Compounding
Encyclopedia
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient. This may be done for medically necessary reasons, such as to change the form of the medication from a solid pill to a liquid, to avoid a non-essential ingredient that the patient is allergic to, or to obtain the exact dose needed. It may also be done for voluntary reasons, such as adding favorite flavors to a medication.
of medications became normal, compounding was a routine activity among pharmacists. Community pharmacists who have experience with compounding techniques are now less common.
Pharmaceutical compounding has ancient roots. Hunter-gatherer
societies had some knowledge of the medicinal properties of the animals, plants, molds, fungus and bacteria as well as inorganic minerals within their environment. Ancient civilizations utilized pharmaceutical compounding for religion, grooming, keeping the healthy well, treating the ill and preparing the dead. These ancient compounders produced the first oils from plants and animals. They discovered poisons and the antidotes. They made ointments for wounded patients as well as perfumes for customers.
The earliest chemist
s were familiar with various natural substances and their uses. These drug
artisans compounded a variety of preparations such as medications, dyes, incense, perfumes, ceremonial compounds, preservatives and cosmetics. Drug compounders seeking gold and the fountain of youth drove the Alchemy
movement. Alchemy eventually contributed to the creation of modern pharmacy and the principles of pharmacy compounding. In the medieval Islamic world
in particular, Muslim pharmacists
and chemists developed advanced methods of compounding drugs. The first drugstores
were opened by Muslim pharmacists in Baghdad
in 754.
The modern age of pharmacy compounding began in the 19th century with the isolation of various compounds from coal tar
for the purpose of producing synthetic dyes. From this one natural product came the earliest antibacterial sulfa drugs, phenol
ic compounds made famous by Joseph Lister
, and plastics.
During the 1800s, pharmacists specialized in the raising, preparation and compounding of crude drugs. Crude drugs, like opium
, are from natural sources and usually contain multiple chemical compounds. The compounding pharmacist often extracted these crude drugs using water
or alcohol
to form extract
s, concoction
s and decoction
s.
Pharmacists began isolating and identifying the active ingredient
s contained within these crude drug concoctions. Using fractionation
or recrystallization
, the compounding pharmacist would separate the active ingredients, like morphine
, and use it in place of the crude drug. During this time modern medicine
began.
With the isolation of medications from the “raw materials” or crude drugs came the birth of the modern pharmaceutical company. Pharmacists were trained to compound the preparations made by the drug companies, but they were unable to do it efficiently on a small scale. So economies of scale
, not lack of skill or knowledge, produced a market
for the modern pharmaceutical drug companies.
With the turn of the 20th century came greater government regulation
of the practice of medicine. These new regulations forced the drug companies to prove that any new medication they brought to market was safe.
With the discovery of penicillin
, modern marketing techniques and brand
promotion, the drug manufacturing industry came of age. Pharmacists continued to compound most prescriptions
until the early 1950s when the majority of dispensed drugs came directly from the large pharmaceutical companies.
. Compounding pharmacists and medicinal chemists develop and test pharmaceutical formulation
s for new drugs so that the active ingredients are effective, stable, easy to use, and acceptable to patients. However, for actual clinical trials, production of drug products is generally considered "manufacturing" because "compounding" is typically defined as being for a single individual patient only.
Compounding pharmacies were the subject of the United States Supreme Court decision Thompson v. Western States Medical Center (535 U.S. 357, 2002), which held that Congressional attempts to restrict advertising by compounding pharmacies were unconstitutional. However, the same statute (FDAMA, amending the FDCA which establishes the FDA) also contained a provision that largely exempted compounded products from the FDA's control by defining many of them as not being "new drugs" for FDA purposes. Since the Supreme Court did not rule on the issue of how broadly to interpret that provision, nor on the issue of whether that provision was "severable" from the struck provision, there remains today a Circuit-split on both of those questions: As of 2008, the 9th Circuit (binding in several western states) holds that the provisions are not severable, and hence the entire FDAMA is void; on the other hand, the 6th Circuit (binding in several southwestern states) holds that the provisions are severable, and hence the non-struck portions of the FDAMA remain intact (including what it interpreted to be a limited exemption from FDA reach for any compounded drugs that meet the requirements given in the statute).
Meanwhile, in Circuits where the FDAMA is void and thus the FDA retains its original reach, the FDA weighs the following (non-exhaustive) mix of factors in deciding whether to "exercise its discretion" to require approval for a custom-compounded drug product, from its 2002 Compliance Policy Guide on the matter: 1. Compounding in anticipation of receiving prescriptions, 2. Compounding drugs removed from the market for safety reasons, 3. Compounding from bulk ingredients not approved by FDA, 4. Receiving, storing, or using drugs not made in an FDA-registered facility, 5. Receiving, storing, or using drugs' components not determined to meet compendia requirements, 6. Using commercial-sale manufacturing or testing equipment, 7. Compounding for third parties for resale, 8. Compounding drugs that are essentially the same as commercially available products, 9. Failing to operate in conformance with applicable state law. Hence, making truly patient-customized products with particular drug(s)/dosage(s) upon receiving valid prescriptions from a physician is likely to be acceptable, especially if the ingredients are FDA approved, etc.
