Editorial: Documentation of Potential Problems in Compounding with Manufactured Products

The 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. To see what can occur, let's look at the following example.

Example:

In the latest issue of the American Journal of Health-System Pharmacists, (Vol 67 Sept 15, 2010 pp 1539-1544), a stability study is reported entitled "Stability of doripenem in polyvinyl chloride bags and elastomeric pumps." The authors conducted an appropriate study and this editorial is definitely not directed to them, but there are some items of interest we need to consider. They 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 were 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 25�C, 4�C, and at 25�C 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 the range would be between 9 and 11 mg/mL. In Table 1, 4 of the 8 solutions were outside of the acceptable range; in Table 2, 3 of the 8 solutions were outside of the acceptable range; and in Table 3, 2 of the 8 solutions were outside of the acceptable range. In other words, 9 of the 24 solutions (37.5%) do not meet the standards of the USP requirement of 90% to 110%.

Summary

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 allowable range of the API may be in the manufactured product or its actual analyzed potency. It may be 90.0% to 110.0%, or it may be 80.0% to 120.0%, or even a broader or different range. If the pharmacist does not know what the potency 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 outside of expected specifications.

In a future issue of IJPC, we will look at stability studies published over a longer time frame to determine the prevalence of out-of-spec (OOS) compounded preparations used in stability studies. The question then arises, "Are these studies valid"? Yes, they definitely are valid, as slight changes in concentrations should have no bearing on the results of these stability studies.

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).


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

Pharmacy Heists are Up Amid Popularity of Rx Drugs
Pharmacy robberies are increasing across the U.S., partly because of the increasing demand for prescription drugs. Prescription painkillers rank second behind marijuana as the country's most common illegal drug problem, according to the Office of National Drug Control Policy.

There are no official numbers on how many pharmacies are robbed each year nationwide as the federal government does not track them, and states vary in how they classify the crimes. However, federal drug officials, drug companies, pharmacies, state authorities, and local police departments nationwide all say they've noticed an increase in recent years.

As a quick example, in Oklahoma only one pharmacy reported an armed robbery in 2007, but that shot to 12 in 2008. In 2009, there were 19. Burglaries increased from 31 in 2007 to 42 in 2008. In 2009, the count was 51, according to the Oklahoma Bureau of Narcotics and Dangerous Drugs Control. In many cases, the employees are the thieves; one employee stole more than 49,000 doses of the painkiller hydrocodone before getting caught.
http://dailycaller.com/2010/09/07/pharmacy-heists-are-up-amid-popularity-of-rx-drugs/#ixzz0zuYn1X1X

Study: Physicians See Gifts As Payback
A new study by Carnegie Mellon University researchers found that physicians rationalize such gifts from drug companies as payback for all the sacrifices they made to get their education (although they may not realize they're doing it). Their attitude is described by the researchers as one of "because I'm worth it."

The gifts have been called "barely disguised bribes," and bribes in other parts of society are illegal. However, many of the 301 physicians in the study didn't see them that way, though other research has shown gifts do influence how doctors treat patients and conduct research.

According to the study, 94 percent of physicians have some kind of relationship with pharmaceutical company's ranging from accepting pens and stationery to free equipment, lunches, consulting fees, and paid talks touting a drug at conferences.

Many physicians consider gifts normal perks of the job because they weren't getting cars or big bonuses. The study showed the more deprived the subjects felt, the more they justified the practice.

The conclusion of the study is that physicians are going to find a way to rationalize accepting these bribes as long as they are offered and are legal. An obvious policy change to consider is eliminating the ability of pharmaceutical companies to pay physicians to prescribe their drugs.
http://pharmalive.com/news/index.cfm?articleID=729410&categoryid=9&newsletter=1

U.S. Physicians Moving More to E-prescriptions
U.S. physicians increasingly are sending prescriptions to pharmacies electronically, lured by up to $27 billion in government funds aimed at speeding the switch to electronic medical records. 200,000 doctors now use e-prescribing, or roughly one in three office-based doctors compared with 156,000 at the end of last year, and 74,000 at the end of 2008. 47 states have more than doubled their use of electronic prescribing last year.

In 2009, Congress authorized funding to promote electronic health records as part of the economic stimulus package. Incentives will be paid out over five years, and by 2015 providers will face penalties if they don't adopt the new technology.

It's a time saver for patients, but not as much for doctors one physician said, because he may have to create new templates if he wants to customize a prescription.
http://www.reuters.com/article/idUSTRE68K0FF20100921

�that the Veterinary Information Network (VIN) plans to survey tens of thousands of veterinarians around the world to determine the extent and significance of accidental exposures of pets to their owners' topical hormone preparations?

Old Stories
Tired of some of the recreational reading books you have had in your home library? Why not consider donating them to children's homes, nursing homes, retirement centers, and other areas that will generally appreciate receiving appropriate types of donated books.