The Art, Science,

and Technology

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of Pharmaceutical
Compounding
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FI FT H E DI T IO N
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Loyd V. Allen Jr., PhD

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EDITOR IN CHIEF
International Journal of Pharmaceutical Compounding
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Edmond, Oklahoma
and
PROFESSOR EMERITUS
College of Pharmacy
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University of Oklahoma
Oklahoma City, Oklahoma
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Washington, D.C.
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Introduction

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Pharmacists are unique professionals who are well trained in the natural, physical, and med-
ical sciences and aware that a single mistake in the daily practice of their profession may
potentially result in patient harm and even death. However, because of their demonstrated
expertise, their demeanor, and the manner in which they have practiced their profession
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over the years, pharmacists continue to be ranked among the most respected individuals in
our society. In general, pharmacists have the reputation of being available to residents of
the local community in times of need, interacting with and providing needed medications
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for patients, and working with patients to regain or maintain a certain standard of health
or quality of life.
Pharmacists possess knowledge and skills that are not duplicated by any other pro-
fession. Their roles can include dispensing and compounding medications, counseling
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patients, minimizing medication errors, enhancing patient compliance, monitoring drug

therapy, and minimizing drug expenditures.
Pharmacy activities that individualize patient therapy include clinical and compound-
ing functions. The functions are related and equally important to the success of such activi-
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ties. A pharmacist’s expertise must be used to adjust dosage quantities, frequencies, and even
dosage forms for enhanced compliance. All pharmacists should be aware of the drug therapy
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options provided by compounding. Members of the pharmacy profession are united in the
belief that they have a responsibility to serve their patients and compound an appropriately
prescribed product in the course of professional practice. Pharmacists have both the right
and the responsibility to compound medications (sterile and nonsterile) to meet the specific
needs of patients.
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What Is Compounding?
The definition of compounding has been the subject of much discussion and has been
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addressed by the United States Pharmacopeia, the standards-setting body for pharmaceu-
ticals in the United States.
Compounding is defined in Chapter <795> of the United States Pharmacopeia as
follows:

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
 xxxii Introduction

practitioner/patient/pharmacist/compounder relationship in the course

of professional practice. Compounding includes the following:

77 Preparation of drug dosage forms for both human and animal patients
77 Preparation of drugs or devices in anticipation of prescription drug
orders based on routine, regularly observed prescribing patterns

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77 Reconstitution or manipulation of commercial products that may
require the addition of one or more ingredients

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77 Preparation of drugs or devices for the purposes of, or as an incident to,
research (clinical or academic), teaching, or chemical analysis
77 Preparation of drugs and devices for prescriber’s office use where permitted
by federal and state law1

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The Drug Quality and Security Act (H.R. 3204) defines compounding as “the combin-
ing, admixing, mixing, diluting, pooling, reconstituting, or otherwise altering of a drug or
bulk drug substance to create a drug.”
Compounding may hold different meanings for different pharmacists. It may mean the
preparation of suspensions, topicals, and suppositories; the conversion of one dose (e.g.,
oral to rectal, injection to oral) or dosage form into another; the preparation of select dosage
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forms from bulk chemicals; the preparation of intravenous admixtures, parenteral nutrition
solutions, and pediatric dosage forms from adult dosage forms; the preparation of radio-
active isotopes; or the preparation of cassettes, syringes, and other devices with drugs for
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administration in the home setting.
Compounding occurs in all different types of pharmacies, including the following:

77 Independent community pharmacies

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77 Chain pharmacies
77 Hospital pharmacies
77 Mail-order pharmacies
77 Compounding-only pharmacies
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• Independent (human and veterinary)

• Specialty (home health care, hospital contract, etc.)
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77 Nuclear pharmacies

Compounding is especially important to select patient-group populations, including

those with needs related to pediatrics, geriatrics, bioidentical hormone replacement therapy,
pain management, dentistry, environmental and cosmetic sensitivities, sports injuries, and
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veterinary compounding (small and large animals, herds, exotic and companion animals).
Reasons for the increase in compounding can be related to the following:

77 Limited dosage forms

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77 Limited strengths
77 Home health care
77 Hospice
77 Unavailable drug products and combinations
• Discontinued drugs
• Drug shortages
77 Orphan drugs
77 Veterinary compounding
 Introduction xxxiii

77 New therapeutic approaches

77 Special patient populations
77 Biotechnology-derived drug products

A pharmacist plays an important role on the hospice team and can greatly enhance
quality of life for hospice patients. Pediatric patient compliance is a challenge, because

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children either do not want or are unable to take tablets or capsules and manufacturers do
not provide liquid dosage forms for many medications; this is where a pharmacist steps
in. Compounding for the geriatric patient can be a much greater challenge than for almost

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any other group of patients. Physical, emotional, and social difficulties often affect compli-
ance, and many geriatric health problems are chronic rather than acute. Pharmacists have
also become intimately involved in working with veterinarians in the treatment of animals
(companion, herd, recreational, food, and exotic).
Compounding has always been a basic part of pharmacy practice; today it continues

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to be a rapidly growing area, and many pharmacists in all types of practice are becoming
involved in compounding sterile and nonsterile preparations. Newly evolving dosage forms
and therapeutic approaches suggest that compounding of pharmaceuticals and related
products specifically for individual patients will become more common in pharmacy prac-
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Approximately 75% of community pharmacists, virtually all hospitals, many chain store
and mail-order pharmacies, and many specialty pharmacies compound. Nonsterile or sterile
compounding is involved in about 10% of all prescribed and ordered medications today, and
compounding is valued up to about $25 billion to $30 billion a year.
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Compounding pharmacy is unique because it allows pharmacists to use more of their
scientific, mathematical, and technology background than do some other types of practices.
Compounding pharmacists develop a unique relationship with the patients they serve. They
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work hand in hand with physicians to solve clinical problems not addressed by commercially
available dosage forms. Ironically, as we in health care become more aware that patients are
individuals, respond as individuals, and must be treated as individuals, some health care pro-
viders appear to be grouping patients into categories for treatment, for reimbursement from
third-party payers, or for a determination of levels of care in managed care organizations.
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Similarly, the trend toward using pharmaceutical manufacturers’ fixed-dose products, which
are available just because the marketing demand is sufficiently high to justify their manu-
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facture and production, seems inappropriate. Since when should the availability, or lack of
availability, of a specific commercially available product dictate the therapy of a patient?

Should Every Pharmacist Compound?

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Only properly trained pharmacists should be involved in pharmaceutical compounding. If

pharmacists wish to compound but do not possess the required techniques and skills, they
should participate in continuing education programs that have been designed to provide
the proper training, including the scientific basis and practical skills necessary for sound,
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contemporary compounding. Today, any pharmacist is legally qualified to compound, but

not all are technically qualified and trained to be a compounding pharmacist. To be capable
of meeting the special or advanced needs of today’s patients, whether human or animal, a
compounding pharmacist must

77 Have access to the most recent information available,

77 Maintain an inventory and provide for proper storage of drugs and flavoring agents
and be capable of obtaining any chemical within a reasonable time,
 xxxiv Introduction

77 Be dedicated to pharmacy and willing to put forth the necessary financial and time
investment,
77 Have the appropriate physical facilities and equipment to do the job properly (the
extent and type of compounding may be determined or limited by the facility),
77 Be committed to lifelong learning and continuing education, because a major
advantage of compounded prescriptions is their provision of treatments that are

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new, undeveloped, and often not commercially available, and
77 Have a willingness to tear down walls and build bridges to share experiences with

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others for the good of all.

Should You Compound?

When considering whether or not to compound, pharmacists should consider the technical

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aspects and economic effect of the service. A new chapter has been added to this edition of
the text, “Pharmaceutical Compounding Errors,” Chapter 33. The purpose of this chapter
is to assist in making one aware of potential errors that can occur in compounding.

