About IAPACEducationAdvocacyConferencesWhat's NewPublicationsJoin IAPACContact UsLinksMain Page

Norvir Advisory

The following presentations were taped and edited by the International Association of Physicians in AIDS Care. Some of the questions were not included because they were not audible on the taped recording, or were not pertinent to the topics of the update.

Norvir Community Update - 10/15/98
Abbott Laboratories, Abbott Park, Illinois
Presentation 3

Steve Lichter
International Pharmaceuticals Manufacturing
Abbott Laboratories

Additional Comments By:

Eugene Sun, MD
Head, Antiviral Venture
Pharmaceutical Products Division (PPD)
Abbott Laboratories

Bill Calhoun
Director, HIV Franchise
Pharmaceutical Products Division (PPD)
Abbott Laboratories

John Bauer, PhD
Abbott Laboratories

LICHTER: I would like to begin by defining two terms. This may be a little redundant after Professor Byrn's presentation, but it is very important that everybody here understands these two terms which are at the crux of the problem that we are here to discuss today. The first term is polymorphism which is the ability of the element or compound to crystallize as more than one distinct crystalline species or form. When polymorphism occurred in Form I ritonavir, we discovered a new form of ritonavir - Form II ritonavir. Form I ritonavir is chemically the same as Form II ritonavir. However, the physical properties of Form II ritonavir are different than the physical properties of Form I ritonavir. One of the physical properties of Form II ritonavir that differs from Form I ritonavir is its dissolution - the next term that we will define.

Dissolution is the ability of a substance to dissolve. Form II ritonavir dissolves slower that Form I ritonavir. Consequently, Form II ritonavir was not bioequivalent to Form I ritonavir in the dosage forms that we had on market at the time and in the soft elastic capsule (SEC) application that had been filed with the FDA. That was the crux of the problem from both a scientific and regulatory perspective.

Some background information about how ritonavir is manufactured may be helpful before we discuss what Abbott has done since the problem was first discovered. Most of the bulk ritonavir drug is made here at our North Chicago site and the rest is manufactured in our Italian site. The semisolid capsule was made in the plant here that I work at. About half of the oral solution of ritonavir is also made here in North Chicago, and the other half is made by our affiliate in the United Kingdom. The soft elastic capsule, or SEC, that we have been discussing, is made by a third party.

At the time the polymorphism occurred, most of the ritonavir taken by the 70,000 people worldwide was manufactured in the semisolid capsule. So within a few weeks time, we were faced with converting our manufacturing process from capsule to liquid to continue providing ritonavir to these 70,000 people. Here is a slide that may give you an overview of our manufacturing process. On the far right is the tail end of the manufacturing process - the capsule production that is here on site at Abbott Park. Before the drug is manufactured into capsules, we have the final synthesis that produces the final bulk drug. This is where we encountered the crystals and seeding of the drug lots.

Before this final synthesis is where the intermediates come in. We have been purchasing most of our intermediates from outside companies that we have worked with. Over time, we have moved some of these intermediates into our own facilities.

QUESTION: Why did you wait so long to tell us? Why did we hear so late?

LICHTER: We got the word out as fast as we could subject to the regulatory dynamics which we were required to follow. But to understand what may have appeared to you as a delay, it is important to understand the manufacturing process and the scientific and regulatory dynamics that essentially controls this process.

This is why I started with a definition of dissolution. The procedures for dissolution testing of ritonavir are different than those for any other drug that we make. This is due to its gelatin nature. When we make the gelatin capsule, it takes considerable time to put the drug into its final form. With most pharmaceuticals, we do dissolution testing within minutes of making the tablets. However, with ritonavir we have to wait five days to do the dissolution test. So we don't know if we have a possible problem for five days. Then we still don't know how serious it is, because there is a two-tiered process to validate a possible manufacturing failure. This two-tiered process is the FDA-approved specification that we are obligated to follow.

