Throughout history, the art of compounding has been part of the practice of pharmacy. The American Pharmacists Association estimates that there are approximately 7,500 compounding pharmacies in the United States.[1] Despite FDA’s issuance of more than 24 Guidance documents regarding compounding, the rules for pharmacy clinicians as to what can and cannot be compounded are confusing, ever changing and, at times, conflicting. Coupled with interstate variability in the patchwork of 50 state Board of Pharmacy requirements and oversight of compounding, these rules become even more challenging. A thorough awareness of what can and cannot be compounded is critical not only from a patient safety perspective but also in the context of state Board of Pharmacy and Food & Drug Administration (FDA) enforcement/discipline. This article will explore key areas of compounding 503A compounding pharmacies and pharmacists should familiarize themselves with.
Compounding Using Bulk Drug Substances
Pursuant to section 503A of the Federal Food, Drug & Cosmetic Act, drug products may be compounded using bulk drug substances (i.e. APIs) that:[2]
- comply with the standards of an applicable USP or NF monograph[3], if a monograph exists, and the USP chapter on pharmacy compounding;
- if such a monograph does not exist, are drug substances that are components of an FDA-approved drug; or
- if neither 1) or 2), the substance appears on a list developed by the FDA through regulations, i.e. the 503A Bulks List.[4]
Compounding ‘Essentially a Copy’ of a Drug
Importantly, 503A compounders may not compound ‘essentially a copy’ of a commercially available drug. If a drug appears on FDA’s 506e Shortage List, however, ‘essentially a copy’ of the commercially available product may be compounded. This is because FDA does not consider drugs on the shortage list to be ‘commercially available.’ Additionally, there are a number of other lists that identify what can and cannot be compounded. For example, any drug on the FDA ‘Demonstrable Difficulties for Compounding (DDC) List’ cannot be compounded. FDA is in the process of developing criteria for adding drugs to the DDC List.[5] Lastly, any drug on the ‘Withdrawn or Removed List’ for safety or efficacy reasons cannot be compounded.
Classes of Drugs to Not Compound
There are also entire classes of drugs which cannot be compounded. Two such classes are investigational drugs (unless they have a USP or NF monograph) and biologicals. In most states, 503A pharmacy compounders cannot compound for “office use” for healthcare providers who need compounded drugs for immediate administration.[6] All 503A compounding must be pursuant to a patient-specific prescription. Biologics cannot be compounded under section 503A and federal law does not provide any pathway for such compounding outside the scope of an approved Biologics License Application (BLA).[7] Furthermore, FDA distinguishes peptides as different from proteins (i.e. biologics). Per FDA’s 2020 definition, peptides have ≤40 amino acids whereas proteins have > 40. As a consequence of this regulation, most injectable peptides are biologics and cannot be compounded. The remaining peptides must “have a USP or NF monograph, be a component of an FDA-approved drug, or appear on the 503A Bulks List.” Few peptides meet this criteria. In addition to all these lists and rules, the active pharmaceutical ingredients themselves must be manufactured by an FDA-registered facility, have an accompanying original Certificate of Analysis (COA) and be pharmaceutical grade (not ‘research use only’).
Training and Education in Compounding
All pharmacists receive training and education in compounding and most routinely prepare non-sterile compounded preparations. Compliance with USP 797, 795 and 800 are considered the minimal standard of practice in pharmacy compounding. The practice of compounding has become more complex and regulated over time and pharmacists need to become knowledgeable with all state and federal laws and regulations governing 503A compounding.
How Frier Levitt Can Help
Challenges may arise in navigating FDA regulations for compounding when a drug is being considered for nomination on the Bulks Lists or when a drug is removed from the FDA shortage list. However, Frier Levitt has experience in representing both 503A compounding pharmacies and pharmacists in these matters. We regularly counsel clients on Section 503A and state-specific compounding requirements, assess compounding practices for state and federal regulatory compliance, including USP 797/795/800, medical necessity documentation, advertising, promotion, reimbursement issues, infrastructure, and preparing compounding policies and procedures that provide clear guidelines, standards and training for staff. Contact us to discuss your specific needs.
[1] https://www.pharmacist.com/Practice/Patient-Care-Services/Compounding/Compounding-FAQs.
[2] FDCA §503A(b)(1)(A)(i).
[3] The term “an applicable USP or NF monograph” does encompass dietary supplement monographs.
[4] Set forth in 21 CFR δ 216.23(b).
[5] FDA Proposed Rule. March 20, 2024.
[6] There may be some state-specific exceptions for Veterinary compounding.
[7] However, they may be mixed, diluted or repackaged in a manner not described in their approved labeling.
