November 5, 2018
Drug compounding is the process of combining (two or more drugs), mixing, or altering ingredients to create a medication tailored to the needs of an individual patient.[1] Unlike prescription drugs, compounded medications are not required under the U.S. Food and Drug Administration (FDA) regulation to undergo premarket approval, be labelled with adequate directions for use or be manufactured according to current good manufacturing practice requirements.[2]
Historically, pharmacy compounding has been regulated by state entities (e.g. state boards of pharmacy), with varying frequency of inspections and oversight.[3] In an attempt to promote patient safety, effectiveness quality and manage compounded medications, the FDA Modernization Act added Section 503A, “Pharmacy Compounding” (1997) to the Federal Food, Drug, and Cosmetic Act (FFDCA). Later, Congress held numerous hearings which led to the enactment of the Compounding Quality Act (2013). This law established FFDCA Section 503B and created a new category of drug compounders called “Outsourcing Facilities”.[4] Accordingly, if a facility wishes to compound medication, it can do so as either as a 503A Pharmacy Compounding facility or a 503B Outsourcing facility.
FEDERAL FOOD, DRUG, AND COSMETIC ACT SECTIONS 503A & 503B
Pharmacy Compounding
According to Section 503A, a drug product may be compounded by a licensed pharmacist in a state-licensed pharmacy or federal facility, or by a licensed physician for an identified patient based on the receipt of a valid prescription, or in limited quantities before the receipt of a prescription for an identified patient.[5]
A Pharmacy Compounding facility may compound using bulk drug substances that are manufactured by an establishment that is registered with the Food & Drug Administration (FDA) and are accompanied by a valid certificate of analysis. In addition, such bulk substances must:
- Comply with the standards of an applicable United States Pharmacopoeia (USP) or National Formulary monograph if such monograph exists and the USP chapter on pharmacy compounding, or
- Be drug substances that are components of FDA-approved drugs, or
- Appear on the Secretary’s list of bulk drug substances developed through regulation.
If a compounder falls under this category, they will be exempt from compliance with current good manufacturing practice (cGMP), and FDA approval and labeling requirements. When taking account of the history and purpose associated with these regulations, these exemptions would be considered reasonable given the significant supervision and control that licensed personnel would have in this context following the distribution of the compounded medication.
Outsourcing facility
Section 503B allows a licensed pharmacist or individual under the direct supervision of a licensed pharmacist in a facility that registers as an outsourcing facility to compound medication. These facilities are subject to inspections according to a risk-based schedule, specific adverse event reporting requirements, and other conditions that help to mitigate the risks of the drug products they compound.[6]
An Outsourcing Facility may compound using bulk drug substances that are manufactured by an establishment that is registered with FDA and are accompanied by a valid certificate of analysis. In addition, such bulk substances must:
- Appear on a list, established by the Secretary, identifying bulk drug substances for which there is a clinical need, or
- The drug compounded from such bulk drug substance appears on the drug shortage list under FFDCA Section 506E, and
- Comply with an applicable monograph under United States Pharmacopoeia, National Formulary monograph, another compendium or pharmacopeia recognized by the Secretary (if one exists).[7]
A registered outsourcing facility is exempt from FDA labeling, approval and track and trace requirements. Unlike Pharmacy Compounding, Outsourcing Facilities are not exempt from cGMP compliance.
LIST OF BULK DRUG SUBSTANCES
A bulk drug substance is defined as “any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function in the body”.[8] The FDA is currently developing a List of Bulk Drug Substances for which there is a clinical need[9] based upon following criteria:
- A statement describing the medical condition(s) that the drug product to be compounded with the nominated bulk drug substances is intended to treat;
- A list of FDA-approved drug products, if any, that address the same medical condition;
- If there are any FDA-approved drug products that address the same medical condition, an explanation of why a compounded drug product is necessary;
- If the approved drug product is not suitable for a particular patient population, an estimate of the size of the population that would need a compounded drug product;
- A bibliography of safety and efficacy data for the drug product compounded using the nominated substance, if available, including any relevant peer-reviewed medical literature; and
- If there is an FDA-approved drug product that includes the bulk drug substance nominated, an explanation of why the drug product proposed to be compounded must be compounded from bulk rather than with the FDA-approved drug product.[10]
Recently, the FDA identified its intention to exclude three bulk drug substances from the List of Bulk Drug Substances, including Bumetanide, Nicardipine Hydrochloride and Vasopressin.[11]
Bumetanide
Bumetanide is a drug product that manages edema associated with congestive heart failure, cirrhosis, and renal disease. The nomination proposed: route of administration as intravenous infusion, dosage form as injection, and strength as 0.1 mg/mL. The FDA has provided that the nominated bulk drug substance is a component of an FDA-approved drug product and is available as a 0.25 mg/mL injection that may be administered parentally (e.g. abbreviated new drug application’s 074332 and 079196).
The FDA has indicated that exclusion from nomination for the Bulk List is due to the availability of an FDA-approved drug option, with the only notable difference being a proposed strength of 0.1 mg/mL versus 0.25mg/mL.
Nicardipine hydrochloride
Nicardipine hydrochloride is a drug product that is used to treat high blood pressure, angina and coronary spasms. The nomination proposed its route of administration as intravenous, dosage form as injection, and strength between 0.1-2.5 mg/mL. In its findings, the FDA indicated that the nominated bulk drug substance is a component of an FDA-approved drug product and is available within similar route of administration, dosage and strength (e.g. new drug application’s 022276 and 019734) and thus, an FDA-approved drug already exists with comparable parameters.
