Traditional Pharmacy Compounding
The FDA defines traditional pharmacy compounding as the combining, mixing, or altering of ingredients to create a customized medication for an individual patient in response to a licensed practitioner’s prescription . The National Association of Boards of Pharmacy (NABP) further describes compounding as the result of a practitioner’s prescription drug order based on the practitioner/patient/pharmacist relationship in the course of professional practice . Traditional pharmacy compounding plays a valuable role in providing access to medications for individuals with unique medical needs, which cannot be met with a commercially available product. For instance, a prescriber may request that a pharmacist compound a suspension for a pediatric or geriatric patient unable to swallow a medication in its commercially available form. In traditional pharmacy compounding, an individualized medicine is prepared at the request of a prescriber on a small scale.
Non-Traditional Pharmacy Compounding
Some pharmacies have seized upon a burgeoning business opportunity to expand their activities beyond the scope of traditional pharmacy compounding . Examples of improper pharmacy compounding include introducing drug moieties that have not been approved for use in the US or have been removed by the FDA for safety reasons, large-scale production of compounded medications without prescriptions, and creating copies (or essentially copies) of FDA-approved drugs.
The FDA issued letters in 2004 to compounding pharmacies obtaining domperidone from foreign sources for women to assist with lactation, noting that domperidone is not approved in the US for any indication. Citing public health risks, including cardiac arrest and sudden death, the FDA recommended that breastfeeding women avoid the use of domperidone .
The FDA has publically expressed concerns regarding “large-scale drug manufacturing under the guise of pharmacy compounding” [1, 2]. The FDA has noted that poor practices on the part of drug compounders can result in contamination or in products that do not possess the strength, quality, and purity required . Unlike FDA-approved products, consumers and prescribers cannot assume that compounded drugs were made by validated processes in properly calibrated and cleaned equipment; that the ingredients in the drug were obtained from FDA-approved sources; that production personnel had the requisite knowledge and training; and that appropriate laboratory testing was performed to verify the compounded drug’s potency, purity, and quality. In the case of sterile compounding, there are also concerns about the adequacy of environmental monitoring, which includes microbiological testing of the facility, equipment, air purification, and water. The shelf-life of compounded products is typically not verified by stability testing; therefore, compounded preparations cannot be assumed to retain their original strength and purity over time.
Pharmacies making copies of commercially available products for economically driven reasons, rather than genuine medical need, are also engaged in improper compounding, as this circumvents important public health requirements . A significant concern is the use of active and inactive ingredients that are from foreign sources and not manufactured under GMPs to create the unapproved copies. The FDA has stated that consumers would be better served by commercially available drugs, which have been determined to be safe and effective and manufactured under rigorous GMP requirements .
In 2001, a Kansas City-based pharmacist was discovered to have adulterated 72 different drugs, including many oncology medications, to increase profits. According to law enforcement estimates, the pharmacist diluted approximately 98,000 prescriptions for 4,200 patients over an 11-year time period . This drug adulteration was detected not by clinicians or patients, but rather by a pharmaceutical sales representative who noted that the pharmacy was selling considerably more drugs than it was buying. Illegal activities of this nature are by no means typical of pharmacy compounding, but this case illustrates that clinical observation alone cannot be relied upon to detect quality problems in medicines.
Compounded Sterile Preparations (CSPs)
The primary standard for the compounding of sterile medications is USP chapter 〈797〉 Pharmaceutical Compounding: Sterile Preparations, which specifies the conditions and practices that should be used to prevent harm to patients from microbial contamination, bacterial endotoxins, chemical and physical contaminants, and ingredients of inappropriate quality. USP 〈797〉 classifies aseptic manipulation of sterile products or ingredients as low-risk sterile compounding. However, the sterility assurance level (SAL) of preparations compounded by an aseptic process is, at best, several orders of magnitude lower than the SAL of terminally sterilized pharmaceutical products manufactured under GMPs. The SAL is much lower still if the aseptic compounding process has not been robustly validated . Incorporating non-sterile ingredients into a compounded preparation prior to terminal sterilization is classified as high-risk sterile compounding . USP 〈797〉 states that high-risk CSPs should be used within 24 h of preparation if stored at room temperature, or 3 days if refrigerated, unless sterility testing is conducted to support extended dating. USP chapter 〈71〉 Sterility Tests emphasizes that sterility tests are not by themselves designed to ensure that a batch of product is sterile; rather, this is primarily accomplished by validation of the sterilization process .
