The Practice of Compounding, Associated Compounding Regulations, and the Impact on Dermatologists

July 2018 | Volume 17 | Issue 7 | Supplement Individual Articles | 17 | Copyright © July 2018

James Quertermous MD,a Seemal Desai MD,b Julie Harper MD,c Mark Lebwohl MD,d Abel Torres MD,e Leon H. Kircik MDd,f

aLoma Linda University School of Medicine, Loma Linda, CA bInnovative Dermatology, Plano, TX; The University of Texas Southwestern Medical Center, Department of Dermatology, Dallas, TX cDermatology and Skin Care Center of Birmingham, Birmingham, AL dIcahn School of Medicine at Mount Sinai, NY eLoma Linda University School of Medicine, Loma Linda, CA fIndiana School of Medicine, Indianapolis, IN Physicians Skin Care, PLLC, Louisville, KY DermResearch, PLLC, Louisville, KY Skin Sciences, PLLC, Louisville, KY

response to these injuries and fatalities, Congress passed regulations on compounding through the Drug Quality and Security Act (DQSA). The DQSA amended Section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA), which led to increased oversight of patient-specific drug compounding taking place in traditional compounding pharmacies and other healthcare settings, including physicians’ offices. Additionally, the DQSA created Section 503B, establishing a new compounding entity, known as outsourcing facilities, to provide safe, non-patient-specific compounding for “office-use” and institutional settings.2 These outsourcing facilities must be registered with the FDA, meet Federal manufacturing standards (ie, follow current good manufacturing practice [cGMP]) and undergo routine inspections.Traditional 503A pharmacies compounding products pursuant to a valid, patient-specific prescriptions and satisfying other conditions are exempt from cGMP compliance and are, instead, subject to only state regulation, which generally requires USP compliance. Prior to the formation of the FDA, the USP established national safety standards for medicines, foods, and dietary supplements. The USP is a private, nongovernmental organization whose role in public health has evolved in American history. Beginning in the early 1900s, all medications in the U.S. must, by law, meet certain USP standards.3 Today, the USP publishes a compendium of drug information to ensure the appropriate identity, quality, purity, and potency of products, that all drugs are manufactured to USP standards.4 USP General Chapter <797> on sterile compounding describes requirements for compounders, including responsibilities of compounding personnel, staff training, facilities, environmental monitoring, and testing and storage of finished preparations. These requirements help ensure patient benefit and reduce risks such as contamination, infection or incorrect dosing. Standards for compounded preparations outlined within the USP may be enforced by both the states and the FDA. Because the needs of clinical medicine are constantly evolving, USP guidelines are continually updated. In fact, the USP is currently revising Chapter <797>, and the American Academy of Dermatology is working on educating government bodies on the repercussions of restrictive guidelines on dermatology, especially as it relates to products such as lidocaine and botulinum toxin. State pharmacy boards often adopt USP recommendations when implementing regulations, but are free not to do so, and thus these laws can vary by state. For example, several states, like Colorado and Connecticut, require that sterile compounding pharmacies comply with the USP and state-specific regulations. Still, other states, like Arizona, have neither state-specific language, nor USP compliance requirements.5Obtaining Compounded MedicationsCurrently, compounded medications may be obtained through three main avenues: 1) traditional 503A compounding pharmacies, 2) 503B outsourcing facilities, or 3) physician-guided “in-office” compounding. Traditional compounding pharmacies, also known as 503A compounding pharmacies, abide by the standards set forth in section 503A of the FDCA. These compounded medications are dispensed after receipt of an individual-specific prescription. Compounded drug products obtained by 503A compounding pharmacies can only be distributed in limited quantities (ie, no more than a 30-day supply) before the receipt of a valid prescription when based on a history of prior valid prescription orders with the same entities within the last year. The compounding of the drug product must be performed by a state licensed pharmacy or by a licensed physician and comply with the standards of the USP and National Formulary (NF).6 Ideally, traditional pharmacies satisfy conditions of section 503A to qualify for exemptions specified in that section. For example, a compounder may be exempt from cGMP and labeling of drugs with adequate directions for use if they satisfy certain conditions.7 However, all other applicable provisions of the FDCA remain in effect for compounded drugs, even if the conditions in section 503A are met. For example, a compounded drug cannot be contaminated or made under insanitary conditions.8Outsourcing facilities, also known as 503B compounding pharmacies, can produce sterile and non-sterile compounded medications in large batches with or without patient-specific prescriptions to be sold by healthcare providers presuming the compounded medication is not an essential copy of a commercially available drug (see below). Outsourcing facilities must comply with current good manufacturing practice (cGMP) requirements. This is distinct from 503A compounding pharmacies which may be exempt from cGMP compliance if they satisfy certain conditions. In addition, outsourcing facilities undergo regular FDA inspection per a risk-based schedule and have adverse event reporting requirements. Thus, outsourcing facilities may provide a higher quality drug product than other facilities and the FDA encourages individuals to obtain compounded drugs through this method.9“In-office” compounding occurs when physicians and their staff prepare medications in the outpatient clinic setting. Several medical specialties, including dermatology, allergy, and oncology, rely on in-office compounding regularly to treat their patients. Advocates in dermatology have suggested use of the term in-office “preparations,” rather than “compounding”, since this is routine clinical practice as opposed to a pharmaceutical function. For example, dermatologists often buffer lidocaine with sodium bicarbonate to reduce pain on injection, they dilute triamcinolone with saline to achieve an optimal concentration, and reconstitute botulinum toxin for medical and cosmetic purposes. These are just a few common routine clinical compounding uses for dermatologists.Medications Eligible for CompoundingWhen compounding under section 503A or 503B of the FDCA, licensed pharmacists and physicians may use only certain bulk active ingredients. The FDA, with input from the public and medical evidence for their safety, has developed criteria to categorize potential bulk active ingredients to be used in compounding into three safety categories. Category 1 includes substances that are eligible for