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The Scientific Evidence Behind USP 797 Eric S. Kastango, BS Pharm, MBA, FASHP
The Scientific Evidence Behind USP 797Eric S. Kastango, BS Pharm, MBA, FASHP
Disclosure information
The Scientific Evidence Behind USP 797
Eric S. Kastango, BS Pharm, MBA, FASHP
• I have no financial relationship to disclose.
Disclosure
3
I am speaking in my own individual capacity and not as representatives of any organization or committee regardless of any
status, membership or affiliations I may have with any entity.
The views and opinions presented are entirely my own. They do not necessarily reflect the views of any other organization that I
may associated with, nor should they be construed as an “official” explanation or interpretation of any USP chapter or any State Board of
Pharmacy rule/law.
www.ivpnsymposium.org
Learning Objectives
• At the end of this session, you will be able to:
• Differentiate between the best practices and evidenced-based science
• Identify the key evidenced-based elements of USP Chapter <797>
• Explain the rationale behind using best practices when evidenced-based science is not available
Health Care Quality Defects Occur at Alarming Rates
Defects
per
million
U.S. Industry Best-in-Class
Breast cancer screening (65-69)
Detection & treatment of depression
Overall Health Care in U.S. (RAND)
Outpatient ABX for Colds
Adverse drug events
Hospital Acquired Infections
Hospital patients Injured through negligence
Airline baggage handling
Anesthesia-related fatality rate
(69%) (31%) (7%) (.6%) (.002%) (.00003%)
σ Level (% defects)
Post MIβ-Blockers
Food Safety
1
10
100
1,000
10,000
100,000
1,000,000
1 2 3 4 5 6
Weight-of-Evidence
6
“Weight-of-evidence is the process by which multiple measurement endpoints are related to an assessment endpoint to evaluate whether significant risk of harm is posed to the environment” (in this case, the patient (or worker)).
Adapted from Massachusetts Weight-of-Evidence Workgroup, 1995
What is evidence-based medicine?
• “Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.” 1
• It is frequently stated that it takes an average of 17 years for research evidence to reach clinical practice2
1. Sackett, et al. BMJ 1996;312:71-72
2. Westfall J, Mold J, Fagnan L Practice-based research – “Blue Highways” on the NIH roadmap. JAMA 2007;297:403–6
Evidence: systematic observation
Meta-Analysis
Randomized Controlled Trial
Uncontrolled Trial
Case Series
Anecdote
Evidence: systematic observation
• Conceptually, evidence starts simply with what is observed
• The more systematic an approach that is taken to gathering and organizing evidence, ranging from the individual anecdote up to the meta-analysis of controlled trials, the higher quality the evidence.
• This process is not without challenges. • “Not everything that can be counted counts, and not everything
that counts can be counted.” – Albert Einstein
Food for Thoughts
• It is ethically inappropriate to systematically conduct clinical evaluations incorporating conditions that do not favor the best possible patient outcomes
• Clinical practices for which there is considerable evidence or expert consensus, and which show promise in improving client outcomes, but which are not yet proven by the highest or strongest scientific evidence1.
• “Achieving safer care has three agendas, all of which are necessary for success: identifying what works (efficacy), ensuring that the patient receives it (appropriate use), and delivering it flawlessly (no errors)”.2
1. Bigfoot D, Bartgis J. Urban Indian Health Knowledge Resource Center website. Accessed November 11, 2019
2. Leape LL, Berwick DM, Bates DW. JAMA. 2002 Jul 24-31;288(4):501-7.
Best Practices Versus Evidence-Based
• Several parts of USP compounding chapters are evidenced-based
• Success will occur when we make changes
Hand Hygiene and Garbing Facility Design
Cleaning and DisinfectionBUD based on Chemical
Stability
Microbial risk minimized by limited BUDs
Parameters for Establishing BUD
• All parenteral dosage forms must be sterility tested per USP <1>
• Recognizes the probability of contamination even under best conditions:
• Optimal employee performance
• 0.1% (1 contaminated dose out of 1,000)
• Contamination rates published in the literature
• 0.3% – 16%
• Patient Safety: Protect patients from dangerous or even fatal overgrowths of microorganisms that may have been accidentally introduced
• USP Chapter <797> BUDs are safe-harbors, assumes compliance with USP chapter requirements.
