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Modified from the original presentation March 9, 2006

By Lawrence A. Trissel, B.S., R.Ph., FASHPSupported by an unrestricted educational grant from Hospira Worldwide, Inc.

Table of Contents

Products vs. Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

Shifting BUD Paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

Microbiological Limits and Risk . . . . . . . . . . . . . . . . . . . . . . . . . .3

Stability Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Professionalism in BUD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Continuing Education Assessment Questions . . . . . . . . . . . . . .6

This NHIA monograph is co-sponsored by theNational Community Pharmacists Association.NCPA is approved by the Accreditation Council for

Pharmacy Education as a provider of continuing pharmacyeducation. NCPA has assigned 1.0 contact hour (0.1 CEUs) ofcontinuing education credits to this monograph. Eligibility toreceive continuing education credits for this monographexpires January 15, 2010. The universal program number forthis program is 207-999-07-019-H01.

Continuing Education Objectives After reading this monograph, the participant should be able to:• Interpret and discuss the scope and intent of USP Chapter<797> the U.S. standard for pharmacy sterile compounding.

• Describe the various risk levels indicated in USP Chapter<797> for differing compounded sterile preparations, and theimpact these have on beyond use dating (BUD).

• Discuss the factors that must be considered in establishing asafe beyond use date for various types of compounded sterilepreparations.

USP Chapter <797>The United States Pharmacopeia (USP) General Chapter <797>“Pharmaceutical Compounding—Sterile Preparations” was pub-lished in the fall of 2003 and went into effect on January 1, 2004.The chapter has had a tremendous impact on home infusionpharmacy operations and will continue to do so as it evolves.*Indeed, USP <797> is the U.S. standard for pre-administra-

tion manipulations of compounded sterile preparations,including compounding, transportation, and storage. Theguidelines apply to all compounding personnel without dis-tinction as to site or profession—all patients deserve to be pro-tected from errors and contamination.Chapter <797> was created through the collective work of

the USP Sterile Compounding Expert Committee, which ismade up of:• Pharmacists in academia• Pharmacists from hospital practice• Pharmacists from retail sterile practice• Pharmacists from government

The experts on the committee did not participate in order topromote the business of compounding pharmacies or the pro-fession of pharmacy, nor did they wish to apply good manufac-turing processes (GMPs) to compounding pharmacy or to find alowest common denominator by which the profession couldoperate. Instead, the experts, guided by USP, were foremostinterested in patient safety—reducing the number of injuries anddeaths from compounding, regardless of the site of practice. The guidelines that resulted from their work are designed to

describe current sterile compounding best practices and tohelp bring lagging pharmacies—and others—up to speed withcurrent best practices.

Products vs. PreparationsThere is a clear, differentiation between drug products that aremanufactured by pharmaceutical companies for widespread useand sterile preparations that are compounded by pharmacists,technicians, physicians, and nurses for small-scale, individualizedadministration. As such, the dating requirements and languageapplied to each differs. For example, in order to avoid confusioncaused by using language with regulatory meaning, USP adoptedits own language for Chapter <797>, which includes “compoundedpreparations” rather than “products.”

2

* USP released a draft revision of General Chapter <797> in May2006 with an associated comment period. A final revision, whichwill take comments into consideration, is expected to go intoeffect sometime in 2007.

USP Chapter <797>: Beyond Use Dating, Stability, and Storage

“Products,” manufactured by drugcompanies under federal standards—FDA good manufacturing practices(GMPs)—carry expiration dates. Expira-tion dates are determined by multiple,scientifically valid, product- and pack-age-specific research studies. They arebased on the Arrhenius Equation withstatistical analysis and approved by theFDA. Expiration dates are very strict,specific, and proven to be valid.Alternatively, “compounded prepara-

tions,” compounded by pharmacy per-sonnel, carry beyond use dates (BUD).BUD is the date or time beyond whichthe drug should not be used and isassigned by the compounding person-nel. A BUD can deviate from the officiallabeling (package insert) of one or moreof the preparation’s ingredients. How-ever, that deviation should be based ondrug-specific, scientifically validresearch studies when possible. Whenspecific information is not available,compounding personnel may use moregeneral guidelines.

