USP 797-US Sterile Compounding Standard CSHP Ontario Branch-Ontario Hospital Pharmacy Management Seminar

Eric S. Kastango, MBA, RPh, FASHP - Clinical IQ, LLC

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Disclaimer Eric S. Kastango, MBA, RPh, FASHP is Principal/CEO of Clinical IQ , LLC and CriticalPoint, LLC .

I am speaking today in my individual capacity and not as a member of the Committee or as a USP representative. The views and opinions presented are entirely my own. They do not necessarily reflect the views of USP or any other organization I may be associated with, nor should they be construed as an official explanation or interpretation of .

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Thought

“You can avoid reality, but you cannot avoid the consequences of avoiding reality.” Ayn Rand (1905-1982)

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What’s the past damage? • U.S. Illnesses and Deaths Associated With Compounded Medications • Contamination of sterile preparations was the most common compounding error, though others were the result of pharmacists' and technicians' miscalculations and mistakes in filling prescriptions. Pew’s drug safety project has identified over 25 reported compounding errors or potential errors associated with 1,076 adverse events, including 90 deaths, since 2001. Because many such events may go unreported this list is probably an underestimation. Contamination of sterile products was the most common error, though others were the result of pharmacists’ and technicians’ miscalculations and mistakes in filling prescriptions. http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/us-illnesses-and-deaths-associatedwith-compounded-medications

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Which of the following statements is not accurate? a. A pharmacist must supervise compounding

b. All 50 states require compliance with USP Chapter

c. Regulatory compliance with USP Chapter is improving

d. The CDC and CMS recognize USP Chapter

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Canadian Oversight of Compounding Practices • Provincial Colleges of Pharmacies – Require/Best Practice USP standards

• Canadian Society of Hospital Pharmacists (CSHP) – 2014 Compounding: Guidelines for Pharmacies

• National Association of Pharmacy Regulatory Authorities (NAPRA) – 2015 Model Standards for Pharmacy Compounding of Non-Hazardous Sterile Preparation

• Health Canada – Health Canada, Health Products and Food Branch Inspectorate. Policy on manufacturing and compounding drug products in Canada. POL051. Ottawa, ON: Health Canada; 2009. Available from: http://www.hc-sc.gc.ca/dhpmps/compli-conform/gmpbpf/docs/pol_0051-eng.php Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

USP Compounding Standards • Chapter : Sterile Compounding – Official on January 1, 2004

– Revised chapter official on June 1, 2008 – Proposed revision – Sept 2015 • 9,000 commenters – Nationally enforceable – 32 states require compliance – More states are modifying regulations • Codify USP • Adopt portions • Develop own regulations • No action

• Chapter : Nonsterile Compounding • Chapter :Hazardous Drugs – Official July 1, 2018

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State Regulation of Pharmacy Compounding

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The Drug Quality and Security Act (DQSA) • Current status: signed into law by President Obama on November 27, 2013

• Divided into 2 major sections called Titles • Title I – Compounding Quality Act – Eliminates the unconstitutional provisions of 503A that “…created uncertainty regarding the laws governing compounding.” – Requires FDA to engage in two-way communication with state regulators – identified as a major deficiency in FDA’s response to the meningitis outbreak.

– Preserve and protect the practice of traditional pharmacy compounding * FDA Guidance for Industry - Interim Product Reporting for Human Drug Compounding Outsourcing Facilities under 503B of FDCA – DEC 2013

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DQSA (continued) • Title 1: Compounding Quality Act: 503B - Outsourcing Facilities. – Permit entities engaged in compounding of sterile drugs to register as “Outsourcing Facilities.” – Under Section 503B, pharmacy outsourcers to voluntarily register as “outsourcing facilities,” making them subject to good manufacturing practices, risk-based inspection and other standards

– As of 5/6/2016, 59 entities have registered with the FDA but not all have been inspected yet

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DQSA (continued) • Section 503A (21USC353a) - Traditional compounding – State-based regulations – State Boards of Pharmacy – Traditional, individualized prescriptions – Requires compliance with USP chapters on compounding

• Section 503B (21USC353b) - Outsourcing facilities – FDA jurisdiction; registration; reporting; cGMPs – Manufacture and interstate shipment of larger quantities of compounded drugs without prescriptions

– Under direct supervision of a pharmacist

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FDA Inspection of Compounding Pharmacies Figures do not include pharmacies dedicated to producing veterinary drugs. Note: years represent fiscal years October 1 – September 30. Fiscal year 2014 includes data through 9/12. Source: US Food and Drug Administration, USA Today Research.

Table excerpted from: Eisler P and Schmaars C. Safety, sanitary problems prompt scores of drug recalls. USA Today. October 7, 2014 retrieved from http://www.usatoday.com/story/news/nat ion/2014/10/07/compounding-pharmacyrecalls-inspectionscontamination/16472741/ on October 7, 2014.

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2013-2016 FDA Actions

• FDA cGMP inspections of many pharmacies and 5 contract testing labs

• FDA Form 483 is a form issued at the end of an FDA inspection if the FDA has observed any conditions during their visit that may represent violations of the FD&C Act.

