Compounding

In the field of pharmacy, compounding (performed in compounding pharmacies) is the preparation of a custom formulation of a medication to fit the unique need of a patient which cannot be met with commercially available products. This may be done for medical reasons, such as to be administered by a different route (ex: tablet to liquid), to avoid a non-active ingredient the patient is allergic to, or to provide an exact dose that isn't commercially available. Medically necessary compounding is referred to as "traditional" compounding. Compounding may also be done for optional reasons, such as preference of flavor or texture, or dietary restrictions.

Pharmacist compounding a medication using a mortar and pestle (c. 1923)

Hospital pharmacies typically engage in compounding medications for intravenous administration, whereas outpatient or community pharmacies typically engage in compounding medications for oral or topical administration. Due to the rising cost of compounding and drug shortages, some hospitals outsource their compounding needs to large-scale compounding pharmacies, particularly of sterile-injectable medications.

Compounding bulk preparations of a given formulation as opposed to preparation for a specific patient is known as "non-traditional" compounding. Different jurisdictions have different rules regarding the applicability of regulations which apply to drug manufacturers to pharmacies which perform bulk compounding.

History
Main article: History of pharmacy

The earliest chemists were familiar with various natural substances and their uses. These professionals compounded a variety of preparations such as medications, dyes, incense, perfumes, ceremonial compounds, preservatives and cosmetics. 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 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 several chemical compounds. The compounding pharmacist extracted these crude drugs using solvents such as water or alcohol to form extracts, concoctions and decoctions. Pharmacists eventually began isolating and identifying the active ingredients contained within these crude drug concoctions. Using fractionation or recrystallization, the compounding pharmacist would separate an active ingredient from the crude preparation, and compound a medication using this active ingredient.

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 could not do it efficiently on a small scale. So economies of scale, not lack of skill or knowledge, produced the modern pharmaceutical industry. 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

A physician may choose to prescribe a compounded medication for a patient with an unusual health need that cannot be met with commercially manufactured products. The physician may choose to prescribe a compounded medication for reasons such as:

  • Patients requiring an individualized compounded formulation to be developed by the pharmacist[3]
  • Patients who cannot take commercially prepared prescriptions of a drug[3]
  • 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 cannot 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[4]
  • Patients who need drugs that have been discontinued by pharmaceutical manufacturers because of low profitability
  • Patients facing a supply shortage of their normal drug[5][6]
  • 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 Medicinal Drug Use Clarification Act (AMDUCA)[4][7]
  • Many types of bioidentical hormone replacement therapy[8]
  • Patients who require multiple medications combined in various doses[9]

Regulation in Australia

In Australia the Pharmacy Board of Australia is responsible for registration of pharmacists and professional practice including compounding. Although almost all pharmacies are able to prepare at least simple compounded medicines, some pharmacy staff undertake further training and education to be able to prepare more complex products. Although pharmacists who have undertaken further training to do complex compounding are not yet easily identified, the Board has been working to put a credentialing system in place. In 2011 the Pharmacy Board convened a Compounding Working Party to advise on revised compounding standards.[10] Draft compounding guidelines for comment were released in April 2014. Pharmacists must comply with current guidelines or may be sanctioned by the Board.[11]

Both sterile and non-sterile compounding are legal provided the compounding is done for theraputic use in a particular patient, and the compounded product is supplied on or from the compounding pharmacy.[12] There are additional requirements for sterile compounding. Not only must a laminar flow cabinet [laminar flow hood] be used, but the environment in which the hood is located must be strictly controlled for microbial and particulate contamination and all procedures, equipment and personnel must be validated to ensure the safe preparation of sterile products. In non-sterile compounding, a powder containment hood is required when any hazardous material (e.g. hormones) are prepared or when there is a risk of cross-contamination of the compounded product. Pharmacists preparing compounded products must comply with these requirements and others published in the Australian Pharmaceutical Formulary & Handbook.

