2008 ashp summer meeting seattle, washington educational … 797 update... · 2009. 9. 19. · 2008...

2008 ASHP Summer Meeting Seattle, Washington

Educational Session Abstracts

116 USP <797> Update 2008 and Personnel-Related Environmental Sampling Trissel, L.A. TriPharma Research, P.O. Box 265, Cashiers, NC 28717, USA. Email: [email protected] Kastango, E.S. Abstract: The United States Pharmacopeia (USP) has published revisions to USP Chapter <797>, the national quality standards for sterile compounding. The revised quality standards become the current standard as of June, 2008. This presentation provides an overview of the content of the USP Chapter <797> with a focus on the new and changed standards to aid practitioners in understanding and interpreting the needed quality assurance measures to protect patients from erroneous and contaminated sterile compounded preparations. Chapter <797> contains standards that begin with defining the responsibilities of compounding personnel. The Chapter also includes discussion and description of various quality assurance steps involving environmental control and monitoring, quality testing of compounded dosage forms, personnel aseptic technique evaluation, determination of product risk, storage and beyond use dating, topics for standard operating procedures, and more. The presentation will focus on these quality assurance components that need to be considered and addressed to safely provide compounded sterile products for use in patient care. Learning Objectives:

1. Outline recent revisions of USP Chapter <797> requirements. 2. Explain the rationale for many of the changed standards. 3. Explain the implications for pharmacists of changes in USP chapter

<797> standards. 4. Describe five principal new sections of USP Chapter <797> needed

to achieve USP chapter <797> compliance for compounding sterile preparations.

Self-Assessment Questions:

1. The revisions to the quality standards of USP Chapter <797> are few in number and minor in nature. a. True

© 2008 American Society of Health-System Pharmacists



b. False 2. Sterile drugs compounded according to the Immediate Use

category requirements: a. Allow home care pharmacies get around the quality

requirements of <797>. b. Are for use within 1 hour after the start of compounding. c. Eliminate the need for a laminar airflow hood or isolator for

compounding parenteral nutrition (TPN and TNA) admixtures. d. May not be stored overnight for use the next day after

compounding. e. Both b and d.

3. For hazardous drugs, such as cancer chemotherapy: a. Compounding must be performed in biological safety cabinets

or compounding aseptic containment isolators vented to the outside and located in a separate negative airflow ISO 7 buffer room.

b. Closed-system vial transfer devices provide a suitable substitute for biological safety cabinets and compounding aseptic containment isolators.

c. The requirements of <797> for hazardous drugs are to be followed no matter how few doses are compounded.

d. Personal protective garb is not needed if a biological safety cabinet is used.

4. USP Chapter <797> specifies the cleaning and disinfection frequencies of sterile compounding facilities. Which of these cleaning and disinfection frequencies is incorrect? a. Floors daily. b. Biological safety cabinets, laminar airflow workbenches, and

compounding aseptic isolators daily. c. Work counters daily. d. Walls and storage shelves monthly. e. Ceilings monthly.

5. For compounding aseptic isolators (CAIs), which of the following are correct? a. Placement in an ISO class 7 buffer room may be needed

depending on the CAI design and functionality. b. Personnel protective garb may be required unless the CAI

manufacturer has proven that the garb is unnecessary.




c. CAIs must be validated at the use site to maintain an ISO class 5 environment under dynamic (in-use) working conditions.

d. CAIs must maintain unidirectional airflow at the critical sites. e. All of the above

Answers: 1. b; 2. e; 3. a; 4. b; 5. e


USP Chapter <797>Update 2008

Lawrence A. TrisselResearch ConsultantTriPharma Research

Disclaimer“Although I am a member of the USP Sterile

Compounding Committee, I am speaking 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, ASHP or any other organization, nor should they be construed as an official explanation or interpretation of <797>.”


Changes and Clarifications in <797>

Introduction (Revised)Definitions section (new)Immediate-Use category (new)Low-Risk Level with 12 hour BUD (new)Single & multiple-dose containers (new)Proprietary vial/bag systems (new)Hazardous drugs (revised)


Radiopharmaceuticals (revised)Allergen Extract CSPs (new)Cleaning and disinfecting facilities (revised)Personnel cleansing and garbing (revised)Environmental controls (revised) Environmental sampling (revised)



Filter integrity testing for High Risk Level compounding (new)Microbiological BUD (revised)“Shall vs. Should” Table (new)Clarified language throughout

Key to Understanding <797>:

Read Chapter <797>!!


IntroductionComplete revision to be more explicitAcknowledges direct contact is the principal source of contamination in CSPs New robust Definitions section for over 2 dozen key termsAlternative technologies proven equivalent or superior to conventional work practices are OK797 applies to CSPs given via application, implantation, inhalation, injection, insertion, instillation, and irrigation

Responsibilities of Compounding Personnel in <797>

14 areas of responsibility are citedEmphasizes training and educationEmphasizes compounding accuracyEmphasizes avoiding contaminationEmphasizes patient safety


CSP Risk CategoriesImmediate Use CSPsLow-Risk LevelLow-Risk Level w/12 hour or less BUDMedium-Risk LevelHigh-Risk Level

Immediate-Use Category

Exempt from all requirements in <797>Only simple aseptic measuring and transfer are neededNMT 3 sterile non-hazardous drugsNo delays/interruptionsNo contact contamination of ingredients or critical sites


Immediate-Use CategoryDose must be labeled if not administered by the preparerAdministration must begin within 1 hour after the start of preparationDose must be discarded if administration has not begun within 1 hour after the start of preparation (No storing. No recycling.)

