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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Drug Compounding for Veterinary Professionals Safely, effectively, and legally tailor drug treatments to the needs of your specific veterinary patients with this accessible guide Drug Compounding for Veterinary Professionals provides an accessible, easy-to-use guide to all aspects of prescribing individualized mixtures of medications in veterinary practice. Its emphasis on practical knowledge and its discussion of both in-house and external options make it a comprehensive introduction to using compounded medications in animals. It guides practitioners through every step of the process, from formulating a compound to working with outside pharmacists. The book presents guidance on how to get more information on current regulations, consider the risks and benefits, develop formulations, and more. Drug Compounding for Veterinary Professionals readers will also find: * Figures and line drawings illustrating effective compounding techniques and concepts * An emphasis on practical knowledge for clinical use * Answers to frequently asked questions about drug compounding Drug Compounding for Veterinary Professionals is essential for any veterinary practitioner, veterinary pharmacologist, or student looking to understand this crucial component of patient care.
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Veröffentlichungsjahr: 2023
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Table of Contents
Cover
Title Page
Copyright Page
Dedication
Foreword
Preface
List of Acronyms
About the Companion Website
Introduction
1 Compounding Regulations
Organizations and Regulatory Agencies Involved with Compounding
Compliance Policy Guides and Guidance for Industry Documents
What Is Compounding?
The Food, Drug, and Cosmetic Act
Animal Medicinal Drug Use Clarification Act
Preparing Compounds from an Approved Product or a Pure Drug Powder
Federal Versus State Law [8]
Office Use Compounding
Drug Quality and Security Act [26]
Finding Additional Information
References
2 Risk–Benefit Analysis of Compounded Medications
Benefits of Compounded Products
Appropriate Use of Compounded Medications
FDA‐Approved Drugs
Compounded Medication Risks
Compounded (USP) Versus Manufactured (cGMP)
Risks Associated with Compounded Medications – A Look at the Literature
Studies Showing Incorrect Potency
Studies Showing Lack of Stability
Studies Showing Lack of Efficacy
Risks Associated with Specific Types of Compounds
Active Ingredient Source Decisions
Patient‐Specific Compounding Versus Office Use Compounding
Adverse Event Reporting
Identifying Potential Formulation Issues
Drugs Recalls
Selecting a Compounding Pharmacy
Client Education
Reducing Risk in Practice
Conclusion
References
3 Beyond‐Use Dating
Factors Considered When Assigning BUDs and Expiration Dates
USP Default BUDs
Stability Studies
Evaluating Stability Studies
Determining BUDs for In‐House Formulations
BUD Considerations When Prescribing Compounded Medications
Conclusion
References
4 Identifying High‐Quality Compounding Pharmacies
Case Study 1
Case Study 2
What to Evaluate
Ways to Evaluate Compounding Pharmacies
Looking Beyond the Pharmacy's Website
What to Look for on a Tour
Questions to Ask the Pharmacist in Charge
Conclusion
References
5 Formulation Development
Dosage Forms
Hazardous Drugs
Beyond‐Use Dates
Formulation Resources
Calculations
Packing Statistic of Drug
Compounding Formulations to Avoid
Formulation Development Process
Developing a Compounding Formula: Example 1 (USP Compounding Compendium)
Developing a Compounding Formula: Example 2 (Stability‐Indicating Assay)
Compounding Formulation Assessment
References
6 Compounding in House
Documentation
Compounding Techniques
Equipment
Training
Species‐Specific Information
Potency Designations
Feasibility for a Veterinary Clinic
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Examples of compounding based on the FDA and USP definitions.
Table 1.2 References for information on current compounding regulations.
Chapter 2
Table 2.1 Pros and cons of administration routes.
Table 2.2 USP and cGMP requirements for final testing and beyond‐use/expira...
Table 2.3 Benefits and risks of using approved products versus bulk chemica...
Chapter 5
Table 5.1 Chemical grades for compounded medications.
Table 5.2 Preservatives for compounding.
Table 5.3 Excipients for nonsterile compounding.
Table 5.4 Examples of excipients and their adverse reactions.
Table 5.5 Compounding equations and examples.
Table 5.6 Drug concentration conversions.
Table 5.7 Metric equivalents.
Table 5.8 Other measurement system equivalents.
Table 5.9 Common pharmacy equivalents.
Table 5.10 Comparison of MFR and CR.
Table 5.11 Sources referenced in text.
Chapter 6
Table 6.1 Species‐specific flavoring options.
Table 6.2 Species‐specific toxicities in compounding formulations.
List of Illustrations
Chapter 2
Figure 2.1 Graph showing ±10% error allowed for compounds. Strengths where e...
Figure 2.2 A decision tree on when compounding is legally appropriate in non...
Chapter 3
Figure 3.1 An SSD + Dexamethasone SP otic solution compound made in three di...