Here is how the two-tiered process works. If the drug does not pass the dissolution test on day five, then we are required to hold the capsules until day 25 at which time we run a second dissolution test. If the drug passes the second dissolution test on the 25th day, then it is considered a good product and we can release it. We discovered a possible manufacturing problem for the first time at the end of May and in early June. We has some batches or lots of drug that failed to pass the first dissolution tests. We were deeply concerned about a potential problem, but we had to wait until the 25th day to conduct the second dissolution test. Meanwhile, we went on trying to correct the problem, but at the same time we had the responsibility to manufacture ritonavir to support the market. So we didn't have a confirmed failure until the end of June when the second tier dissolution 25-day testing didn't pass.

Here is the history of the problem. In this late May to early June time frame, we had ten successive batches or lots of drug that failed. Previous to that we had manufactured about 240 batches of ritonavir and none of those batches had ever failed a dissolution test. They were all well within the FDA-approved manufacturing specifications and were good products. So we began to investigate why these lots had failed the dissolution tests. We discovered the emergence of a new crystal, a new polymorph form, which we called Form II. This form, as we have explained, has different physical properties than the initial form - specifically a slower dissolution and reduced solubility.

QUESTION: So all the capsules come through Abbott here in Chicago, allowing you to test them better because they're all in one spot?

LICHTER: Yes. All the semisolid capsules were made across the street. They were distributed to the United Kingdom for final packaging for the European market. All the other markets were packaged here. It was one location, one analytical lab, and really one organization that released the product.

Here is a graph that may help illustrate this process. This goes back to the first part of 1997. These are our dissolution results. As you can see, we were manufacturing drug, testing each of the batches as part of the quality control process, and then boom, in the May/June time frame the results fall off the map. There was no general trend. There was no gradual trend. Something occurred that caused the new form to occur and created the failure. There was no early warning.

At that time, we had identified the new form in the laboratory. All that we knew about this new form was that the presence of the new form correlated with dissolution failure. We did not know how to detect for the new form. We did not know how to test for it. We did not know what caused it. We didn't know how to prevent it. And we kept asking the question, why now? Why did it occur now after 240 successive trouble-free lots? We did not know the physical properties of the new form, although we subsequently did a lot of work to determine that. We did not know how to clean it, and we did not know how to get rid of it.

As you'll see in a few moments, our initial activities were directed towards eliminating Form II from our environment. Then we finally accepted that we could not get rid of Form II. Then our subsequent activities were directed to figuring out how to live in a Form II world.

This slide shows the different crystalline structure between Form I and Form II. Form I is the longer than what we expected to see, more rod-like. They resemble tongue depressors. Form II is more needle like. But as you can see, both Form I and Form II are still chemically equivalent. But when magnified a hundred times under the microscope, we see a completely different physical form.

Let us discuss the progressive nature of Form II. We first identified Form II in our primary capsule line at the Abbott Park plant where we made the semisolid capsules. When we identified the new form, we immediately went to a different manufacturing line. We had two manufacturing lines: a small scale line that we used for launch; and a larger scale line that we used for the commercialized product. We went to the secondary line to manufacture ritonavir. Shortly thereafter, we found Form II crystals in the secondary line. We reconditioned the second line that was designed for oral dosage pharmaceuticals and tried to make it a clean room, such as we use for injectables. We redesigned it: put in new tanks, new piping, and a new filtering system for cleaner air to try to remove Form II from the product. That failed. The first batch of capsules off the line had crystals in them. Shortly thereafter, our analytical laboratories became contaminated. We rebuilt the primary line, making the same type of investment that we made originally, to try one more time to get rid of this problem. That failed. Form II appeared again.

As I mentioned, we had an SEC application filed with the FDA for which we were waiting approval. We began the validation lots on those products at our third-party company. Crystals formed there immediately. Then we worked back into our bulk drug and oral liquid, both in Italy and North Chicago and discovered the presence of Form II crystals.

Abbott responded to this problem through a unique dynamic process in which the entire infrastructure of Abbott reorganized around the problem. There was one oversight team of top senior staff at Abbott. From the beginning, they met daily, sometimes more frequently, often through the weekends, to oversee the problem-solving efforts to bring ritonavir capsules back on the market.