Immediate-Use CategorySome Examples:

At a patient’s bedsideIn an ambulanceIn an ERIn a Code situation


Low-Risk Level CSPs

Low-Risk Level remains largely unchangedCompounded from NMT 3 commercial sterile containers using commercial sterile devicesMaintained in ISO Class 5 environment in an ISO 7 buffer area at all timesOnly a few basic, closed-system, simple aseptic transfers and manipulations

Is Low-Risk Level Really Low Risk of Contamination?

Research study of 1035 tuberculin syringe media fills sealed with tip capsScrubbed, gowned and gloved Techs performed at the end of the dayUpon incubation, no growth was observedThis simplest of preparations does appear to be at a lower risk of contamination

Trissel LA, Ogundele AB, Ingram DS et al. Using a media fill simulation to establish a benchmark microbiological contamination rate for low risk level compounding. AJHP. 2003;60:1853-6.


Missing Research

Determination of the potential contamination rate of aseptic compounding of iv bags with two drug containers added.

Is this really a low risk of contamination?

Low-Risk Level w/12 hour BUD

New subsection for an ISO 5 device in an uncontrolled air environmentMust be in a segregated compounding area not in a high traffic areaAll personnel cleansing and garbing requirements applyNo Hazardous DrugsAdministration must begin within 12 hours or as stated in the package insert, whichever is less


Medium-Risk Level CSPs

Four or more sterile commercial drug containers Multiple pooled sterile commercial products for multiple patients or one patient multiple timesComplex aseptic manipulationsCompounding requires long duration

Is Medium-Risk Level really higher risk than Low-Risk Level?

Evaluated 2 years of media fill tests of aseptic technique – over 600 testsGowning and gloving not required10-step complicated preparation A trainer provided guidance as to proper techniqueContamination rate was found to be 5.2%!!!

Trissel LA, Gentempo JA, Anderson RW et al. Using a media fill simulation to evaluate the microbial contamination rate for USP medium risk level compounding.

AJHP. 2005;62:285-8.


Reducing the Contamination Rate by Changing Work Practices

Evaluated 2 more years of media fill tests of aseptic technique using the same 10-step preparation

Year 1- gowns and non-sterile gloves required with initial 70% IPA wiping – reduced to about 1% contamination

Year 2- Sterile gloves with repeated 70% IPA wiping of gloves – reduced to 0.3% contamination

Trissel LA, Gentempo JA, Saenz LM et al. Reducing the microbial contamination rate of pharmacy-compounded sterile preparations: Evaluation of two simple and inexpensive work practice changes. AJHP. 2007;64:837-41.

High-Risk Level CSPsPrepared from non-sterile ingredientsPreparation from sterile ingredients but exposed to less than ISO Class 5More than 6 hour delay from compounding to sterilizationPurity of components is assumed but not verified by documentationSterilization by filtration - the manufacturer’s recommended integrity test must be performed on the filter


Is High-Risk Level compounding really high risk?

Unfortunately, High-Risk Level compounding has led to repeated and numerous episodes with many injuries and deaths among patientsThe potential for mass casualties occurring makes this compounding much more riskyLow- and Medium-Risk Level compounding contamination typically impact fewer patients Failure to sterilize properly has been the principal problem in High-Risk Level compounding

Old Expired BUD Paradigm

Assume the compounded preparation is sterile

Base the BUD solely on the drug’s chemical stability


Chapter<797> BUD Paradigm

Recognize the possibility that the preparation was inadvertently contaminated during compounding

For patient safety, base the BUD on the drug’s chemical stability in conjunction with microbiological limits, whichever is shorter

Calculated Microbial GrowthCundell AM, USP Committee on Analytical Microbiology,

Pharmacopeial Forum 2002; 28 (6) Stimuli to the Revision Process

6.9 X 10924

1.7 X 10718

41,00012

6409

106

Microbial Count(CFU per mL)

Time (Hours)


<797> Microbiological BUDThere is an ever-present chance, indeed likelihood, that some CSPs will be inadvertently contaminatedTime and warm temperatures are the enemy, speeding the potential for growth of dangerous amounts of microbial contaminationGuidance for limits is needed to avoid unacceptable risks of harming patients

Microbiological Beyond-Use Dating

N/A1 hour1 hourImmediate Use

N/A12 hours or less

12 hours or less

Low w/12-hr BUD

45 days3 days24 hoursHigh

45 days9 days30 hoursMedium

45 days14 days48 hoursLow

Freezer(≤-10 °C)

