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Norvir Advisory

Temperature Questions & Answers
from Presentation 3, Norvir Community Update

Exerpt from Presentation 3, Norvir Community Update - Steve Lichter, MD

QUESTION: If heat affects the solubility, couldn't ritonavir be taken with warm water to improve the solubility?

BAUER: Solubility depends on what you're trying to dissolve it in. The solubility of Form II in water is very low regardless of the temperature. So that wouldn't work. The concept of warming something up to get it to dissolve is, as Steve said, the basis for storing the oral liquid at a higher temperature.

LICHTER: I also want to discuss alternative labeling. This is what has allowed us to stay in the market today with the oral solution. A change in labeling was negotiated with the FDA, EMEA, and many agencies around the world shortly thereafter. We had data to support the six month shorter shelf life and that tight temperature controls. That gave the agencies the assurance that, whether it's Form II or Form I, we still have an effective bioavailable drug.

Although it's hard for me to pinpoint the exact time and date without going back to the files, we finally figured out we couldn't get rid of Form II. That was when we began to accept that we were in a Form II world. And in a Form II world, we realized that the dosage forms that we were offering at that time were not going to work. So then we worked rapidly to get a new product out, with a dosage in which ritonavir, whether it's Form I or Form II, would be bioavailable in the body.

Where are we now? We still don't know and may never know whether the bulk drug or the formulation was the cause of the original problem. One hypothesis is that an event occurred somewhere along the line to cause Form II to be created. We're not able to recreate that event or discover what that event was, if indeed an event occurred. Our other hypothesis, which is probably better supported, is that we more likely had a set of conditions in which the bulk drug was produced in or the dosage form was produced in that enabled ritonavir to learn the new crystal form. And if you go back to the literature, impurity profile changes in the drug, pH changes in the drug, temperature cycling, these are environmental changes that have in the past caused new forms to develop.

It is more probable that an environmental change created Form II, but I doubt if we will ever know for certain. All markets are currently converted to the oral solution under the new labeling. We are still making bulk drug and we are attempting to inhibit the Form II. We are trying to make bulk drug that is nearly all Form I. We are also making liquid and soft elastic capsules those that will accommodate either 100 percent Form I, 100 percent Form II or any ratio in between. So we are proceeding down both paths.

We are also working on a reformulation for the oral solution to get us out of the temperature requirements with which some of you have been trying to contend. We are also trying to expand that temperature range as rapidly as possible, at least to get it back into the refrigerator. We are also working on a longer shelf life than six months.

The final point is our rapid reformulation of the SEC. What helps us is that we had an SEC product application filed with the FDA. It was going to be both 100 milligram and 200 milligram strength. It was going to offer less capsules per day with the 200 milligram strengths. It was going to have an improved temperature storage profile than the current medication. We were very excited about it and we were near approval with that product when the Form II occurred. All that we have done with that formulation is to make as few minor modifications to that formulation to allow our new SEC to handle Form II.

QUESTION: What do you mean, handle Form II?

LICHTER: The bulk ritonavir that goes into the formulation on a lot-by-lot basis could either be the Form I ritonavir, Form II ritonavir, or anywhere in between. We are reformulating the SEC so that it will handle the worse case scenario.

QUESTION: But it has to be tested?

LICHTER: Absolutely. It has to be tested.

Posted 12/28/98

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