Hearing of the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee - The Heparin Disaster: Chinese Counterfeits and American Failures
Interview
Hearing of the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee - The Heparin Disaster: Chinese Counterfeits and American Failures
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REP. JAN SCHAKOWSKY (D-IL): Thank you, Mr. Chairman. The consequences of the contamination of the drug heparin have been truly tragic. I want to sincerely thank the family members of those who fell victim to this crime for being here today and testifying before our subcommittee. We really appreciate your being here.
Heparin as well as many other innovative drugs and biologics have come to us in the past few decades, have made great contributions to medical care in this country. Unfortunately, with great innovation and the use of cutting-edge medical technology also comes a certain vulnerability to corruption and exploitation.
The heparin disaster is just another in a line of dangerous prescription drug events that have exposed vast weaknesses in how we regulate drug safety in this country. Thanks to the leadership of Chairman Dingell and the chairman of our subcommittee, Mr. Stupak, we have learned a lot about what we can do to strengthen regulation and oversight at FDA and reinforce its presence overseas.
My hope is that these hearings will also provide us with some concrete answers and steps to take as a Congress to make all points of our drug development, sourcing, manufacture and sales safer for consumers.
In the case of heparin, there are several points along this process where fingers can be pointed, but with ongoing investigations in China and an unclear timeline for getting real answers, we need to be able to move forward quickly and comprehensively to ensure that we are making our drug supply more secure and reliable. I hope that today we'll make progress toward that end.
Mr. Chairman, the confidence of American consumers has been shaken; the safety of their children's toys, the food they put on their table and the prescription drugs they take is questionable. One of the reasons I'm so proud to be on this committee is that we can address those fears and we are taking action to do just that. I know that Chairman Dingell has been hard at work on a large legislative package aimed at making our drugs, devices, food and cosmetics safer, and I look forward to working with him and all my colleagues on the committee to pass as strong a bill as possible.
But it is also time for the administration to take some leadership. President Bush says he is committed to going to Beijing for the Olympics. I hope he also takes time to meet with Chinese officials to force action on their part to get them to give our inspectors the access they need to protect our consumers.
I look forward to hearing from our witnesses today, and again I thank the family members for being here. I yield back.
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REP. SCHAKOWSKY: First, let me express my gratitude to David Nelson for the great work that he and the investigative staff have done on this; really appreciate it.
I wonder if the committee -- has the committee gotten the documents and interviews that we requested regarding the preapproval inspection process at the FDA?
MR. NELSON: We've gotten interviews of all the operational people that we requested to be interviewed. We have not gotten interviews with the counsels that make many of these decisions or at least have veto authority over these decisions.
REP. SCHAKOWSKY: And why is it necessary to get documents and interviews from FDA lawyers?
MR. NELSON: Because they have a very influential role in policy. There's a -- an expression that I've heard from more than one member of the food and drug bar that goes like this: If FDA wants to do something and we agree with it, it's a question of policy, and they can do it; if we disagree with it, it's a question of law, and it's our call. And that has been -- consistent through many administrations. The office of chief counsel exerts an enormous amount of influence over FDA policy and, in this particular case, over enforcement decisions.
REP. SCHAKOWSKY: So you're saying that the -- that they actually have veto power over any policy change?
MR. NELSON: Generally, yes.
REP. SCHAKOWSKY: Okay.
MR. NELSON: I mean, I don't have 100 percent certainty of that, but that's certainly the events that -- the questions that we've looked into, that's been true.
REP. SCHAKOWSKY: Would the lawyers also have a say in the issuance of import alerts?
MR. NELSON: Yes.
REP. SCHAKOWSKY: All of them? They sign off on them, is that --
MR. NELSON: At least all the broad ones they do, and also the warning letters.
REP. SCHAKOWSKY: Has this constrained the agency in taking action to protect the public from unsafe food and drugs?
MR. NELSON: Yeah, there seems to have been a shift in policy in recent years, and I don't mean to attribute it solely to the -- to this administration. There's a pendulum that swings back and forth, but where we've been in the more deregulatory era of this administration, there has been interpretations coming out of the office of general counsel that have restricted -- they have a very restrictive or conservative view of what FDA's authority is that is not consistent with precedents in earlier years and, as far as I know, is not the result of court decisions but rather a change in FDA's -- counsel's view of the law.
REP. SCHAKOWSKY: Well, we were told after the deaths in Haiti and Panama from diethylene glycol that have been substituted or added to glycerin in China in cough syrup and other medications that CDER asked for an import alert that would require testing of all batches of glycerin from China. The office of chief counsel said such an alert would exceed the legal authority of the agency, but they cited no law to that effect. Is that --
MR. NELSON: That's what we were told by FDA enforcement personnel.
REP. SCHAKOWSKY: So the position of the chief counsel was that Americans had to die before importers would be required to test their glycerin from China?
