Pharmacy compounding regulatory issues

Adapted from an original submission by Carol Lam, Pharm.D., M.S., Project Manager, Kaiser Permanente, Oakland, CA.

altering ingredients to prepare a customized medication for an individual patient upon receipt of a valid prescription. Driven by medical needs, this professional practice is founded upon a trusted physicianth pharmacist-patient relationship. The golden age of compounding dated back to early 19 century when compounding involved not only the preparation of medications, but also the extraction of ingredients from crude, natural materials. It is believed that approximately 80% of the prescriptions were compounded until 1950s when drug manufacturing, the mass production of drug products, began to dominate the supply of the mainstream market. The often time-consuming and costly nature of the drug approval process, however, makes it impractical for pharmaceutical companies to apply for NDAs and ANDAs for products with minor variations in dosages, strengths or indications. The fact that majority of pharmaceuticals are manufactured and supplied on a one-size-fits-all basis has redefined the value of pharmacy compounding in an era of patient-driven health care. In some special populations, commercially available products need to be re-formulated or made from different basic ingredients to accommodate specific medical needs, to enhance medication adherence and to achieve desired therapeutic outcomes. In fact, compounded products have gradually regained popularity in recent years driven by the need for individualized therapies. Therefore, many view compounding as a niche in the pharmacy profession. Few official surveys were conducted to track the amounts of compounded prescriptions annually; however, it has been estimated that approximately 30 million prescriptions are written for compounded products per year, accounting for 1-5% of total prescriptions within the United States. For instance, in a study conducted in the states of Illinois, Missouri, Kansas and Iowa, the prevalence of compounding in independent community pharmacy practice was found to be 2.3% of all prescriptions (McPherson et al. 2006). All compounded products can be viewed more or less as unapproved drugs since the content and/or the formulation deviates from their FDA-approved counterparts. This has raised concerns about safety and efficacy when altering a formulation or combining multiple ingredients. Thus, despite the benefits, compounded products may also carry inherent risks. Without extensive research, prescribing practice for compounded products relies primarily on professional judgment or available observational studies and case reports. However, potential risks cannot be overlooked. For instance, many compounded products are used for special populations such as neonates, pediatric and geriatric patients whose pharmacokinetic and pharmacodynamic profiles are different from normal adults. Thus, clinical factors must be carefully evaluated prior to prescribing and dispensing. Systemic agents such as parenteral and inhalation products pose higher risks of microbial contamination if the compounding processes are not conducted in sterile conditions. The consequences may involve severe health problems or even deaths. Despite the long history of pharmacy compounding, many compounded preparations are criticized for not having undergone the scrutiny of clinical trials, as have mass-manufactured drugs. Safety and efficacy become more relevant especially in manufacture-scale compounding where a larger number of compounded products are dispensed to the public. Adding to the limited scientific proof is the lack of well-defined regulations on compounding and the unclear jurisdictions, which the federal and state authorities have over compounding pharmacies.

Traditional pharmacy compounding in the United States involves the act of combining, mixing or