Shifting BUD ParadigmsUSP Chapter <797> and its subsequentrevision(s) reflect a shifting BUD para-digm that puts an increased emphasis onpatient safety and protection from conta-mination. In the past, compounding personnel

worked under the assumption that thecompounded preparation was sterile.BUD was based solely on the chemicalstability of the drug. This dating methodis simple, but not necessarily safe, giventhat the drug and/or other ingredientsare not always sterile—they may becontaminated with microorganisms. Inaddition, this mindset fails to recognizethe possibility that the preparation wasinadvertently contaminated duringcompounding. Practitioners mustembrace the mindset that if you’re mix-ing preparations all day, some of those

batches may have bugs in them and youdon’t know which ones.The new BUD paradigm accepts this

precept and bases BUD on the drug’schemical stability in conjunction withmicrobiological limits for increasedpatient safety. For non-sterile prepara-tions, BUD is based on chemical stabilityof the drug in the formulation andpackaging at specific storage condi-tions. For sterile preparations, BUD isbased on: 1.) chemical stability in con-junction with, 2.) microbiological lim-its—whichever is shorter.The addition of microbiological limits

is designed to protect patients from dan-gerous, or even fatal, overgrowths ofmicroorganisms that may have beenaccidentally introduced. These limits varyin duration by the likelihood, or risk level.They are applied whenever an actualsterility test in accordance with USPChapter <797> has not been performed.

Microbiological Limitsand RiskUSP designated risk levels for com-pounded preparations because differentsterile preparations represent differentamounts of risk and because pharmacistsand other compounding personnel havenot always recognized these differences. Ultimately, improved patient safety

requires a change of mindset—we oweit to our patients and ourselves toadopt a different way of thinking aboutrisk. Not only is there a risk of com-pounded preparations being contami-nated, there are associated risks to thepatient’s health, risks to the com-pounder’s career and financial well-being, and risks to our profession andour compounding privilege.

Generally, complexity in compound-ing can lead to contamination. Withthis in mind, USP designated three risklevels for compounded sterile prepara-tions (CSPs). Following is a briefoverview of each: • LLooww--RRiisskk.. Compounded from sterile,commercial drugs using commercialsterile devices. Maintained in an ISOClass 5 environment at all times.Compounded using only a few basic,closed-system aseptic transfers andmanipulations.

• MMeeddiiuumm--RRiisskk.. Multiple pooled, ster-ile, commercial products com-pounded for multiple patients or onepatient multiple times. Complexaseptic manipulations where thecompounding covers a long dura-tion. No bacteriostat is used and thepreparation is administered over sev-eral days.

• HHiigghh--RRiisskk.. Prepared from non-sterileingredients, or from sterile ingredi-ents but exposed to less than ISOClass 5 environment. Involving adelay of more than six hours fromcompounding to sterilization. Purityof components is assumed but notverified by documentation.

It is the responsibility of the com-pounder to determine the risk level foreach preparation. With the exception ofa preparation made from non-sterileraw materials, which is always a High-Risk preparation, USP’s general descrip-tive statements (above) are designed toaid compounding personnel in theirdecision-making. There is no iron-cladway of making this determination—itrequires professional judgment andmust consider a variety of factors. For

Determining Beyond Use Date (BUD)An appropriate beyond use date (BUD) takes into consideration:• Microbiological limits based on risk level • Chemical stability limits from literature or testing• USP Chapter <797> guidance for other cases

USP Chapter <797>: Beyond Use Dating, Stability, and Storage 3

example, diphenhydramine 10 mg/0.2mL drawn into tuberculin syringes forpediatric IM administration would beconsidered a Low-Risk preparation.However, if the compounder werepreparing 1,000 doses, then it would beconsidered a Medium-Risk preparation. See the case studies on this page to

work through more exercises on deter-mining risk levels for specific medica-tions under specific conditions.

Stability ConsiderationsDrugs and CSPs are subject to chemicaland physical instabilities, which must alsobe considered when assigning a BUD. Chemical processes, such as hydroly-

sis, oxidation, reduction, and racemiza-tion are occurring all the time. CSPs arealso affected by physical factors, includ-ing temperature, exposure to light andoxygen, varying formulation compo-nents, water content, pH, containersand closures, and more. The result canbe a preparation that is hazy or turbid,contains precipitation, color changes, orgas formation. See Exhibit 1 for more onhow temperature affects BUD.Since it is so difficult for pharmacists

alone to judge drug stability, the new,patient safety-oriented paradigm sug-gests that they apply the “iceberg rule”of chemical stability. Only 10 percent ofan iceberg is visible above the surfaceof the water, leaving 90 percent unde-tected until it is often too late. Whenconsidering chemical stability, pharma-cists should assume that they won’tknow about 90 percent of the problemsassociated with any mixture.There are a variety of sources for sta-

bility information that can aid in thedecision-making process. Using exter-nal, documented sources allows forprofessional judgment while providingsound footing in the event that thecompounder’s decision is called intoquestion. Pharmacists can consider the

Case StudiesMicrobiological Limits and RiskDetermine the risk level (low, medium, or high) for each compounded sterilepreparation using the stability information provided. Answers and explanationsare listed below.

