Compounding Sterile Preparations [4 ed.] 158528484X, 9781585284849

Citation preview

Compounding Sterile Preparations E. Clyde Buchanan, RPh, MS, FASHP Senior Director of Pharmacy (Ret.) Emory Healthcare Atlanta, Georgia

Philip J. Schneider, MS, FASHP, FFIP, FASPEN Professor and Associate Dean for Academic & Professional Affairs University of Arizona College of Pharmacy Phoenix Biomedical Campus Phoenix, Arizona

Ryan A. Forrey, PharmD, MS, FASHP Senior Manager, Market Development for Hazardous Drug Safety Becton, Dickinson and Company Franklin Lakes, New Jersey

Any correspondence regarding this publication should be sent to the publisher, American Society of Health-System Pharmacists, 4500 East-West Highway, Suite 900, Bethesda, MD 20814, attention: Special Publishing. The information presented herein reflects the opinions of the contributors and advisors. It should not be interpreted as an official policy of ASHP or as an endorsement of any product. The authors would like to acknowledge the contributions of The U.S. Pharmacopeial Convention (USP), including allowing the generous references throughout this book to the United States Pharmacopeia and the National Formulary (USP–NF). At the time of publishing, USP 39–NF 34 (2016) is the current version of the USP–NF; however, references herein have also been made to USP 32–NF 27 (2009), USP 36–NF 31 (2013), and USP 39–NF 34 First Supplement (2016) as indicated in the copyright notice for each USP–NF excerpt. The presentation and interpretation of USP–NF provided by the authors do not necessarily reflect the views of USP or the requirements of USP–NF, and readers should be aware that all of USP’s standards are subject to revision. Because of ongoing research and improvements in technology, the information and its applications contained in this text are constantly evolving and are subject to the professional judgment and interpretation of the practitioner due to the uniqueness of a clinical situation. The editors and ASHP have made reasonable efforts to ensure the accuracy and appropriateness of the information presented in this document. However, any user of this information is advised that the editors and ASHP are not responsible for the continued currency of the information, for any errors or omissions, and/or for any consequences arising from the use of the information in the document in any and all practice settings. Any reader of this document is cautioned that ASHP makes no representation, guarantee, or warranty, express or implied, as to the accuracy and appropriateness of the information contained in this document and specifically disclaims any liability to any party for the accuracy and/or completeness of the material or for any damages arising out of the use or non-use of any of the information contained in this document. Editorial Project Manager, Books and eLearning Courses: Ruth Bloom Editorial Project Manager, Publications Production Center: Kristin Eckles Cover and Page Design: David Wade Composition: Carol Barrer Library of Congress Cataloging-in-Publication Data Names: Buchanan, E. Clyde, editor. | Schneider, Philip J., editor. | Forrey, Ryan A., editor. | American Society of Health-System Pharmacists, issuing body. Title: Compounding sterile preparations / [edited by] E. Clyde Buchanan, Philip J. Schneider, Ryan A. Forrey. Description: Fourth edition. | Bethesda, MD : American Society of Health-System Pharmacists, [2017] | Includes bibliographical references and index. Identifiers: LCCN 2017001193 | ISBN 9781585284849 Subjects: | MESH: Technology, Pharmaceutical--standards | Drug Compounding--standards | Sterilization--standards | Drug Contamination--prevention & control Classification: LCC RS199.S73 | NLM QV 778 | DDC 615/.19--dc23 LC record available at https://lccn.loc.gov/2017001193. © 2018, American Society of Health-System Pharmacists, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without written permission from the American Society of Health-System Pharmacists. ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S. Patent and Trademark Office. ISBN: 978-1-58528-484-9 First printing: October 2017 10 9 8 7 6 5 4 3 2 1

This edition is dedicated to the victims of the fungal meningitis outbreak of 2012, who serve as an enduring reminder of the consequences of poor compounding practice. E. Clyde Buchanan Philip J. Schneider Ryan A. Forrey

Table of Contents

Acknowledgments.............................................................................................................................ix Preface................................................................................................................................................xi Contributors ..................................................................................................................................... xiii Reviewer............................................................................................................................................ xv Part I STERILE PREPARATION 1 Imperative for Change: Adverse Sterile Compounding Events.............................................. 1 Philip J. Schneider, MS, FASHP, FFIP, FASPEN

2 Standards for Compounded Sterile Preparations.................................................................... 7 E. Clyde Buchanan, RPh, MS, FASHP

3 Immediate-Use Compounding................................................................................................ 35 Jeannell M. Mansur, PharmD, RPh, FASHP

4 Sterile Preparation Formulation................................................................................................ 51 Mark G. Klang, RPh, MS, BCNSP, PhD

5 Parenteral Nutrition Compounding......................................................................................... 67 Todd W. Canada, PharmD, BCNSP, BCCCP, FASHP, FTSHP

6 Special Considerations in Pediatric Compounding............................................................... 81 Kathleen M. Gura, PharmD, BCNSP, FASHP, FPPAG, FASPEN

7 Special Considerations in Compounding Biologicals.......................................................... 113 Susan Spivey, PharmD; Kelley Reece, PharmD; and Ryan K. Roux, PharmD, MS, RPh, FASHP

8 Ancillary Equipment and Supplies......................................................................................... 121 Ryan A. Forrey, PharmD, MS, FASHP

9 Primary Engineering Controls.................................................................................................. 133 Richard C. Capps, PharmD

10 Personnel Cleansing and Garbing......................................................................................... 153 Richard B. Osteen, DPh

11 Aseptic Technique................................................................................................................... 161 Linda F. McElhiney, PharmD, MSP, RPh, FIACP, FASHP, FACA

12 Hazardous Drugs as Compounded Sterile Preparations..................................................... 171 Luci A. Power, RPh, MS and Joseph W. Coyne, BS Pharm, RPh

13 Radiopharmaceuticals as Compounded Sterile Preparations.......................................... 203 George H. Hinkle, RPh, MS, BCNP

v

 

vi 

Compounding Sterile Preparations

14 Storage and Beyond-Use Dating............................................................................................ 213 Caryn Dellamorte Bing, RPh, MS, FASHP

15 Labeling Sterile Preparations.................................................................................................. 227 Patricia J. Kuban, RPh, MBA

16 Documentation of Compounded Sterile Preparations....................................................... 243 Ryan A. Forrey, PharmD, MS, FASHP

17 Sterility Assurance of Compounded Sterile Preparations.................................................... 249 Angela W. Yaniv, PharmD

18 Finished Preparation Release Checks and Tests................................................................... 257 Angela W. Yaniv, PharmD

19 Microbiological Issues in Compounding Sterile Preparations............................................. 267 Keith H. St. John, MT(ASCP), MS, CIC, FAPIC and Radhakrishna S. Tirumalai, PhD

20 Handling Sterile Commercial Products and Compounded Sterile Preparations Within the Pharmacy............................................................................................................... 283 Ryan A. Forrey, PharmD, MS, FASHP

21 Maintaining Sterility, Purity, and Stability of Dispensed and Distributed CSPs.................... 295 Caryn Dellamorte Bing, RPh, MS, FASHP

22 Batch Compounding............................................................................................................... 303 Richard B. Osteen, DPh

Part II QUALITY MANAGEMENT 23 Pharmacist Education............................................................................................................. 315 Philip J. Schneider, MS, FASHP, FFIP, FASPEN

24 Pharmacy Technician Education, Certification, Training, Evaluation, and Regulation..... 323 Mary Ann Stuhan, PharmD, RPh

25 Secondary Engineering Controls............................................................................................ 333 E. Clyde Buchanan, RPh, MS, FASHP

26 Sterile Compounding Technology......................................................................................... 363 Bruce A. Erickson, RPh, MS and Craig A. Boyce, RPh

27 Cleaning and Disinfecting...................................................................................................... 409 Ryan A. Forrey, PharmD, MS, FASHP

28 Environmental Quality and Control........................................................................................ 425 Patricia C. Kienle, RPh, MPA, FASHP

29 Dealing with Latex Allergies.................................................................................................... 437 Stephen K. Hetey, RPh, MS, FASHP

30 Personnel Training and Competency Evaluation................................................................. 445 Linda F. McElhiney, PharmD, MSP, RPh, FIACP, FASHP, FACA

31 Policies, Procedures, and Quality Assurance Programs....................................................... 453 Patricia C. Kienle, RPh, MPA, FASHP

32 Outsourcing the Compounding of Sterile Preparations...................................................... 473 E. Clyde Buchanan, RPh, MS, FASHP

Table of Contents 

vii 

APPENDIXES Appendix A: ASHP Guidelines on Compounding Sterile Preparations.................................... 489 Appendix B: ASHP Guidelines on Handling Hazardous Drugs................................................... 517 Appendix C: Selected ASHP Guidelines Pertaining to Sterile Compounding........................ 545 Appendix D: Selected Websites Pertaining to Compounding Sterile Preparations............... 547 Glossary........................................................................................................................................... 551 Index................................................................................................................................................ 567

Acknowledgments

Every day many pharmacists and pharmacy technicians participate in compounding sterile preparations. In the vast majority of cases, their preparations are accurate, stable, pure, and sterile. We salute these health professionals who maintain essential high standards. Such work requires great attention to detail and genuine care for patients.

Publishing, who began working with us on this book in 2014. Without his encouragement and support, our work would not have been possible. Finally, to our family members and friends who gave us the space and emotional support to finish, we express our heartfelt appreciation.

We are grateful to Ruth Bloom, Beth Campbell, Kristin Eckles, and the many other ASHP staff members who reviewed and edited each chapter of this text. We express special gratitude to Jack Bruggeman, former ASHP Director of Special

E. Clyde Buchanan Philip J. Schneider Ryan A. Forrey

ix

Preface

trained on standards for safe compounding practices and that CMS amend its interpretive guidelines to address hospitals’ contracts with standalone compounding pharmacies. In October 2015, CMS did so. In May 2016, one of the CMS accreditation agencies, the Healthcare Facilities Accreditation Program, published updates to its pharmaceutical standards. These standards identify extensive and specific requirements for compounded sterile preparations. The other agencies that accredit pharmacies and healthcare organizations will update their pharmacy standards too.

This professional reference for pharmacists and pharmacy technicians who compound sterile preparations also will serve well as a textbook for student pharmacists and pharmacy technicians. To assist with classroom use, ASHP plans to publish learning objectives and review questions and answers for each chapter. There is a robust list of references at the end of each chapter for those scholars who wish to dig deeper into this rich material. Since the current version of USP Chapter Pharmaceutical Compounding—Sterile Preparations became official in June 2008, much has happened in the world of sterile compounding. Perhaps the most significant event, as well as the most tragic, was the multistate outbreak of fungal meningitis and other infections that occurred in 2012 (www.cdc.gov). The Centers for Disease Control and Prevention (CDC) counted 753 infected patients in 20 states, and 64 of those infected patients died. Contaminated steroid injections compounded at the New England Compounding Center in Framingham, Massachusetts, caused these infections. As a direct consequence, in 2013 the U.S. Congress passed the Drug Quality and Security Act (DQSA) to be enforced by the Food and Drug Administration. The meningitis outbreak also sparked concerns about compounding pharmacies and prompted an investigation by the Office of the Inspector General (OIG) regarding the use of compounding pharmacies by hospitals and oversight of hospital compounding by the Centers for Medicare & Medicaid Services (CMS) and its accrediting organizations (OIG report OEI-01-13-00400). The OIG recommended that accreditation surveyors be

In February 2016, the United States Pharmacopeia finalized USP Chapter Hazardous Drugs— Handling in Healthcare Settings. This enforceable chapter applies to all healthcare personnel and entities that handle hazardous drugs. Compounding Sterile Preparations, Fourth Edition, updates all chapters for DQSA and USP Chapter but refers to the 2008 version of USP Chapter , which is current as of this publication. The fourth edition does not cover USP Chapter proposed in late 2015 which is still under review and revision. When a new, final USP Chapter becomes available, ASHP will publish a revised edition. All previous chapters have been updated, and several new chapters and chapter authors have been added. New chapters include the following: • Imperative for Change: Adverse Sterile Compounding Events • Immediate-Use Compounding • Special Considerations in Pediatric Compounding

xi

 

xii 

Compounding Sterile Preparations

• Special Considerations in Compounding Biologicals • Microbiological Issues in Compounding Sterile Preparations • Sterile Compounding Technology

New authors include Craig A. Boyce, Todd W. Canada, Richard C. Capps, Bruce A. Erickson, Ryan A. Forrey, Kathleen M. Gura, Patricia C. Kienle, Mark G. Klang, Jeannell M. Mansur, Linda F. McElhiney, Richard B. Osteen, Kelley Reece, Ryan K. Roux, Keith H. St. John, Susan Spivey, Mary Ann Stuhan, Radhakrishna S. Tirumalai, and Angela W. Yaniv. All chapter authors are listed with their credentials in the front matter and anyone who compounds sterile preparations will recognize the experts assembled for this work. With all the new material, we needed another coeditor, so we are fortunate to welcome Ryan A. Forrey and his expertise. Having served as the Associate Director of Pharmacy and Infusion

Services at the Ohio State University Wexner Medical Center and as the Director of Pharmacy at Emory University Hospital Midtown, he is now Senior Manager, Market Development for Hazardous Drug Safety at Becton, Dickinson and Company. Dr. Forrey is also on the Compounding Expert Committee for the United States Pharmacopeia. Many challenges face the pharmacy staff members who compound sterile preparations. Let us meet those challenges by providing our patients with the safest compounded sterile preparations possible and protecting the healthcare employees who handle hazardous drugs. Our professional reputation depends on it.

E. Clyde Buchanan Philip J. Schneider Ryan A. Forrey September 2017

Contributors Caryn Dellamorte Bing, RPh, MS, FASHP Co-Editor, Extended Stability for Parenteral Drugs CB Healthcare Consulting Las Vegas, Nevada

Ryan A. Forrey, PharmD, MS, FASHP Senior Manager, Market Development for Hazardous Drug Safety Becton, Dickinson and Company Franklin Lakes, New Jersey

Craig A. Boyce, RPh Pharmacy Systems Consultant ARxIUM Inc. Buffalo Grove, Illinois

Kathleen M. Gura, PharmD, BCNSP, FASHP, FPPAG, FASPEN Pharmacy Clinical Research Program Manager Clinical Pharmacist, Gastroenterology/ Nutrition Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

E. Clyde Buchanan, RPh, MS, FASHP Senior Director of Pharmacy (Ret.) Emory Healthcare Atlanta, Georgia Todd W. Canada, PharmD, BCNSP, BCCCP, FASHP, FTSHP Clinical Pharmacy Services Manager & Nutrition Support Team Coordinator Division of Pharmacy The University of Texas MD Anderson Cancer Center Houston, Texas

Stephen K. Hetey, RPh, MS, FASHP Associate Chief Pharmacy Officer (Ret.) Department of Pharmacy Duke Children’s Hospital and Health Center Duke University Medical Center and Health System Durham, North Carolina George H. Hinkle, RPh, MS, BCNP University Radiation Safety Officer Radiation Safety Section—Environmental Health & Safety Faculty Emeritus Pharmacy Practice and Science The Ohio State University Columbus, Ohio

Richard C. Capps, PharmD Manager of Pharmacy Operations GHS Oconee Memorial Hospital Seneca, South Carolina Joseph W. Coyne, BS Pharm, RPh Director of Field Operations Clinical IQ, LLC Mundelein, Illinois

Patricia C. Kienle, RPh, MPA, FASHP Director, Accreditation and Medication Safety Cardinal Health Innovative Delivery Solutions Laflin, Pennsylvania

Bruce A. Erickson, RPh, MS Pharmacy Automation Consultant (Ret.) Director of Pharmacy (Ret.) VA Medical Center, Minneapolis Placida, Florida

xiii

 

xiv 

Compounding Sterile Preparations

Mark G. Klang, RPh, MS, BCNSP, PhD Core Manager, Research Pharmacy Memorial Sloan Kettering Cancer Center New York, New York Patricia J. Kuban, RPh, MBA Director of Pharmaceutical Services Emory University Hospital, Emory University Orthopaedics and Spine Hospital, and Emory Wesley Woods Hospital Atlanta, Georgia Jeannell M. Mansur, PharmD, RPh, FASHP Principal Consultant Medication Management and Safety Joint Commission Resources/Joint Commission International Oak Brook, Illinois Linda F. McElhiney, PharmD, MSP, RPh, FIACP, FASHP, FACA Compounding Pharmacist Indiana University Health Indianapolis, Indiana Richard B. Osteen, DPh Former Manager Narcotics, Sterile, and Non-Sterile Compounding Vanderbilt University Medical Center Nashville, Tennessee Luci A. Power, RPh, MS Senior Pharmacy Consultant Power Enterprises San Francisco, California Kelley Reece, PharmD Assistant Pharmacy Manager The University of Texas MD Anderson Cancer Center Houston, Texas

Ryan K. Roux, PharmD, MS, RPh, FASHP Director of Pharmacy Operations The University of Texas MD Anderson Cancer Center Houston, Texas Philip J. Schneider, MS, FASHP, FFIP, FASPEN Professor and Associate Dean for Academic & Professional Affairs University of Arizona College of Pharmacy Phoenix Biomedical Campus Phoenix, Arizona Susan Spivey, PharmD Pharmacy Manager The University of Texas MD Anderson Cancer Center Houston, Texas Keith H. St. John, MT(ASCP), MS, CIC, FAPIC Vice President, Clinical Affairs PDI Infection Prevention Orangeburg, New York Mary Ann Stuhan, PharmD, RPh Pharmacy Program Manager Cuyahoga Community College Highland Hills, Ohio Radhakrishna S. Tirumalai, PhD Microbiology Professional North Potomac, Maryland Angela W. Yaniv, PharmD Assistant Director for Sterile Products Cleveland Clinic Cleveland, Ohio

Reviewer Lisa D. Ashworth, BS Pharm, RPh, FACA Compounding Specialist and Clinical Pharmacist (All Campuses) Children’s Health Dallas, Texas

xv

Part I:

Sterile Preparation

1

Imperative for Change: Adverse Sterile Compounding Events............................................................................... 1

2

Standards for Compounded Sterile Preparations...................................................................................................... 7

3

Immediate-Use Compounding.................................................................................................................................. 35

4

Sterile Preparation Formulation.................................................................................................................................. 51

5

Parenteral Nutrition Compounding........................................................................................................................... 67

6

Special Considerations in Pediatric Compounding................................................................................................ 81

7

Special Considerations in Compounding Biologicals............................................................................................ 113

8

Ancillary Equipment and Supplies........................................................................................................................... 121

9

Primary Engineering Controls................................................................................................................................... 133

10 Personnel Cleansing and Garbing.......................................................................................................................... 153 11 Aseptic Technique..................................................................................................................................................... 161 12 Handling and Compounding Hazardous Drugs.................................................................................................... 171 13 Radiopharmaceuticals as Compounded Sterile Preparations............................................................................ 203 14 Storage and Beyond-Use Dating............................................................................................................................. 213 15 Labeling Sterile Preparations.................................................................................................................................... 227 16 Documentation of Compounded Sterile Preparations......................................................................................... 243 17 Sterility Assurance of Compounded Sterile Preparations...................................................................................... 249 18 Finished Preparation Release Checks and Tests.................................................................................................... 257 19 Microbiological Issues in Compounding Sterile Preparations............................................................................... 267 20 Handling Sterile Commercial Products and Compounded Sterile Preparations within the Pharmacy................................................................................................................................................. 283 21 Maintaining Sterility, Purity, and Stability of Dispensed and Distributed CSPs...................................................... 295 22 Batch Compounding................................................................................................................................................ 303

xvii

Chapter

1

Imperative for Change: Adverse Sterile Compounding Events Philip J. Schneider

Introduction It has been over 20 years since the publication of the first edition of Compounding Sterile Preparations.1 One might like to think that the circumstances prompting its publication would be less the case today than it was in 1995. There is evidence to suggest otherwise.

Rationale for Pharmacy Role Until the late 1960s, a nurse prepared doses of medications in a nonsterile environment— either in a medication room or at the bedside—for hospitalized patients for administration by the intravenous (IV) route. These doses were usually administered either in an unlabeled volume control chamber between a large volume parenteral and the patient, or by IV push using an unlabeled syringe. One of the foundational works that charted the growth of pharmacy practice in the hospital setting was Mirror to Hospital Pharmacy. Published in 1964, recommendations for the expanded role for hospital pharmacists were made based on a national audit of pharmacy practices. One recommendation was that “hospitals be encouraged to assign to pharmacists the responsibility and to provide for the preparation and quality control of sterile medicinal products produced in hospitals.”2 Following the publication of Mirror to Hospital Pharmacy, problems with the safety of IV drug therapy were reported as a justification for pharmacy-based programs. Patterson et al. expressed concerns about drug incompatibilities and the length of time between preparation and administration of medications prepared at the bedside after finding that 60% of IV fluids used at their hospital contained more than one drug, and many were administered more than an hour after preparation.3 These authors recommended that the pharmacy assume responsibility for compounding IV admixture doses to resolve these problems. Flack et al. reported requests for “technical help from the pharmacy service” by the surgeons investigating the effectiveness and safety of parenteral nutrition to resolve

1

  2  Compounding Sterile Preparations

problems of contamination and incompatibilities with the formulas that were being “hand mixed in open laboratory surroundings.”4 Thur et al. observed nurses preparing parenteral admixtures in patient care areas and reported an error rate of 21%. The rate of wrong doses prepared was 9%, incompatible drugs mixed was 6%, wrong drug or solution used was 3%, and preparation of drugs not ordered was 3%. Deviations from accepted sterile technique were observed, with counters not being cleaned (99%), hands not washed (97%), touching sterile areas of the IV container (47%), and vial or bottle tops not being cleaned (31%).5 O’Hare et al. used a disguised observer method to evaluate physicians’ and nurses’ errors in preparation and administration of IV medications. They found that physicians made at least one error in 98% of the doses prepared and 83% of these doses were administered by nurses.6 Taxis and Barber also observed nurses who prepared and administered IV drugs on 10 wards in a hospital in the United Kingdom. Of 249 errors identified, at least one error occurred in 212 of the 430 doses observed. Most errors occurred when bolus doses were prepared and administered or for doses requiring multiple preparation steps. One strategy recommended for decreasing errors was to reduce the amount of preparation on the ward.7 Even if properly ordered, errors can occur in preparation. Thompson et al. evaluated the concentrations of admixed medications delivered to patients and found evidence of incomplete mixing of medications in IV solutions prepared at the bedside. They also found that there was more uniformity of concentrations of potassium chloride when these doses were prepared in the pharmacy.8 Calculation errors are also a root cause of error in preparing medications. Perlstein et al. found that one of 12 doses calculated by nurses had an error, which resulted in a tenfold dose compared to that ordered. Pediatricians made errors in one of 26 computations. Pharmacists made fewer errors than nurses and physicians.9 Although these studies provide a historical basis for the pharmacist role in compounding sterile preparations, a recent systematic review and meta-analysis of the risk of microbial contamination of parenteral doses (prepared under aseptic

techniques in clinical and pharmaceutical environments) remind us of the risks associated with compounded sterile preparations, particularly when they are prepared in the clinical environment.10 In a review of 16,552 doses from 34 studies for all data combined, a significantly higher frequency of contamination of doses prepared in clinical settings was found than in pharmaceutical environments. Contamination of doses was significantly higher when prepared as individual lots than as part of a batch in pharmaceutical environments. The authors concluded that reported rates of parenteral dose contamination were orders of magnitude higher than accepted reference standards and may increase infection risk, and the data supported dose preparation in pharmaceutical rather than in clinical environments.

Self-regulation As a result of these reports, pharmacy-based, centralized IV admixture programs emerged as a potentially safer medication-use system. According to ASHP National Surveys of Pharmacy Practice in hospital settings, this system is present in the vast majority of U.S. hospitals. By 2008, only 10% of U.S. hospitals relied on nurses to prepare IV medications as the primary method. Most hospitals use the minibag system to administer medications by the IV route, and doses are prepared in the pharmacy.11 Twenty years after adoption of pharmacy-based IV admixture programs, reports of patient harm resulting from improperly compounded sterile preparations began to be published. In 1990, four deaths resulting from contaminated cardioplegia solutions prepared in a hospital were reported.12 In the same year, several infections and cases of blindness were traced to ophthalmic preparations compounded in a community pharmacy.13 Under pressure from the U.S. Food and Drug Administration (FDA) to strengthen their oversight of pharmacist compounding of sterile preparations, ASHP began a multistep plan to assist its members to improve practices. The first step was to convene an invitational conference in 1991 to discuss quality assurance for pharmacy-prepared sterile preparations.14 A Technical Assistance Bulletin on

Chapter 1  Imperative for Change: Adverse Sterile Compounding Events  3 

Quality Assurance for Pharmacy-Prepared Sterile Products was published by ASHP in 1993.15 The first edition of this book, then titled Principles of Sterile Product Preparation, was published in 1995. In spite of these efforts, evidence of complacency existed in pharmacies that undermined the potential benefits of a pharmacy-based IV admixture program and efforts to ensure quality. Sanders et al. reported that pharmacists had an error rate of 7.24% and a contamination rate of 7%.16 These errors and contamination rates were higher than that observed for pharmacy technicians. Pharmacists made fewer errors and contaminated fewer IV preparations when they knew they were being observed, suggesting the emergence of complacency and the need for continuing vigilance. Flynn et al. also reported high error rates in pharmacy-based IV admixture programs. They found an error rate of 9% in five hospital pharmacies studied using an observation-based method.17 Trissel et al. evaluated the aseptic technique of pharmacists and technicians when compounding complex United States Pharmacopoeia (USP) medium-risk sterile preparations using media fill tests. Pharmacist compounding resulted in a contamination rate of 4.4% compared to a rate of 6.2% for technicians. The overall contamination rate was 5.2%.18

Standards of Practice As a result of the limited impact of voluntary efforts to improve quality in the preparation of sterile medications, there have been increasingly stringent enforceable standards developed by the U.S. Pharmacopeial Convention (USP) and enforced by state boards of pharmacy and accreditation bodies. Starting with an information chapter in 1992 directed toward “dispensing practices for sterile products intended for home use,” USP created the legally enforceable Chapter Pharmaceutical Compounding—Sterile Preparations in 2004, which applies to all compounded sterile preparations regardless of setting.19 In 2016, USP separated standards for handling hazardous drugs into a new Chapter Hazardous Drugs—Handling in Healthcare Settings.20 Unfortunately, there are problems with awareness of and adherence to these standards.

In their annual USP Chapter Compliance Surveys, Douglass et al. report significant challenges in meeting published standards of practice including financial and budgetary restrictions, physical plant limitations, time required to implement changes, and a lack of available training and competency resources. It was noted that only 39% of respondents reported full compliance with USP Chapter requirements. Comparing results of the most recent survey to previous surveys, they note that little or no improvement in compliance has been demonstrated. Twelve percent did not know if their state board of pharmacy had increased emphasis on this standard or not. Only 57% had read the chapter closely. Some of the lowest areas of compliance with the requirements of USP Chapter included fingertip testing (46.1%), policies for use of cleaning materials (46.7%), policies for surface and air sampling (48.7%), and quality assurance/improvement program (55.9%).21 The U.S. Department of Health and Human Services, Office of the Inspector General, has published a report about Medicare’s oversight of compounded pharmaceuticals used in hospitals. They found that surveyors receive limited training specific to compounding, and most do not include a pharmacist in their hospital surveys.22 None of the respondents incorporate recommended practices related to hospital contracts with “standalone compounding pharmacies.” Therefore, both current practices and oversight of these practices are in need of improvement.

