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Improving Sterile Compounding: Impact of New Regulations, Standards and GuidelinesPharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

Improving Sterile Compounding:Impact of New Regulations, Standards and Guidelines

September 9, 2016

Featured Speaker: Darryl S. Rich, PharmD, MBA, FASHP

Medication Safety SpecialistInstitute for Safe Medication Practices

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Improving Sterile Compounding: Impact of New Regulations, Standards

and Guidelines

Presented by:

Darryl S. Rich, PharmD, MBA, FASHP

Medication Safety Specialist

Institute for Safe Medication Practices

September 9, 2016

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Disclosure

• Darryl S. Rich reports no relevant financial relationships.

• The information presented related to accreditation requirements and regulations is the personal opinion of the presenter and is not an official position of the related organization or agency.

• ISMP is a federally‐listed patient safety organization and the only nonprofit organization dedicated entirely to medication error prevention and safe medication use. It is not a regulatory agency or accrediting body and has no direct affiliation with any agencies or bodies.

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Learning Objectives• Cite five ways federal and state regulatory agencies and the Joint

Commission have increased their focus on sterile compounding in the past 4 years in both hospitals and compounding pharmacies.

• List three organizations whose standards/guidelines related to the preparation and administration of sterile medications hospitals must now comply with.

• List one facility certification and one staff certificate/credentialing program planned for sterile compounding.

• Describe three ways how recent regulatory and standard changes in sterile compounding are driving hospitals and 503b pharmacies’ practices in the future.

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The Issues: Sterility

• FDA: 200 adverse events reported involving 71 compounded sterile products from 1990‐2012, some of them with "devastating repercussions”

• 1990‐2014: At least 26 incidents of contaminated pharmacy‐prepared products reported nationally infecting over 900 patients, resulting in 92 deaths

– Outsourced pharmacies: 834 infected patients ‐ 88 deaths

– NECC alone: 751 infected patients – 64 deaths

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The Issues: Compounding Errors

– 2005‐2014: Serious cases of compounding errors reported involving 18 patients, including 9 deaths, related to:

Wrong concentration/strength dispensed (overdose)

Wrong product or diluent used in compounding

Product mislabeling by the pharmacy

3 cases involved outsourced compounders

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The Regulatory Response

Drug Quality and Security Act (DQSA)• FDA – 503b• Boards of Pharmacy (BOP) – 503a

Hospitals• CMS• State: BOP and Dept of Health• Accreditation (TJC, DNV, HFAP, CIHQ)

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New CMS Interpretative Guidelines1

• Revised Hospital Guidance for Pharmaceutical Services and Expanded Guidance Related to Compounding of Medications:

– In addition to all applicable laws and regulations, hospitals must be consistent with accepted standards of practice based on guidelines or recommendations issued by nationally recognized organizations with expertise in medication preparation and administration. Examples of such organizations include, but are not limited to:

• American Society of Health‐System Pharmacists (ASHP)

• Infusion Nurses Society (INS)

• Institute for Safe Medication Practices (ISMP)

• National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP)

• U.S Pharmacopeia (USP)

121. Center for Medicare and Medicaid Services. CMS S&C Memo: 16‐01, October 30, 2015. Available at: https://www.cms.gov/Medicare/Provider‐Enrollment‐and‐Certification/SurveyCertificationGenInfo/Downloads/Survey‐and‐Cert‐Letter‐16‐01.pdf




• “The applicable standards of practice for safe sterile compounding are, at a minimum, the standards published in USP/NF Chapter <797>”

– For non‐sterile: USP/NF Chapter <795>

• “Hospitals must ensure that they meet all currently accepted standards for safe preparation and administration for CSPs.”

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1. Center for Medicare and Medicaid Services. CMS S&C Memo: 16‐01, October 30, 2015. Available at: https://www.cms.gov/Medicare/Provider‐Enrollment‐and‐Certification/SurveyCertificationGenInfo/Downloads/Survey‐and‐Cert‐Letter‐16‐01.pdf


• All clinicians/nurses everywhere must adhere to USP<797> immediate use and labeling requirements

– Simple transfer of no more than 3 sterile products and no more than 2 entries into any one container.