1. Cefazolin 1 g admixed into 50 mL of 0.9% Sodium Chloride for IV useSSttaabbiilliittyy iinnffoorrmmaattiioonn:: 7% loss in 5 days at RT5% loss in 24 days at 4º C

2. TPN with AA 4.5%, dextrose 22%, 4 electrolytes, multiple vitamins, trace ele-ments, insulin, ranitidine. SSttaabbiilliittyy iinnffoorrmmaattiioonn:: No stability data on this specific formulation butother data allows for extrapolation of 15-30 days refrigerated

3. Morphine 50 mg/mL + Bupivacaine 10 mg/mL in NS for use in a SynchroMed®pump (18 mL) for IT use. Prepare 40 mL and package in two 20-mL syringes.Ship to physician’s office for instillation.SSttaabbiilliittyy IInnffoorrmmaattiioonn:: No loss of either drug in 60 days at RT or 4º C

4. Alprostadil 12.5 mcg/mL, Papaverine HCl 4.5 mg/mL, Phentolamine mesylate0.125 mg/mL for intracavernosal injection.SSttaabbiilliittyy IInnffoorrmmaattiioonn:: 8% loss in 5 days at RT6% loss in 30 days at 4º C

Answers:1. LLooww RRiisskk LLeevveell - 48 hours at room temperature and 14 days refrigerated, perUSP Microbiological limits

2. MMeeddiiuumm RRiisskk LLeevveell - 36 hours at room temperature and 7 days refrigerated.3. HHiigghh RRiisskk LLeevveell - Must be prepared from non-sterile powder; 24 hours at roomtemperature and 3 days refrigerated, per USP Microbiological limits.

4. Risk Level determined by preparation techniques – see below: • If a single vial is prepared from commercial sterile vials: LLooww RRiisskk LLeevveell- 48 hours at room temperature and 14 days refrigerated.

• If prepared in a large batch of vials using commercial sterile drugs:MMeeddiiuumm RRiisskk LLeevveell - 36 hours at room temperature and 7 days refrig-erated.

• If prepared from non-sterile powders: HHiigghh RRiisskk LLeevveell - 24 hours atroom temperature and 3 days refrigerated.

USP Chapter <797>: Beyond Use Dating, Stability, and Storage

4

following stability sources:• Stability information from drug manu-facturers, including the package insert

• Stability information derived fromvalid testing of the specific preparationand container

• Relevant published stability informa-tion in original articles or reliable printcompilations and electronic databases

The above sources aside, it is oftenchallenging to locate appropriatechemical stability information. It is aslow and expensive process to collectadequate data and is not usually withinthe capability of most pharmacists,nurses, and physicians. USP recognizesthis and provides an alternative methodfor determining BUD in the absence ofspecific stability information: followingthe guidelines of USP Chapter <795>.For example, USP <795> guidelines

recommend that for solids and non-aqueous liquids, the BUD should be 25percent of the remaining expiration

period or six months. For USP bulk sub-stances, the BUD should not be morethan six days, and for aqueous formula-tions, 14 days refrigerated. For all oth-ers, not more than 30 days or theintended duration of therapy. Whenyou can’t find any other standard,benchmark your activity as you go.

Professionalism in BUDIt should go without saying that it isunacceptable to subject patients toincreased risk of harm for convenience orprofit. But as professionals we must gobeyond ill intent and take the steps nec-essary to reduce risk to the patientthrough inadvertent actions. That is why all standard operating

procedures should include specific BUDguidelines. Compounding personnelmust also recognize that accuracy andconsistency are critical in theirprocesses, as is proper documentation—we all know the saying, “If it isn’t writ-ten, it didn’t happen.”