• Closure/remediation against 483s

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x

Year

# Unique Documents

# Unique Establishments

2013

88

72

2014

77

61

2015

131

115

2016

44

34

(as of 5/6/16)

Learning Assessment Question Which document can be issued at the end of an FDA inspection if the FDA observes any significant objectionable conditions during their visit?

a) b) c) d)

FDA Form 482 FDA Form 483

FDA Warning Letter FDA Consent Decree

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Personnel Related Metrics

Training Training & Competency Verification

Air Cleanliness via HEPA, ACPH, & Pressure Differential/Displacement

Viable Sampling Garbing

1. Gloved Fingertip Sampling (GFS)

 Head, face, shoe covers  Hand hygiene  Gown/Frock  Application of alcohol based hand rub w/persistent activity  Sterile Gloves  Sterile Alcohol

2. Surface Sampling 3. Volumetric Air Sampling

Facility Design Requirements

Primary/Secondary Engineering Control Certification

Materials/Construction Equipment Calibration & Use

Non Viable Particle Counts Component Type (sterile/nonsterile, PBP, SDV, MDV, bulk API) Material Handling Processes  Formulary Development  Drug/Supply Procurement  Standardization of compounding practices and batch records  Inventory control  Staging/Double-check  Sanitize components  Area Clearance  Reconciliation  Labeling, Storage, Transport

Components & Materials

Selection cleaning and disinfecting agents Equipment and supplies

Process verification with media Sterilization Cycle Verification

CSP Testing Program of cleaning activities Documentation

Cleaning & Disinfection

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Filter integrity testing

 Strength (Potency) Testing  Sterility Testing  Bacterial Endotoxin Testing

Final release checks Documentation

Process Control Metrics

Maintaining a Sterile Compounding State of Control

 Fundamental Principles  Aseptic Technique/Media Fill Units with GFS  Hand Hygiene/Garbing/GFS  Conduct inside ISO environments  Cleaning/Material handling  SOPs

Environment Related Metrics

Determination of Risk Level • Responsibility of the person completing the compounding pharmacist

• No single ‘iron-clad’ determination • Requires professional judgment • General descriptive statements to aid people performing compounding (not prescriptive)

Exception: Non-sterile raw materials or equipment always high risk level

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CSP Microbial Risk Levels • • • •

High Risk

Medium Risk

True emergency situations Compounded outside of a hood Expectations: Handwashing 6 Criteria which all must be met

Low Risk

Low Risk with 12 h BUD

1. Simple transfer ≤ 3 commercially manufactured non-hazardous products 2. Not > 2 entries into any container 1. Compounding is continuous and is no longer 3. Compounding than one hourcontinuous/not > 1 hour 4.2.Aseptic Aseptictechnique techniqueisisfollowed followed 3. Administration begins within 1 hour of start 5. Admin begins ≤ 1 hour from start of compounding of preparation 6. Appropriately labeled

4. Appropriately labeled

Immediate Use

Example: initial dose of norepinephrine drip in ICU after pharmacy hours Nurses prepare 14-16% of IV doses from vials and ampules (2011 AJHP Dispensing and Administration)

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CSP Microbial Risk Levels (continued) • Segregated Compounding Area

High Risk

– CSPs made in a hood that is not placed in a cleanroom

Medium Risk

• Cannot be used for hazardous drugs • Expectations still include – Hand hygiene and garbing – Daily & monthly cleaning – Environmental sampling

Low Risk

Low Risk with 12 h BUD

Immediate Use

Example: initial dose of norepinephrine compounded in satellite pharmacy in the ER Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

CSP Microbial Risk Levels (continued) High Risk

• Not > 3 sterile drug packages used

Medium Risk

• •

Low Risk

•

Low Risk with 12 h BUD

•

(including diluent and container) Using sterile equipment Compounded in an ISO Class 5 device usually in an ISO Class 7 environment Limited, basic, closed-system aseptic transfers and manipulations Expectations: all QA components with annual aseptic media fill and GFS

Immediate Use

Example: 1 dose of 1000 mL D5W with 30 mEq potassium chloride added

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CSP Microbial Risk Levels (continued) • Using 4 or more sterile ingredients,

High Risk

complex aseptic manipulations • Filling of reservoirs, cassettes or bags that will be infused over multiple days • For multiple patients (anticipatory batch compounding) OR • For 1 patient on multiple occasions (patient-specific batch)

Medium Risk

Low Risk

Low Risk with 12 h BUD

Immediate Use

Example: Parenteral Nutrition or Batch of IV minibags/syringes

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CSP Microbial Risk Levels (continued) • Made with non-sterile ingredients

High Risk

Medium Risk

Low Risk

Low Risk with 12 h BUD

and/or using non-sterile containers, devices or equipment • Prepared from sterile ingredients but exposed to < ISO Class 5 air This is a mistake in the chapter. This item describes • > 6 hour delay fromimmediate-use compounding to sterilization • Purity of components is assumed but cannot be verified by documentation

