IV Sterile Compounding Risks and Safety Scarlett S. Eckert, Pharm. - - PDF document
1/20/2019 1 IV Sterile Compounding Risks and Safety Scarlett S. Eckert, Pharm. D. 2 Relevant Financial Relationships with Commercial Interests Speakers disclosure of any relevant financial relationships with any commercial interest. 1
1/20/2019 1
IV Sterile Compounding Risks and Safety
1
Scarlett S. Eckert, Pharm. D.
Relevant Financial Relationships with Commercial Interests
Speaker’s disclosure of any relevant financial relationships with any commercial interest.
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Objectives
Review the severity of IV compounding errors.
Review the New ‘proposed’ USP <797> requirements addressing IV compounding safety.
Review the USP <800> personnel, environment and patient safety requirements.
Describe the components of IV compounding errors.
Identify which risk factors and safety issues can be mitigated.
Discuss how to mitigate risk factors and improve safety of your cleanroom practices and compounded sterile products.
3
Pre-Test Questions
would be the best accuracy percent you could expect?
B.
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2. The primary contributing factor of IV compounding errors can be contributed to:
A.
Consumable labeling, vials and bags
B.
Detailed and difficult to follow SOPs
C.
USP <797> lack of regulatory guidance
D.
Compounding staff and checking staff
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Pre-Test Questions
Category 1 CSP? True or False
NIOSH table 1, 2 and 3. True or False
5.
It is possible to eliminate 100% of the risk associated with manual compounding? True or False
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Sterile Compounding Safety and Risk
What is “Safety”? Condition of being protected from hazards, risks, and
harm
What is “Sterile Compounding”
Performing manipulations of presumed sterile ingredients in a manner which prevents introduction
(Proper nomenclature = Aseptic Compounding)
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What is in the bag?
Sterile compounding is the least transparent and most technique-critical process in the pharmacy:
Start with sterile drug vial, diluent bags, needles, syringes
form
Two potential safety risks that must be mitigated:
fluid transfer was performed within acceptable tolerance
technique 100% of the time
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Sterility Assurance – The Invisible Problem
How do we assure sterility ?
Impossible to achieve 100% sterility using aseptic compounding
assurance limit is 1x10-6
With best practices used 100% of the time, the residual risk is 1:1000 for
a contaminated dose.
For each contact of the sterile item with a non-sterile object, risk of
contamination rises at least 30-fold (contamination recovery rate range 3 - 67%)
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Contaminated Doses Rate with 99.9% Sterility Rate
ANNUALIZED POTENTIALLY CONTAMINATED DOSES WHEN STERILITY RATE 99.9%
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DOSES PER BED PER DAY BED SIZE 1 2 3 4 5 100 37 73 110 146 183 200 73 146 219 292 365 300 110 219 329 438 548 400 146 292 438 584 730 500 183 365 548 730 913 600 219 438 657 876 1095 700 256 511 767 1022 1278 800 292 584 876 1168 1460 900 329 657 986 1314 1643 1000 365 730 1095 1460 1825
QUESTION 1
What are two (2) potential CSP safety risks that must be
mitigated:
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QUESTION 1 Answer
What are (2) two potential CSP safety risks that must be
mitigated:
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The Pew Charitable Trusts
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Pew’s drug safety project has identified more than 71 reported compounding errors or potential errors associated with 1,416 adverse events, including 115 deaths, from 2001 to 2017. However, a 2015 survey found that only 30 percent of states (13 or the 43 that responded) require sterile compounding pharmacies to report serious adverse events. Of the states that require reporting, they type of information that is required to be reported may vary, further contributing to an incomplete picture of adverse events associated with compounded
illnesses and deaths caused by compounded drugs are not always linked to the compounding error. Because many such events may go unreported, this chart is likely an underestimation of the number of compounding errors since 2001, Contamination of sterile products was the most common error, others were the result of pharmacist and technicians miscalculation and mistakes in filling prescriptions.
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Under reported Errors
WHY under reported?