There were several sub-teams of three to 600 people per team working full time in different areas. We also called on as many resources as we could. Our pharmaceutical product development group and technical center in the United Kingdom were both heavily involved, as were some of the technical specialists from our chemical and hospital divisions, and from corporate engineering.

Steve Byrn and several other consultants joined us. We used contract labs, our discovery group, and our drug safety group. Our chairman of the board was there from the onset. He attended several of the meetings. His directions were clear. He told us is that it didn't matter what it cost to guarantee that no patient would have his or her supply of ritonavir interrupted. We would continue to supply all patients. The imperative from senior management was to provide uninterrupted therapy for our patients regardless of the cost.

We tried everything. We conducted countless experiments. We reconditioned our facilities. We rebuilt facilities and new lines. We looked at alternative sites. We visited a number of hard-capsule-filling organizations around the world. We looked at procuring their capacity to see if we could start clean in a new environment free of Form II.

We committed several million dollars to building a new plant in Puerto Rico with an eight-week completion schedule. We halted that activity when we discovered Form II in the semisolid capsules and realized that we didn't have a product free of Form II that we could bring to market. And those millions of dollars that we had committed to the project could not be recovered.

And quite honestly, having lived through this for several months, we were pretty ineffective. Although we had a backup in terms of the Norvir liquid, none of us were pleased in having to rely on this backup. As some of you may done, we were also losing sleep about this problem. Our objective was to continue to supply capsules to everybody that was on capsules and wished to be on capsules. It didn't work out. We were ineffective. But we had to explore all of these possibilities before we focused all of our efforts on the soft elastic capsule.

We also have the responsibility to maximize the available semisolid capsule supply throughout the world. Once we knew we were going to have to convert to the liquid formulation. We tried to distribute the remaining capsule supply as equitably as possible. We managed that as well as we could. And then we tried to make an orderly conversion to the liquid - which Rob Dintruff will talk about later.

QUESTION: Could you explain more about the new facility in Puerto Rico?

LICHTER: We were building a new facility in Puerto Rico. We made capital and engineering investments to start that facility. The facility was to make the semisolid capsules, the existing product, the existing formulation. And when we learned about the solubility of the Form II crystal, we knew that this new facility designed to produce the semisolid capsule could not give us a product that we could rely on. So we halted the project. In a matter of weeks - maybe five or six weeks, every place the product was, became contaminated with Form II crystals.

QUESTION: So you don't think this happened independently? You think there was something, that something was transferred from one lab to the other?

LICHTER: I believe that something happened in Lake County and, within two months, it somehow spread to every other facility. It is inconceivable to me that these were all independent occurrences. We know that these molecules could transfer on individuals going from the production area to the lab or to product samples.

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.

QUESTION: Can you do anything to improve the taste of the liquid

SUN: None of the protease inhibitors are easy drugs to formulate. This is why you don't see the other protease inhibitors being formulated as liquids. You have to use ingredients that do not taste particularly good. If you are trying to formulate a liquid that is bioavailable, it must be capable of being absorbed. This requires solvents that often have an unpleasant flavor.

We initially tried nearly 200 different formulations with ritonavir to find that acceptable range between something that people could stomach as well as something that met the technical criteria that we needed. I will be one the first to admit that ritonavir doesn't taste good. All the people from Abbott here have tasted it. We even have people here that have tasted it every day for weeks to be able to better understand what some patients have contend with. We are all aware of the problem. Later you will hear about the results of a taste panel to find, in a systematic way, food items or tricks, that people have found to be helpful in at least masking the taste. However, we are limited to some extent by the solvents that we have to use to make the formulation.

QUESTION: There's a mail order company in Massachusetts - Medco, owned by Merck, that will not mail order Norvir. Who I can speak with about that and find out what has to happen so that they will approve whatever the shipping requirements are to get that drug to clients?

CALHOUN: We are working with Merck and Medco to ensure that our drug is shipped via their mail service. We provided them with additional information and we are in process of working with them to rectify the situation.

Posted 12/28/98