Adverse Clinical Events Violations in standards of care can result in adverse patient outcomes including death. These highly publicized events have resulted in public and regulatory concern about the quality of sterile preparations compounded in pharmacies. Such was the case at the New England Compounding Center (NECC) facility where violations in standards for compounding sterile preparations resulted in 753 adverse events including 64 deaths. NECC, a compounding pharmacy that distributed medications to more than 3,000 facilities in all 50 states, had been investigated by the FDA on

  4  Compounding Sterile Preparations

at least three separate occasions prompted by reports of adverse events associated with their preparations. Patients receiving steroid preparations compounded at NECC developed meningitis, spinal infections, strokes, and peripheral joint infections. The predominant fungus identified in patients was common in the environment but not transmitted from person-to-person. Therefore, environmental conditions and practices at NECC came into question. When the FDA inspected NECC, significant breaches from acceptable standards were found. Examples included water from leaking equipment on the floors, gaps between doors that transition to clean areas, and microbial contaminants detected during air sampling and surface testing in cleanrooms.23 Federal prosecutors charged 14 former NECC employees, including their president, and a pharmacist with a host of criminal offenses. A federal bankruptcy judge approved a $200 million settlement plan that set aside funds for victims of the outbreak and their families.24 In another example, 19 patients in six Alabama hospitals were infected by a bacterial contaminant in parenteral nutrition formulations compounded by a single pharmacy from whom these preparations were outsourced. In their inspection of this facility, the FDA noted in a warning letter that several lots of drug products were contaminated and indicated that these products were “prepared, packed, or held under unsanitary conditions whereby they may have been contaminated.”25 Following this incident, the pharmacy license was surrendered. Nine of these patients died, and the former head pharmacist and president of this compounding pharmacy agreed to plead guilty to two misdemeanor violations of the Federal Food, Drug, and Cosmetic Act for distributing contaminated drugs.26 Staes et al. analyzed healthcare-associated infections related to compounding pharmacies between 2000 and 2012, but this was before the NECC events. They evaluated 11 outbreaks involving 207 patients and 11 deaths after exposure to contaminated compounded drugs. It was concluded that lapses in sterile compounding procedures led to contamination of compounded drugs, exposure to patients, and a threat to public health.27

Future Challenges Several factors may explain why we still face challenges ensuring that patients receive quality sterile medications compounded in a pharmacy: • Drug shortages • Consolidation of sterile compounding pharmacies and outsourcing by hospitals • Increasingly rigorous standards of practice • Decreased emphasis on sterile compounding in pharmacy education

Although most of the medications that are used in clinical settings are now commercially available, pharmacists are frequently called on to compound medications, often from raw ingredients when commercial supplies are not available. In the third quarter of 2014, there were more than 300 active drug shortages.28 Because of the rigorous standards for compounding high-risk preparations, including those compounded from nonsterile components, many health-system pharmacists purchase these products from outsourcing pharmacies. This has resulted in the growth of the number of compounding pharmacies that make sterile injectable drugs, which is now estimated to number about 3,000, only 55 of which are registered with the FDA as Human Drug Compounding Outsourcing Facilities.29 Continued reports of contaminated preparations from outsourcing facilities raise serious questions about the quality of facilities, staff, and procedures resulting in harm to patients.30-32 It is likely that increased regulatory oversight resulting from these highly publicized events will cause more outsourcing and perhaps some consolidation of the outsourcing pharmacies because of the cost of compliance. Although this may theoretically strengthen the industry, it may also result in the evolution of manufacturing-level operations, without meeting the requirements of Good Manufacturing Practices regulations. Larger compounding pharmacies prepare products that are not patient-specific in larger batches, which are stored for longer periods of time and are often shipped over long distances. Compounding preparations on such a large scale may result in harm to a larger patient population if and when an error occurs as was seen with the NECC incident that

Chapter 1  Imperative for Change: Adverse Sterile Compounding Events  5 

resulted in 64 deaths and 753 cases of confirmed or probable fungal cases.23 The line is becoming blurred between compounding as the practice of pharmacy and manufacturing. This large-scale incident involving a compounding pharmacy highlights the continued urgency of ensuring quality in compounding sterile preparations in pharmacies. Even more rigorous standards and regulations have been proposed and developed to protect the public, including an update of USP Chapter , a new USP Chapter , and the Drug Quality and Security Act, which provides the opportunity for human drug compounding outsourcing facilities to be registered with the FDA as specified in section 503b of the regulation. These new standards and regulations are reviewed in detail in Chapter 2, Standards for Compounded Sterile Preparations. One might argue there is a need to properly educate and train new pharmacists so they are prepared to competently compound sterile preparations. With the evolution of a more clinically oriented curriculum in colleges of pharmacy, however, there has actually been a decrease in the amount of classwork and practical exposure to compounding in general and compounding sterile preparations in particular. It is not uncommon for recent and current graduates to have very limited understanding of the concepts of aseptic technique and experience in this area. A review of the current status of this topic is discussed in Chapter 23, Pharmacist Education. Alternatively, compounding in general and compounding sterile preparations specifically may evolve as a specialty in pharmacy practice with certificate programs or even board certification.

Summary Despite ample scientific evidence that pharmacists can improve the quality of compounded sterile preparations, patients are still being harmed by contaminated and improperly prepared doses—even those coming from pharmacies. Increasing external regulation of pharmacy practice reflects a lack of confidence in the ability of pharmacists to ensure safety in compounding sterile doses of medications. Even if there have not been such incidents in your

pharmacy or hospital, constant vigilance is needed to meet the standards of practice that are regularly revised/updated and intended to prompt patient and employee safety. Do not wait for such a tragedy to occur before taking proactive measures to ensure safe and accurate compounding of sterile preparations.

References 1. Buchanan EC, BT McKinnon, DJ Scheckelhoff et al. Principles of sterile product preparation. Bethesda, MD: American Society of Health-System Pharmacists; 1995. 2. Francke DE, CJ Latiolais, GN Francke et al. Mirror to hospital pharmacy. Washington DC: ASHP; 1964:4. 3. Patterson TR, Nordstrom KA. An analysis of IV additive procedures on nursing units. Am J Hosp Pharm. 1968; 25:134-7. 4. Flack HL, Gans JA, Serlick SE et al. The current status of parenteral hyperalimentation. Am J Hosp Pharm. 1971; 28:326-35. 5. Thur MP, Miller WA, Latiolais CJ. Medication errors in a nurse-controlled parenteral admixture program. Am J Hosp Pharm. 1972; 29:298-304. 6. O’Hare MCB, Bradley AM, Gallagher T et al. Errors in the administration of intravenous drugs. Br Med J. 1995; 310:1536-7 7. Taxis, K, Barber N. Ethnographic study of incidence and severity of intravenous drug errors. Br Med J. 2003; 326:684-7. 8. Thompson WL, Feer TD. Incomplete mixing of drugs in intravenous solutions. Crit Care Med. 1980; 8:603-7. 9. Perlstein PH, Callison C, White M et al. Errors in drug computations during newborn intensive care. Am J Dis Child. 1979; 133:376-9. 10. Austin PK, KS Hand, E Marinos. Systematic review and meta-analysis of the risk of microbial contamination of parenteral doses prepared under aseptic techniques in clinical and pharmaceutical environments. J Hosp Infec. 2015; 91:306-18. 11. Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration—2008. Am J Health-Syst Pharm. 2009; 66:926-46. 12. Hughes DF, AF Frant, BD Leckie et al. Cardioplegic solution: a contamination crisis. J Thorac Cardiovas Surg. 1986; 91:296-302. 13. Eye drops injuries prompt an FDA warning. www. nytimes.com/1990/12/09/us/eye-drop-injuriesprompt-an-fda-warning.html (accessed 2016 Feb 21).

  6  Compounding Sterile Preparations 14. American Society of Health-System Pharmacists (ASHP). ASHP invitational conference on quality assurance for pharmacy-prepared sterile products. Am J Hosp Pharm. 1991; 48:2391-7. 15. American Society of Health-System Pharmacists (ASHP). ASHP technical assistance bulletin on quality assurance for pharmacy-prepared sterile products. Am J Hosp Pharm. 1993; 50:2386-98. 16. Sanders LH, Mabadeje SA, Avis KE et al. Evaluation of compounding accuracy and aseptic technique for intravenous admixtures. Am J Hosp Pharm. 1978; 35:531-6. 17. Flynn EA, Pearson RE, Barker KN. Observational study of accuracy in compounding i.v. admixtures in five hospitals. Am J Hosp Pharm. 1997; 54:90412. 18. Trissel LA, Gentempo JA, Anderson R et al. Using a medium-fill simulation to evaluate the microbial contamination rate for USP medium-risk level compounding. Am J Health-Syst Pharm. 2005; 62:285-8. 19. U.S. Pharmacopeial Convention. USP chapter pharmaceutical compounding—sterile preparations. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 20. U.S. Pharmacopeial Convention. USP chapter hazardous drugs—handling in healthcare settings In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 21. Douglass K, ES Kastango, P Cantor. The 2013 USP chapter compliance survey. Pharmacy Purchasing & Products. 2014; 11:S6-24. 22. Levinson DR. Medicare’s oversight of compounded pharmaceuticals used in hospitals (oei-01-13-00400). Washington DC: U.S. Department of Health and Human Services, Office of Inspector General; 2015. 23. Centers for Disease Control and Prevention. Multistate outbreak of fungal meningitis and other infections—case count. www.cdc.gov/hai/ outbreaks/meningitis-map-large.html (accessed 2016 Mar 15). 24. United States Department of Justice, Office of Public Affairs. 14 indicted in connection with New England compounding center and nation-

25.

26.

27.

28.

29.

30.

31.

32.

wide fungal meningitis outbreak. www.justice. gov/opa/pr/14-indicted-connection-new-englandcompounding-center-and-nationwide-fungalmeningitis (accessed 2016 Mar 15). U.S. Food and Drug Administration. Advanced specialty pharmacy dba meds IV. www.fda. gov/ICECI/EnforcementActions/WarningLetters/2012/ucm296483.htm (accessed 2016 Mar 15). The Birmingham News. Alabama pharmacists to plead guilty after contaminated drug linked to 9 deaths. www.al.com/news/birmingham/index. ssf/2016/01/alabama_pharmacists_to_plead_g. html (accessed 2016 Mar 15). Staes C, J Jacobs, J Mayer et al. Description of outbreaks of healthcare-associated infections related to compounding pharmacies, 2000–12. Am J Health-Syst Pharm. 2013; 70:1301-12. University of Utah Drug Information Service. Annual new shortages by year: January 2001 to June 30, 2015. www.ashp.org/DocLibrary/Policy/ DrugShortages/Drug-Shortages-Statistics.pdf (accessed 2016 Mar 15). U.S. Food and Drug Administration. Registered outsourcing facilities. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm378645.htm (accessed 2016 Mar 15). U.S. Food and Drug Administration. Specialty compounding, LLC issues nationwide voluntary recall of all lots of unexpired sterile products due to reports of adverse events. www.fda.gov/Safety/ Recalls/ucm364643.htm (accessed 2016 Mar 15). U.S. Food and Drug Administration. FDA alerts health care professionals and patients not to use products from the prescription center pharmacy in Fayetteville, NC. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm440974. htm (accessed 2016 Mar 15). U.S. Food and Drug Administration. Compounding: inspections, recalls, and other actions. www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/PharmacyCompounding/ ucm339771.htm (accessed 2016 Mar 15).

Chapter

2

Standards for Compounded Sterile Preparations E. Clyde Buchanan

Introduction Poor sterile compounding practice has caused much patient harm and many deaths, but it was the New England Compounding Center tragedy that caused 64 deaths and 753 illnesses in 2012, which changed the world of sterile compounding laws, regulations, and standards (Chapter 1).1 Such changes included the federal Drug Quality and Safety Act (DQSA) of 2013 and renewed emphasis by accrediting agencies on the compounding and outsourcing of sterile preparations. The purpose of this chapter is to alert compounding personnel to the agencies that will change their training, practices, and facilities. The chapter covers the major changes wrought by national and state bodies since the previous edition of this textbook. The agencies below are arranged in descending order of the likelihood they will enforce standards for pharmacists and pharmacies that compound sterile preparations. Make no mistake— citations by agencies such as these can lead to revoked licenses, ruined reputations and careers, bankrupted businesses, and even imprisonment for perpetrators.2-6 According to a 2015 Survey of Pharmacy Compounding of 349 hospitals, regulators had visited more hospitals asking about sterile compounding in the previous 2 years: 75% of hospitals by state board of pharmacy inspectors, 63% by accrediting surveyors, and 31% by Centers for Medicare & Medicaid Services (CMS) surveyors.7

State Boards of Pharmacy As of April 2015, 27 states require direct compliance with USP Chapter Pharmaceutical Compounding—Sterile Preparations. Another 21 states have compounding regulations although they do not directly refer to USP Chapter . Compliance with this chapter was a strong focus in 70% of the most recent state board inspections. Not surprisingly, in states that require compliance with USP Chapter , more hospitals report being in full compliance.7

7

  8  Compounding Sterile Preparations

For those hospitals that were cited for sterile compounding noncompliance, a variety of issues came to light: incomplete or missing logs, timing of training and documentation of competency assessments, inaccurate room pressure monitoring, calibration of automatic compounding devices, improper handwashing technique, and conducting hazardous drug (HD) compounding outside of a negative pressure room.7

National Association Pharmacy

of

Boards

of

Founded in 1904, the National Association of Boards of Pharmacy (NABP) is an impartial professional organization that supports the state boards of pharmacy in protecting public health. NABP’s member boards of pharmacy are grouped into eight districts that include all 50 United States, the District of Columbia, Guam, Puerto Rico, the Virgin Islands, Australia, eight Canadian provinces, and New Zealand. Because the 50 state boards of pharmacy and the District of Columbia are members of the NABP, the NABP has much influence on the rules and regulations that the respective state boards create. The NABP has long held that prescription compounding is a pharmacist’s responsibility and should be regulated by state boards of pharmacy.8 NABP is recognized as having a consulting role in the DQSA. (See U.S. Food and Drug Administration [FDA] section below.) To distinguish between compounding and manufacturing, NABP defines these terms in its Model State Pharmacy Practice Act: Compounding means the preparation, mixing, assembling, altering, packaging, and Labeling of a Drug, Drug-Delivery Device, or Device, unless performed in a Food and Drug Administration (FDA)-registered Outsourcing Facility in conformance with Federal law, are in accordance with a licensed Practitioner’s prescription, medication order, or initiative based on the Practitioner/patient/ Pharmacist/compounder relationship in the course of professional practice. Compounding includes the following: 1. preparation of Drug dosage forms for both human and animal patients;

2. preparation of Drugs or Devices in anticipation of Prescription Drug Orders based on routine, regularly observed prescribing patterns; and 3. reconstitution or manipulation of commercial Products that may require the addition of one or more ingredients for patient-specific needs. Manufacturing means the production, preparation, propagation, conversion, or processing of a Drug or Device, either directly or indirectly, by extraction from substances of natural origin or independently by means of chemical or biological synthesis. Manufacturing includes the packaging or repackaging of a Drug or Device or the Labeling or relabeling of the container of a Drug or Device for resale by pharmacies, Practitioners, or other Persons.9 Although NABP strives for uniformity in state board of pharmacy regulations, the boards themselves run the gamut of oversight of sterile compounding. In 2015, Pew Charitable Trusts sponsored a survey to assess the national landscape of state policies on compounding sterile drugs.10 Authors of the study used public websites and a questionnaire sent to all 50 states and the District of Columbia. Forty-three of the state boards of pharmacy responded to the survey. Alarming inconsistencies surfaced among state policies: • Only 49% of states require strict adherence to USP Chapter (see discussion below). • Only 56% track the pharmacies that perform sterile compounding. • Only 44% track pharmacies that ship or dispense compounded drugs into their state for patients or healthcare providers. • Only 30% require pharmacies to report serious adverse events and reactions related to sterile compounding. • Only 24% require pharmacies to report voluntary recalls to either the state or FDA. • Sixty-five percent allow pharmacies to compound without patient-specific prescriptions. • Only 21% require pharmacists to have a separate license or registration to perform sterile compounding.

Chapter 2  Standards for Compounded Sterile Preparations  9  • Only 28% reported that when inspecting sterile compounding pharmacies, they prioritized inspections for pharmacies where high-risk compounding occurs. • Nineteen percent of states estimate that their inspectors spend less than 4 hours per inspection. • Only 23% of state inspectors are required to directly observe sterile compounding activities and facilities. • Only 9% of state inspectors are required to have prior experience in compounding pharmacy. • Only 17% require that physicians be held to the same compounding standards as pharmacies. In fact, only one state has a mechanism to track nonpharmacy locations (e.g., physicians’ offices) where sterile compounding occurs. • Eight state boards that did not respond to the survey: Alaska, Delaware, Florida, Georgia, Maine, North Carolina, Ohio, and Wisconsin.

In understating the matter, the authors of the study concluded, “The variations in sterile compounding policy across states suggest that an opportunity exists to review state oversight systems for potential weaknesses, and consequently to advance regulatory practices to better protect patients.”10

Accrediting Agencies for Healthcare Organizations Via the Social Security Act, hospitals accredited by the CMS-approved agencies must meet CMS Conditions of Participation to serve Medicare and Medicaid patients and thereby receive reimbursement for those services.11 Four accrediting bodies (i.e., with deeming authority) accredit hospitals for participation in Medicare and Medicaid services: The Joint Commission (TJC), the American Osteopathic Association’s Healthcare Facilities Accreditation Program (HFAP), DNV GL–Healthcare, and the Center for Improvement in Healthcare Quality (CIHQ).12 TJC accredits the majority of accredited hospitals, critical access hospitals, and ambulatory surgery centers. Few U.S. hospitals can afford not to be accredited because of the large number of Medicare and Medicaid patients. Independent compounding pharmacies do not have to be accredited to serve patients.

In 86% of surveys, hospital accrediting agencies brought no actions against hospital pharmacy sterile compounders. However, surveyors did make recommendations for improvements in sterile compounding in 11% of surveys and issued citations in 3% of surveys.7 In 2010, 70% of accrediting agency surveyors were physicians, while pharmacists represented less than 10%. In recent accreditation surveys, pharmacists comprised 22% of surveyors and, therefore, may be more knowledgeable and more likely to cite pharmacy operations during surveys.7 All four accreditation (deeming) agencies survey for many details contained in USP Chapter and USP Chapter Hazardous Drugs—Handling in Healthcare Settings. In January 2015, the Office of the Inspector General made two recommendations to CMS13: 1. Ensure that hospital surveyors receive training on standards from nationally recognized organizations related to safe compounding practices. 2. Amend its interpretive guidelines to address hospitals’ contracts with standalone compounding pharmacies.

Centers

for

Medicare & Medicaid Services

Following the Office of Inspector General (OIG) recommendations in an October 15, 2015, memorandum to state survey agency directors, the CMS Director of Survey and Certification Group stated the following: Pharmaceutical Services—Revisions were made to portions of the pharmaceutical services CoP [conditions of participation] to bring them into alignment with current accepted standards of practice. To improve clarity, the revised guidance addresses: accepted professional pharmacy principles, including United States Pharmacopeia (USP) standards; compounding of medications, particularly compounded sterile preparations (CSPs); determining beyond-use dates (BUDs); safe and appropriate storage and use of medications; and, policies and procedures related to high-alert medications and minimizing drug errors.14 The OIG further “clarified that a hospital must have pharmaceutical services administered in ac-

  10  Compounding Sterile Preparations

cordance with accepted professional principles, such as those found in the U.S. Pharmacopeia–National Formulary (USP–NF) . . . We have expanded our hospital guidance on the requirements for compounding of medications, particularly for CSPs.”14 To confirm that deeming agencies are performing effectively, state agencies conduct surveys following the guidance outlined in the interpretive guidelines maintained by CMS.15 My experience is that the state authorities are stricter than TJC in reviewing pharmacy operations.

The Joint Commission An independent, not-for-profit organization, TJC accredits and certifies more than 21,000 U.S. healthcare organizations and programs. TJC accreditation and certification is recognized nationwide as an organization’s commitment to meeting certain quality performance standards.16 Table 2-1 describes sterile compounding locations that TJC often accredits.

TJC expects organizations to comply with USP Chapter and will survey for compliance with provisions of USP Chapter that overlap with their standards, including those in the following 2016 Hospital Accreditation Manual: Medication Management, Infection Control, Environment of Care, Human Resources, Provision of Care, Treatment and Services Leadership, and Performance Improvement.17 (Table 2-2.)

Healthcare Facilities Accreditation Program The HFAP is a nationally recognized accreditation organization with deeming authority from CMS. Their mission is to advance high quality patient care and safety through objective application of recognized standards. This accreditation agency had moved ahead to adopt the CMS guidance described above. In April 2016, HFAP approved several accreditation standards that will directly

Table 2-1.

The Joint Commission–Accredited Healthcare Sites with Operations (e.g., pharmacies) That Compound Sterile Preparations Ambulatory Care Ambulatory centers

Critical Access Hospitals

Hospitals

Home health

General hospitals

Outpatient surgery centers

Hospice

Children’s hospitals

Physician office-based surgery

Personal care

Long-term acute care

Imaging centers

Infusion pharmacy

Oncology hospitals

Urgent care centers

Definition: Maintains no more than 25 total beds; keeps patients hospitalized no longer than 96 hours; receives critical access designation by a state agency

Home Care

Psychiatric hospitals Rehabilitation hospitals Specialty hospitals (e.g., cardiac, orthopedic, surgical)

Chapter 2  Standards for Compounded Sterile Preparations  11  Table 2-2.

USP Chapter Crosswalk with The Joint Commission 2015 Standardsa USP Chapter Requirements

TJC 2015 Hospital Standards and National Patient Safety Goals

Adequate training of personnel

HR.01.04.01 and HR. 01.05.03

ADR and error reporting

MM.07.01.03

Air quality and environmental monitoring of sterile compounding area

EC.02.04.01 and EC.02.04.03

Beyond-use dating

MM.05.01.09

Cleaning and disinfecting of sterile compounding area

IC.02.02.01

Competence assessment

HR.01.06.01 and HR.01.07.01

Compounder and repeater pump accuracy testing

EC.02.04.01 and MM.02.04.03

Contaminants

EC.02.05.01 and MM.05.01.07

Environmental design of the sterile compounding area

MM.05.01.07

Facilities Space and equipment ISO 5 compliance

LD.04.01.11 and EC.02.05.01 MM.05.01.07

Hand hygiene

IC.01.04.01 and NPSG.07.01.01

Hazardous drugs

EC. 02.02.01 and MM.01.01.03

High-alert medications

MM.01.01.03

Infection prevention and control

IC.01.05.01

Look-alike and sound-alike medications

MM.01.02.01

Labels

MM.05.01.09 and NPSG.03.04.01

Patient education

PC.02.03.01

Patient monitoring

MM.07.01.01

Patient’s own medications

MM.03.01.05

Procedures

MM.05.01.07

Quality assurance and performance improvement Responsibility for safe and quality care Evaluates effectiveness of system Monitors performance Compiles and analyzes data Improves performance

LD.01.03.01 MM.08.01.01 PI.01.01.01 PI.02.01.01 PI.03.01.01 (continued)

  12  Compounding Sterile Preparations Table 2-2. (continued)

USP Chapter Crosswalk with The Joint Commission 2015 Standardsa USP Chapter Requirements

TJC 2015 Hospital Standards and National Patient Safety Goals

Radiopharmaceuticals

MM.05.01.07

Recalls

MM.05.01.17

Redispensing preparations

MM.05.01.19

Regulation and compliance with laws

LD.04.01.01 and MM.05.01.11

Supplies (garb, disposables, etc.)

IC.01.02.01

Temperature testing and documentation

EC.02.06.01 and MM.03.01.01

ISO = International Organization for Standardization. a For more information, see Uselton JP, Kienle PC, Murdaugh LB. Review of United States Pharmacopeia (USP) Chapter : pharmaceutical compounding—sterile preparations. In: Assuring continuous compliance with Joint Commission standards: a pharmacy guide. Bethesda, MD: ASHP; 2010:275-81.

affect the compounding of sterile preparations in hospitals.18 (Table 2-3.)

Center for Improvement Quality

in

Healthcare

Serving healthcare organizations since 1999, the CIHQ is a member-based organization comprised of hospitals and other healthcare entities throughout the United States. CIHQ is a CMS-approved deeming authority for acute care hospitals. Their accreditation program is designed to ensure that hospitals comply with the Medicare Conditions of Participation and improve the quality of care, treatment, and service in their communities. CIHQ accreditation is awarded to an organization for a maximum of 36 months.19 CIHQ has medication management standards very similar to those of TJC.20

DNV GL—Healthcare A merger between Det Norske Veritas (DNV) and GL was cleared by international competition authorities and the new company DNV GL–Healthcare became operational on September 12, 2013. In 2008, DNV had received CMS deeming authority and since then has accredited nearly 500 hospitals of all sizes and in every region of the United States. DNV GL melds the healthcare accreditation survey

process with a gradual compliance with ISO 9001, the international standard for quality management systems. DNV GL accreditation requires an annual survey and the organization’s continual compliance with the DNV GL accreditation process. DNV GL accreditation standards cover the following key aspects of organizational governance and clinical care: • Quality management system and governance • Proactive risk management • Higher risk services such as anesthesia, obstetrics, and ER • Medication management • Patient rights • Physical environment • Accreditation standards developed for the following types of healthcare organizations: ■■

Hospitals

■■

Primary care providers

■■

Specialist outpatient clinics

DNV GL surveyors have a healthcare background, and they specialize in one of three areas: management systems, clinical care, or physical environment.21

Chapter 2  Standards for Compounded Sterile Preparations  13  Table 2-3.

Healthcare Facilities Accreditation Program—2016 Pharmacy Services/ Medication Use—Acute Care Manual Standard/Element Standard 25.01.02 Supervision of Pharmacy Activities This regulation identifies extensive and specific requirements for compounded preparations.

Scoring Procedure Can the hospital demonstrate that compounded medications used and/or dispensed by the hospital are being compounded consistent with standard operating procedures and quality assurance practices equivalent to or more stringent than the standards described in USP and ? If the hospital obtains compounded products from external compounding sources, are the external source(s) registered with the FDA as outsourcing facilities? If not, can the hospital demonstrate that it systematically evaluates and monitors whether the outside compounding pharmacy adheres to accepted standards for safe compounding? For example, does the contract include provisions ensuring that the hospital has access to quality assurance data verifying that the vendor is adhering to current USP and requirements, and can the hospital document that it obtains and reviews such data? Can the pharmacy director explain the risk level(s) of the CSPs being produced inhouse and/or obtained from external sources? Can he or she demonstrate that the assigned risk levels are consistent with USP or equivalent/more stringent standards? If any CSPs are produced in the hospital: ●● Ask for one or more examples of situations in which a BUD had to be determined for a CSP based on the policy. ●● Interview pharmacy personnel assigned to carry out this function within the hospital and/or to assess how this is done by external source(s) of CSPs. ■■ Is there evidence that the BUDs are determined consistent with the hospital’s policies and procedures? ■■ Interview staff who engage in sterile compounding. Are they knowledgeable about applicable levels of aseptic practices? ■■ Ask the pharmacy director to demonstrate how the following are accomplished to ensure that sterile compounding practices are consistent with USP or equivalent/more stringent standards for the risk level(s) of CSPs being produced for/dispensed to hospital patients: ◆◆ Verification of compounding accuracy and sterility ◆◆ Environmental quality and controls, including environmental sampling; testing and monitoring; and cleaning and disinfection ◆◆ Personnel training and competency assessment, including but not limited to accuracy/precision in identifying and measuring ingredients; cleansing and garbing; aseptic manipulation skills; environmental quality and disinfection; appropriate work practices within and adjacent to the direct compounding area; verification/ calibration of equipment; sterilization; and postproduction quality checks

(continued)

  14  Compounding Sterile Preparations Table 2-3. (continued)

Healthcare Facilities Accreditation Program—2016 Pharmacy Services/ Medication Use—Acute Care Manual Standard/ Element

Scoring Procedure Review the hospital’s procedures for maintaining the quality of CSPs during storage, transport and dispensing. ●● Are CSPs packaged in a manner to protect package integrity and sterility? How are CSP-specific requirements with respect to motion, light exposure, temperature and potentially hazardous contents addressed? ●● How does the hospital ensure that such information is effectively conveyed to nonpharmacy healthcare personnel and/or to patients/caregivers, if applicable? ●● Can the hospital document that it is systematically monitoring and tracking adherence to all of the quality assurance and personnel training and competency standards described above?

BUD = beyond-use date; CSP = compounded sterile preparation; FDA = Food and Drug Administration. Source: Adapted with permission from AOA/HFAP. HFCA 2016 pharmacy services/medication use—acute care manual and 25.01.02 supervision of pharmacy activities. http://hfap.org/resources/manuals.aspx.

Accrediting Agencies for Standalone Compounding Pharmacies Three agencies accredit pharmacies that are not a part of a hospital or health system (i.e., independent or standalone compounding pharmacies). Many pharmacies seek these accreditations on a voluntary basis. The pharmacies might comprise home infusion pharmacies, large or small outsourcing facilities, community compounding pharmacies, and other types of pharmacies that compound and dispense based on an individual patient prescription or on wholesale orders from other healthcare entities. Standalone pharmacy accrediting agencies each have distinct standards and methods of survey. The most recently established and the most powerful of these surveyors is the FDA.

U.S. Food

and

Drug Administration

Since 1990, the FDA has sent warning letters to pharmacies that manufacture, distribute, and promote unapproved drugs for human use outside the bounds of licensed pharmacy practice.22 The U.S. Congress passed the Food and Drug Admin-

istration Modernization Act in 1997 to clarify the roles of compounding pharmacies versus pharmaceutical manufacturers but law suits resulted in the invalidation of part 503A of the act. The fungal meningitis tragedy brought large compounding operations into national headlines and caused the U.S. Congress to enact the DQSA on November 27, 2013.23

Drug Quality

and

Security Act

The DQSA contains two titles: Title I covers drug compounding and Title II relates to drug supply chain security. Title I creates a “safe harbor” for traditional pharmacy compounding pursuant to a specific patient prescription under Section 503A. The act leaves jurisdiction of traditional compounding to the states thereby exempting this type of compounding from FDA regulations such as current good manufacturing practices (CGMP), drug product labeling, and FDA approval prior to selling. DQSA applies to all pharmacies, although some medications are not covered under the act (i.e., radiopharmaceuticals that are regulated by the Nuclear Regulatory Commission, investigational drugs, and veterinary compounds).

Chapter 2  Standards for Compounded Sterile Preparations  15 

Hospital and health-system pharmacies and community pharmacies generally operate within the safe harbor of Section 503A as long as such operations include drug compounding allowed under 503A. DQSA defines what drugs can be compounded under Section 503A24:

4. The drug product is compounded using bulk drug substances that are manufactured by an establishment that is registered under section 510 of the FD&C Act (including a foreign establishment that is registered under section 510(i) of the FD&C Act) (section 503A(b)(1) (A)(ii) of the FD&C Act).

1. The drug product is compounded for an identified individual patient based on the receipt of a valid prescription order, or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient.

5. The drug product is compounded using bulk drug substances that are accompanied by valid certificates of analysis for each bulk drug substance (section 503A(b)(1)(A)(iii) of the FD&C Act).

2. The compounding of the drug product is performed by the following: ■■

■■

A licensed pharmacist in a state licensed pharmacy or a federal facility, or by a licensed physician on the prescription order for an individual patient made by a licensed physician or other licensed practitioner authorized by state law to prescribe drugs. A licensed pharmacist or licensed physician in limited quantities before the receipt of a valid prescription order for such individual patient and the following: ◆◆

◆◆

Based on a history of the licensed pharmacist or licensed physician receiving valid prescription orders for the compounding of the human drug product. Orders that been generated solely within an established relationship between the licensed pharmacist or licensed physician and either such patient for whom the prescription order will be provided or the physician or other licensed practitioner who will write the prescription order.

3. The drug product is compounded in compliance with the USP chapters on pharmacy compounding using bulk drug substances, as defined in 21 CFR 207.3(a)(4), that comply with the standards of an applicable USP or NF monograph, if one exists. If such a monograph does not exist, the drug substance(s) must be a component of an FDA-approved human drug product. If a monograph does not exist and the drug substance is not a component of an FDA-approved human drug product, it must appear on a list of bulk drug substances for use in compounding developed by FDA through regulation (section 503A(b) (1)(A)(i) of the FD&C Act).