– Administration begins no more than 1 hour after preparation

– Unless administered by preparer or administration witnessed by preparer, must be labeled with at least:

• Patient identification information;

• The names and amounts of all ingredients;

• The name or initials of the person who prepared it; and

• The exact one hour “beyond use date” 1. Center for Medicare and Medicaid Services. CMS S&C Memo: 16‐01, October 30, 2015. Available at: https://www.cms.gov/Medicare/Provider‐Enrollment‐and‐Certification/SurveyCertificationGenInfo/Downloads/Survey‐and‐Cert‐Letter‐16‐01.pdf

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• The hospital must demonstrate how it assures that the compounded medications it receives from a 503a compounding pharmacy have been prepared in accordance with accepted professional principles for compounded drugs, and state laws and regulations.

– The hospital documents that it obtains and reviews quality assurance data verifying that the vendor is adhering to current USP <795> and <797> requirements.

– Requiring the vendor to meet the requirements of Section 503A of the FDCA concerning pharmacy compounding of human drugs.

– Not required for medications from a 503b outsourced providers.1. Center for Medicare and Medicaid Services. CMS S&C Memo: 16‐01, October 30, 2015. Available at: https://www.cms.gov/Medicare/Provider‐Enrollment‐and‐Certification/SurveyCertificationGenInfo/Downloads/Survey‐and‐Cert‐Letter‐16‐01.pdf

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What Are the Other Relevant USP Guidelines?

• USP <800> Hazardous Drugs– Released February 2016, effective July 2018 (July 2017 in CA).

• List of Hazardous Medications from NIOSH List in Use in the Hospital

• Documented Risk Assessment– Alternative strategies for antineoplastics that you only count and package, and non‐antineoplastics, & reproductive hazards

• Negative pressure & engineering controls, PPE specifications, CSTDs, decontamination, environmental monitoring

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ASHP Guidelines1

• ASHP Best Practices – 2015‐2016 Edition

– ASHP Guidelines on Compounding Sterile Preparations (2014)

– ASHP Guidelines on Preventing Medication Errors with Chemotherapy and Biotherapy

– ASHP Guidelines on Outsourcing Sterile Compounding Services

– Position Statement on Standardization of Intravenous Drug Concentrations

– ASHP Statement on Bar‐Code Verification During Inventory, Preparation, and Dispensing of Medications

– ASHP Guidelines on the Safe Use of Automated Compounding Devices for the Preparation of Parenteral Nutrition Admixtures

171. American Society of Health‐System Pharmacists. Best Practices 2015‐16. Bethesda, Maryland: ASHP Publications, 2015.

INS and NCCMERP Guidelines

• Intravenous Nursing Society

– Infusion Therapy Practice Standards (2016 Edition)

• National Coordinating Council for Medication Error Reporting and Prevention

– Recommendations for Reducing Medication Errors

– Recommendations for Enhancing the Accuracy in Dispensing/Administration of Medications

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www.nccmerp.org



2013 Guidelines to Reduce IV Compounding Errors

• Original summit in October 2011

• Revised 2015

– Updated version to be released in 2016

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Why Revise the Guidelines?• Continued development and enhancement of technology designed to verify that the correct drug product, dose, and diluents were used to prepare CSPs

• Reports of error that could have likely been prevented with the use of some form of technology

• Increase regulatory pressure to use existing guidelines and standards of practice in this area– Wanted to ensure they are current and relevant

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What’s Different

• Eliminated priority ranking of guidelines

• New section with expanded recommendations for compounding done outside the pharmacy

• Stronger recommendations on the implementation of automation and technology and use of 503b outsourced compounders.

• Minor language changes throughout the document

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What’s Different

• Technology solutions (eg., barcode scanning, gravimetrics, robotics) are utilized to augment manual processes for preparing and verifying CSPs.

– At a minimum both barcoding and gravimetrics are used when preparing chemotherapy and ideally, for pediatric CSPs .

• Have a strategic plan for implementation of automation & technology in sterile compounding

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Sterile Compounding Strategies

– Standardize concentrations wherever possible

– Standardize workflow processes, including quality control and checking

• Use of a process checklist

• Proper formulation worksheets

• Preproduction checks in high‐alert drugs, pediatrics, intrathecal

• One product/one patient at a time

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Sterile Compounding Strategies– Use of technology (barcode, camera, software)

– Independent double‐check of order entry, batch setup

and automated compounder setup

– Segregate and differentiate products

– Standardize base solutions

– Separate pediatrics from adult compounding (time and

location)

– Standardize label to match information on the order

– Conduct a proactive risk assessment of the process

(FMEA)24



• Purpose: to identify, inspire, and mobilize widespread, national adoption of consensus‐based best practices on specific medication safety issues that continue to cause fatal and harmful errors in patients, despite repeated warnings in ISMP publications.