Immediate Use

Example: Morphine sulfate from nonsterile powder for PCA

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Single/Multiple Dose Vials • Definitions of SDV and MDV are in USP Chapter Packaging and Storage Requirements

• Single dose vials: – Punctured in ISO 5 environment may be used for up to 6 hours – Punctured in worse than ISO 5 must be used within 1 hour or discarded

• Single dose ampules must be discarded after opening and not stored for any time period

Image courtesy www.flickr.com

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Why 6 hours?...Microbial Growth Phases CFUs/mL Stationary Phase or Steady State 10,000,000 1,000,000 100,000

Log Phase/Exponential Growth Phase

Death/Decline Phase

10,000 1000 100 10

Lag Phase 4-6 hours Time in hours

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Multiple Dose Vials • Multiple dose vials – Contain antimicrobial preservative(s) • Designed for entry on multiple occasions – BUD: 28 days after initial entry unless specified otherwise by the manufacturer

• Based on USP Antimicrobial Preservative Testing • Expiration date on vial is based on an unopened, properly stored vial

Image courtesy of www.pfizerinjectables.ca

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Pharmacy Bulk Package (PBP) • Definition of PBPs is found in USP Chapter

• •

• • •

Packaging and Storage Requirements Sterile preparation for parenteral use that contains many single doses Restricted to the preparation of admixtures for infusion or filling empty sterile syringes Closure penetrated only once Used in a suitable work area such as a laminar flow hood Includes a statement limiting the time frame in which the container may be used once it has been entered

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Image courtesy of http://www.hospira.com

Cefazolin 20 gram PBP • Typical package insert – After entry, use entire contents of the vial promptly – Dispense and discard PBP within 4 hours of initial entry

Image courtesy of http://www.wgcriticalcare.com

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Proposed USP 797: Category 1 CSPs PEC placement Not in ISO classified air Sterility Not required Testing Endotoxin Not required Testing ≤ 12 hours room temperature or ≤ 24 BUD hours refrigerated

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Proposed USP 797: Storage for Category 2 CSPs PEC placement

Placed in ISO classified air

Sterility Testing Based on BUD Assignment below Endotoxin Testing

Required if nonsterile components

Storage

> 12 hour room temperature or > than 24 hours refrigerated Method

Sterility Testing

Preservative Added

No

No

Refrigerate d

Frozen

Made from 1 or more non sterile components

7 days

45 days

Made with sterile components

Yes

erminally rilized CSPs

Controlled Room

4 days

Aseptically Prepared CSPs

BUD Assignment

No

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Yes

6 days

9 days

Yes (USP 51)

28 days

42 days

No

28 days

42 days

Yes (USP 51)

42 days

42 days

No

14 days

28 days

Yes (USP 51)

28 days

42 days

No

28 days

42 days

45 days

45 days

Beyond-Use Dating (BUD)

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Parameters for Establishing BUD • Recognizes the probability of contamination even under best conditions: – Optimal employee performance: 0.1% (1 contaminated dose out of 1,000) – Contamination rates in the literature: 0.3% – 16%

• Patient Safety – Protect patients from dangerous or even fatal overgrowths of microorganisms that may have been accidentally introduced

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Why is garbing important? • Humans are “particle generators.” Even though we can’t “see” them, it is generally agreed that we shed about 9 pounds of dead skin cells from the stratum corneum (the outer layer of the skin) per year1.

• Particles generated by humans, our clothes, and our activities can transport microorganisms to critical sites (e.g. vial septa, needles) during the compounding process.

1 Menton, DN.

Skin, Our Living Armor. Retrieved on May 22, 2013 from http://www.answersingenesis.org/articles/am/v4/n4/skin

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Garbing…why? Compounding personnel are the chief particle generators. 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/minute

Makeup/Cosmetics2

Particles/Applica tion

Eye shadow

82,000,000

Typical mascara application

3,000,000,000

Total for typical makeup application

5,100,000,000

1Particle Measuring 2Goldstein K.

Systems. Basic Guide to Particle Counters and Counting. 2011. Cosmetics in Cleanrooms…again. Cleanrooms. 2001

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Just how many bacteria?

• Each of us carries 3-5 pounds of bacteria in our bodies! • Bacteria cells outnumber human cells 10:1 • Bacterial cells are much smaller than human cells so they only account for 1-2% of our body mass The bacteria in our body would fill a large soup can like this one

Source: Lita Proctor, National Institutes of Health’s Human Microbiome Project

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Why is hand hygiene important? • There are 10,000 to 10,000,000 microbes on each hand1 • So even if hand hygiene is performed with an agent that is 99.99% effective (assuming your hand washing technique is perfect), there will still be 100 to 100,000 left on your hands

• It only takes one to make a patient sick!

Hand hygiene is the single most important factor in preventing the spread of pathogens in healthcare settings.