6. The drug product is compounded using ingredients (other than bulk drug substances) that comply with the standards of an applicable USP or NF monograph, if one exists, and the USP chapters on pharmacy compounding (section 503A(b)(1)(B) of the FD&C Act). 7. The drug product does not appear on the list, published at 21 CFR 216.24, that includes drug products that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective (section 503A(b)(1)(C) of the FD&C Act). 8. The licensed pharmacist or licensed physician does not compound regularly or in inordinate amounts any drug products that are essentially copies of commercially available drug products (section 503A(b)(1)(D) of the FD&C Act). 9. The drug product is not a drug product identified by FDA by regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product (section 503A(b)(3)(A) of the FD&C Act). 10. The drug product is compounded in a state that has entered into a memorandum of understanding (MOU) with FDA that addresses the distribution of inordinate amounts of compounded drug products interstate and provides for appropriate investigation by a state agency of complaints relating to compounded drug products distributed outside such state; or, in states that have not entered into such an MOU with FDA, the licensed pharmacist, licensed pharmacy, or licensed physician does not distribute, or cause to be distributed, compounded drug products out of the state in which they are compounded, more than 5% of the total prescription orders dispensed or distributed by such pharmacy or

  16  Compounding Sterile Preparations physician (sections 503A(b)(3)(B)(i) & (ii) of the FD&C Act).24

outsourcing facilities.28 The FDA provides a list of registered outsourcing facilities.29

Under 503A compounding does not include mixing, reconstituting, or other acts necessary in following the directions on a manufacturer’s label.25

In consultation with NABP, the secretary of the U.S. Department of Health and Human Services (HHS) is required to receive information from state boards of pharmacy about compounding pharmacies and outsourcing facilities. This information could include descriptions of actions they have taken against these entities, such as imposing sanctions or penalties, suspending or revoking a pharmacy license or registration, or the recall of a compounded drug. A state board of pharmacy also could submit to the HHS any concerns that a compounding pharmacy could be acting contrary to section 503A. The secretary of the HHS would be required to notify all state boards of pharmacy when information is received from a state board regarding actions taken against a compounding pharmacy or when the secretary determines a pharmacy is acting contrary to Section 503A.26

Title I also gives compounding pharmacies the option of registering with the FDA as outsourcing facilities governed under section 503B (Chapter 32).26 An FDA-registered outsourcing facility must adhere to CGMP but does not need to receive FDA approval for its compounded products prior to marketing and can qualify for exemptions regarding labeling products with adequate directions for use. In addition, outsourcing facilities must adhere to the following: • They are not required to be state-licensed pharmacies. • They must compound under the supervision of a licensed pharmacist or physician. • They may or may not obtain patient-specific prescriptions. • They may only use drugs from a bulk ingredients list. • They are not allowed to compound products already commercially available unless the products are in short market supply. • They must undergo regular FDA inspections on a risk-based schedule. • They must submit information about products compounded within the facility to the FDA every 6 months. • They must report product-related adverse events to the FDA. • They must pay an annual fee of $15,000 (to increase annually) to the FDA to cover inspection costs.27

Pharmacy compounders, that choose not to register with the FDA as an outsourcing facility and are not traditional compounders under 503A, are subject to the same requirements as conventional manufacturers under the FD&C Act (i.e., new drug approval, adequate directions for use, and CGMP requirements).28 When a 503A compounding pharmacy cannot prepare a CSP, the FDA encourages healthcare systems and providers to buy compounded medications from registered

The secretary of the HHS has convened the Advisory Committee on Compounding to issue regulations that identify the drugs that are demonstrably difficult to compound and are reasonably likely to lead to adverse effects.30 Pharmacists could compound substances unlikely to be on the “bulk drug substances list” by submitting “treatment” investigational new drug (IND) applications. With a standing treatment IND, individual healthcare providers would not have to pursue the approval of an institutional review board before having a patient use the drug substance.31 To enforce its inspections and actions, FDA may issue warning letters, seize products, obtain court injunctions against pharmacies, and support criminal prosecutions for compounding violations. Although DQSA compounding performed by health-system pharmacies is not changed, regional compounding centers operated by a health system are in a grey area and could fall under 503A or 503B. Drug products compounded in accord with 503A are exempt from certain requirements in the FD&C Act, as described above; however, they remain subject to all other provisions of the FD&C Act that apply to conventional drug manufacturers, including, but not limited to, the prohibition on preparing, packing, or holding drugs under insanitary conditions.32 For more on FDA Guidance documents, see Appendix D.

Chapter 2  Standards for Compounded Sterile Preparations  17 

Accreditation Commission for Health Care The Accreditation Commission for Health Care (ACHC) is a national organization developed by home care and alternate-site healthcare providers to establish a standard of care for those types of facilities. It is uniquely concerned with healthcare providers from a wide array of practicing locations, and its focus is helping those providers deliver optimum care for their patients. ACHC specializes in accrediting not just pharmacies, but also home health (Medicare-certified); community retail pharmacies; hospice: durable medical equipment, prosthetics, orthotics and supplies; private duty nurses (non-Medicare certified), sleep labs, and behavioral health organizations. ACHC collaborates with industry experts to create standards to ensure that quality is maintained throughout all aspects of the organization.

• Ambulatory infusion center (AIC)—An AIC is a centralized location where a patient can receive infusion therapy administered by appropriate clinical personnel. • Specialty pharmacy—A specialty pharmacy dispenses medications (injectable, IV, or oral) in a client’s/patient’s home, physician’s office, or clinic specializing in certain disease states. These medications target a specific population with a chronic and sometimes life-threatening disease. Specialty pharmacy includes diseasespecific clinical monitoring as well as patient compliance and adherence programs. • Long-term care pharmacy—Long-term care pharmacy is the management of medications for residents of institutional facilities to ensure proper drug therapy, as well as packaging and delivery of medications.

Onsite surveys are conducted every 3 years by healthcare experts. A comprehensive review is conducted of organizational structure, policies and procedures, compliance with federal/state/ local laws, leadership, patients’ rights and responsibilities, fiscal operations, human resource management, provision of care, patient records, quality outcomes, performance improvement, infection control, and patient/employee safety. At the time of survey, organizations demonstrate how they have maintained continuous compliance with the ACHC Standards for Accreditation.33

Pharmacy Compounding Accreditation Board

ACHC is a recognized leader in the area of pharmacy accreditation. ACHC pharmacy surveyors are licensed pharmacists who draw on relevant experience to provide a comprehensive assessment of an organization as well as provide helpful, consultative advice. ACHC accredits pharmacies that dispense medications pursuant to a prescription order for an individually identified patient for the following pharmacy services34:

ACHC administers PCAB accreditation for nonsterile and sterile pharmacy compounding. PCAB accreditation assesses the compounding process based on a specific set of standards that concentrate on the quality and consistency of medications produced. The ACHC/PCAB describes the presurvey process, the onsite process, the postsurvey process, standards, and informational resources.35

• Infusion pharmacy—The infusion pharmacy continuum of care includes intravenous (IV) drug admixture preparation, IV administration, therapy monitoring, client/patient counseling and education. It is the administration of medications using IV, subcutaneous, and epidural routes. Accreditation for sterile compounding includes compliance with USP Chapter .

The Pharmacy Compounding Accreditation Board (PCAB) is a voluntary accrediting organization founded in 2004. PCAB was formed by eight national pharmacy organizations, including USP, to serve as a voluntary accrediting body for the practice of pharmacy compounding. This type of accreditation is suitable for a smaller compounding pharmacy that is not part of a large health system or outsourcing facility. Beginning July 1, 2014, PCAB became a service of ACHC.

The Joint Commission Medication Compounding Certification Program In early 2017, TJC announced the development of a new medication compounding certification program. The certification is open to all compounding pharmacies operating or shipping to

  18  Compounding Sterile Preparations

states with regulations that require compliance with USP Chapters and/or .36 It is unclear whether many standalone sterile compounding pharmacies will seek Joint Commission certification.

United States Pharmacopeia–National Formulary The U.S. Pharmacopeial Convention (USP) is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed, and consumed worldwide. The FDA enforces the USP’s drug standards that are used in more than 140 countries.37 Standards in USP–NF for compounded preparations may be enforced by the state boards of pharmacy, the health-system accrediting agencies, and the FDA. In the late 1980s, USP decided that compounding sterile IV preparations for home use involved special concerns (e.g., extended parenteral nutrition storage and patient manipulations prior to use). Therefore, they established a Home Health Care Advisory Panel in 1989 to draft a chapter on compounding sterile preparations for home use. USP Chapter Sterile Drug Products for Home Use appeared in the 1995 USP–NF and was revised in the 2000 USP–NF.38,39

USP Chapter Pharmaceutical Compounding—Sterile Preparations In March 2002, the USP changed Chapter to USP Chapter , and the first official version was published in USP’s Pharmacopeial Forum.40 USP Chapter became official on January 1, 2004. Unlike USP Chapter , which was limited to home care, USP Chapter pertains to all healthcare organizations’ preadministration manipulations and procedures involved in preparation of sterile compounds for application, implantation, infusion, inhalation, injection, insertion, instillation, or irrigation including preparation, storage, and transportation. The chapter does not pertain to actual clinical administration of CSPs to patients. The intent of USP Chapter is to prevent

patient harm that may result from nonsterility, excessive endotoxin load, large content errors in strength of correct ingredients, or the presence of incorrect ingredients.41 The change in number to USP Chapter made this chapter enforceable because the 1938 federal FD&C Act set up the FDA as the enforcement authority and recognized USP as the official compendia of standards. All USP–NF chapters numbered under 1,000 are enforceable, whereas numbers over 1,000 are intended to provide information on, give definition to, or describe a particular subject.42 In other words, the FDA can use USP Chapter to determine whether CSPs have been contaminated, misbranded, or adulterated.43 Because the first USP Chapter brought hundreds of comments from professional organizations, healthcare institutions, and individual pharmacists, USP appointed a new committee of experts to review and improve USP Chapter . This committee, the Sterile Compounding Committee (SCC), served from 2005 to 2010 and was composed of 12 persons representing pharmacy academia, institutional pharmacy, home care, microbiology, and controlled environments. Based on the USP standards development process, the SCC considered more than 500 comments and published the revised USP Chapter on December 3, 2007 as a revision bulletin. The chapter became official and enforceable on June 1, 2008, replacing the original USP Chapter that had become official on January 1, 2004.40 The 2008 revision to USP Chapter provided more extensive information (61 pages versus the original’s 15 pages) and focused more on personnel training, garbing, and cleaning. Sections were added on HDs (see USP Chapter below), radiopharmaceuticals, and allergen extracts as CSPs. There were new sections on definitions, immediate-use CSPs, single-dose and multiple-dose containers, personnel training, competency and evaluation of garbing, aseptic work practices and cleaning/disinfection, elements of quality control, and abbreviations and acronyms. All previous sections were revised (e.g., environmental sampling now includes microbial air and surface testing), and there were four new appendixes.44

Chapter 2  Standards for Compounded Sterile Preparations  19 

Responsibility

of

Compounding Personnel

USP Chapter requires the following of compounding personnel: Compounding personnel are responsible for ensuring that compounded sterile preparations (CSPs) are accurately identified, measured, diluted, and mixed and are correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed, and distributed. These performance responsibilities include maintaining appropriate cleanliness conditions and providing labeling and supplementary instructions for the proper clinical administration of CSPs. Compounding supervisors shall ensure, through either direct measurement or appropriate information sources, that specific CSPs maintain their labeled strength within monograph limits for USP articles, or within 10% if not specified, until their BUDs. All CSPs are prepared in a manner that maintains sterility and minimizes the introduction of particulate matter. A written quality assurance procedure includes the following in-process checks that are applied, as appropriate, to specific CSPs: accuracy and precision of measuring and weighing; the requirement for sterility; methods of sterilization and purification; safe limits and ranges for strength of ingredients, bacterial endotoxins, and particulate matter; pH; labeling accuracy and completeness; BUD assignment; and packaging and storage requirements. The dispenser must, when appropriate and practicable, obtain and evaluate results of testing for identity, strength, purity, and sterility before a CSP is dispensed.44 Copyright © 2016 U.S. Pharmacopeial Convention. Reprinted with Permission.

In addition, USP Chapter lists 14 objectives that qualified licensed healthcare professionals who supervise compounding and dispensing of CSPs must ensure. Allen and Okeke provide an extensive discussion on the responsibilities of sterile compounding personnel.45

CSP Microbial Contamination Risk Levels USP Chapter requires that the licensed healthcare professionals who supervise sterile compounding be responsible for determining the procedural and environmental quality practices and attributes that are necessary for the risk level they assign to specific CSPs. The three risk levels for CSPs are assigned primarily according to the potential for microbial contamination during the compounding of low-risk CSPs and medium-risk level CSPs or the potential for not sterilizing highrisk level CSPs.44 Table 2-4 defines risk levels and examples within each risk level. The USP expert SCC considered whether to add product simulation sterility testing for medium-risk CSPs (e.g., batch preparations) in lieu of testing actual CSPs, but the committee declined to add process simulation. Instead, the chapter includes greater emphasis in personal aseptic work practices to prevent microbial contamination of CSPs.46

Exemptions to the Microbial Contamination Risk Levels USP Chapter allows certain exemptions to meeting the compounding conditions of microbial risk levels (Table 2-5). Low-risk level CSPs with 12-hour or less BUDs must meet all the following criteria to allow low-risk level compounding outside of the controlled environment of an ante-area and buffer area suite: • Primary engineering controls (i.e., LAFW [laminar airflow workbench], BSC [biological safety cabinet] or CAI [compounding aseptic isolator]) must be certified and maintained at ISO Class 5 or better for exposure of critical sites and must be in a segregated compounding area (SCA) restricted to sterile compounding of nonhazardous or radiopharmaceutical CSPs pursuant to a physician’s order for a specific patient. • The SCA must not be in a location with unsealed windows or doors that connect to the outdoors or high traffic flow or that is adjacent to construction sites, warehouses, or food preparation.

  20  Compounding Sterile Preparations Table 2-4.

USP Chapter Classification and Examples of Risk Levels44 Risk Levels Defineda Low-Risk Conditions—All of the following conditions: ●● Aseptic compounding within ISO Class 5 or better air quality with only sterile ingredients, products, components, and devices ●● Aseptically opening ampuls, penetrating disinfected stoppers on vials with sterile needles and syringes ●● Transferring, measuring and mixing with no more than three sterile commercially available products and with no more than two entries into any one sterile container ●● In the absence of passing a sterility test, not storing finished preparations longer than 48 hours at room temperature, longer than 14 days under refrigeration and longer than 45 days in solid frozen state Medium-Risk Conditions—All low-risk conditions plus one or more of the following conditions: ●● Combining or pooling multiple individual or small doses of sterile commercially available products to make CSPs that will be administered to multiple patients or to one patient multiple times ●● Complex manipulating process using other than single-volume transfer ●● Compounding for unusually long durations (e.g., to complete dissolution or homogeneous mixing) ●● In the absence of passing a sterility test, not storing finished preparations longer than 30 hours at room temperature, longer than 9 days under refrigeration and longer than 45 days in solid frozen state High-Risk Conditions—Any of the following conditions: ●● Incorporating nonsterile ingredient(s) or employing nonsterile device(s) ●● Exposing any of the following to air quality worse than ISO Class 5 for more than 1 hour— sterile contents of commercially manufactured products, CSPs without effective antimicrobial preservatives, or sterile surfaces of devices or containers ●● Personnel gloving and/or gowning improperly ●● Storing nonsterile water-containing preparations for more than 6 hours before being sterilized ●● Assuming and not verifying that the chemical purity and content strength of ingredients meet their original or compendial specifications in unopened or opened packages of bulk ingredients ●● In the absence of passing a sterility test, not storing finished preparations longer than 24 hours at room temperature, longer than 3 days under refrigeration and longer than 45 days in solid frozen state Examples Low Risk ●● Single-volume transfers of sterile dosage forms from ampuls, bottles, bags, and vials using sterile syringes with sterile needles, other administration devices, and other sterile containers. The solution content of ampuls should be passed through a sterile filter to remove any particles ●● Simple aseptic measuring and transferring with not more than three packages of manufactured sterile products,including an infusion or diluent solution to compound drug admixtures and nutritional solutions (continued)

Chapter 2  Standards for Compounded Sterile Preparations  21  Table 2-4. (continued)

Classification and Examples of Risk Levels Medium Risk Compounding of total parenteral nutrition fluids using manual or automated devices during which there are multiple injections, detachments, and attachments of nutrient source products to the device or machine to deliver all nutritional components to a final sterile container ●● Filling of reservoirs of injection and infusion devices with more than three sterile drug products and evacuation of air from those reservoirs before the filled device is dispensed ●● Transfer of volumes from multiple ampuls or vials into one or more final sterile containers ●●

High Risk ●● Dissolving nonsterile bulk drug and nutrient powders to make solutions that will be terminally sterilized ●● Exposing the sterile ingredients and components used to prepare and package CSPs to room air quality worse than ISO Class 5 for more than 1 hour ●● Measuring and mixing sterile ingredients in nonsterile devices before sterilization is performed ●●

Assuming, without appropriate evidence or direct determination, that packages of bulk ingredients contain at least 95% by weight of their active chemical moiety and have not been contaminated or adulterated between uses

CSPs = compounded sterile preparations; ISO = International Organization for Standardization. a The conditions described above for low-, medium-, and high-risk-level CSPs are a guide to the breadth and depth of care necessary but they are neither exhaustive nor prescriptive.

• Personnel must follow USP Chapter procedures for cleansing, garbing and additional personnel requirements prior to compounding. • Sinks should be separated from the immediate area of the ISO Class 5 primary engineering control. • USP Chapter standards for cleaning and disinfecting, personnel training and competency evaluation of garbing, aseptic work practices and cleaning/disinfection procedures, viable and nonviable environmental air sampling must be followed.44 Copyright © 2016 U.S. Pharmacopeial Convention. Adapted with permission.

Preparing CSPs with a 12-hour or less BUD under the above conditions might be necessary in pharmacy satellites with too little space for an ante-area and buffer area (Chapter 25). An immediate-use provision (or exemption) is intended only for those situations where there is a need for emergency or immediate patient administration of a CSP. Such situations may include cardiopulmonary resuscitation, emergency department treatment, preparation of diagnostic

agents, or critical therapy where the preparation of the CSP under conditions described for lowrisk level CSPs subjects the patient to additional risk due to delays in therapy. Immediate-use CSPs are not intended for storage for anticipated needs or batch compounding. Preparations that are HDs, medium-risk level, and high-risk level CSPs must not be prepared as immediate-use CSPs.44 The SCC selected the 1-hour preparation and storage time limit to minimize the opportunity for microbial contamination and colonization based on the expected growth rates of microbes that might be accidentally introduced during compounding and to fulfill the purpose of “immediate use.”46 Immediate-use CSPs are exempt from the primary and secondary engineering control requirements described for low-risk level CSPs only when all of the following criteria are met44: 1. The compounding process involves simple transfer of not more than three commercially manufactured packages of sterile, nonhazardous products or diagnostic radiopharmaceutical products from the manufacturers’ original containers and not more than two entries into

X

Proprietary bag and vial systems used according to commercial manufacturer labeling X

Handwashing and Garb

X

X

X

Primary Engineering Control (ISO 5)

X

X

ISO Class 8 or cleaner air

X

X

Secondary Engineering Control (ISO 7 buffer and ISO 8 ante areas)

X

X

X

Viable and Nonviable Air Sampling

BUDs = beyond-use dates; CSPs = compounded sterile preparations; ISO = International Organization for Standardization.

X

X

Personnel Training and Evaluation (observation, testing, media fills, fingertip sampling, etc.)

Allergen extract multiple-dose CSPs that meet 11 criteria

Low-risk level radio-pharmaceutical CSPs

Immediate-use CSPs with 1-hr or less BUDs (not including hazardous drugs)

Low-risk CSPs with 12-hr or less BUDs (not including hazardous drugs)

Name of Exemption (below) and USP Chapter Standards to Which Exempted (to right)

Summary of Exemptions to USP Chapter Standards

Table 2-5.

X

X

X

Cleaning and Disinfecting of Compounding Area

  22  Compounding Sterile Preparations

Chapter 2  Standards for Compounded Sterile Preparations  23  any one container or package (e.g., bag, vial) of sterile infusion solution or administration container/device. For example, antineoplastics shall not be prepared as immediate-use CSPs because they are hazardous drugs.

for handling and storing proprietary bag and vial systems.44 This exemption may allow these systems to be stored and activated outside of primary and secondary engineering controlled areas, depending on manufacturer instructions.

2. Unless required for the preparation, the compounding procedure is a continuous process not to exceed 1 hour.

Under certain conditions, radiopharmaceutical CSPs may be exempt from some USP Chapter standards (Chapter 13). Under other certain conditions, allergen extract CSPs may be exempt from some USP Chapter standards (Chapter 3). For a summary of exemptions to USP Chapter standards, see Table 2-5. Many other chapters in this book explain how to interpret and implement the detailed sterile compounding standards set forth in USP Chapter .

3. During preparation, aseptic technique is followed and, if not immediately administered, the finished CSP is under continuous supervision to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other CSPs, and direct contact of outside surfaces. 4. Administration begins not later than 1 hour following the start of the preparation of the CSP. 5. Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer, the CSP shall bear a label listing patient identification information, the names and amounts of all ingredients, the name or initials of the person who prepared the CSP, and the exact one-hour BUD and time. 6. If administration has not begun within 1 hour following the start of preparing the CSP, the CSP shall be promptly, properly, and safely discarded.44 Copyright © 2016 U.S. Pharmacopeial Convention. Reprinted with Permission.

USP Chapter does not specify that a LAFW, BSC, or CAI must be used for immediate-use sterile compounding. USP Chapter specifies what personnel cleansing and garbing is required for immediate-use sterile compounding. Under certain conditions, proprietary bag and vial systems may be exempt from some USP Chapter standards. The sterility storage and stability BUD times for attached and activated (where activated is defined as allowing contact of the previously separate diluent and drug contents) container pairs of drug products for intravascular administration (e.g., ADD-Vantage, Mini-Bag Plus, Add AVial, Add-Ease, Duplex, etc.) must be applied as indicated by the manufacturer. In other words, follow manufacturers’ instructions

USP Chapter Hazardous Drugs —Handling in Healthcare Settings Published in final form on February 1, 2016, USP Chapter consolidates the requirements for healthcare personnel who handle HDs.47 The purpose of USP Chapter is to minimize exposure with HDs for patients, healthcare personnel, and the environment. USP Chapter builds on standards established by existing compounding USP Chapter and USP Chapter , setting standards for HD containment in both sterile and nonsterile handling processes so as to contain HDs to as low a limit as reasonably achievable. USP Chapter incorporates standards from the Occupational Safety and Health Administration (OSHA), the National Institute for Occupational Safety and Health (NIOSH), and ASHP as well. USP Chapter standards include but are not limited to receipt, storage, mixing, preparing, compounding, dispensing, administering, disposing, and otherwise altering, counting, crushing, or pouring HDs. USP Chapter applies to all personnel who handle HDs and to all places where HDs are prepared, stored, transported, and administered. Because of the extensive changes that some healthcare organizations will require to become compliant with USP Chapter , USP has set the official (enforceable) expected date as December 1, 2019. It is likely that regulatory and accrediting agencies will embrace USP Chapter standards.

  24  Compounding Sterile Preparations

Sections within USP Chapter include the following: • List of HDs (see NIOSH below) • Types of exposure • Responsibilities of personnel handling HDs • Facilities and engineering controls (Chapters 9 and 25) • Environmental quality and control • Personal protective equipment (Chapter 10) • Hazard communication program • Personnel training • Receiving • Labeling, packaging, transport, and disposal • Dispensing final dosage forms • Compounding • Administering • Deactivating, decontaminating, cleaning, and disinfecting (Chapter 27) • Spill control • Documentation and standard operating procedures • Medical surveillance • Appendix 1: Acronyms and Definitions • Appendix 2: Examples of Design for HD Compounding Areas • Appendix 3: Types of Biological Safety Cabinets • References

More details on USP Chapter are supplied in Chapter 12 and in many other chapters in this book. To ensure compliance with USP Chapter , each entity must have a designated person who is qualified and trained to be responsible for developing and implementing appropriate procedures; overseeing entity compliance with this chapter and other applicable laws, regulations, and standards; ensuring competency of personnel; and ensuring environmental control of the storage and compounding areas. The designated person must thoroughly understand the rationale for riskprevention policies, risks to themselves and others, risks of noncompliance that may compromise

safety, and the responsibility to report potentially hazardous situations to the management team. The designated person must also be responsible for the oversight of monitoring the facility, maintaining reports of testing/sampling performed in facilities, and acting on the results.47 Because USP Chapter is more recent than USP Chapter , USP Chapter supersedes any differences from USP Chapter with regard to handling HDs. USP Chapter differences from include the following: • By inclusion, makes the NIOSH Alert (below) enforceable • Prohibits handling HDs in any area that is positive pressure relative to the surrounding areas • Requires spill kits to be available in HD receiving areas • Prohibits HDs, even at a low volume, from being compounded in a non-negative pressure room • Requires all HD compounding to be done in a separate area designated for HD compounding only • Allows a containment segregated compounding room to be used for compounding low- and medium-risk HDs if the containment primary engineering control (C-PEC) is located in a noncontrolled room (i.e., non-ISO Class 7) with at least 12 air changes per hour and if CSPs have a maximum BUD of 12 hours • Prohibits HD storage in a buffer room other than the buffer room used for HD compounding • Requires a C-PEC to be externally vented but not necessarily to be 100% externally vented • Requires closed system drug transfer devices to be used for HD administration

Other USP Chapters The following are some of the other USP general chapters that relate to pharmacy compounding practice: • General Notices • Pharmaceutical Compounding— Nonsterile Preparations • Pharmaceutical Calculations in Pharmacy Practice

Chapter 2  Standards for Compounded Sterile Preparations  25  • Quality Assurance in Pharmaceutical Compounding • Prescription Balances and Volumetric Apparatus • Injections and Implanted Drug Products (Parenterals)—Product Quality Tests • Labeling

• Good Packaging Practices • Good Repackaging Practices • Stability Considerations in Dispensing Practice • Good Distribution Practices for Bulk Pharmaceutical Excipients

• Prescription Container Labeling

• Sterilization and Sterility Assurance of Compendial Articles

• Volumetric Apparatus

• Depyrogenation

• Balances

• Dry Heat Depyrogenation

• Antimicrobial Effectiveness Testing

• Depyrogenation by Filtration

• Biological Indicators—Resistance Performance Tests

• Endotoxin Indicators for Depyrogenation

• Sterility Tests

• Biological Indicators for Sterilization

• Bacterial Endotoxins Test • Pyrogen Test

• Physicochemical Integrators and Indicators for Sterilization

• Elastomeric Closures for Injections

• New Sterilization Methods

• Packaging and Storage Requirements

• Sterilization-in-Place

• Containers—Glass

• Water for Pharmaceutical Purposes

• Plastic Packaging Systems and their Materials of Construction

• Weighing on an Analytical Balance

• Containers—Performance Testing • Deliverable Volume • Loss on Drying • Osmolality and Osmolarity • Particulate Matter in Injections • pH • Refractive Index • Specific Gravity • Biological Indicators for Sterilization • Cleaning Glass Apparatus • Physical Environments That Promote Safe Medication Use • Disinfectants and Antiseptics • Good Storage and Distribution Practices for Drug Products • Microbiological Control and Monitoring of Aseptic Processing Environments • Packaging and Repackaging—SingleUnit Containers • Pharmaceutical Dosage Forms

Occupational Safety and Health Administration The Occupational Safety and Health Act of 1970 created both NIOSH and OSHA. OSHA, under the U.S. Department of Labor, has authority to go into workplaces, inspect worksite conditions, cite employers found in violation of agency standards, and levy fines. Under the General Duty Clause, OSHA may cite employers for “obvious and serious workplace hazards.”48 Specific OSHA standards of concern to healthcare organizations include personal protective equipment, blood-borne pathogens, hazard communication, ergonomics, and others. OSHA has identified worker exposure to HDs as a problem of increasing health concern.49 Highlights of OSHA standards and standard interpretations include the following: • 29 CFR 1910.102050—Access to employee exposure and medical records. OSHA requires the reporting of employee exposure to hazardous medications and allows employees access to these records.

  26  Compounding Sterile Preparations • 29 CFR 1910.120051—Hazard communication; requires any drugs posing a health hazard, with the exception of those in solid, final form for direct administration to the patient (i.e., tablets or pills) to be included on lists of hazardous chemicals to which employees are exposed. In compliance with this standard, all personnel involved in any aspect of the handling of covered hazardous medications must receive information and training to apprise them of the hazards in the work area. • Safety data sheets must be provided to employees who package/process drugs for distribution into final form if they contain hazardous chemicals.52 • Hazard communication standard and pharmaceuticals explains that the pharmaceutical manufacturer and the importer have the primary duty for the evaluation of chemical hazards and that the employer may rely on the hazard determination performed by the pharmaceutical manufacturer or importer.53 • OSHA standard interpretation letter for the requirements of Material Safety Data Sheets (MSDS), now Safety Data Sheets (SDS), for drugs provides a response to a letter specifically questioning the requirement to maintain an SDS for drugs.54

OSHA standards for storing, handling, preparation, administration, and disposal of HDs are covered in Chapter 12.

