Baker Slides

USP <797> USP <797> Pharmaceutical Pharmaceutical

Compounding-Sterile Compounding-Sterile PreparationsPreparations

Mary Baker, Pharm.D., MBAMary Baker, Pharm.D., MBA

August 15, 2007August 15, 2007

United States Pharmacopeia United States Pharmacopeia (USP)(USP)

Volunteers with extensive science expertise from Volunteers with extensive science expertise from clinical practice, academia, and industryclinical practice, academia, and industry

Standards for medications, health care Standards for medications, health care technologies and related practicestechnologies and related practices

Chapters >1000 are informational; <1000 are Chapters >1000 are informational; <1000 are enforceable; undergo continuous revisionenforceable; undergo continuous revision

Basis for Joint Commission and state pharmacy Basis for Joint Commission and state pharmacy board inspectionsboard inspections

2005-10 USP SCC2005-10 USP SCC11

♦♦ Dr. Sam Augustine Dr. Sam Augustine ♦♦ Mr. Eric KastangoMr. Eric Kastango♦♦ Dr. Mary Baker Dr. Mary Baker ♦♦ Dr. Dave Newton Dr. Dave Newton22 ♦♦ Dr. Jim Cooper Dr. Jim Cooper ♦♦ Mr. Keith St. John Mr. Keith St. John♦♦ Dr. Don Filibeck Dr. Don Filibeck ♦♦ Dr. Laura Thoma Dr. Laura Thoma ♦♦ Mr. Larry Griffin Mr. Larry Griffin ♦♦ Mr. Larry Trissel Mr. Larry Trissel33

♦♦ Mr. Ken Hughes Mr. Ken Hughes ♦♦ Mr. Jim WagnerMr. Jim Wagner--------------------------------------------------------------------------------------------------------------------------1 1 Dr. Claudia C. Okeke, Dr. Claudia C. Okeke, [email protected]@usp.org, is USP staff liaison to the SCC, is USP staff liaison to the SCC2 2 Chairman Chairman 33 Vice Chairman Vice Chairman

Why is USP <797> Needed?Why is USP <797> Needed?

Deaths in the 60s and 70s due to Deaths in the 60s and 70s due to contaminated injectablescontaminated injectables

Series of ASHP recommendations in the Series of ASHP recommendations in the 80s and 90s did not impact practice80s and 90s did not impact practice CostCost Perceived lack of value; ‘not a problem here’Perceived lack of value; ‘not a problem here’

Injury and death due to contamination Injury and death due to contamination continuescontinues Publicized on television and in newspapersPublicized on television and in newspapers

<797> is not just about<797> is not just about non-sterilitynon-sterility

<797> very concerned with <797> very concerned with correctcorrect identities identities and amounts of ingredientsand amounts of ingredients, e.g.,, e.g.,

♦ ♦ Deaths of 3 premature babies in 1990 in Philadelphia from Deaths of 3 premature babies in 1990 in Philadelphia from KCl that should not have been in their IVs KCl that should not have been in their IVs ((NY TimesNY Times, Section 1, , Section 1, p. 22, June 24, 1990)p. 22, June 24, 1990)

♦ ♦ Death of baby after year 2001 from sterile IV CaHPODeath of baby after year 2001 from sterile IV CaHPO44 precipitate precipitate ((DWN DWN consulted)consulted)

♦ ♦ Death of 2 yr old girl in 2006 from sterile 23.4% instead of Death of 2 yr old girl in 2006 from sterile 23.4% instead of 0.9% NaCl inj.0.9% NaCl inj. ((The Plain DealerThe Plain Dealer, Nov.15, 2006; a Cleveland, OH newspaper) , Nov.15, 2006; a Cleveland, OH newspaper)