Chapter 4
Figure 4.1 The homepage of the NECC website as it appeared on May 18, 2011. ...
Figure 4.5 The NECC webpage detailing the nationwide recall of all products ...
Figure 4.6 The homepage of the Franck's Pharmacy website as it appeared on J...
Figure 4.8 The Quality Assurance webpage for Franck's Pharmacy as it appeare...
Chapter 5
Figure 5.1 Colored gelatin capsules.
Figure 5.2 Oral capsule sizes.
Figure 5.3 Bulk powder on stainless steel spatula.
Figure 5.4 Bulk powder in mortar.
Figure 5.5 Liquid and powdered flavors.
Figure 5.6 Example formulation record sheet ingredient calculations for an o...
Figure 5.7 Example formulation record sheet ingredient calculations for an o...
Figure 5.8 Example QS compounding formula.
Figure 5.9 Capsule formula worksheet for using bulk powder as the drug sourc...
Figure 5.10 Capsule formula worksheet for using manufactured tablet as the d...
Figure 5.11 Steps to developing a compounding formulation.
Chapter 6
Figure 6.1 Combined MFR/CR document example. Information with white backgrou...
Figure 6.2 Completed MFR/CR.
Figure 6.3 Sieve on mortar.
Figure 6.4 Small amount of vehicle to wet powder.
Figure 6.5 Mortars and pestles size 4 oz. (left) and 2 oz. (right).
Figure 6.6 Graduated cylinders.
Figure 6.7 Beakers.
Figure 6.8 Varying sizes of drams.
Figure 6.9 Varying sizes of oral dispensing bottles.
Figure 6.10 Oral dispensing inserts.
Figure 6.11 Adaptacaps.
Figure 6.12 Electronic balance.
Figure 6.13 Torsion balance.
Figure 6.14 Varying types of spatulas.
Figure 6.15 Compounding training checklist.
Figure 6.16 Equipment and ingredients for enrofloxacin/synotic (1 : 2) compo...
Figure 6.17 Equipment and ingredients for calcitriol 0.1‐mg/ml compound.
Figure 6.18 Equipment and ingredients for trazodone 10‐mg/ml compounded susp...
Guide
Cover Page
Title Page
Copyright Page
Dedication
Foreword
Preface
List of Acronyms
About the Companion Website
Introduction
Table of Contents
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Drug Compounding for Veterinary Professionals
Lauren R. Eichstadt Forsythe, PharmD, DICVP
Pharmacy Service Head
Clinical Assistant Professor – Department of Veterinary Clinical Medicine
University of Illinois at Urbana‐Champaign
College of Veterinary Medicine
Veterinary Teaching Hospital
1008 West Hazelwood | M/C 004
Urbana, IL
Alexandria E. Gochenauer, PharmD, DICVP
Clinical Staff Pharmacist
University of Illinois at Urbana‐Champaign
College of Veterinary Medicine
Veterinary Teaching Hospital
1008 West Hazelwood | M/C 004
Urbana, IL
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Paperback ISBN: 9781119764960
Cover Design: WileyCover Image: Courtesy of Alexandria Gochenauer
Dedication
Lauren R. Eichstadt Forsythe: For my husband who always encourages me to push beyond my limits, and for my mom for serving as my inspiration for the questions plaguing veterinarians outside of academia.
Alexandria E. Gochenauer: To each and every person who has supported me along the way during my journey to becoming a veterinary pharmacist.
Foreword
It is a pleasure to offer this introduction to Nonsterile and Sterile Compounding for the Veterinary Practitioner.
Compounding of drugs administered for the prevention or treatment of diseases in animals has always been a critically important aspect of veterinary medicine. The number of drugs approved by the Food and Drug Administration (FDA) for the treatment of animals is limited. Approval is challenging given the diversity of species (thus physiology and pathology), patient numbers (e.g. herds and lab animals) and facilities (e.g. farms, wildlife, zoo, or marine facilities). Compounding offers the opportunity for the administration of formulations customized for the individual patient, regardless of the situation, in the absence of approved drugs. The use of compounded drugs by veterinarians is protected by law through the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA). The Act not only delineates conditions under which veterinarians can use compounded drugs, but it also legalizes the act of compounding by veterinarians. It is the responsibility of the FDA's Center for Veterinary Medicine to regulate the law and, specifically, the compounded drugs that are considered unapproved new drugs. However, the path to regulation by the Center for Veterinary Medicine, delineated in nonlegally binding guidance documents for industry, has been difficult. This partially reflects the lack of clarity in the law, leading to differences in interpretation between compounders and regulatory agencies.