Regulation in the United States

In the United States, compounding pharmacies are licensed and regulated by states. National standards have been created by Pharmacy Compounding Accreditation Board (PCAB),[13] however, obtaining accreditation is not mandatory and inspections for compliance occur only every three years.[14] The Food and Drug Administration (FDA) has authority to regulate "manufacturing" of pharmaceutical products – which applies when drug products are not made or modified as to be tailored in some way to the individual patient – regardless of whether this is done at a factory or at a pharmacy.

In the Drug Quality and Security Act (DQSA) of 2013 (H.R. 3204),[15] Congress amended the Federal Food, Drug, and Cosmetic Act (FFDCA) to clarify limits of FDA jurisdiction over patient-specific compounding, and to provide an optional pathway for "non-traditional" or bulk compounders to operate. The law established that pharmacies compounding only "patient-specific" preparations made in response to a prescription (503A pharmacies) cannot be required to obtain FDA approval for such products, as they will remain exclusively under state-level pharmacy regulation. At the same time, section 503B of the law regulates "outsourcing facilities" which conduct bulk compounding or are used as outsourcing for compounding by other pharmacies. These outsourcing facilities can be explicitly authorized by the Food and Drug Administration under specified circumstances, while being exempted from certain requirements otherwise imposed on mass-producers. In any pharmacy, compounding is not permitted for a drug product that is "essentially a copy" of a mass-produced drug product, however outsourcing pharmacies are subject to a broader definition of "essentially a copy". For traditional/patient-specific compounding, 503A's definition of "copy" retains its original focus on drug products or ultimate dosage forms rather than drug substances or active ingredients,[16] and in any event it explicitly excludes from its definition any compounded drug product that a given patient's prescribing practitioner determines makes a "significant difference" for the patient.

The FDA weighs the following factors in deciding whether it has authority to "exercise its discretion" to require approval for a custom-compounded drug product:[17]

  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-scale 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.

Outsourcing facilities

The DQSA amended the FFDCA to create a new class of FDA-regulated entities known as "outsourcing facilities" whose compounding activities "may or may not" be patient-specific based on individualized prescriptions.[18] Registered outsourcing facilities, unlike traditional compounding facilities, are subject to the FDA's oversight. In addition to being subjected to Food and Drug Administration inspections, registration, fees, and specified reporting requirements, other requirements of outsourcing facilities include:

  1. Drugs are compounded by or under the direct supervision of a licensed pharmacist.
  2. The facility does not compound using "bulk drug substances" (unless certain exceptions apply) and its drugs are manufactured by an FDA-registered establishment.
  3. Other ingredients used in compounding the drug must comply with the standards of the applicable United States Pharmacopeia or National Formulary monograph, if a monograph exists.
  4. The drug does not appear on a list published by FDA of unsafe or ineffective drugs.
  5. The drug is not "essentially a copy" of one or more marketed drugs (as defined uniquely in section 503B, notably more broadly and with narrower exclusions than for "traditional" compounding).
  6. The drug does not appear on the FDA list of drugs or categories of drugs that present "demonstrable difficulties" for compounding.
  7. The compounding pharmacist demonstrates that he or she will use controls comparable to the controls applicable under any applicable risk evaluation and mitigation strategy (REMS).
  8. The drug will not be sold or transferred by an entity other than the outsourcing facility.
  9. The label of the drug states that it is a compounded drug, as well as the name of the outsourcing facility, the lot or batch number of the drug, dosage form and strength, and other key information.

