Compounding with Commercial Drug Products Can Cause Errors!

Is it wise to use commercial products in compounding? When doing so, can the pharmacist be assured of a quality preparation? Is it possible to meet the standards of United States Pharmacopeia (USP) Chapter <795>, Chapter <797>, and Chapter <1163> when using commercial products as the source of drugs? The answer to these questions is "sometimes, but not always." Commercial drug products are commonly used for compounding human drug preparations. However, pharmacists are placed in an interesting position because the federal government dictates that commercial products be used for veterinary compounding. However, doing so sometimes results in preparations that are outside USP standards and specifications.

Historically, pharmacists have used commercially available medications to prepare different dosage forms. The most common examples are the use of oral tablets and capsules to prepare oral liquids (solutions and suspensions) for pediatric patients and the use of injectable drugs to prepare intravenous admixtures. Even though U.S. Food and Drug Administration (FDA)-approved commercial products may be used, the final compounded preparation does not have FDA approval.

Considerations

Considerations concerning commercial product use include the following:

1. Using commercial products as a source of active drugs usually will result in a higher prescription cost to the patient than would using bulk drug substances. This is especially true when injectables are used as the drug source.
2. All the excipients present in the commercial dosage form must be considered for their effects on the efficacy, safety, stability, and assay potency of the final compounded preparation.
3. When using solutions as the source of drugs, the pharmacist must be aware of the pH of the solution and the pH of the compounded preparation. If there is a significant difference in pH (i.e., 2 to 3 pH units), the solubility and stability of the drug and formulation may change. If the pH of the final solution is insufficient to keep the drug in solution, the preparation may be a suspension rather than a solution.
4. The presence of buffers in the commercial drug product can affect the pH of the final compounded preparation.
5. Before using a commercial product to compound large batches, it may be advisable to assay the product for potency. An assay is especially important if the USP allowable range for the commercial product exceeds the 90% to 110% potency range acceptable for compounded preparations. For most commercial drugs, the potency range is 95% to 105% or 90% to 110% of the labeled quantity; for some, the range is 80% to 120% and may even be different and/or more broad. Even if the compounding pharmacist performed every step correctly, the final preparation could fail to meet specifications because wide variability was allowed in the commercial product.
6. Some dosage forms should not be used in compounding. Modified-release dosage forms (e.g., extended-release, delayed-release, repeat-action, targeted-release) should not be used unless their suitability for use in compounding has been documented.
7. When commercial products are used in compounding, it is important to list their manufacturer and lot number. This is especially important in the case of multisource generic drugs, as different excipients may be used by different manufacturers.
8. A limiting factor can be the quantity of commercial product that must be used to provide the required amount of active drug. Often, the required quantity makes use of the commercial product impractical.

The Problem

The USP standard for compounded medications is the range from 90.0% to 110.0% of the labeled content; this range must be met unless there is a specific monograph in the USP with a different standard which may be either greater than or less than the +/- 10%. As an example, if Hydrocortisone Gel USP or Hydrocortisone Lotion USP is compounded, the requirement is +/- 10%; but, if Amoxicillin Capsules USP are appropriately compounded, the range is from 90% to 120%; the standard for Procainamide Hydrochloride Injection USP is 95.0% to 105.0% and Riboflavin Injection USP is from 95.0% to 120.0%. However, most USP product monographs (as compared to substance monographs) have the standard range for both manufactured products and compounded preparations as 90.0% to 110.0%. When tested, it is important when results are reported as "out of specification (OOS)" to determine whether or not there is an official USP-National Formulary (NF) monograph on the preparation that was compounded and tested.

One difficulty occurs when commercial products are used as the source of the drug. As pharmacists, we only know that they meet the USP or FDA specifications; we don't know if the tablets, capsules, injections, etc. used in compounding contain 90.1% of drug or 109.9% of the drug (almost a 20% difference). Consequently, the source of the OOS compounded preparation may be the commercial product used and not the pharmacy manipulations. For example, if a commercial product can contain 90.0% to 110.0% active drug, and compounding pharmacists are allowed a 90.0% to 110.0% variation, then the overall variation that may theoretically occur is 0.90 × 0.90 = 0.81 or 81% and 1.10 × 1.10 = 1.21 or 121%. So, we now have a potential range of 81.0% to 121.0% that may occur if both the commercial product and pharmacy manipulations were in the low end, and the opposite if both entities were working at the high end. Therefore, in instances where commercial products are used in compounding and they are tested by a state board of pharmacy or the FDA, then the tolerance for their testing purposes should be 81.0% to 121.0%, not 90.0% to 110.0%. It should be noted, however, that even the USP does not recognize this as an option, and the range of 90.0% to 110.0% for compounding is the standard.