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Prior to November 21, 1997, there were no specific federal or state laws governing the practices of pharmacy compounding; thus, the distinction between manufacturing and compounding was ill defined. The Federal Food and Drug Association Modernization Act (FDAMA) of 1997, Section 127, details the federal law governing pharmacy-compounding practices. The amendment, which adds section 503A to the FD&C Act, serves to clarify the status of pharmacy compounding. The amendment distinguishes compounding from manufacturing practices and inserts three major exemptions under which compounded products will not be viewed as new and unapproved drugs. The major provisions of the Act state that compounded products need not follow the requirements for drug adulteration, misbranding and new drug approval as manufactured products do. In other words, compounding pharmacies are not required to have cGMP in place, labeling with adequate directions for use or drug approval applications. To qualify for the exemptions, the compounded products must fulfill the requirements stated in Section 127. Public health concerns are minor when mass production is not involved. The compounder can typically control quality if drug products are prepared in small quantities. The FDA defers to state authorities in regulating compounding pharmacies; however, in cases when significant violations or manufacturing practices are identified, the FDA cooperates with state authorities for inspections and follow-up actions. These exemptions are not meant to undermine the safety and efficacy of compounded products; rather, they are based on the assumption that compounded products are typically used for a small group of patients with tailored medical needs. Safety and effectiveness become more significant where mass production is involved because of its potential impact on public health. The regulations on compounding and manufacturing are significantly different in terms of product exemptions and manufacturing practices. Compounders who attempt to blur the line between compounding and manufacturing and engage in large-scale, non-cGMP compounding are vulnerable to citations and enforcement actions. The definition of pharmacy compounding may be confused with reconstitution at times because compounding can involve grinding a tablet into powder to prepare a suspension. Reconstitution, the addition of compatible solvents such as saline, dextrose or sterile water to a product, does not always fall within the scope of compounding. For instance, in community pharmacy settings, amoxicillin, an antibiotic commonly prescribed for Otitis Media in the pediatric population, is available in powder form. The pharmacist is required to reconstitute the powder at the time of dispensing. This act is not to be confused with compounding because it is done according to the manufacturers instructions. Another day-to-day pharmacy practice is the preparation of parenteral/intravenous products in hospitals. Most antibiotics are available in powder form, which require reconstitution to achieve a final concentration for specific medical needs. Again, mixing a commercially available product with a compatible solvent per manufacturers instructions is not classified as pharmacy compounding. In some cases, drug manufacturers attempt to bypass the new drug approval process by classifying the new product as a compounded product that requires reconstitution. In manufacturing, no new drugs are exempt from the marketing approval requirement even if medical needs are present or if a minor change is concerned. Manufacturers must apply for ANDAs when new dosage forms or strengths are added to their current product list on the market. Failure to recognize the differences between compounding and manufacturing might result in regulatory actions such as immediate removal of all products from the market. Compounding can involve altering the formulation of a commercially available product as well as combining or mixing active ingredients, also known as active pharmaceutical ingredient (API). Under the FD&C Act, an API is essentially viewed as a finished pharmaceutical. In other words, all new APIs must apply for NDAs or ANDAs, and the manufacturing of APIs must be compliant with all cGMP regulations. The manufacturers must be registered with the agency and be able to supply certificates of analysis for their products to ensure quality, purity and potency. This explains why the federal law on compounding prohibits the use of ingredients from non-FDA registered facilities. Besides FDA-approved APIs, compounders may also use active ingredients that are covered by the United States Pharmacopeia (USP) or NF monograph, and FDAs

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list of bulk drug for pharmacy compounding. Active ingredients that have received marketing approvals but are currently regarded as unsafe or ineffective may not be used for compounding. The FDA mandates the use of certified API to prevent compounders from utilizing ingredients that may potentially be impure, sub-potent or illegally imported. As mentioned above, the FDA oversees the manufacturing of pharmaceutical products, whereas the oversight of compounding pharmacies is a state function. On the state level, the responsibilities are generally delegated to the State Boards of Pharmacy. The state boards typically consist of pharmacists and/or health care professionals appointed by the Governor. USP, the official public standard-setting authority for prescription and over-the-counter products, often serves as a reference for the state boards. In addition, the Pharmacy Compounding Accreditation Board (PCAB), established in January 2006 in response to the criticisms on the absence of regulations, also aims at standardizing practices of compounding. State regulations may vary from state to state, but nationwide professional organizations including the Academy of Compounding Pharmacists (IACP), the American Pharmacists Association (APhA), the National Community Pharmacists Association (NCPA) and USP work in concert with the state authorities to ensure safe and legal practices of pharmacy compounding. Typically, the State Board of Pharmacy is involved in regulating sterile compounding in the retail setting. Topical products or other formulations that are not systemically absorbed do not commonly require aseptic techniques, whereas parenteral or intrathecal products require sterile conditions during the preparation process. Products that require sterile compounding are under more stringent regulations at the state level because of higher risk for life-threatening systemic infections. The California Board of Pharmacy, for example, mandates separate licensing for all retail pharmacies that compound sterile products. The license is renewed annually after inspection by the state board. All pharmacy records must be retained for a minimum of three years for inspection purposes. In contrast, a retail pharmacy that intends to engage in simple compounding of formulations such as topicals, tablets and capsules, may need only a retail pharmacy permit. Hospital pharmacies, home care agencies and skilled nursing facilities that compound sterile products are not regulated by the California State Board. The state board requires no separate licensing if these facilities are accredited. Accreditation can be obtained through the Joint Commission on Accreditation of Healthcare Organization (JACHO) or other agencies recognized by the Department of Health Services (Weissman, FG. 2007). Of interest, compounded inhalation products fall into a gray area of compounding. Although these products do not require separate licensing, the state board and professional organizations such as the California Pharmacist Association (CPhA) recommends following the sterile compounding requirements in practice due to the concerns about adverse events associated with non-sterile compounding of these products. The impact of non-sterile inhalation products will be discussed in last section of this article. Following incidents of microbial contamination in compounded injectables, USP established the first st enforceable set of standards for compounding sterile products in January 1 , 2004. The USP Chapter 797, Pharmaceutical Compounding: Sterile Preparations, details the procedures and requirements for sterile compounding and sets standards for all practice settings. Because compounding pharmacies are not required to follow cGMP as does manufacturing, there was an absence of consensus about which standards or guidelines to follow in sterile compounding prior to the establishment of the new standards. The USP standards may be adopted and enforced by state boards of pharmacy, and surveyed by accreditation organizations. A recent survey on the impact of USP Chapter 797 shows that the standards have contributed to a decrease in compounding high-risk preparations, an increase in budgetary allocations and improvements in quality assurance practices in hospital pharmacies nationwide (Kastango, ES. 2004 and Candy et al. 2006). Although the FDA has deferred enforcement discretion to the states, large-scale compounding and unregulated promotion and advertising of compounded products on the Internet have prompted in-depth investigations by the agency. As a gatekeeper, the FDA is particularly concerned about pharmacies that might be manufacturing under the guise of compounding, and pharmacies that make untruthful, misleading claims

