Interview with Eugene Sun, MD, by Charles Farthing, MD, Medical Director, AIDS Healthcare Foundation, Los Angeles, and Chair, IAPAC Norvir Advisory CommitteeFarthing: Although the majority of my patients on ritonavir are making an uneventful switch from capsules to liquid, I attribute at least part of this success to the fact that I spend time with them to explain the manufacturing problem, and answer any questions they may have without making the need to switch a big issue. However, I realize that some physicians, who may not have had the experience that I and others have with ritonavir, have valid concerns. It might be helpful to them if you could address some of these concerns directly. Let's begin with your position and responsibilities at Abbott Laboratories.
Sun: I lead the team responsible for clinical development of Norvir (ritonavir) and ABT-378, as well as Abbott's other antiviral compounds. We're responsible for doing everything involved in bringing a drug from the lab all the way to the filing of a New Drug Application (NDA). We design and conduct clinical studies, work with investigators and regulatory bodies around the world, and do everything we can to understand and enhance the safety and efficacy of the pharmaceutical compounds we study.
Farthing: What role do you have in solving the manufacturing problem with Norvir capsules?
Sun: Part of our charter in developing drugs is to formulate them, i.e., to make pure drugs into capsules, tablets, solutions, etc., or what we call "dosing forms" that patients can take. As the Norvir problem seems to be one of formulation, Im involved in troubleshooting the situation and examining remedies, including alternative formulations.
Farthing: When did Abbott first contact the FDA about this problem, and what was the FDA's response?
Sun: We contacted the FDA in July, shortly before we made our annoucement, and as soon as we realized that we wouldn't be able to manufacture enough capsules to meet patient needs while we tried to solve this problem. We met with them to brief them on the situation and discuss our communications. They were extremely helpful, understanding the urgency of informing the public about the situation and working with us to find a solution. In fact, we benefited from their experience as they've seen similar problems before with other products.
Farthing: What role and responsibility does the FDA have in overseeing Abbott's resolution of the manufacturing problem?
Sun: As always, the FDA's charter is to ensure that food and drug products are safe and effective for consumer use. We've been working very closely with the agency on this. They share our goal of getting Norvir capsules back into use as soon as possible for the people who need them. We need to show the FDA that we can produce Norvir capsules that will meet that charter. They've committed to helping us expedite that process.
Farthing: Could you name some of the experts that are working with Abbott to solve the crystallization problem?
Sun: Our primary advisor has been Steve Byrn, the Dean of the School of Pharmacy at Purdue University. Hes an expert on polymorphism -- which is the phenomenon were experiencing with ritonavir -- and has worked on similar situations in our industry before.
Farthing: There appears to be some confusion about the crystallization process. Would you explain exactly what is happening and how it affects the efficacy of Norvir capsules?
Sun: Crystals are simply a form that solid substances can take, especially highly pure substances, such as drugs. This is an important point: there is no contamination of Norvir with any foreign substance. In fact, in formulating ritonavir, as with many other drugs, we start with pure crystals of the compound. What has happened is that a new crystal form of ritonavir has appeared. Although it has the same purity, this form has different properties that make it more difficult fo formulate Specifically, the crystalline structure makes ritonavir dissolve more slowly from its original capsule formulation, which affects its bioavailability.
Farthing: Did Abbott recently change the manufacturing process of Norvir in a way that may have contributed to the crystallization process?
Sun: We, quite honestly, have not been able to pinpoint the precise conditions which led to the appearance of the new crystal form. We now know that the new form is, in fact, more stable than the earlier form, so nature would appear to favor it.
Farthing: There have been questions about the possibility that crystallization may have occurred in previous capsules, but that it was simply undetected. How do you respond to those concerns?
Sun: We are quite sure that this has not occurred in previous capsules. This problem was detected on routine quality testing of the capsules prior to their release. This is an extremely rigorous process that is constantly reviewed. Furthermore, we retain samples from every batch of drug produced, and we've examined them thoroughly. Form II is new.
Farthing: Has there ever been any crystallization problems with the manufacturing of Norvir liquid?
Sun: Norvir liquid is unaffected by the Form II crystals, as long as its stored within the indicated temperature range. We have altered the recommended storage conditions to further safeguard against the possibility of crystals in the liquid.
Farthing: Could you compare the similarities and differences between the manufacturing of Norvir liquid and Norvir capsules?
Sun: Both the capsule and the liquid use the same purified ritonavir. They also share a few ingredients in the formulation. However, the formulation processes are very different; they are done in different plants with very different equipment and procedures.
Farthing: There have been some concerns that temperatures may be an issue in the formation of crystals and that was the reason for the recent change in the label indication for storage temperature. Would you comment on these concerns?
Sun: Temperature is an important factor in the balance between the dissolved and the solid -- or crystalline -- state of not only Norvir, but all chemical substances. The alteration in recommended storage conditions was undertaken to safeguard against the possibility of crystallization following the discovery of the new ritonavir crystal form.
Farthing: Could you explain the new storage temperature guidelines and the data that supports these guidelines? (See Question 4 on Abbott's Frequently Asked Questions for information about new temperature recommendations. Also, see Practical Considerations on New Temperature Guidelines for Norvir Liquid.)
Sun: Norvir liquid should be stored at room temperature -- between 68º and 77º Fahrenheit (20º - 25º Celsius) -- and shaken well before using. The reason we changed storage to room temperature was really as a precautionary measure. We think there is the potential, though small, for crystals to form if the liquid remains refrigerated, while it is exceedingly unlikely that they would form if the liquid is kept within the recommended temperature range. Shaking the liquid before each dose means that any crystals that could form would dissolve back into the liquid, ensuring the liquid retains its potency for every dose. (
Farthing: What about greater extremes in temperature? Is there data on the consequences of storage of Norvir liquid at higher temperatures? What happens if there is a "brown out" and/or electricity is lost and someone's home temperature shoots up to 100 degrees-plus for several hours?
Sun: Temperature extremes should be avoided if possible. As with all drugs, maintaining optimal storage conditions ensures that they retain their potency. However, it is important to realize that it is not an on-off situation, but a gradation. Short excursions outside the recommended range are less consequential than prolonged ones -- but precisely how consequential, we cant say with any certainty.
Farthing: What have you learned since the manufacturing problem occurred? Are there potential causes of crystallization that can be totally ruled out? What are some of the theories you are not checking out?
Sun: Our approach is twofold: to try to understand the conditions that favor crystallization, and to also accommodate the new crystal form in our formulations.
Farthing: Has this been a unique experience in the pharmaceutical industry, or have other companies faced similar problems?
Sun: We know that others have had very similar problems. A parallel situation occurred in the manufacturing of ranitidine [the widely used acid suppressant Zantac]. The issue was satisfactorily resolved in that case, and we hope to do the same.
Farthing: If you had a son or daughter who was HIV-positive and on Norvir capsules, what advice would you give them?
Sun: I'd give my child the same advice I've given patients who have called me directly over the past month. If they are successfully being treated with Norvir capsules, I would advise them to transition to the liquid. With the life and death nature of this disease, a treatment regimen that works just shouldn't be disrupted. I know that the liquid isn't as attractive a formulation for many patients as the capsules, but it is still Norvir.
The Problem Consequences Tolerability Temperature Portability Adherence Regimens
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