– Realistic practices, already adopted by many hospitals.

– Reviewed by an external expert advisory panel

Find at: www.ismp.org/Tools/BestPractices

2016‐2017

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Best Practice 7 (New)1

Segregate, sequester away, and differentiate all neuromuscular blocking agents (NMBs) from other medications, wherever they are stored in the organization.

1. Institute for Safe Medication Practices. 2016‐2017 Targeted Medication Safety Best Practices for Hospitals. Bethesda, MD: ISMP Publications, 2016.

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When compounding sterile preparations, perform an independent verification to ensure that the proper ingredients (medications and diluents) are added, including confirmation of the proper amount (volume) of each ingredient prior to its addition to the final container.

• Specifically, eliminate the use of proxy methods of verification (e.g., the “syringe pull‐back method,” checking a label rather than the actual ingredients).


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• Use technology to assist in the verification process (eg., barcode scanning verification of ingredients, gravimetric verification, robotics, IV workflow software) to augment the manual processes

• The technology is maintained, the software is updated, and the technology is always used in a manner that maximizes its medication safety features.


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IV Workflow Technology1

• Percent of hospitals using increased from

– 12% in 2015 to

– 19% in 2016

• Another 36% saying implementation is under consideration

• While concentrated in larger facilities, the number of hospitals <100 beds that implemented this technology doubled to 8%

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1. Pharmacy Purchasing and Products Magazine, August 2016: State of PharmacyAutomation. Volume: 13 Number: 8. Available at: http://www.pppmag.com/article/pppv13n8s0. Accessed September 4, 2016.

Where do the states fit in?

• Department of Health hired by CMS to do CMS surveys of hospitals– “For cause” and validation surveys (5% sample)

– According to the CMS interpretative guidelines

• Board of Pharmacy– New sterile compounding regulations

– Inspectors trained in sterile compounding/USP <797>

– Required compliance to USP <797> directly or indirectly

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USP <797> State Requirements1

• Direct Compliance: 26

– CO, CT, GA, HI, IN, FL, MA, MD, ME, MI, MN, MT, NC, NE, NM, OH, OK, RI, SD, TN, TX, UT, VA, VT, WV, WY

• Indirect Compliance: 23

– AK, AL, AR, AZ, CA, DC, DE, IA, ID, IL, KS, KY, LA, MO, MS, OR, ND, NH, NV, NY, SC, WA, WI

• No reference (1): PA

1. CriticalPoint, LLC. Sterile compounding state regulatory map: updated August 8, 2016. Available at: http://www.criticalpoint.info/Statemap/story.html. Accessed September 4, 2016.

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One Example – California BOP• Business and Professions Code: Chapter 9, Article 7.5: Compounded Sterile Drug Products – Sterile compounding pharmacy license

– The board shall review any formal revision to General Chapter 797 of the USP–NF relating to the compounding of sterile preparations, not later than 90 days after the revision becomes official, to determine whether amendments are necessary for the regulations

• California Code of Regulations: – Title 16, Section 1751 ‐ Sterile injectable compounding regulations.

– Title 24: clean room requirements32



One Example – California DPH• Medication Error Reduction Plan (MERP)

HEALTH AND SAFETY CODE SECTION 1339.63

– Must address how plan has evolved.

– Implementation of technology is a required element

– Must evaluate, assess, and address each of the 11 “procedures and systems” – compounding is one.

– The MERP must be reevaluated at least annually.

– MERP is modified when weaknesses/deficiencies are noted.

– Identification of errors must be proactive and include both concurrent and retrospective review of clinical care.

– Errors are to be analyzed through a multi‐disciplinary process.

– Incorporate external medication‐related error alerts.

– Method to assess effectiveness.

331. California Department of Pharmacy. Survey process for medical error reduction plans (MERP). CDPH Memo AFL 08‐39, Dec 2008. Available at: https://www.cdph.ca.gov/certlic/facilities/Documents/LNC‐AFL‐08‐39.pdf. Accessed September 4, 2016.

Accreditation Standards, by organization• Det Norske Veritas (DNV) and Center for Improvement

in Healthcare Quality (CIHQ) – survey against the CMS interpretative guidelines

• Healthcare Facilities Accreditation Program (HFAP) –currently revising standards in light of new CMS interpretative guidelines.

