usp : ensuring a state of control

PowerPoint Presentation

USP : Ensuring a State of ControlAAHP Fall Seminar 2016

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Thanks to Critical Point LLC (www.criticalpoint.info) for allowing me to use their slides:

Kate Douglas, MS, RN, CRNIEric Kastango, MBA, BS Pharm, FASHPJames Wagner

Review the learning objectives by paraphrasing what is on the screen2

Learning and Performance ObjectivesAt the end of this session you will be able to:Describe documented patient harm caused by inadequate sterile compounding operationsList common sources of contamination of a compounded sterile productDescribe methods to ensure a proper state of control for sterile compounding operationsState commonly violations of USP by the Arkansas Board of Pharmacy

Review the learning objectives by paraphrasing what is on the screen3

History of Sterile CompoundingDespite the chapters uniform sterile compounding standards, schools of pharmacy may not always include sterile compounding Only 1 in 6 graduates are prepared for sterile compounding work* In 2014, less than 10 schools of pharmacy conducted training in real cleanroom settings

Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.*Hellums M, Alverson SP, Monk-Tutor MR. Instruction on compounded sterile preparations at U.S. schools of pharmacy. AJHP. Volume 64, Nov 1, 2007: 2267-74.

As the degree program for pharmacists transitioned from a baccalaureate degree to PharmD, sacrifices have been made to the curriculum.

As mentioned earlier, it is important to embrace that compounding and dispensing which continue to be integral parts of the profession. We need to know what we are doing when we compound or supervise compounding activities. 4

DQSACopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Section 503A (21USC353a) - Traditional compoundingState-based regulations State Boards of PharmacyTraditional, individualized prescriptionsRequires compliance with USP chapters on compoundingSection 503B (21USC353b) - Outsourcing facilitiesFDA jurisdiction; registration; reporting; cGMPsManufacture and interstate shipment of larger quantities of compounded drugs without prescriptionsUnder direct supervision of a pharmacist

This slides summarizes the major differences between the traditional compounding practices (503A pharmacies) vs. the newly created regulatory licensure category for outsourcing facilities (503B operations). READ the elements. Compounding in a 503B outsourcing facility must be done under the direct supervision on a pharmacist. 5

Patient Harm Caused by Inadequate Compounding Operations

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Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Our patients have never had a problem

7This statement is routinely used by pharmacists when justifying their non-compliance with USP Chapter .

Whats the past damage?U.S. Illnesses and Deaths Associated With Compounded MedicationsContamination of sterile preparations was the most common compounding error, though otherswere the result of pharmacists' and technicians' miscalculations and mistakes in filling prescriptions.

Since 2001 over 25 pharmacy compounding incidents with 1,049 adverse events, including89 deaths, have been reported.Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

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YearStateDescription1990Nebraska4 patients died of a bacterial infection from non-sterile cardioplegia solution compounded in a hospital 1990Pennsylvania2 patients lost their vision after becoming infected by Pseudomonas aeruginosa found in indomethacin eye drops compounded in a drug store even though commercial non-steroidal drops were available at the time1998California11 children became septic10 tested positive for Enterobacter cloacae bloodstream infections associated with contaminated prefilled saline syringes 2001Missouri4 children contracted Enterobacter cloacae infections from IV ranitidine compounded in a hospital pharmacy

Brutal FactsCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

These select events detail the major contamination events that occurred in hospitals and in compounding pharmacies.

The 2001 contamination event in California was the infamous Docs Pharmacy event where a batch of betamethasone (high-risk) were improperly sterilized and the contamination killed 5 of 11 affected patients.

The 2001 Missouri contamination event involved a multiple-dose vial. Despite the preservative in the vial, the operator contaminated the vial. Enterobacter is an indigenous microorganism of our GI tract. Most likely, the employee did not wash their hands after using the toilet. 9

YearStateDescription2002North Carolina, South Carolina5 patients developed Exophiala infections from contaminated injectable methylPREDNISolone that was prepared by a compounding pharmacy; one patient died 2002MichiganPharmacy preparing injectable methylPREDNISolone and baclofen recalled the products because of contamination with Penicillium mold, Methylobacterium, and/or Mycobacterium chelonae 2003MissouriBacteria contamination with Burkholderia cepacia found in at least 2 batches of a compounded inhalant solution used by 19,000 patients with chronic lung diseases 2004Texas, New York, Michigan, Missouri36 patients developed Pseudomonas bloodstream infections after receiving heparin/saline flushes from multiple lots of preloaded syringes.

Brutal Facts (continued)Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

2002 NC/SC event involved a mold that had not caused any human disease. This event was a true CSI situation mobilizing the CDC. The patient who died had received their injection 152 days earlier!

We dont have a robust and routine way of tracing and linking patient illnesses, infections and deaths to contaminated compounding medications. The link between the contaminated medication and the patient death was identified through genotyping/phenotyping the bug in the patients CSF and the contaminated medication.

