Pros and Cons of Using Bulk Chemicals to Compound
Gina Peacock, PhD
When compounding extemporaneously, pharmacists must carefully choose the source for ingredients in order to assure the quality of the final preparation. United States Pharmacopeia (USP) Chapter <795> provides guidelines for selecting components used in compounding. The chapter states "a United States Pharmacopeia (USP), National Formulary (NF) or Food Chemicals Codex (FCC) substance is the recommended source of ingredients for compounding all preparations." This includes both active ingredients and excipients. USP <795> Pharmaceutical Compounding—Nonsterile Preparations also states that "compounders shall first attempt to use components manufactured in an FDA-registered facility." When these components are not available, compounders should establish quality and purity by using information such as reputation and the Certificate of Analysis (CofA) that is provided by the manufacturer. USP <795> also provides guidance for using manufactured drug products as the source of active ingredients for compounded preparations. In choosing an appropriate source for active ingredients, compounders should consider the pros and cons of using bulk chemicals or unformulated active pharmaceutical ingredients (APIs) as compared to manufactured products.
Advantages of Using Bulk Chemicals to Compound
One of the major advantages of bulk chemicals over manufactured dosage forms is that the actual purity and strength have been determined and are reported on the CofA that is provided for each lot of material. When using manufactured products, the actual strength is not known but only that the product meets USP specifications if the product is a USP article, or U.S. Food and Drug Administration (FDA) specifications if it is not. Most USP monographs for manufactured products establish the content range from 90.0% to 110.0% of the labeled amount. Even though some articles have slightly tighter ranges (e.g., Mercaptopurine Tablets USP NLT 93.0% and NMT 110.0%), they are not as tight as the monograph strength specifications for the APIs which tend to be not less than (NLT) 97.0% or 98.0% to not more than (NMT) 102.0% (e.g., Mercaptopurine USP NLT 97.0% and NMT 102.0%). Therefore, if a compounder unknowingly uses a manufactured product that is 90.0% of labeled strength to compound, then the compounded preparation may not be in the required strength range when prepared, let alone by the time it reaches the beyond-use date (BUD). For many drugs that do not have a narrow therapeutic range, this may not be clinically significant, but it is always preferable to compound with ingredients for which the specific strength and purity are known.
Another advantage of using bulk chemicals in compounding is that there are no excipients to consider in the compounding procedure and stability of the formulation. USP <795> states that "when compounding with manufactured drug products the compounder shall consider all ingredients, including excipients, present in the drug product relative to the intended use of the compounded preparation and the effect of manipulating the drug product on the therapeutic appropriateness and stability of the components." One example of compounding where the excipients can be problematic is preparing suspensions from manufactured tablets. This can present a problem, particularly when compounding suspensions because the excipients may increase viscosity and affect the rate and extent of settling, the dispersibility or homogeneity, and the pourability, as well as the palatability of the suspension.
For many tablet or capsule drug products, there are generic equivalents available from multiple manufacturers, and the excipients in each manufacturer's product are not required to be the same. Pharmacies often purchase tablets and capsules from many different generic manufacturers depending on availability and pricing. The interchangeable use in compounding of these drugs may influence the quality of the resulting compounded preparations due to the variability of excipients. Therefore, when multiple sources of manufactured products are used for compounding, it is important to evaluate the physical and chemical stability of compounded suspensions made from the specific source of manufactured drug products before they are compounded for patient use. In the author's stability study for extemporaneously compounded mercaptopurine suspensions made using tablets from multiple manufacturers, the excipients in one of the generic tablets resulted in a suspension that was so viscous that it was not pourable and thus not acceptable. This variability in excipients points to another advantage of using bulk chemicals in compounding. Bulk active ingredients sourced from multiple suppliers does not present a problem because as long as the manufacturer is FDA-registered and the CofA is provided, the strength and purity of the active ingredient are known and there are no excipients to consider.
Finally, cost can be an advantage of using bulk chemicals to compound versus manufactured dosage forms. Often the API is available at a fraction of the cost of the manufactured products, making some preparations compounded with manufactured products cost prohibitive for patients paying directly for their prescriptions.
Disadvantages of Using Bulk Chemicals to Compound
The major disadvantage of using bulk chemicals to compound is that sometimes APIs are not readily available to compounding pharmacists. This can be due to limited market distribution, widespread ingredient shortage, or production problems. In these instances, the manufactured dosage forms are often still available, at least temporarily; therefore, commercially available dosage forms must be used as the API source.
Another disadvantage of using bulk chemicals to compound is that many insurance companies, as well as state and federal medical assistance programs, do not reimburse for compounding ingredients. They usually pay for only the manufactured product that is the source for the active ingredient. Although this may not be a problem in community compounding pharmacies, it is often a problem in hospitals.
The next consideration is not a problem for human patients but is related to a guidance document from the FDA regarding veterinary compounding with bulk drug substances. Compliance Policy Guides Manual Sec. 608.400 - Compounding of Drugs for Use in Animals states that when compounders engage in the act of "compounding finished drugs from human or animal drugs that are not the subject of an approved application, or from bulk drug substances, other than those specifically addressed for regulatory discretion by the FDA, Center for Veterinary Medicine…" the agency will consider initiating enforcement action. In other words, FDA inexplicably discourages veterinary compounding from bulk APIs.
One final potential disadvantage may arise when APIs are not available from an FDA-registered facility. There is an allowance in USP <795> for compounders to establish quality and purity by using professional judgment and information such as reputation of the manufacturer and the CofA that is provided by the manufacturer. However, in these situations more liability may be incurred by the compounder if the information regarding the unregistered manufacturer is inaccurate or proves unreliable.
For ease of extemporaneous compounding and assurance of the strength and quality of preparations, compounding with bulk chemicals is preferable in most circumstances. One further consideration in the use of bulk chemicals in compounding is that in addition to the CofA to determine purity and strength, the compounder should consider testing for microbiological suitability as advised in USP Chapter <1111> Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use. This USP <1111> testing includes one fungal and three bacterial pathogens. In situations where manufactured tablets or capsules must be used as the source of active ingredients, the compounder should consider having the manufactured product assayed to determine the actual strength before compounding. In addition, regardless of active ingredient source, it is important to adhere to all USP standards for quality assurance of compounded preparations.
Gina Peacock, PhD
Associate Professor, Biopharmaceutical Sciences
Bernard J. Dunn School of Pharmacy