Technical Considerations
There are three types of compounded prescriptions: isolated, routine, and batch prepared.
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An isolated prescription is one that a pharmacist is not expecting to receive and does not
expect to receive again. A routine prescription is one that a pharmacist may expect to receive
on a routine basis in the future; there may be some benefit in standardizing such prepara-
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tions (maintaining preparation protocols on file) to ensure product quality. A batch-pre-
pared prescription is one that is prepared in multiple identical units as a single operation in
anticipation of the receipt of future prescriptions.
Pharmacists must consider not only their technical qualifications to compound a
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preparation, but also the technical validity of the prescription. Box I-1 presents a series of
questions designed to aid in evaluating the technical considerations for compounding. The
batch compounding of sterile preparations, especially in the hospital and home health care
environments, has increased noticeably. There are a number of reasons for this increase,
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including the following:

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77 The changing patterns of drug therapy, such as home parenteral therapy and
patient-controlled parenteral administration
77 The use in hospitals of injectable drugs that are not commercially available to meet
individual patient needs or the prescriber’s clinical investigational protocols
77 Cost containment, whereby a pharmacy batch produces drug products that are
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intended to be similar to commercially available products

Batch compounding can reduce the cost of a medication that must be taken over a long
period or continuously for a chronic condition. This process allows a patient to store the
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preparation at home and reduce the number of pharmacy visits. Pharmacists who choose
to perform batch compounding should be capable and willing to do it properly, particularly
when sterile drug products are involved (see Box I-2).

Economic Considerations
Several economic considerations must be weighed when making the decision to compound
prescriptions, including a pharmacist’s compensation for the service and the effect of the
service on health care costs. Both factors are equally important.
 Introduction xxxv

BOX I-1 Technical Considerations for Compounding a Prescription

The following are technical considerations for compounding a prescription:

77 Is the preparation commercially available in the exact dosage form, strength, and
packaging?

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77 Is the prescription rational concerning the ingredients, intended use, dose, and
method of administration?
77 Are the physical, chemical, and therapeutic properties of the individual ingredients

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consistent with the expected properties of the ordered preparation?
77 Will this compounded preparation satisfy the intent of the prescribing physician
and meet the needs of the patient?
77 Is there an alternative (e.g., different dosage form, different route of administration)
by which the patient will receive a benefit?

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77 Is there a bona fide prescriber–pharmacist–patient relationship?
77 Can ingredient identity, quality, and purity be assured?
77 Does the pharmacist have the training and expertise required to prepare the
prescription?
77 Are the proper equipment, supplies, and chemicals or drugs available?
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77 Is there a literature reference that might provide information on use, preparation,
stability, administration, and storage of the compounded preparation?
77 Can the pharmacist perform the necessary calculations to compound the
preparation?
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77 Can the pharmacist project a reasonable and rational beyond-use date for the
prescription?
77 Is the pharmacist willing to complete the necessary documentation to compound
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the preparation?
77 Can the pharmacist do some basic quality control to check the preparation before
dispensing (e.g., capsule weight variation, pH, visual observations)?
77 What procedures are in place for investigating and correcting failures?
How long will the patient be using the preparation, and is the expected duration
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of therapy consistent with an appropriate expiration date? Alternatively, should
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the preparation be compounded in small quantities and dispensed to the patient

at short intervals?
77 Does the patient have the necessary storage facility, if required, to ensure the
potency of the preparation until its beyond-use date?
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Pharmaceutical compounding is a cognitive service; therefore, appropriate reimburse-

ment is justified. The pricing of a compounded prescription should account for pharmaco-
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dynamic and pharmacotherapeutic decision making, formulation expertise, time involved,

and reimbursement for materials. Compounding prescriptions can be attractive for a
pharmacist both professionally and financially. Historically, compounding has been said
to be an act whereby the professional and scientific knowledge of a pharmacist can find
its expression. For those pharmacists dedicated to performing quality compounding, the
professional, psychological, and financial rewards can be substantial.
Compounding prescriptions can be one way of lowering the cost of drug therapy. In
some cases, a pharmacist’s preparation of a specific prescription for a patient may be less
 xxxvi Introduction

BOX I-2 Technical Considerations for Batch Compounding

The following are technical considerations for batch compounding:

77 Will the processes, procedures, compounding environment, and equipment used
to prepare this batch produce the expected qualities in the finished preparation?

