Use caution when tilting stock pill bottles and dust liberated in
production and transport often accumulates in the bottle of bottles.
OSHA Technical Manual
Safe Handling of Oral Chemotherapeutic Agents in Clinical Practice: Recommendations From an International Pharmacy Panel
Cyclophosphamide Contamination in the
Home and Family Exposure
 2 Patients Receiving IV Cyclophosphamide
 Testing occurred in the 48 hours post-
administration
 8/12 Surface Samples in HOME were
positive for CTX
 Sink
floor
faucets, toilet seat, door knobs, bathroom
 CTX detected in all samples of family
members urine (9 or 9)
Yuki, et al. Exposure of family members to antineoplastic drugs via excreta of treated cancer patients. J Oncol Pharm
Pract 2013 19: 208
Time-course profiles of CPM excretion in urine samples of Patient 1 and Family
Member 1. CPM: cyclophosphamide
Safe Handling for Patients
Healthcare Professional should counseling
patient and family members on:
 Safe Handling (manipulation to minimize





contamination)
Proper Administration
Review Dosing Instructions
Potential Side Effects and what to do if they occur
Review current Medications and Supplements
Proper Storage and Disposal

Consider patients who repackage their drug into pill cases
with other medications
Safe Handling of Oral Chemotherapeutic Agents in Clinical Practice:
Recommendations From an International Pharmacy Panel 2011 (ASCO)
DO’s





Inform other health care professionals
that you are on oral chemotherapy (eg,
surgeons and dentists).
Minimize the number of individuals
coming in contact with the cytotoxic
medications.
Wash the patient’s clothes and bed
linen separately from other items.
Double-flush the toilet after use, during
use of and 4 to 7 d after discontinuing
oral chemotherapy.
It is recommended that caregivers wear
gloves at all times while handling oral
chemotherapeutic agents as well as
contaminated items in order to
minimize risk of exposure
DON’T’s






Leave medication in open areas, near
sources of water, direct sunlight, or
where they can be accessed by
children or pets.
Store medications in the areas where
food or drinks are stored or consumed.
Crush, break, or chew tablets.
Double-up on doses, unless instructed
by a health care professional.
Assume that oral chemotherapy is
safer than intravenous chemotherapy.
Skip doses unless instructed by your
physician
Conclusion
The goal is to decrease environmental
contamination to a level “as low as
reasonably achievable” (ALARA)
through education, safe handling
practices and employer support.
Any Questions ??