Also from the 2002 CPG document, the FDA assures compounding pharmacies that its main concern is those who effectively engage in multi-patient "manufacturing" under the guise of compounding. "FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. This traditional activity is not the subject of this guidance."
As a related point regarding the broad professional discretion to customize patient care, note that about 20-30% of prescription medications in the US are estimated to be "off-label," meaning the physician believes the drug to be beneficial for a patient despite it not being approved for that particular use/condition. This too is perfectly legal, subject only to state regulations on the practice of medicine, etc.
History
Before mass productionMass production
Mass production is the production of large amounts of standardized products, including and especially on assembly lines...
of medications became normal, compounding was a routine activity among pharmacists. Community pharmacists who have experience with compounding techniques are now less common.
Pharmaceutical compounding has ancient roots. Hunter-gatherer
Hunter-gatherer
A hunter-gatherer or forage society is one in which most or all food is obtained from wild plants and animals, in contrast to agricultural societies which rely mainly on domesticated species. Hunting and gathering was the ancestral subsistence mode of Homo, and all modern humans were...
societies had some knowledge of the medicinal properties of the animals, plants, molds, fungus and bacteria as well as inorganic minerals within their environment. Ancient civilizations utilized pharmaceutical compounding for religion, grooming, keeping the healthy well, treating the ill and preparing the dead. These ancient compounders produced the first oils from plants and animals. They discovered poisons and the antidotes. They made ointments for wounded patients as well as perfumes for customers.
The earliest chemist
Chemist
A chemist is a scientist trained in the study of chemistry. Chemists study the composition of matter and its properties such as density and acidity. Chemists carefully describe the properties they study in terms of quantities, with detail on the level of molecules and their component atoms...
s were familiar with various natural substances and their uses. These drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
artisans compounded a variety of preparations such as medications, dyes, incense, perfumes, ceremonial compounds, preservatives and cosmetics. Drug compounders seeking gold and the fountain of youth drove the Alchemy
Alchemy
Alchemy is an influential philosophical tradition whose early practitioners’ claims to profound powers were known from antiquity. The defining objectives of alchemy are varied; these include the creation of the fabled philosopher's stone possessing powers including the capability of turning base...
movement. Alchemy eventually contributed to the creation of modern pharmacy and the principles of pharmacy compounding. In the medieval Islamic world
Islamic Golden Age
During the Islamic Golden Age philosophers, scientists and engineers of the Islamic world contributed enormously to technology and culture, both by preserving earlier traditions and by adding their own inventions and innovations...
in particular, Muslim pharmacists
Islamic medicine
In the history of medicine, Islamic medicine, Arabic medicine or Arabian medicine refers to medicine developed in the Islamic Golden Age, and written in Arabic, the lingua franca of Islamic civilization....
and chemists developed advanced methods of compounding drugs. The first drugstores
Pharmacy
Pharmacy is the health profession that links the health sciences with the chemical sciences and it is charged with ensuring the safe and effective use of pharmaceutical drugs...
were opened by Muslim pharmacists in Baghdad
Baghdad
Baghdad is the capital of Iraq, as well as the coterminous Baghdad Governorate. The population of Baghdad in 2011 is approximately 7,216,040...
in 754.
The modern age of pharmacy compounding began in the 19th century with the isolation of various compounds from coal tar
Coal tar
Coal tar is a brown or black liquid of extremely high viscosity, which smells of naphthalene and aromatic hydrocarbons. Coal tar is among the by-products when coal iscarbonized to make coke or gasified to make coal gas...
for the purpose of producing synthetic dyes. From this one natural product came the earliest antibacterial sulfa drugs, phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
ic compounds made famous by Joseph Lister
Joseph Lister, 1st Baron Lister
Joseph Lister, 1st Baron Lister OM, FRS, PC , known as Sir Joseph Lister, Bt., between 1883 and 1897, was a British surgeon and a pioneer of antiseptic surgery, who promoted the idea of sterile surgery while working at the Glasgow Royal Infirmary...
, and plastics.
During the 1800s, pharmacists specialized in the raising, preparation and compounding of crude drugs. Crude drugs, like opium
Opium
Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...