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on compounded products. The agency stepped forward and inspected several compounding pharmacies that were registered with the states. In response to the inspections, 10 pharmacies filed a case against the FDA, questioning its jurisdiction to regulate compounding pharmacies and inspect pharmacy records. On August 30, 2006, The U.S. District Court for the Western District Court of Texas, the Midland-Odessa Division ruled in favor of the 10 pharmacies. The key rulings stated that: compounded drugs do not fall under the new drug definitions; retail pharmacies that are compliant with applicable state laws are exempt from the requirement to submit to an FDA inspection of their records, and that veterinary products can be legally compounded from bulk pharmaceutical ingredients. The judge concluded that the FDA can only conduct limited inspections of items such as equipment, materials and labels unless the pharmacies violate state laws and dispense compounded products without valid prescriptions. Note that compounded veterinarian products had been deemed illegal by the FDA for many years; this was the first court decision to allow compounding for animal use. Although the rulings apply to pharmacies in the state of Texas only, the courts decision has been speculated to have impact across state borders. However, the U.S. District Courts ruling did not discourage the agency from passing on its jurisdiction to regulate compounding. The FDA continues to exercise its enforcement options against major violations of the Act. Shortly after the ruling, the agency issued warning letters to five different pharmacies that compound topical anesthetic creams that were marketed for general distribution rather than for customized patient needs. The FDA expressed concerns about these products because two deaths were associated with compounded topical creams for pain relief in laser hair removal, tattoos, and skin treatments. Anesthetics such as lidocaine, tetracaine, benzocaine, and prilocaine, given at higher strengths, can greatly enhance systemic absorption. Users of these products are subject to high risk for seizures, irregular heartbeats and even death (FDA News, December 5, 2006). Two affiliated organizations, the Allergy & Asthma Network Mothers of Asthmatics (AANMA) and the Consumer Health Alliance for Safe Medication (CHASM), both advocates for patients with respiratory conditions, applauded FDAs enforcement actions. They urged the FDA to regulate pharmacies that compound inhalation products because some pharmacies compound in large amounts and substitute the commercially available products without the knowledge of the physicians and patients. The non-profit organizations are particularly concerned about the sterility of these products, and whether or not they contain airway irritants or toxins. They requested more transparency and disclosure about these products. In response to a letter sent in July 2006 by Senator Charles Grassley (R-IA) regarding the mass compounding of inhalation products and the Medicare fraud associated with them, the Chairman of Centers for Medicare and Medicaid Services (CMS) sent a letter to the Senator in Iowa, promising to create new payment codes for compounded drugs, especially for compounded inhalation products under Medicare Part B, that would lower the rate on reimbursement than the current codes. Of note, compounded inhalation products are not required to be prepared in sterile conditions unlike parenteral and intrathecal products. However, in manufacturing, aqueous-based oral inhalation products must be made under sterile conditions to prevent microbial contamination as of May 27, 2002. This is a direct result of adverse events and a nationwide recall due to contaminated inhalation products. Unlike topical agents and other formulations, oral inhalation products pose higher risk of lung infections and other severe health consequences if contamination occurs. Microbial contamination may also lead to product degradation and result in decrease in efficacy. All prescription and over-the-counter oral inhalation products are subject to sterile manufacturing under the new ruling. Even with the double standard, the FDA did not specify whether inhalation preparations require sterile compounding. However, the agency would consider whether the products present difficulties for compounding that would compromise safety and efficacy of the preparations. Despite continual efforts to improve and enforce compounding practices, the FDA received reports of 155 product quality problems associated with compounded products in 1990-2002. In 2001, FDAs Division of Prescription Drug Compliance and Surveillance collected 37 products via the Internet from 12 communitycompounding pharmacies. These samples included 5 different dosage forms sterile injectables, ophthalmic