♦ ♦ Deaths of 3 patients in Portland, OR and Yakima, WA in Deaths of 3 patients in Portland, OR and Yakima, WA in 2007 from 10 X colchicine inj. after weighing error at 2007 from 10 X colchicine inj. after weighing error at compounding pharmacy in Texas compounding pharmacy in Texas (Sarah Skidmore, AP 4-27-2007) (Sarah Skidmore, AP 4-27-2007)

♦ ♦ Deaths from mix-ups of heparin and insulin Deaths from mix-ups of heparin and insulin (ISMP Med. Safety (ISMP Med. Safety Alert 5-3-2007 Vol. 12, Issue 9) Alert 5-3-2007 Vol. 12, Issue 9)

<797> Public Information Summary –1<797> Public Information Summary –1((from USP Staff Officers, June 23, 2007)from USP Staff Officers, June 23, 2007)

♦♦ SCC meeting q 2 wks by phone since March, SCC meeting q 2 wks by phone since March,

2007 2007

♦♦ Revision nearly complete based on thorough Revision nearly complete based on thorough review and consideration of more than 500 review and consideration of more than 500 comments during May-August, 2006 regarding comments during May-August, 2006 regarding [In-Process] proposed revision.[In-Process] proposed revision.

♦♦ SCC aware of delicate balance of practicality SCC aware of delicate balance of practicality issues to compounding practitioners and issues to compounding practitioners and protecting public healthprotecting public health

<797> Public Information Summary –2<797> Public Information Summary –2

♦♦ A 2007A 2007 Roundtable meeting on compounding aseptic Roundtable meeting on compounding aseptic isolators, CAIs, at USP, isolator vendors, experts, and isolators, CAIs, at USP, isolator vendors, experts, and FDA and NIOSH representatives helped SCC better FDA and NIOSH representatives helped SCC better understand the understand the design, performance, and other aspects design, performance, and other aspects of the effective use of CAIs for preparing CSPs.of the effective use of CAIs for preparing CSPs.

♦♦ Several sections completed and approved by Several sections completed and approved by SCC are undergoing editorial review at USP SCC are undergoing editorial review at USP scheduled for scheduled for USP 31-NF 26USP 31-NF 26 in November 2007. in November 2007. Plan to post on Plan to post on www.usp.orgwww.usp.org this summer when this summer when finalized.finalized.


♦♦ Disinfectants and Cleaning, and Environmental Disinfectants and Cleaning, and Environmental Monitoring sections currently in progress, as are Monitoring sections currently in progress, as are two appendices – hope to include these in two appendices – hope to include these in Supplement 1Supplement 1 of of USP 31-NF 26USP 31-NF 26, and post on , and post on website. website.

♦♦ Two external expert advisory panels reported to Two external expert advisory panels reported to SCC on radiopharmaceuticals, and disinfectants SCC on radiopharmaceuticals, and disinfectants and cleaning.and cleaning.


♦♦ When revised chapter is posted on When revised chapter is posted on www.usp.orgwww.usp.org USP plans a USP plans a major educational and major educational and communications effort to help healthcare communications effort to help healthcare professionals and organizations understand and professionals and organizations understand and implement the new responsibilities, implement the new responsibilities, requirements, and standards associated with requirements, and standards associated with sterile compounding.sterile compounding.

Manuscript Reviewers’ CommentsManuscript Reviewers’ Comments

May 2006

May 2006 – Jan. 2007

20 pp & 12 authors

>1000 pp & ~ 500 [com/tor]mentors

Sterile vs Nonsterile Sterile vs Nonsterile CompoundingCompounding

Sterile compounding requiresSterile compounding requires Cleaner facilitiesCleaner facilities Specific personnel training and testing in Specific personnel training and testing in

aseptic techniqueaseptic technique Air quality standardsAir quality standards Knowledge of solutions sterilization and Knowledge of solutions sterilization and

stabilitystability

Main Sections of <797>Main Sections of <797>

Risk levelsRisk levels Automated compounders for TPNAutomated compounders for TPN EquipmentEquipment Verification of compounding accuracy and Verification of compounding accuracy and

sterilizationsterilization

Main Sections of <797> Main Sections of <797> (continued)(continued)

