R E G U L A T O R Y

Application of

USP-NF Standards
to Pharmacy Compounding
Gail Bormel, RPh, JD Joseph G. Valentino, JD Roger L. Williams, MD United States Pharmacopeial Convention, Inc. Rockville, Maryland

Background
The United States Pharmacopeial Convention, Inc. (USP) is the publisher of the United States Pharmacopeia-National Formulary (USP-NF). The rst USP was published in 1820 and began as a recipe book to promote uniformity in drugs (a drug includes its active ingredient[s] and excipients) that were generally available in the United States at that time. Prior to the publication of the USP, the quality of drugs varied between cities and regions and from apothecary to apothecary. In 1820, and for many years after, the preparation of a medicine by a pharmacist or other professional, now termed compounding, was the order of the day. However, this practice has generally been supplanted by modern pharmaceutical manufacturing; and at this time, only a small fraction of medicines is compounded. In recognition of this transition, through the activities of its Council of Experts (formerly the Committee of Revision), the USP changed the content of the USP, reduced the recipes for the compounding professional and increased monographs with analytical tests for pharmaceutical and other manufacturers to provide standards that help ensure strength, quality and purity. These standards can be enforced by the federal, state and other regulatory bodies in the United States and are also used in many other countries. In 1975, the USP acquired the NF, which is published together with the USP as a combined text. The NF now primarily contains standards for excipients.

Currently, the USP-NF is published annually and updated with two supplements between publications. It provides monographs for ingredients and products, which contain standards, ie, denitions, descriptions, labeling and storage statements, and specications, for drugs, biologics, devices and dietary supplements. (A specication provides specic tests, together with procedures for the tests and acceptance [pass/fail] criteria.) The USP-NF continues to contain recipes for compounded preparations, but these are only a small fraction (approximately 100) of the many monographs (approximately 4000) provided. As before, the purpose of the USP-NF is to provide a single standard for medicines used in the United States to ensure product uniformity and quality. This is especially important given the number of manufacturers and compounding professionals who prepare drugs that have the same names.

Standards Applied to Both Manufactured and Compounded Drugs

The Federal Food, Drug and Cosmetic Act (FDCA) recognizes the USP-NF as the official compendia of the United States. 1 The FDCA also states that drugs in the United States that are recognized in the USP-NF must adhere to compendial standards for quality, purity and strength. If the drug does not meet these standards, it is considered to be adulterated, unless the drug product is labeled as not USP and provides the differences from the compendia in strength, quality, or purity standards. 2 The FDCA does not differentiate between manufactured and compounded drugs. Therefore, this section of the law applies to all drugsmanufactured and compoundedthat are available in the United States. With respect to manufactured drugs, pharmacists who purchase drugs from reputable manufacturers and store them appropriately are most likely to dispense drugs that adhere to compendial standards. Compounded drugs prepared pursuant to a practitioners prescription must also

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meet compendial requirements, if the prescription uses the compendial name. Pharmacists must be aware that if they prepare medications that are named in the USP-NF, these products must meet USP-NF standards for strength, quality and purity, and this includes adherence to ingredient standards and/or recipes provided in the compendia for their preparation. Alternatively, if a drug does not meet USP-NF standards, the drug label should include not USP and state the way in which the product differs from the standards in the USP-NF. When a physician writes a prescription for a manufactured or compounded drug that appears in the USP-NF, the law expects the pharmacist to dispense the drug called for in the prescription or else the dispensed drug may be considered misbranded. A physician does not have to designate the item as USP.

Standards Applied to Compounded Drugs

The appearance of compounding monographs in the USPNF is one of several important elements to ensure the quality and benet of a compounded medicine. It provides uniformity in the prescribing and preparation of these medicines, as required by law. A prescriber who writes a prescription for a

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particular compound that appears in the USP-NF has dened the medicine to be prepared. Pharmacists who adhere to the compendia prepare a medicine with dened quality standards. Most importantly, adherence to compendial requirements is required by the FDCA, the law responsible for the denition of the standards for drug products in the United States. The health benet (safety and efficacy) of a compounded preparation is the responsibility of the practitioner who writes the prescription, subject to practice standards and applicable federal and state laws. When the USP-NF does not contain a monograph for a compounded preparation or ingredient, compounding professionals should use their professional judgment and conform to the standards of practice, as well as applicable laws, in compounding a medicine. The USP-NF is a positive force for practitioners who prescribe, prepare and dispense compounded drugs. In recognition of this fact, the USP develops monographs for compounded medicines by input from compounding experts who participate in the standards-setting activities of the Council of Experts. How these standards are monitored and enforced is beyond the scope of this brief article but relies on a combination of rst-party (the compounding professional), second-party (a retailer), or third-party (governmental agency, other independent body) assessments for conformity to standards in the USP-NF. A professional who compounds a drug that has a recipe that is recognized in the USP-NF must adhere to that recipe. If the compounding professional does not do so, he or she should check with the prescriber to authorize an alternative formula. Then, dependent upon the nature of the difference, the product should be labeled appropriately, either with a different name or by an indication that it is not USP. If an ingredient appears in the USP-NF, a pharmacist should compound the medicine using ingredients that meet the compendial standards. A drug product monograph that appears in the USP-NF with analytical standards but that has no formula for preparation may be compounded by a pharmacist, who must use his or her professional judgment; but the compounded product must technically meet the standards required in the monograph when tested with the analytical procedure in the monograph. This is likely to be an issue if the pharmacist prepares an inferior product that is subsequently shown to fall outside compendial standards.

Recipes for Compounded Products

The USPs Pharmacy Compounding Expert Committee has issued several recipes for the preparation of compounded products. These recipes appear in the USP-NF and include:

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Cefazolin Ophthalmic Solution; Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical Solution; Hydralazine Oral Solution;

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R E G U L A T O R Y

Indomethacin 1% Topical Gel; Ketoconazole Oral Suspension, Plain; Ketoconazole Oral Suspension, Sugar-Free; Morphine Sulfate High-Potency Suppositories, Polyethylene Glycol (PEG) and Fatty-Acid Base; Progesterone Suppositories, PEG and Fatty-Acid Base; Rifampin 1% Oral Suspension; Sodium Hypochlorite Topical Solution; Suspension Structured Vehicle, Plain; Suspension Structured Vehicle, Sugar-Free; Tetracycline Oral Suspension, Plain; Tetracycline Oral Suspension, Sugar-Free; and Xanthan Gum Solution.

Conclusion
Overall, compounded preparations are generally agreed to be a useful element in the therapeutic armamentarium of the practitioner. This is particularly true in an era of discontinuations and shortages of manufactured drugs, and it has also become increasingly important as a means of tailoring the dose of a drug to an individual patient. Together, federal and state officials, the USP, practitioners, consumers, and many others can create an environment whereby patients can receive wellcompounded preparations that contribute to their health and well-being.

References
1. Code of Federal Regulations, Title 21 U.S.C. 321 (j). 2. Code of Federal Regulations, Title 21 U.S.C. 351 (b).

Many more (approximately 1000) of these recipes would be needed to cover the types of preparations now compounded in the United States. The development of these recipes for the USP is difficult and requires laboratory testing to conrm that the preparation works, ie, that the drug produced in the compounding process has the requisite quality attributes stated in the monograph and that these attributes are maintained during the period of use by the patient.

Address correspondence to: Gail Bormel, RPh, JD, United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852. E-mail: fgb@usp.org

International Journal of Pharmaceutical Compounding 363 Vol. 7 No. 5 September/October 2003