Lack of recognition
Seeing adverse events and errors as just part of the routine
Fear of retribution
You have to feel safe to report someone else’s error, or your own. “Most hospitals have yet to create a safety culture.”
A sense of disbelief
“I remember talking to a hospital CEO once right after the report,”
Gibson recalls. “He said that after a significant error, he would get up in the morning and look in the mirror and think, ‘Did this really happen here?’ There’s almost a sense that if you don’t see it, it didn’t exist.”
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The Hospitalist. 2012 July;2012(7)
Under reported Errors
Competing pressures
“The requirements of healthcare reform have taken up so much
time and energy that I fear safety has moved to the back burner”
“Someone in a quality and safety leadership role at one hospital
said to me, ‘Safety was just a fad. We’re not doing that anymore.’” Productivity demands
“Healthcare’s mantra today has become volume, volume,
we would like, and you ramp up the volume so people have to do more in the name of productivity, what’s going to happen?”
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The Hospitalist. 2012 July;2012(7)
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U.S. Illnesses and Deaths Associated With Compounded Medications or Repackaged Medications
15 U.S. Illnesses and Deaths Associated With
U.S. Illnesses and Deaths Associated With Compounded Medications or Repackaged Medications
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U.S. Illnesses and Deaths Associated With Compounded Medications or Repackaged Medications
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U.S. Illnesses and Deaths Associated With Compounded Medications or Repackaged Medications
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U.S. Illnesses and Deaths Associated With Compounded Medications or Repackaged Medications 19
U.S. Illnesses and Deaths Associated With Compounded Medications or Repackaged Medications
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Studies and Statistics
Flynn, Pearson, Barker (1997)
9% mean error rate and 2% clinically significant
Essentially 1 out of every 10 sterile preps are flawed
Still quoted to this day by Institute for Safe Medication Practices (ISMP) Moniz, Chu, Tom, et al (2014)
Study of over 425,000 compounded doses
6.8 errors per 1,000 doses - 23% undetectable by inspection
167 of the errors (0.04%) had potential for moderate or severe harm 4/10,000 of all doses compounded Hingl, Deng, Lin (2015)
6 errors per 1,000 doses
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Studies and Statistics
Poppe, Savage, Eckel (2014)
13% of doses outside acceptable variance (+/-
10%) Reece, Lozano, Roux et al (2016)
7% of doses had error in process 74% would not have been detected by
visual inspection
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United States Pharmacopeia (USP)
A scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed worldwide. USP’s drug standards are enforceable in the United States by the Food and Drug Administration, and these standards are used in more than 140 countries.
USP <797>:Pharmaceutical Compounding—Sterile Preparations (under revision)
http://www.usp.org/compounding/general-chapter-797
USP <800>:Hazardous Drugs—Handling in Healthcare Settings
http://www.usp.org/sites/default/files/usp/document/our-
work/healthcare-quality-safety/general-chapter-800.pdf
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USP CHAPTER RELEASE DATES
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USP <797>
USP <797>
Guidelines for handling all CSP, personnel, training, compounding,
environment, quality assurance and monitoring.
Represent the minimum requirements to be applied in
compounding sterile preparations; however, it is always possible to exceed these standards.
Major Point:
Specific processes for Microbial control. 25
Proposed USP <797>, Changes
Risk Categories:
Cleanroom design Primary Engineering Control (PEC) classification Sink location options Environmental monitoring frequency Personnel monitoring frequency Personnel Protective Equipment (PPE) Beyond Use Date Sterility Testing samples requirement Action Level for Personnel and Environment samples In-Use time: addition of compounded source containers
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Proposed USP <797>: RISK Categories
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Proposed USP <797>: Cleanroom Design
All HEPA filtered airflow must come from the ceiling with
HEPA filter at the ceiling.
ACPH is based on number of personnel, particulates generated by
activity, equipment located in area, pressure and effects of temperature.