Despite this lack of clarity – or perhaps because of it – the last two decades have been accompanied by a marked increase in the use of compounded products by veterinarians. This increase likely reflects improved diagnostics and a greater expectation of owners regarding the delivery of state‐of‐the‐art medical care to their animals. The promotion of commercial compounded products by pharmacies or outsourcing facilities has facilitated the access of these products. On the one hand, this expansion of compounding has had a positive influence on the delivery of state‐of‐the‐art care for veterinary patients. But challenges also have emerged, ranging from the compounding of products that mimic approved drugs to the promotion of novel and sophisticated delivery systems that are not supported by scientific evidence of safety or efficacy.
The FDA perceives that compounded drugs present a greater risk of adversity than approved formulations, and this is particularly true if the end result of compounding is a poor product. Adversities can include too much drug, too little drug, poor delivery, or the presence of unanticipated chemicals. Although the use of compounded preparations by veterinarians has increased, the skill sets and knowledge base needed to effectively prescribe or compound animal drugs are generally not addressed by veterinary curricula. Indeed, it is not a topic easily taught. The regulations are complicated and dynamic and involve multiple role players, including regulatory (the FDA, state boards of pharmacy) and nonregulatory (United States Pharmacopeia) agencies, each of which must be consulted. The knowledge necessary to compound is equally complex and requires an understanding of basic chemistry, mathematical equations, and proper equipment and facilities. For the veterinarian sufficiently interested in compounding, finding information to guide legitimate, quality compounded products is confusing and time consuming.
Enter Dr. Lauren Forsythe's text. Her rich experience in the practice of veterinary pharmacy comes with a unique perspective of the therapeutic needs of the animal patient and the educational needs of the veterinary practitioner. She has recognized the voids and has shared her perspective through the provision of a concise, informative resource that goes a long way to filling the void. This text is the first of its kind in that it tackles both the act of veterinary compounding and the complex rules and regulations intended to minimize the risks while enhancing the benefits of safe and effective compounding of animal drugs.
Importantly, Dr. Forsythe has helped the reader to understand what constitutes a well‐compounded product and how one might assess the expertise of the compounder. Assurance of the quality of a compounded preparation goes a long way to reducing the risk of adverse events, and accordingly, one chapter is dedicated to that topic. Understanding the implications of prescribing through a 503A pharmacy versus obtaining products from a 503B outsourcing facility will go a long way to helping veterinarians make the best choices for their patients.
Dr. Forsythe also provides guidance for the practice that chooses to perform their compounding in‐house. A chapter addresses the physical requirements for a practice to be able to produce quality products while meeting the guidelines of the United States Pharmacopeia and the requirements of state boards of pharmacy. Equally important is support for the calculations necessary to compound. While pharmacists might be intimately familiar with the math of compounding, converting % to weight/volume, mcg to kg, and ounces to liters are tasks that are foreign to many veterinarians. Being able to reach for a one‐text‐does‐it‐all will serve the new and experienced veterinary compounder alike.
The ability to use, prescribe, or make compounded drugs is both a gift and a responsibility. Meeting the responsibility through understanding the regulations, appreciating the challenges, and accessing supportive resources is markedly facilitated by this text. This text is not intended only to the practice that currently uses compounded drugs in their patient. Rather, any practice that provides veterinary care can benefit from an understanding of the benefits of compounded medications.
Dawn Boothe
Preface
I grew up watching my parents treat everything that came to the door 24/7 for their mixed animal general practice in rural Pennsylvania. This evolved into pharmacy school and an interest in compounding. Throughout pharmacy school, clinical rotations in veterinary teaching hospitals, and a veterinary pharmacy residency, I learned that compounding is essential in many areas of veterinary practice, but it is complicated to understand the regulations, there is limited information included in most veterinary curriculums, and there is potential for unethical practices in compounding pharmacies in the name of high profits. All of this can lead to some of the high‐profile compounding errors where fault is decided in court. Therefore, I found myself passionate about teaching veterinarians and veterinary students what they need to know to prescribe compounds for their patients while maximizing benefits and reducing risks. In the process of this, I learned that veterinarians have a lot of practical questions for which there is no good reference for. Therefore, the veterinarian is often left to sort through the information provided by a variety of compounding pharmacies, intermixed with an occasional CE session, and determine the validity and applicability of information that may not align.
As I spoke at conferences throughout the United States and provided webinars on basic compounding information, I frequently wished for a reference to direct people toward for further reading beyond what could be explained in a 50‐minute CE. I also realized that many veterinarians are preparing at least a few compounded medications in‐house but have likely not had training on techniques for ensuring that their compounds are high quality and necessary records are maintained. Understanding techniques for compounds requires a firm understanding of the regulatory, risk/benefit, and formulation development concepts. Once this information is understood, techniques can be further developed through hands on practice.