MR. NELSON: So it would appear. I mean, the question is, can you show that there is an appearance that the product is violative, and apparently, if it's violative elsewhere to the point of being fatal, it doesn't count.
REP. SCHAKOWSKY: And so you're -- I think you answered this. Is this consistent with the legal constraints passed on FDA in the past? You're saying that seems to have been a change in policy in this regard
MR. NELSON: In recent years. There's been announced change in policy. I mean, the number of warning letters that were permitted under the first chief counsel in the current Bush administration were greatly -- greatly restricted use of warning letters and, presumably, of import alerts.
REP. SCHAKOWSKY: So what does this tell us about the need to enhance the ability of FDA to stop drugs and other imported products that threaten the public health?
MR. NELSON: Well, I think it clearly shows that Congress, if it wants tighter enforcement, if it wants the FDA to be able to act to protect the public health more readily and easily, regardless of who happens to be the chief counsel at the time, that it needs to make that authority very explicit in law so there's no ambiguity.
REP. SCHAKOWSKY: So would you say, then, since that apparent change then, in general, Americans are less safe when it comes to feeling secure -- and secure when it comes to their prescription drugs?
MR. NELSON: That's not just my opinion, that's the opinion of a lot of the operational field personnel inside FDA that we've talked to.
REP. SCHAKOWSKY: Okay. Once again, as I did in my opening statement, let me thank the family members. You know, putting a human face on that, talking about your loved ones, as hard as it may be, adds an urgency to the issue, and I can assure you that this committee will do everything it can under our -- the leadership of Mr. Stupak and Mr. Dingell to adequately respond to the pain that you're feeling.
Thank you.
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REP. SCHAKOWSKY: Thank you, Mr. Chairman.
Ms. Brown, I'd like to ask you a few questions.
From February 20th of this year to February 26th, you were the investigator on an FDA team who inspected the Chinese plant -- actually went there, known as Changzhou -- after all this time, I'm still wondering how to pronounce it; is it Changzhou? Changzhou? Yes? -- SPL, which supplied the purported tainted heparin, is that correct?
MS. BROWN: Yes.
REP. SCHAKOWSKY: And your inspection of Changzhou SPL revealed significant deviations from U.S. current good manufacturing practices, isn't that correct?
MS. BROWN: Yes.
REP. SCHAKOWSKY: And I'd like to ask you some questions about this inspection and your findings.
First, isn't it true that you found that Changzhou SPL's processing steps provided no assurance that they were capable of removing impurities?
MS. BROWN: Yes.
REP. SCHAKOWSKY: And isn't it also true that you found that Changzhou SPL failed to have adequate systems for evaluating both the crude heparin and the suppliers of crude heparin to ensure that the product was acceptable for use?
MS. BROWN: Yes.
REP. SCHAKOWSKY: And in fact, didn't you find that the Changzhou SPL received crude heparin material from an unacceptable workshop that was used to manufacture heparin -- manufacture heparin API and that this API was imported into the United States?
MS. BROWN: Yes.
REP. SCHAKOWSKY: And you also found that Changzhou SPL failed to ensure raw materials were of acceptable identity, quality and purity before use, isn't that correct?
MS. BROWN: Yes.
REP. SCHAKOWSKY: Now, can you tell us why understanding the origin, quality and purity of these materials are essential for meeting good manufacturing practices, particularly when you're making a biologic such as heparin?
MS. BROWN: In particular for heparin, the certificate of analysis that came with the crude material into Changzhou SPL was the only source identifying it as crude heparin from a porcine source.
REP. SCHAKOWSKY: From a --
MS. BROWN: From pigs.
REP. SCHAKOWSKY: I see. So and why is that important, the fact that that was the only document?
MS. BROWN: Because Changzhou SPL actually had just begun PCR testing, which verifies the pig origin of the crude heparin in June or July of '07, so it was a relatively new test that they were doing. Prior to that, they hadn't done it at all in China.
REP. SCHAKOWSKY: I see. Didn't you find that the test methods performed by Changzhou SPL had not been verified to ensure suitability under actual conditions of use? Is that what you're saying, that it was unverified?
MS. BROWN: Yes, unverified. The tests that they ran were USP compendial methods, and we ask firms to verify that the methods are suitable for use with their particular product.
REP. SCHAKOWSKY: I see. So what does it mean when the FDA says that Changzhou SPL's test method had not been verified to ensure suitability under actual conditions of use, and why is this important?
MS. BROWN: Well, one of the tests that they ran was a protein test. That was a turbidity test. They put a required solution in a big test tube and then added their substance to it, and if turbidity showed up then the crude heparin did not have protein in it. And if it didn't show up, then there was protein there. Or I think it was the opposite -- if it got turbid, there was protein in it.
