Are you are concerned about the level of arsenic, cadmium, lead or mercury that may slip through manufacturing processes and find their way into pharmaceuticals? Well, the US Pharmacopeia is working to ease any worries. The non-profit, which sets standards for the identity, strength, quality, and purity of medicines, is working on two new ‘chapters’ that would help drugmakers upgrade their testing for so-called heavy metals. The new guidance becomes official on December 1, although implementation will not be required until May 1, 2014. Why? We spoke with Kahkashan Zaidi, a senior scientific liaison at USP, about these new chapters and the implications…
Q: So why are these new chapters needed?
Zaidi: So there are two chapters. One includes a list of elements that need to be controlled and the other discusses procedures – it provides guidance on what methodology to use… Anybody who is involved in the manufacturing, and not just of pharmaceutical drug products, but also active pharmaceutical ingredients and substances, excipient manufacturers, contract labs, all need to know this information.
The biggest problem is that, although we say we’ve had a chapter and methodology to control current USP (in Chapter 231), we know the procedures and methodology don’t work. The methods included are very non-specific. They don’t tell you about the elements you are testing for or any info about the identity of the element.. There are 10 elements in Chapter 231, but you don’t know which one would be present. You have no way of finding out which of the 10 would be present in the sample (that is being tested).
Q: So you’re saying the existing chapter is incomplete?
Zaidi: With the old method, there is no way of knowing which elements exceeded limits. Chapter 231 includes test methods where the end result is compared, but you would have no way of knowing how much of each of those elements are present. And this matters, of course. Take mercury, which is one of the most toxic metals that needs to be controlled. The problem is with the methods that are in the written procedure (in the current chapter).
The old chapter is based on old technology – detection methods and toxicology assessments have progressed. New standards take into account current toxicological data that show element A as toxic to humans at such a level and element B at a different level. They vary. If you go by a gross total – and some would have been destroyed or altered due to sample preparation – you get a false and misleading reading. And so you have know way of knowing of the toxicity of your product from element to element. If you have trace elements of something in a sample – iron, as an example – each individual level makes a big difference.
Q: How old is this existing chapter, anyway?
Zaidi: The current chapter was introduced in 1905. There have been tweaks, but nothing major has been done to this chapter. So this is really the first time we have introduced a lot of issues (here is the old chapter).
There are 10 elements listed in this chapter, but each has different toxicities noted. For instance, mercury does not respond to the tests in Chapter 231. You may have a heavy metal content, but most toxic elements may be present at levels that exceed current toxicity levels. The point is that you have to pay attention to controlling them as well as making sure your products meet the limits.
Q: So tell us about the new chapters.
Zaidi: There is the limits chapter and has a list of 15 elements (and this is called Chapter 232). Of those, four are impurities present in the environment – arsenic, cadmium, lead and mercury… These are the most toxic ones…. The rest of the elements listed are commonly used as catalysts in synthesis… (The other chapter is 233 and addresses testing for elemental impurities).
There are efforts going on right now to test a lot of products in order to see where these impurities may be found. The good news is there are a lot of products tested for, and what has been tested have shown that are impurities under control, although there are exceptions… This will give (manufacturers) the opportunity, after 2014, to either reformulate or purify their products to bring them to a better quality level.
There is a regulatory and legal dimension to this. Under the Food, Drug & Cosmetic Act, manufacturers have to demonstrate to FDA that (their) product conforms to any standard in USP… The standard has been in USP for awhile, but that doesn’t mean a reputable manufacturer is prohibited from developing its own test… But what we’re doing is bringing this standard into the 21st century, so the law tracks better to what current practice should be (read more from the USP here).
Q: How would you describe industry reaction so far? What have been the issues?
Zaidi: The biggest concern from manufacturers was the time. It’s been about 10 years since this process began, and the first article was published in 2008… When we first came up with the list, there was no objection. But they questioned the time, that they needed more time to implement changes… The first article had 32 elements, and is now down to 15 elements. The limits are about the same as those proposed in 2008… Since the International Conference on Harmonization came out with their limits, they are in the same ballpark… But we went from one toxicologist to a panel. At the same time, the Europeans came out with a list of 16 limits (for catalysts). So we sort of came into agreement with our list.
But my impression is they were happy to use Chapter 231. Everything was working and they didn’t have to make such a big effort and overhaul their entire systems… But we had a number of workshops and stakeholder forums with industry participation, and we’re at the point now where we’re working on implementation… They have to meet these standards and if they dont, the agency’s positon is to come up with guidance and see what action needs to be taken.
Q: So a lot of work is involved, yes?
Zaidi: There’s a lot of work they need to do to be in compliance, but this has been going on for years. So they should be on track and staying up to date. But some companies are under the misconception this will go away, but it’s not (going away). They have to meet the standards if they want their products approved. We’re in constant contact with FDA… Some FDA oficias are on the USP panel as ad hoc members.
They have to purchase new equipment, hire technicians, train staff. But for big pharma, it is not a problem. They already have the equipment. The smaller companies may have to think and plan strategy to make sure they have what they need. Maybe the need to send out to a contract lab or purchase more equipment… But on May 1,2014, all drug products must meet the new requirement.