I decided if I wanted a reference for veterinary compounding written for veterinarians, then I needed to write it. This book is the product of that. I set out to explain what I thought veterinarians should know to make informed decisions about the use of compounded medications and explained the additional concepts that came up along the way. I also enlisted the help of another veterinary pharmacist that is passionate about teaching formulation development and hands‐on compounding techniques to write the chapters relating to those topics. The end result is a book written for vets to answer the frequently asked questions and provide the background necessary for critically evaluating compounds that often is not feasible to provide in the limited time/word count associated with CE and editorials.
List of Acronyms
ACHC
Accreditation Commission for Health Care
AMDUCA
Animal Medicinal Drug Use Clarification Act
ANADA
Abbreviated New Animal Drug Application
API
active pharmaceutical ingredient
ASHP
American Society of Health‐System Pharmacists
BOP
Board of Pharmacy
BUD
beyond‐use date
CAS
Chemical Abstracts Service
cGMP
Current Good Manufacturing Practice
CNS
central nervous system
CoA
certificate of analysis
CPG
Compliance Policy Guide
CR
compounding record
CVM
Center for Veterinary Medicine
DEA
Drug Enforcement Administration
DQSA
Drug Quality and Security Act
EMP
electric mortar and pestle
EPM
equine protozoal myeloencephalitis
FD&C
Food, Drug, and Cosmetic
FDA
Food and Drug Administration
FOI
Freedom of Information
GFI
Guidance for Industry
GI
gastrointestinal tract
HPLC
high‐performance liquid chromatography
IJPC
International Journal of Pharmaceutical Compounding
IM
intramuscular
IV
intravenous
LOD
loss on drying
LWQ
least weighable quantity
MFR
master formulation record
NADA
New Animal Drug Application
NDC
National Drug Code
NECC
New England Compounding Center
NF
National Formulary
NIOSH
National Institute for Occupational Safety and Health
NSAID
nonsteroidal anti‐inflammatory drug
o/w
oil‐in‐water
PCAB
Pharmacy Compounding Accreditation Board
PIC
pharmacist in charge
QA
quality assurance
QC
quality control
QS
quantum satis
RO
reverse osmosis
SDS
safety data sheets
SOP
standard operating procedure
SQ
subcutaneous
USP
United States Pharmacopeia
UV
ultraviolet
w/o
water‐in‐oil
About the Companion Website
This book is accompanied by a companion website.
www.wiley.com/go/forsythe/drug
This website includes:
Figures from the book as PowerPoint slides
Tables from the book as PDFs
Introduction
Whether you are looking to be an informed prescriber when utilizing compounded medications or want to be able to prepare some common compounds in‐house, this book is designed to provide you with the necessary information. Chapters 1–4 provide a foundation to understand the regulations at play in the veterinary compounding landscape, the risks and benefits of compounded medications, how beyond‐use dates are determined, and how to select a compounding pharmacy. Chapters 5 and 6 discuss formulation development and compounding techniques for those interested in preparing common nonsterile compounds in‐house. This book is written to explain what goes into answering the questions “Can this be compounded?” “Should this be compounded?” and “How do I compound this?”
In Chapter 1, the content pertaining to regulations is intentionally a more general overview. Due to the frequently changing nature and gray areas of compounding regulations, a prescriptive description of what exactly is and is not legal is not feasible to create and if created would be outdated before this book made it to print. Therefore, Chapter 1 seeks to provide background on the history of compounding regulations and review the various regulatory bodies that have an impact on compounding regulations. This information will provide you with the foundation needed to follow and interpret new regulations and critically evaluate the information surrounding them that is provided by a variety of sources.
Chapter 2 moves into the clinical considerations that accompany the regulations. The benefits of compounded medications are discussed as well as the risks. There is substantial literature supporting that the risks are prevalent in practice and not simply theoretical. Therefore, a literature review is included to provide summaries of studies looking at potency, stability, and efficacy of compounded medications prepared for both human and animal patients. The second part of this chapter will then discuss ways to decrease your risks in practice. Chapter 3 pulls out the concern about stability to provide an in‐depth review of the difference between expiration and beyond‐use dates and the reasoning behind how they are established. This information is then applied to understand the beyond‐use variability in compounds from the same and different pharmacies.
Chapter 4 applies the information from Chapters 1–3 to evaluate a compounding pharmacy. This chapter uses two case studies of high‐profile compounding errors to determine what evaluation would have been necessary to identify the quality concerns with the associated pharmacies. Following the case studies, the chapter provides detailed information about how to go about conducting an evaluation of a compounding pharmacy beyond a review of their website.
Chapters 5 and 6 assume an understanding of the information covered in Chapters 1–4 and build off that to cover formulation development considerations and compounding techniques. Chapter 5 goes through the characteristics of different types of dosage forms and the excipients that may be present. This information is then used to develop a master formulation and utilize appropriate compounding techniques in Chapter 6.