1

Health Protection Agency. Fun Facts about Handwashing. http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1254510461483

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What is garbing? • Garbing is the act of donning required PPE before compounding begins or before a worker enters a particular controlled pharmacy compounding space (such as a buffer area or the clean side of an anteroom or segregated compounding area) to work inside of a Primary Engineering Control that provides an ISO Class 5 environment.

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What is garbing? • Garbing must occur before entering the buffer area (or Segregated Compounding AreaSCA) to compound or to perform cleaning, environmental sampling or any activity that occurs inside a cleanroom.

• Garbing must also occur before using isolators (CAIs) unless the isolator manufacturer provides written documentation (based on validated environmental testing) that any component/s of PPE are not required to maintain the ISO Class 5 area.

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Which PPE? • PPE stands for “Personal Protective Equipment” • PPE is the collective name for all of the protective items that must to be worn in either non-hazardous and hazardous ISO classified sterile compounding environments.

• PPE for non-hazardous compounding includes: – Hair cover – Facial hair cover (if needed) – Face mask – Eye protection (when splashing can occur) – Shoe covers or dedicated shoes – Non-shedding gown – Sterile gloves Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Learning Assessment Question Which of the following is the largest source of particulate contamination in controlled compounding environments? a) b) c) d)

Equipment Facility structure Corrugated cardboard Personnel

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Garbing “Shalls” • Remove before LOD – – – –

outer garments jewelry no piercings above neck no artificial nails

• Garb dirtiest to cleanest – Don hair and beard cover, mask and shoe covers before performing hand hygiene – Hand hygiene includes nails and arms up to elbows – After drying hands must apply antimicrobial rub with persistent activity before donning gloves (Avagard D or Sterillium)

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• Use Sterile gloves ONLY • If exposed to < ISO Class 8 air, repeat hand hygiene and garb

Why no cosmetics? Personnel are the chief particle generators.

1Particle

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/minute

Makeup/Cosmetics2

Particles/Application

Eye shadow

82,000,000

Typical mascara application

3,000,000,000

Total for typical makeup application

5,100,000,000

Measuring Systems. Basic Guide to Particle Counters and Counting. 2011. K. Cosmetics in Cleanrooms…again. Cleanrooms. 2001

2Goldstein

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Learning Assessment Question USP Chapter requires the use of sterile gloves while compounding.

a) True b) False

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Aseptic Technique and Conduct of Personnel • Touch contamination by compounding personnel is the most

common cause CSP contamination. • Most CSPs are administered intravenously or intraspinally where the body’s natural defense mechanisms have been circumvented. • Principles and practices of aseptic technique and the risk to the patient resulting from non-compliance and lack of vigilance should be understood by all personnel. • CSP integrity must be maintained and every precaution taken to assure sterility. Personnel non-compliance and lack of vigilance relative to aseptic technique and other work practices (such as cleaning, hand hygiene and garbing) can and has overcome the protections afforded by even the best primary and secondary engineering controls. © 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

A word about garbing and isolators…

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Aseptic Technique “Shalls” Personnel Training and Competency Assessment

• Training must be completed & documented before any compounding is performed • Aseptic skill observation must be completed successfully and documented. • Media-Fill Testing (MFT) must be performed and successfully completed (incubation totally complete) – Initially before being allowed to perform compounding – Annually (low/medium risk) or semi-annually (high risk) thereafter Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

• Evidence of mechanisms to reinstruct and re-evaluate employees who fail testing, skills observation, MFUs, GFS, or other evaluation.

How often is Media-Fill Testing Performed? • Initially it is used to verify the technique of: – Current personnel (so if a pharmacy has not started performing MFT, all staff must go thru MFT) – Newly hired staff members

• Ongoing – Every 12 months (low and medium risk operations) – Every 6 months (high risk operations)

– Can be performed more often such as in the event of the observation of unacceptable technique or outcome

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What is gloved fingertip sampling? • Gloved Fingertip Sampling detects the presence of microorganisms on the fingertips of gloves from improper donning of sterile gloves, poor aseptic technique and improper disinfection of gloves.

Initial GFS During the initial hand hygiene and garbing competency

Ongoing GFS On an ongoing basis during the preparation of personnel aseptic mediafill units

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Ongoing GFS • Ongoing GFS is required in association with the annual or semiannual personnel aseptic media fill unit preparation – annually for low and medium risk compounding operations

– semi-annually for high risk compounding operations

• Performed by presenting the staff member with 2 plates (one for each hand) immediately after they complete their MFUs.

• This must be performed inside of an isolator if that is where compounding occurs. Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

• Though the operator should be routinely disinfecting hands with sIPA and during MFU is no exception, the samples will be obtained immediately after the completion of the MFU procedure (e.g., the staff are not allowed to resanitize hands after completing the MFUs).