Speaker focus on the different microorganisms, many that are highly pathogenic in each of the contamination events.10

YearStateDescription2005New Jersey, CaliforniaUp to 25 patients contracted Serratia marcescens infections due to contaminated magnesium sulfate mini-bags prepared by a compounding pharmacy 2005Minnesota2 patients were blinded after receiving a compounded trypan blue ophthalmic injection contaminated with Pseudomonas aeruginosa and Burkholderia cepacia; the injectable product is a commercially available product2005CaliforniaSterile talc vials with unwashed stoppers were not sterility tested before distribution from an outsourcing compounding pharmacy 2005Maryland10 patients died after exposure to cardioplegia solution from 2 lots contaminated with gram-negative rods


Most of contamination events involving large # of patients were associated with medications compounded by national outsourcing companies like PharMEDium and CAPS. 11

YearStateDescription2011California, Florida, Tennessee16 patients being treated for wet macular degeneration developed severe eye infections due to contamination of AVASTIN (bevacizumab) during compounding; one patient blinded, another patient developed brain infection 2011Alabama9 patients among 19 died when PN solutions that were administered were contaminated with Serratia marcescens during compounding using non-sterile components to prepare amino acids Link to: CDC/USP Webinar on Incident2012California 9 patients developed fungal endophthalmitis after use of the compounded product Brilliant Blue-G (BBG) or receiving injections of triamcinolone-containing products dispensed from the same compounding pharmacy


The Avastin contamination event involved the pharmacy pulling the stopper out of the vial and drawing the doses from an open system. Working with an open system significantly increases the risk of contamination during compounding.

2011 Alabama contamination event will be detailed more on the next slide12

New England Compounding Center (NECC) Meningitis OutbreakDateSeptember 21, 2012 October 23, 2013 (no further CDC updates expected)LocationUSA (20 States)CauseFungal meningitis contamination of steroid medicationInjuries751 total case count; 384 meningitis and spinal infection; 7 stroke; 325 paraspinal/spinal infection; 33 peripheral joint infection; 2 spinal and peripheral joint Some patients recovering from the meningitis are falling ill again. Sufferers of the new infection are now coping with epidural abscesses and infections near the injection site.Death(s)64LitigationMore than 20 lawsuits filed against NECC

The scale of the meningitis outbreak makes this event the worst among a series of fatal or harmful infections and overdoses linked to pharmacy compounding practices in the US rivaling other key drug safety issues in the past that have led to substantial drug safety legislation. Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

This slide will be updated each month if it changes so a new pptx must be downloaded from the dropbox.

As of now CDC site hasnt updated since October 23, 2013

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YearStateDescription2013ConnecticutFDA announced that a compounding pharmacy in New Jersey was voluntarily recalling all of its products after a Connecticut hospital reported that 5 bags of magnesium sulfate from the pharmacy were contaminated with mold. The pharmacy has since been closed by the NJ Division of Consumer AffairsGeorgia, Louisiana, South Carolina and Indiana A compounding pharmacy in Augusta, Georgia, is voluntarily recalling 79 lots of bevacizumab-filled syringes (Avastin, Genentech) intended for retinal injections because of the risk for eye infection, the US Food and Drug Administration (FDA) announced yesterday.TexasA batch of compounded IV Calcium Gluconate found to be contaminated with Rhondococcus equii. 15 infected patients, 2 deaths (relationship to drug not known)

Brutal Facts Continue Since NECC 2013 & 2014Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

This slides details the subsequent contamination events that have happened post-NECC. The next slide will provide the specific details on contamination of the magnesium sulfate minibags.14

Another Recent EventCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Outbreak of Burkholderia contaminans linked to Intravenous Fentanyl from an Institutional Compounding PharmacyOccurred at Duke University Hospital from August 31-Sept 6, 20127 patients affected Prepared drug from bulk API: High-risk compoundingReport published in JAMAAvailable online: JAMA Intern Med. Published online February 03, 2014. doi:10.1001/jamainternmed.2013.13768

This slides details the specifics of a hospital-related contamination event that involved the preparation of fentanyl from non-sterile ingredients. The source of the contamination was pH testing probe solution. 15

FDA Inspection of Compounding PharmaciesCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.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/nation/2014/10/07/compounding-pharmacy-recalls-inspections-contamination/16472741/ on October 7, 2014.

This table was taken from an article in USA today in October of 2014 and it shows the increased inspection activity of the FDA in the last couple of years.16

What went wrong?Leadership: Inadequate and ineffective oversightEducation, competence and proficiencyUntrained employeesLack of competency and proficiency evaluation systemsHand Hygiene and GarbingEngineering controls and equipmentInadequate for intended activitiesImproper useCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Failure of LeadershipImage courtesy http://www.guardian.co.uk/uk/2009/jan/21/1

When a root cause analysis (RCA) is conducted of these events, what we find that at the top of list is a failure of leadership. It is critical that supervisors, managers or directors hold people accountable to the standards of USP Chapter .

