FDA 483 #8 – Using ungraded ingredients

Learning Objectives

  1. Discuss the use of USP graded ingredients in pharmaceutical preparations and the importance
  2. Explain what prompted the FD&C act of 1938 to be enacted

In this weeks 483 Friday we’re going to be talking about the use of ungraded ingredients in pharmaceutical preparations. First, I’d like to show you a 483 where this was done, then we’ll look at a case where non-USP ingredients led to real issues in patients where the drug product contained non-USP graded ingredients.

Let’s take a look at the first 483:

In this 483 it looks like the use of grain alcohol was used to make several products. Of course, using everclear 95% is NOT a USP graded alcohol and is actually meant to be for consumption, but not as a pharmaceutical ingredient.

So what’s the difference of whether something is USP-graded and a substance that doesn’t carry that same grade? First, USP graded ingredients are tested for a number of things including the stability of the ingredient itself. This is the major difference between those ingredients that carry the USP grading and those that do not.

First, is there such a product that exists for this pharmacy? Are there USP graded ethanols that could’ve been used in this product? The answer is yes. There is in fact a USP monograph for ethanol which typically means that alcohol USP can be found in the market that’s been tested for impurities and degradation products. So the easiest way to solve the issue for this pharmacy is to simply use USP graded 200 proof alcohol.

I would like to note that in this particular 483 it’s noted that this pharmacy is a “Producer of Non-Sterile Drug Products”. So one thing I can say is that all of their products were being used for topical use and not to be consumed. Nonetheless, the alcohol used was not USP-graded so the point that the final preparation wasn’t consumed orally or by given by injection still doesn’t necessarily matter.

The next question in my mind, if there is no substitute for something that is intended to be laboratory grade, is there a way to qualify this ingredient for use in your drug product. I would say yes, however much research and testing would need to be done prior to its use. How to go about doing that goes beyond what this episode will cover but the possibility is there.

Next, let’s look at a scenario where using non-USP graded ingredients were used in an injection and actually caused harm to the patient.

In 2017, there were two infusions of curcumin compounded with non-USP graded polyethylene glycol (PEG) 40 castor oil. As a result when these injections were administered patients had hypersensitivity reactions to the IV product. Note that in this preparation it actually was administered intravenously, so this was a sterile product.

So what happened to these patients and why? The FDA reports:

On March 10, 2017, the U.S. Food and Drug Administration received an adverse event report concerning a 30-year-old female patient who experienced cardiac arrest after IV administration of a curcumin emulsion product…The patient reportedly had a history of allergies and was being treated for eczema by a naturopathic doctor. Within minutes of starting the infusion, the patient became pulseless and required CPR. The patient suffered anoxic (depleted oxygen) brain injury and subsequently died. An adverse reaction to infused curcumin solution was identified as a cause of death by the local authorities.

FDA investigates two serious adverse events associated with…compounded curcumin emulsion product for injection

In a second case where this drug was administered the FDA reports:

On May 1, 2017, FDA received an adverse event report concerning a 71-year-old male patient who developed a hypersensitivity reaction after IV administration of (name of facility removed) compounded curcumin emulsion product. The patient had a history of allergies and was being treated for thrombocytopenia (a low platelet count) at a holistic health center. According to information FDA received from the center, within minutes of starting the infusion, the patient developed a cough and erythema (skin reddening). Diphenhydramine (an antihistamine) was administered; however, symptoms escalated to include shortness of breath, itching, and hypotension (low blood pressure). The patient was treated with IV epinephrine and transferred to a nearby emergency room where he was treated and then released.

FDA investigates two serious adverse events associated with…compounded curcumin emulsion product for injection

What’s particularly interesting about this injection is that the ungraded PEG 40 Castor oil sort of has a history with the FDA. In 1937, a sulfinilamide was compounded using diethylene glycol. The Diethylene Glycole (DEG) was used as a solvent to dissolve the sulfinilamide (an antibiotic). Diethylene glycol is now known to cause kidney failure in patients. As a result over 100 people in 15 states died as Far East as Virginia and as far west as California.

Diethylene glycol, while it is a great solvent, it’s normally used as antifreeze, a deadly poison. Unfortunately, prior to making this oral preparation of sulfinilamide, there were no studies conducted for toxicity and at the time the food and drugs law did not exist. The FDA responded to this disaster with the Food, drug and cosmetic act of 1938 which established quality standards for food, drugs, medical devices and cosmetics manufactured and sold in the United States.

Back to our original 483. What you may or may NOT know about polyethelene glycol is that one of its degradation products is diethylene glycol. Perhaps if the PEG castor oil was USP graded or if studies were done prior to dispensing the curcumin injection, the fatality and injury as a result of the injection would never have occurred. Diethylene glycol is a known manufacturing impurity in polyethylene glycol. What’s more is that it was found that the polyethylene glycol that was used to make this curcumin preparation had the labeling of “CAUTION: for manufacturing or laboratory use only.” Unfortunately, there is currently no USP monograph for PEG 40 castor oil.

I cannot stress this enough, using USP graded ingredients is absolutely paramount to compounding a safe and effective product for your patients. If you have the resources to do studies on the individual ingredients that may not have a USP grade then it’s possible that you’re able to show that the use of such an ingredient is safe to be used in your preparation. It’s also important to know the history of the FDA and why some of the laws that have been enacted over the past 100 or so years have been enacted.

The last thing I’ll say is that just because something CAN be compounded doesn’t always mean it SHOULD be compounded. Be sure to do your research on any of the ingredients you’re using in the compounding of your preparations.

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