, are from natural sources and usually contain multiple chemical compounds. The compounding pharmacist often extracted these crude drugs using water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
or alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
to form extract
Extract
An extract is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol or water. Extracts may be sold as tinctures or in powder form....
s, concoction
Concoction
A concoction is, strictly speaking, a combination of various ingredients, usually herbs, spices, condiments, powdery substances or minerals, mixed up together, minced, dissolved or macerated into a liquid so as they can be ingested or drunk...
s and decoction
Decoction
Decoction is a method of extraction, by boiling, of dissolved chemicals, or herbal or plant material, which may include stems, roots, bark and rhizomes. Decoction involves first mashing, and then boiling in water to extract oils, volatile organic compounds, and other chemical substances...
s.
Pharmacists began isolating and identifying the active ingredient
Active ingredient
An active ingredient is the substance of a pharmaceutical drug or a pharmaceutical ingredient and bulk active in medicine; in pesticide formulations active substance may be used. Some medications and pesticide products may contain more than one active ingredient...
s contained within these crude drug concoctions. Using fractionation
Fractionation
See also: Fractionated spacecraftFractionation is a separation process in which a certain quantity of a mixture is divided up in a number of smaller quantities in which the composition changes according to a gradient. Fractions are collected based on differences in a specific property of the...
or recrystallization
Recrystallization (chemistry)
-Chemistry:In chemistry, recrystallization is a procedure for purifying compounds. The most typical situation is that a desired "compound A" is contaminated by a small amount of "impurity B". There are various methods of purification that may be attempted , which includes recrystallization...
, the compounding pharmacist would separate the active ingredients, like morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, and use it in place of the crude drug. During this time modern medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
began.
With the isolation of medications from the “raw materials” or crude drugs came the birth of the modern pharmaceutical company. Pharmacists were trained to compound the preparations made by the drug companies, but they were unable to do it efficiently on a small scale. So economies of scale
Economies of scale
Economies of scale, in microeconomics, refers to the cost advantages that an enterprise obtains due to expansion. There are factors that cause a producer’s average cost per unit to fall as the scale of output is increased. "Economies of scale" is a long run concept and refers to reductions in unit...
, not lack of skill or knowledge, produced a market
Market
A market is one of many varieties of systems, institutions, procedures, social relations and infrastructures whereby parties engage in exchange. While parties may exchange goods and services by barter, most markets rely on sellers offering their goods or services in exchange for money from buyers...
for the modern pharmaceutical drug companies.
With the turn of the 20th century came greater government regulation
Regulation
Regulation is administrative legislation that constitutes or constrains rights and allocates responsibilities. It can be distinguished from primary legislation on the one hand and judge-made law on the other...
of the practice of medicine. These new regulations forced the drug companies to prove that any new medication they brought to market was safe.
With the discovery of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, modern marketing techniques and brand
Brand
The American Marketing Association defines a brand as a "Name, term, design, symbol, or any other feature that identifies one seller's good or service as distinct from those of other sellers."...
promotion, the drug manufacturing industry came of age. Pharmacists continued to compound most prescriptions
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
until the early 1950s when the majority of dispensed drugs came directly from the large pharmaceutical companies.
During research and development
Pharmaceutical compounding is a branch of pharmacy that continues to play the crucial role of drug developmentDrug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
. Compounding pharmacists and medicinal chemists develop and test pharmaceutical formulation
Pharmaceutical formulation
Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product.-Stages and timeline:...
s for new drugs so that the active ingredients are effective, stable, easy to use, and acceptable to patients. However, for actual clinical trials, production of drug products is generally considered "manufacturing" because "compounding" is typically defined as being for a single individual patient only.
Patients with unique or unusual medication needs
Physicians may prescribe an individually compounded medication for a patient with an unusual health need. This allows the physician to tailor a prescription to each individual. Compounding preparations are especially prevalent for:- Patients requiring limited dosage strengths, such as a very small dose for infants
- Patients requiring a different formulation, such as turning a pillPillPill or The Pill may refer to:* Pill , referring to anything small and round for a specific dose of medicine. The term is used colloquially in several ways:** A tablet or capsule which replaced dosing via pill...
into a liquid or transdermal gel for people who can't swallow pills due to disability - Patients requiring an allergen-freeAllergyAn Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
medication, such as one without glutenGlutenGluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
or colored dyes - Patients who absorb or excrete medications abnormally
- Patients who need drugs that have been discontinued by pharmaceutical manufacturers because of low profitability
- Patients facing a supply shortage of their normal drug
- Children who want flavored additives in liquid drugs, usually so that the medication tastes like candy or fruit
- Veterinary medicine, for a change in dose, change to a more easily-administered form (such as from a pill to a liquid or transdermal gel), or to add a flavor more palatable to the animal. In the United States, compounded veterinary medicine must meet the standards set forth in the Animal Medical Drug Use Clarification Act (AMDUCA)
- Many types of bioidentical hormone replacement therapyBioidentical hormone replacement therapyBioidentical hormone replacement therapy , also known as bioidentical hormone therapy or natural hormone therapy, is a poorly-defined term referring to the use of hormones that are identical, on a molecular level, with endogenous hormones in hormone replacement therapy...