Vasopressin
Vasopressin is a drug product that is used to treat septic shock, post-cardiotomy shock, diabetes insipidus and hypotension. The FDA has indicated that the nominated bulk drug substance is the active ingredient of the FDA-approved drug VASOSTRICT (new drug application A204485) which is currently approved as a 20 U/mL intravenous infusion to be diluted with normal saline or 5 percent dextrose in water to 0.1 U/mL or 1 U/mL. One nomination proposed vasopressin so that it can be used to compound a drug product whose concentration of vasopressin is higher than that of undiluted VASOSTRICT.
The FDA is considering excluding this nomination from the Bulk List due the lack of clinical need to include this when the drug substance is the active ingredient of an FDA-approved drug and lack of clinical support for a higher concentration. In order to support the inclusion of this substance under the Bulk List, evidence must be provided justifying the need for for higher concentrations of the drug product when an FDA-approved drug already exists and why this drug product should be utilized instead of the FDA-approved product.
EXCLUDED LIST OF BULK DRUG SUBSTANCES
The overall objective of these regulations is an attempt to strike a balance between the unique needs of each patient and upholding consumer protections. FDA-approved drugs provide patients with significant public health safety due to the stringent process and procedure associated with marketable approval. As a result, preference is given to compounding these drugs over bulk drug substances where an FDA-approved product would meet the patients’ medical needs. Furthermore, permitting this activity can have the potential to undermine the drug approval process by reducing incentive for drug manufacturers to seek approval of brand or generic drugs.[12]
One of the conditions that must be met for a compounded drug product to qualify for the exemptions under section 503B of the FFDCA is that “the drug is not essentially a copy of one or more approved drugs”.
If it is decided that the above drug products will not be included in the Section 503B Bulk List, the facilities will be affected as follows:
- Compounding Pharmacies facilities will be limited to using the FDA-approved drug products referenced within the FDA’s response according to labelled instructions, unless, Bumetanide, Nicardipine Hydrochloride and Vasopressin appear on the Secretary’s drug shortage list under FFDCA Section 506E at the time of compounding, distribution and dispensing, these medications, and
- Outsourcing Facilities will not be able to utilize Bumetanide, Nicardipine Hydrochloride and Vasopressin or the FDA-approved drug products, unless, Bumetanide, Nicardipine Hydrochloride and Vasopressin appear on the Secretary’s drug shortage list under FFDCA Section 506E at the time of compounding, distribution and dispensing these medications.
If the FDA determines that an individual or firm compounds a drug product that does not meet the above conditions, they will be subject to a warning letter, seizure of product, injunction, and/or criminal prosecution for violations of Sections 501(a)(2)(B), 502(f)(1), and 505 of the FFDA.[13]
If you have any questions about the exclusion of the three substances or related compounding questions, please contact a member of the Hancock Daniel’s Life Sciences team.
The information contained in this advisory is for general educational purposes only. It is presented with the understanding that neither the author nor Hancock, Daniel & Johnson, P.C., is offering any legal or other professional services. Since the law in many areas is complex and can change rapidly, this information may not apply to a given factual situation and can become outdated. Individuals desiring legal advice should consult legal counsel for up-to-date and fact-specific advice. Under no circumstances will the author or Hancock, Daniel & Johnson, P.C. be liable for any direct, indirect, or consequential damages resulting from the use of this material.
[1] Compounding and the FDA: Questions and Answers, U.S. Food & Drug Administration, June 22, 2018.
[2] FDA’s Human Drug Compounding Progress Report Three Years After Enactment of the Drug Quality and Security Act, January 2017, p. 4.
[3] National Conference of State Legislatures, “State regulation of Compounding Pharmacies,” October 1, 2014, http://www.nscl.org/research/health/regulating-compounding-pharmacies.aspx.
[4] National Conference of State Legislatures, “State regulation of Compounding Pharmacies,” October 1, 2014, http://www.nscl.org/research/health/regulating-compounding-pharmacies.aspx, p. 3.
[5] National Conference of State Legislatures, “State regulation of Compounding Pharmacies,” October 1, 2014, http://www.nscl.org/research/health/regulating-compounding-pharmacies.aspx, p. 4.
[6] Compounded Drug Products that are essentially copies of approved drug products under section 503B of the Federal Food, Drug, and Cosmetic Act, Guidance for Industry, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, January 2018, p. 2.
[7] To determine if a bulk drug substance is the subject of an applicable United States Pharmacopoeia or National Formulary monograph, see the United States Pharmacopoeia or National Formulary at www.uspnf.com. To determine if a drug substance is a component of an FDA approved drug, see the FDA’s Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, available at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.
[8] 21 Code of Federal Regulations s 207.1(b).
[9] In applying this standard, the FDA interpreted the phrase “bulk drug substances for which there is a clinical need” to mean that the 503B Bulk List may include a bulk drug substance if: (1) there is a clinical need for an outsourcing facility to compound the drug product, and (2) the drug product must be compounded using the bulk drug substance.
[10] Department of Health and Human Services, Food and Drug Administration [Docket No. FDA-2015-N-3469], “Bulk drug substances that can be used to compound drug products in accordance with section 503B of the federal food, drug and cosmetic act; establishment of public docket”.
[11] In applying this standard, the FDA interpreted the phrase “bulk drug substances for which there is a clinical need” to mean that the 503B Bulk List may include a bulk drug substance if: (1) there is a clinical need for an outsourcing facility to compound the drug product, and (2) the drug product must be compounded using the bulk drug substance.
[12] Statement from FDA Commissioner Scott Gottlieb, M.D., on a key step in advancing FDA’s oversight of drug compounding and implementing new laws governing outsourcing facilities, March 23, 2018.
[13] Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, June 2016, p. 7.