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reserved
Microbiological Beyond Use Dating
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reserved
▪ Hand washing is defined as the vigorous,
rubbing together of all surfaces of soap lathered
hands (30 sec.), followed by rinsing under a
stream of water.
▪ The process of hand washing mechanically
removes microorganisms of the hands.
▪ The single most important way to reduce the risk
of transmitting microorganisms causing
infections.
▪ Human GI microorganisms have been involved
in CSP contamination events.
Hand Hygiene - USP <797>
https://www.cdc.gov/handwashing/posters.html
Important Definitions
Aseptic Technique
A set of specific work practices and procedures performed under carefully controlled conditions with the goal of minimizing the introduction of contamination.1
1Kastango ES. Spread the Word: Aseptic Technique Prevents Infection. Pharmacy Purchasing and Products Magazine. April 2009. Retrieved on 2/20/18 from https://www.pppmag.com/article/522/.
Notice the definition says “specific” work practices…make sure the elements of aseptic technique are defined in your SOPs.
General Conduct in Controlled Environments
• Move slowly, it really does make a difference!
Activity1 Particles Generated
Sitting quietly 100,000/minute
Walking slowly (1.9 miles/hour) 5,000,000/minute
Walking medium (3 miles/hour) 7,500,000/minute
Walking fast (5 miles/hour) 10,000,000/minute1Particle Measuring Systems. Basic Guide to Particle Counters and Counting. 2011. Accessed on 3/6/19 from
Pharmaceutical Online.
General Conduct: No PEDs!
• Personal electronic devices (PEDs) brought into the controlled environments is problematic!
• 100% of phones contaminated with either single or mixed bacterial agents1
• Most prevalent methicillin-resistant S. aureus and coag negative staphylococci1
• Mean organisms per phone between 1720 to 21921
1Selim HD, Abaza AF. Microbial contamination of mobile phones in a health care setting in Alexandria, Egypt. GMS Hyg Infect Control 2015. Retrieved on 3/8/2019 from http://www.egms.de/static/en/journals/dgkh/2015-10/dgkh000246.shtml.
General Conduct: Do not touch your face!
• Remember the movie, Contagion? “the average person touches their face 2,000 to 3,000 times per day.” That’s an average of 3 to 5 times per waking minute!
• Students studied touched their face 16 times per hour1
• Another study of medical students identified 23 times per hour2
1Nicas M, Best D. A study quantifying the hand-to-face contact rate and its potential application to predicting respiratory infection. J Occup Environ Hyg. 2008. 5(6): 347-52. Available for purchase at PubMed.gov2Kwok YL, Gralton J. McLaws ML. Face touching: a frequent habit that has implications for hand hygiene. Am J Infect Control. 2015. 43(2):112-114
Garbing – Sterile Gloves
Facility Design Requirements
• Cleanroom Design Requirements
• Most contamination within the pharmaceutical facility can be traced to humans working in cleanrooms1
• Control of contamination from people in cleanrooms is achieved by application of two principles2:
• We “wrap” the people to minimize the amount of “shedding” of microorganisms.
• We put localized protection around the product to minimize the amount of contact with the people.
1 Whyte, W. (1981) J. Paren. Sci. Technol., 36: 255-268,
2 Sandle T. (2014) IVT Network. http://www.ivtnetwork.com/article/people-cleanrooms-understanding-and-monitoring-personnel-factor
Air Cleanliness
• ISO classification
• The smaller the number, the cleaner the air
• Refers to number of particles allowed per volume of air
• PEC = ISO 5
• Buffer area = ISO 7
• Ante area
• ISO 8 if it opens only into a positive pressure cleanroom
• ISO 7 if it opens into a negative pressure cleanroom
Cleanliness Classification Comparison
• Class limits for sterile compounding based on the number of particles ≥0.5µm per m3 (ISO) or per ft3 (former Federal Standard 209E)
• Count locations are determined based on room size and classification and are measured under dynamic operating conditions.
