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18 Pharmaceutical Technology ® | BioPharm International ® Trends in Manufacturing May 2025 PharmTech.com COMPOUNDING determined using molarity calculations. Prodrugs are related but are different chemical compounds; prodrugs per se are not pharmaceutical alternatives; prodrugs are compounds that convert to an active moiety drug in the body. Several other similar terms may be conf used or misused when discussing pharmaceutical alterna- tives. Pharmaceutical equivalents are generic drugs— same drug, same dose, same route of administration, but different appearance. Therapeutic equivalents are the same as pharmaceutical equivalents (generic drugs) that have been tested for bioequivalence. Ther- apeutic alternatives, therapeutic interchange, and therapeutic substitution are related terms associated with drug substitution with same clinical effects as authorized through a hospital formulary (18). Regulations There are numerous regulatory documents address- ing product naming, dosage, and labeling for com- mercial products that are relevant to compounding (19,20). Respective 503A and 503B bulk drug lists identify approved drugs. Specific compounded dos- age form labeling requirements are exempt from FD&C regulations identified in Section 503 (21). 503B compounded preparations must state "This is a com- pounded preparation" or similar wording (22). Selec- tion, naming, and labeling of compounded dosage forms containing non-salt (covalent) active moieties/ drugs is straightforward (23–25); non-salt active moi- eties are generally identical to their drug. Selection, naming, and labeling of compounded dosage forms containing active moieties that are salt molecules is more complex. Salt (ionic) drugs. The 2013 USP Salt Policy (26) is the basis for FDA guidance (27,28) on calculating and naming salt drugs. The FDA guidance states: 1. "When a drug in a drug product is a salt, the drug product monograph title will contain the name of the active moiety (or neutral form) and not the name of the salt (e.g., 'newdrug tablets'—not 'newdrug hydrochloride tablets'). 2. The strength also will be expressed in terms of the active moiety (e.g., '100 mg newdrug') rather than the salt strength equivalent (e.g., '123.7 mg newdrug hydrochloride'). 3. If the name and strength of a drug product are expressed in terms of the active moiety, the full name and full strength (or proportion, if CDER [Center for Drug Evaluation and Research] has determined proportion is more appropriate) of the drug (e.g., salt) will appear elsewhere on the drug product label and labeling. 4. The USP Salt Policy provides for exceptions to the 'active moiety' naming approach when the name of the salt conveys vital information from a clinical perspective. In these cases, the drug product monograph title will include the name of the salt, and the strength of the drug product also is expressed in terms of the salt form (drug). 5. USP does not a nt ic ipate ch a ng i ng e x i s t i ng monograph titles unless necessar y for safet y. USP and FDA have agreed to coordinate regard- ing any necessary retrospective name changes." Policy-exception salts. FDA expects t hat new chemical entities that are salts will be named using the active moiety in accordance with the USP Salt Policy described above. However, the FDA guidance also identifies exceptions (#4 above) to this approach. Therapeutic and historic reasons are cited as justi- fication for exceptions. Many historic drugs were dosed according to their dr ug weights including counterions (e.g., atropine sulfate, codeine phosphate, morphine sulfate). The following are salt drug poli- cy-exceptions per FDA guidance (28): • Drug is a simple salt and administration is ther- apeutically important (e.g., lithium carbonate, iron sulfate and other intravenous iron, calcium gluconate and other calcium salts, potassium chloride, magnesium sulfate, and other common intravenous additives). • Scientific evidence demonstrates the salt form affects the absorption, distribution, metabolism, and excretion that inf luences product selection. • Clinically significant amounts of cations (so- dium, potassium, magnesium, calcium) accom- pany the active moiety of a drug product related to the daily electrolyte intake in special popu- lations (e.g., sodium in cardiac treatment and potassium in renal treatment). • There is significant evidence-based safety con- cern that the counter-ion part of the salt could cause acid-base disturbances; hepatic, renal, or other organ damage; or hypersensitivity reac- tions. • The name of the salt is necessar y to maintain consistency with other dosage forms of the same drug (salt). For example, drug products approved before 2013 with the salt in its established name and dosage based on the salt form would not change naming for a new dosage form with the same salt drug. • The USP Salt Policy should not be applied if there are relevant, documented safet y reasons in a closely related product. Labeling Compounded dosage forms are exempt from com- mercial product labeling requirements. 503A com- pounded dosage form labeling is also governed by state pharmacy regulations. Accurate compounded product labeling requires attention to detail (i.e., la-