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77 Will all the critical processes and procedures be carried out exactly as intended so
that every batch produces the same high-quality preparation?
77 Will the finished preparation have all the qualities as specified on completion and

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packaging of each batch?
77 Will each batch retain all the qualities within the specified limits until the labeled
expiration date?
77 Will pharmacy personnel be able to monitor and trace the history of each batch,
identify potential sources of problems, and institute appropriate corrective measures

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to minimize the likelihood of their occurrence?

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expensive than a manufactured version, which may mean that the patient may actually
obtain the drug rather than have to do without it. If compounding a prescription will enable
a patient to afford the drug therapy, it must be considered.
Another way in which compounding may lower drug costs concerns the economic use
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of very expensive drug products that may have short shelf lives. If a patient does not need the
entire contents of a vial or dosage unit, the remaining drug product is often discarded and
wasted. In numerous instances, however, a pharmacist can divide the commercial product
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into smaller usage units, store it properly, and dispense the required quantity on individual
prescriptions.
A related economic question involves the commercialization of compounded prep-
arations. Over the years, many compounded preparations have eventually become com-
mercially available. Table I-1 lists commercial products recently introduced to the market.
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Inevitably, a pharmaceutical manufacturer will produce a product when it becomes eco-

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nomically profitable to do so.

Summary
Compounding pharmacists are interested in and excited about their practice. In fact, many
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pharmacists intimately involved in pharmaceutical care have come to realize the impor-
tance of providing individualized patient care through the compounding of patient-specific
preparations. As compounding pharmacy continues to grow, it will provide an opportunity
for more pharmacists to use their innovative skills to solve patients’ drug problems.
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Pharmaceutical compounding provides pharmacists with a unique opportunity to

practice their time-honored profession. It will become an even more important part of
pharmacy practice in the future, particularly for those involved in community, hospital,
long-term care, home health care, veterinary care, and specialty practices.
Although pharmacists should not hesitate to become involved in pharmacy com-
pounding, they should be aware of the requirements for and uniqueness of formulating
a specific drug product for a specific patient. This service is an important component in
 Introduction xxxvii

TABLE I-1 Compounded Preparations That Are Now Commercially Manufactured

Aminopyridine (4-) capsules (fampridine)

Bevacizumab (Avastin—new packaging to Lucentis)
Buffered hypertonic saline solution
Buprenorphine nasal spray

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Clindamycin topical solution
Colchicine injection

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Colchicine tablets (Colcrys)
Dalfampridine (Ampyra) tablets
Dextromethorphan hydrobromide with quinidine sulfate capsules (Nuedexta)
Diazepam rectal gel (Diastat)
Erythromycin topical solution

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Estradiol topical gel
Fentanyl lozenges
Fentanyl sublingual spray
Hydroxyprogesterone caproate injection (Makena)
Minoxidil topical solution
Nitroglycerin rectal ointment
Nystatin lozenges
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Omeprazole and sodium bicarbonate liquid (Zegerid)
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Premixed intravenous solutions (select ones)
Progesterone vaginal gel (Crinone)
Quinine sulfate capsules
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Testosterone topical gel (Androgel)

Tetracaine–adrenalin–cocaine (TAC) solution
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providing pharmaceutical care. After all, without the pharmaceutical product, there is no
pharmaceutical care.

Reference
1. National Association of Boards of Pharmacy. Model State Pharmacy Act and Model Rules of the
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National Association of Boards of Pharmacy. Available at: www.nabp.net/publications/model-act.

Accessed: September 22, 2015.
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