Personalized medicine and polypharmacy
While the regulatory boundaries aren't always clear (see "Regulation"), there is general acceptance of the need for physicians to have wide discretion to prescribe customized drug products containing unique drug/dosage combinations specifically for individual patients. While very few pharmacies offer such service, they do exist and can be usually be utilized via mail-order with sufficient notice and planning.Regulation
In the United States, compounding pharmacies are licensed and regulated by their respective state like all other pharmacies. National standards have been created by Pharmacy Compounding Accreditation Board (PCAB).Compounding pharmacies were the subject of the United States Supreme Court decision Thompson v. Western States Medical Center (535 U.S. 357, 2002), which held that Congressional attempts to restrict advertising by compounding pharmacies were unconstitutional. However, the same statute (FDAMA, amending the FDCA which establishes the FDA) also contained a provision that largely exempted compounded products from the FDA's control by defining many of them as not being "new drugs" for FDA purposes. Since the Supreme Court did not rule on the issue of how broadly to interpret that provision, nor on the issue of whether that provision was "severable" from the struck provision, there remains today a Circuit-split on both of those questions: As of 2008, the 9th Circuit (binding in several western states) holds that the provisions are not severable, and hence the entire FDAMA is void; on the other hand, the 6th Circuit (binding in several southwestern states) holds that the provisions are severable, and hence the non-struck portions of the FDAMA remain intact (including what it interpreted to be a limited exemption from FDA reach for any compounded drugs that meet the requirements given in the statute).
Meanwhile, in Circuits where the FDAMA is void and thus the FDA retains its original reach, the FDA weighs the following (non-exhaustive) mix of factors in deciding whether to "exercise its discretion" to require approval for a custom-compounded drug product, from its 2002 Compliance Policy Guide on the matter: 1. Compounding in anticipation of receiving prescriptions, 2. Compounding drugs removed from the market for safety reasons, 3. Compounding from bulk ingredients not approved by FDA, 4. Receiving, storing, or using drugs not made in an FDA-registered facility, 5. Receiving, storing, or using drugs' components not determined to meet compendia requirements, 6. Using commercial-sale manufacturing or testing equipment, 7. Compounding for third parties for resale, 8. Compounding drugs that are essentially the same as commercially available products, 9. Failing to operate in conformance with applicable state law. Hence, making truly patient-customized products with particular drug(s)/dosage(s) upon receiving valid prescriptions from a physician is likely to be acceptable, especially if the ingredients are FDA approved, etc.
Also from the 2002 CPG document, the FDA assures compounding pharmacies that its main concern is those who effectively engage in multi-patient "manufacturing" under the guise of compounding. "FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. This traditional activity is not the subject of this guidance."
As a related point regarding the broad professional discretion to customize patient care, note that about 20-30% of prescription medications in the US are estimated to be "off-label," meaning the physician believes the drug to be beneficial for a patient despite it not being approved for that particular use/condition. This too is perfectly legal, subject only to state regulations on the practice of medicine, etc.
See also
- ApothecaryApothecaryApothecary is a historical name for a medical professional who formulates and dispenses materia medica to physicians, surgeons and patients — a role now served by a pharmacist and some caregivers....
— the ancestral practitioner of compounding, and his shop - Bioidentical hormone replacement therapyBioidentical hormone replacement therapyBioidentical hormone replacement therapy , also known as bioidentical hormone therapy or natural hormone therapy, is a poorly-defined term referring to the use of hormones that are identical, on a molecular level, with endogenous hormones in hormone replacement therapy...
— Compounding is involved in the surrounding controversy - Gluten-free dietGluten-free dietA gluten-free diet is a diet that excludes foods containing gluten. Gluten is a protein found in wheat , barley, rye, malts and triticale. It is used as a food additive in the form of a flavoring, stabilizing or thickening agent, often as "dextrin"...
- Plastic compoundingPlastic compoundingCompounding consists of preparing plastic formulations by mixing or/and blending polymers and additives in a molten state. There are different critical criteria to achieve a homogenous blend of the different raw material...
- Professional Compounding Centers of AmericaProfessional Compounding Centers of AmericaIn 1981, the Professional Compounding Centers of America was incorporated to provide compounded medications to patients, when the medicine became unavailable commercially. PCCA provides education and pharmaceutical consultation on this subject. The organization's philosophy revolves around a triad...