1Compounding Regulations
A quick search of the news will provide a variety of historical cases in both human and veterinary medicine where poor‐quality compounds resulted in significant morbidity and mortality. In these cases, it is often argued that something was not done legally, and if all relevant laws had been followed, the compounds would not have been made. Therefore, it behooves anyone preparing compounded medications to be well aware of the regulations surrounding compounding.
Clenbuterol Toxicosis in Three Horses in 2006 [1–3]: Three horses displayed toxicity symptoms between 12 and 24 h after receiving a clenbuterol compound that contained 70‐fold the amount of clenbuterol indicated on the labeling. The label indicated that the product contained 72.5 mcg/ml of clenbuterol when it actually contained 5 mg/ml. The commercial product containing clenbuterol at 72 mcg/ml had previously been used in at least one of the horses without issue. Two of the three horses were euthanized due to complications. The illegal “compounded” product was obtained from an unidentified source and administered without a prescription.
Twenty‐one Polo Ponies Die Due to Compounding Error in 2009 [4, 5]: Twenty‐one polo ponies competing at the US Open Polo Championship in 2009 collapsed with most dying within hours due to a selenium overdose. Franck's Pharmacy in Ocala, FL had made an error when compounding a vitamin mixture containing B‐12, selenium, and other minerals, which resulted in 100 times more selenium than intended. It was determined that the horses had 10–15 times more selenium in their blood and 10–20 times more in their liver than the normal amount, which led to their deaths. The prescribed compound was intended to mimic Biodyl, which is used commonly in Europe, Asia, and Latin America. However, Biodyl is not a Food and Drug Administration (FDA)–approved product.
Fungal Meningitis Outbreak in 2012–2013 [6–8]: Three lots of a contaminated preservative‐free methylprednisolone acetate injection compounded by the New England Compounding Center (NECC) in Framingham, MA were responsible for 778 fungal infections resulting in 76 deaths across 20 states. The three lots included more than 17 000 vials of the medication which were improperly sterilized through a nonverified sterilization process and improperly tested to ensure sterility prior to being shipped throughout the United States.
Upon investigation of the compounding facility, it was noted that drugs were routinely shipped before sterility testing results were received, compounds were prepared utilizing expired ingredients, and cleaning logs were ignored as was the presence of mold and bacteria in the clean rooms. Additionally, the NECC was attempting to conceal that a technician whose license had been revoked by the Massachusetts Board of Pharmacy (BOP) was responsible for compounding sterile products.
Compounded Equine Protozoal Myeloencephalitis (EPM) Drug Linked to Equine Deaths in 2014 [9, 10]: Ten horses (eight in Florida and two in Kentucky) experienced adverse effects including seizures and fever with four horses dying after receiving a compounded EPM medication. A toltrazuril/pyrimethamine product was compounded as a paste and suspension by Wickliffe Veterinary Pharmacy of Lexington, KY containing more pyrimethamine than indicated on the labeling. Typically, the compounded paste contains 416‐mg/ml toltrazuril and 17‐mg/ml pyrimethamine. The lawsuit states that when the implicated product was tested, it actually contained 22 mg/ml of toltrazuril and 229 mg/ml of pyrimethamine.
Compounded EPM Drug Linked to Equine Deaths in 2019 [11, 12]: One lot of a compounded paste labeled to contain 416‐mg/ml toltrazuril and 17‐mg/ml pyrimethamine and compounded by Rapid Equine Solutions in Aston, PA was found to contain 18–21 times the labeled pyrimethamine concentration. The product was recalled and tested after adverse effects followed by death were noted in at least three horses. Specifically, the affected lot was found to contain 13.5 and 11.2 mg/ml of toltrazuril (3% of the labeled concentration) and 361 and 307 mg/ml of pyrimethamine (2122 and 1808% of the labeled concentration) in the two separate samples that were tested by the FDA.
However, veterinary compounding regulations are not always black and white. Common causes of confusion include the following:
Regulations may not clearly address practical concerns.
Human compounding regulations are often unclear whether they apply to veterinary compounding.
Federal regulations that exempt animal patients on the federal level may be applied to animal patients at the state level.
Compounding is largely regulated by the states resulting in significant state‐to‐state variation.
Guidance for Industry (GFI) and Compliance Policy Guides (CPG) do not have the force of law but are often given significant weight.
The regulatory landscape surrounding veterinary compounding is continuously changing and evolving to address problems and concerns that arise.
What qualifies as compounding varies depending on which definition is being referenced.
Due to wide state‐to‐state variation, and regulations and standards that frequently change, this chapter is only designed to provide an overview and a starting point for further research into regulations applicable to your practice.