• The Joint Commission (TJC)– Surveying against the current standards (haven’t changed since

2004) – no new changes planned for 2017 related to sterile compounding.

– Currently requires compliance with all applicable laws and regulations required –both federal and state.

– Currently reviewing standards in light of the new CMS interpretive guidelines

• TJC does NOT survey against the interpretative guidelines.

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MM.05.01.07 Drug Preparation

• EP 1 ‐ Pharmacy compounds or admixes all compounded sterile preparations except in urgent situations in which a delay could harm the patient or when the product’s stability is short

• EP 2 ‐ Staff use clean or sterile techniques and maintain clean, uncluttered, and functionally separate areas for product preparation to avoid contamination of medications.

• EP 3‐ During preparation, staff visually inspect the medication for particulates, discoloration, or other loss of integrity.

• EP 4‐ The hospital uses a laminar airflow hood or other ISO Class 5 environment in the pharmacy for preparing intravenous (IV) admixture or any sterile product that will not be used within 24 hours.

• EP 5‐Medications are prepared in accordance with the orders of a licensed independent practitioner.

35Source: The Joint Commission: Medication management standards.

MM.05.01.09 – Labeling

• Labeled whenever prepared but not immediately administered.

• Label information displayed in a standardized format in accordance with law, regulations and standards of practice.

• All medications labeled with:– Medication name, strength & amount (if not apparent from container)

– Expiration date

– Expiration time (if less than 24 hours)

– Date prepared and diluent (all compounded IV admixtures/PN)

• If individualized– Patient name

– Location where the medication is to be delivered

– Directions for use and auxiliary labels36

Source: The Joint Commission: Medication management standards. 36



ISMP’s Label Guidelines

• Principles of Designing a Medication Label for Intravenous Piggyback Medication for Patient Specific, Inpatient Use

– WWW.ISMP.ORG/TOOLS/GUIDELINES/LABELFORMATS/PIGGYBACK.ASP

• Principles of Designing a Medication Label for Injectable Syringes for Patient Specific, Inpatient Use

– WWW.ISMP.ORG/TOOLS/GUIDELINES/LABELFORMATS/INJECTABLE.ASP

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MM.05.01.11 – Dispensing

• EP 2: Dispenses medications and maintains records in accordance with law and regulation, licensure, and standards of practice.

– Compliance with USP 797, when mandated by state

– See also: LD.04.01.01 – hospital complies with law and regulations.

• EP 4: Medications are dispensed in the most ready‐to‐administer forms commercially available and, if feasible, in doses that have been prepared by the pharmacy or licensed repackager (outsourced)

– See also MM.03.01.01, EP 10 (floor stock)

38Source: The Joint Commission: Medication management standards.

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The Joint Commission: What’s Next

• Despite a lack of standard changes, there is expected to be an increased survey focus on sterile compounding.

• In 2015, hospital surveyors were educated (webinar) in sterile compounding and USP <797>– Developing an in‐depth surveyor training program

• Sterile compounding risk assessment process using survey checklist tool– Currently in use in home care, pilot testing in hospitals.

– Focusing on surveying the current standards better.

– Focus on LD.04.03.09 for contracted 503a outsourced pharmacies.

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Sterile Compounding Survey Tool

– EC: Facilities (including airflow), equipment, equipment calibration and oversight, adequate space.

– MM: Selection, storage, and labeling; product testing; beyond‐use and extended‐use dating

– HR: Competence assessment of compounding staff

– IC: Policies and practices in the compounding facilities

– LD: Overall responsibility for (and provision of) resources; adherence to applicable laws & regulations; contracted services oversight.

– PI: Monitoring and evaluation of the compounding process

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Key Elements of the Directed Risk Assessment

• Know risk level‐‐‐low, medium, or high

• Compounding will be observed

• Clean room monitoring records reviewed

• Clean room certification report reviewed and validation that it is understood by manager

• Licenses reviewed• Key policies reviewed

• Most recent board of pharmacy inspection report reviewed

• Staff competency• Drug storage• Packing and shipping (HC)• Recalls• Controlled substance

process• Other areas as

appropriate

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Outsourced 503a Pharmacy Services

• LD.04.03.09: Care, treatment, and services provided through contractual agreement are provided safely and effectively – Must have a contract or written agreement

– Must establish performance expectations

– Must communicate the expectations in writing

– Must monitor contracted services by evaluating these services in relation to the hospital’s expectations

– Must take steps to improve contracted services that do not meet expectations

• This standard not required for 503b services

42Source: The Joint Commission Leadership standards.