Minimum ACPH: ISO 7= 30,
ISO 8 = 20, non-HD SCA= no requirement HD SCA= 12
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Proposed USP <797>: Cleanroom Design
Anteroom Sink can be inside or outside classified area/ anteroom No floor drain in anteroom No water source or drain can be in buffer area ACPH >/= 20 required ISO 8, >/= 30 required ISO 7 Garbing PPE order and location set by facility ISO 8 or better, positive pressure for access to only non-hazardous
buffer area
ISO 7 or better, positive pressure for access to hazardous area Or shared anteroom between non-HD and HD buffer areas.
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Proposed USP <797>: PEC Classification
PEC Type Device Type Placement for Category 1 CSPs Placement for Category 2 CSPs LAFS LAFW Unclassified SCA ISO 7 positive pressure buffer with ISO 8 positive pressure ante-room IVLFZ N/A ISO 7 positive pressure buffer with ISO 8 positive pressure ante-room BSC Unclassified SCA or C-SCA ISO 7 positive pressure buffer with ISO 8 positive pressure ante-room ISO 7 negative pressure buffer with ISO 7 positive pressure ante-room RABS CAI or CACI Unclassified SCA or C-SCA CAI: ISO 7 positive pressure buffer with ISO 8 positive pressure ante-room CACI: ISO 7 negative buffer/ ISO 7 positive anteroom Isolator Isolator Unclassified SCA or C-SCA ISO 8 or better positive pressure room
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Proposed USP <797>: PPE Minimum Requirements
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GOWNS: May NOT be saved for use later, non-hazardous or hazardous
Proposed USP <797>: Personnel Qualifications 32
Category 1 CSPs Category 2 CSPs Personnel Qualifications Visual Observation of hand hygiene and garbing Every 6 months Every 6 months Gloved fingertip sampling (GFS) Every 6 months Every 6 months Media fill testing Every 6 months Every 6 months Requalification Every 12 months Every 12 months
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Proposed USP <797>: Environmental, Building and Facilities
Category 1 CSPs Category 2 CSPs Building and Facilities Primary engineering control (PEC) Not required to be placed in a classified area Required to be placed in a classified area Recertification Every 6 months Every 6 months
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Category 1 CSPs Category 2 CSPs Environmental Monitoring Nonviable airborne monitoring Every 6 months Every 6 months Viable airborne monitoring Every 6 months Every 6 months Surface sampling Monthly Monthly
Proposed USP <797>:
Release Testing and BUD Assignment
Category 1 CSPs Category 2 CSPs Physical inspection Required Required Sterility testing Not Required Based on assigned BUD Endotoxin testing Not Required Required if prepared from non-sterile ingredient(s) BUD BUD assignment </= 12 hours at controlled room temperature or </=24 hours if refrigerated > 12 hours at controlled room temperature or >24 hours if refrigerated
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Proposed USP <797>: PEC Cleaning Clarification
Disinfect all interior surfaces of the PEC at the beginning and end of each shift, after spills, and when surface contamination is known or suspected. Disinfect the horizontal work surface at least every 30 minutes while compounding if the compounding process takes 30 minutes or less. If compounding takes more than 30 minutes do NOT disrupt the process, and disinfect PEC work surface once compounding completed.
Once daily:
At least Monthly, use a sporicidal detergent 3.
Final sanitize with STERILE 70% IPA
Subsequent work surface cleaning: STERILE 70% IPA
35 Proposed USP <797>: BUD Category 1 CSPs 36
Immediate use: Must be administered within 1 hour of first puncture of compounding process.