GFS Recap Initially When: Prior to preparing CSPs for human use, compounding staff must successfully complete: • the hand hygiene and garbing competency evaluation and • 3 consecutive GFS fingertip/thumb samples How: GFS samples taken immediately after donning sterile gloves to verify that compounder can garb without contaminating hands (in anteroom or in isolator if isolators are used) Passing results: 0 CFUs both hands

Ongoing When: At the time Personnel Aseptic Media Fill is performed • Annually (low/medium risk) • Semiannually (high risk)

How: Obtain samples while employee is in ISO Class 5 environment during preparation of personnel media-fill units but not immediately after gloves have been disinfected with sIPA Passing results: ≤ 3 CFUs (total both hands) if collected in ISO Class 5 air

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Aseptic Technique “Shalls” (continued) • Compounding – Proper use of Direct Compounding Area (DCA) – No interruption HEPA filtered “first air” over critical sites – Sterile gloves disinfected with sIPA before entry/reentry to ISO Class 5 and whenever touching nonsterile item

“First Air”

– Inspect sterile gloves regularly for wear and tear; replace if needed © 2006 -2012 Clinical IQ, LLC and Controlled Environment Consulting

The DCA is only the portion of the PEC where the Critical Site is exposed to unidirectional HEPA-filtered air during an aseptic manipulation. © 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Learning Assessment Question The image below demonstrates proper use of first air? a) Yes b) No

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Proper Use of First Air

Horizontal Flow

Vertical Flow

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Blocked first air

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What about Surface Sampling? • Surface sampling tests for viable contamination on surfaces.

• Evaluates: • effectiveness of the daily cleaning and disinfection and

• degree to which compounding personnel properly disinfect the deck during compounding

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Surface Sampling “Shalls” • Perform in all ISO Classified spaces on a “periodic basis”

• Use plate (24-30 cm2) containing tryptic soy agar with polysorbate 80 and lecithin added to neutralize cleaning agents

• Perform using swab or plate method • Incubate by inverting plates and incubate plates at 30-35°C for 48 to 72 hours

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Surface Sampling “Shalls”

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Learning Assessment Question A LAFW (laminar airflow workbench) is an example of a secondary engineering control?

a) True b) False

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Cleanliness Classification Environmental and Quality Control

• Sterile preparations must be manipulated in an ISO Class 5 environment (Class 100) or better • The ISO Class 5 environment is housed in an ISO Class 7 (Class 10,000) or better environment • The ante areas are at least ISO class 8 (Class 100,000)

Ante Area ISO Class 7 or 8 Buffer Area ISO Class 7 PEC ISO Class 5

DCA Direct Compounding Area

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What are Primary Engineering Controls (PECs)? • There are 5 types of PECs designed to eliminate particles through delivery of unidirectional HEPA filtered air to the direct compounding area (DCA): – Laminar Airflow Workbench (LAFW) – Vertical Cleanbench (VCB)

– Compounding Aseptic Isolator (CAI) – Biological Safety Cabinet (BSC) – Compounding Aseptic Containment Isolator (CACI)

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What are Secondary Engineering Controls? • Secondary Engineering Controls are designed to reduce particles through the delivery of HEPA filtered air to the room to facilitate the operation of the primary engineering controls. • The Buffer Area commonly referred to as a cleanroom – This room is where the PECs are placed – requires it to attain ISO Class 7 air cleanliness or better

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What are Secondary Engineering Controls? • The Ante-area (anteroom) is the room directly outside the buffer area – This room is to perform hand hygiene, garbing and stage components for entry to the buffer area – Anterooms must maintain ISO Class 8 air if they serve only a buffer area in which non hazardous compounding is performed – If the anteroom also serves an HD buffer room, then the anteroom is required to maintain ISO Class 7 air

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Primary/Secondary Engineering Control “Shalls” • 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):

– Velocity across entire opening maintains 40 feet/minute and verified by smoke – Not allowed if HD compounding

• 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: no requirement but at least 20 ACPH common © 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Learning Assessment Question Primary Engineering Controls (LAFWs, Isolators and BSCs) must be supplied with which type of HEPA filtered air? a) Unidirectional b) Turbulent c) Either is fine as long as it is HEPA filtered air

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Primary/Secondary Engineering Control “Shalls” • Once PECs are placed, smoke studies were conducted to verify unidirectional airflow in DCA • PECs certified according to CETA guidelines (CAG-003-2006) or similar – BSCs: NSF/ANSI 49

• If LAFWs or BSCs not placed in ISO Class 7, then compounding is limited to low risk level CSPs with 12 hour BUD (non hazardous)

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Primary/Secondary Engineering Control “Shalls” • Isolators not placed in ISO Class 7 must meet all of the following: – Maintain ISO Class 5 conditions during dynamic operating conditions including during transfer of components and compounding – Particle counts remain ISO Class 5 during compounding – Not > 3250 particles 0.5μm and larger per m3 are counting during material transfer (with counter probe nearest possible to transfer door)

• Recovery time to achieve ISO Class 5 and written compounding procedures ensure adequate recovery time after material transfer and compounding. © 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Facility Design “Shalls” • Line of demarcation in anteroom or SCA • Furniture, equipment and physical plant • •

• • • •

surfaces nonporous, smooth and cleanable Climate conducive to comfort (68°F) Materials limited to what is essential for compounding Ceiling: hydrophobic panels caulked around perimeter Floors: cleanable with coved molding Walls: solid or locking panels impervious, cleanable and non-shedding Sink: hands-free water and soap

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Secondary Engineering Controls Test

Non Haz Buffer

Anteroom

HD Buffer

Airflow

30 ACPH (at least 15 ACPH from outside the room)

Not specified but 20 ACPH is desirable

30 ACPH; 12 ACPH if CACI is used

Minimum differential pressure of 0.02” w.c. + from cleanroom to anteroom and all adjacent spaces

Minimum differential pressure of 0.02” w.c. + from anteroom to all adjacent spaces

Minimum differential pressure of 0.01” w.c. - from the HD cleanroom to the anteroom.