So it's kind of a crude test, and the first steps of the purification process for heparin involved getting rid of protein. So when they do -- they tried to do a process validation and they used this turbidity test in the process validation, too. And they never showed that it was repeatable and --
REP. SCHAKOWSKY: Okay.
MS. BROWN: So it may not have been suitable for use as an in- process test and even as a finished product test.
REP. SCHAKOWSKY: And you reported that.
MS. BROWN: Yes.
REP. SCHAKOWSKY: Yes. You found that the equipment SPL used to manufacture heparin was unsuitable for its intended use, isn't that correct?
MS. BROWN: Yes.
REP. SCHAKOWSKY: And how was it unsuitable and why is this important?
MS. BROWN: There were three different pieces of equipment that I found unsuitable for use. The first one was these big polyethylene tanks that they dissolved heparin up in just prior to the last manufacturing step, which was the lyophilization, a freeze-drying step. And these PE tanks were scratched on the bottom -- very scratched -- as though somebody had been chopping stuff out of them with, you know, plastic, like, I could -- I ran my fingernail along it; it was like playing an accordion.
And there was also stuff adhering to the bottom of these tanks, and they were marked --
REP. SCHAKOWSKY: This is inside the tank.
MS. BROWN: On the inside of the tanks, where crude heparin would be right before it became the API. Right? So I scratched stuff off the inside of the tank, and this was a tank that was marked clean.
A second PE tank I turned over and liquid fell out of the handles, the molded, you know, PE -- it comes from a mold, polyethylene -- and stuff, a liquid, fell out of the handles into the bottom of the tank, and it was marked clean. So it wasn't a clean tank.
REP. SCHAKOWSKY: "Stuff." Do we know what stuff was in there?
MS. BROWN: The stuff I scratched off? No, I don't know what it was. It was a little gray-colored, it wasn't white. That's all I know.
Another piece of equipment that -- was the centrifuges that they use to get rid of the waste protein. They used two of them. They had one that would be in use, and then they'd clean the sludge out of the other one while -- to find out how long they should run the one that was going, like, will it last 30 minutes without getting too full?
And that was a very unusual manufacturing step. It wasn't described in the procedures for how to use the centrifuges, so you had to actually be at the plant to figure out what they were doing. Normally, you see one centrifuge and you run your material through it and separate the solid from the liquid.
The third piece of equipment that was a little -- that was outstanding to me was their lyophilizer. It was -- they didn't have the software that would provide for the person running it, for the parameters that he put in.
REP. SCHAKOWSKY: Well, what is that?
MS. BROWN: Oh, the lyophilizer is the big freeze-dryer. So you put in these trays of liquid and they turn into solid after days, sometimes. You freeze the liquid and then you warm it up slowly, and they're under vacuum so it turns into a solid material.
And all right, so for this lyophilizer there were no records of the actual parameters that were punched into the screen at the front of it, but there was no screen at the front of it. There was no way to tell what temperatures they actually used to dry the material.
REP. SCHAKOWSKY: So this is clearly substandard or not up to par on what should be.
MS. BROWN: Yeah, the settings weren't there.
REP. SCHAKOWSKY: They just weren't there. Why couldn't Baxter's audit have found these things, do you think?
MS. BROWN: I don't know. I walk through facilities as part of my inspection. I don't know if they did that.
REP. SCHAKOWSKY: Hm. In your book, if you would -- do you have it? The -- oh, it's over -- okay. If you could hand that to her.
Page 18 -- if someone could help me, I want to turn to that too.
It says 18, which is Exhibit 18 in the exhibit book.
MS. BROWN: Okay.
REP. SCHAKOWSKY: Okay, Item F of that EIR states the following: "There was" -- where are we? Okay. "There was no person with special knowledge of heparin at the firm to guide decisions made by the quality unit."
So, Ms. Brown, I would assume that if a plant was making heparin API it would want to have a person with, quote, "special knowledge," unquote, of that product in case deviations from any manufacturing process were observed. Wouldn't you agree?
MS. BROWN: I think it's -- they had a quality unit there which consisted, I believe, of four people, and they were trying to track what was going on at the firm. The person with the special knowledge I mentioned because when I arrived, they -- management was aware of that there were Baxter recalls and that there were adverse drug events and death in the United States. It was middle of February.
And the general manager of the firm, Mr. Wang, was the one who described the process to me and the process of how he thought that impure materials were removed from the crude heparin to make it into the heparin API. And he said he wasn't a heparin expert, and so he was really the person who gave me my fullest extent of knowledge during the inspection.
REP. SCHAKOWSKY: So he -- neither he nor the others had any special knowledge. He had the most knowledge, you're saying.
MS. BROWN: I believe so, yes.
REP. SCHAKOWSKY: Okay. Thank you very much; I think I've run out of time. Appreciate your answers.
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