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Proposed USP <797>: BUD Category 2 CSPs
Preparation Characteristics Storage Conditions Sterilization Method Sterility Testing Performed and Passed Controlled Room Temperature (20° – 25° ) Refrigerator (2° – 8° ) Freezer (-25° to -10° ) Aseptically prepared CSPs No Prepared from
nonsterile starting components: 1 day Prepared from one or more nonsterile starting components: 4 day Prepared from
nonsterile starting components: 45 day Prepared from
components: 4 days Prepared from only STERILE components: 9 days Prepared from
components: 45 days Yes 30 days 45 days 60 days Terminally No 14 days 28 days 45 days
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Proposed USP <797>: Sterility Testing
The BUDs specified in the table indicate the days after the Category 2 CSP is prepared beyond which the CSP cannot be used. The BUD is determined from the time the CSP is
The integrity of the container–closure system with the particular CSP in it must have been demonstrated for length of frozen storage. The container–closure integrity test needs to be conducted only once one ach formulation in the particular container–closure system in which it will be stored or released/dispensed. Multi-dose CSP formulation must pass antimicrobial effectiveness testing in accordance with <51> at the time of preparation. The compounder may rely on 1. AET conducted or contracted for, or 2. AER results published in peer-reviewed literature sources if the CSP formulation (including any preservative) and container-closure system are exactly the same as those tested. The test must be completed and the results obtained on the specific formulation before any of the CSP is dispensed. The test needs to be conducted only once on each formulation in the particular container–closure system in which it will be stored or released/dispensed. Multi-dose CSP formulation must pass antimicrobial effectiveness testing in accordance with <51> at the completion of sterility test (i.e., 14 -28 days after preparation per category and type of organism testing for). The test must be completed and the results obtained on the specific formulation before any of the CSP is dispensed. The test needs to be conducted only once on each formulation in the particular container–closure system in which it will be stored or released/dispensed.
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Sterility testing follows USP <71> Table 2 and Table 3 for minimum quantity tested of each
to the next whole number. Example 1 CSP requires 1 additional for testing, 39 CSP requires 4 additional for testing.
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Proposed USP <797>: IN-Use time
Manufacturer’s vials/containers:
Single Dose/Use = 6 hours once punctured Removed within ISO 5 to allow for refrigerated item storage Multi-dose = 28 days or per manufacturer if less
In-house compounded source containers:
Single Dose/Use = 6 hours once punctured for draws Removed within ISO 5 to allow for refrigerated item storage Multi-dose = 28 days or less depended on drug stability
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QUESTION 2
Which of the following statement is False per the proposed revision of USP <797>?
A.
GFS and Media Fill testing increased to every 6 months
B.
Training of compounding personnel must be completed annually
C.
Surface sampling is specified to be completed at a minimum monthly
D.
Visual inspection is not required for Category 1 CSPs
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QUESTION 2 Answer
Which of the following statement is False per the proposed revision of USP <797>?
A.
GFS and Media Fill testing increased to every 6 months
B.
Training of compounding personnel must be completed annually
C.
Surface sampling is specified to be completed at a minimum monthly
D.
Visual inspection is not required for Category 1 CSPs
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USP <800>
USP <800> address activities with potential risk of HD exposure and
the PPE required for handling IV HD drugs in any healthcare environment, by any and all personnel.
USP <800> sets guidelines for handling all types of HD, IV, oral,
and topical, throughout any and all healthcare settings. Major Point:
Specific processes for containment of possible HD contamination
and mitigation of exposure risks.
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USP <800>
This chapter describes practice and quality standards for handling hazardous drugs to promote patient safety, worker safety, and environmental protection for both sterile and nonsterile products and preparations.
Includes, but is not limited to:
receipt, storage, compounding, dispensing, administration, disposal.
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USP <800>
Applies to all healthcare personnel who handle HD preparations, and entities which store, prepare, transport, or administer HDs, includes but not limited to: pharmacists, pharmacy technicians, nurses, home healthcare workers, physicians, physician assistants, veterinarians, veterinary technicians
Entities that handle HDs must incorporate these standards into their
Engineering controls Competent personnel Safe work practices Proper use of appropriate PPE Policies for HD waste segregation and disposal
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USP <800>
Elements Required:
Personnel requirements, training and competency
Facilities layout
Environmental quality and control
PPE
Hazardous Communication
Receiving
Transport
Administering
Deactivation/decontamination, cleaning and disinfection
Spill control
Disposal
Quality Assurance: product, environment and personnel
Medical surveillance
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USP <800>: Assessment of Risk Elements
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All NISOH listed drugs, and drugs with
similar risk components, must be handled per USP <800> containment requirements UNLESS: An Assessment of Risk is completed for Table 1 drugs in final dosage form, Table 2 and 3 drugs requiring manipulation and in final dosage form.
https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf
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USP <800>: Assessment of Risk Elements
Assessment of Risk must consider:
Drug
Dosage form
Risk of exposure
Situational risk
Packaging
Manipulation / compounding
Documentation of alternative containment strategies and / or work practices
Review, at minimum, annually (document annual review)
Process to review and add new drugs
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https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf
USP <800>: Risk Elements
Not all hazardous defined drugs pose a significant direct occupational exposure risk because of their dosage form:
These products may pose a risk if the dosage form requires alteration.