Centers for Disease Control and Prevention NIOSH Alert NIOSH, a part of the Centers for Disease Control and Prevention (CDC), is an agency established to help ensure safe and healthful working conditions for workers by providing research, information, education, and training in the field of occupational safety and health. In September 2004, NIOSH published an alert entitled, “Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”55 The purpose of this alert is to increase awareness among healthcare workers and their employers about the health risks posed by working with HDs and to provide them with measures for protecting their health. Healthcare workers who prepare or administer HDs or who work in areas where these

drugs are used may be exposed to these agents in the air or on work surfaces, contaminated clothing, medical equipment, patient excreta, and other surfaces. The health risk is influenced by the extent of the exposure and the potency and toxicity of the HD. This alert applies to all workers who handle HDs (for example, pharmacy and nursing personnel, physicians, operating room personnel, environmental services workers, workers in research laboratories, veterinary care workers, and shipping and receiving personnel). Under USP Chapter , the NIOSH list of HDs becomes a minimum standard, so a healthcare organization must include all items on this list on its own list (provided that the use of the HD is allowed at the organization). NIOSH updates the list typically every 2 years based on new drugs that come to market and comments from stakeholders. As of this writing, the list from September 2016 is the most recent.56 This list is sorted into three different HD groups: antineoplastics, non-neoplastic HDs, and reproductive hazardous medications. The list also provides links that detail why the drug is included on the list. Each pharmacy needs to prepare itself by identifying which of these drugs on the list they handle. USP Chapter makes the NIOSH Alert and HD list enforceable by incorporating parts of the alert into the chapter itself. The handling, preparation, administration, and disposal of HDs are covered in Chapter 12.

ASHP ASHP is the national professional association that represents pharmacists and pharmacy technicians who practice in hospitals, health maintenance organizations, long-term care facilities, home care, and other components of healthcare systems. ASHP has continually promoted appropriate pharmacy compounding in the institutional setting since the 1940s. Specific to sterile compounding, ASHP developed a practice standard for the quality assurance of pharmacy CSPs. First published in 1993 as a technical assistance bulletin, this standard was updated and republished in 2000.57 This guideline has been superseded by USP Chapter , which is an enforceable sterile compounding standard.

Chapter 2  Standards for Compounded Sterile Preparations  27 

Guidelines

ASHP Resources

To harmonize with USP Chapter , ASHP updated its guidelines on compounding sterile preparations in 2014 (Appendix A).58 ASHP also published a technical assistance bulletin on compounding ophthalmic preparations and guidelines on the safe use of automated compounding devices for compounding of parenteral nutrition admixtures.59,60 In a follow-up to the NIOSH Alert above, ASHP published guidelines on handling hazardous drugs (Appendix B).61

The ASHP website has a compilation of tools and resources to help pharmacists ensure the quality of CSPs.64

ASHP Accreditation Residency Programs

of

Pharmacy

The ASHP Accreditation Standard for postgraduate year 1 and 2 (PGY1 and PGY2) pharmacy residency programs says that pharmacies where residents are trained must meet high standards: 6.2 Residency programs must be conducted only in those practice settings where management and professional staff have committed to seek excellence in patient care, demonstrated substantial compliance with professionally developed and nationally applied practice and operational standards, and have sufficient resources to achieve the educational goals and objectives selected for the residency program.62

on

Sterile Compounding

American Society for Parenteral and Enteral Nutrition Guidelines for Parenteral Nutrition Recognizing the importance of safe practices associated with these preparations, American Society for Parenteral and Enteral Nutrition (ASPEN) publishes their guidelines, which are organized under 12 questions that include background evidence to support specific recommendations.65 A few of the questions touch on sterile compounding. For example, Question 12 answers the question, “What beyond-use date should be used for (a) intravenous fat emulsion (IVFE) dispensed for separate infusion in the original container and (b) repackaged IVFE?”

Miscellaneous Agencies American Society Materials

for

Testing

and

ASHP Accreditation of Pharmacy Technician Training Programs

American Society for Testing and Materials (ASTM) International is a globally recognized leader in developing voluntary consensus standards. ASTM standards are used to improve product quality, enhance health and safety, strengthen market access and trade, and build consumer confidence. Through more than 140 technical standards-writing committees, ASTM serves a broad range of industries: metals, construction, petroleum, consumer products and many more.66

The ASHP Accreditation Standard for Pharmacy Technician Training programs says: “All experiential sites shall comply with all federal, state, and local laws, codes, statutes, regulations, and licensing requirements.”63 Where the state board of pharmacy requires full or partial compliance with USP Chapter and USP Chapter , these monographs become a requirement for ASHP-accredited pharmacy technician training programs in those states.

According to USP Chapter , when chemotherapy gloves are required they must meet ASTM Standard D6978 (or its successor). Chemotherapy gloves should be worn for handling all HDs including nonantineoplastics and for reproductive risk only HDs. Chemotherapy gloves must be powder-free because powder can contaminate the work area and can adsorb and retain HDs. When used for sterile compounding, the outer chemotherapy gloves must be sterile (Chapter 12).

ASHP Residency Accreditation Surveyors will inspect pharmacy and other practice setting facilities for compliance with national standards of practice such as USP Chapter and USP Chapter .

  28  Compounding Sterile Preparations

Controlled Environment Testing Association Controlled Environment Testing Association (CETA) is devoted to promoting and developing quality assurance within the controlled environment testing industry. USP Chapter and USP Chapter make specified CETA guidelines enforceable by inclusion. CETA guidelines related to sterile compounding and HDs include the following: • CAG-001-2005—Applications Guide for the Use of Compounding Isolators in Compounding Sterile Preparations in Healthcare Facilities (revised December 2008) • CAG-002-2006—Compounding Isolator Testing Guide (revised December 2008) • CAG-003-2006—Sterile Compounding Facilities (revised May 2015) • CAG-004-2007—Application Guide for the Use of Surface Decontaminants in Biosafety Cabinets • CAG-005-2007—Servicing Hazardous Drug Compounding Primary Engineering Controls • CAG-006-2010—CETA High Efficiency Filter Application Guide • CAG-007-2010—Application Guide for Exhaust System Requirements of Class II, Type B Biosafety Cabinets • CAG-008-2010—CETA Certification Matrix for Sterile Compounding Facilities (updated January 2012) • CAG-009-2011v3—CETA Certification Application Guide USP Chapter Viable Environmental Sampling & Gowning Evaluation • CAG-010-2011—Application Guide for Informational Notes to Meeting the NSF/ANSI 49:2010a Standard Requirements

As of January 2012, CETA application guides are available to CETA members as a free download. Nonmembers may access the guides for a nominal fee. CETA has a national board of testing for cleanroom certification professionals.67

Environmental Protection Agency The United States Environmental Protection Agency regulates the disposal of hazardous wastes

under the Resource Conservation and Recovery Act of 1977.68 See Chapters 12, 20, and 21 for a full discussion of the strong implications of this act for virtually all health-system pharmacies.

Institute for Environmental Sciences Technology

and

The Institute for Environmental Sciences and Technology (IEST), founded in 1953, is a multidisciplinary, international society whose members are internationally recognized for their contributions to the environmental sciences in the areas of contamination control in electronics manufacturing and pharmaceutical processes; design, test, and evaluation of commercial and military equipment; and product reliability issues associated with commercial and military systems.69 IEST has recommended practices for cleanroom design (Chapter 25).70

Institute

for

Safe Medication Practices

The Institute for Safe Medication Practices (ISMP) is a nonprofit organization that aims to educate the healthcare community and consumers about safe medication practices. In 2013, ISMP published guidelines for the safe preparation of CSPs. Experts developed these guidelines to provide procedures and safe practices for reducing errors in CSP preparation.71 The guidelines address drug storage, compounding, product labeling, and staff management. CMS specifically cites the ISMP guidelines for review by accredited health systems and pharmacies.14 In 2015, ISMP published targeted medication safety best practices for hospitals.72 Table 2-6 illustrates a new best practice to improve sterile compounding accuracy along with its rationale.

International Organization Standardization

for

The International Organization for Standardization (ISO) is a nongovernmental organization (i.e., its members are not delegations of national governments). ISO occupies a position between the public and private sectors. Some member institutes are part of the governmental structure of their countries or are mandated by their government. Other members have their roots in the private sec-

Chapter 2  Standards for Compounded Sterile Preparations  29  Table 2-6.

ISMP: A New Best Practice for Sterile Compounding Best Practice 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 for compounded sterile preparations of medications (e.g., the “syringe pull-back method,” checking a label rather than the actual ingredients). ●● Except in an emergency, perform this verification in all locations where compounded sterile preparations are made, including patient care units. ●● At a minimum, perform this verification for all high-alert medications (including chemotherapy and parenteral nutrition), pediatric/neonatal preparations, pharmacy prepared source/ bulk containers, products administered via high-risk routes of administration (e.g., intrathecal, epidural, intraocular), and other compounded sterile preparations that the organization believes are high-risk. ●●

Use technology to assist in the verification process (e.g., barcode scanning, verification of ingredients, gravimetric verification, robotics, IV workflow software) to augment the manual processes. It is important that processes are in place to ensure the technology is maintained, the software is updated, and that the technology is always used in a manner that maximizes the medication safety features of these systems.

Rationale ●● The goal of this best practice is to prevent medication errors during sterile compounding of drugs, especially for high-alert medications, that are not detected with proxy checks, such as the “syringe pull-back method.” ●● Between 2004 and 2011, ISMP has reported serious compounding errors involving 16 patients, 9 of whom died, mostly due to wrong concentration/strength, or wrong product or diluent. Many of these would have been identified prior to dispensing if preproduction checks or sterile processing technology would have been utilized. ●● ISMP continues to receive reports of errors resulting in serious harm and death that were specifically attributed to a failed check system when using the “syringe pull-back method.” This error-prone method has been used in pharmacies during the sterile compounding process for years. Using this method, an ingredient is injected from the syringe into the final container, and the plunger is then pulled back to the amount on the syringe that was injected. It is this “pulled-back” syringe which is checked to determine the accuracy of the amount injected. Errors may not be detected if the syringe does not reflect the actual amount added or when the pulled-back syringes are partnered with the wrong container of medication. Since 2010, ISMP has repeatedly warned against using this method of verification, especially for high-alert and pediatric medications. The practice also may be illegal in some states (e.g., Minnesota). ISMP = Institute for Safe Medication Practices. Source: Courtesy of ISMP. 2016–2017 targeted medication safety best practices for hospitals. www.ismp.org/tools/ bestpractices/TMSBP-for-Hospitals.pdf.

tor, which were set up by national partnerships of industry associations. ISO has published a series of standards for cleanrooms and associated controlled environments. The U.S. federal government now uses the terminology set forth by the ISO in place of its former standard (Federal Standard 209e; Chapters 9 and 25). Table 2-7 summarizes the

ISO monographs on cleanrooms and associated controlled environments.

NSF International Founded in 1944 as the National Sanitation Foundation, this organization’s name changed to

  30  Compounding Sterile Preparations Table 2-7.

ISO Standards for Cleanrooms and Associated Environmentsa ●●

●●

●● ●●

●● ●●

●●

●●

●●

ISO 14644-1:2015 Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness and A Statistical Approach to Site Selection and Number of Sampling Locations ISO 14644-2:2015 Cleanrooms and Associated Controlled Environments—Part 2: Specifications for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1 ISO 14644-3:2005 Cleanrooms and Associated Controlled Environments—Part 3: Test Methods ISO 14644-4:2001 Cleanrooms and Associated Controlled Environments—Part 4: Design, Construction, and Start-up ISO 14644-5:2004 Cleanrooms and Associated Controlled Environments—Part 5: Operations ISO 14644-7:2004 Cleanrooms and Associated Controlled Environments—Part 7: Separative Devices (Clean Air Hoods, Gloveboxes, Isolators, and Mini-environments) ISO 14644-8:2013 Cleanrooms and Associated Controlled Environments—Part 8: Classification of Air Cleanliness by Chemical Concentration (ACC) ISO 14644-9:2012 Cleanrooms and Associated Controlled Environments—Part 9: Classification of Surface Cleanliness by Particle Concentration ISO 14644-10:2013 Cleanrooms and Associated Controlled Environments—Part 10: Classification of Surface Cleanliness by Chemical Concentration

ISO = International Organization for Standardization. a See www.iso.org for more information.

NSF International in 1990 as services expanded beyond sanitation. The letters no longer represent any specific words. NSF International develops public health standards and certification programs to protect food, water, consumer products, and environment. NSF International’s mission is to protect and improve global human health. The international standard for Class II biological safety cabinets is NSF Standard 49 (Chapter 9).73

Summary Pharmacists who are responsible for compounding sterile preparations face many issues unknown 30 years ago. With current publicity, governmental scrutiny, and technological changes, pharmacists are greatly challenged to meet this responsibility. To compound sterile preparations appropriately,

pharmacists must understand the guidelines of state boards of pharmacy, accrediting agencies, FDA, USP, OSHA, CDC, NIOSH, ASHP, ASPEN and other agencies. It looks like the accrediting agencies will force pharmacists to meet USP– NF standards. USP Chapter has become the de facto national standard by which licensing, and accreditation bodies judge the compliance to standards by pharmacies and other healthcare organizations that compound sterile preparations. USP Chapter is a new national standard that pharmacists must understand and apply.

References 1. Centers for Disease Control and Prevention. Multistate fungal meningitis outbreak investigation. www.cdc.gov/hai/outbreaks/meningitis.html (accessed 2016 Feb 18).

Chapter 2  Standards for Compounded Sterile Preparations  31  2. Collins S. Two years after meningitis outbreak: Massachusetts passes compounding overhaul. Pharm Today. 2014; 20:61. 3. Belz KH. Tennessee health officials warn about drugs from Cleveland pharmacy. Times Free Press (2014 Sep 24). www.timesfreepress.com/news/ local/story/2014/sep/24/state-warns-about-drugsfrom-cleveland-pharmacy/267857/ (accessed 2017 Mar 27). 4. Anon. U.S. seizes $18 million from owners of pharmacy tied to meningitis outbreak. Pharmacist Today Daily (2015 Jan 7 2015). www.pharmacist. com/us-seizes-18-million-owners-pharmacy-tiedmeningitis-outbreak (accessed 2017 Mar 27). 5. Justice News. Two pharmacists sentenced to prison for adulteration of drugs in connection with Alabama-based compounding pharmacy. www. justice.gov/opa/pr/two-pharmacists-sentencedprison-adulteration-drugs-connection-alabamabased-compounding (accessed 2017 Mar 23). 6. Associated Press. Judge approves $200M settlement in 2012 meningitis outbreak. New York Times (2015 May 19). www.nytimes.com/aponline/2015/05/19/us/ap-us-meningitis-outbreaksettlement.html (accessed 2015 May 21). 7. Kastango E, Douglass K. State of pharmacy compounding—2015. Pharm Purch Prod. 2015; 15:S1-44. 8. Delegates approve 20 resolutions at annual meeting, resolution No. 89-1-93. NABP News. 1993; 22:57. 9. Anon. Model State Pharmacy Act and model rules of the National Association of Boards of Pharmacy—August 2016. www.nabp.pharmacy/ publications-reports/resource-documents/modelpharmacy-act-rules/ (accessed 2017 Feb 21). 10. Pickard S, Law EH, Crawford SY et al. National assessment of state oversight of sterile drug compounding—February 2016. Philadelphia: The Pew Charitable Trusts; 2016. 11. Social Security Act. 1865, 42 U.S.C. 1395bb; 42 CFR 488.12. 12. Centers for Medicare & Medicaid Services. CMSapproved accrediting organizations contacts for prospective clients (2016 Sep 2). www.cms.gov/ Medicare/Provider-Enrollment-and-Certification/ SurveyCertificationGenInfo/Downloads/Accrediting-Organization-Contacts-for-ProspectiveClients-.pdf (accessed 2017 Mar 21). 13. Office of Inspector General. Medicare’s oversight of compounded pharmaceuticals used in hospitals. Report (OEI-01-13-00400). www.oig.hhs.gov/ oei/reports/oei-01-13-00400.asp (accessed 2017 Mar 22). 14. Hamilton TE. Revised hospital guidance for pharmaceutical services and expanded guidance related to compounding of medications. www.

15.

16. 17.

18.

19. 20. 21.

22.

23. 24.

25.

26.

27.

cms.gov/Medicare/Provider-Enrollment-andCertification/SurveyCertificationGenInfo/Downloads/Survey-and-Cert-Letter-16-01.pdf (accessed 2017 Mar 22). Centers for Medicare & Medicaid Services. State Operations Manual, Appendix A (rev. 2015 Nov 20). www.cms.gov/Regulations-and-Guidance/ Guidance/Manuals/downloads/som107ap_a_hospitals.pdf (accessed 2017 Mar 22). Anon. Facts about The Joint Commission. www. jointcommission.org/about_us/fact_sheets.aspx (accessed 2016 Feb 18). Uselton JP, Kienle PC, Murdaugh LB. Chapter 19 review of USP chapter : pharmaceutical compounding—sterile preparations. In: Assuring continuous compliance with Joint Commission standards: a pharmacy guide. 8th ed. Bethesda, MD: ASHP; 2010:275-81. Healthcare Facilities Accreditation Program. 2016 prepublication announcement—acute care manual. www.hfap.org/blog/?p=10755 (accessed 2017 Mar 22). Center for Improvement in Healthcare Quality. www.cihq.org/ (accessed 2016 Feb 18). CIHQ Accreditation Standards. www.cihq.org/ home.asp (accessed 2016 Feb 18). DNV GL International Healthcare Accreditation. www.dnvgl.com/services/internationalhealthcare-accreditation-7516 (accessed 2016 Feb 18). Teshome BF, Reveles KR, Lee GC et al. How gaps in regulation of compounding pharmacy set the stage for a multistate fungal meningitis outbreak. J Am Pharm Assoc. 2014; 54:441-5. Drug Quality and Security Act of 2013. www.gpo. gov/fdsys/pkg/BILLS-113hr3204eh/pdf/BILLS113hr3204eh.pdf (accessed 2017 Mar 22). Pharmacy compounding of human drug products under section 503A of the Federal Food, Drug and Cosmetic Act (revision 2, 2016 Jun). www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469119. pdf (accessed 2017 Mar 22). The Drug Quality and Security Act (H.R.3204) section 503A of the Food, Drug and Cosmetic Act (2013 Nov 18). www.ashp.org/-/media/assets/ advocacy-issues/docs/drug-quality-and-securityact-section-503a-of-the-food-drug-cosmetic-act. ashx?la=en (accessed 2017 Mar 22). The Drug Quality and Security Act (H.R. 3204) section 503B of the Food, Drug and Cosmetic Act (2013 Nov 18). www.ashp.org/-/media/assets/ advocacy-issues/docs/drug-quality-and-securityact-section-503b-of-the-food-drug-cosmetic-act. ashx?la=en (2017 Mar 22). Gabay M. The Drug Quality and Security Act. Hosp Pharm. 2014; 49:615, 676.

  32  Compounding Sterile Preparations 28. U.S. Food and Drug Administration. Letter from Margaret A. Hamburg, MD, Commissioner of Food and Drugs, to hospital pharmacists (2014 Jan 8). www.fda.gov/downloads/Drugs/ GuidanceCompliance-RegulatoryInformation/ PharmacyCompounding/UCM380599.pdf (accessed 2017 Jan 3). 29. Anon. Registered outsourcing facilities: facilities registered as human drug compounding outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (updated 2017 Feb 17). www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm378645.htm (accessed 2017 Mar 23). 30. Traynor K. FDA revives compounding advisory committee. Am J Health-Syst Pharm. 2015; 72:598-9. 31. Thompson CA. Substances doubtful for bulk substances list could be INDs. Am J Health-Syst Pharm. 2016; 73:512-4. 32. DHHS FDA Notice (related to inspections of 503A pharmacies). www.fda.gov/downloads/ drugs/guidancecomplianceregulatoryinformation/ pharmacycompounding/ucm510684.pdf (accessed 2017 Mar 23). 33. Anon. Accreditation: the standard of quality. www.achc.org/getting-started/what-is-accreditation (accessed 2017 Mar 23). 34. Anon. ACHC pharmacy accreditation services. www.achc.org/programs/pharmacy (accessed 2016 Feb 18). 35. Anon. ACHC accreditation—pharmacy. www. achc.org/programs/pharmacy (accessed 2016 Feb 18). 36. Bronk KL. The Joint Commission launches medication compounding certification. www.jointcommission.org/joint_commission_launches_medication_compounding_certification/ (accessed 2017 Mar 23). 37. Anon. About USP. www.usp.org/about-usp (accessed 2016 Feb 18). 38. USP chapter sterile drug products for home use. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 1994:1963-75. 39. USP chapter sterile drug products for home use. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2000; 2130-43. 40. USP chapter pharmaceutical compounding—sterile preparations. Pharmacopeial Forum. 2003; 29:940-65. 41. Allen LV, Okeke CC. Basics of compounding for the implementation of United States Pharmacopeia chapter pharmaceutical compounding—sterile preparations, part 1. Int J Pharma Comp. 2007; 11:230-6.

42. General notices. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 43. Thompson C. USP publishes enforceable chapter on sterile compounding. Am J Health-Syst Pharm. 2003; 60:1814, 1817-8, 1822. 44. U.S. Pharmacopeial Convention. USP chapter pharmaceutical compounding—sterile preparations. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 45. Allen LV, Okeke CC. Basics of compounding: the responsibilities of compounding personnel in implementing USP chapter pharmaceutical compounding—sterile preparations, part 2. Int J Pharma Comp. 2007; 11:314-23. 46. Sterile Compounding Committee. Commentary—to revision bulletin for general chapter, pharmaceutical compounding —sterile preparations. In: USP guidebook to pharmaceutical compounding sterile preparations. Rockville, MD: U.S. Pharmacopeial Convention; 2008:79-93. 47. U.S. Pharmacopeial Convention. USP chapter hazardous drugs—handling in healthcare settings. In: USP 39–NF 34. Rockville MD: U.S. Pharmacopeial Convention; 2016. 48. Occupational Safety and Health Administration, Department of Labor. CFR title 29. Labor: subtitle—regulations relating to labor, part 1910, general article 1910.2 definitions. Washington, DC: U.S. Government Printing Office; 2004. 49. Anon. Hazardous drugs. www.osha.gov/SLTC/hazardousdrugs/index.html (accessed 2017 Mar 24). 50. Anon. Toxic and hazardous substances. www.osha. gov/pls/oshaweb/owadisp.show_document?p_ table=STANDARDS&p_id=10027 (accessed 2017 Mar 24). 51. Anon. Hazard communication. www.osha. gov/pls/oshaweb/owadisp.show_document?p_ table=STANDARDS&p_id=10099 (accessed 2017 Mar 24). 52. Fairfax RE. Letter of standard interpretation dated May 8, 2005. www.osha.gov/pls/ oshaweb/owadisp.show_document?p_ table=INTERPRETATIONS&p_id=25054 (accessed 2017 Mar 24). 53. Coe CP. Letter of standard interpretation: hazard communication and pharmaceuticals dated January 3, 1994. www.osha.gov/ pls/oshaweb/owadisp.show_document?p_ table=INTERPRETATIONS&p_id=21354 (accessed 2017 Mar 24). 54. Clark RA. Letter of standard interpretation: MSDS requirements for drugs dated August 13, 1993. www.osha.gov/pls/oshaweb/owadisp.show_ document?p_table=INTERPRETATIONS&p_ id=21231 (accessed 2017 Mar 24).

Chapter 2  Standards for Compounded Sterile Preparations  33  55. National Institute for Occupational Safety and Health. Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. www.cdc.gov/niosh/docs/2004-165/ (accessed 2017 Mar 25). 56. Anon. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. www.cdc. gov/niosh/docs/2016-161/default.html (accessed 2017 Mar 25). 57. ASHP Council on Professional Affairs. ASHP guidelines on quality assurance for pharmacyprepared sterile products. Am J Health-Syst Pharm. 2000; 57:1150-69. 58. ASHP Council on Pharmacy Practice. ASHP guidelines on compounding sterile preparations. Am J Health-Syst Pharm. 2014; 71:145-66. 59. ASHP Council on Professional Affairs. ASHP technical assistance bulletin on pharmacyprepared ophthalmic products. Am J Hosp Pharm. 1993; 50:1462-3. 60. ASHP Council on Professional Affairs. ASHP guidelines on the safe use of automated compounding devices for the preparation of parenteral nutrition admixtures. Am J Health-Syst Pharm. 2000; 57:1343-8. 61. ASHP Council on Professional Affairs. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-93. 62. ASHP Commission on Credentialing. ASHP accreditation standard for PGY1 pharmacy residency programs. www.ashp.org/DocLibrary/Accreditation/ASD-PGY1-Standard.aspx (accessed 2016 Feb 18). 63. ASHP Commission on Credentialing. ASHP accreditation standard for pharmacy technician education and training programs. www.ashp.org/ DocLibrary/Accreditation/Regulations-on-Ac-

64. 65.

66. 67. 68. 69. 70.

71.

72.

73.

creditation-of-Pharmacy-Technician-Education. pdf (accessed 2016 Feb 18). ASHP Catalog. http://elearning.ashp.org/catalog (accessed 2017 Mar 25). Boullata JI, Karen Gilbert K, Sacks G et al. ASPEN clinical guidelines parenteral nutrition ordering, order review, compounding, labeling, and dispensing. JPEN. 2014; 38:334-77. ASTM International. www.astm.org/ABOUT/ full_overview.html (accessed 2017 Mar 26). CETA National Board of Testing. https://coeta. memberclicks.net/ceta-application-guides-fornonmembers- (accessed 2017 Mar 26). Anon. Hazardous waste regulations. www.epa. gov/osw/laws-regs/regs-haz.htm (accessed 2017 Mar 26). Anon. IEST Organization. www.iest.org/AboutIEST (accessed 2017 Mar 27). Anon. IEST-RP-CC012: considerations in cleanroom design. www.iest.org/Standards-RPs/ Recommended-Practices/IEST-RP-CC012 (accessed 2017 Mar 27). Institute for Safe Medication Practices. Proceedings from the ISMP sterile preparation compounding safety summit: guidelines for SAFE preparation of sterile compounds 2013. (Revised 2016.) www.ismp.org/tools/guidelines/IVSummit/ IVCGuidelines.pdf (accessed 2017 Mar 27). Institute for Safe Medication Practices. ISMP 2016–2017 targeted medication safety best practices for hospitals. www.ismp.org/tools/bestpractices/TMSBP-for-Hospitals.pdf (accessed 2017 Mar 27). NSF/ANSI Standard 49—2011: biosafety cabinetry: design, construction, performance, and field certification. Ann Arbor, MI: NSF International and American National Standards Institute; 2011.

Chapter

3

Immediate-Use Compounding Jeannell M. Mansur

Introduction In the United States, until approximately 2005, sterile compounding was widely performed at the bedside by personnel other than pharmacy staff. Although the extent of compounding was widespread throughout the hospital setting, it was especially prevalent in intensive care units, where the presumption was that in this fast-changing, highly intense environment, it was difficult to anticipate the needs of a critically ill patient. Currently, compounding on nursing units by nurses has dramatically declined. Several reasons account for this change. The Joint Commission (TJC) released Medication Management Standard MM.05.01.07 stating “a pharmacist, or pharmacy staff under the supervision of a pharmacist, compounds or admixes all compounded sterile preparations (CSPs) except in urgent situations in which a delay could harm the patient or when the product’s stability is short.”1 Thereafter, routine bedside preparation of sterile admixtures did not meet TJC expectations. At the same time, the availability of premixed medication admixtures from pharmaceutical manufacturers resulted in a supply of precompounded preparations for stocking on the nursing unit that would meet the expectation of MM.05.01.07. The Centers for Medicare & Medicaid Services (CMS) address medication compounding in both Pharmaceutical Services (§482.25) and Nursing Services (§482.23) depending on where preparation occurs.2,3 CMS expects that medication preparation will be performed in accordance with state and federal laws and regulations and also according to accepted standards of practice.

Defining Immediate Use In 2015, CMS issued updated interpretive guidelines specifying that USP Chapter Pharmaceutical Compounding—Sterile Preparations. would be used as the best practice resource for compounding.4 As part of this reinterpretation, CMS required hospitals to meet all currently accepted standards for safe preparation and administration of CSPs (1) whether they are compounded as low-, medium- or high-risk preparations, as defined by USP Chapter , within the pharmacy, or (2) whether they are compounded by

35

  36  Compounding Sterile Preparations

nursing or other healthcare personnel outside of the pharmacy and intended for “immediate use.”5 These interpretive guidelines state that immediateuse CSPs are prepared for “immediate or emergency use for a particular patient and are not to be stored for anticipated needs.”6 CMS references within these interpretive guidelines the following requirements, many of which are derived from USP Chapter : • Preparation of an immediate-use CSP must only involve “simple transfer of not more than three commercially manufactured…sterile nonhazardous products from the manufacturer’s original containers and not more than two entries into any one container or package (e.g., bag, vial) of sterile infusion solution or administration container/device.” Note: USP Chapter does not allow immediate-use compounding of hazardous drugs.4 • Administration begins no later than 1 hour following the start of the preparation of the CSP (if not, the CSP must be appropriately discarded). • Meticulous aseptic technique must be followed during all phases of preparation. If the CSP is not administered to the patient as soon as it is ready, the finished CSP is under continuous supervision to minimize the potential for contact with nonsterile surfaces…contamination and/ or confusion with other CSPs. • Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer,… the CSP must be labeled with at least the following: ■■

Patient identification information

■■

The names and amounts of all ingredients

■■

■■

The name or initials of the person who prepared it The exact 1-hour “beyond-use date”5

CMS defines the beyond-use date as the date after which medications may not be used, stored, or transported. The revised interpretive guidelines clarify that the immediate-use product compounded outside of the pharmacy must be initiated within 1 hour of preparation. This applies to injections as well as infusions and is applicable to immediate-use products that are compounded in the operating

room, procedural areas, and other clinical settings including nursing units. Immediate-use CSPs are singly prepared and are exempt from the requirements of USP Chapter low-risk CSPs (e.g., full garbing, admixture in an International Organization for Standardization [ISO 5 environment within an ISO 7 buffer area] as part of a controlled environment cleanroom, etc.).4 At the time of printing of this chapter, TJC has not yet chosen, in its accreditation standards, to adopt the term immediate use for compounding. However, as part of the standard, MM.05.01.07, TJC defines when compounding outside the pharmacy is acceptable (“in urgent situations in which a delay could harm the patient or when the product’s stability”) and when the use of a laminar airflow hood or other ISO 5 environment is required (when “...preparing intravenous (IV) admixture or any sterile product that will not be used within 24 hours.”). TJC defines an intravenous (IV) admixture as “a pharmaceutical product whose preparation requires the addition of a measured amount of medication to a 50 mL or greater bag or bottle of IV fluid. It does not include the drawing up of medications into a syringe, the addition of a medication to a Buretrol (inline burette) or the assembly or activation of IV system that does not involve the measurement of an additive.”1 The American Pharmacists Association defines sterile compounding as the mixing of ingredients, including dilution, admixture, repackaging, reconstitution, and other manipulations of a sterile product to make it ready for patient use.7 Effective January 2017, TJC launched a new Medication Compounding Certification program for hospital and home care agency compounding pharmacies. The certification program includes assessment of compliance of USP Chapters and . Also, at this time, TJC is in the process of reviewing its standards relating to compounding as part of its general accreditation process. It is expected that future versions of the Comprehensive Accreditation Manual for Hospitals will have standards more closely aligned with both CMS and USP Chapter requirements.