By law, USP 〈797〉 is enforceable by the FDA, but in practice the agency generally defers regulation of pharmacies to states . The NABP has incorporated USP 〈797〉 into its Model State Pharmacy Act and Model Rules. Although some states have adopted USP 〈797〉 in its entirety, most State Boards of Pharmacy have only incorporated selected portions of USP 〈797〉 into their regulations or board policies . Any requirements that are not adopted are not legally enforceable by the state. For example, in 2010 the Texas State Board of Pharmacy rejected a proposal to require the use of sterile gloves and alcohol by pharmacy personnel compounding sterile preparations, despite this being a specific requirement of USP 〈797〉 .
A 2011 outbreak of Serratia marcescens bacteremia, which infected 19 patients at six Alabama hospitals, 9 of whom died, was caused by contaminated total parenteral nutrition bags from a compounding pharmacy [17, 18]. As a result of this incident, the Institute of Safe Medication Practices (ISMP) recommended that State Boards of Pharmacy require compounding pharmacies within their state to comply with all aspects of USP 〈797〉, and inspect these pharmacies regularly to enforce compliance . ISMP stated, “partial compliance will not even partially protect patients from the risk of infection from contaminated CSPs.” ISMP concluded, “Unfortunately, there are too many in healthcare who feel that if it hasn’t happened to them, the adverse experiences of others do not apply.”
USP 〈797〉 is an appropriate and practical guidance to implement in a pharmacy that invests in the required equipment and training. However, USP 〈797〉 does not afford the same degree of sterility assurance for compounded drugs that GMPs provide for FDA-approved sterile products . USP 〈797〉 does not provide the necessary protection when compounding expands to mass production of drugs, which requires GMP controls.
Comparison of Compounded Drugs with FDA-Approved Drugs
There are significant differences between compounded drugs and FDA-approved drugs. One important difference is that pharmacy compounded products are not clinically tested for safety and efficacy, nor is bioequivalence testing conducted as is required for generic drugs. The type and extent of quality control testing required for FDA-approved drugs is greater than the testing done on compounded preparations. Compounding pharmacies often rely upon Certificates of Analysis from suppliers rather than retesting incoming bulk ingredients as pharmaceutical manufacturers are required to do by GMPs. Another dissimilarity is that compounding pharmacies are exempt from the federal GMP regulations that are obligatory for all approved pharmaceutical manufacturers. The FDA typically only inspects or takes action against pharmacies after serious health problems occur.
Unlike the product labeling of FDA-approved drugs, the labeling of compounded preparations is neither regulated nor standardized. Thus, compounded medications may be dispensed without any instruction regarding contraindications to use, warnings and precautions, drug interactions, etc. Advertising and promotion of approved drugs is subject to FDA oversight and restriction, including fair balance of safety information. By contrast, compounding pharmacies advertise and promote their products without such oversight and may make unsupported claims of efficacy while failing to mention any potential risks and side effects . In order to ensure that patients and healthcare providers are properly informed, it has been proposed that the labeling on compounded preparations should state that they have not been approved as safe and effective by the FDA .
Another major difference is that compounding pharmacies are not required to report adverse events to the FDA, whereas adverse event reporting is mandatory for manufacturers of FDA-regulated medications. Thus, adverse events associated with compounded drugs may be difficult to detect, particularly if the affected patients are widely scattered in different geographic areas.
Although the focus of this article is on drugs produced and used in the US, Canadian regulatory authorities have similarly addressed the issue of pharmacy compounded medications. The “Policy on Manufacturing and Compounding Drug Products in Canada” acknowledges compounding as a legitimate part of medical practice, but says it should not be used as a means to bypass the federal drug review and approval system. The policy also states that compounded products must provide a customized medication, without duplicating an approved drug product .