Personnel responsibilities and trainingPersonnel responsibilities and training Environmental qualityEnvironmental quality StorageStorage Finished product checksFinished product checks Beyond-use datingBeyond-use dating

Risk LevelsRisk Levels

Low, Medium and HighLow, Medium and High Probability of contaminating a product with Probability of contaminating a product with

microbes, chemicals or other mattermicrobes, chemicals or other matter People are a major source of People are a major source of

contaminationcontamination Applies to final mixed or filled productApplies to final mixed or filled product Pharmacist responsible for determining Pharmacist responsible for determining

risk level at his/her institutionrisk level at his/her institution

Dressing ProperlyDressing Properly

Shoe coversShoe covers Head and facial hair coversHead and facial hair covers Face masksFace masks Sterile glovesSterile gloves Non-shedding gownsNon-shedding gowns No makeupNo makeup No long fingernails or artificial nails No long fingernails or artificial nails

Employee hand hygiene and garbingEmployee hand hygiene and garbing

Hair netHair net Beard cover and face Beard cover and face

maskmask GownGown GlovesGloves Shoe coversShoe covers

Personnel Cleansing and Garbing Personnel Cleansing and Garbing

Clarify garbing process by emphasizing the Clarify garbing process by emphasizing the “dirtiest to cleanest” order“dirtiest to cleanest” order

Discussion of personal garments, cosmetics, Discussion of personal garments, cosmetics, jewelry, fingernails (natural and artificial)jewelry, fingernails (natural and artificial)

Don garb that covers non-hand areas first, Don garb that covers non-hand areas first, followed by proper hand hygiene, then donning followed by proper hand hygiene, then donning gowns and sterile glovesgowns and sterile gloves

Frequent disinfection of sterile gloves with 70% Frequent disinfection of sterile gloves with 70% IPAIPA

Evidence-based scienceEvidence-based science An Intervention to Decrease Catheter-Related Bloodstream Infections An Intervention to Decrease Catheter-Related Bloodstream Infections

in the ICU. N Engl J Med 2006;355:2725-32. in the ICU. N Engl J Med 2006;355:2725-32. An evidence-based intervention resulted in a large and sustained An evidence-based intervention resulted in a large and sustained

reduction (up to 66%) in rates of catheter-related bloodstream reduction (up to 66%) in rates of catheter-related bloodstream infection that was maintained throughout the 18-month study infection that was maintained throughout the 18-month study period.period.

The average infection rate fell from 7.7 percent to 1.4 percent after The average infection rate fell from 7.7 percent to 1.4 percent after 18 months. 'More than half the hospitals (103) in this study were 18 months. 'More than half the hospitals (103) in this study were able to report that they had able to report that they had ZEROZERO infections after implementing infections after implementing the program,'the program,'

Consistent and vigilant work practices were key factor:Consistent and vigilant work practices were key factor: Assuring that participants wash their hands before the Assuring that participants wash their hands before the

procedure.procedure. Assuring full barrier protection -- a sterile bed sheet rather than Assuring full barrier protection -- a sterile bed sheet rather than

just keeping the insertion site sterile, just keeping the insertion site sterile, Staff wear sterile gloves, gowns, hats and masksStaff wear sterile gloves, gowns, hats and masks.. Cleansing the skin surfaceCleansing the skin surface with chlorhexidine.with chlorhexidine.