Chapter 3  Immediate-Use Compounding  37 

Risks Associated with Medication Preparation in Clinical Care Areas Compounding of sterile admixtures in the pharmacy is preferred from a medication safety perspective because there is the greatest likelihood of achieving sterility of the final product when trained personnel using proper hand hygiene and wearing proper garb prepare a product in a regulated cleanroom, within an ISO 5 primary engineering control. The National Institute for Occupational Safety and Health does not allow sterile compounding of hazardous drugs without suitable environmental controls.8

Microbial Contamination Although there is little time for pathogenic microbes to multiply in the solution of a contaminated CSP made for immediate use, the administration of those microbes poses hazards for immunocompromised and critically ill patients. Austin and colleagues, in a systematic review of 34 published studies, sought to determine whether compounding of sterile doses in the pharmacy resulted in decreased risk of microbial contamination as compared to a clinical or patient care environment. The authors showed there was a significantly higher frequency of contamination of doses prepared in clinical settings (i.e., a significantly higher contamination of doses when admixtures were prepared as single doses rather than as part of a batch) and a significantly higher frequency of dose contamination if additions were made to sterile parenteral doses in clinical environments.9

Medication Errors There are other benefits that pharmacy sterile compounding affords. Having one individual prepare the product while a second individual checks the final product creates an opportunity to catch an error in preparation more often than when one individual controls the entire process. New pharmacy technology that is widely available and affordable facilitates CSP checking, with the use of camera-generated photo images and barcodedriven confirmation that the right ingredients were selected for inclusion in the final CSP.

Pharmacy applications provide computergenerated labels that display ingredients in a legible, complete, and standardized manner as well as supports timely product labeling at the time of preparation. However, sometimes it is not feasible to prepare the CSP in the pharmacy to meet the patient’s needs, such as an urgently needed medication dose that does not allow time for the pharmacy to prepare and transport it. Another example is limited medication stability (e.g., ampicillin injection for pediatric patients or levothyroxine injections) that requires preparation immediately before the time of medication administration in the clinical care area. With more than an estimated 90% of hospitalized patients receiving some form of IV drug therapy, errors in the preparation or administration have a significant impact on many individuals.10,11 Hicks and Becker, in their analysis of IV medication errors, from the MEDMARX database, found that 3–5% of errors associated with IV medications caused harm.12 From a prospective evaluation of errors in pediatric settings in two hospitals, actual medication errors were reported to occur in 5.7% of medication orders and an additional 1.1% of medication orders involved potential adverse drug events (ADEs) which were caught before they reached the patient. Most of the medication errors (28%) and potential ADEs (34%) were dosing errors and more than half involved the IV route.13 Taxis and Barber published important studies looking at error rate associated with IV medications in the United Kingdom. In 2003, they published two reports based on a prospective analysis over a 6to 10-day period where they used observation under disguise and informal staff interviews to determine the prevalence and types of IV medication errors in various settings at two U.K. teaching hospitals. One study sought to determine the incidence and importance of errors in preparation and administration of IV drugs and where these errors occurred in the medication process. They found an astounding rate of errors: one or more errors were noted in 49% of doses. They found that 7% of errors were associated with preparation, 36% were associated with administration, and another 6% of errors were found in both processes. Errors were potentially severe in 1% of doses, potentially moderate in 29% of

  38  Compounding Sterile Preparations

doses, and potentially minor in 19% of doses. Most errors occurred in the administration of bolus doses or preparation processes involving multiple steps.14 Taxis and Barber’s other study, using data from the same prospective analysis, provided more details on the causes of error in IV drug preparation and administration. The researchers found, on review of the IV drug preparation and drug administration errors, that 67% were deliberate violations, 23% were mistakes, and 10% were slips/lapses (i.e., the clinician knew better but forgot procedure). The researchers reported a lack of perceived risk, poor role models, and technology design as contributing to the violations; a lack of knowledge and complex equipment design were attributed for the mistakes as well as the slips/lapses.15 In 2012, the Institute for Safe Medication Practices (ISMP) published the results of a survey of 540 nurses and their practices with cartridge-type prefilled syringes. The report identified practices wherein nurses would withdraw the medication from the cartridge syringe into another syringe for administration or would reuse the cartridge syringe for subsequent doses for the same patient rather than wasting the medication. Reasons cited for withdrawing the medication from the cartridge syringe into another syringe included a lack of cartridge holders for the cartridge syringes, lack of instruction on how to use this type of syringe, difficulty discerning the markings denoting volume on the cartridge syringe, and a desire to further dilute medication.16 Studies have shown that reconstitution of medications contributes to upward of 49% of IV medication errors.17,18 Errors occur as a result of slips/lapses and mistakes including dose calculation errors, selection of the wrong drug or diluent, or omission of a step in the process.18 Parshuram et al. evaluated steps in the preparation process for IV medications to identify factors associated with preventable medication errors. The authors detected errors in 4.9% of drug– volume calculations, 2.5% in rounding calculations, 1.6% of volume measurements, and 1.6% in drug mixing. For infusions prepared, 34.7% contained concentration errors. They concluded that provider fatigue and complexity of calculation of proper drug amounts and fluid volumes are risk factors for error.19

An ISMP survey of over 1,700 practitioners revealed nonstandardized dilution practices as a hazard. Over 83% of nurse respondents reported that they further dilute IV medications even if they have been dispensed by the pharmacy in a concentration that is ready to administer.20 Another ISMP survey highlighted unsafe practices that were confirmed by observations in U.S. hospitals and outpatient settings.21 To provide recommendations for safe practices for IV push administration in adult patients, a 2-day summit was held in September 2014 of a cross-section of professionals from a variety of healthcare disciplines, regulatory agencies, professional organizations, and product vendors. The summit’s objectives included the following: 1. Identify and gain consensus on the most common risks associated with IV push administration of medications to adults. 2. Standardize and simplify the safe administration of parenteral medications to adults through the IV push administration route. 3. Develop and communicate safe practices associated with the use of IV push medications for adults. 4. Establish a minimum level of knowledge and competency associated with the administration of IV push medications to adults, regardless of a clinician’s healthcare discipline.21

The summit resulted in publishing the set of recommendations known as the ISMP Safe Practice Guidelines for Adult IV Push Medications. Although the focus of this initiative was to address both administration and preparation risks, the recommendations that pertained to preparation of IV push medications were wide in scope and included recommendations to address a lack of standard methodology for preparing doses on nursing units, a lack of recommended solutions for performing dilutions, and the use of containers of normal saline (syringe or infusion bag) where drug is added but labeling is not updated to reflect the medication and concentration. TJC, through its Sentinel Event database, has identified human factors as the leading root cause of medical errors for the years 2013–2016 and the third leading cause of medication errors for the

Chapter 3  Immediate-Use Compounding  39 

period of 2004–2016.22 Garnerin et al. assessed the influence of human factors associated with manual preparation and arithmetic calculations in the operative setting with anesthesiologists who drew up injections and nurses who drew up oral doses. The human error probability for preparing doses was 3% for nurses and 6.5% for anesthesiologists. In the arithmetic tasks, the human error probability was 23.8% for nurses and 8.9% for anesthesiologists. Error was related to individual nurses to a much greater degree than to individual anesthesiologists, and the results between the two groups were statistically significant.23 In another study of anesthesiologists’ accuracy in IV medication preparation, Stucki et al. assessed the contents of 500 unused syringes and found that 29% had drug concentrations outside of the + 10% of targeted concentration. Of the preparations analyzed, 18% deviated from the labeled dose by + 20%, 8% deviated by + 50%, and 4% exceeded stated concentrations by 100%, suggesting that in addition to incorrect dilution procedure, other factors were evident such as selection of the wrong medication vial.24

Chapter Scope—The Safe Preparation of Injections and Infusions Preparing sterile medication doses in the clinical setting is a decision that must be dictated by patient need and performed to ensure CSP accuracy, sterility, and stability. Compounding of injectable products should be performed only when an equivalent commercial product is not available. The best choice is to provide medications either as commercially available or pharmacy-prepared in ready-to-administer doses.21 The rest of this chapter addresses the safe preparation of injections and infusions, including IV, intrathecal, intradermal or other sites where administration is made by a needle or catheter. The focus is to provide instruction on the preparation by nonpharmacists in areas outside of the pharmacy, where laminar flow hoods and controlled cleanrooms would not be used. In many cases, the methods for preparing a sterile dose are standardized regardless of the setting or route of administration. However, there are often different methods for preparing doses that are ad-

ministered by less common routes, such as the use of preservative-free ingredients and diluents for medications to be administered via intrathecal, spinal, or epidural routes.

Preparation of Injections and Infusions The selection of the location for injectable medication preparation is important. The workspace for sterile product preparation should be a dedicated space, which is clean, uncluttered, and organized so that necessary items to prepare the dose, including the medication, diluents, syringes, needles, transfer sets, disinfectants, and labels are all readily available. There should be facilities to perform hand hygiene close enough to the preparation area so that hands are not recontaminated after cleansing while moving to the preparation area. It is advisable that the medication preparation area is not placed directly beside a sink because microbes reside in drains and can serve as a source of contamination. Ideally, the preparation surface should be nonporous and able to withstand cleaning with appropriate antimicrobial cleaners without affecting the surface material (Figure 3-1). Prior to initiating preparation, the prescription/ medication order should be reviewed for appropriateness, and a plan for preparing the medication should be developed, including how the medication will be diluted, what solution will be used to dilute it, how much diluent will be used, what the final concentration of the diluted medication will be, what volume of diluted solution would be equivalent to the prescribed dose, and, for infusion, what fluid is appropriate for the final admixture. It is a good practice, and having a second individual double-check this plan can be a requirement of an organization’s policies and procedures.

Assembly

of

Materials

Assemble all the materials prior to beginning preparation. The following materials should be used: • Drug vial • Diluent, if necessary • Infusion bag into which diluted injectable medication will be mixed

  40  Compounding Sterile Preparations • Indication if an infusion, diluent and final volume • Patient’s name and other identifier, and location • Beyond-use date and time • Name of the practitioner preparing the medicine

Cleaning

Figure 3-1. A well-organized sterile compounding area in a clinical setting. Source: Used with permission from Ferrar Home, Malone, NY.

• Needle • Syringes • Sterile alcohol wipes • Label • Seals for injection port

The container (e.g., syringe, infusion bag, or other sterile container) in which the final dose will be placed should be labeled after preparation has been completed. The label should be created prior to beginning preparation so that it is ready to be affixed to the medication container immediately afterward. The label should include the following minimum information: • Name of the medicine • Amount/concentration • Route of administration

the

Preparation Surface

The use of a germicidal cleaner is the first step in cleaning the preparation surface. Cleaning agents will contain surfactants and facilitate the removal of soil or microbes or other contamination. Cleaning agents include quaternary ammonium compounds, hydrogen peroxide–containing products, peracetic acid plus hydrogen peroxide combination products, or phenolic compounds. The manufacturer instructions should be followed for application of the product, as well as ensuring that proper “wet time” is maintained for the recommended duration. Staff members who use these products must use personal protective equipment that is recommended by the manufacturer.

Hand Hygiene Prior to beginning the preparation process, hands must be cleansed. Cousins et al. found that prior to IV drug preparation, nurses washed their hands none of the time in U.K. hospital patient care areas, only washed hands correctly in 5% of German patient care areas, and washed properly in 91% of French hospital patient care areas.17 The option to use either an alcohol-based hand sanitizer or nonantibacterial soap and water or antibacterial soap and water are all supported by the Infusion Nurses Society (INS) and Association for Professionals in Infection Control and Epidemiology (APIC).25-27 This author recommends using one pump of waterless alcohol-based hand sanitizer product (or a dime-sized amount) with a minimum of 60% ethanol to all surfaces of the hands and rubbing the hands together to ensure that the product covers all surfaces of the hands and fingers until the hands are dry. If hands are visibly soiled, antibacterial or nonantibacterial soap and water should be used to clean hands rather than an alcohol-based hand sanitizer. The INS provides evidence-based recommendations for many nursing procedures in the clinical

Chapter 3  Immediate-Use Compounding  41 

setting through its Policies and Procedures for Infusion Therapy and its Infusion Therapy Standards of Practice.25,26 The use of gloves throughout these recommendations is focused on protecting the clinician from exposure to materials or fluids that might cause infectious harm to the nurse. Gloves, per INS, are worn “…if there is potential contact with blood, …body fluids, mucous membranes, and non-intact skin.”26

Product Selection

and

Preparation

Errors in calculating required volumes for drug products and diluents have been documented in the literature.18,19 Enlisting the assistance of a pharmacist to provide instructions for preparing the medication and determining the proper amount of volume that corresponds to the prescribed dose may be beneficial. If this is not an option, enlisting a second professional to provide a doublecheck for the calculated dose and process is an alternative. Selection of the Medication

Errors can occur as medication products are picked out for dose preparation. The implementation of barcode technology to confirm the correct medication and strength provides safeguards but typically more for medications to be administered in their final dosage form and strength. When immediateuse CSPs are compounded, barcode technology is limited to confirming the proper drug in the vial. Barcode technology will not confirm whether the medication was properly diluted or prepared or whether the correct volume was drawn up. In the clinical setting, floor stock medications are increasingly available through automated dispensing cabinets (ADCs). If the ADC is patientprofiled, this becomes a mechanism to limit access to a medication until a pharmacist has verified the medication order. Even if routine medications appear on patient profiles, ADCs will allow access to other medications through an override function for medications needed urgently. Medications prepared for immediate use will often be obtained via override function. ADC technology allows the use of cubicles that stock a single drug product. If the user selects the specific medication needed and the ADC is set up with cubicles, the user will have

access only to this single medication, following selection on the screen of options. This feature prevents the selection errors that occur with matrix types of drawers, which provide open access to several drug products. Sadly, many facilities continue storing medications in cabinets or closets that do not provide technological assistance to confirm a pharmacist review or to direct selection of the correct product. Many medications look or sound like other medications, and this can result in confusion and incorrect selection when medications are accessed directly from clinical unit supplies not dispensed by the pharmacy. Look-alike/sound-alike (LASA) medications point to the need to evaluate medications stored in clinical areas for these risks. LASA medications ideally are not stored in the same storage area, but if it is required that they are, they should be separated, and labeling should warn that these are LASA medications. Tall man lettering is a technique of using uppercase letters within the drug name to distinguish that part of the name that is different from its LASA counterpart. Tall man lettering can be used in labeling of shelves and containers of medication as well as on drug selection display screens within ADCs or in choices offered to a prescriber using the electronic medical record to create a prescription order. To reconstitute a sterile medication in lyophilized form with a sterile diluent, the clinician must use aseptic technique (Chapter 11). Manufacturer’s instructions (product labeling) state the proper diluent. After reconstitution, a volume of the sterile medication is drawn into a sterile syringe for administration of the prescribed dose. Some medications may require further dilution in the syringe or in an IV solution to be ready to administer. The prescription order and manufacturer’s instructions determine how the medication should be administered. Clinicians must recognize whether a drug product is in a single use (or single dose) or a multiple dose (multidose) vial. Multidose vials generally contain preservatives—such as benzyl alcohol, methyl paraben, and propyl paraben—and are manufactured to be used multiple times in multiple patients. CMS prohibits the return to general storage for reuse of a multidose vial if the vial was taken

  42  Compounding Sterile Preparations

to an immediate patient care area (i.e., a setting in which one can touch both the vial and patient). For instance, operating rooms and patient rooms are immediate patient care areas. Single-dose vials do not contain preservatives and are meant for one-use administration. Sometimes single-use vials and multidose vials do not have clear designations as to how the vials are to be used (i.e., “single dose” or “multiple dose” are not on the label). Misuse of single-use and multidose vials led TJC to publish a Sentinel Event Alert in 2014 entitled “Preventing Infection from the Misuse of Vials.”28 Single-use/single-dose vials. The following are recommendations for single-use and multiuse vials from this publication: • Use a single-use or single-dose vial for only one patient and during the course of a single procedure, discarding the vial after this single use. Never return vials to stock on clinical units, drug carts, or anesthesia carts. • If a single-use vial must be accessed one more time for a single patient during the procedure, an unused needle and an unused syringe should be used to enter the vial for medication removal. • Do not combine or pool leftover contents of single-dose/single-use vials. • Multiple syringes of medication created from the single-use vial for future use should be prepared in an ISO 5 environment, with proper labeling including a beyond-use date.

Multiple-dose/multidose vials. • When multidose vials are used more than once, a new needle and new syringe should be used for each entry. Needles should not be left in the rubber diaphragms between uses. • Disinfect the vial’s rubber stopper with sterile 70% isopropyl alcohol or another approved antiseptic swab. Allow the septum to dry prior to inserting a needle to withdraw medication. • Once a multidose vial is punctured, it should be dated with a beyond-use date, typically 28 days unless manufacturer expiration dating differs.

The Centers for Disease Control and Prevention (CDC) and the Safe Injection Practices Coalition created the “One and Only Campaign” to create awareness in the healthcare world as to the proper

use of needles and syringes.29 The Injection Safety Checklist, one of many tools created through this campaign, contains important messages on safe injection techniques (Figure 3-2).

Point-of-Care Activation Systems Manufacturers have developed medication vial and infusion bag systems, also called point-of-care activation systems, that allow the assembly of the medication vial with the infusion bag (with a physical barrier between the two to prevent mixing of medication with the solution) until a barrier is broken to allow mixing. Activation is performed just prior to administering the medication to the patient, allowing a longer dating of the adjoined vial and bag. If assembly is performed more than 1 hour from the time of activation, ASHP recommends performing the assembly in an ISO 5 (or laminar airflow hood) environment.30 Staff training on the proper activation process for each proprietary system in use is essential because there have been many examples of improper activation or failure to activate, resulting in the delivery of plain infusion solution without the prescribed amount of medication. Manufacturer instructions should be followed as to beyond-use dating for assembly as well as activation of the system.

Incompatibility

with

Other Medications

When two medications come in contact with each other in solution, a chemical reaction between the two can change or inactivate one or both ingredients and can cause a physical precipitation of ingredient(s). Such reactions or precipitations are termed incompatibilities. Drug incompatibilities are different from drug interactions because they take place in the admixture itself rather than within the patient. Besides mixing in the same IV bag, there are other means by which two drugs can come in contact: (1) using a Buretrol (inline burette or volumetric chamber) that allows partitioning a volume of IV fluid into which one or more drugs are added; (2) running a medication admixed in a piggyback solution through an infusion line where another medication is infusing; or (3) infusing a medication directly through a Y-site into an IV line. The less contact between two medications in the same infusion line the better.

Chapter 3  Immediate-Use Compounding  43  Injection Safety

Practice Performed?

Injections are prepared using aseptic technique in a clean area free from contamination or contact with blood, body fluids or contaminated equipment.

Yes

No

Needles and syringes are used for only one patient (this includes manufactured prefilled syringes and cartridge devices such as insulin pens).

Yes

No

The rubber septum on a medication is disinfected with alcohol prior to piercing vial.

Yes

No

Medication vials are entered with a new needle and a new syringe, even when obtaining additional doses for the same patient.

Yes

No

Single dose (single-use) medication vials, ampules, and bags or bottles of intravenous solution are used for only one patient.

Yes

No

Medication administration tubing and connectors are used for only one patient.

Yes

No

Multidose vials are dated by HCP when they are first opened and discarded within 28 days unless the manufacturer specifies a different (shorter or longer) date for that opened vial. Note: This is different from the expiration date printed on the vial.

Yes

No

Multidose vials are dedicated to individual patients whenever possible.

Yes

No

Multidose vials to be used for more than one patient are kept in a centralized medication area and do not enter the immediate patient treatment area (e.g., operating room, patient room/cubicle). Note: If multidose vials enter the immediate patient treatment area they should be dedicated for single-patient use and discarded immediately after use.

Yes

No

If answer is No, document for remediation

Figure 3-2. Centers for Disease Control and Prevention injection safety checklist. The checklist items are a subset of items, which can be found in the CDC Infection Prevention Checklist for Outpatient Settings: Minimum Expectations for Safe Care. The checklist, which is appropriate for both inpatient and outpatient settings, should be used to systematically assess adherence of healthcare personnel to safe injection practices. Assessment of adherence should be conducted by direct observation of healthcare personnel during the performance of their duties. Sources: www.cdc.gov/HAI/pdfs/guidelines/ambulatory-care-checklist-07-2011.pdf and www.cdc.gov/HAI/pdfs/guidelines/standatds-of-ambulatory-care-7-2011.pdf.

  44  Compounding Sterile Preparations

Manufacturer information for each medication that might come in contact with another should be consulted to determine if an incompatibility is likely and how to avoid that (e.g., flushing the line between doses). Alternatively, established IV incompatibility references provide data based on published studies. These are usually available in the pharmacy.

Medication Labeling Unlabeled injectables are usually in liquid form and may be indistinguishable from other unlabeled liquids. The ISMP has highlighted a number of incidents where lack of medication labeling resulted in patient harm or death.31 Examples include the following: • A 69-year-old woman who died when she was injected with a skin antiseptic instead of contrast media • A reporter for a local newspaper who died when glutaraldehyde, a preservative, was mistaken for spinal fluid and injected intrathecally • A physician who applied contrast media, with a very basic pH, to a male patient’s genitalia, believing that it was vinegar and causing the patient to suffer severe burns

Medications prepared in clinical settings are less likely to be labeled. The American Nurses Association in 2007 published the results of a study of over 1,000 nurses on labeling practices. While 97% of nurses who took the survey reported being worried about medication errors and 68% of nurses stated that they believed medication errors could be reduced by more consistent labeling of syringes, only 37% of nurses reported that they always labeled medication syringes. Of note, 28% of nurses who responded stated that they never labeled medication syringes.32 With concern for proper labeling, TJC issued specific requirements for labeling medication as part of standard MM.05.01.09 and National Patient Safety Goal NPSG.03.04.01, which set medication (and other solutions) labeling requirements in the operating room and areas where procedures are performed, both on and off the sterile field. Medications are labeled if they are not immediately administered after being placed into an unmarked

container. Figure 3-3 lists the required Elements of Performance for NPSG.03.04.01.

Preparation of the Infusion Administration

for

After an infusion has been compounded, the IV line must be inserted to infuse the medication. In many procedure areas, there may be a practice of prespiking IV infusions, often hours before or the day before they are needed. Although there are no definitive data to suggest a specific time limit in advance of administration when an infusion solution may be spiked, the APIC recommends preparing all IV solutions as close to the time of administration as feasible.27 Another practice issue that can arise is the length of time an IV solution can remain infusing in a patient (otherwise known as hang time). After the CDC reviewed existing scientific data, theoretical rationale, applicability, and economic impact, they declared that there were insufficient data to make recommendations for the hang time of nonlipid-containing parenteral fluids. Lipidcontaining solutions (e.g., 3-in-1 solutions) were recommended to be completed within 24 hours of hanging the solution, and lipid emulsions infused alone were recommended to be completed within 12 hours of hanging the emulsion.33

Allergen Extracts as Compounded Sterile Preparations Allergen immunotherapy has been a treatment modality since the early twentieth century. Intradermal and subcutaneous injection of allergen proteins, diluted in varying concentrations, have been used to reduce the severity of allergic symptoms, including the reduction of life-threatening allergic reactions.34 Allergen therapy requires the administration of repeated doses of identified allergens in a controlled process, escalating the exposure over the treatment period to build resistance to allergic reactions from exposure to each dose. The compounding of doses of allergens is complex, and medical personnel of various backgrounds often perform them in a clinic setting. A number of risk points must be considered if allergen immunotherapy is used to manage patient symptoms. These include specific

Chapter 3  Immediate-Use Compounding  45 

National Patient Safety Goal—Label all medications, medication containers, and other solutions on and off the sterile field in perioperative and other procedural settings. Elements of Performance for NPSG.03.04.01 1. In perioperative and other procedural settings both on and off the sterile field, label medications and solutions that are not immediately administered. This applies even if there is only one medication being used. Note: An immediately administered medication is one that an authorized staff member prepares or obtains, takes directly to a patient, and administers to that patient without any break in the process. Refer to NPSG.03.04.01, EP 5, for information on timing of labeling. 2. In perioperative and other procedural settings both on and off the sterile field, labeling occurs when any medication or solution is transferred from the original packaging to another container. 3. In perioperative and other procedural settings both on and off the sterile field, medication or solution labels include the following: ■■

Medication or solution name

■■

Strength

■■

Amount of medication or solution containing medication (if not apparent from the container)

■■

Diluent name and volume (if not apparent from the container)

■■

Expiration date when not used within 24 hours

■■

Expiration time when expiration occurs in less than 24 hours

Note: The date and time are not necessary for short procedures, as defined by the hospital. 4. Verify all medication or solution labels both verbally and visually. Verification is done by two individuals qualified to participate in the procedure whenever the person preparing the medication or solution is not the person who will be administering it. 5. Label each medication or solution as soon as it is prepared, unless it is immediately administered. Note: An immediately administered medication is one that an authorized staff member prepares or obtains, takes directly to a patient, and administers to that patient without any break in the process. 6. Immediately discard any medication or solution found unlabeled. 7. Remove all labeled containers on the sterile field and discard their contents at the conclusion of the procedure. Note: This does not apply to multiuse vials that are handled according to infection control practices. 8. All medications and solutions both on and off the sterile field and their labels are reviewed by entering and exiting staff responsible for the management of medications. Figure 3-3. Elements of Performance for NPSG.03.04.01. Source: Used with permission from Hospital National Patient Safety Goals, The Joint Commission, Oakbrook, IL. Copyright © 2015.

  46  Compounding Sterile Preparations

directions from the physician or other individual directing the therapy on what the treatment should include. An allergy specialist who is directing this therapy must create the detailed prescriptions that list the allergen extracts and the concentrations as well as the timing. Prescriptions should contain the following information35: • Patient identifying and contact information • Name of preparer • Date of preparation • Name, concentration and volume for each allergen • Type and volume of diluents

Stock allergen manufacturer and lot number and expiration date of the preparation should be part of the documentation created for the compounded allergen preparation. Risks associated with the preparation of the allergen doses include the source product quality and stability, breaches in aseptic technique resulting in contamination of the product, compounding errors, labeling errors, and the risk of systemic reactions, including anaphylaxis, after exposure to specific allergens. The rate of systemic reactions associated with allergenic immunotherapy is estimated to be approximately 0.1%.36 Therefore, training—of both medical staff members who manage and oversee the treatment of patients undergoing allergen immunotherapy as well as training and competency of those healthcare workers who prepare the allergen doses—is of paramount importance. Published guidelines for the preparation of allergen immunotherapy doses include USP Chapter and a collaboration (the Joint Task Force) between the American Academy of Allergy, Asthma, and Immunology; the American College of Allergy, Asthma, and Immunology; and the Joint Council of Allergy, Asthma, and Immunology. The guidelines were reviewed and endorsed by the American Academy of Otolaryngic Allergy.4,37

The goal of USP Chapter focuses on ensuring the highest level of sterility for allergen compounding, while the goal of the Joint Task Force guidelines is not only to ensure sterile mixing, but also to ensure optimal stability and potency of treatments and standardization of practice. All guidelines emphasize aseptic technique, handwashing, storage temperatures, use of personal protective equipment, expiration dating, and patient identification on labels, and all guidelines require that staff members preparing treatment vials pass a written examination and an annual media fill test. USP Chapter lists 11 criteria that must be met for allergen extract compounding to be exempt from the personnel, environmental, and storage standards in force for other types of CSPs (Figure 3-4).4

Summary Although compounding sterile preparations has transitioned mainly to the pharmacy in most U.S. hospitals, preparation of sterile products does occur in clinical settings like nursing units, operating rooms, emergency departments, procedure areas, and clinical settings. Those who compound or prepare sterile medication doses in these nonpharmacy settings are nurses, physicians, and other healthcare professionals. Regulatory and accreditation organizations have provided guidelines for when compounding should occur outside the pharmacy and the required environment for this compounding. This chapter has defined the steps involved in the preparation of sterile doses. USP Chapter provides detailed requirements for compounding that occurs in a pharmacy cleanroom setting; however, it provides fewer details as to the specific environmental and process requirements for compounding outside of a cleanroom. This chapter has outlined more specifically the types of products and clinical circumstances that might require preparation on an immediate-use basis.