Organizations and Regulatory Agencies Involved with Compounding
Compounding regulations fall under a variety of agencies including:
Food and Drug Administration
United States Pharmacopeia (USP)
Drug Enforcement Administration (DEA)
State Boards of Pharmacy
State Veterinary Boards
Food and Drug Administration
The FDA is an agency with an overall mission to “protect the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation's food supply, cosmetics, and products that emit radiation …” [13]. It is further divided into nine centers, which includes the Center for Veterinary Medicine, which has a mission of “protecting human and animal health.” The FDA is responsible for drug approval in the United States. Compounded drugs are not approved products, but the FDA maintains oversight through compounding regulations. However, patient‐specific compounding is largely turfed to the states to regulate. Potentially, the FDA could conduct inspections, issue warning letters, and take additional actions such as injunctions, seizures, and criminal prosecution. Practically, the FDA only inspects compounding pharmacies on a “for cause” basis. Limiting factors that prevent the FDA from conducting regular inspections of compounding pharmacies include a lack of a comprehensive list of all compounding pharmacies because there is no requirement to register with the FDA, and a lack of resources to inspect the thousands of compounding pharmacies and veterinarians [14].
The FDA does complete a handful of compounding pharmacy inspections each year based on reports of adverse effects or illegal compounding. Between 2003 and 2015, the FDA conducted 39 inspections. Two reasons for warning letters issued by the FDA include large‐scale compounding from bulk chemicals and compounding without a documented medical need. As a result of these inspections, multiple legal cases over the past two decades have challenged the FDA's oversight of compounded medications demonstrating that the exact role of the FDA in regulating compounded medications for nonfood animals remains unclear [14].
United States Pharmacopeia
The USP is an independent, nonprofit organization established in 1820 by a group of physicians. The physicians had noticed that ordering the same compounded medication from different apothecaries produced very different efficacy and safety. The initial intent of the USP was to standardize the quality of compounded medications. The USP evolved over the years to incorporate representatives from many different professions and to adjust to new advances such as the transition from using primarily compounded medications to manufactured medications being the predominant medication source. USP's mission statement is “To improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods” [15].
The USP is not a government agency. Instead, it operates as a standard setting body that works with FDA representatives and other government agencies. USP‐NF is two compendia: the USP and the National Formulary (NF). Standards that are included in the USP‐NF are based in science and developed through a transparent process that seeks stakeholder input. Active drugs that meet the USP standards are indicated with “USP” following the drug name (e.g. methimazole, USP). Compounding excipients that meet the USP standards are indicated with “NF” following the excipient name (e.g. Simple Syrup, NF). Since the USP is not a regulatory body, it does not enforce its standards. USP‐NF is recognized in the Food, Drug, and Cosmetic (FD&C) Act as an official compendium, which connects USP standards with adulterating and misbranding provisions. However, the compounding standards are largely enforced by state Boards of Pharmacy. Some states incorporate USP standards into their state regulations by reference, and others may include the content with their own edits resulting in compounding regulations that vary throughout the country. While it is currently unclear and state specific whether USP standards apply to and/or are enforced for veterinarians compounding in their practices, they do clearly apply to pharmacies that compound for veterinary patients in all states.
A new version of USP‐NF is published yearly with two supplements each year. The first supplement is published in February and becomes official on August 1, and the second supplement is published in June and becomes official on December 1. The content from the previous year's supplements is incorporated into each new version. The USP‐NF contains chapters numbered less than 1000, which are legally enforceable, and chapters numbered greater than 1000, which are considered general information.
USP‐NF provides standards for drugs (including dosage forms and compounded medications), excipients, biologics, dietary supplements, and medical devices. From the compounding aspect, there are three main chapters, USP <795> Pharmaceutical Compounding – Nonsterile Preparations, USP <797> Pharmaceutical Compounding – Sterile Preparations, and USP <800> Hazardous Drugs – Handling in Healthcare Settings. However, there are also several supporting chapters that provide additional information and requirements on topics including, but not limited to, sterility testing, quality assurance, balances and volumetric apparatus, and compounding for drug studies. USP chapters are written by expert committees made up of experts from a variety of fields relevant to the topic of the chapter. A brief summary of what each of the three main chapters mentioned above include follows. However, the exact requirements will not be discussed in this section due to their changing nature. It is expected that anyone compounding will review the relevant chapters prior to compounding and refer to them frequently.
USP Chapter <795> Pharmaceutical Compounding – Nonsterile Preparations is the chapter that outlines minimum standards for preparing nonsterile compounds. Examples of nonsterile compounds include, but are not limited to, oral liquids, topical creams, and otic medications. Topics covered include training and evaluation of those compounding, hygiene and garbing requirements, compounding facilities, cleaning and sanitizing requirements, equipment considerations, formulation considerations, compounding records and documentation, quality assurance/quality control, labeling, establishing beyond‐use dates, and standard operating procedures (SOPs) as they relate to nonsterile compounding.
