Compounding

Pharmaceutical compounding (done in compounding pharmacies) is the creation of a particular pharmaceutical product to fit the unique need of a patient. To do this, compounding pharmacists combine or process appropriate ingredients using various tools. 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(s) needed or deemed best of particular active pharmaceutical ingredient(s). It may also be done for more optional reasons, such as adding flavors to a medication or otherwise altering taste or texture. Compounding is most routine in the case of intravenous/parenteral medication, typically by hospital pharmacists, but is also offered by privately owned compounding pharmacies and certain retail pharmacies for various forms of medication. Whether routine or rare, intravenous or oral, etc., when a given drug product is made or modified to have characteristics that are specifically prescribed for an individual patient, it is known as "traditional" compounding.

Due to the rising cost of compounding and the shortage of drugs, many hospitals have shown a tendency to rely more upon large-scale compounding pharmacies to meet their regular requirement, particularly of sterile-injectable medications. When compounding is done on bulk production of a given formulation rather than patient-specific production, it is known as "non-traditional" compounding (which, as discussed below, is arguably not "compounding" but rather "manufacturing"). This development raises concerns about patient safety and makes a case for proper regulatory control and monitoring.^[1]

History

Before mass production of medications became widespread, 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 used 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 and 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.^[2][3]

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 several 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 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

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 combinations of active pharmaceuticals and delivery systems for new pharmaceutical formulations 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 small batch or single individual patient production 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 an individualized compounded formulation to be developed by the pharmacist^[4]
• Patients who cannot take commercially prepared prescriptions^[4]
• 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^[5]
• Patients who need drugs that have been discontinued by pharmaceutical manufacturers because of low profitability
• Patients facing a supply shortage of their normal drug^[6][7]
• 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)^[5][8]
• Many types of bioidentical hormone replacement therapy^[9]

Personalized medicine and polypharmacy

While the regulatory boundaries are not 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 and/or formulations thereof specifically for individual patients. Most mass-produced drugs often have only one or two readily available dosage levels (except the most dominant drugs), and fixed-dose combination products – despite their many benefits – are even less likely to have the optimal combination of drugs and respective dosages for any given patient. Hence, the opportunity to tailor the drug(s)/dosage(s) in a given drug product as specifically contemplated for individual patients (as deemed optimal by one's physician) is an application of the classic principles underlying compounding.

Some kinds or compositions of polypills or other drug products are more amenable to custom-compounding than others, and most retail pharmacies no longer offer compounding services at all, although hospital pharmacies still commonly compound intravenous medications. But while fewer pharmacists are trained and experienced in the relevant skills anymore; especially regarding oral dosage forms, which are almost always mass-produced now instead; such compounding pharmacies nevertheless can be found and utilized via mail-order (if not available locally) with sufficient notice and planning.^[10]

Technologies are under development to facilitate production of customized polypills, such as for example by the use of ink-jet printing mechanisms to precisely deposit selected drug substance(s) onto sheets which can then be inserted into capsules, enabling "individualized dosing and automated fabrication of medicines containing multiple drugs," in addition to custom single-drug products.^[11] Similar technology can also be used to print tablets, more directly. Ink-jet or fluid-jet approaches do require each drug substance to be dissolved in a liquid solvent, but they can be particularly conducive to custom formulation with various possible excipients, in addition to custom drug/dose selections.

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 pharmacies 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.^[12] Draft compounding guidelines for comment were released in April 2014. However it should be noted that pharmacists are required to comply with the current Board requirements and if this is not happening the Board can be notified.^[13]

Both sterile and non-sterile compounding are legal provided the medicines are provided for a particular patient for therapeutic application to that patient, and the compounded product is supplied on or from the compounding pharmacy premises.^[14] 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 their respective states like all other pharmacies. National standards have been created by Pharmacy Compounding Accreditation Board (PCAB).^[15] However, accreditation is not mandatory and inspections for compliance occur only every three years.^[16] As mentioned, some confusion has arisen when the traditionally patient-specific nature of compounding gets blurred by the making the multi-product "batches" such as in anticipation of similar orders. Notably, the Food and Drug Administration (FDA) has always had authority to regulate "manufacturing" – which is 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. And conversely, truly legitimate/traditional compounding does not cease to be so merely by having a high frequency or occurrence – indeed, progressing towards more prevalent drug product customization is an appealing aspect of personalized medicine (see above).