Chapter 3  Immediate-Use Compounding  47  1. Compounding process—The compounding process must involve just simple transfer via sterile needles and syringes of commercial sterile allergen products and appropriate added substances (e.g., glycerin, phenol in sodium chloride injection). 2. Allergen extracts—The allergen extract product must contain appropriate substances in effective concentrations to prevent the growth of microorganisms. Nonpreserved allergen extracts must comply with all appropriate CSP risk level requirements in USP Chapter . 3. Handwashing—Before beginning compounding activities, personnel must adhere to the following handcleansing procedure: a. Scrub fingernails using a nail cleaner under running warm water. b. Scrub hand and arms to the elbow for at least 30 seconds using nonantimicrobial or antimicrobial soap and water. 4. Garbing—Compounding personnel must don the following: a. Hair covers, facial hair covers b. Gown c. Face masks 5. Additional hand cleansing—Hands must be cleansed with an alcohol-based surgical hand scrub before donning the sterile gloves. 6. Sterile gloves—Compounding personnel must wear powder-free, sterile gloves during compounding. The gloves must be compatible with sterile 70% isopropyl alcohol (IPA). 7. Sanitizing of sterile gloves—Compounding personnel must disinfect their gloves with sterile 70% IPA intermittently during the mixing process. 8. Sanitizing ampuls and vials—Ampul necks and vial stoppers of manufactured products must be disinfected with sterile 70% IPA. The IPA must remain wet for at least 10 seconds on and be allowed to dry before starting the compounding process. 9. Minimizing contamination—Critical sites (e.g., needles, opened ampuls, vial stoppers) used for compounding of allergens must be protected from direct contact contamination (i.e., from glove fingertips, blood, nasal and oral secretions, shed skin, cosmetics, and other nonsterile material). 10. Labeling—The label of the multiple dose vial of allergen extract must include the following: a. One specific patient’s name b. Storage temperature range c. Beyond-use date that is assigned according to manufacturer’s recommendations or peer-reviewed publications 11. Single-dose vials—Allergen extract products that do not have a preservative or that are labeled as single-dose vials cannot be stored for later use and must be discarded after initial use. Figure 3-4. List of criteria for allergen extract exemption. Source: Used with permission from U.S. Pharmacopeial Convention, Rockville, MD. Copyright © 2016.

  48  Compounding Sterile Preparations

References 1. Anon. Medication management. In: Comprehensive accreditation manual for hospitals. Oakbrook Terrace, IL: The Joint Commission; 2016. 2. 42 CFR. Public health part 482—conditions of participation for hospitals § 482.23 condition of participation: nursing services. www.ecfr.gov/ cgi-bin/text-idx?SID=37bf9ca3679249b84c9eb82 95b4b44ad&mc=true&node=se42.5.482_123&r gn=div8 (accessed 2017 Aug 1). 3. 42 CFR. Public health part 482—conditions of participation for hospitals § 482.25 condition of participation: pharmaceutical services. www.ecfr. gov/cgi-bin/text-idx?SID=8a2d765b74edb6ee5ef e9f0d25520651&mc=true&node=se42.5.482_12 5&rgn=div8 (accessed 2017 Aug 1). 4. U.S. Pharmacopeial Convention. USP chapter pharmaceutical compounding—sterile preparations. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 5. Centers for Medicare and Medicaid Services (CMS). Appendix A—survey protocol, regulations and interpretive guidelines for hospitals. In: CMS manual system state operations. Baltimore, MD: CMS; 2015. (Updated through Rev. 151; effective 2015 Nov 20; issued 2015 Nov 20.) 6. Center for Clinical Standards and Quality/Survey & Certification Group. Revised hospital guidance for pharmaceutical services and expanded guidance relating to compounding of medications (Memorandum Ref: S&C:16-01 Hospital). Baltimore, MD: Centers for Medicare & Medicaid Services; 2015. 7. Allen LV. Guidelines for compounding practices. Washington, DC: American Pharmacists Association; 2012. 8. Connor TH, MacKenzie BA, DeBord DG et al. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2016. Atlanta, GA: National Institute for Occupational Safety and Health; 2016. (Publication number 2016-161; supersedes 2014-138.) 9. Austin P, Hand KS, Elia M. Systematic review and meta-analysis of the risk of microbial contamination of parenteral doses prepared under aseptic techniques in clinical and pharmaceutical environments: an update. J of Hosp Infect. 2015; 91:306-18. 10. Baranowski L. Presidential address: take ownership. J Intraven Nurs. 1995; 18:162-4. 11. Corrigan A. Infusion nursing as a specialty. In: Alexander M, Corrigan A, Gorski L et al., eds. Infusion nursing: an evidence-based approach. 3rd ed. St. Louis: Saunders Elsevier; 2010. 12. Hicks RW, Becker SC. An overview of intravenous-related medication administration errors as

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

reported to MEDMARX, a national medication error-reporting program. J Infus Nurs. 2006; 29:20-7. Kaushal R, Bates DW, Landrigan C. Medication errors and adverse drug events in pediatric patients. JAMA. 2001; 285:2114-20. Taxis K, Barber N. Ethnographic study of incidence and severity of intravenous drug errors. Br. Med J. 2003; 326:684-7. Taxis K, Barber N. Causes of intravenous medication errors: an ethnographic study. Qual Saf Health Care. 2003; 12:343-7. The Institute for Safe Medication Practices. ISMP survey reveals user issues with Carpuject prefilled syringes. ISMP Medication Safety Alert! 2012; 17:1-3. Cousins DH, Sabathier B, Begue D et al. Medication errors in intravenous drug preparation and administration: a multicenter audit in the UK, Germany, and France. Qual Saf Health Care. 2005; 14:190-5. McDowell SE, Mt-Isa S, Ashby D et al. Where errors occur in the preparation and administration of intravenous medications: a systematic review and Bayesian analysis. Qual Saf Health Care. 2010; 19:341-5. Parshuram CS, To T, Seto W et al. Systematic evaluation of errors occurring during the preparation of intravenous medication. Can Med Assoc J. 2008; 178:42-8. Institute for Safe Medication Practices. Some IV medications are diluted unnecessarily in patient areas, creating undue risk. ISMP Medication Safety Alert! 2014; 19:1-5. Institute for Safe Medication Practices. ISMP safe practice guidelines for adult IV push medications, 2015. www.ismp.org/Tools/guidelines/ ivsummitpush/ivpushmedguidelines.pdf (accessed 2017 Apr 18). The Joint Commission. Sentinel event data: contributing factors by error type 2004–2016 (internal communication April 18, 2017). Oakbrook Terrace, IL: The Joint Commission; 2017. Garnerin P, Pellet-Meier B, Chopard P et al. Measuring human-error probabilities in drug preparation: a pilot simulation study. Eur J Clin Pharmacol. 2007; 63:769-76. Stucki C, Sautter AM, Wolff A et al. Accuracy of preparation of IV medication syringes for anesthesiology. Am J Health-Syst Pharm. 2013; 70:137-42. Infusion Nurses Society. Infusion therapy standards of practice. 5th ed. Norwood, MA: Infusion Nurses Society; 2016. Infusion Nurses Society. Policies and procedures for infusion therapy. 5th ed. Norwood, MA: Infusion Nurses Society; 2016.

Chapter 3  Immediate-Use Compounding  49  27. Dolan SA, Felizardo G, Barnes S et al., for the Association for Professionals in Infection Control and Epidemiology (APIC). Position paper: safe injection, infusion, and medication vial practices in health care. Am J of Infect Control. 2010; 38:167-72. 28. The Joint Commission. Sentinel event 52: preventing infection from the misuse of vials. Oakbrook Terrace, IL: The Joint Commission; 2014. 29. Centers for Disease Control and Prevention (CDC) and the Safe Injection Practices Coalition (SIPC). One & only campaign. www.oneandonlycampaign.org (accessed 2017 Apr 18). 30. ASHP guidelines on compounding sterile preparations. Am J Health-Syst Pharm. 2014; 71:145-66. 31. Cohen MR, Smetzer JL. Unlabeled containers lead to patient’s death. Jt Comm J Qual Patient Saf. 2005; 31:414-7. 32. American Nurses Association. Medication errors and syringe safety are top concerns for nurses according to a new national study, June 18, 2007. www.nursingworld.org/FunctionalMenuCategories/

33.

34. 35.

36.

37.

MediaResources/PressReleases/2007/Syringe SafetyStudy.aspx (accessed 2017 Apr 18). O’Grady NP, Alexander M, Dellinger EP et al. Guidelines for the prevention of intravascular catheter-related infections. MMWR. 2002; 51:1-26. Daigle BJ, Rekkerth DJ. Practical recommendations for mixing allergy immunotherapy extracts. Allergy Rhinol. 2015; 6:e1-e7. Nelson MR, Cox L. Allergen immunotherapy extract preparation manual. In: AAAAI practice management resource guide. Milwaukee, WI: American Academy of Allergy, Asthma and Immunology; 2012:1-39. Epstein TG, Liss GM, Murphy-Berendts K et al. AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008–2012: an update on fatal and nonfatal systemic allergic reactions. J Allergy Clin Immunol Pract. 2014; 2:161-7. Cox L, Nelson H, Lockey R et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011; 127:S1-55.

Chapter

4

Sterile Preparation Formulation Mark G. Klang

Introduction This chapter will provide insight into the issues of formulation when applied to compounding sterile preparations. The majority of options discussed in this chapter will involve high-risk compounding as defined by USP Chapter Pharmaceutical Compounding—Sterile Preparations.1 Also, sterile compounding that requires specialized formulations may be designated difficult to compound by the newly created U.S. Food and Drug Administration (FDA) Task Force. This group examines specialized formulations and the resources available to pharmacists to safely conduct such procedures. This group then decides which modality or therapy is outside the scope of compounding. The Pharmacy Compounding Advisory Committee has met several times to evaluate what drug products are exempt from compounding under both Sections 503A and 503B of the Federal Food, Drug and Cosmetic Act. The compounder will be prohibited from using these ingredients, in some cases at specific quantities outlined in the document.2 Please refer to Chapter 21 for the stability and incompatibility of drugs, Chapter 15 for labeling compounded preparations, Chapter 16 for documentation, Chapter 17 for sterilization methods, and Chapter 18 for finished preparation release checks and tests.

Federal Regulations New Compounding Drug Regulations The following is an excerpt of an FDA release pertinent to compounding sterile preparations: On November 27, 2013, President Obama signed the Drug Quality and Security Act (DQSA), legislation that contains important provisions relating to the oversight of compounding of human drugs. Note: The author acknowledges E. Clyde Buchanan who authored this chapter in the previous edition.

51

  52  Compounding Sterile Preparations

Title I of this new law, the Compounding Quality Act, removes certain provisions from section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) that were found to be unconstitutional by the U.S. Supreme Court in 2002. Section 503A describes the conditions under which certain compounded human drug products are exempt from three sections of the FDCA requiring: • Compliance with current good manufacturing practices (CGMPs) (section 501(a)(2)(B)); • Labeling with adequate directions for use (section 502(f)(1)); and • FDA approval prior to marketing (section 505).

The new law also creates a new section 503B in the FDCA. Under section 503B, a compounder can become an outsourcing facility. An outsourcing facility will be able to qualify for exemptions from the FDA approval requirements and the requirement to label products with adequate directions for use, but not the exemption from CGMP requirements. Outsourcing facilities: • Must comply with CGMP requirements, • Will be inspected by FDA according to a risk-based schedule, and • Must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound.3

When formulating and compounding sterile preparations, pharmacists must follow both state laws and FDA regulations. State pharmacy practice acts and board of pharmacy regulations cover these activities. The FDA also regulates formulation and compounding under adulteration, misbranding, and new drug provisions of the FDA.4 Since 1980, in their Field Regulatory Guidance, “Hospital Pharmacies Status as Drug Manufacturer,” FDA Guide 7132.06 states that “a physician may prescribe an unusual preparation that requires compounding by a pharmacist from drugs readily available for other uses and which is not generally

regarded as safe and effective for the intended use.”5 If the pharmacy fills each prescription as received, clearance under the “new drug” provisions is not required.5 Compounding Phase 1 investigational drugs does not require full compliance with CGMPs because of the low volume of patients.6 Compounding medications for Phase II and III trials requires complete adherence to CGMPs, and products prepared for Phase I cannot be used for the subsequent phases if not prepared under full CGMPs. If a pharmacist compounds finished drugs from bulk active ingredients that are not obtained from an FDA-approved facility or are not compliant with compendial standards (i.e., The United States Pharmacopeia and The National Formulary [USP– NF]), these finished preparations must be covered by a new drug application.7 In other words, bulk compounded preparations must conform to USP Chapter Pharmaceutical Compounding— Nonsterile Preparations and USP Chapter ; otherwise, FDA requires that a new drug application be filed and accepted for the bulk compounded preparation.1 If a pharmacist changes the strength, dosage form, or components of a commercially available preparation in a compounded prescription, good compounding procedures should be used.7 Pharmacists are responsible for compounding and dispensing finished preparations pursuant to prescribed therapy, and for compounding and preparing those preparations in compliance with established boards of pharmacy and other regulatory agencies. These requirements vary from state to state.

Professional Standards Formulating, compounding, and sterilizing a pharmaceutical from nonsterile ingredients or in nonsterile containers is the most difficult and is considered a high-risk procedure.1 The chemical purity and content strength of ingredients must meet their original or compendial specifications in unopened or in opened packages of bulk ingredients in compliance with the Ingredient Section of USP Chapter .8 Batch master worksheets should include comparisons of actual with anticipated yields, sterilization methods, and quality control

Chapter 4  Sterile Preparation Formulation  53 

and validation of procedures used. Presterilized sealed containers should be used when feasible. Final containers must be sterile and capable of maintaining product integrity through the beyonduse date (BUD). The sterilization method must be based on the preparation’s properties. Whatever method of sterilization is used, a sterility test is still required to ensure safety of the contents. The sterility test must be validated to determine if a contamination could be isolated if one were present as well as to determine the sensitivity of the assay (USP Chapter Sterility Test). See Table 4-1 for a review of the different types of terminal sterilization, their advantages, and their disadvantages. See reference 9 for a review of the FDA perspective on terminal sterilization.9 USP Chapter specifies that nonsterile active ingredients and added substances, or excipients, for compounded sterile preparations (CSPs) should preferably be official USP–NF articles.1 When unofficial ingredients are used, they must be accompanied by certificates of analysis from

their suppliers to aid compounding personnel in judging the identify, quality, and purity in relation to the intended use in a particular CSP.10 Bulk or unformulated drug substances and added substances, or excipients, must be stored in tightly closed containers under temperature, humidity, and lighting conditions, which are either indicated by official monographs or approved by suppliers. Also, the date of receipt in the compounding facility must be clearly and indelibly marked on each package of ingredient. Careful consideration and evaluation of nonsterile ingredient sources is especially warranted when the CSP will be administered into the vascular, central nervous system, and eyes. Upon receipt of each lot of the bulk drug substance or excipient, the individual compounding the preparation performs a visual inspection of the lot for evidence of deterioration, other types of unacceptable quality and mislabeling, as described in a written protocol.

Table 4-1.

Terminal Sterilizationa Sterilization Method

Specifications

Advantages

Disadvantages

Dry heat

180 °C for 30 min or 170 °C for 1 hr 160 °C for 2 hr

Destroys pyrogens

Heat sensitivity

Moist eat

Pressure: 15 lb/sq inch Temperature: 121 °C

Uses biological indicator to verify sufficient heat/pressure

Heat/moisture sensitivity

Filter integrity test, verifies filter did not rupture

Filter must be certified for volume and filtrate load

Autoclave, gravity sterilizer

Time: 15 min

Filtration

0.2 μm Numerous fiber/size and load specifications

Gamma irradiation

~25 kGy; requires very high radiation to be effective

Containers and packaging may remain intact

Not good for some, heat sensitive

Ethylene oxide/nitrous oxide, hydrogen peroxide fog

Depending on gas used different saturation and permeation

Less invasive, good for heat sensitive but has compatibility issues

Requires tight wrap to avoid leaks, contaminates adjacent areas

See Chapter 17 for a more detailed review.

a

  54  Compounding Sterile Preparations

Written Procedures The compounder of sterile preparations should develop and comply with the following written procedures (Chapters 16, 22, and 31): • There must be a specifically designated and adequate area for the orderly placement of equipment and materials to be used in compounding. CSPs should be prepared in a separate and distinct area from nonsterile compounding.1 • USP Chapter requires that presterilization procedures for high-risk level CSPs, such as weighing and mixing, be completed in at least an International Organization for Standardization Class 8 environment. • For hazardous material, the storage should be in an environment of negative pressure to ensure safety of the compounder according to National Institute for Occupational Safety and Health and USP Chapter Hazardous Drugs— Handling in Healthcare Settings (expected to become official December 1, 2019).11 This new chapter supersedes the section on Hazardous Drug handling outlined in USP Chapter earlier. • Special attention should be made to handling bulk agents, which would be expected when formulating a sterile compound that contains a hazardous material. • Careful selection of respiratory and personal protective wear is crucial as is appropriate engineering controls to ensure safety of staff. • Liquid preparations are especially hazardous as the vapor easily will pass through filtration-based transfer systems, rendering them ineffective for exposure control.12 • Biological-based pharmaceuticals should be handled in accordance with the Biosafety Level designation as outlined by the Centers for Disease Control and Prevention (CDC): The CDC operates an excellent “Quick Learn Lesson,” which outlines the appropriate precautions and identifications of biological risks level.13 • When USP–NF compendial monographs are not available, another high-quality ingredient source may be acceptable (e.g., certified analytical reagent) certified by the American Chemical Society or Food Chemicals Codex grade.

The pharmacist ensures that the sterile components under their supervision meet acceptable criteria of stability and sterility by the following14: • Observing expiration dates and dispensing the oldest stock first. The expiration date of a compounded preparation’s ingredients should not exceed the expiration date set for the final product. Not all chemicals used in pharmaceuticals have been assigned an expiration date. The pharmacist should use good judgment to ensure the purity of any additive. A shelf-life of no longer than 3 years after the container has been opened is considered a good maximum. • Storing components under the environmental conditions stated in the individual monographs and labeling. • Visual observation is an ineffective measure of instability. Most chemical changes fail to demonstrate a visible change. A certified laboratory must compile a stability indicating analysis that will ensure safety through use of validated procedures to identify degradants.15 If a component has undergone a physical change not explained in the labeling, such an ingredient should never be dispensed. Visual checks are of limited value in this setting as the best observations will detect 20–50 µm diameter. Although a microscope will enhance the size of the particles, the volume needed to be tested is quite large according to USP Chapter Particulate Matter in Injections.16 Light obscuration particle sizer is the ideal as it can detect fine precipitates that may occlude small blood vessels (4–9 µm in diameter). • Testing sterility using validated procedures as outlined in USP Chapter . Sufficient numbers of test samples are required for adequate strength of the analysis. Sterility test by membrane filtration is the ideal methodology, but viscous liquids cannot pass the 0.4–μm filters used. For those samples that cannot be filtered, an inoculation test may be used, but it has a much lower capacity to catch microbial contamination.17 Visual observations are not an effective measure of sterility. Evidence that the integrity of the seal has been violated should make the component suspect of microbial contamination. • Properly handling and labeling preparations that are repackaged, diluted, or mixed with other products.

Chapter 4  Sterile Preparation Formulation  55  • Dispensing in the proper container with the proper closure. • Using sterile compounding equipment that is appropriate in design, size, and composition so that surfaces contacting components are not reactive, additive, or absorptive. These surfaces should not alter the required safety, identity, strength, quality, and purity of the components.1 Prescription balances and volume-measurement devices should meet USP specifications.18 • Inspecting and approving or rejecting all formulas, calculations, substances, containers, closures, and in-process materials. There should be a written standard operating procedure in the event of nonconformance of bulk chemicals or compounded preparations to quality assurance tests.19

Pharmacists who compound batches of parenteral preparations must follow a master formula sheet to reproduce preparations that consistently meet all purported norms. For more information about this, readers are referred to USP Chapter Quality Assurance in Pharmaceutical Compounding.20

Components Components are any ingredients used in compounding, whether or not they appear in the final preparation (i.e., intermediate ingredients). Commercially sterile components should be used whenever available. These ingredients should be made in an FDA-approved facility and meet official compendial requirements.10 If these requirements cannot be met, pharmacists should determine if alternative substances should be procured.19

Vehicles Vehicles for most liquid sterile preparations should have no therapeutic activity or toxicity. Rather, they serve as solvents or mediums for the administration of therapeutically active ingredients. For parenteral preparations, the most common vehicle is water. Vehicles must meet USP requirements for the pyrogen or bacterial endotoxin tests.21,22 Water for Injection

Water for injection is purified by distillation or reverse osmosis and is free of pyrogens. Water for

injection USP is sterilized and packaged in singledose containers. Bacteriostatic water for injection is sterilized and contains one or more bacteriostatic agents. Sterile water for inhalation is sterilized and packaged in single-dose containers that are labeled with the full name. As implied, this component cannot be used to prepare parenterals. Sterile water for irrigation is sterilized and packaged in singledose containers with no added substances. Sterile water for injection is not intended for direct injection. The low tonicity will cause hemolysis of the cells and may be fatal. Purified water may be used for enteral medication compounding but cannot be used for compounding sterile preparations. See a detailed review of water for pharmaceutical purposes in USP.23 Aqueous Isotonic Vehicles

Aqueous isotonic vehicles are often used in sterile preparations. A common vehicle is sodium chloride injection, a 0.9% solution (also known as normal saline) that is sterilized and packaged in single-dose containers no larger than 1,000 mL. Bacteriostatic sodium chloride injection is a 0.9% sodium chloride injection that contains one or more bacteriostatic agents in a container no larger than 30 mL. Sodium chloride irrigation also is a 0.9% solution. It has no preservatives and may be packaged in a container larger than 1,000 mL. Other isotonic vehicles include Ringer’s injection, dextrose injection 5%, and lactated Ringer’s injection. None of these components is available in containers larger than 1,000 mL. Water-Miscible Solvents

Several water-miscible solvents are used as a portion of the vehicle in sterile preparations (i.e., as cosolvents). These solvents (e.g., ethyl alcohol, liquid polyethylene glycol, propylene glycol) dissolve drugs with low water solubility. Preparations compounded with these components are usually administered intramuscularly or require significant dilution for parenteral administration.24 Examples of drugs in cosolvent formulations include some vitamins, antihistamines, and cardiac glycosides. When the solvent has toxic properties or produces toxic

  56  Compounding Sterile Preparations

decomposition products (e.g., Cremophor), the formulation requires extra caution (e.g., limiting the final cosolvent concentrations). Administration of these viscous liquids as an undiluted intravenous (IV) injection has resulted in complications.25 Nonaqueous Vehicles

Nonaqueous vehicles such as fixed oils can be used to formulate parenteral preparations. USP specifies that fixed oils must be vegetable (metabolizable) in origin and odorless (or nearly so) and also have no rancid odor or taste.26 Examples include peanut, cottonseed, corn, and sesame oils. Some vitamins and hormones can only be solubilized in these oils. Moreover, oil-based parenterals can only be given intramuscularly. However, emulsified oils (e.g., soybean and safflower) prepared as liposomes, mimic the natural chylomicrons which circulate in the bloodstream. Liposomes may be used as vehicles for lipid-based drugs such as propofol and amphotericin, or as a source of essential fatty acids in nutrition support. Sterile compounding of total parenteral nutrition (TPN) often includes lipids along with the amino acids and dextrose. These combined products are called 3-in-1 or total nutrient admixtures. Special handling is necessary for these formulations as they are easily contaminated (Chapter 5). Special limitations on compatibility are also required as the destabilized emulsions can lead to pulmonary and immunological consequences. Review USP Chapter Globule Size in Lipid Emulsions for a detailed method to evaluate stability of IV lipid emulsions.27

Solutes Solute chemicals dissolved in vehicles should be USP grade or better because their contaminants, especially metals such as aluminum can alter solubility and compatibility of other solutes, cause catalytic chemical reactions, or cause toxicity to patients. Added substances can increase stability or usefulness. Some additives are used although they have limited effectiveness or have a narrow range of usefulness before producing complications. Solubilizers prepared from castor oil have been used for many injectables despite a high incidence of side

effects and compatibility issues. Cyclodextrins are linked sugars that enhance water solubility but can cause nephrotoxicity at higher concentrations.28 A pharmacist must consider the total formulation of active ingredients and added substances; moreover, no coloring agent should be added to a sterile preparation solely to color it. Antimicrobial Preservatives

Antimicrobial preservatives may be added up to a concentration that is considered bacteriostatic or fungistatic. Some preservatives, however, have innate toxicity within these concentrations (e.g., phenylmercuric nitrate 0.01%, benzalkonium chloride 0.01%, and phenol 0.5%). Because of their toxicity, these preservatives are used mostly in ophthalmics and with multidose injectables intended for intramuscular or subcutaneous injections. Benzyl alcohol (usually 0.9%) and the parabens (methyl 0.18% combined with propyl 0.02%) are commonly used in injectables. In oleaginous preparations, no antimicrobial is highly effective. However, hexylresorcinol 0.5% and phenylmercuric benzoate 0.1% are reported to be moderately bacteriocidal.29 Mercurial-based preservatives have fallen into disfavor as they are associated with mercury contaminants such as those found in some fish. Although there is no such relationship, many manufacturers have avoided their use. An antimicrobial agent may be effective in one formula of ingredients but not in another. For example, large molecule components such as polysorbate 80, polyvinylpyrrolidone, and polyethylene glycol form complexes that inactivate the parabens. To select a preservative, an appropriate reference should be consulted and its effectiveness should be verified.30 USP provides a test for the efficacy of antimicrobial preservatives.31 USP Chapter limits antimicrobial effectiveness in multiple-dose vials to 28 days or what a manufacturer states. Allergen extracts for multidose sterile injectables require antimicrobial preservatives like phenol or glycerin (Chapter 9). Compoundingtoday.com has a database of commonly used preservatives and antioxidants.32 Note that simply adding a preservative to a CSP does not automatically extend the BUD unless the compounder has a verifiable sterility testing program in place.

Chapter 4  Sterile Preparation Formulation  57 

Preservatives should be avoided with preparations for neonates and premature infants. Surfactant-based preservatives are toxic to neurological tissue and must be avoided in injectables for intrathecal administration. pH buffers

Buffering agents stabilize an aqueous solution of a chemical against degradation. Limit the use of sodium bicarbonate to neutralize acid in an injection as it can form gas as a reactant and precipitate salts. Buffer systems are formulated at the lowest concentration needed for stability so that the body’s physiologic pH is not disturbed. Acid salts such as citrates, acetates, and phosphates are commonly used as buffers. For an in-depth review of parenteral buffering systems, readers should consult reference 33. Cysteine is added in pediatric and neonatal parenteral nutrition compounding solutions. It acts to reduce pH and enhances solubility of the calcium and phosphate, which would normally form a precipitate (Chapter 5). Tables are available to predict the limits of calcium and phosphate in solutions of varying amino acid concentrations. It must be noted that these are probability tables that do not consider other additives that may contribute to precipitate formation (e.g., dextrose). The consequences of a lack of understanding of this phenomenon have resulted in patient complications.34 Despite the use of solubilization enhancers, a filter should always be used with parenteral nutrition solutions as the potential for precipitation can be significantly reduced, but it cannot be eliminated. Antioxidants

Antioxidants help to prevent oxidation of the active drug. The most common antioxidants are the sodium and potassium salts of metabisulfite and sulfite ions.35 However, the choice of salt depends on the pH of the system to be stabilized. Metabisulfite is used for low pH values, bisulfite for intermediate pH values, and sulfite for high pH ranges. The administration of large amounts (500 mg/L) of sodium bisulfite in peritoneal dialysis fluids causes toxicity with large volumes (10–40 L/ day). Allergic reactions have been noted with the use of this preservative. Other antioxidants include

acetone metabisulfite, ascorbic acid, and cysteine hydrochloride. Chelating Agents

Chelating agents enhance the effectiveness of antioxidants. They form complexes with trace amounts of heavy metals, thereby eliminating the catalytic activity of metals during oxidation. The most commonly used chelating agent is edetate disodium. Tonicity Agents

Some injectable preparation monographs require that the osmolar concentration appear on the preparation’s label. Ideally, parenteral preparations are formulated to be isotonic by use of an isotonic vehicle (e.g., normal saline). When the desired concentration of the active ingredient is hypertonic, the drug must be administered by slowing the rate of injection or by infusion into a large vein (e.g., administration of TPN into subclavian vein).24 In peripheral parenteral nutrition (PPN), the solution is administered through one of the smaller veins. PPN requires that the overall osmolarity of the combined ingredients are below 900 mOsm/L to maintain the integrity of the vein (Chapter 5). Solubilizers

Pharmacists must know the solubility characteristics of new drug substances (especially in aqueous systems) because they must possess some aqueous solubility to elicit a therapeutic response. To maintain some drugs in solution, pharmacists may have to include either a miscible cosolvent or a chemical solubilizer (Table 4-2). Polyethylene glycols 300 and 400, propylene glycol, glycerin, and ethyl alcohol frequently are used. However, toxic levels of these solvents must be avoided as well as amounts that make the preparation too viscous for parenteral use. Emulsifiers

Some drugs are minimally soluble in water. Emulsifiers are used to suspend tiny oil globules in water to create an emulsion that contains a uniform concentration of the active drug through-

  58  Compounding Sterile Preparations Table 4-2.

Modalities to Improve Solubility of Parenteral Formulations Intervention Lyophilization

Issues

Advantages

Requires a sugar to structure crystal formation

Has stability against hydrolysis Enhances speed of dissolution of reconstituted powders

Cyclodextrin

B-cyclodextrins are associated with nephrotoxicity

α, β,and γ types contain 6, 7, and 8 glucopyranose units

Surfactants

Castor oil-based has higher incidence side effects

Allows lipophilic drugs to have aqueous solubility

Liposomal (emulsions)

Limits on droplet size, USP

Can target droplets for immune clearance: amphotericin Or can be designed for “stealth” mode and avoid immune clearance: doxorubicin

PFAT5

PFAT5 = percentage of fat residing in globules larger than 5 µm.

out the volume of the liquid. Emulsions may serve as a caloric source in parenteral nutrition. One example is soybean oil and water emulsion manufactured with egg yolk phospholipids 1.2% and glycerol 1.7% as emulsifiers. An example of an active drug is propofol that is dissolved in soybean oil which is emulsified at a concentration of 10 mg/mL in water with glycerol (22.5 mg/mL) and egg lecithin (12 mg/mL) as emulsifiers. Lipids are also used to encapsulate the active pharmaceutical ingredient.