Cutting
Crushing
Dissolving
Piercing or opening
Compounding
MIND THE DUST!
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USP <800>: HD Storage Requirements
Hazardous drugs that may be stored with other inventory:
Antineoplastic HD requiring manipulation other than counting and all HD APIs MUST be stored:
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Sterile and non-sterile HDs may be stored together outside of buffer area of cleanroom, but ONLY sterile HDs should be stored in a buffer room under negative pressure.
Question 3
To implement alternative containment and protection strategies less than the requirements in USP <800>, each facility must complete an Assessment of Risk. The Assessment of RISK does not apply to antineoplastic listed on NIOSH Table 1 requiring manipulation and/or compounding other than re-packaging the final dosage form. True False
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Question 3 Answer
To implement alternative containment and protection strategies less than the requirements in USP <800>, each facility must complete an Assessment of Risk. The Assessment of RISK does not apply to antineoplastic listed on NIOSH Table 1 requiring manipulation and/or compounding other than re-packaging the final dosage form. True False
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RISK Likelihood
Dying from influenza: Causing a car accident while using cell phone: Being struck by lightning in lifetime: Dying in a car accident: Dying in a plane crash: Contaminating a sterile dose during compounding: Perfect March Madness bracket:
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RISK Likelihood
Causing a car accident while using cell phone: 1:75 Contaminating a sterile dose during compounding 1:1,000 Being struck by lightning in lifetime: 1:3,000 Dying in a car accident: 1:5,000 Dying from influenza 1:10,000 Dying in a plane crash: 1:11,000,000 Perfect March Madness bracket: 1:9,223,372,036,854,775,808
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Components of IV compounding Errors
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Components of IV compounding Errors
People are the problem.
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Components of IV compounding Errors
People are the problem.
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People: Contamination generally comes from skin flakes and oil, cosmetics and perfume, spittle, clothing debris (lint, fibers, etc.), and hair. People are a major sources of particles. People are the #1 cause
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Components of IV compounding Errors
How have we dealt with the problem?
effective particle barriers
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Components of IV compounding Errors
The problem remains: People.
+ Increasing propensity to take shortcuts + Decreased attention to detail = Increased risk of error slipping through
PEOPLE are our biggest safety risk in sterile compounding.
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Sterile Compounding Safety and Risk
Have we improved the process?
people follow the processes as designed.
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Question 4
The primary contributing factor of IV compounding errors can be contributed to:
A.
Consumable labeling, vials and bags
B.
Detailed and difficult to follow SOPs
C.
USP <797> lack of regulatory guidance
D.
Compounding staff and checking staff
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Question 4 Answer
The primary contributing factor of IV compounding errors can be contributed to:
A.
Consumable labeling, vials and bags
B.
Detailed and difficult to follow SOPs
C.
USP <797> lack of regulatory guidance
D.
Compounding staff and checking staff
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Sterile Compounding Safety and Risk
Where are the hazards and risks ? What kinds of harm can occur ? What can we eliminate (protect from)
?
What should we/ can we mitigate
(reduce likelihood) ?