Drug testing and reporting of incidents

Poor practices on the part of drug compounders can result in contamination of products, or products that do not meet their stated strength, purity, or quality. Unless a complaint is filed or a patient is harmed, drugs made by compounders are seldom tested. In Texas, one of only two states that does random testing, significant problems have been found. Random tests by the state’s pharmacy board over the last several years have found that as many as one in four compounded drugs was either too weak or too strong. In Missouri, the only other state that does testing, potency varied by as much as 300 percent.[19]

In 2002, the Food and Drug Administration, concerned about the rising number of accidents related to compounded medications, identified "red flag" factors and issued a guide devoted to human pharmacy compounding, These factors include instances where pharmacists are:[20]

  • Compounding drug products that have been pulled from the market because they were found to be unsafe or ineffective.
  • Compounding drugs that are essentially copies of a commercially available drug product.
  • Compounding drugs in advance of receiving prescriptions, except in very limited quantities relating to the amounts of drugs previously compounded based on valid prescriptions.
  • Compounding finished drugs from bulk active ingredients that aren't components of FDA-approved drugs, without an FDA-sanctioned, investigational new-drug application.
  • Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDA-registered facility.
  • Failing to conform to applicable state law regulating the practice of pharmacy.

New England Compounding Center incident
See also: New England Compounding Center meningitis outbreak

In October 2012 news reports surfaced of an outbreak of fungal meningitis tied to the New England Compounding Center, a pharmacy which engaged in bulk compounding. [21] At that time it was also disclosed that the United States and Massachusetts state health regulators were aware in 2002 that steroid treatments from the New England Compounding Center could cause adverse patient reactions.[22] It was further disclosed that in 2001–02, four people died, more than a dozen were injured and hundreds exposed after they received back-pain injections tainted with a common fungus dispensed by two compounding pharmacies in California and South Carolina.[23]

In August 2013 further reports tied to the New England compounding center said that about 750 people were sickened, including 63 deaths, and that infections were linked to more than 17,600 doses of methylprednisolone acetate steroid injections used to treat back and joint pain that were shipped to 23 states. At that time, another incident was reported after at least 15 people at two Texas hospitals developed bacterial infections. All lots of medications dispensed since May 9, 2013, made by Specialty Compounding, LLC of Cedar Park, Texas were recalled. The hospitals reported affected were Corpus Christi Medical Center Bay Area and Corpus Christi Medical Center Doctors Regional. The patients had received intravenous infusions of calcium gluconate, a drug used to treat calcium deficiencies and too much potassium in the blood. Implicated in these cases is the Rhodococcus bacteria, which can cause symptoms such as fever and pain.[24]

Misuse prompting regulatory changes

The FDA, among others, claims that larger compounding pharmacies act like drug manufacturers and yet circumvent FDA regulations under the banner of compounding. Drugs from compounding pharmacies can be cheaper or alleviate shortages, but can pose greater risk of contamination due in part to the lack of oversight. "Non-traditional" compounders behave like drug manufacturers in some cases by having sales teams that market non-personalized drug products or production capability to doctors, by making drugs that are essentially the same as commercially available mass-produced drug products, or by preparing large batches of a given drug product in anticipation of additional prescriptions before actually receiving them.[25][26] An FDA spokesperson stated, "The methods of these companies seem far more consistent with those of drug manufacturers than with those of retail pharmacies. Some firms make large amounts of compounded drugs that are copies or near copies of FDA-approved, commercially available drugs. Other firms sell to physicians and patients with whom they have only a remote professional relationship."[20] The head of the FDA has recently requested the following authority from Congress:[27]

Various ideas have been proposed to expand federal US regulation in this area, including laws making it easier to identify misuse or misnomered-use[28] and/or stricter enforcement of the longstanding distinction between compounding versus manufacturing.[29][30] Some US states have also taken initiatives to strengthen oversight of compounding pharmacies.[31] A major source of opposition to new Food and Drug Administration regulation on compounding is makers of dietary supplements.[32]