Containers Containers are defined as “that which holds the article and is or may be in direct contact with the article. The closure is part of the container.”36 All containers for sterile preparations must be sterile and free of both particulate matter and pyrogens. These containers should not interact physically or chemically with formulations to alter their required strength, identity, quality, or purity. Containers also must permit inspection of their contents.26 Container volumes are specified by USP standards. Each container of an injection is filled with liquid, slightly in excess of the labeled size or volume that is to be withdrawn. USP provides a guide showing recommended excess volumes for both mobile and viscous liquids.26

Single

or

Multiple Dose

Sterile, single-dose containers are intended for parenteral, inhalation, irrigation, otic, and ophthalmic administration. Examples are prefilled syringes, cartridges, ampuls, and vials (when labeled as single-use). Multiple-dose containers permit withdrawal of successive portions of their contents without changing the strength, quality, or purity of the remaining portion. Sterile, multiple-dose containers are available for preserved parenterals, ophthalmics, and otics.37 Glass

Glass is the most popular material for sterile preparation containers. USP classifies glass as Type I (borosilicate glass), Type II (soda-lime-treated glass), Type III (soda-lime glass), or NP (sodalime glass unsuitable for parenteral containers).38 Different glass types vary in their resistance to attack by water and chemicals. For pharmaceutical containers, glass must meet the USP test for chemical resistance.39 Because most pharmacists do not have the time or facilities to perform glass chemical interaction studies, they should use only Type I glass to minimize sterile preparation incompatibilities.40

Chapter 4  Sterile Preparation Formulation  59 

Syringes

• Zinc oxide or stearic acid as an activator

Polypropylene syringes are not considered an approved long-term storage for compounded medications.41 Although the concept of packaging the medication in a syringe enhances the readyto-use concept to improve patient care, packaging in a syringe is only for short-term use. The syringe allows air exposure, higher contamination risks, and, in some cases, reactions have been noted with the rubber plunger leading to reduced drug effectiveness. Two-part syringes are available (without lubricant and rubber plunger) but do not resolve sterility issues.

• Carbon, kaolin, or barium sulfate as a filler

Plastic Plastic polymers can be used as sterile preparation containers but present three problems: 1. Permeation of vapors and other molecules in either direction through the container 2. Leaching of constituents from the plastic into the preparation 3. Adsorption of drug molecules onto the plastic

Plastics must meet USP specifications for biological reactivity and physicochemicals.26 Most plastic containers do not permit ready inspection of their contents because they are not clear. Most plastics also melt under heat sterilization.24 Rice and Markel reviewed parenteral medications that require selected containers because of adsorption to or leaching of plasticizers from polyvinyl chloride (PVC) plastic bags.42 Lipophilic drugs can leach the plasticizer from the container into the patient. Avoid lipids and lipophilic drugs when using PVC containers. PVC containers also allow for evaporation of fluid over time and should not be stored outside protective overwrap for extended periods.

Closures Rubber closures must be rendered sterile and free from pyrogens and surface particles. To meet these specifications, multiple washings and autoclavings are required. Closures are made of natural, neoprene, or butyl rubber. In addition, rubber contains the following43: • Sulfur as a vulcanizing agent • Guanidines or sulfide compounds as accelerators

• Dibutyl phthalate or stearic acid as a plasticizer • Aromatic amines as antioxidants

Latex closures have been implicated as a risk factor for patients with latex allergies (Chapter 29). Removal of the stopper does not alter the latex exposure. Despite the prevalence of latex allergies, there has not been a single documented case of anaphylaxis due to exposure of a latex sensitive patient to a drug prepared from a container with a latex stopper. Thus, the rubber sealing of a vial or the plug in a syringe is a complex material that can interact with the ingredients of a formula. Rubber closures also are subject to coring. Therefore, pharmacists should consult compendial or literature standards when selecting a rubber closure for sterile preparations.

Parenteral Preparations Parenteral preparations are classified into six general categories24: 1. Solutions ready for injection 2. Dry, soluble preparations ready to be combined with a solvent before use 3. Suspensions ready for injection 4. Dry, insoluble preparations ready to be combined with a vehicle before use 5. Emulsions 6. Liquid concentrates ready for dilution prior to administration

Most CSPs are aqueous solutions (first category). Other categories usually require the equipment and expertise of a licensed pharmaceutical manufacturer. In addition to using the appropriate vehicle, solvent, and container, the pharmacist must ensure that the final CSP maintains the appropriate physiologic and physical norms.

Physiologic Norms When injectable solutions are formulated, every effort should be made to mimic the body’s normal serum values for pH and tonicity and to create a pyrogen-free preparation.

  60  Compounding Sterile Preparations

pH

• Containers and closures

Normal human serum pH, a logarithmic measure of the hydronium ion concentration in solution, is 7.4. Drugs that are acids or bases or their salts sometimes must be buffered to a pH near normal (e.g., 3–8) to prevent pain or tissue damage. As mentioned previously, acid salts are commonly used as buffers. Stranz and Kastango have provided a good review of pH considerations in parenterals.44

• Chemicals used as solutes

Tonicity

Any chemical dissolved in water exerts a certain osmotic pressure (i.e., a solute concentration related to the number of dissolved particles—un-ionized molecules, ions, macromolecules, and aggregates per unit volume).45 Blood has an osmotic pressure corresponding to sodium chloride 0.9%; thus, its common name is normal saline. Normal saline is said to be iso-osmotic with blood and other physiologic fluids.

• Human touch

If sterile water for injection USP is the vehicle, the risk of pyrogens in water is eliminated. Equipment, containers, and closures can be decontaminated by dry heat or by washing or soaking with acids or bases. Dry heat depyrogenation must be used to render glassware or containers such as vials free from pyrogens as well as viable microbes. USP Chapter requires that the description of the dry heat depyrogenation cycle and duration for specific load items shall be included in written documentation in the compounding facility. The effectiveness of the dry heat depyrogenation cycle must be verified using endotoxin challenge vials (ECVs).21,22 The bacterial endotoxin test should be performed on the ECVs to verify that the cycle is capable of achieving a 3-log reduction in endotoxin.

In the medical setting, the term isotonic is used synonymously with iso-osmotic. A solution is isotonic with a living cell if no net gain or loss of water is experienced by the cell and no other change is present when the cell contacts that solution. Very hypotonic IV preparations can cause hemolysis of red blood cells. Very hypertonic injections can damage tissue and cause pain on injection or crenation of red blood cells. Parenteral solutions usually exert an osmotic pressure of 150–900 mOsm/kg compared to a physiologic norm of 282–288 mOsm/kg for blood. The greater the volume of solution to be injected, the closer the parenteral preparation should be to isotonicity.

Bulk supplies of chemicals may be specified as pyrogen free, although they usually are not. Therefore, sterile preparations made from bulk chemicals must undergo a USP pyrogen test.21 Touch contamination is most easily prevented with proper aseptic technique. The maximum limit of endotoxin in preparations labeled for intrathecal use is set at 0.2 USP endotoxin units/kg/hr. Thus, to prepare high-risk intrathecal dosage forms, the compounding pharmacist must be much more critical during the procedural protocol than during that for IV administered preparations.22

Pyrogenicity

Particulates

Pyrogens are fever-producing endotoxins from bacterial metabolism. They are contaminants that are unacceptable in final CSPs. As large proteins, pyrogens are not removed by normal sterilization procedures and can exist for years in aqueous solution or dried form.

Parenteral solutions must be free of particulate matter—mobile, undissolved solids not intended for sterile preparations. Examples include lint, cellulose and cotton fibers, glass, rubber, metals, plastics, undissolved chemicals, rust, diatoms, and dandruff. To determine levels of particulates, USP sets limits and provides tests.16

The following are sources of pyrogens in sterile preparations: • Aqueous vehicles • Equipment

Physical Norms

However, a careful choice of components, containers, and closures can minimize particulate contamination. Moreover, filtration can remove particles and bacteria from sterile preparations.46

Chapter 4  Sterile Preparation Formulation  61 

The USP Chapter states that visual checks for particles are an unreliable method of evaluation only capable of reliably noting particles 150-µm in diameter. It is possible to detect smaller with enhanced techniques but nothing smaller than 20 µm. The USP sets limits on the number of allowable 10- and 25-µm particles that can be detected using a microscope or a light obscuration device. The automated device has the higher reliability. Pulmonary blood vessels have a 4–9-µm diameter and will occlude if the only quality assurance for undissolved particles is a visual check.34 Stability

Stability of parenteral preparations must be ensured so that patients receive the intended dose. Hydrolytic and oxidative drug degradations are the most common forms of instability but rarely show as cloudiness, precipitates, or color changes. The rate of hydrolysis may be affected by storage temperature or pH of the solution. Oxidation is affected by temperature, pH, exposure to light, oxygen concentration of the solution, impurities (e.g., heavy metals), and concentration of the oxidizable drug. Other types of degradation (e.g., racemization, polymerization, isomerization, and deamination) also can occur in solution. The method chosen for stability should have the capacity to view the breakdown products as well as the original entity. Attempts should be made to force degradation and determine the changes to the original entity. To determine stability, it must be known what instability looks like.47 Because many factors affect the stability of drug molecules, pharmacists who compound parenterals from bulk chemicals should use a short BUD or know from the literature that longer stability exists. Antioxidant and chelation additive systems should be reserved for formulas that are verified in the literature as stable for a given period. The choice of packaging also is important for parenteral drug stability. ASHP publishes the following guides that include information about sterile preparation stability and compatibility: • Bing CD, Nowobilski-Vasilios A. Extended stability for parenteral drugs. 6th ed. Bethesda, MD: ASHP; 2017.

• ASHP. Handbook on injectable drugs. 19th ed. Bethesda, MD: ASHP; 2016.

Impurities FDA requires that large volume parenterals used in TPN limit the aluminum content to 25 mcg/L.48 Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.49 The FDA requires that small volume parenterals used to compound TPN show on the product container the maximum concentration of aluminum at expiry or state that the product contains no more than 25 mcg/L of aluminum. Renal-impaired patients who receive parenteral aluminum at >5 mcg/kg/day may accumulate aluminum at levels associated with central nervous system and bone toxicity.49 When formulating TPN, pharmacists should measure and calculate the soluble aluminum load that a patient will receive and notify the patient’s physician if the FDA limit will be exceeded.48 The physician is responsible for making a clinical decision as to patient risk for aluminum exposure versus the risk of a reduced or different treatment. Heavy metals (e.g., lead and mercury) are also to be minimized in sterile preparations. Heavy metals can be toxic and can catalyze the degradation of active ingredients and preservatives. Introduction of these impurities is most likely when nonsterile, raw materials are used in compounding. This is why the pedigree of a chemical source is necessary either by meeting USP–NF standards or by written manufacturer certification of analysis and purity. Of particular concern for formulators of TPN are the relative concentrations of calcium salts and phosphate salts. If either is too high, an insoluble calcium phosphate precipitate results and has led to deaths.50 Although some pharmacists rely on a “magic sum” of calcium and phosphorus to prevent calcium phosphate precipitates, this practice is unsafe because many variables affect the likelihood of precipitation, such as the type of calcium salt (chloride or gluconate) or amount of proteins (as amino acids) in a parenteral nutrition solution. A widely used guide to resolving the calcium– phosphate problem is available.51

  62  Compounding Sterile Preparations

Parenteral Formulas The American Pharmacists Association (APhA) has published a collection of 168 formulas, some of which are parenteral, organized by therapeutic category, including analgesics, antiemetics, anti-infective agents, and anti-inflammatory agents.52 The International Journal of Pharmaceutical Compounding (IJPC) maintains a website (www. ijpc.com) that lists formulas for many parenteral medications, including some products that have been discontinued by pharmaceutical manufacturers.53 The IJPC website lists files for purchase that contain articles and formulations from back issues of the journal, including sterile medication compounding, stability, and compatibility studies.

Ophthalmic Formulations Ophthalmic preparations share many of the same properties as parenteral preparations but present additional concerns. For example, ophthalmic formulations may use different added substances (e.g., buffers, antimicrobial preservatives, tonicity-adjusting chemicals, and thickening agents). Furthermore, ophthalmic preparations include solutions (eye drops or washes), suspensions, and ointments. Because pharmacists rarely compound sterile suspensions or ointments, this discussion is limited to solutions.

Physiologic Norms Buffers and pH

Lacrimal fluid has a pH of approximately 7.4 and limited buffering capacity. Ophthalmic solutions of weak bases (e.g., alkaloids), for which therapeutic efficacy depends on the bioavailability of the alkaloid base, are buffered to acidity but as near pH 7.4 as possible while keeping the alkaloid in solution after instillation.54 The buffer system (e.g., phosphate or acetate) should maintain pH within the drug’s solubility range for the duration of expiration or beyond-use dating.55 A moderately acidic solution does not cause discomfort on instillation unless the buffer system overcomes the buffer capacity of lacrimal fluid. Nonisotonic ophthalmic solutions below pH 6.6 or above pH 9

have been associated with irritation, reflex tears, and blinking.55 Tonicity

Lacrimal fluid has an osmotic pressure or tonicity similar to aqueous sodium chloride 0.9% solution. Eye tissue can tolerate tonicities of 0.5–1.8% sodium chloride without much discomfort. 54 However, the tonicity of eyewashes is more important than drops because a larger volume of solution contacts the eye. The tonicity of intraocular solutions also should be as close as possible to physiologic. When formulating ophthalmic solutions, pharmacists should adjust the tonicity to approximate lacrimal fluid by adding a substance such as sodium chloride. Several methods can be used to calculate the amount of sodium chloride needed. The following example uses the colligative property, freezing-point depression. Lacrimal fluid lowers the freezing point of water by 0.52 °C. To make a boric acid 1% solution isotonic, sodium chloride crystals are added. Boric acid 1% lowers the freezing point by 0.29 °C; therefore, sodium chloride must be added to lower the freezing point further by 0.23 °C. To use a proportion: 0.52 °C 0 .9 %

=

0.23 °C X

Therefore, X = 0.4%. Thus, sodium chloride is added to a boric acid 1% solution to make it a sodium chloride 0.4% solution.57 Another easy method of calculation is to add the sodium chloride equivalent. See Chapter 31, Appendix A, of Remington’s The Science and Practice of Pharmacy for the sodium chloride equivalents, freezing-point depressions, and hemolytic effects of nearly 400 medicinal chemicals.58 Viscosity

Viscosity is important in ophthalmic preparations. Viscosity sometimes is increased to extend contact between the solution and eye. Moreover, waterdispersible polymers (e.g., methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol) are used as thickening agents.

Chapter 4  Sterile Preparation Formulation  63 

A good review of viscosity agents, including their maximum concentrations, may be found in IJPC.59 Although USP discusses use of cellulose derivatives, precautions are necessary. Cellulose derivative solutions cannot be filtered. When autoclaved, the derivative precipitates from solution because of decreased water solubility at high temperatures but redissolves at room temperature.60 When a heat-labile drug is formulated with a cellulose derivative, all components must be sterilized separately and then recombined aseptically. The drug in solution is sterilized by filtration, and the cellulose derivative is sterilized by autoclaving.60 Viscosity of 25–50 centipoises improves contact time with the eye, whereas higher viscosity offers no contact advantage but usually leaves a residue on eyelid margins.61 Sterility

Ophthalmics are made clear or particle free by filtration; therefore, nonshedding filters, containers, and closures must be used. Stability depends on the chemical nature of the drug, preparation pH, preparation method (especially temperature), solution additives, and packaging. If oxidation is a problem, sodium bisulfite (up to 0.3%), ascorbic acid, or acetylcysteine can be added. Surfactants are used in low concentrations to achieve solution or suspension of active ingredients.

Ophthalmic Formulas APhA has published a handbook that contains some ophthalmic formulas along with their stability information.61 IJPC has published an issue containing formulas for 15 ophthalmic preparations60:

To ensure sterility of ophthalmic solutions, pharmacists must prepare them in a sterile environment in single-dose containers or use antimicrobial preservatives in multiple-dose containers. The microbe that causes great concern is Pseudomonas aeruginosa; however, no preservative is 100% effective against all strains of it.

1. Acetylcysteine 15% ophthalmic solution

The most common preservative is benzalkonium chloride (0.004–0.02%), but high concentrations of it irritate the eye. This preservative is incompatible with large anions (e.g., soaps) as well as with nitrates and salicylates. Other preservatives include phenylmercuric acetate and nitrate (0.001– 0.01%), phenyl-ethanol (0.5%), parabens (0.1%), and chlorobutanol (0.5%). Because chlorobutanol is stable only near pH 5–6, it is used only with solutions within this pH range.

6. Dexamethasone sodium phosphate 0.05% ophthalmic ointment

Remington’s Chapter 43 discusses different ophthalmic preservatives.54 The properties of various ophthalmic preservatives have been discussed above. Some ophthalmologists prefer nonpreserved solutions because of allergic reactions to common preservatives. This is particularly true for ophthalmic solutions injected during cataract surgery.62

Physical Norms Required physical characteristics of ophthalmics include clarity, stability, and compatibility.

2. Amphotericin B 2 mg/mL ophthalmic solution 3. Ascorbic acid 10% ophthalmic solution 4. Calcium gluconate 1% ophthalmic irrigation solution 5. Cyclosporin 2% ophthalmic solution

7. Fluconazole 0.2% ophthalmic solution 8. Fortified gentamicin ophthalmic solution 9. Glucose 40% ophthalmic ointment 10. Idoxuridine 0.5% ophthalmic ointment 11. Idoxuridine 0.1% ophthalmic solution 12. Lissamine Green 0.5% ophthalmic solution 13. Ophthalmic lubricant 14. Rose Bengal 1% ophthalmic solution 15. Vancomycin 25 mg/mL ophthalmic solution

These formulas are accompanied by the method of preparation, packaging, labeling, stability, discussion, and references. ASHP has published extemporaneous formulations for ophthalmics in Extemporaneous Formulations for Pediatric, Geriatric, and Special Needs Patients, Third Edition56: • Bacitracin ophthalmic solution 9,600 units/mL

  64  Compounding Sterile Preparations • Cefazolin ophthalmic solution 33 mg/mL • Cidofovir intravitreous solution 0.2 mg/mL • Cidofovir intravitreous solution 8.1 mg/mL • Fumagillin ophthalmic solution 70 mcg/mL • Ganciclovir intravitreous solution 20 mg/mL • Gentamicin ophthalmic solution 13.6 mg/mL (fortified) • LET (lidocaine 4%/racepinephrine 0.225%/ tetracaine 0.5%) topical solution • Tobramycin ophthalmic solution 13.6 mg/mL • Tobramycin ophthalmic solution 15 mg/mL • Vancomycin ophthalmic solution 31 mg/mL • Voriconazole ophthalmic solution 1 mg/mL • Voriconazole ophthalmic solution 10 mg/mL

Summary In many cases, no commercial product is available for a final sterile preparation. Legally, pharmacists may compound these preparations under the FDCA regulations. However, various sterile components (e.g., vehicles, buffers, and solubilizers) are required. It is the pharmacist’s responsibility to ensure that they meet the appropriate compendial requirements. When formulating sterile preparations, a pharmacist should use components so that the final sterile preparation achieves both physiologic and physical norms.

References 1. U.S. Pharmacopeial Convention. USP chapter pharmaceutical compounding—sterile preparations. In: USP 37–NF 32. Rockville, MD: U.S. Pharmacopeial Convention; 2014. 2. U.S. Food and Drug Administration, Science Board to the Food and Drug Administration. Advisory Committee; Notice of Meeting. Doc No. 80 FR 67766. www.federalregister.gov/a/2015-27957 (accessed 2017 May 8). 3. U.S. Food and Drug Administration. Compounding Quality Act Title I of the Drug Quality and Security Act of 2013. www.fda.gov/drugs/ guidancecomplianceregulatoryinformation/ pharmacycompounding/default.htm (accessed 2016 Mar 15).

4. U.S. Food and Drug Administration (FDA), Office of Enforcement, Division of Compliance Policy. Manufacture, distribution, and promotion of adulterated, misbranded, or unapproved new drugs for human use by state-licensed pharmacies. FDA Guide 7132.16. Washington, DC: FDA; 2016 Mar. 5. U.S. Food and Drug Administration. FDA CPG sec. 460.100 hospital pharmacies—status as drug manufacturer. www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ ucm074397.htm (accessed 2017 May 8). 6. U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research. Guidance for industry, CGMP for phase 1 investigational drugs. Washington, DC: FDA; 2008 Jul. 7. National Association of Boards of Pharmacy. Appendix J: good compounding practices applicable to state licensed pharmacies. In: Model state pharmacy act and model rules of the National Association of Boards of Pharmacy. Mount Prospect, IL: National Association of Boards of Pharmacy; 2012 Aug. 8. U.S. Pharmacopeial Convention. USP chapter pharmaceutical compounding—nonsterile preparations. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 9. U.S. Food and Drug Administration (FDA). FDA guidance: guidance for industry and FDA staff; submission and review of sterility information in premarket notification (510(k)) submissions for devices labeled as sterile. Washington, DC: FDA; 2008. 10. Anon. Standard operating procedure: certificates of analysis of materials used for pharmaceutical compounding. Int J Pharm Compd. 2001 (Mar/ Apr); 5:147. 11. U.S. Pharmacopeial Convention. USP chapter hazardous drugs—handling in healthcare settings. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 12. Centers for Disease Control and Prevention (CDC). NIOSH A vapor containment performance protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs (NIOSH docket number 288, CDC-2015-0075). Atlanta, GA: CDC; 2015. 13. Centers for Disease Control and Prevention. Quick learn lesson. www.cdc.gov/training/ QuickLearns/biosafetyCE/index.html (accessed 2016 Mar 15). 14. U.S. Pharmacopeial Convention. USP chapter stability considerations in dispensing practice. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016.

Chapter 4  Sterile Preparation Formulation  65  15. Tamizi E, Jouyban A. Forced degradation studies of biopharmaceuticals: selection of stress conditions. Eur J Pharm Biopharm. 2016; 98:26-46. 16. U.S. Pharmacopeial Convention. USP chapter particulate matter in injections. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 17. U.S. Pharmacopeial Convention. USP chapter sterility test. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 18. U.S. Pharmacopeial Convention. USP chapter prescription balances and volumetric apparatus. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 19. Anon. Standard operating procedure: procedures in the event of nonconformance of bulk chemicals or compounded preparations. Int J Pharm Compd. 2006 (Jan/Feb); 10:381. 20. U.S. Pharmacopeial Convention. USP chapter quality assurance in pharmaceutical compounding. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 21. U.S. Pharmacopeial Convention. USP chapter pyrogen test. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 22. U.S. Pharmacopeial Convention. USP chapter bacterial endotoxins. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 23. U.S. Pharmacopeial Convention. USP chapter water for pharmaceutical purposes. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. 24. Akers MJ. Parenteral preparations. In: Allen LV, ed. Remington: the science and practice of pharmacy. 22nd ed. London and Philadelphia: Pharmaceutical Press; 2013:861-98. 25. Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. J Pediatr Pharmacol Ther. 2014; 19:277-82. 26. U.S. Pharmacopeial Convention. USP chapter injections. In: USP 37–NF 32. Rockville, MD: U.S. Pharmacopeial Convention; 2014. 27. U.S. Pharmacopeial Convention. USP chapter globule size in lipid emulsions. In: USP 37–NF 32. Rockville, MD: U.S. Pharmacopeial Convention; 2014. 28. Gidwani B, Vyas A. A comprehensive review on cyclodextrin-based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. Biomed Res Int. 2015; 2015:198268. 29. Akers MJ. Considerations in selecting antimicrobial preservative agents for parenteral product development. Pharm Technol. 1984; 8:36. 30. Ando HY, Radebaugh GW. Property-based drug design and preformulation. In: Troy DB, ed. Rem-

31.

32. 33. 34.

35. 36.

37.

38. 39.

40.

41.

42.

43.

44. 45.

ington: the science and practice of pharmacy. 21st ed. Baltimore: Lippincott Williams & Wilkins; 2005:720–44. U.S. Pharmacopeial Convention. USP chapter antimicrobial effectiveness testing. In: USP 37–NF 32. Rockville, MD: U.S. Pharmacopeial Convention; 2014. Anon. Preservatives and antioxidants [database]. www.compoundingtoday.com (accessed 2016 Feb 15). Wang YJ, Kowal RR. Review of excipients and pHs for parenteral products used in the United States. J Parenter Drug Assoc. 1980; 34:452-62. Knowles JB, Cusson G, Smith M et al. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. JPEN. 1989; 13:209-13. Akers MJ. Preformulation screening of antioxidant efficacy in parenteral products. J Parenter Drug Assoc. 1979; 33:346-56. U.S. Pharmacopeial Convention. General notices and requirements. In: United States pharmacopeia, 39th rev./national formulary, 34th ed. Rockville, MD: U.S. Pharmacopeial Convention; 2016. Turco SJ. Characteristics. In: Turco SJ, ed. Sterile dosage forms, their preparation, and clinical application. 4th ed. Philadelphia: Lea & Febiger; 1994:28-38. U.S. Pharmacopeial Convention. USP chapter containers. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. Turco SJ. Extemporaneous preparation. In: Turco SJ, ed. Sterile dosage forms, their preparation, and clinical application. 4th ed. Philadelphia: Lea & Febiger; 1994:57-78. U.S. Pharmacopeial Convention. USP chapter biological reactivity tests, in vitro. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016. Anon. ISMP comments on BD syringe potency issue (2015 Aug 27). www.ismp.org/newsletters/ acutecare/showarticle.aspx?id=117 (accessed May 8, 2017). Rice SP, Markel JA. A review of parenteral admixtures requiring select containers and administration sets. Int J Pharm Compd. 2002 (Mar/ Apr); 6:120-2. Turco SJ. Large-scale preparation. In: Turco SJ, ed. Sterile dosage forms, their preparation, and clinical application. 4th ed. Philadelphia: Lea & Febiger; 1994:39-56. Stranz M, Kastango ES. A review of pH and osmolarity. Int J Pharm Compd. 2002 (May/Jun); 6:216-20. U.S. Pharmacopeial Convention. USP chapter osmolarity. In: USP 39–NF 34. Rockville, MD: U.S. Pharmacopeial Convention; 2016.

  66  Compounding Sterile Preparations 46. McKinnon BT, Avis KE. Membrane filtration of pharmaceutical solutions. Am J Hosp Pharm. 1993; 50:1921-36. 47. Tamizi E, Jouyban A. Forced degradation studies of biopharmaceuticals: selection of stress conditions. Eur J Pharm Biopharm. 2016; 98:26-46. 48. U.S. Food and Drug Administration. Aluminum in large and small volume parenterals used in total parenteral nutrition: delay of effective date. Fed Reg. 2003; 68:32979-81. 49. Smith BS, Kothari H, Hayes BD et al. Effect of additive selection on calculated aluminum content of parenteral nutrient solutions. Am J Health-Syst Pharm. 2007; 64:730-9. 50. U.S. Food and Drug Administration. Safety alert: hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm. 1994; 51:1427-8. 51. Trissel LA. Trissel’s calcium and phosphate compatibility in parenteral nutrition. Bethesda, MD: ASHP; 2001. 52. Allen LV. Allen’s compounded formulations: complete collection. Washington, DC: American Pharmacists Association; 2003. 53. International Journal of Pharmaceutical Compounding [website]. www.ijpc.com (accessed 2016 Feb 20). 54. Chowhan M, Lang JC, Missel P. Ophthalmic preparations. In: Allen LV, ed. Remington: the science and practice of pharmacy. 22nd ed. London and Philadelphia: Pharmaceutical Press; 2013:907-29.

55. Allen LV Jr. Buffer solutions for ophthalmic preparations. Int J Pharm Compd. 1998 (May/ Jun); 2:190. 56. Jew RK, Soo-Hoo W, Erush SC et al. Extemporaneous formulations for pediatric, geriatric, and special needs patients. 3rd ed. Bethesda, MD: American Society of Health-System Pharmacists; 2016. 57. Turco SJ. Ophthalmic preparations. In: Turco SJ, ed. Sterile dosage forms, their preparation and clinical application. 4th ed. Philadelphia: Lea & Febiger; 1994:344-54. 58. Ingham A, Poon CY. Tonicity, osmoticity, osmolality and osmolarity. In: Allen LV, ed. Remington: the science and practice of pharmacy. 22nd ed. London & Philadelphia: Pharmaceutical Press; 2013:641-64. 59. Allen LV Jr. Basics of sterile compounding: ophthalmic preparations, part 1: ophthalmic solutions. Int J Pharm Compd. 2016 (Sep/Oct);20:399-404. 60. Allen LV Jr. Preservation, sterilization and sterility testing of ophthalmic preparations. Int J Pharm Compd. 1998 (May/Jun); 2:192-5. 61. McElhiney LF. Compounding guide for ophthalmic preparations. Washington DC: American Pharmacists Association; 2013. 62. Anderson NJ, Edelhauser HF. Ophthalmic solutions in cataract surgery. Int J Pharm Compd. 1998 (May/Jun); 2:196-202.