The following two slides continue to detail the major findings of the post-mortem to the compounding events detailed in the previous slides. 17

What went wrong? (continued)Inadequate cleaning/disinfecting practicesInadequate preventive maintenanceInadequate policies and proceduresEquipmentImproper use of sterilizing equipmentFailure to validate systemsRecord keepingInadequate quality assuranceInadequate documentation

Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Review the information on the slide18

Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ."Unfortunately, there are too many in health care who feel that if it hasn't happened to them, the adverse experiences of others do not apply.

Michael Cohen, MS, FASHPInstitute for Safe Medication Practices (ISMP)

19The intent of the contamination slides and this presentation was to stress that we need to learn from others mistakes. Lets be vigilant and understand that we can impact either positively or negatively.

Whats the past damage?Since 2001 over 25 pharmacy documented compounding incidents with 1,049 adverse events, including89 deaths, have been reported

TrueFalse

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Sources of Contamination

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Why is garbing important?Humans are the biggest particle generators Though we cant see them, we shed about 9 pounds of dead skin cells from the outer layer of the skin each year1Particles generated by humans, our clothes, and our activities can act as transport vehicles for microorganisms and introduce them into the compounding process

Photo Quest Ltd/Science Photo Library/Corbis1Donovan S. Stay Clear!: What You Should Know about Skin Care. Health Zone. Lerner Books. September 2008.Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Sets up the next slide. This is a great pic and makes an impression on people relative to their skin. Review these bullets.22

Just how many bacteria?Each of us carries 3-5 pounds of bacteria in our bodies!Bacteria cells outnumber human cells 10:1Bacterial cells are much smaller than human cells so they only account for 1-2% of our body mass

The bacteria in our body wouldfill a large soup can like this oneSource: Lita Proctor, National Institutes of Healths Human Microbiome ProjectCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

This is a fun slide. Review the bullets and then click and the soup can and caption appear.23

Garbingwhy?Compounding personnel are the chief particle generators.

Activity1Particles GeneratedSitting quietly100,000/minuteWalking slowly (1.9 miles/hour)5,000,000/minuteWalking medium (3 miles/hour)7,500,000/minuteWalking fast (5 miles/hour)10,000,000/minuteMakeup/Cosmetics2Particles/ApplicationEye shadow82,000,000Typical mascara application3,000,000,000Total for typical makeup application5,100,000,000

1Particle Measuring Systems. Basic Guide to Particle Counters and Counting. 2011. 2Goldstein K. Cosmetics in Cleanroomsagain. Cleanrooms. 2001Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Garbing is required in all risk levels except true immediate use situation where handwashing is the only QA activity required.

Review the information in this table. Helps with the rationale for garbing.

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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 handsIt only takes one to make a patient sick!

1 Health Protection Agency. Fun Facts about Handwashing. http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1254510461483Hand hygiene is the single most important factor in preventing the spread of pathogens in healthcare settings.Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Review bullets25

Critical Factors in Aseptic TechniqueIllnesses in Children's Hospital Prompts Discovery of Contaminated Alcohol Pads Science Daily (June 12, 2012): A small cluster of unusual illnesses at a Colorado children's hospital prompted an investigation that swiftly identified alcohol prep pads contaminated with Bacillus cereus bacteria, according to a report in the July issue of Infection Control and Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America. The investigation ultimately led to an international recall of the contaminated products.Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

This slides reviews the guidance in using sterile IPA and a major recall event involving nonsterile IPA wipes that resulted in patient harm.

IPA does not kill spores and Bacillus cereus is common spore forming bacteria found in cleanrooms and in CSPs. 26

Contamination CONTROLCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Seasonal variation: Spring and SummerBe careful of EVERYTHING you bring into controlled environments (e.g., sharpie marker caused fungal contamination)Cleaning is necessary to address mistakes in contamination controlIf it doesnt get into controlled environments, then it doesnt pose a risk!

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A Word about Material Handling60% packaging contaminated with bacteria and 40% with bacterial spores*If wipe with IPA (not a sporicidal) only 27.6% of spores would be removed through mechanical means*Spraying alone not effective since bacteria and spores can create a protective biofilm that must be removed by wiping**Mold is endemic to all brown cardboard and if it gets damp mold actively grows*Cockcroft et al. Validation of Liquid Transfer Disinfection Techniques for Transfer of Components into Hospital Pharmacy Cleanrooms. Hospital Pharmacist. 2001;8:226-32**Stubbs S. How to Minimize Contamination When Transferring Items Into Hospital Cleanrooms. Controlled Environments. June. 2006.


