A Long Wait for Ritonavir Capsules

As TI reported this summer, Abbott Laboratories encountered a serious problem in the manufacture of its protease inhibitor, ritonavir (Norvir), that forced a shutdown of production of the capsules and required all users to switch to the liquid formulation (see Treatment Issues, July/August 1998). In an October meeting at their headquarters outside of Chicago, Abbott officials announced that the original capsules would not be seen on the market again. The company will have to formulate a new capsule version to insure continued bioavailability of the active drug. Although Abbott representatives could not say how long this process would take, they did confirm that it could not be completed until sometime in the first half of 1999 at the earliest. In the meantime, ritonavir users will have to make do with the liquid. Finally, Abbott provided assurances that the current problems are not interfering with the development of their new protease inhibitor, ABT-378.

The Problem

In mid-June, production lots of ritonavir capsules started failing quality control tests. The ritonavir in the capsules did not dissolve properly due to the sudden appearance of a new, less soluble crystalline form of ritonavir (dubbed Form II by Abbott). Crystals are a rigid assembly of molecules that pure solid substances such as drugs assume as they separate out of solution. At the end of the manufacturing process, a drug may be able to precipitate several crystalline forms, but the structure of the drug's individual molecules remains the same as when it is dissolved.

Although the appearance of new crystal structures in drug manufacturing has been known to occur, it is unpredictable. Abbott maintains that it detected no sign that such a phenomenon was imminent. Obviously, subtle changes occurred in the manufacturing process, perhaps due to aging of the equipment or to increased production. Once Form II appeared in the manufacturing process, it predominated because it is more stable than the original crystal structure (Form I).

Abbott was unable to prevent the dominance of Form II crystals in the production lots despite attempts to clean and replace equipment. The construction of a new facility was undertaken in Puerto Rico, but later discontinued because of the potential of the problem emerging again. Abbott is now focusing all its attention on developing a new capsule formulation that will assure the bioavailability of the drug, in Form I or Form II.

Soft Elastic Capsules

Even prior to the appearance of Form II, Abbott was developing a new 200 mg capsule version of ritonavir, called the soft elastic capsule (SEC). The SEC would allow ritonavir to be stored unrefrigerated and taken without food. It was nearly ready for FDA approval at the time of the emergence of Form II. Abbott has now adjusted the nonritonavir components within the SEC to keep the active drug in solution within the capsule despite the appearance of Form II crystals.

Bioequivalence must be demonstrated between the SEC and the old "semisolid" capsule before the FDA will grant marketing clearance. According to Eugene Sun, M.D., Antiviral Venture Head at Abbott, this can be accomplished through a relatively small, phase I pharmacokinetic study in healthy volunteers. As long as the exposure of ritonavir is equivalent between the SEC and the original semisolid capsule, there should be no need to conduct head-to-head comparisons of virologic response because the original formulation has already demonstrated adequate antiviral activity. Abbott will also have to establish that the SEC will remain stable under its specified storage conditions. The length of time needed to demonstrate stability will be negotiated between Abbott and the FDA.

Dr. Sun stated that Abbott has produced only small batches of the new SEC until now. The company needs to manufacture larger lots to insure the quality and uniformity of the SEC product. Only then will the SEC undergo testing in humans.

Ritonavir Liquid

Until the SEC is on the market, ritonavir is available as a liquid. This version has been on the market since the FDA approved ritonavir and is generally used for pediatric patients. The oral solution is not affected by the appearance of Form II crystals because its composition prevents the active drug from crystallizing. As a further safeguard, the storage conditions have been revised. Abbott no longer advises refrigerating the liquid, as crystals form more readily at lower temperatures. According to Dr. Sun, crystals theoretically cannot form in the oral solution at room temperature (between 68° and 77°). If the liquid solution does get too cold and crystals appear to have precipitated, giving the liquid a hazy appearance, it may be possible to redissolve them by warming the bottle and then shaking the contents. If there is a continuing problem, it is advisable to return the liquid to the pharmacy for a fresh bottle. Ritonavir's liquid formulation must be used within 30 days of dispensing.

Many people find the flavor of liquid ritonavir distasteful. Abbot is seeking to alter the liquid's composition to improve palatability. In the meantime, a consumer survey was conducted to determine which foods could best ameliorate the taste of the present liquid formulation. The top four products selected represent a motley collection of brand names: Nutella Hazelnut Spread on graham crackers, Oats n' Honey Crunch Granola Bars, peanut butter crackers and Riesen Chocolate Chews. These foods reduced the intensity of the medicinal aftertaste two and ten minutes after the liquid was administered.

Some ritonavir users are making their own ritonavir capsules by using eyedroppers to fill empty gelatin capsules with the liquid formulation. Such capsules must be used soon after they are opened and filled. Otherwise the liquid will start breaking through the capsule walls. Abbott emphasizes that no studies have been conducted on this method. It is possible, the company says, that the ingredients used to make the gelatin capsules will interfere with the activity or bioavailability of the drug. Anyone attempting to do this should check with his or her physician or pharmacist on dosing and other concerns. Another alternative method is to use an oral syringe to shoot the liquid behind the tongue and into the back of the throat.

Back to GMHC Treatment Issues October 1998 contents page.