Compounding PersonnelCompounding Personnel

A human person in a cleanroom is considered a broad A human person in a cleanroom is considered a broad spectrum particle generator enclosed by inefficient spectrum particle generator enclosed by inefficient mechanical filters which may also be sources of particlesmechanical filters which may also be sources of particles

The human body harbors an average of 150-200 different The human body harbors an average of 150-200 different classes of bacteriaclasses of bacteria

Hands have an average of 100,000 organisms / sq mmHands have an average of 100,000 organisms / sq mm The body sheds 5 grams of skin fragments each day along The body sheds 5 grams of skin fragments each day along

with shedding 1 layer of skin every 5 days (size range 10 to with shedding 1 layer of skin every 5 days (size range 10 to 300 micron – 1000300 micron – 1000thth of a mm) of a mm)

““Our greatest asset and biggest liabilityOur greatest asset and biggest liability!”!”

““But I was just talking”But I was just talking”

* Photo courtesy of Francis P. Mitrano, MS, RPh, Director of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, November, 2005.

Hair and Jewelry DO Matter!Hair and Jewelry DO Matter!**

uncovered hair – head shake

* Blood agar cultures courtesy of Francis P. Mitrano, MS, RPh, Director of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, November, 2005.

covered hair at 1 hr – head shake

Low Risk LevelLow Risk Level

Aseptic manipulations entirely within ISO Aseptic manipulations entirely within ISO Class 5 (Class 100) or better air quality in Class 5 (Class 100) or better air quality in a ISO Class 8 (Class 100,000) cleanroom a ISO Class 8 (Class 100,000) cleanroom using only sterile ingredients, products, using only sterile ingredients, products, and devicesand devices

Transfer, measuring and mixing with Transfer, measuring and mixing with closed or sealed packaging systems that closed or sealed packaging systems that are performed promptlyare performed promptly

Low Risk Level (continued)Low Risk Level (continued)

Aseptically opening ampuls, penetrating Aseptically opening ampuls, penetrating sterile stoppers on vials with sterile sterile stoppers on vials with sterile needles and syringes and transferring needles and syringes and transferring sterile liquids in sterile syringes to sterile sterile liquids in sterile syringes to sterile administration devices and packages of administration devices and packages of other sterile productsother sterile products

Low Risk Level (continued)Low Risk Level (continued)

Storage-Unless documented by sterile Storage-Unless documented by sterile test, no more than: test, no more than: 48 hrs controlled room temperature48 hrs controlled room temperature 14 days cold (refrigerated)14 days cold (refrigerated) 45 days in a solid frozen state at –20 degrees 45 days in a solid frozen state at –20 degrees

C or belowC or below

Low Risk ExamplesLow Risk Examples

Compounding piggybacks or hydration Compounding piggybacks or hydration fluids in a ISO 5 laminar flow hood located fluids in a ISO 5 laminar flow hood located in an ISO 8 cleanroomin an ISO 8 cleanroom

Dual Chamber parenteral nutrition Dual Chamber parenteral nutrition container with no more than 3 additivescontainer with no more than 3 additives

Low Risk Quality Assurance Low Risk Quality Assurance ProceduresProcedures

Annual media fillAnnual media fill Appropriate personnel garbAppropriate personnel garb Visual inspectionVisual inspection Does not require chemical analysis or Does not require chemical analysis or

pyrogen testingpyrogen testing

Medium Risk=Low Risk Plus…Medium Risk=Low Risk Plus…

Multiple individual doses of sterile Multiple individual doses of sterile products are combined or pooled to products are combined or pooled to prepare a product that will be given to prepare a product that will be given to multiple patients or one patient multiple multiple patients or one patient multiple timestimes

Complex manipulationsComplex manipulations Long duration of the compounding processLong duration of the compounding process No bacteriostat and administered over No bacteriostat and administered over

several days (implantable pumps)several days (implantable pumps)

Medium Risk StorageMedium Risk Storage

Unless documented with sterility test, no Unless documented with sterility test, no more than:more than: 30 hours at controlled room temperature30 hours at controlled room temperature 7 days refrigerated7 days refrigerated 45 days in solid frozen state at –20 degreed C 45 days in solid frozen state at –20 degreed C

or colderor colder

Medium Risk ExamplesMedium Risk Examples

TPN using automated compounder where TPN using automated compounder where all ingredients are sterileall ingredients are sterile

Filling device reservoirs with multiple Filling device reservoirs with multiple sterile drug products and evacuating airsterile drug products and evacuating air

Batch preparation of syringesBatch preparation of syringes

Medium Risk Quality Assurance Medium Risk Quality Assurance ProceduresProcedures

More stringent media fillMore stringent media fill MD Anderson study (2002-2003)*MD Anderson study (2002-2003)*

Bare hands and nonsterile gloves with initial Bare hands and nonsterile gloves with initial disinfection with 70% isopropyl alcohol (IPA)disinfection with 70% isopropyl alcohol (IPA)

539 evaluations over a 2 year period539 evaluations over a 2 year period 5.2% yielded microbial growth5.2% yielded microbial growth Inadvertent touch contamination principal Inadvertent touch contamination principal

sourcesource

*Trissel LA et al *Trissel LA et al AJHP AJHP 2005: 62: 285-2882005: 62: 285-288

Medium Risk Quality Assurance Medium Risk Quality Assurance ProceduresProcedures

Follow up study MD Anderson Follow up study MD Anderson Group A-previous studyGroup A-previous study Group B-non-sterile chemo gloves with initial and Group B-non-sterile chemo gloves with initial and

repeated disinfection with IPArepeated disinfection with IPA Group C-sterile gloves with initial and repeated Group C-sterile gloves with initial and repeated

disinfection with IPAdisinfection with IPA Contamination rate: B=0.96%; C=0.34%Contamination rate: B=0.96%; C=0.34% Statistically significant differences between A Statistically significant differences between A

and B and A and Cand B and A and C Those who worked regularly in sterile Those who worked regularly in sterile

preparation had the worst recordpreparation had the worst record Trissel et al Trissel et al AJHP AJHP 2007; 64: 837-412007; 64: 837-41

High RiskHigh Risk

Nonsterile ingredients or devices used Nonsterile ingredients or devices used before sterilizationbefore sterilization

Air quality inferior to ISO Class 5Air quality inferior to ISO Class 5 Nonsterile exposure for 6 hrs before Nonsterile exposure for 6 hrs before

sterilizedsterilized Storage-no more than 24 hours controlled Storage-no more than 24 hours controlled

room temperature, 3 days refrigerated or room temperature, 3 days refrigerated or 45 days in solid frozen state at –20 deg C45 days in solid frozen state at –20 deg C

High Risk ExamplesHigh Risk Examples

Nonsterile bulk and nutrient powders that Nonsterile bulk and nutrient powders that will be sterilized (morphine, glutamine)will be sterilized (morphine, glutamine)

Sterile ingredients in nonsterile containersSterile ingredients in nonsterile containers Bladder irrigations made from bulk powderBladder irrigations made from bulk powder With low and medium risk, start out sterile With low and medium risk, start out sterile

and maintain sterility; with high risk a and maintain sterility; with high risk a nonsterile component needs to be made nonsterile component needs to be made sterile.sterile.

High Risk Quality Assurance High Risk Quality Assurance Procedures Procedures

Semi-annual media fill testingSemi-annual media fill testing Sterilization procedures must be validatedSterilization procedures must be validated

Beyond Use Dating Beyond Use Dating

Microbiologic as well as chemical dataMicrobiologic as well as chemical data BUD is shorter of the twoBUD is shorter of the two

Valid scientific dataValid scientific data Differs from the expiration date which Differs from the expiration date which

applies to manufactured drug productsapplies to manufactured drug products

Parenteral NutritionParenteral Nutrition

All compounders are medium riskAll compounders are medium risk Verifying accuracy of compoundersVerifying accuracy of compounders Calibration and weigh modeCalibration and weigh mode Maintenance and documentationMaintenance and documentation Cleaning!Cleaning!

OutsourcingOutsourcing

Another pharmacy prepares the admixtureAnother pharmacy prepares the admixture All compounding or certain preparationsAll compounding or certain preparations Waste, cost, expiration issueWaste, cost, expiration issue You are still responsible for the product You are still responsible for the product

given to the patientgiven to the patient Quality recordsQuality records

ProposedProposed Immediate Use CSPs

♦ ♦ Begin administration within 1 hour of Begin administration within 1 hour of compounding. ≤3 non-hazardous sterile compounding. ≤3 non-hazardous sterile productsproducts

♦ ♦ No direct contact contamination No direct contact contamination

♦ ♦ Exempt from <797> personnel and Exempt from <797> personnel and environmental standardsenvironmental standards

♦ ♦ Potentially great health hazard to patients Potentially great health hazard to patients if contaminated, esp. multi-dayif contaminated, esp. multi-day infusionsinfusions

Multi-Dose & Single-Dose VialsMulti-Dose & Single-Dose Vials

Definitions in the Definitions in the General Notices and Requirements General Notices and Requirements USP29—NF24 USP29—NF24

Emphasizes storage once opened or needle-punctured Emphasizes storage once opened or needle-punctured based on:based on: Air quality of the environmentAir quality of the environment Type of container involvedType of container involved

Multiple-dose container intended for multiple entries has Multiple-dose container intended for multiple entries has a 28 day beyond-use date from date and time of entry a 28 day beyond-use date from date and time of entry unless otherwise specified by the manufacturerunless otherwise specified by the manufacturer

Selection of 28 days based on the antimicrobial Selection of 28 days based on the antimicrobial preservative effectiveness test preservative effectiveness test General Chapter <51> General Chapter <51> Antimicrobial Preservative TestingAntimicrobial Preservative Testing

Multi-Dose & Single-Dose VialsMulti-Dose & Single-Dose Vials Opened or needle-punctured single-dose containers such Opened or needle-punctured single-dose containers such

as ampuls, bags, bottles, syringes, and vials of sterile as ampuls, bags, bottles, syringes, and vials of sterile products and CSPs shall be used in products and CSPs shall be used in ONE hourONE hour if opened in if opened in worse than ISO Class 5 air quality.worse than ISO Class 5 air quality.

Remaining content must be discarded.Remaining content must be discarded. Single-dose vials exposed to ISO Class 5 or cleaner air Single-dose vials exposed to ISO Class 5 or cleaner air

quality may be used up to quality may be used up to SIX hoursSIX hours after needle puncture. after needle puncture. Opened single-dose ampuls shall not be stored for anytime Opened single-dose ampuls shall not be stored for anytime

period.period. The concern is PATIENT RISK!The concern is PATIENT RISK! As early 1970, Michael Cohen of ISMP was raising the red As early 1970, Michael Cohen of ISMP was raising the red

flags on MDVs. flags on MDVs.

Calculated Microbial GrowthCalculated Microbial Growth

Review of the Media Selection and Incubation Review of the Media Selection and Incubation Conditions for the Compendial Sterility and Microbial Conditions for the Compendial Sterility and Microbial Limit TestsLimit Tests. . Anthony M. Cundell , Ph. D.,* USP Expert Anthony M. Cundell , Ph. D.,* USP Expert Committee on Analytical Microbiology. USP Pharmacopeial Committee on Analytical Microbiology. USP Pharmacopeial Forum 28(6) Stimuli to the Revision Process:Forum 28(6) Stimuli to the Revision Process:

Things to Take HomeThings to Take Home

USP <797> is more than building a new USP <797> is more than building a new facility. What can you do now vs several facility. What can you do now vs several years from now?years from now?

Training and documentation is keyTraining and documentation is key Leadership from pharmacists and Leadership from pharmacists and

technicians-don’t rely on one persontechnicians-don’t rely on one person Consistent work practices-nights, Consistent work practices-nights,

weekends and holidaysweekends and holidays Passing the ‘loved one’ testPassing the ‘loved one’ test

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