This slide provides some additional data that should convince them to move in the direction of best practice.28

When to use Sterile Water?Sterile water (SWInj or SWIrrig) is strongly recommended to dilute disinfectant solution concentrates (not ready to use) that are used inside of the ISO Class 5 areas. Though these areas and cleaning supplies are not sterile, use of sterile water reduces pyrogens and potential bioburden.

Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Type WaterCFU/mL*Pyrogens*Tap Water500 100 EU/mLPurified Water1000.25 EU/mLWater for Inj.< 10 < 0.25 EU/mL

*Sources: USP NF defines standards for Purified water and Water for Injection; US EPA defines drinking water standards

This slide starts out with just the title so you can ask the question. See if anyone in the group calls out.

The chapter does not explicitly require the use of sterile water for dilution of cleaning agents to be used inside of the ISO Class 5 spaces however the chapter does state the following relative to cleaning inside of PECs:

Items shall be removed from all areas to be cleaned, and surfaces shall be cleaned by removing loose material and residue from spills; for example, water-soluble solid residues are removed with sterile water (for injection or irrigation) and low-shedding wipes.

So, look at the table on this screen. In keeping with the rationale of not introducing bioburden, we recommend use of sterile water for irrigation to dilute cleaning agents. Now it is possible to argue that the cleaning agent itself will deactivate any microbes in the water. That may be true but until there is further science-based evidence we will recommend use of sterile water for irrigation.

In FDA operations, they must use sterile water and sterile disinfecting agent.

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Sterility Assurance Level (SAL)Aseptic processing only achieves a SAL of 10-3 versus 10-6 when terminally sterilized

Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

It is important to stress that we need to use objective tools to evaluate compounding personnel's aseptic technique. It is also important to know that the problem with a standard media test is its inherent lack of sensitivity in detecting low levels of contamination. Statistically, if we want to detect a contamination rate of 0.1% (1:1000) at a 95% confidence level, at least 3000 units must be filled.

SAL is an acronym for sterile assurance level and is a term used in microbiology to describe the probability of a single unit being non-sterile after it has been subjected to the sterilization process. SAL of aseptic compounded medication is lower than those medications terminally sterilized. There is a greater chance of contamination when drugs are aseptically manipulated and given to the patient than if they undergo robust sterilization procedures like steam or gamma irradiation.

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Terminally Sterilized

SAL 10-6

1 contaminated CSP per million CSPs

Aseptically Prepared

SAL 10-3

1 contaminated CSP 1000 CSPs

Which of the following are SOME of the potential sources of contamination for CSP preparation?Improper hand hygiene, clothing, and cardboardTap water, non-sterile alcohol, and exposed skin

Non-sterile gloves, spring, and summerAll of the above

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Ensuring a State of Control

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Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Take advantage of this free resource Register at http://797gaptool.com Take advantage of this free resource Register at http://800gaptool.com

Heres the link to the study. You can register at any time (you dont have to wait for that years study to officially open). You can register and answer the questions after which you will receive not only an overall compliance score and score for each content domain but you will receive a detailed action plan which is customized based on your actual answers.33


Not to beat a dead horse but this graphic again summarizes a concept that we believe is essential for adequate understanding of environmental sampling within a sterile compounding operation.34

DisinfectingChemical process that uses specific products to destroy 100% harmful bacteria, viruses and fungi but not necessarily their spores on environmental surfaces.

DisinfectingSporicidal AgentsChemical process that destroys 100% of harmful microorganisms and spores

SanitizingChemical process of reducing the number of disease-causing germs on cleaned surfaces to a safe level.

CleaningMechanical process (scrubbing) using soap or detergent and water to remove dirt, debris and many germs. It also removes invisible debris that interferes withdisinfection.SporicidalSanitizingCleaningDefinitionsCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

We tend to use a lot of terms when discussing cleaning. Sometimes we use terms interchangeably and we shouldnt so I wanted to review some important definitions with you as we get started.

Click and each square will reveal the definition.

Cleaning is a mechanical process that prepares a surface for disinfection Sanitizing is a chemical process and reduces the number of germs on a surfaceDisinfecting is a chemical process that removes 100% of bacteria, viruses and fungi (not spores)Sporicidal agents chemically remove 100% of the microorganisms AND their spores

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Factors in Selecting Agents for CleaningCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Cleaning is a mechanical process enhanced by germicidal detergents to remove dirt, debris, biofilm and microbesCleaning prepares a surface to be disinfectedMost general cleaning agents have a surfactant that removes dirtBleach is not a cleaning agent and does not have surfactantAlcohol is not a cleaning agent, it is a disinfectantMany cleaning agents also work to disinfect but application of a cleaning agent that also disinfects does NOT replace the use of sterile 70% IPA inside C-PECs!