RefrigeratorRoom TempRisk Category


Single/Multiple Dose VialsDefinitions of SDV and MDV are in the USP General Notices and RequirementsSingle dose vials – Opened or punctured in ISO 5 environment may be used for up to 6 hours. Opened or punctured in worse than ISO 5 must be used within 1 hour or discarded.Single dose ampuls must be discarded after opening and not stored for any time period

Single/Multiple Dose VialsMultiple dose vials – Contain antimicrobial preservative(s) Designed for entry on multiple occasions. BUD – 28 days after initial entry unless specified otherwise by the manufacturer.BUD of 28 days based on USP <51> Antimicrobial Preservative Testing


Proprietary Bag/Vial SystemsADD-Vantage; Add-a-Vial, Minibag Plus, etc.Follow the manufacturer’s instructions for handling and storing.These devices and their instructions have been approved by the FDA

Hazardous DrugsSection extensively revisedNIOSH Guidelines for guidanceBSC or CACI requiredHazardous drug storage and preparation in separate negative pressure ISO 7 with ISO 7 ante area


Hazardous DrugsPersonnel protection specifiedUse of closed-system transfer devices must be within BSC or CACIDisposal according to state and federal regulations

Allergen ExtractsIntradermal and subcutaneous MDVsand SDVs (No IV or IT)Unpreserved allergen extracts must fully comply with all aspects of <797>Allergen extracts are exempt from personnel, environment, and storage requirements only if all of the following criteria are met:


Allergen ExtractsPersonnel perform hand hygiene with alcohol-based surgical hand scrubHair and beard covers, gown, face mask, and sterile gloves are usedCompounded by simple aseptic transferMust contain an effective amount of antimicrobial preservativeFor one patient only

Allergen ExtractsGloves are intermittently disinfected with sterile 70% IPA during preparationVial stoppers and ampul necks are disinfected with sterile 70% IPADirect contact contamination is avoidedAllergen extract is labeled with a specific patient name and BUD


Cleaning and Disinfecting Facilities

Based on Infection Control Advisory Committee recommendationsGoal: Reduce bioburden in compounding areas Use of disinfecting agent such as sterile 70% IPAPerformed in ISO 5 environment:1. At the beginning of each work shift2. At the beginning of each batch3. At least every 30 minutes 4. When surface contamination is known or suspected

Cleaning and Disinfecting Facilities

Cleaning should proceed from buffer area (cleanroom) to ante area Use suitable dedicated mops, etc. and disinfecting cleanersFloors, counters, work surfaces – at least dailyWalls, ceilings, shelving – at least monthly


Personnel Cleansing and Garbing

Remove outer garments and jewelry (including piercings above the neck)Garb order from dirtiest to cleanestDon shoe covers, hair covers, face masksPerform hand/arm hygiene Don disposable gowns


Cleanse hands and arms with alcohol-based surgical hand scrub with persistent activity After hands and arms are dry, don sterile powder-free gloves compatible with sterile 70% IPARepeatedly apply sterile 70% IPA to contact areas of gloves whenever nonsterile surfaces are touched (e.g., vials, counter tops, carts)


Direct Contact is the Most Likely Source of Contamination in CSPs


All of the cleansing, garbing and gloving requirements also apply to compounding in CAIs and CACIs.Exception: If the manufacturer of the CAI or CACI provides written documentation of statistically validated testing supporting any garbing component(s) that are not required.Do your “Due Diligence” to verify the accuracy of any such claim.


Environmental ControlsAimed at creating ISO 5, 7, and 8 environmentsISO 5 – LAFW, BSC, CAI, CACI are “Primary Engineering Controls”Must maintain ISO 5 during dynamic (in use) working conditionsUnidirectional airflow specified

Environmental Controls

ISO 7 buffer area and ISO 8 (or 7) ante area – are “Secondary engineering controls”Must maintain ISO 7 or 8 during dynamic (in use) working conditionsAirflow and balance testing required at the installation siteOnly personnel and materials essential for compounding and cleaning are permitted


Environmental ControlsISO 5 Primary engineering control (LAFW, BSC, CAI, CACI) to be in an ISO 7 environmentException: CAI if its design provides ISO 5 and isolation from the room during dynamic operating conditions as placed and tested at your site (including transferring materials in and out) using CETA testing requirementsDo your “Due Diligence” to verify the accuracy of any such claim

Missing Research

Paucity of independent research evaluations and comparisons of pharmacy applications of primary and secondary engineering controls.


Other Changes in <797>Radiopharmaceuticals quality assurance based on Radiopharmaceuticals Advisory Committee recommendationsSimplified environmental samplingExpanded explanatory and descriptive material in many sections“Should vs. Shall” table Clarified language throughout (We hope!)

Remember…

USP <797> is about much more than cleanrooms, hoods, and isolatorsThese “Magic Boxes” will NOT create a sterile preparationPoor work practices contaminate more CSPs than any other single cause


Remember…

Preparing CSPs safely is NOT“So easy a cave man can do it!!”

Specialized education and training, proper environments and work practices, and

repeated reassessment are all required to protect patients.

Remember…

YOU are the key ingredient


Thank You!


2008 ashp summer meeting seattle, washington educational … 797 update... · 2009. 9. 19. · 2008...

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