Compounding

For financial compounding, see Compound interest. For the compounding of words, see Compound (linguistics).

Compounding (also pharmaceutical compounding and compounding pharmacy) 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.

History

Main article: History of pharmacy

Before mass production 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 chemists 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.^[1][2]

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, phenolic 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 extracts, concoctions and decoctions.

Pharmacists began isolating and identifying the active ingredients 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.

Roles

During research and development

Pharmaceutical compounding is a branch of pharmacy that continues to play the crucial role of drug development. Compounding pharmacists and medicinal chemists develop and test pharmaceutical formulations 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 pill into a liquid or transdermal gel for people who can't swallow pills due to disability
• Patients requiring an allergen-free medication, such as one without gluten or colored dyes
• Patients who absorb or excrete medications abnormally^[3]
• Patients who need drugs that have been discontinued by pharmaceutical manufacturers because of low profitability
• Patients facing a supply shortage of their normal drug^[4][5]
• 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)^[3][6]
• Many types of bioidentical hormone replacement therapy^[7]

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.^[8]

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).^[9]

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:^[10] 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." <emphasis added>^[11]

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

• Apothecary — the ancestral practitioner of compounding, and his shop
• Bioidentical hormone replacement therapy — Compounding is involved in the surrounding controversy
• Gluten-free diet
• Plastic compounding
• Professional Compounding Centers of America

References

1. ^ Information taken from the abstract of Hadzović, S (1997). "[Pharmacy and the great contribution of Arab-Islamic science to its development] (Article in Croatian)". Medicinski arhiv 51 (1–2): 47–50. ISSN 0350-199X. PMID 9324574. 
2. ^ Sharif Kaf al-Ghazal, Journal of the International Society for the History of Islamic Medicine, 2004 (3), pp. 3–9 [8].
3. ^ ^{a b} "International Academy of Compounding Pharmacists: Definition of Compounding". http://www.iacprx.org/site/PageServer?pagename=What_is_Compounding. Retrieved 2010-07-18. 
4. ^ "ArmourThyroid". http://www.armourthyroid.com/. Retrieved 2010-07-17. 
5. ^ "Options for thyroid treatment | Stop The Thyroid Madness". http://www.stopthethyroidmadness.com/options-for-thyroid-treatment/. Retrieved 2010-07-17. 
6. ^ "www.fda.gov". http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm137148.htm. Retrieved 2010-07-18. 
7. ^ Boothby LA, Doering PL (August 2008). "Bioidentical hormone therapy: a panacea that lacks supportive evidence". Curr. Opin. Obstet. Gynecol. 20 (4): 400–7. doi:10.1097/GCO.0b013e3283081ae9. PMID 18660693. 
8. ^ http://www.bayviewrx.com/bayview-blog/bid/18766/5-in-1-PolyPill-Treatment-May-Prevent-Heart-Disease
9. ^ "International Academy of Compounding Pharmacists: Frequently Asked Questions". http://www.iacprx.org/site/PageServer?pagename=FAQs. Retrieved 2010-07-18. 
10. ^ http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm134919.htm
11. ^ http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM118050.pdf

External links

• International Academy of Compounding Pharmacists
• International Journal of Pharmaceutical Compounding
• Compounding Pharmacies Directory in the U.S.A
• RDS Medical Compounding