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Cleaning Agent ClassesCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.No residues, no rinsing, not corrosiveEffective against yeast, fungi, bacteria, virus and spores based on concentrationEasy to store and stableHydrogen Peroxide AgentsPeroxyacetic Acid and Hydrogen Peroxide AgentsBroad-spectrum; sporicidal at low concentrations and ambient temperaturesInactivates gram+, gram-, fungi, yeasts, viruses and sporesNot inactivated by organics and enhance their removal; Byproducts: oxygen, acetic acid and waterPhenolic AgentsMany of these also EPA-registered disinfectants on environmental surfacesBased on dilution are fungicidal, virucidal and bactericidalUnpleasant odor; leave gummy residue that requires rinsing; may damage surfacesNever sporicidal; poor activity against mycobacterium; poor activity against hydrophilic viruses Must be rinsed; may be irritating to eyesEfficacy reduces by hard water and organic materialQuaternary Ammonium Compounds

Material Handling DOES MATTER!Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.USP Chapter :"Supplies and equipment removed from shipping cartons shall be wiped with a suitable disinfecting agent (e.g., 70% IPA) delivered from a spray bottle or other suitable delivery method. After the disinfectant is sprayed or wiped on a surface to be disinfected, the disinfectant shall be allowed to dry, during which time the item shall not be used for compounding purposes."Best Practice:Suggest use of a sporicidal agent such as PeridoxRTUBleach (5000 ppm = 0.5%)Other Sporicidal agentsInstead of IPA since there have been reports of mold spores in corrugated cardboard.IPA is also used by laboratories as a transport vehicle for spores.

This slide starts out with just the header.

Click for what the chapter says about wiping down supplies that come into the cleanroom.

Though IPA is the example used in the chapter with regard to wiping supplies, it is that. Just an example.

Then click and the Best Practice Recommendation appear:

We believe it is better to use a sporicidal disinfectant especially those items that are removed from corrugated (brown) cardboard which is known to be contaminated with mold spores.

Theres a lot of confusion about Bleach. Firstly make sure they all know that Clorox household bleach is not full strength bleach. It is only 5-6% active sodium hypochlorite.

Mix bleach solution by using: 1 part bleach (household bleach 5.25-6% sodium hypochlorite), 1 part white vinegar, 8 parts water which yields 5000 ppm (.5% solution)

Bleach must be 5000 ppm to be considered a disinfectant.

Tell them the reference is in their list. US EPA. Pesticides: Topical & Chemical Fact Sheets. Retrieved from: http://www.epa.gov/pesticides/factsheets/chemicals/bleachfactsheet.htm on August 11, 2014.

Knowledge Pearl: PeriodoxRTU and 2% sodium hypochlorite solutions can also be used to deactivate most HDs. If bleach is used to deactivate chemo, it must be used at 2%.

Contec Inc. PeridoxRTU Hazard Drug Decontamination System Testing. Unpublished Study obtained directly from Contec.Contec Inc. PeridoxRTU Sporicidal Disinfectant for Decontaminating Hazardous Drugs. Contec Inc. PeridoxRTU Sporicidal Disinfectant Application Bulletin. 2014-01 Decontamination of Surfaces Soiled with Hazardous Drugs

Though IPA is an all purpose disinfecting agent, it does not have activity against spores and in fact is used by labs to transport spores. 38

When to perform daily cleaning?The daily cleaning (and disinfection) best occurs at the end of the day to leave the room to rest clean.Disinfection with sterile 70% IPA (sIPA) must occur to the interior surfaces of the PEC before compounding is begun the next day (or the same day for 24 hour pharmacies)Cleaning activities may not occur while compounding is taking place

This is excerpt from 797 but was not the intended meaning.Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Slide starts with just header. Ask the group. See what they think. Then click and excerpt from chapter appears with comment.

Click again to see bullets

Unfortunately the chapter talks about cleaning and disinfecting occurring before compounding. The expert committee meant that disinfection (wiping with sIPA) needs to occur then but the room is best left to rest in a clean state39

A cleanable step stool is essential.Some type of step stool must be available in controlled spaces to properly clean:Wall clocksLife Safety SignsTop of PECsTops of doors


Cleaning ProceduresClean from cleanest to dirtiestISO 5 PECBuffer areaAnte areaGeneral supply areaUse suitable dedicated mops and cleanersMust use germicidal detergent everywhere including PEC


The chapter provides some specific guidance about cleaning.

Cleaning should always start in the cleanest area (I ask them what that is) to the dirtiestOnly authorized compounders can clean inside the primary engineering controlsUse dedicated mopsUse diluted germicidal detergent everywhereeven inside the PEC (this is another misunderstood area; the way the chapter is written isnt very clear but germicidal detergent must be used inside of the PEC followed by sIPA (sterile IPA)41

Environmental SamplingCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Designed to demonstrate that the primary and secondary engineering controls, disinfecting procedures, and work practices result in a suitable environment for aseptic compoundingUtilizes several approaches to assess and evaluate:Total particle countsAir viable organism cfuSurface viable organism cfuFinger touch platesMonitors State of Control

Environmental Sampling (ES) provides data about the success that the primary and secondary engineering controls, cleaning procedures and work practices have working together to achieve and maintain an environment that is suitable for compounding sterile preparations.