In the Drug Quality and Security Act (DQSA) of 2013 (H.R. 3204),^[17] Congress amended the Federal Food, Drug, and Cosmetic Act (FFDCA) to clarify some limits of FDA jurisdiction over traditional (i.e., patient-specific) compounding, and to provide a regulated (albeit optional) pathway for "non-traditional" compounders to operate. So now, Section 503A essentially establishes that pharmacies compounding only "patient-specific" drug products made in response to each prescription (among certain other related situations) 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 creates a new category of facilities called "outsourcing facilities" - by which non-traditional compounding facilities (i.e., those whose products include "non-patient-specific" batches) can be explicitly authorized by the Food and Drug Administration under specified circumstances, while being exempted from certain requirements otherwise imposed on mass-producers. Notably, in both cases the compounding cannot encompass a drug product that is "essentially a copy" of a mass-produced drug product, but in 503B the definition of "essentially a copy" is broader than in 503A. (In earlier DQSA drafts the definitions were kept the same for both sections,^[18] but the final version goes further for "outsourcing facilities" in subsection (d)(2)(B) of 503B, by deeming a compounded drug a "copy" even if it just has an active ingredient that is also present in any mass-produced product.) However, this definition is indicated at the beginning of subsection (d) as applying only for section 503B. 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,^[19] 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. (503B's definition includes a similar but narrower safe harbor exclusion from the definition; that definition, which applies only to the "outsourcing facilities," defines "copy" based on the active ingredient(s) a drug product contains, rather than the overall drug product or dosage form, and it explicitly excludes situations where the prescribing practitioner determines that the change/difference makes a "clinical difference" for the patient.)

In general, to whatever extent the Food and Drug Administration ever has authority to regulate compounding, 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:^[20]

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.

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.

Outsourcing facilities

The DQSA amends the FFDCA to create a new class of FDA-regulated entities known as "outsourcing facilities," whose compounded drug products notably "may or may not" be patient-specific based on individualized prescriptions.^[21] Registered outsourcing facilities, unlike traditional compounding facilities, are subject to the FDA's oversight. Currently this is a voluntary program.

In addition to being subjected to Food and Drug Administration inspections, registration, fees, and specified reporting requirements, other notable requirements of outsourcing facilities include that:

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.

Analogy to "off-label" use

Regarding traditional/patient-specific compounding, the practice of "off-label use" can be considered a related analogous point regarding the broad professional discretion to customize patient care. About 20–30% of prescription medications in the US are estimated to be used "off-label," meaning the physician believes the drug to be beneficial for a patient despite its not being approved for that particular use/condition. This too is perfectly legal, subject only to state regulations on the practice of medicine, etc.

The appropriateness of prescribing approved drugs for uses not included in their official labeling is sometimes a cause of concern and confusion among physicians. This has been addressed by the American Society of Health-System Pharmacists in their Statement on the Use of Medications for Unlabeled Uses:^[22] Under the Federal Food, Drug and Cosmetic (FD&C) Act, a drug approved for marketing may be labeled, promoted, and advertised by the manufacturer only for those uses for which the drug's safety and effectiveness has been established and which the FDA has approved. These are commonly referred to as "approved uses." This means that adequate and well-controlled clinical trials have documented these uses, and the results of the trials have been reviewed and approved by the FDA.

The FFDCA does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in the above labeling. Such "unapproved" or more precisely, "unlabeled" uses may be appropriate and rational in certain circumstances, and, may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature. Thus the term "unapproved uses" is, to some extent, misleading. Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic investigations. Before such advances can be added to the approved labeling, however, data substantiating the effectiveness of a new use or regimen must be submitted by the manufacturer to the Food and Drug Administration for evaluation. This may take time, and without the initiative of the drug manufacturer whose product is involved, and physicians who are persuaded that a given usage is valid before there is broad scientific consensus, it may never otherwise occur. For that reason, accepted medical practice often includes so-called "off label" uses.

