Documentation of Potential Problems in Compounding with Manufactured Products
Intravenous admixtures and pediatric oral liquids are examples of preparations that are routinely compounded using commercially manufactured products as the source of the drug.
The United States Pharmacopeia (USP) standards for pharmaceutical compounding require the active pharmaceutical ingredient (API) in a compounded preparation to be present in an amount equal to 90.0% to 110.0% of the label. This can pose a problem when compounding using commercially manufactured products due to the variation in allowable strengths by USP dosage form monographs or from the standards set in the individual New Drug Application. The compounding pharmacist does NOT have access to the actual analytical data, so all that is known is that it is somewhere in the "range" allowed. To see what can occur, let's look at the following examples; these examples are not a reflection on the investigators studies but are simply illustrative.
Example 1: Sterile Intravenous Solution
A recent stability study (AJHP 67: 1539-1544) involving doripenem in polyvinyl chloride (PVC) bags and elastomeric pumps was reported. The authors conducted an appropriately designed study, but there are some items of interest one needs to consider. The investigators utilized 500-mg vials of doripenem and reconstituted them with 10 mL of 0.9% sodium chloride injection as recommended by the manufacturer. Then, the contents of one or two vials was added to either 100-mL PVC containers or 100-mL elastomeric infusion pumps containing either 90 mL or 80 mL of either 0.9% sodium chloride injection or 5% dextrose injection to produce solutions with doripenem concentrations of 5 mg and 10 mg per mL, respectively. Six replicate bags were made for each combination of doripenem concentration, diluent, and infusion container.
In a study such as this, it is routine to place data in the tables of results with a column having the actual analyzed concentration of the solutions at time-zero. In this case, there are three tables; one each for storage at 25ºC, 4ºC, and at 25ºC after being frozen and thawed, and each value is the average of the six samples.
An acceptable range for the 5-mg/mL concentration would be between 4.5 and 5.5 mg/mL; for the 10-mg/mL concentration would be between 9 and 11 mg/mL. In Table 1, four of the eight solutions were outside of the acceptable range; in Table 2, three of the eight solutions were outside of the acceptable range and in Table 3, two of the eight solutions were outside of the acceptable range. In other words, nine of the 24 solutions (37.5%) do not meet the standards of the USP requirement of 90% to 110%.
Example 2: Oral Pediatric Suspension
A study in 2006 involving Nitrofurantoin 10-mg/mL suspension prepared from commercially available Nitrofurantoin 50-mg tablets in a 1:1 mixture of Ora-Plus and Ora-Sweet showed the initial concentrations at 86.1% and 85.9% (refrigerated, room temperature) of the labeled amount of 10 mg/mL. This, too, would be outside the 90% to 110% standard for compounded medications. (Can J Hosp Pharm 2006: 59; 29-33). Nitrofurantoin Tablets USP have a requirement of 90% to 110.0% of the labeled amount of Nitrofurantoin.
Example 3: USP Allowable Range Example
If one uses a product, such as tetracycline hydrochloride capsules, as the source of the drug for compounding, the USP range is between 90.0% and 125.0% of the labeled amount of tetracycline hydrochloride. Pharmacists do not have access to the analytical quality results information of what that lot of tetracycline hydrochloride capsules actually contains. For example, it may contain 120% of the labeled amount of the drug and still meet the standard for distribution. For a 250-mg capsule, that would be 300 mg, and for a 500-mg capsule, it would be 600 mg of tetracycline hydrochloride. If a pharmacist is asked to prepare 100 mL of a 25-mg/mL suspension for a child, this would require 2.5 g of tetracycline hydrochloride, or 10 of the 250-mg capsules, or 5 of the 500-mg capsules. However, instead of actually getting 2.5 g of tetracycline hydrochloride, the pharmacist would unknowingly be using 3 g of tetracycline hydrochloride for the suspension and, if analyzed, would show a level of 120% of the labeled amount in the compounded preparation. However, the compounding standard is between 90% to 110% of the labeled amount. Therefore, the compounded preparation would be out of specification (OOS).
Pharmaceutical compounding is vital for today's healthcare practice. One can readily see that compounding using manufactured products can place the pharmacist in a situation where their final preparations are not in compliance with the USP standards. The pharmacist has no way of knowing what the actual analyzed strength is in the manufactured product. It may be 90.0% to 110.0%, or 80.0% to 120.0%, or even a broader or different range. If the pharmacist does not know what the strength of the API is in the commercial product, then there is a possibility that the compounded preparation will be outside the allowable USP standards that have been adopted by most states in their laws and regulations. Obviously, in many clinical situations, this variation will not be significant. It does become significant, however, when samples are selected and analyzed by regulatory agencies and found to be OOS. It is a problem when different government agencies obtain samples, have them analyzed, and broadcast the results for all to see without investigating the potential issues involved.
This situation is easily resolved by compounding using bulk substance APIs and not compounding from commercial drug products. However, it is well recognized that this is not always feasible, and the pharmacist must have the authority and flexibility of using the most appropriate source for APIs (bulk substances or manufactured products). Bulk APIs generally have a standard of about 98% to 102%.
In summary, use bulk drug substances (APIs) when compounding to be more accurate, as appropriate. This is not feasible, however, in many cases; especially those involving intravenous admixtures, cancer chemotherapy, etc.
Loyd V. Allen, Jr., Ph.D., R.Ph.