About the AuthorLawrence Trissel, B.S., R.Ph., FASHP, hasmore than 30 years experience in drugresearch with approximately 150 originalpublications to his credit—mostly in thearea of drug stability. He serves as theVice Chair of the USP Sterile Compound-ing Expert Committee, and along withother committee members is a principalauthor of the USP Chapter <797>Beyond Use Dating requirements.Trissel is best known as the author of

the Handbook on Injectable Drugs, acore pharmacy reference work found innearly every hospital and home carepharmacy in the United States—andmost of the rest of the world. Firstappearing in 1977, this work has beenin continuous publication for nearly 30years. In addition to the Handbook,Trissel has written the Pocket Guide toInjectable Drugs, Trissel’s Stability ofCompounded Formulations, Trissel’sTables of Physical Compatibility, and for10 years wrote the National CancerInstitute’s Investigational Drug - Phar-maceutical Data Book. He recentlyauthored the new book Trissel’s Calciumand Phosphate Compatibility in Par-enteral Nutrition. Much of his publishedworks are now collected in electronicformat in Trissel’s 2 Clinical Pharmaceu-tics Database.Trissel has served as a consultant to

several pharmaceutical companies andthe FDA on sterile drug product design,formulation and clinical use and servedon the Pharmacy Professional AdvisoryCommittee to the Surgeon General ofthe United States. He has been therecipient of a number of awards andhonors throughout his career, includingthe APhA Distinguished AchievementAward in 2002 and the Award for Sus-tained Contributions to the PublishedLiterature from ASHP in 1996.

Exhibit 1Beyond Use Dating and TemperatureRisk Level Room Temperature Refrigerator Freezer (< -20º C)Low 48 hours 14 days 45 days Medium 30 hours 7 days 45 days High 24 hours 3 days 45 days

Source: USP

Recommended ReadingUnited States Pharmacopeia, Inc. U.S.Pharmacopeia 27. Chapter <797>: Phar-maceutical Compounding - Sterile Prepa-rations. Rockville, MD: United StatesPharmacopeial Convention. 2004;2461-77.

American Society of Health-System Phar-macists. ASHP guidelines on qualityassurance for pharmacy-prepared sterileproducts. Am J Health-Syst Pharm. 2000;57:1150-69

Trissel LA. Handbook on Injectable Drugs.14th ed. Bethesda, MD: American Societyof Health-System Pharmacists; 2006.

Bing CM. Extended Stability for ParenteralDrugs. 3rd ed. Bethesda, MD: American Soci-ety of Health-System Pharmacists; 2005.

Kastango E. USP chapter <797>: The nextphase. Infusion. 2006. 12(4):25-9.

Bickley S. USP compliance: A journey.Infusion. 2006. 12(5):32-6.

USP Chapter <797>: Beyond Use Dating, Stability, and Storage 5

JANUARY 15, 2007Expires JANUARY 15, 2010

Copyright © 2007 NHIA

1. The intent of USP Chapter <797> is to make surethat all compounding pharmacies apply good man-ufacturing processes (GMPs). a. True b. False

2. Which of the following is NOT considered one of thesteps in the pre-administration manipulations ofcompounded sterile preparations (CSPs)? a. Compounding b. Storagec. Length of infusion

3. The U.S. Food and Drug Administration (FDA) deter-mines the beyond use dates (BUD) for compoundedsterile preparations. a. True b. False

4. A CSP that is compounded from multiple pooledsterile commercial products for use by multiplepatients is considered to be:a. low-risk b. medium-risk c. high-risk

5. The determination of USP risk-level is the responsi-bility of the licensed health care professionals whosupervise compounding. a. True b. False

6. A CSP that is compounded from non-sterile ingredi-ents is always a high-risk preparation a. Trueb. False

7. Drawing a drug up into a syringe for IM administra-tion would always be considered a low-risk prepara-tion a. True b. False

8. When considering beyond use dating (BUD) for aCSP which of the following sources of informationshould be considered a. Chemical stability information b. Risk-level of the CSP c. Time and temperature at which the preparation is

stored and used d. All of the above

9. USP Chapter <795>, Pharmaceutical Compound-ing—Nonsterile Preparations, provides guidance ondetermining chemical stability when specific pub-lished information is not available a. True b. False

10. Microbiological beyond-use dating (BUD) recom-mendations published in USP Chapter <797> applyonly to preparations that are not tested for sterility a. Trueb. False

Continuing Education Assessment Questions

JANUARY 15, 2007Expires JANUARY 15, 2010

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This monograph is co-sponsored by the National CommunityPharmacist Association. NCPA is approved by the AccreditationCouncil for Pharmacy Education as a provider of continuingpharmacy education. NCPA has assigned 1.0 contact hours (0.1

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This publication is a supplement to INFUSION (ISSN 1080-3858), the bimonthly journal of the National Home InfusionAssociation, 100 Daingerfield Rd., Alexandria, VA 22314 (703-549-3740). Originally published in January/February2007 (Vol. 13, Number 1). Copyright 2007 by NHIA.