Chapter

5

Parenteral Nutrition Compounding Todd W. Canada

Introduction Parenteral nutrition (PN) is a potentially life-saving therapeutic intervention for neonates, children, or adults with a dysfunctional gastrointestinal tract (e.g., chronic intestinal failure). It is used in a variety of healthcare environments from the intensive care unit (ICU) to the home care setting. Generally, PN is provided as an intravenous (IV) mixture of crystalline amino acids and dextrose, commonly referred to as a 2-in-1 solution, while also containing electrolytes, multivitamins, trace elements, or non-nutritive medications. The addition of IV oil-in-water fat emulsion (IVFE) to PN is commonly referred to as a total nutrient admixture (TNA) or 3-in-1 emulsion with the same constituents mentioned above added. PN is a complex and high-alert medication with stability and compatibility issues depending on the formulation used (i.e., 2-in-1 versus 3-in-1). Stability with PN refers to the deterioration or degradation of an active drug changing its pharmacologic or pharmaceutical characteristic (e.g., oil-in-water IVFE coalescence to eventual emulsion cracking). Compatibility refers to a disruption in the coexistence of two or more components in the PN formulation (e.g., potassium phosphate and calcium gluconate forming the nearly insoluble dibasic calcium phosphate).1 Pharmacy personnel involved in PN order review and compounding must know the complexity of these stability and compatibility concerns, along with a knowledge of PN indications, dosing, and monitoring parameters for the individual components. Pharmacist and pharmacy technician involvement in the management and compounding of PN has changed over the past several years as evidenced from the results of the ASHP surveys of hospital pharmacy practice: • The 2012 survey—The 2012 survey showed pharmacists were providing PN management (e.g., initiating, modifying, and monitoring) in 4.7% (hospitals with less than 50 beds) to 44% (hospitals with 600 beds or greater) of inpatients (overall mean for all hospitals: 11.1%).2

Note: The author acknowledges Jay M. Mirtallo and Philip J. Schneider for their work in “Safe Use of Automated Compounding Devices in Compounding Sterile Preparations” in the previous edition of this book.

67

  68  Compounding Sterile Preparations • The 2013 survey—The 2013 survey showed pharmacists were providing PN consults (i.e., medical record review with oral or written prescriber follow-up) in 45.1% (hospitals with less than 50 beds) to 75% (hospitals with 300–399 beds) of inpatients (overall mean for all hospitals: 43.2%).3 It also showed pharmacists were providing PN management (e.g., standing protocol or prescriber delegation) in 32.4% (hospitals with less than 50 beds) to 59.7% (hospitals with 400–599 beds) of inpatients (overall mean for all hospitals: 55.9%).3 • The 2014 survey—The 2014 survey showed institutions were providing PN as commercially available amino acids/dextrose (2-in-1) in 7.7% (hospitals with 400–599 beds) to 64.6% (hospitals with 100–199 beds) (overall mean for all hospitals: 43%). Preparation of PN was outsourced to a compounding facility in 10.6% (hospitals with less than 50 beds) to 41.3% (hospitals with 600 beds or greater) (overall mean for all hospitals: 18.6%). Fully 70.1% of hospitals outsourced some compounded sterile preparations (CSPs) with 21.9% (hospitals with 100–199 beds) to 52.1% (hospitals 300–399 beds) partially or completely outsourcing PN. These formulations were compounded with an automated compounding device (ACD) in 1.2% of hospitals with less than 50 beds and up to 60% of hospitals with 400–599 beds (overall mean for all hospitals: 16.8%). PN formulations were compounded by gravity in no hospitals with 600 beds or greater, but in 16.7% of hospitals with 50–99 beds (overall mean for all hospitals: 10.4%). No PN formulations at all were prepared in 32.5% of hospitals with less than 99 beds because this therapy was not used (overall mean for all hospitals: 11.2%). The 2014 survey also showed cleanroom compliance with the USP Chapter Pharmaceutical Compounding—Sterile Preparations in 43.5% (hospitals with less than 50 beds) to 93.5% (hospitals with 600 beds or greater) of pharmacy departments (overall mean for all hospitals: 64.7%).4 • The 2015 survey—The 2015 survey revealed an overall lower percentage (8.7%) of all hospitals with a pharmacist assigned to daily nutrition support compared to the 2011–2014 (range 11.6–13.6%) surveys. Overall, 2.4% of hospitals with 50–99 beds to 56.7% of hospitals with 600 beds or more had a pharmacist assigned to daily nutrition support.5

Clearly, the management and compounding of PN is different based on the size and characteristics of each institution, with most providing between 5 to 15 daily admixtures in combined populations of neonatal, pediatric, and adult patients.6 The use of standardized, commercial PN is predominantly used in smaller facilities (i.e., less than 200 beds), while larger teaching hospitals tend to utilize ACDs more for customized PN. An American Society for Parenteral and Enteral Nutrition (ASPEN) survey revealed that only 60.2% of hospital pharmacies dedicate 0.6 full-time equivalents of a pharmacist position to review, verify, and clarify these complex, high-alert PN orders.6 Surprisingly, 23.1% of respondents did not allocate any pharmacist time for PN order review and verification. This is especially important because ACDs, which require properly trained personnel, were used in 35.7–60% of hospitals with 200 or more beds and these ACDs rarely (16–28%) have an electronic interface with the pharmacy or hospital information system.4,6,7 The ASPEN survey showed either a pharmacist (54.4%) or a pharmacy technician (27.4%) manually entered the PN order into the ACD.6 Sacks and others have previously shown that 39% of PN errors occur during the transcription process (e.g., selecting the wrong electrolyte salt or dose, wrong amino acids solution, and drug omission).8 The extent of the adoption of ACDs has been primarily based on considerations of their cost and the risks of manual transcription errors as previously mentioned. Break-even analyses have been performed determining the volume of PN admixtures required to justify the costs comparing ACDs to manual compounding.9,10 Besides improvements in efficiency, the value of ACDs offsetting cost also has been reported based on improvements in clinical practice including implementing a 24-hour PN admixture system, which is recommended by the ASPEN Safe Practices for PN.11,12 A survey of compliance with USP Chapter standards in hospitals found that more than half of respondents did not validate the accuracy of ACDs and more than a third of respondents had no plans to change in response to the chapter revision.13 Errors related to ACDs occurred when actual practices bypassed the safety check system intended to verify the correct sterile product was placed in the right station on the ACD. Manipulating sterile products outside of the laminar flow hood was also a breach in ac-

Chapter 5  Parenteral Nutrition Compounding  69 

cepted aseptic procedures.14 The USP, ASHP, and ASPEN have recognized the problems associated with the use of ACDs, and each of these organizations has suggested standardization of methods used to compound IV admixtures with ACDs and published PN guidelines and standards for safe pharmacy practices.10,12,15-19 The use of compounding workflow management systems also has emerged to integrate barcode scanning and real-time digital images to standardize the IV process and reduce errors. These management systems have revealed four factors associated with an increased risk of IV compounding errors including (1) dose preparation during the morning shift; (2) on a Sunday or Monday; (3) preparation of doses in ICUs or emergency departments; and (4) technician versus pharmacist compounding.20 Fortunately, the use of gravity compounding of PN, which does not use any of the above safety (e.g., ACD software, IV management systems), is less frequently used compared to the other methods of preparation across the United States and more often used in smaller hospitals.

Reported PN Errors The importance of pharmacy personnel training cannot be overstated when evaluating the different types of PN errors reported. Wrong dose and wrong drug are the most common PN error observations.21 Error rates related to PN were the highest of all compounded sterile IV products reported in an observational study of five large hospitals (i.e., 400 to 815 beds) with manual preparation as high as 47.2% and partly automated compounding up to 44.4% at individual hospitals.14 The incorrect selection of 5% dextrose for 50% dextrose or 10% dextrose for 70% dextrose parenteral containers because of packaging similarity, substitution of 70% dextrose for 10% amino acids without barcoding verification on an ACD, incorrect order entry into ACD software with wrong units (e.g., milligrams [mg] for milliequivalents [mEq]), and incorrect use of various electrolytes (e.g., 14.6% and 23.4% sodium chloride, 4 mEq/mL for 2 mEq/mL potassium acetate) because of drug shortages have all occurred.21,22 Patient deaths reported from PN compounding errors simulating a pulmonary embolus from precip-

itated dibasic calcium phosphate, and development of unexplained interstitial pneumonitis, have also occurred over the last 30 years in the home care and hospital environments.23-26 Central venous access loss due to precipitated dibasic calcium phosphate also has been reported, often requiring IV line replacement and patient inconvenience.27 It should be noted that a pharmacy PN compounding error was not the initial suspicion in any of the above mentioned events, as it was only determined from autopsy or simulation of PN formulations for these unfortunate patients. Drug shortages also have been linked to patient deaths from compounding of nonsterile amino acid solutions with breaches in the mixing, filtration, and sterility testing practices at a compounding pharmacy with administration to patients receiving PN in surrounding hospitals.28,29 Although hazards of infusing unstable oil-in-water IVFE-containing PN have not been reported in humans (i.e., unethical to perform such a study), animal models have demonstrated abnormalities in lung histology and lipid deposition in the lungs similar to pulmonary fat embolism syndrome.30 Patient deaths related to improper use of ACDs also have been reported.12 A fatal zinc overdose occurred in an infant when a pharmacy technician, who had not completed sufficient training for use of the device, compounded the sterile preparation.31 Because PN is considered a USP medium-risk compounded product, pharmacy personnel should pass a written test and validate aseptic manipulative skills using media fill testing initially and at least annually thereafter or according to state laws governing IV compounding practices. Unfortunately, most facilities are not aware of their microbial contamination rates for medium-risk IV CSPs and rates in the published literature range from 0.96–5.2%.32 To further minimize microbial contamination, USP suggests that sterile products having no preservatives used to compound sterile preparations in ISO Class 5 environments should be used only for up to 6 hours after initial needle puncture.15

Safety Aspects of PN Compounding ASPEN has developed Safe Practices, Consensus Recommendations, and Clinical Guidelines specific to PN, as well as a PN safety toolkit

  70  Compounding Sterile Preparations

(www.nutritioncare.org/pnsafety).12,16,17 The PN Safety Consensus Recommendations also provide a checklist to be completed at each facility for development of quality improvement initiatives with your PN process.18 The ASPEN Safe Practices, Consensus Recommendations, and Clinical Guidelines relate to the following pharmacist responsibilities: prescribing PN, reviewing the PN order, compounding and labeling PN, and quality assurance of the PN process.

Prescribing PN The prescribing of PN is a complex process that can have significant impact on patient morbidity and potentially mortality if done inappropriately. Prescribers must know appropriate medical and surgical PN indications, suitable vascular access devices (i.e., peripheral versus central IV administration methods), protein and energy requirements, fluid and electrolyte management, and micronutrient and vitamin daily allowances, as well as therapeutic PN goals.16,17 Physicians are no longer the only prescribers of PN, as physician extenders or midlevel providers (e.g., advanced nurse practitioners, physician assistants, residency-trained pharmacists, and certified nutrition support clinician dietitians) are becoming more commonly involved in this role because formal nutrition support teams (i.e., physician-led team with nurse, dietitian, and pharmacist) are rarely found in institutions. The following are Consensus Recommendations from the ASPEN clinical guidelines: Healthcare organizations shall use a standardized process for PN management, and this process shall include clinicians with expertise in the area of nutrition support, preferably from multiple disciplines. PN shall be prescribed using a standardized PN order format and review process applicable to patients of every age and disease state within a healthcare organization. When reordering PN, each PN component should be reordered in its entirety, including full generic names and doses.16 Educating healthcare professionals on PN prescribing has been shown to reduce inappropriate use, decrease prescribing errors, lower the rate

of overfeeding, and decrease associated costs of providing PN.17 Standardizing the PN ordering process (i.e., electronic order set or form) for prescribers can also reduce the variation commonly seen in the nutrient dosing formats (e.g., amount/ day, amount/liter, percent final concentration of macronutrient).33 ASPEN also has developed standardized competencies as follows: The prescriber may be certified as a nutrition support clinician or other related nutrition board certification. If not certified in nutrition support, the prescriber should complete a didactic/interactive course such as the ASPEN PN Order Writing Workshop or a facility/organization developed program for initial competency. The prescriber will complete at least 10 PN orders for the initial competency evaluation (via patient case scenarios and actual patients) under the supervision of an experienced preceptor. These cases should reflect the spectrum of medical and nutrition conditions, body weights, and age range. The prescriber should follow these patients and modify daily PN orders over a period of several days. This allows demonstration of the ability to modify PN orders as needed for changing clinical conditions. For annual or every other year competency reevaluation, completion of ongoing continuing education requirements on nutrition support combined with PN order assessment of at least 5 cases or patients should be reviewed using the PN Order-Writing Competency Tool.33

Reviewing

the

PN Order

Healthcare professionals who prescribe PN often have inconsistent or no formal training in nutrition support.34 Reports to USP of medication errors suggest that this inexperience often leads to errors in writing PN orders resulting in a need to clarify the order or resolve omitted nutrients. The ASPEN guidelines note, “The clinician and compounding pharmacist shall assess the PN formulation to determine whether its contents are within an acceptable standard range based on the specific patient

Chapter 5  Parenteral Nutrition Compounding  71 

population (e.g., adult or pediatric). They shall also assess whether a clinical disease state or condition warrants a dose outside the standard range.”12 Review of the zinc dose compared to the standard dose based on the patient’s weight might have prevented the overdose in the case referred to earlier.30 Errors are common when PN is prescribed, especially those related to transcription (i.e., reentering a PN order from a paper order or electronic medical record to an ACD).8 ACDs have safeguards programmed into the software that alerts the pharmacist when a dose is outside an acceptable range, and these can be customized to your own patient population receiving PN. Despite the availability of this safety feature, surprisingly it is often not used or bypassed by untrained pharmacy staff.30 PN is a multicomponent product and is therefore prone to problems of nutrient omission, compatibility, and stability.34 The following are ASPEN guidelines pertinent to these issues: The calorie, protein, fluid, electrolyte, vitamin, trace element and medication content are reviewed for each and every PN prescription to assure that a complete and balanced nutrient formulation is provided. Balanced is defined as the presence of the proper proportion of calories, protein, fluid, electrolytes, vitamins, and trace elements to assure adequate use by and assimilation into the body. Each of the PN components should be assessed for appropriateness of dose and for the potential of a compatibility or stability problem. Any dose of a nutrient outside a normal range that is not explained by a specific patient condition or history shall be questioned and clarified before the PN is compounded.12 Pharmacists and pharmacy technicians must follow a standardized process for PN order review to safely prepare these complex formulations for IV administration. ASPEN has developed these standardized competencies for PN order review given the reduced number of board-certified nutrition support pharmacists in positions overseeing the PN process and lack of pharmacy technician certification: The pharmacist should be board-certified, preferably as a nutrition support phar-

macy specialist. An alternative is to have a board-certified nutrition support pharmacy specialist on staff who develops and oversees competencies for colleagues in the organization who review and prepare PN. If not board-certified in nutrition support, the pharmacist shall complete a didactic/ interactive course such as the ASPEN professional development material (e.g., Interdisciplinary Review Course, Nutrition Support Fundamentals and Review Course, the module-based Self-Assessment program, or any of a number of on-demand webinars) in addition to the ASHP resources for sterile compounding. An alternative course would be a facility or organizationally developed program for initial competency. The pharmacy technician should be certified and receive in-depth training in PN preparation to include the following: proper personal hygiene and protective equipment; cleaning of the ACD and compounding environment; setup and verification of the ACD and individual components; review formulation, label, and select appropriate bag; scan and check barcodes, pump admixture, or activate multichamber bag; be familiar with dosing differences between PN components intended for neonatal, pediatric, and adult patients, as institutionally appropriate; verify ingredients, including those that require manual admixture; safely combine components of PN, including the manual addition of ingredients; affix patient-specific label, auxiliary labels; store properly; and inventory management for individual PN components. Pharmacist shall review at least 10 PN orders for the initial competency evaluation (via patient case scenarios and actual patients) under the supervision of an experienced pharmacy preceptor. Pharmacist and pharmacy technician shall prepare at least 10 PN orders for each patient population managed by the organization (e.g., adult, pediatric, or neonate). For annual competency, completion of ongoing continuing education requirements on nutrition support should be combined with the following: PN order assessment of at

  72  Compounding Sterile Preparations

least 2 cases or patients reviewed using the PN Order Review Competency Tool or PN preparation of at least 2 population-specific PN orders using the PN Preparation Competency Tool.19

Labeling PN The PN Safety Consensus Recommendations state that a standardized ordering format include a standardized sequence of ingredients with standard units so that the label will have all the PN ingredients listed in the same sequence and same units of measure as the PN order.16 The pharmacygenerated PN label then becomes a vital tool for other pharmacists, pharmacy technicians, and nurses to compare the PN ingredients and rate of IV administration against the original order. The following guideline addresses this importance: “The PN label is compared with the PN order and for beyond-use date before administration.”12 ACDs can produce a PN label in accordance with the ASPEN Safe Practice guidelines and Consensus Recommendations. The standardized PN ordering format must be used with the necessary information (i.e., PN ingredients ordered in amounts per day for adults and amounts per kilogram per day for pediatric and neonatal patients) for the PN label to be programmed into the ACD. Consistency between the PN order and the label facilitates final review by the nurse (or caregiver/ patient) before administration of the sterile IV preparation.

PN Compounding Pharmacists and pharmacy technicians involved in the direct compounding of PN must demonstrate initial and annual proper aseptic technique according to USP Chapter standards for CSPs. The ASPEN PN Safety Consensus Recommendations state that pharmacy technicians shall be certified by the Pharmacy Technician Certification Board if they are involved in PN compounding.16 An initial and annual compounding competency for pharmacy staff members must include common PN calculations for all age populations, compounding of PN base solutions, preparing dilutions (e.g., PN product shortage, glucose or electrolyte laboratory

analysis), aseptic technique manipulations for a medium-risk level CSP, proficient use of ACD technology for PN preparation, and the ability to identify PN incompatibilities.16

Standardized, Commercial PN Multichamber Bags

with

Given the complexities of prescribing PN and limited healthcare prescriber PN training, pharmaceutical companies developed commercially available, premade multichamber PN bags for clinical use. These generally are available for peripheral and central venous administration intended to meet the daily maintenance nutritional requirements of a specific patient population including 2-in-1 and 3-in-1 PN formulations with varying final concentrations of each macronutrient (e.g., amino acids, dextrose, IVFE) with or without electrolytes. The ASPEN Clinical Guidelines suggest commercially available, premade multichamber PN bags be considered as an available option for an institution to best meet their patient needs alongside customized compounded PN.17 Because these products require minimal compounding, and, if the healthcare organization’s pharmacy is not compliant with USP Chapter, an appropriately trained nutrition support clinician should make this determination. The primary drivers of standardized, commercial PN use are determining desired clinical outcome (e.g., nutrition for a patient with a postoperative ileus unable to eat at hospital days 7 to 10), safety of utilizing such a system (e.g., minimal compounding required), and overall costs. It has been estimated that approximately 15 PN patients/day utilizing a commercially available, premade multichamber PN bag are required for a hospital pharmacy to breakeven from a cost standpoint when compared to compounded customized PN, while others have shown premade multichamber PN bags to be less expensive than compounded customized PN.35,36 The primary advantages of using the commercially available, premade multichamber PN bags includes fewer compounding steps, up to a 2-year shelf-life if not removed from external covering package, and pharmacy time savings of up to 60 minutes per PN bag compared to a compounded customized PN (Figure 5-1).37 Fluid restriction and severe electrolyte abnormalities are the primary reasons to

Chapter 5  Parenteral Nutrition Compounding  73 

avoid using these commercially available, premade multichamber PN bags in complicated hospitalized patients requiring PN.

Customized PN In the United States, PN is generally compounded to a patient’s needs from either using defined standard formulations for the given institution (preferred) or specifically formulated from individual components. When PN is custom compounded as a 3-in-1 formulation for a given patient, the PN clinical guidelines recommend maintaining final concentrations of amino acids ≥4%, dextrose ≥10%, and IVFE ≥2% for stability reasons (i.e., at room temperature or refrigeration according to USP standards).17 ASPEN guidelines for compounding PN with ACDs were adapted from the ASHP guidelines for use of ACDs.10,12 The ASPEN guidelines relate to the pharmacist’s responsibility to perform specific functions such as the following (Figure 5-1): • Perform checks of the final preparation to verify compounding accuracy by ensuring that data entered into the compounder are correct, the stations contain the correct ingredients, and the correct quantities of ingredients were used in compounding. • Periodically observe the operation of the device to ensure it is working properly.

Input of the correct formula into the compounder is critical because electronic systems of ordering PN seldom interface with the ACD computer.6,7,34 Ensuring correct ingredients are in place is also important because it has been reported that the barcode system used to verify the identity of products on ACD stations may be bypassed.14 Driscoll et al. reported a quality control process to verify the accuracy of the volume transfer by the ACD by using a pharmaceutical balance to weigh the vials used in compounding before the daily preparation of PNs and at the end of the compounding process to ensure there are no errors in volume transfers of critical ingredients such as potassium.38 This procedure was initiated because it was felt that weighing the final product was insufficient to detect improper compounding of potentially harmful ingredients such as potassium. In their example, a 2-liter PN having an acceptable 5% error could have up to

100 mL of excess volume. If this entire volume was potassium at a concentration of 2 mEq/mL, administration of the PN could result in a potassium overdose. ASHP recommends that the amount pumped for each ingredient should be verified.10 ASPEN Safe Practices for PN states the following: Manufacturers of automated methods of PN compounding shall provide an additive sequence that ensures the safety of the compounding device. This compounding sequence should be reviewed with the manufacturer of the parenteral nutrient products used by the institution. As most institutions in the United States are represented by buying groups with many participants, such buying groups should not only ensure the safety and support of the ACD, but should avoid splitting PN contracts (mixing brands of amino acids, dextrose and IVFE) unless such combinations have adequate physicochemical data that ensures the stability, compatibility and safety of the final formulations commensurate with the data for single source PN products.12 This practice was recommended after the Food and Drug Administration safety alert resulting from two patient deaths associated with a PN compounding error that occurred when the brand of amino acid products was changed.25,39 The compounding sequence was not correct using the new product resulting in precipitation of calcium and phosphate. The PNs contained IVFE (i.e., milky white appearance) so the pharmacy or nursing staff could not visualize the dibasic calcium phosphate precipitate while these were administered to several patients. Gravity custom compounding of PN is discouraged as it is labor intensive and prone to mistakes in preparation with error rates reported between 5.3–47.2%.14 Fortunately, only a small subset (16.7%) of hospitals with less than 100 beds routinely gravity compound PN.4 The most relevant ASPEN guideline when considering the use of gravity compounding is the following: If the manual method currently in use at an institution has not been recently reviewed,

  74  Compounding Sterile Preparations 1. Review and verification of PN order for appropriateness in given patient by a trained pharmacist. 2. Prepare and print PN label with PN order that has undergone an independent trained pharmacist double-check. 3. Review PN components for completeness of materials (including sterile syringes and needles if manual additives are needed) required including tubing for ACD. 4. Complete hand hygiene, garbing, and gloving following USP standards. 5. Collect all individual PN components for ACD in cleanroom. 6. Perform disinfection process of ACD and laminar flow hood. 7. Power up the ACD and follow instructions on touch screen. 8. Perform load-cell verification with calibration weight of ACD. 9. Perform aseptic completion of line setup process and introduction of individually barcoded components to ACD. 10. Complete verification by pharmacist of ACD setup to specified standards (e.g., verify any syringe contents and used vials) and during replacement of each ingredient during compounding. 11. Attach a sterile calibration bag to the ACD and labeled “Not for Human Use” with system calibration completed via touch screen; then, both pharmacy technician and pharmacist sign the daily ACD setup report. 12. Apply printed label to empty appropriately sized PN bag and scan barcode to verify the correct PN formulation. 13. Empty labeled PN bag is connected to the ACD (e.g., load cell) and pharmacist verifies it is correct PN formulation. 14. Ensure inclusion by pharmacist of all required components available in ACD; then, PN bag is disconnected from ACD. 15. Weigh PN bag and approve as per quality control weight standards. 16. Prepare any manually added individual components (i.e., below minimal volume of ACD delivery). A trained pharmacist verifies and the pharmacy technician introduces to PN bag, and then cap is sealed. 17. Apply appropriate auxiliary label (e.g., “Refrigerate”) to PN bag and labeling quality control is complete after an independent trained pharmacist double checks with original PN order. 18. Store PN bag at appropriate refrigerated temperature prior to delivery with 1.2-µm inline filter for nursing use. 19. Power down ACD once all PN compounding is completed, and then remove and discard all tubing daily. 20. Clean all components of the ACD.

If utilizing a 2-in-1 (amino acids/dextrose/sterile water for injection) PN formulation: 1. Review and verify PN order with IVFE for appropriateness in given patient by a trained pharmacist. 2. Prepare and print IVFE label with PN order that has undergone an independent trained pharmacist doublecheck. 3. Collect appropriately sized IVFE bag (e.g., 100, 250, 500 mL). 4. Apply printed label to IVFE bag, and have independent trained pharmacist double check with original PN order to verify all labeling information is correct. 5. Place IVFE bag with PN bag prior to delivery with 1.2-µm inline filter for nursing use. Figure 5-1. Example of standardized workflow process with ACD setup for PN compounding. ACD = automated compounding device; IVFE = intravenous fat emulsion; PN = parenteral nutrition.

Chapter 5  Parenteral Nutrition Compounding  75 

If utilizing a standardized, commercial PN formulation: 1. Review and verify PN order for appropriateness in given patient by a trained pharmacist. 2. Prepare and print PN label with PN order that has undergone an independent trained pharmacist double-check. 3. Collect appropriate commercial PN product and volume based on the PN label. 4. Verify commercial PN product’s expiration date, remove any packaging overwrap, and inspect for any defects (e.g., broken seal, leaking, or color changes). 5. Follow manufacturer’s recommendations on breaking seals between chambers to ensure uniformity of mixing. 6. Prepare any manually added individual components (e.g., multivitamins, trace elements, regular human insulin). A trained pharmacist verifies and the pharmacy technician introduces to PN bag; then, the cap is sealed. 7. Apply appropriate auxiliary label (e.g., “Refrigerate”) to PN bag and complete labeling quality control after independent trained pharmacist double checks with original PN order. 8. Store PN bag at appropriate refrigerated temperature prior to delivery with 1.2-µm inline filter for nursing use. Figure 5-1. (continued)

or if the contract with a particular manufacturer of macronutrients is about to change, then a review of the compounding method is strongly recommended. This review shall include an evaluation of the most current literature as well as consultation with the manufacturer when necessary.12 Another important factor to consider in the compounding of PN is the storage time, light exposure, and temperature that it is kept at prior to IV administration. Vitamin A decomposition occurs in the presence of light (i.e., sunlight) and patient morbidity has been reported when pharmacists have added IV multivitamins to home PN formulations for a week or more instead of before each daily infusion as is recommended.40 Current beyond-use dating for PN at a controlled room temperature of 20–25 °C is 30 hours or less and if refrigerated at 2–8 °C is 9 days or less.15 PN is also not recommended to serve as a vehicle for nonnutrient medications unless their addition to the PN is supported by pharmaceutical data describing compatibility and stability of the additive medication and of the final preparation under conditions of typical use and clinical data confirming the expected therapeutic actions of the medication.17

Quality Assurance ASPEN guidelines provide several methods to ensure accurate compounding by ACDs.12 Gravimetric analysis is most frequently used. The final product is weighed and compared to an expected weight. As noted earlier, when applied to the total final PN volume only, the accuracy of individual ingredient transfer is not assessed. The individual monitoring using a gravimetric method for certain additives, such as potassium and phosphate salts, is recommended and may be accomplished within the compounding facility daily. Chemical analysis also has been used to measure the dextrose concentration in the final preparation. Dextrose concentration may be measured directly in the final PN formulation. The accuracy of the assay is dependent on proper dilution techniques because the concentration of glucose in PN samples is outside the limits of the assay used for analysis of biologic fluids. This also applies to PN samples for potassium, phosphorus, and other electrolytes. If institutional laboratory procedures are to be used for PN quality control, the procedure should comply with USP requirements for the assay.15 Refractometric analysis may be used as an indirect measure of glucose content. This method

  76  Compounding Sterile Preparations

requires adequate staff training (i.e., accuracy of the procedure improves with experience and training; Chapter 30). Because it is based on how light is refracted as it passes through the PN, it cannot be used for PN that contains IVFE. In-process testing of PN is recommended and may be done before, during, or after PN compounding.12 For example, the amount of the stock potassium chloride bottle used in compounding may be determined by gravimetric methods at several times during the day and compared with the amount predicted to be used based on the content of the PNs compounded to that point of the compounding process. This requires that the number of patients who received a portion of the stock from the container be properly recorded so that the PN can be remade if there is an accuracy problem identified. Another check of the decision support software is entering an extraordinary amount of ingredient to determine if an alert is provided or if a hard-stop functions properly. A hard-stop is a command that does not allow a PN to be compounded when certain conditions are met or not met. For example, the software should be programmed such that this PN would not be able to be compounded if a 1,000-fold overdose of an additive was entered. There are several practice guidelines related to quality control in the ASPEN Safe Practice Guidelines, with the most pertinent being the following: “End-product testing of PN formulations prepared with ACDs is recommended to verify compounding accuracy.”12

Compounding Accuracy USP Chapter provides methods to ensure volume accuracy of ACD compounding using Sterile Water for Injection and gravimetric accuracy by testing the ACD balance with weights that represent the amounts likely to be compounded by the ACD.15 A variety of ACDs are available for compounding with each device offering different options: • Pinnacle (B. Braun Medical Inc.)—a 6- to 9-lead set device with a minimal volume of 5 mL41 • Exactamix (Baxter Healthcare Corporation)— a 12- to 24-lead set device with minimal volume

of 0.2 mL with the following delivery accuracy of ± 0.03 mL at 0.2 mL; ± 0.03 mL at 0.4 mL; ± 0.06 mL at 1 mL; ± 5% at 10 mL and greater.42

The manufacturers of PN ACDs provide an accuracy level (e.g., within 5–15%) of the volume delivered and the pharmacy staff utilizing these devices must know how frequently this accuracy is achieved.42,43 The volume of ingredient used to compound a sterile preparation influences ACD accuracy as noted with the minimal volumes mentioned with the ACDs above. Crill et al. identified problems with PN compounding using small volumes accurately.44 Additive volumes in amounts