Room Segregation

If displacement airflow, then velocity of 40 feet/minute from cleanroom to the anteroom across the entire opening

Not allowed in HD compounding

HEPA Filter Leak Test

All HEPA filters in the secondary engineering controls are tested at each certification. Maximum allowable leakage is 0.01% of the upstream aerosol concentration.

Smoke Pattern Testing

Buffer rooms must be segregated from the ante-area and all other adjacent spaces with the doors close using smoke to observe airflow under dynamic operating conditions (with pharmacy staff compounding).

Non-Viable Particle Counts

ISO Class 7

ISO Class 8 unless it serves HD buffer then ISO Class 7

ISO Class 7

Airborne particle counter used to samples particle levels in all locations under dynamic operating conditions.

Temperature

No specific requirement other than comfortable typically a temperature of 68°F

Humidity

Not a mandatory test but Relative Humidity between 35% and 60% is recommended

Adapted from CETA Certification Matrix for Sterile Compounding Facilities CAG-008-2010. Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Traditional Primary Engineering Controls TEST

LAFW

BSC (NSF International Criteria)

Placement of Primary Engineering Control

Placed in ISO Class 7 cleanroom; 0.2” w.c. or SCA

Placed in ISO Class 7 Cleanroom, 0.1” negative w.c. to anteroom

Airflow Velocity

Velocity 80 to 100 feet/minute 6-12” from the filter

Downflow Velocity Profile and Face Velocity Tests

HEPA Filter Leak Test

HEPA filters must be certified to be free from leaks > 0.01% of upstream aerosol concentration

HEPA filters must be certified to be free from leaks > 0.01% of upstream aerosol concentration or aerosol penetration not > 0.005% of upstream concentration

Backstreaming Test

Verifies LAFW is free from unsealed construction joints & particles not being introduced into critical work area

In BSCs, this test is called the Pressure Decay/Soap Bubble Test and verifies that the cabinet is not leaking to the exterior

Airflow patterns smoke test

An observation using smoke to visualize airflow under dynamic operating conditions (with pharmacy staff compounding) to confirm laminarity of the air is undisturbed Verifies that the BSC is properly integrated into the facility testing airflow and sash alarms; interlocks and exhaust system performance

Site Installation Assessment Tests Non-Viable Particle Counts

Particles counters capable of detecting particles 0.5 μm are used to verify ISO Class 5 air conditions

Adapted from CETA Certification Guide for Sterile Compounding Facilities. CAG-003-2006-11 and NSF/ANSI 49-2012.

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Unidirectional Isolators Test

CAI

CACI

Placement of PEC

Preferably room/area devoted to compounding

Room certified to have at least 12 ACPH and be 0.1” w.c. negative to adjacent room

Airflow Velocity

Measurement of actual airflow to manufacturer’s design intent. The main chamber is expressed as a range of feet/min with a designated % uniformity.

Chamber Pressure Test

Determines that pass-through and main chamber pressures adequate to provide isolator separation between main chamber and ambient spaces. Pressure range determined by manufacturer.

Site Installation Assessment Tests

Tests to verify proper alarm function; pass-through door interlock function; and proper canopy or exhaust connection performance.

HEPA Filter Integrity Leak Test

All HEPA filters in the secondary engineering controls are tested at each certification. Maximum allowable leakage is 0.01% of the upstream aerosol concentration.

Particle Containment and Enclosure Leak Test

N/A

Test determines particle integrity of the cabinet at points of potential leakage; leaks detected do not exceed ISO Class 5 air cleanliness.

Volatile HD Containment Test

N/A

Verifies that CACI is properly connected to exhaust and provides personnel protection from volatilized HDs

Hazardous Particle Containment Test

N/A

Verifies that CACI provides worker protection from the escape of HD particles during compounding.

Airflow Smoke Pattern Test Preparation Ingress and Egress Test Non-Viable Particle Counts

An observation using smoke to visualize airflow under dynamic operating conditions (with pharmacy staff compounding) to confirm laminarity of the air is undisturbed

Determine if the pass-through system is capable of supporting material transfer while maintaining the designated cleanliness classification during the transfer. Particles counters capable of detecting particles 0.5 μm are used to verify ISO Class 5 air conditions both at rest and during dynamic operating conditions.

