cGMPs / QRM Process

Stopping Counterfeits and Substandard Drugs

An interview with Patrick Lukulay, Director of USP’s Drug Quality and Information Program, a grant-funded program funded by US AID with the goal of strengthening QA and QC in developing countries. The program is now working in Africa, Latin America and Southeast Asia.

PhM:  Tell us who your partners generally are.

P.L.: The work we do, generally, is with the drug regulatory authorities, like the equivalent of the FDA. We work to strengthen their quality control laboratories so that they could exercise better oversight of drugs coming in to their country.

PhM: Are you doing any work in Nigeria with Dr. Akunyili?

P.L.:  We are doing a study with Dr. Akunyili evaluating the quality of anti-malaria drugs in Nigeria, as well as in ten other African countries. But let me just give you a sense of the major activity that we engage in, in these developing countries. 

We set up what they call Drug Quality Monitoring Sites at various strategic points within the countries and we pull pharmaceutical products randomly from the market, but from the formal and informal markets, test those products, and bring the results to the attention of the authorities, generally through the Minister of Health.

And we hope that the counterfeit products that we find on the market, and the substandard products, that the government will take action by closing shops, by prosecuting those involved [and by withdrawing] those products from the market.  And we have examples of how governments have taken those actions in several countries.

PhM:  Can you highlight any of the recent victories?

P.L.: Yes, in Madagascar, they have just withdrawn sixteen lots of anti-malarial from the market. Senegal was identified with some counterfeit products, and the government is in the process of taking action. They are a little slower than in Madagascar and in other countries that we've seen. In Southeast Asia, we have identified some substandard anti-malarias and Interpol, which is the international police, is now working with our group to identify the pharmacies that these products were identified at. 

PhM: It seems that there might be a new group of operators out there that are very savvy about analytical testing. They’re not just taking tap water and putting it in vials, but deliberately exploiting the limits of analytical instrumentation. Is this something new that you're seeing or has it always been that way?

P.L.: Well, what we have seen is the sophistication of the counterfeited products has gone up. Previously in Africa and in Asia, counterfeit products comprised of either nothing in the capsule or just putting some starch or some inferior raw material, like, say, a raw material for acetyl, you know, for aspirin, which might be cheaper than for anti-malarias. 

Now what they're doing is actually using the real material but of poor quality. So what you find, really, is more of what you call a substandard . . . well, it could be both substandard and counterfeited if it's claiming the wrong things on the packaging, for example, so you call that counterfeit.  But they are actually trying to go halfway in meeting the requirements of the regulators, at least having the right material in there, but it may just be of poor quality. 

PhM:  Is the boundary between counterfeit and substandard then just getting . . .

P.L.: Blurred? Yes, it's really getting blurred because the definition of a counterfeit product is product that is deliberately mislabeled, while substandard is something that falls short of the requirements by accident.  So the counterfeiters are moving away from deliberately misbranding something by putting the right stuff in there, but just don't meet the pharmacopeia standards that you'd expect for that product. 

And you might say, "Well, how are they making their money?" Well, low-quality products could be five to ten times lower in price than the good quality products. . . .

PhM: Much of this activity is probably intentional, but can it also reflect lack of education and stupidity? There was a case in China where a number of deaths were tied to this one drug and the problem was traced to a raw material being sold by a broker who was really a tailor without any education and he didn't seem to know the difference between two very similarly named intermediates, and sold the dangerous one. What are you seeing or is it really becoming more sophisticated and intentional or is it a mixture?

P.L.: Generally for products that are made locally in the countries, they fall short because of lack of good GMP compliance in the manufacturing process. 

And so what we tend to find with local manufacturers is generally substandard products, substandard for several reasons: one, for example, they might end up making a given product, say, for malaria, and within that same facility, they use the same equipment to make a product for hypertension. And so because they are not following good GMP compliance, they end up having some of the hypertensive drug in the malaria drug by accident. 

The real counterfeited ones are usually ones that are imported into the country from either India or China and those groups are really looking to conduct fraud. So we tend to treat the imported products with a special vigilance than the local manufactured products. 