ES includes total particle counts (non viable) as well as viable counts of air, surfaces and gloved fingertips.

If there is anything you take away from this presentation, understand that ES is the only way you can monitor what?

Then click and monitors state of control appears

Why Is ES Important?Facilitates early detection of contamination and its source which may include:PersonnelWork surfacesSuppliesEquipmentFailure of engineering controlsCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Courtesy CBS NewsThis is a image of the fungus growing from a sample taken from a patients spinal fluid.

Let this picture sink in.

It usually results in a gasp from the audience. You can underscore that this was a picture of the growth obtained from one NECC patients spinal fluid. Its always good to mention that if they had followed the requirements of the chapter, this would not have happened.

The more frequent the data points obtained from sampling, the more quickly you will be able to detect a drift away from your state of control.43

Environmental Sampling (continued)Facility Related MetricsSurface SamplingGloved Fingertip SamplingMedia-Fill TestingNon Viable SamplingTemperaturePressure/VelocityParticle SamplingViable Air SamplingPersonnel Related Metrics


ES can be described as primarily related to the personnel work practices or to the operation of the facility . Then I review them.44

Actions to Take When Action Levels ExceededAn investigation into the source of the contamination must be conducted.Sources:HVAC systems: changes externallyDamaged HEPA filtersChanges in personnel garbing habitsChanges in work practicesFailure to follow PnP New employees


The chapter requires that when Action Levels are exceeded, something must be done about it. There must be some type of investigation. At a minimum the area is cleaned and resampled at the end of the day however more detailed investigations are often required. These investigations must be conducted AND documented.45

Environmental Sampling Plan RequirementsAn ES program provides a way to monitor that the equipment, cleaning and other work practice controls result in a compounding facility controlled environment that is suited for compounding sterile preparations and detects any drift from an ongoing state of control.

When sampling occursWhere sampling occursNumber/size of samplesUnder what conditions sampling occursMaterials required including media types and incubation conditionsAction LevelsDocumentationActions required in the event of excursionsCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Not to overstate but repeat that the ES program provides the only way to monitor that the primary and secondary engineering controls, cleaning procedures and work practices result in an environment suitable for sterile compounding and detects any drift from the state of control.

As weve mentioned, we believe to be sensitive enough to REALLY detect a drift away from the state of control, then ES must be performed more frequently than what is required by the chapter.

Every pharmacy is required by the chapter to have an ES program and an ES plan that must provide the following informationreview the bullets on the right hand column.46

Speciation to Genus Level Currently RequiredRegardless of the number of cfu identified in the pharmacy, further corrective actions will be dictated by the identification of micro-organisms recovered (at least the genus level) by an appropriate credentialed laboratory of any microbial bioburden

- USP Chapter USP 34-NF 29Proposed Chapter requires that when samples exceed the action levels, genus must be identified and if possible, the species of microorganisms must be identified with the assistance of a credentialed microbiology laboratoryCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

Regardless of whether or not Action Levels are triggered, CFUs need to be speciated to the genus level. This is a frequent area of non compliance especially when certifiers are performing this. So often, the Certifiers report isnt even reviewed. Certifiers frequently dont get CFUs speciated. This examination provides valuable information about the potential source of contamination so that appropriate actions can be taken.

Image: Shutterstock47

CFU Identification and SourcesCopyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reservedUse of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Microorganisms IndicationStaphylococcus/ MicrococcusPersonnel habits or gowning problemsGram negative rodsWater condensation, leaking, aerosols Bacillus speciesDust, dirt, floor traffic, possible air handlingMoldsInflux of unfiltered air, mold from street clothing or mold-contaminated cardboard, water reservoir, i.e. incubator humidification systemYeastPossible outdoor air influx; clothing-borne, especially in late summer/ fall; possible human contaminant Diptheroids/ coryneformsPoor air conditioning (leading to sweating and personnel discharge from gowns)Source: Microbiological Environments (www.microbioenv.com)

For instance, look at this table which provides just a few examples of the type of microbe and its potential source.48

What are SOME methods to ensure a state of control?PROPER selection of cleaning, disinfection, and sporicidal agentsPROPER order of cleaning, disinfection, etcPROPER staff training, validation, and accountabilityPROPER environmental monitoring and trending of this dataAll of the above

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Opportunities Recommended by the ABoP

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Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Design of sterile compounding area Discuss proper design for non-HD and HD roomsPressure differentials between classified and non-classified roomsInsufficient air-exchanges in classified areasLack of HEPA filter leak tests (discuss access port expectations)HEPA air supply expectationsCertification company expectationsClean and dirty side designation for anteroomsVolumetric/viable air sampling expectationsPlan for corrective actions when alert levels reached/exceededArkansas Board of Pharmacy

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Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.Inadequate documentation ofTemperature, pressure, and humidityPEC and SEC cleaning/disinfectionPersonnel training , media fill, and glove fingertip testing (initial and ongoing)Improper storage of chemotherapy medicationsStored with other medicationsNot stored in a negative pressure room with at least 12 ACH (dont make non-HD room negative pressure)

Arkansas Board of Pharmacy (cont.)