Let's look at three examples to demonstrate the issues here.

Example 1: Hospital Pharmacy

In a recent published stability study, doripenem 500-mg vials were prepared with either 0.9% sodium chloride injection or 5% dextrose injection and placed in elastomeric pumps at concentrations of 5 mg/mL and 10 mg/mL. Solutions were prepared sufficient for three temperature sets (room, refrigerated, frozen).

Using the USP standard of 90.0% to 110.0% for the allowable concentrations range, the allowable ranges in this study would be 4.5 to 5.5 mg/mL for the 5-mg/mL concentration and 9 to 11 mg/mL in the 10-mg/mL. In looking at the t_zero concentrations where the actual analyzed concentrations are provided, the following results were published:

Overall, 9 of the 24 solutions (37.5%) did not meet the USP standards! However, it should be mentioned that even though the concentrations were OOS, the pharmacists had no idea what the original assayed concentrations of the doripenem vials were, as that information was unavailable.

Example 2: Pediatric Preparation

A prescription was received for baclofen 5-mg/mL oral suspension, 100 mL. Using baclofen tablets, they have an allowable range of 90% to 110%. The tablets, when assayed prior to release at the manufacturer, assayed at 93%. The tablets were pulverized and mixed with the oral liquid vehicle to 100 mL. With the compounding allowable range of 90% to 110%, the actual concentration may be between 83.7 and 102.3 mg/mL, which is outside of the 90% to 110% allowable range. Compounding with the Baclofen USP powder is the best way, as it has a 99.0% to 101.0% requirement.

Example 3: Veterinary Pharmacy

Let's look at a situation where a pharmacist receives a prescription from a veterinarian for a tetracycline hydrochloride oral paste at a concentration of 500 mg per 5 g. The source of the drug may be tetracycline hydrochloride 500-mg capsules. Tetracycline Hydrochloride Capsules USP have a standard of not less than 90.0% and not more than 125.0% of the active pharmaceutical ingredient (API). The manufactured capsule could contain anywhere between 450 mg and 625 mg of tetracycline hydrochloride, but the pharmacist has no way of knowing the exact quantity per capsule. If the manufactured capsules actually had 600 mg of tetracycline hydrochloride (which meets the USP requirement of 90.0% to 125.0%: actually 600 mg is 120% of label), and the pharmacist is required to use those capsules but has absolutely no idea that they contain 600 mg instead of the labeled 500 mg, then the final preparation that is compounded will be 120% of label which does not meet the standard requirement for compounded preparations of 90.0% to 110.0%. The pharmacist will now be noncompliant with the standards. Monographs for bulk substances or APIs generally have a tight requirement (e.g., 98% to 102%) or in the case of antibiotics must be labeled with their activity/potency as this is "lot specific." The Certificate of Analysis (CofA) (lot specific) is used by pharmacists to obtain the actual strength of an API. Consequently, compounding with APIs is the most accurate way to compound in this situation.

Another difficulty is that many of the most popular human and veterinary drugs used as a source of the active drug in compounding do not even have a USP monograph. The manufacturers have never submitted the necessary information for a public standard to be prepared and published for professional use. This keeps healthcare professionals, especially pharmacists, in the dark and more likely to have compounded preparations that are outside of the compounding quality standards through no fault of their own.

Obviously, if USP-NF- or equivalent-grade bulk substances are used, the pharmacist is generally starting with substances with a standard generally ranging from 98.0% to 102.0%; this is much better to work with than 90.0% to 110.0% or even broader ranges for commercial products. The CofA is also available to provide the assay results for the specific lots of each substance that can be used for calculations, etc. during the compounding process.

Conclusion

Bottom line, bulk substances are the only rational source of drugs for ALL compounding activities, unless they are not available. Excipients in commercial dosage forms can also contribute to compatibility and stability problems as well as elegance and compliance considerations.


Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief