|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
International Pharmaceuticals Manufacturing
Additional Comments By:
Eugene Sun, MD
Head, Antiviral Venture
Pharmaceutical Products Division (PPD)
Director, HIV Franchise
Pharmaceutical Products Division (PPD)
John Bauer, PhD
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
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
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
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
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
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
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
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.