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Environment vs. Personnel*Thomas M, Sanborn M, Couldry R. IV admixture contamination rates: Traditional practice site versus a class 1000 cleanroom. Am J Health-Syst Pharm. 2005; 62:2386-92 The most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in whichthe drugs were compounded.* Copyright 2013-2017 CriticalPoint's Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement from CriticalPoint or Clinical IQ.

I usually ask them when the screen is blank (before I click) by a show of hands If you had to choose between the primary and secondary engineering controls or the work practices of personnel, which is the most important variable, which would you choose?

Most often it is 50-50 or more folks say engineering controls, and then I click.

This is what we must emphasize to our staff. This is why training is so important. Certainly not to minimize the importance of the primary and secondary engineering controls. They are important, but no matter how perfect the cleanroom is, our non compliance and lack of understanding can overcome all of the positive actions of the engineering controls.

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Facility Design and EquipmentClassified space function and designPrimary engineering controlsBuffer areaAnte areaAir supplyHEPAPressureSegregated compounding areaEquipment, surfaces, and supplies


The chapter clearly defines the physical plant and equipment needed in controlled compounding environments.54

Airflow DefinitionsTurbulent flowDilution control to reduce particulate levelsAdequate HEPA filtered airflow supplied to the cleanroom and anteroom is required to maintain cleanliness classification during operational activity

Copyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved

State of Control Point

Cleanrooms less clean than ISO class 5 are not unidirectional airflow.

ISO class 7 & 8 rooms employed in sterile compounding use turbulent airflow in which all of the air supplied to the cleanroom is HEPA filtered.

The state of control points are the amount of air delivered to the room and the cleanliness of that air (HEPA filtration).

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Ante-AreaNon-hazardous applications: Anteroom must achieve at least ISO class 8 conditions & be positive pressure to uncontrolled spaces Negative to compounding roomCopyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved

This is traditional cleanroom paradigm. Pressures flow from clean to dirty to avoid infiltration of contaminated air from support rooms into the cleanroom. 56

Ante-AreaHazardous applications: Anteroom must achieve at least ISO class 7 & be positive to uncontrolled spaces Positive to the HD compounding roomCopyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved

Obviously, there is no good answer to that question. The compromise is to make HD compounding room negative pressure to accommodate the hazard and then to make the ante area at least as clean as the HD cleanroom (ISO Class 7). The ante room should also be positive to outside areas to ensure air is not drawn in from outside. Explain it here.

Here is where we answer the question asked two slides ago. A negative pressure room is okay for compounding hazardous drugs if that room is protected by an ante or other room that is at least as clean as the HD buffer room and that room is positive to adjacent spaces. 57

Secondary Engineering ControlsCopyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved Adequate HEPA filtered airflow supplied to the cleanroom and anteroom is required to maintain cleanliness classification during operational activity through the number of air changes per hour.Minimum of 30 HEPA filtered Air Changes Per Hour (ACPH) in Buffer AreaNo less than 15 ACPH must be provided as fresh HEPA air supplied through the rooms HVAC systemThis assumes additional HEPA filtered air is provided to the room through the primary engineering control.Supply airflow typically not continuously monitoredRoom pressure monitored

State of Control Point

The minimum air values specified here are just thatMINIMUM. Depending on the situation more than that is needed, often much more.

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Secondary Engineering ControlsCopyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved Ventilation efficiencyHEPA filtered supply air is introduced at the ceiling with low-wall mounted returns, creating a general top-down dilution of room air with HEPA filtered make-up air. Ceiling-mounted returns are not recommendedRecommend ceiling-mounted HEPA filtersHEPA filters and returns well distributed throughout the roomReturn locations at least as important as supply inlet locations

Notice that the statement in USP is ceiling mounted returns are not recommended.

Ceiling mounted returns are not a good idea in a cleanroom (particles should be swept off the floor not pulled up to the ceiling).

Use the schematic on the next slide to illustrate this.59

Ceiling mounted HEPA filters

Low-wall mounted returns


This is a picture from an ideal compounding cleanroom.

Note that the large number of returns here is unusual. This is actually an ISO class 6 room, therefore many more air changes are required and much more air is moved through the room.