Adapted from CETA Compounding Isolator Testing Guide. CAG-002-2006. Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Why Is Environmental Sampling Important? • Facilitates early detection of contamination and its source which may include: – Personnel – Work surfaces

– Supplies – Equipment – Failure of engineering controls

Courtesy CBS News

This is a image of the fungus growing from a sample taken from a patient’s spinal fluid.

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Environmental Sampling • Designed to demonstrate that the primary and secondary engineering controls, disinfecting procedures, and work practices result in a suitable environment for aseptic compounding

• Utilizes several approaches to assess and evaluate: – Total particle counts

– Air viable organism cfu – Surface viable organism cfu – Finger touch plates

Monitors State of Control

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Two Categories of Environmental Sampling Facility-related

• Viable air sampling – Volumetric method (impaction) – at least every 6 months – linked with re-certification activities

Personnel-related

• Personnel gloved fingertip sampling (GFS)

– Initial is related to hand hygiene and garbing competency – Ongoing is associated with media fill testing

• Surface sampling – for viable microorganisms – Effectiveness of cleaning and disinfection (another employee related work practice)

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General Environmental Sampling “Shalls” • Detailed written PnP on all aspects of environmental sampling

• Sampling occurs in all ISO areas from cleanest to dirtiest ISO 5  ISO 7  ISO 8

• CFU Action Levels established • Evidence of logical plan of action in the event sampling exceeds Action Levels Table 2 in Chapter

Classification

Volumetric Air Sample Required*

ISO Class 5

>1

ISO Class 7

> 10

ISO Class 8

> 100

CFU/m3 air/plate(1000 liters) If < 1000 liters air sampled, convert to equivalent AL (e.g., 400 liter sample in ISO Class 7 then AL = >4 CFU/plate) Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

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Viable Air Sampling “Shalls” • Viable air sampling performed: – at time of initial certification of PECs/SEC – every 6 months in association with physical plant recertification – after major service or device relocation

• Air sampling performed with volumetric sampler (not settling plates or paddles) • Air sampling volume at each location is 400 to 1000 liters • General growth medium and fungal specific medium • Evidence that if Action Level is exceeded, area is cleaned and resampled

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Learning Assessment Question If you took a 500 liter sample in an ISO 8 anteroom, which of these would be the correct Action Level? a) > 10 b) > 100 c) > 50 d) > 5 ISO Class ISO Class 5 ISO Class 7 ISO Class 8

Action Level* >1 > 10

> 100

* CFUs per cubic meter of air per plate (cubic meter = 1000 liters) Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Growth Media • Soybean Casein Digest Media (Trypticase Soy Broth/Agar) to support the growth of bacteria

• Malt Extract Agar or other media that supports the growth of fungi

• Must use plates with lecithin and polysorbate 80 which are chemicals that neutralize cleaning agents when performing: – Surface sampling

– Personnel glove sampling associated with MFUs

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Sampling for Air Viable Organisms • Volumetric air sampling is

• Settling Plates cannot be the

required – Predefined amounts of air

only method of evaluating air viable organisms – Not qualitative – Settling of particles influenced by size of particle and air movement

Courtesy of MSI, Inc. Houston, TX (www.microbiologyspecialists.com)

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CFU Identification and Sources Microorganisms

Indication

Staphylococcus/ Micrococcus

• Personnel habits or gowning problems

Gram negative rods

• Water condensation, leaking, aerosols

Bacillus species

• Dust, dirt, floor traffic, possible air handling

Molds

• Influx of unfiltered air, mold from street clothing or mold-contaminated cardboard, water reservoir, i.e. incubator humidification system • Possible outdoor air influx; clothing-borne, especially in late summer/ fall; possible human contaminant • Poor air conditioning (leading to sweating and personnel discharge from gowns)

Yeast Diptheroids/ coryneforms Source: Azzur Labs (www.azzurlabs.com)

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Key Environmental Quality Metrics Environmental Sampling

Required Frequency in USP Chapter

Suggested Best Practice Frequency

Gloved Fingertip Sampling (personnel metric)

• Initially during garbing x 3 • During MFT every 6 months for high risk • During MFT annually for low/medium risk

• Initially during garbing x 3 • During MFT weekly for high risk • During MFTs monthly for low/medium risk

Surface Sampling (personnel metric)

• “Periodic” • SOPs define when, where and how SS is performed

• Weekly for high risk • Monthly for low/medium risk

Non Viable Particle Counts (facility metric)

• Initial facility commissioning • As required • Every 6 months during recert of facility and engineering controls in compounding areas

Viable Volumetric Air Sampling (facility metric)

• Every 6 months

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• Weekly for high risk • Monthly for low/medium

Actions to Take When Action Levels Exceeded • An investigation into the source of the contamination must be conducted.

• Sources: – HVAC systems: changes externally – Damaged HEPA filters – Changes in personnel garbing habits – Changes in work practices – Failure to follow PnP – New employees

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Cleaning and Disinfection "Shalls” • Written PnP detailing cleaning agents, nonshedding wipes, mop materials, procedure, frequency and documentation.