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See also

References
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  2. Kaf al-Ghazal, Sharif (2004). "The valuable contributions of Al-Razi (Rhazes) in the history of pharmacy during the middle ages". Journal of the International Society for the History of Islamic Medicine. 3: 3–9 [8].
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  4. "International Academy of Compounding Pharmacists: Definition of Compounding". Archived from the original on 2007-02-07. Retrieved 2010-07-18.
  5. "ArmourThyroid". Retrieved 2010-07-17.
  6. "Options for thyroid treatment". stopthethyroidmadness.com. Retrieved 2010-07-17.
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  8. 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.
  9. "The Benefits of Compounding Sports Meds into a Single Dose". compoundingrxusa.com. Retrieved 2018-12-04.
  10. "Pharmacy Board of Australia Nov 2011 Communique".
  11. "Pharmacy Board of Australia - notifications". Archived from the original on 2014-03-09. Retrieved 2014-04-09.
  12. "Therapeutic goods regulations: Exempt goods" (PDF). Australian Government. Department of Health and Aging. Therapeutic Goods Administration. December 1997. Retrieved 2017-02-21.
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  14. Kotz, Deborah (2012-10-11) How risky are compounding pharmacies?. Boston.com. Retrieved on 2013-05-13.
  15. "Text of H.R. 3204: Drug Quality and Security Act (Enrolled Bill version)". GovTrack.us. November 21, 2013. Retrieved 2014-02-18.
  16. "Compounding Legislation Action Center - Section 503A". National Home Infusion Association. 2010. Archived from the original on 2013-12-03. Retrieved 2014-02-18.
  17. "Medical Center Pharmacy v. Mukasey". Food and Drug Administration. Archived from the original on 2010-03-09. Retrieved 2012-02-05.
  18. Michael Werner (November 19, 2013). "Drug Quality and Security Act Gives FDA Authority to Regulate Drug Compounding and Creates Uniform Federal Standards for Distribution". JDSupra. Retrieved 2014-02-18.
  19. Bogdanich, Walt and Tavernise, Sabrina (2012-10-22). U.S. Concern Over Compounders Predates Outbreak of Meningitis. New York Times.
  20. "The Special Risks of Pharmacy Compounding". Food and Drug Administration. 2012-12-03. Archived from the original on January 7, 2015. Retrieved 2012-12-19.
  21. Meningitis outbreak toll: 119 cases, 11 deaths. Usatoday.com (2012-10-09). Retrieved on 2012-12-19.
  22. Morgan, David (October 22, 2012). "Health officials knew of problem steroids in 2002: U.S. House panel". Reuters.
  23. Burtin, T. M.; Grimaldi, J. V. and Martin, T. W. (2012-10-14). Pharmacies Fought Controls; Industry at the Focus of Meningitis Outbreak Beat Back More Federal Oversight, Wall Street Journal
  24. "Texas compounding pharmacy recalls drugs after 15 infections". CBS News. 2013-08-12. Retrieved 2014-02-18.
  25. Grady, Denise; Pollack, Andrew and Tavernise, Sabrina (2012-10-07). Scant Oversight of Drug Maker in Fatal Meningitis Outbreak. New York Times.
  26. Martin, T. W.; Burton, T. M.; Dooren, J. C. (2012-10-09). "Outbreak Spurs Calls for New Controls". The Wall Street Journal. The Wall Street Journal. Retrieved 2012-10-09.
  27. A Continuing Investigation into the Fungal Meningitis Outbreak and Whether It Could Have Been Prevented. Statement of Margraret A. Hamburg, M.D., Commissioner of Food and Drugs, April 16, 2013.
  28. Pikesville man joins push for drug oversight reform after meningitis outbreak – Baltimore Sun. Articles.baltimoresun.com (2012-11-14). Retrieved on 2013-05-13.
  29. Morin, Monte. (2013-04-16) FDA chief vows to get 'aggressive' with compounding pharmacies. latimes.com. Retrieved on 2013-05-13.
  30. Michigan Journal of Law Reform » Compounding Reform: Reconsidering the Draft Safe Drug Compounding Act of 2007 in Light of the Ongoing Fungal Meningitis Outbreak. Mjlr.org (2013-03-17). Retrieved on 2013-05-13.
  31. Proposed Legislative Reforms Addressing Compounded Drugs Archived 2013-05-12 at the Wayback Machine. cidreview.cidmcorp.com
  32. Barrett, Paul M. (2012-11-14) America's Shadow Pharmacies. Businessweek. Retrieved on 2013-05-13.
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