New TJC Certification Program (?)

• Sterile compounding facility certification –growing requirement trend in states

• As part of TJC’s formal certification programs

• Optional, not a part of accreditation – need not be accredited by TJC.

• Hospitals vs. 503a pharmacies vs. 503b pharmacies.

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Staff Credentialing and Certificate Programs

• American Society for Health‐System Pharmacists (ASHP) certificate program in sterile compounding: http://elearning.ashp.org/products/4481/sterile‐product‐preparation‐training‐and‐certificate‐program

• Board of Pharmacy Specialties (BPS)considering board certification in sterile compounding. – Will it be required???

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Reasons for Slow Adoption of Technology and Other Strategies1

• Depreciating importance of the compounding and dispensing processes in pharmacy practice

• Lack of knowledge and standardization around best practices

• Training based on traditions handed down from one pharmacist to another

• Learned workplace tolerance of risk and routine practice deviations that persist

• A reluctance to learn from the mistakes of others

451. Institute for Safe Medication Practices. ISMP Medication Safety Alert!: Jan 15, 2015. Available at:https://www.ismp.org/newsletters/acutecare/showarticle.aspx?id=98. Accessed September 4, 2016.

Need for Evidence

• Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomized controlled trials

Gordon C S Smith, Jill P Pell

Ref: BMJ Vol 327, 20‐27 December 2003

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Driving Forces in Hospitals

• Pressure to spend more on sterile compounding – staff, facilities and technology.

– Will increase in next 5 years

• More use of 503b outsourced compounded sterile products.

– HOWEVER…….

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FDA Inspections of 503b Pharmacies

• Inspection report details (483) available online:– http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompou

nding/ucm378645.htm

• In past 3.5 years

– 170 inspections – all but one received a Form 483

• Past 12 months ‐ 126

– 81 warnings issued (36%)

• Past 12 months – 40 (32%)

– PharMEDium: 10 inspections, 5 warnings, 2 recalls

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Top 10 Issues Reported to FDA • Most affect sterility and were cited > 60% of the time:

1. Inadequate facilities designs and controls, inadequate smoke studies

2. Inadequate or lack of environmental monitoring of facility and people

3. Inadequate laboratory procedures and controls (definition of a “batch”, sampling and testing controls)

4. Lack of Standard Operating Procedures to prevent microbial contamination

5. Inadequate deviation/variance controls and lack of adequate investigation

6. Stability program nonexistent or does not support beyond use dating

7. Validation of final sterilization (filter or terminal), media fill design

8. Inadequate cleaning and disinfecting programs

9. Batch release (most done at risk or with no testing for sterility, potency, identity and pyrogens)

10. Control of equipment (preventive maintenance and calibration program inadequate or nonexistent) 49

Driving Forces on 503b Pharmacies

• Increased competition

– 64 as of August 2016 ‐ up from 44 in May 2015

• Differentiation

– Improved performance on FDA inspections and adherence to Current Good Manufacturing Practices (cGMP)

– Improved adherence to accepted standards of practice

– Certification/Credentialing

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Improving Safety

• Become a Highly Reliable Organization (HRO)– Identification of threats to safety, even if no errors

– Workers always report any deviation from expected.

– Recognize errors quickly and contain them

• Implement a Culture of Safety– “Just Culture” (behaviors, not outcomes), reporting & learning

• Create a medication safety infrastructure– Medication Safety Officer, Committee,

– Proactive assessment process; CQI process

• Address multiple steps with higher leverage strategies.

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Error‐Reduction Strategies

Strategy

– Fail‐safes and Constraints– Forcing Functions– Automation & computerization

– Standardize & simplify– Segregate & differentiate– Redundancies (double checks)– Reminders and checklists

– Rules and policies– Education and information– “Be more vigilant”

Power (Leverage)

– High

– Medium

– Low

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A Word about Automation• Automation holds great promise for error reduction but has generally failed to realize its full potential.– Irrelevant or outdated databases

– Ineffective decision support; alert fatigue

– Software companies unwilling to make changes based on patient safety.

– Software not written based on human factors• Leads to dangerous workarounds

– Lack of effective or error‐prone back‐up systems

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Be Ahead of the Curve!

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Questions?

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