USP Chapter <797> Pharmaceutical Compounding – Sterile Preparations is the chapter that outlines minimum standards for preparing sterile compounds. Examples of sterile compounds include, but are not limited to, injectable medications (intramuscular, subcutaneous, and intravenous [IV]) and ophthalmic preparations. Topics covered include training and evaluation of those compounding, hygiene and garbing, compounding facilities and equipment, equipment certification and recertification, air and surface monitoring for microbiological contamination, cleaning and disinfecting, sterilization, formulation considerations, compounding documentation and records, quality assurance/quality control, labeling, beyond‐use dates, and SOPs as they relate to sterile compounding.
While USP chapters <795> and <797> focus on the quality of the compound, which relates to the safety of the patient, USP Chapter <800> Hazardous Drugs – Handling in Healthcare Settings focuses on the safety of the compounder while preparing the medication. USP <800> applies to both sterile and nonsterile compounding of hazardous medications. The National Institute for Occupational Safety and Health (NIOSH) publishes a list of hazardous drugs titled NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings. This list includes different groups of hazardous drugs, and USP <800> references this list when determining if a drug is considered hazardous. However, it is important to note that USP <800> requires compounders to evaluate medications new to market since the list was last published and other drugs not considered for inclusion (i.e. veterinary‐only drugs) to determine if they appear to meet the NIOSH definition of hazardous. Potential points to evaluate include drug class, drug structure, and warnings provided on the manufacturer's labeling. USP <800> includes topics such as types of exposure, responsibilities for those handling hazardous drugs, facility and engineering controls, environmental evaluations, personal protective equipment, training, hazard communication, spill control, documentation, SOPs, and handling requirements from drug receipt to administration.
Compounded Preparation Monographs present formulations used in human and/or veterinary patients. These monographs provide a specific formula including ingredients and quantities, directions to prepare the compound, a maximum beyond‐use date determined by stability studies, storage and packaging information, acceptable pH ranges, and stability‐indicating assays. Compounded Preparation Monographs have been included in the USP since 1820. A list of currently available monographs as well as failed studies can be found at www.usp.org. Using a compounded preparation monograph from the USP is a reliable way to make sure that a compound is being prepared in accordance with necessary stability data and formulation considerations. There are dozens of veterinary‐specific monographs as well as about 200 nonveterinary specific monographs, many of which can be used for veterinary patients [16].
The USP Compounding Compendium is a collection of USP chapters and monographs that are applicable to compounding. In addition to general chapters <795>, <797>, and <800>, the Compounding Compendium includes the following general chapters:
<825> Radiopharmaceuticals – Preparation, Compounding, Dispensing, and Repackaging
<1160> Pharmaceutical Calculations in Prescription Compounding
<1163> Quality Assurance in Pharmaceutical Compounding
<1168> Compounding for Phase I Investigational Studies
<1176> Prescription Balances and Volumetric Apparatus
The Compendium also includes the supporting general chapters that are referenced in the compounding‐specific chapters listed above.
Drug Enforcement Administration
The DEA's mission is “to enforce the controlled substance laws and regulations of the United States and bring to the criminal and civil justice system of the United States, or any other competent jurisdiction, those organizations and principal members of organizations, involved in the growing, manufacture, or distribution of controlled substances appearing in or destined for illicit traffic in the United States; and to recommend and support nonenforcement programs aimed at reducing the availability of illicit controlled substances on the domestic and international markets” [17]. Based on this mission, the DEA is concerned with compounding that involves controlled substances, but they are not involved in compounding of noncontrolled substances. Practically, DEA compliance with regards to compounding involves following all controlled substance regulations when preparing compounded medications utilizing controlled substances.
State Boards of Pharmacy
State Boards of Pharmacy are responsible for overseeing the practice of pharmacy within their state, which includes compounding done by those licensed under the BOP such as pharmacists and pharmacy technicians. Pharmacy boards also require out‐of‐state pharmacies to be licensed for each state they are shipping to. This allows the pharmacy board to hold out‐of‐state pharmacies to the same standards as those located within the state. This becomes significant with compounded medications because states may have vastly different requirements for compounding pharmacies with regard to licensure and inspection. Depending on the way a state is set up, the pharmacy board may have oversight of all drug dispensing regardless of profession. Therefore, in some states, the pharmacy board has oversight of medication‐related professional activities that veterinarians are engaged in which would include compounding.
The amount of oversight and available data from each state varies greatly. One example of a state program is the Missouri BOP. In 2003, the Missouri BOP started a program that tests a sample of compounded products each year of several different drug types and dosage forms. In 2020, the board tested 57 compounds for potency and, if applicable, sterility and endotoxins. The dosage forms tested include capsules, IV solutions, inhalation solutions, injectables, oral suspensions, tablets, topical creams/ointments, and topical solutions. Of the 57 compounds tested, 11 (19.3%) compounds representing 10 different active ingredients had unsatisfactory results due to potency being outside of the allowed ±10% or USP stated range [18].