ISO Class US FS 209E ISO m3 FS 209e (ft3)
3 Class 1 35.2 1
4 Class 10 352 10
5 Class 100 3500 100
6 Class 1000 35,200 1000
7 Class 10,000 352,000 10,000
8 Class 100,000 3,520,000 100,000
LAFW
Facility Design
• If differential pressure design, then pressure gauges installed and monitored at least daily:
• Buffer anteroom (0.02” w.c. positive or 0.01” negative)
• Anteroom non-classed (0.02” w.c. positive)
• If open concept (air displacement design):
• No longer an acceptable design
• Air Cleanliness
• Buffer ISO Class 7
• Anteroom ISO Class 7/8
• Air Exchanges
• Buffer room: at least 30 ACPH with 15 of those from HEPA filtered air supplied to room
• Ante-area: At least 20 ACPH common
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Decontamination/Disinfection
• Transfer of material into and out of the isolator is one of the greatest potential sources of contamination. Routes include bags, boxes, paper and markers.
• Research has shown that:• 60% of consumables are contaminated with bacteria
• 40% of consumables are contaminated with bacterial spores
• Spraying alone is not enough:
Organism Spray Spray + Wipe
Aspergillus
Niger 84% 98.5%
Bacillus subtilis 27% 94%
M. G. Cockcroft, D. Hepworth, J. C. Rhodes, P. Addison, A. M. Beaney. “Validation of Liquid
Transfer Disinfection Techniques for Transfer of Components Into Hospital Pharmacy
Cleanrooms,” Hospital Pharmacist (September, 2001).
Contaminated Material
Table 1: Sample testing of items routinely used in
isolators
Item % contaminated% Bacillus
(spores)
Syringe
package60.0 40.0
Swab package 66.7 16.6
Needle package 60.0 20.0
Sharps bin 57.1 42.9
M. G. Cockcroft, D. Hepworth, J. C. Rhodes, P. Addison, A. M. Beaney. “Validation of Liquid
Transfer Disinfection Techniques for Transfer of Components Into Hospital Pharmacy
Cleanrooms,” Hospital Pharmacist (September, 2001).
Best Practices Versus Evidence-Based
• Chapters based on• clear linkage between certain
processes and observed adverse events
• Reasonable estimation of potential risks and benefits of the interventions
• understanding of human factors principles (Complex Adaptive Systems)
• Learned from the safety practices in other industries
• Aviation
• Nuclear energy
• Anesthesia
Best Practices Versus Evidence-Based
• We cannot always wait for evidence-based interventions alone.
• Would be tragic to abandon certain safety initiatives like aseptic compounding quality systems simply because they’re not backed by rigorous scientific evidence.
• Waiting for irrefutable proof of effectiveness is simply not an option!
• We must make informed decisions based on the best available information and common sense.
Summary
• There will never be complete evidence for everything that must be done in healthcare. The prudent alternative is to make reasonable judgments based on the best available evidence combined with successful experiences in healthcare1.
Leape, L., Berwick, D., & Bates, D. What Practices Will Most Improve Safety? Evidence –Based Medicine Meets Patient Safety. JAMA, July 24/31, (288) 4, 507.
Additional Literature/References
• Leape LL, Berwick DM, Bates DW. What practices will most improve safety? Evidence-based medicine meets patient safety. JAMA. 2002 Jul 24-31;288(4):501-7.
• Center for Evidence-Based Medicine (http://www.cebm.net/)
• Agency for Healthcare Research and Quality (http://www.ahrq.gov/clinic/epcix.htm)
• Sandle T., People in Cleanrooms: Understanding and Monitoring the Personnel Factor. IVT website. http://www.ivtnetwork.com/article/people-cleanrooms-understanding-and-monitoring-personnel-factor Accessed November 11, 2019
Thank you
My contact information:
Eric S. Kastango, MBA, RPh, FASHP
Clinical IQ, LLC
235 Main Street, Ste 292
Madison, NJ USA 07940
973.765.9393
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