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Likelihood
Severity
Likelihood
Detection
Safety in Sterile Compounding
Risk Factors and Safety Issues
Potential harm from CSPs
Risk Factors and Safety Issues
From a risk perspective, we must assume an unmitigated hazard that reaches the patient will cause some degree of harm
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standards allow as much as +/- 10% variance
product and may not detect defects in the intermediary compounding steps
intended dose, not what is actually in the finished dose
Risk Factors and Safety Issues
Detection of hazards in CSPs is unlikely
Likelihood of detecting CSP problems
and when performed only demonstrate that the tested samples meet the specification
without contamination, not whether it is followed 100% of time (Observer effect) Methods to reduce likelihood of occurrence
reliably inconsistent
process in accordance with design
Risk Factors and Safety Issues
Likelihood of occurrence is the element of risk over which we have the greatest level of control to target for mitigation
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Likelihood of Occurrence
Severity
Likelihood
Detection
RISK Reduction in likelihood of
reduces risk
Safety in Sterile Compounding
Risk Factors and Safety Issues
Improve safety in CSP compounding
Methods to reduce likelihood of occurrence Eliminate root cause Detect and stop hazards earlier in process Reduce exposure to hazard source Decrease complexity Decrease variability
The #1 method to reduce likelihood of an
identified hazard occurring is… 68
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Improve safety in CSP compounding
Methods to reduce likelihood of occurrence Eliminate root cause Detect and stop hazards earlier in process Reduce exposure to hazard source Decrease complexity Decrease variability
The #1 method to reduce likelihood of an
identified hazard occurring is… 69
PPP article from ISMP 9/21/2018
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ISMP recommends use of technology to augment the manual process
PPP magazine September 2018
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Question 5
Which component of Risk is easiest to control or mitigate?
A.
Severity of Harm caused by a contaminated CSP
B.
Detecting which CSP has been contaminated
C.
Reducing the likelihood of contamination occurring
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Question 5 Answer
Which component of Risk is easiest to control or mitigate?
A.
Severity of Harm caused by a contaminated CSP
B.
Detecting which CSP has been contaminated
C.
Reducing the likelihood of contamination occurring
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IV Workflow Systems
Mitigates non-contamination errors
Drug, Diluent
Dosing, Concentration
Does NOT mitigate possible contamination Still Manual Process
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Every related process should incorporate Safety
by Design-Look beyond the hood
Automation addresses the inherent human flaws in manual compounding,
most of which are difficult or impossible to detect by inspection
The right automation uses each of the key strategies that reduce likelihood of
Improve Safety in CSP Compounding
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IV Automation Requirements
WHAT TO LOOK FOR IN IV AUTOMATION
IV Automation safety features must include:
ISO-5 or better aseptic environment maintained throughout the compounding
process.
Unidirectional airflow with first air passing over critical sites. No compounding process is completed over top of other consumables or products. Inventory is stored in an ISO-5 environment, separate from the compounding area. Provide dose accuracy and production repeatability. No share needles or use IV tubing to transfer reconstitution diluents, or drugs. Automatically disinfect critical sites, vials stoppers and bag ports. Sanitize beyond what human cleaning of critical sites with sterile 70% IPA Correctly label and gravimetric verification of the final product. Direct validation of the fluid transfers.
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IV Automation Requirements
WHAT TO LOOK FOR IN IV AUTOMATION
The automation should not introduce risks back in to the process : Remove human interaction from the compounding process. Consumables should be verified within the automation process. Eliminate the reliance on manual checks and inspections to identify
errors.
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IV compounding robots
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KIRO - Grisfol RIVA - ARxIUM IV Station - Omnicell WEINAS - Weibond EQUASHIELD
IV Automation Requirements
Compounding process needs to fully automate:
No manual intervention in the compounding process. Products prepared are to be in final form ready for patient
use.
–
Cost per dose, pay-back.
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Question 6
Which Key Features IV Automation should include:
environment maintained throughout the compounding process.
B.
No compounding is completed over other consumables or products.
E.
No use share needles or use of IV tubing during compounding.
F.
Consumables are verified within the automation process.
ports.
CPS.
I.
System correctly labels for dispensing and verifies the final product.
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Question 6 Answer
Which Key Features IV Automation should include:
environment maintained throughout the compounding process.
B.
No compounding is completed over other consumables or products.
E.
No use share needles or use of IV tubing during compounding.
F.
Consumables are verified within the automation process.
ports.
CPS.
I.
System correctly labels for dispensing and verifies the final product.
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