Drug testing and reporting of incidents

Poor practices on the part of drug compounders can result in contamination or in products that don't possess the strength, quality, and purity required. 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.^[23]

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:

• 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.^[24]

The DQSA of 2013 recognized and authorized certain non-traditional compounders to operate as "outsourcing facilities," who register with the FDA and become subject to various reporting requirements - including adverse events and supply chain matters.

New England Compounding Center incident

In October 2012 news reports surfaced of an outbreak of fungal meningitis tied to the New England Compounding Center. ^[25] 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.^[26] 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.^[27]

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.^[28]

Misuse prompting regulatory changes

The DQSA of 2013 implements certain statutory changes and clarifications to the authority of the Food and Drug Administration, based in part on growing concerns about "non-traditional" or non-patient-specific compounding - particularly of sterile injectable drug products. Traditional, patient-specific compounding remains essentially unaffected and continues to fall under the domain of state pharmacy practice regulation without controversy.

The FDA and others say that some larger compounding pharmacies were acting like drug manufacturers and yet circumventing 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. Compounding pharmacies had been regulated by laws that were developed when they solely made custom prescriptions for individual patients, but the FDA has sought additional authority to regulate what they term "non-traditional" compounders who in essence are more like "miniature drug manufacturers" than true pharmacies. Such "non-traditional" compounders behave like manufacturers in various ways – such as by having sales teams that market non-personalized drug products or production capability to doctors, and by making drugs that are essentially the same as commercially available mass-produced drug products, and most importantly by pre-making large batches of a given drug product in anticipation of additional same prescriptions but before actually receiving them (the latter being directly the opposite of patient-specific tailoring).^[1][29]

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."^[24] The head of the FDA has recently requested the following authority from Congress:^[30]

"Nontraditional compounding should, because of the higher risk presented, be subject to a greater degree of oversight. Sterile products produced in advance of or without a prescription and shipped interstate should be subject to the highest level of controls, established by FDA and appropriate to the activity, similar to cGMP standards applicable to conventional drug manufacturers. In addition, FDA believes that with noted exceptions, certain products are not appropriate for compounding under any circumstances. These products would include: 1) what are essentially copies of FDA-approved drugs, absent a shortage justification based on the drug appearing on FDA’s shortage list; and 2) complex dosage forms such as extended release products; transdermal patches; liposomal products; most biologics; and other products as designated by FDA. Producing complex dosage forms would require an approved application and compliance with cGMP standards, along with other requirements applicable to manufactured drug products."

This statement also went on to advocate certain auditing and testing powers, record-keeping and reporting obligations, etc. While the first part (regarding a lack of prior prescription) is indeed consistent with limiting compounding to its traditional domain of customization, it would however be unprecedented for the Food and Drug Administration to regulate truly individualized drug products solely on the basis of their formulation's "complexity" (although Congress could preempt the states traditional role in this regard). At the same time, this position statement does suggest perhaps some willingness by the FDA to embrace the occasional "non-traditional compounding" of copies of FDA-approved drug products – albeit with greater regulation – in cases of specified shortages.

Various ideas have been proposed to continue strengthening federal US regulation in this area, including new laws making it easier to identify misuse or misnomered-use^[31] and/or stricter enforcement of the longstanding distinction between compounding versus manufacturing.^[32][33] Also, some US states have taken initiatives to strengthen their own oversight of compounding pharmacies.^[34]

A major source of opposition to new Food and Drug Administration regulation on compounding stems from certain dietary supplement makers.^[35]

See also

• Apothecary — the ancestral practitioner of compounding, and his shop
• Professional Compounding Centers of America
• New England Compounding Center meningitis outbreak
• Bioidentical hormone replacement therapy — Compounding is involved in the surrounding controversy

References

External links

• International Academy of Compounding Pharmacists
• International Journal of Pharmaceutical Compounding
• "Federal Authority to Regulate the Compounding of Human Drugs" (PDF). Congressional Research Service. Federation of American Scientists.