The National Association of Boards of Pharmacy provides contact information and websites for each state pharmacy board at https://nabp.pharmacy/about/boards‐of‐pharmacy.
State Veterinary Boards
State veterinary boards are responsible for overseeing the practice of veterinary medicine within their state. Since veterinarians are legally allowed to compound medications for their patients, veterinary boards would oversee this. However, not all states have compounding laws written into their veterinary practice act, which can make this a gray area.
The American Association of Veterinary State Boards provides contact information and websites for each state veterinary board at https://www.aavsb.org/public‐resources/find‐regulatory‐board‐information.
Compliance Policy Guides and Guidance for Industry Documents
Other important concepts to define are CPGs and GFIs. The FDA issues CPGs and GFIs when it determines something is illegal but necessary under certain circumstances or they determine that a topic requires additional clarification. These documents indicate the FDA's current regulatory priorities and are subject to modification and withdrawal. They do not have the force of law. However, they are often the best indicator available of how the FDA intends to enforce various regulations and may be used by states to guide their compounding regulations. While CPGs and GFIs appear similar, they are written for different audiences. CPGs are written to guide inspectors on what to look for during inspections, while GFIs are written to guide the industry on compliance. For practical purposes, both types of documents provide insight into the FDA's current thought process and should be used to guide compliance with the regulations.
CPGs and GFIs are used when the FDA plans to exercise its regulatory discretion. The following is a daily life example of this concept.
In a specific area, the speed limit is 50 miles per hour (mph). However, the local police department has decided that they will only pull someone over for speeding if they are going faster than 60 mph. Since the speed limit is 50 mph, it is illegal to go faster than that. However, the police department is exercising its regulatory discretion by choosing not to enforce the speed limit unless someone is exceeding it by more than 10 mph.
What Is Compounding?
The exact definition of compounding varies depending on whether the FDA or the USP definition is being referenced. The FDA defines compounding as, “the process of combining, mixing or altering ingredients to create a medication tailored to the needs of an individual patient. Compounding includes the combining of two or more drugs. Compounded drugs are not FDA approved” [19]. In Section 503a of the FD&C Act, which applies to patient‐specific compounding, the FDA states, “as used in this section, the term ‘compounding’ does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling” [19].
Historically, the USP defined compounding as, “The preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug‐delivery device, or device 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” [20]. However, with the 2022 revisions, the nonsterile compounding definition was updated to, “combining, admixing, diluting, pooling, reconstituting other than as provided in the manufacturer's labeling, or other altering a drug product or bulk drug substance to create a nonsterile preparation.” The updated Chapter <795> goes on to state that the following are not considered compounding:
Reconstitution of a conventionally manufactured nonsterile product in accordance with the directions contained in the manufacturer approved labeling
Repackaging of conventionally manufactured drug products
Breaking or cutting a tablet into smaller portions
Preparation of a single dose for a single patient when administration will begin within 4 h
[21]
These updates bring the USP and FDA definitions in line with regard to what is and is not considered compounding. Table 1.1 shows the difference in compounding definitions between the two USP versions and the FDA version. It should be noted that other groups such as AVMA have provided definitions of compounding, and these may vary from the USP and FDA definitions.
In contrast, manufacturing is defined as, “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 and includes any packaging or repackaging the substance(s) or the labeling or re‐labeling of its container and the promotion and marketing of such drugs or devices. Manufacturing also includes any preparation of a drug or device that is sold for resale by pharmacies, practitioners, or other persons [22].”
Table 1.1 Examples of compounding based on the FDA and USP definitions.
Example
Compounding under the FDA definition
Compounding under the old USP definition
Compounding under the new (2022) USP definition
Notes
Reconstituting Clavamox (amoxicillin/clavulanate) powder for suspension with 14 ml of water to a final concentration of 62.5 mg/ml with a 10‐d beyond‐use date when stored in the fridge
which is in accordance with the manufacturer's labeling
.
No
Yes
No
This is an example of preparing a medication based on the manufacturer's labeling.
Reconstituting doxycycline powder with
25 ml
of water to make a
10
‐
mg/ml
suspension that can be stored at room temperature for 2 wk when the manufacturer labeling indicates using
50 ml
of water for a
5
‐
mg/ml
suspension.
Yes
Yes
Yes
This is another example of reconstituting an antibiotic, but there are changes from what the manufacturer's labeling indicates. By adjusting the final concentration of the product, it now falls under compounding based on the FDA definition in addition to the USP definition.
Crushing 250‐mg metronidazole tablets and mixing with water to make a 50‐mg/ml oral suspension.
Yes
Yes
Yes
