USP's DeStefano on Defining, and Detecting, Pharmaceutical Impurities

Economically-motivated adulteration is one of many issues that industry, and USP, is tackling

By Agnes Shanley, Editor in Chief

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Pharmaceutical impurities aren’t as simple as they used to be. 

Today, instead of having to worry about traces of metals from catalysts, ingredients or equipment, manufacturers must also consider the potential of economically motivated adulteration, and grapple with the complexity of different forms of complex biopharmaceutical molecules. 

Defining safe exposure limits, improving testing methods, and even deciding what an impurity is, are more challenging than ever, especially as scientifically-astute criminals engage in tampering for profit.

At USP, Patrick Lukulay [director of the USP-US AID program, Promoting the Quality of Medicines] and his team have been working on a database that could eventually serve as a resource for regulatory bodies, not only in the developing nations but globally.  These efforts tie in with FDA’s recent announcement on its collaboration on drug anticounterfeiting with the World Health Organization (WHO).  USP expects to be able to make an announcement on this early next year.

In the meantime, USP is working to modernize monographs and testing methods. For elemental impurities, the Pharmacopeia is in the process of updating its 105-year-old elementals impurities test.  In concert with ICH, the U.S. Pharmacopeia is also working to set acceptable metal exposure limits.

On his way to an ICH Q3D working group meeting in Japan this week, USP’s Vice President for General Chapters, Anthony DeStefano, described the Pharmacopeia's plans and some of the issues involved. 

He will return the following week for a special workshop on November 13-14 in New Orleans, “Impurities, Adulteration and the Changing Role of the USP in Global Drug Quality,” which will precede the annual AAPS conference.

PhM: When did USP first realize that the entire area of impurities was becoming such a problematic one? 

ADS: Impurities are a major problem on many levels. There are the elemental impurities, then the contaminants and adulterants, such as diethylene glycol (DEG), not only in drugs and APIs, but in dietary supplements, traditional medicines and biologicals. 

USP’s test for elemental impurities, for metals, first appeared in the USP in 1905.  We knew that that test needed to be upgraded.  Going back to 1995, we’ve had articles in our comment journal, the Pharmacopeial Forum, suggesting that they be revised, so this initiative has really picked up over the past few years. 

We’ve proposed toxicologically-based limits for metals that are known to be toxic, as either catalysts or contaminants. 

The ICH Q3D working group has picked up on this issue as well. 

USP has proposed methodologies for how to get to suggested levels because the current methodology is not viable.  But this methodology is focusing on addressing public safety, rather than exploring detection limits and “how little can we see?”

PhM: Are there specific detection technologies that have been proposed?

ADS: For metals, we are proposing primarily inductively-coupled plasma (ICP) with optical emission spectroscopy and ICP/MS as the primary detection tools, but other tools including atomic absorption spectroscopy can also be used. 

We’re going to propose some acceptance criteria for precision, accuracy and selectivity at the proposed limits of permissible daily exposure (PDE). 

As long as you meet these precision, accuracy and specificity criteria, you can choose a method that works.  For instance, if you don’t like ICP and you want to use atomic absorption with, say, a platinum lamp because you only need to look for platinum, you’ll be able to do that.

In general, we’re moving away from visual tests to instrumental tests.  The current USP elemental impurities test is precipitation followed by visual observation, which is very difficult to do with any level of accuracy or precision.

We’re working with ICH to see whether we can agree on which metals should be limited, and what the proper PDE levels should be.

PhM: Is there a timeline for setting PDE’s?

ADS: We hope to come out after this meeting with a Stage 2 draft, so that we’d have settled on which metals and which limits to focus on.  We’ll then put them out for initial public comment over the next few months. 

USP has also drafted some relevant chapters which we hope to put out for comment in the spring, and we expect these efforts to dovetail with those of ICH.  We’re assuming that all will go well and we’ll have a good idea of metals and limits over the next three months.

PhM: What are USP’s plans for biopharma impurity testing?

ADS: The biggest problem on the large molecule front has been heparin contaminated with  oversulfated chondroiten sulfate (OCS). The Pharmacopeia is really designed to characterize what is there, rather than find what is not there. 

So, for example, with DEG, as was found in the glycerin case, we have to test the identity of something that isn’t supposed to be there. So the identity is in part defined by something’s absence. 

Similarly, for heparin, there’s a test for level of OSC, and part of the heparin identity test is absence of OSC.  That’s done deliberately because of the way that GMPs are set up.  When materials come into a plant, GMPs require material identity tests.  So, we can only discover that something is missing during identity testing.  The other tests can be done any time.  When the truck is out there, at the door, you have to be able to answer the question, “Do I want this shipment or not?”  That’s done through identity testing.

But heparin is just the tip of the iceberg.  There are all these other biologics, which beg the questions: How does one characterize them, and what do you even call impurities in a biologic?  Let’s say you are dealing with a drug that is heavily glycosylated….are all those levels of glycosylation different forms of the drug or aren’t they? 

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