PhM: Well, the whole heparin example, it seems to fit a profile of a type of drug that's very widely used, it's a bio-molecule, made from using an animal derivative that could be sold into chemical and industrial markets in many different grades. I was just wondering, do you see other potential heparins out there? I mean, I'm sure there are many, but are there particular classes of drugs that are riskier?

P.L.: Generally, lifestyle drugs, like a Viagra or a Cialis, are most often copied.  But generally the three classes of disease areas and where we often tend to operate is either HIV/AIDS, TB drugs or anti-malaria and we tend to see a little bit of counterfeit activity with the lifestyle products. . . . Under the contracted terms of our contract with USAID, we focus mainly on the anti-malaria, TB and HIV drugs.

PhM: Please comment on enforcement. That seems to be a real problem. Do you see governments stepping up with enforcement?

P.L.: Right, and it depends on the country. So some countries, they are very vigilant in taking enforcement actions, like Madagascar. The way we set up the programs generally to facilitate enforcement is at the beginning of this quality monitoring activity, we tend to involve all the key players from the government ministries and get them to commit to signing a memorandum stating that when these products are found, for U.S. government funding to continue, we need to see actions taken by the government.

What we try to do is make alliances with international agencies like Interpol, as well as, there's another one called UNODC [United Nations Office on Drugs and Crime] because they tend to have a bigger voice with governments. Governments get a lot of financial assistance from WHO and so when they speak up, [governments] tend to listen. So we have tried to collaborate with those guys and establish some contact with those offices so that we are starting to share our results with them. 

Before, we just shared our results with the government and hoped that something would come out of it but now we tend to also share with WHO and Interpol and UNODC and kind of lead them to where we found our problems and it seems to be helping.

PhM:  How many people are working on this project with you and....?

P.L.: There are fifteen staff members and two consultants overseas. . .

PhM:  That's a lot of ground to cover for [so few] people.

P.L.: A lot of ground to cover, and the program is growing rapidly. There are 24 countries now; nine countries in Africa and, I think, another nine in Latin America, and six or so in Southeast Asia.

PhM: What are your top goals for the program over the next year?

P.L.: The top priority that we have set for ourselves is to have these drug quality monitoring programs basically cover all critical border areas in each country where we are. So in Senegal, we hope to have sites at all the critical border crossings and all the nine African countries, same thing with Southeast Asia and Latin America. So that's one objective that was said and discussed with USAID. 

The other objective that was set is to actually try and work with local manufacturers and get them to be compliant so that the countries will have a supply of good quality drugs. So we're trying to encourage local production but when you do that, you have to be sure that they are capable of producing good quality products.

PhM: Are you working with other branches of USP to do that since USP now has the offices in India and China?

P.L.: Exactly. So we're working with their Verification Program, because they conduct GMP verification of the products. So we're trying to get them to basically conduct some assignments with us when we go out so we could use the expertise in conducting these GMP practices. The sites in India, also, we're using them to test some products that we obtain from Africa.  Instead of shipping them to the U.S. we ship them to the India lab to conduct tests.

PhM: Does USP have this kind of a program in China now?  I know there was talk about it but I only really heard formally about the Indian program.

P.L.: Yes, the China site is now up and running. They will have the capacity to test. We've been using them to also conduct training and education. Sometimes it's distance learning training. They'll reach out to the Pharmacopeia education group here and we would conduct training over the Internet, or sometimes we send stuff and conduct training of Chinese manufacturers, pharmacies . . . We'll conduct these seminars and USP staff will conduct the training.

PhM: I guess that the number of companies signing up for the materials verification has increased but it seemed that it was really the large companies, like Dr. Reddy’s, that would sign up for this. Is there a sliding scale for a really small, local company? Is cost an issue and then how do you get over that?

P.L.: Yeah, we have not yet tried the verification with the smaller companies and we're sure they'll be looking at cost/benefit. What is the benefit to them to be in the program and what is the cost of the program to them?  What USP is now working on is actually getting another version of the verification program for developing nations, a scaled-down program that will be affordable. 

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