Also note that the LAFW in this room provides additional particulate removal via the low intake grilles. 60

Secondary Engineering ControlsAll HEPA filters should be efficiency tested at the most penetrating particle size leak tested at the factory and leak tested again in situ after installation.IEST type C or K HEPA filterCETA guide CAG-003-2006 for field certification

Copyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved Filter leak tested and repaired

State of Control Point (HEPA filtered air- the filters must be certified leak free)

HEPA filters shall be integrity tested as part of the initial commissioning project and then again every 6 months and whenever they are moved/relocated. It is okay to patch a filter, but that patch should not exceed 3% of the filter media area or exceed 1.5 width. Regulators have cited facilities for excessive patching.

Make sure you specify the types of filters listed here to ensure that they will pass the integrity test in-situ.

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Hazardous Drug (HD) ApplicationsCopyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved Hazardous drugs shall be stored separately from other inventory in a manner to prevent contamination and personnel exposure.Minimum of 12 ACPHNegative pressureThe ISO class 5 BSC or CACI shall be placed in an ISO class 7 room that is physically separated, e.g., a different room from other preparation areas, and optimally has no less than 0.01 inches water column (w.c.) negative pressure to adjacent rooms.HD Buffer rooms housing CACIs must meet the minimum 0.01 w.c. negative pressure and 12 ACPH requirements.

State of Control Points

The outside of HD vials have been shown to contain HD residue as they are received from the distributors. Touch contamination of surfaces and gloved hands is likely.

If nonhazardous and hazardous drugs were stored in the same room, it is very likely that non HD drug supplies would become contaminated with HD residue. Separation of HD and non HD drugs is intended to protect the non HD drugs/patients.

Adequate room air change (12 ACPH) will allow the room to dilute aerosols created in the event of an HD spill.

Negative pressure (0.01 w.c.) will reduce the escape of HD aerosols in the event of a spill or aerosol release. 63

Pass-Through Usage/LocationPass-Through PositionClassified to ClassifiedClassified to UnclassifiedFDA PositionBOP PositionsCopyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved

Lay the ground work that the FDA prefers passing from classified to classified. Discuss the advantages and disadvantages of this set up. Going through the ante room can be disruptive and requires setting the HDs on surfaces within the ante area. Position the PT on the clean or dirty side or as in this slide, straddle the LOD. Discuss advantage and disadvantages. Discuss that , does not prohibit passing from classified to unclassified.64

Secondary Engineering CertificationNSF certification for BSCCAG-003-2006: CETA Certification Guide for Sterile Compounding FacilitiesAirflow testingAirflow smoke pattern testHEPA Filter Installation Leak TestParticle Count SurveyOptional testsLight, sound, temperature, humidity Copyright 2013-2016 CriticalPoints Sterile Compounding Boot Camp - All rights reserved

state of control points Secondary Engineering Controls

Ensuring Proper airflow volume to the cleanroom based on USP minimum acceptable valuesHEPA filters are leak freeRoom segregation (pressure or displacement airflow)

desired outcomes

Ensuring Particle count survey to ensure compliance with ISO Classification under dynamic operating conditionsSmoke pattern test

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Adapted from CETA Certification Matrix for Sterile Compounding Facilities CAG-003-2006-13, USP , Proposed USP , and USP on 3/11/2016.Secondary Engineering ControlsTestNon Haz BufferAnteroomC-SECC-SCAAirflow30 ACPH (at least 15 ACPH from outside the room) usually more 20 ACPH (from FDA guidance) but usually more is desirable 30 ACPH 12 ACPH for C-SCA or any area where HDs are storedRoomSegregationMinimum differential pressure of 0.02 w.c. positive from buffer to anteroom and then again from anteroom to adjacent spacesMinimum differential pressure of negative 0.01 to 0.03 w.c. from C-SEC/C-SCA to adjacent spaceIf displacement airflow (will no longer be acceptable when Proposed USP 797 becomes official), then velocity of 40 feet/minute from cleanroom to the anteroom across the entire openingDisplacement airflow not allowed in HD compoundingHEPA Filter Leak TestAll 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 TestingBuffer rooms must be segregated from the ante-area and all other adjacent spaces. Use smoke around the opening of doors to ensure air is traveling in the correct direction.Non-Viable Particle CountsISO Class 7ISO Class 8 unless it serves HD buffer then ISO Class 7ISO Class 7 in buffer roomNo ISO classification required in C-SCAAirborne particle counter used to sample particle levels in all ISO classified locationsunder dynamic operating conditions.TemperatureComfortable, typically a temperature of 64-66F but Proposed USP 797 requires 20C or coolerHumidityNot mandatory at this time but Proposed USP 797 requires relative humidity at or below 60% at all times


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What is the best pressure gradient between a HD room and its associated anteroom?Greater than + 0.02 W.C. (with at least 12 ACPH)Greater than - 0.01 W.C. (with at least 12 ACPH)Between - 0.01 and - 0.03 W.C. (with at least 12 ACPH)

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Thanks again to Critical Point LLC (www.criticalpoint.info) and especially Kate Douglas, MS, RN, CRNI

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usp : ensuring a state of control

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