• Personnel who perform cleaning successfully complete – Hand hygiene and garbing competency

– Cleaning and Disinfection competency

• Floors and easily cleanable horizontal surfaces in the buffer area, anteroom and SCA are cleaned daily with designated cleaning agent

• Walls, ceilings, empty shelving, supply bins are cleaned monthly with designated cleaning agent © 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Cleaning and Disinfection "Shalls” • Only trained compounding personnel clean inside of the ISO Class 5 areas

• ISO Class 5 critical work area disinfected: – Beginning of each work shift – Between batches – Every 30 minutes continuous compounding – After spills – Anytime contamination is suspected

• Sterile 70% IPA (sIPA) remains in contact with the surface being disinfected for 10-30 seconds and allowed to dry before compounding is started © 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC Copyright © 2008-2015 ClinicalIQ, LLC® - All Rights Reserved

Cleaning and Disinfection "Shalls” • Equipment that is reused is labeled and dedicated according to area of use

• Mops, wipes, etc. are non-shedding

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Learning Assessment Question USP Chapter requires that cleaning solution preparation be documented. a) True b) False

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Use of Disinfectants • • • •

Must be germicidal detergent (most are cleaning and disinfecting agents) Follow manufacturer instructions for mixing, use and storage

Dilution of agent and contact time are critical to efficacy Is documentation of cleaning solution prep required? – Depends on interpretation of the chapter

– Probably not but listed in Appendix V, Sample competency

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Learning Assessment Question Cleaning agents use should be rotated to prevent microbial resistance to the agents. a) True b) False

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Resistance and Rotation of Cleaning Agents “The development of microbial resistance to disinfectants is less likely, as disinfectants are more powerful biocidal agents than antibiotics and are applied in high concentrations against low populations of microorganisms usually not growing actively, so the selective pressure for the development of resistance is less profound.” “It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent.” Excerpted from USP Chapter Disinfectants and Antiseptics

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Establishing a Cleaning Program • Work with Infection Control department

• If building new facility, design for cleaning

• Important to understand design and materials of construction – Determine required materials/equipment – Assess compatibility of agents

• Develop procedure – What, when, where and how

– Agent rotation – Consider existing organizational policies or procedures

• Train personnel to procedure • Document cleaning activities performed

• Monitor adequacy of program – Environmental sampling – Observation

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1. 2.

3.

4. 5. 6. 7.     

Cleaning Primary Engineering Controls At A Glance What’s the same? What’s different? Complete hand hygiene & garbing LAFW: Same appropriate to compounding area Integrated VLF: Same except Cleaning solution is germicidal detergent;  Surfaces need to be reached with mop  Clean/disinfect inside surface of Lexan® sporicidal may be rotated in CAI: Same except weekly/monthly  Surfaces may need to be reached with isolator tool (preferable to Cleaning solution prepared in container open CAI if in controlled space) dedicated for use in ISO Class 5 areas &  Surfaces of main chamber are cleaned and disinfected followed documented by the ante-chamber and in same order BSC: If used for HD, same except All surfaces cleaned with cleaning agent st  Add 1 step: deactivate HD residue on all surfaces with diluted with sterile water appropriate agent followed by cleaning agent and sIPA Use low-linting wipes and/or tools  Additional surface to decontaminate/clean (inside of the sash dedicated to ISO Class 5 areas view screen) Disinfect all surfaces with sIPA after  PPE/trash from decontamination discarded in black RCRA bag; cleaning rest discarded in yellow HD trace trash. CACI: If used for HD same except Order of cleaning with cleaning agent and st  Add 1 step: deactivate HD residue on all surfaces with IPA: appropriate agent followed by cleaning agent and sIPA Ceiling  Surfaces may need to be reached with isolator tool (preferable to Back open CACI if in controlled space)  Surfaces of main chamber are decontaminated and cleaned Sides, IV bar and hooks followed by the ante-chamber and in same order Anything in PEC  Additional surface to decontaminate/clean (inside of the sash Deck view screen)  PPE/trash from decontamination discarded in black RCRA bag; rest discarded in yellow HD trace trash.

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Summary • Patient’s will always be at risk of compounding errors • State Boards of Pharmacy are responding the challenges in providing regulations and oversight

• The FDA is taking control of the outsourcing industry and will regulate it, improving the quality of the product manufactured

• Employees must skilled, educated and trained! You must invest in a knowledgeable workforce

• Employee Vigilance and adherence to robust work practices are required to maintain a state of control.

• Building a compliant facility isn’t enough! • Maintaining the facility and regularly measuring and adjusting its

performance during regular service from certification professionals is necessary.

• Environmental Sampling provides the ongoing evidence of the effectiveness

of the facility, cleaning and work practices in achieving an environment that is suitable for compounding sterile preparations.

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Patient Safety remains Priority #1! • Patient Safety is a partnership involving multiple disciplines and is not achieved in “isolation”

• It takes all of us working together • The goal  “zero tolerance” for preventable healthcareassociated infections, whether at the patient’s bedside or in the pharmacy.

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