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products, pellet implants, inhalation products and oral preparations. The compounded samples were subsequently analyzed for quality, purity, and potency according to the USP standards. The results showed that 34% of the samples failed one or more standard quality tests with varied potency ranging from 59% to 89%. Although the survey was criticized for lacking scientific validity due to the small sample size and irreproducibility, the results raised concerns about the quality of compounded products nationwide. Recognizing the need for federal regulations, Senators from Massachusetts, Kansas and North Carolina drafted a proposed legislation entitled, the Safe Drug Compound Act of 2007. Although the bill failed passage into law, the impact of such a bill on pharmacy compounding is speculated to be significant. The proposed legislation would allow the FDA to regulate compounding pharmacies, enabling the agency to inspect all retail compounding pharmacies and their records. The bill would also restrict interstate distribution of compounded products, by requiring pharmacists to provide detailed documentation on all intrastate orders and advising state boards to discourage distribution of inordinate amounts of interstate compounded products. Furthermore, the Act would require physicians to document when compounded medications are needed. FDA would be called to establish federal requirements for sterile compounding. Reactions to the proposed bill were mixed. Many believe that the bill would correct any deficiencies in the FDAMA of 1997 on compounding, heighten awareness of patient safety and prevent illegal mass compounding. Opponents to the proposed legislation argue that it is not practical to regulate compounded products as new drugs. The costs and time for applying new drug approvals, and the additional efforts to comply with the documentation requirements, would complicate the prescribing and dispensing processes, and ultimately delay and restrict access to patients who present with medical needs. Several professional pharmacy organizations such as APhA, NCPA, and IACP filed a joint letter to the Senators, expressing their concerns about restricting patients access to compounded products. They also noted that the anti-patient compounding bill would interfere with the physician-pharmacist-patient relationship and defeat the purpose of pharmacy compounding by granting the FDA authority to determine when the medications are needed. In conclusion, Pharmacy compounding, if conducted lawfully, can be generally safe and serves a necessary purpose for patients with special medical needs. In light of the adverse events, substandard quality of products, large-scale pharmacy compounding and Medicare fraud, there is a need to tighten the existing federal and state regulations. The Safety Drug Compounding Act of 2007 provided the preliminary volley of assaults on what is seen in some quarters as potentially unsafe compounding practices. However, if the jurisdiction to inspect pharmacies is handed over to the FDA, the agency should ensure that they have the resources to handle all compounding pharmacies nationwide. The agency should continue to acknowledge inputs and suggestions from state authorities and professional pharmacy organizations, and play a supporting role in states with limited resources. The safety of patients and the practice of evidence-based medicine should be kept in mind in making all regulatory decisions. Edited by Daya Perkins, M.S.R.S., Ph.D. (diyer@usc.edu, Roger Clemens, Dr.Ph. (clemens@usc.edu) & Frances Richmond, Ph.D. (fjr@usc.edu). References available upon request.

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