LSR O-rings adding to HIV protection

Intra vaginal rings have been made for many years in various polymer materials such as EVA, LSR and polyurethane elastomers and thermoplastics, to slowly release active pharmaceutical ingredients. This has been in the form of polymer “reservoir rings” (“core”) with a hollow core containing dissolved APIs, “sandwich” (“shell”) ring versions or solid “matrix” rings with one or more APIs incorporated within the polymer matrix.

Researchers at Queens University Belfast in Northern Ireland have observed that reservoir and sandwich rings involve complex production but release API at a low but constant rate, while matrix rings are easier to produce, but with a tendency of some API level depletion with time in the outer part of the material.

Results of clinical trials published in February 2016 by the non-profit organization IPM International Partnership for Microbicides in Silver Spring, Md., and MTN Microbiocide Trials Network found an LSR matrix ring containing 25 milligrams of the antiretroviral non-nucleoside reverse transcriptase inhibitor drug Dapivirine had reduced HIV infection rates by respectively 31 and 27 percent when used for 28 days.

QPharma AB in Malmö, Sweden, produced the platinum catalyzed LSR O-rings of outer diameter 56 millimeters, thickness 7.7 millimeters and weighing 8 grams used in the trials. The company has been producing this type of ring by static mixing micronized Dapivirine API dispersed with 30 percent silica in silicone oil in equal proportions into both LSR A and B components.

The LSR used by QPharma comes from Trelyst LLC, as subsidiary of NuSil Technology LLC, set up in Carpinteria, Calif., to focus on medical silicone applications.

The materials are mixed and dosed at QPharma with 0.001 mm precision,

using PFM Process Flow Mix equipment from 2 Komponenten Maschinenbau GmbH (2KM) in Marienheide‑Rodt, Germany. Injection molding takes place with 6.5 seconds injection time via a 232 gram injection unit and with 250 bar holding pressure in a 16-cavity mold from Rico Elastomere Projecting GmbH in Thalheim/Wels, Austria. The mold is equipped, as usual with LSR injection molding, with a cold runner system, preventing premature vulcanization outside the hot mold.

Rico talks with pride about low 0.145 mm outer diameter deviation and maximum 20 mg weight deviation across the 16 cavities. The low weight deviation and high mixing homogeneity are both crucial to ensure that the required amount of Dapivirine is available for HIV protection, within a range of 22.5 to 27.5 mg. QPharma controls this with Raman spectroscopic inspection equipment, along with optical dimension.

The mold has a seal around the cavity area and is mounted on a stainless steel-housed 150 metric ton electric drive Allrounder 520A 1,500‑400 injection press from Arburg GmbH + Co. KG in Lossburg, Germany. After one to two minutes vulcanization in the mold at 185° C, a six-axis articulated arm industry robot from Kuka AG in Augsburg, Germany, removes sets of 16 rings at a time, held with hangers on a stripper plate, and lays down the rings onto a conveyor belt by tilting the stripper plate. The robot is a key feature of the automation system designed by FPT Robotik GmbH & Co. KG in Amtzell, Germany, and it operates in an ISO Class 3 ionized clean room environment that also includes the mold area. Arburg says it had overall responsibility for the entire turnkey vaginal ring production cell at QPharma.

Following publication of successful HIV protection clinical trials with QPharma's Dapivirine based LSR vaginal ring, IPM said the next moves are open-label studies and regulatory review, with product launch foreseen for 2018.

The IPM Access Strategy report in May 2011 estimated that at a potential low 0.5 percent rate of market uptake, 786,000 rings would be required in the first year, requiring around 60 kg of Dapivirine as API.

Supported by more than 35 years of manufacturing and analytic testing experience with fast scale-up capability, QPharma was contracted by IPM in 2010 to produce vaginal O-rings with Dapivirine embedded in the LSR matrix. The decision followed a competitive bidding and evaluation process for secondary manufacturing during the Phase III evaluation stage leading to 2016 clinical trial results.

The IPM Access Strategy report estimated that relatively small-scale monthly production of Dapivirine LSR matrix O-rings during Phase III would involve a $7.95 per ring production cost.

QPharma managing director Kenneth Stokholm later addressed volume-related production costs in a September 2014 live webinar hosted by the CAMI coalition on advancing multipurpose innovations, on manufacturing issues under the IMPT initiative for multipurpose prevention technology. Stokholm showed a graph in which production of 100,000 rings per year should cost around $50 a ring, falling to $10 per ring at one million per year and $3 per ring at 10 million per year, as fixed costs become less significant with rising production volume.

IPM's May 2011 Access Strategy report referred to equipment at QPharma as capable of producing 2 million to 3 million rings/year, adding, “negotiations with manufacturers and increased volume would most likely drive the cost down considerably.”

It added, however, that as there was no direct competitor (to the Janssen Sciences Ireland UC subsidiary of Johnson & Johnson) for the Dapivirine microbiocide product, it will be difficult to set a launch price for the LSR rings, potentially in late 2018.

Speaking at the October 2015 MTN regional meeting in Cape Town, South Africa, on the Dapivirine ring roadmap, Dr. Zeda Rosenberg, IPM founding CEO said that although QPharma will be retained as the commercial launch partner, IPM is also working with Trelyst as a potential long-term, low-cost commercial supply partner, saying Trelyst already had capacity in place to meet commercial demand, with ability to scale up. Rosenberg expected a launch price of around $5 a ring, with potential to fall to around $2 a ring.

IPM is working on a 90-day Dapivirine LSR matrix ring, also in a dual version preventing HIV and as a contraceptive to prevent pregnancy. A Phase I trial of such a multipurpose ring containing Dapivirine and a contraceptive hormone has been planned for April 2017. The ring technology may also be adapted in future to deliver ARVs targeting HIV at different points in its life, potentially providing greater protection than a single drug alone and reducing chances of acquiring drug-resistant HIV.

In its 2015 annual report, IPM talks about pioneering prototypes of the first Dapivirine/Maraviroc ring together with Oak Crest Institute of Science, which should release higher levels of Maraviroc, for which IPM acquired a royalty-free license with ViiV Healthcare in 2008. It has suspended development with Maraviroc however, suspecting its microbiocide efficacy may be limited.

But IPM considers Darunavir potent protease inhibitor from Janssen Sciences Ireland UC as being a promising ARV product for combined drug embedded vaginal O-rings. Prototypes of such rings are in development.

Kenneth Stokholm at QPharma stated in May 2014 that QPharma had started working with scientists on a LSR vaginal ring with controlled hormonal drug release to treat cancer, saying such a ring could be available by around 2019.

With its LSR competence center in Stein am Rhein, Switzerland, Trelleborg Sealing Solutions AG (TSS) says the site is one of four worldwide sites specializing in LSR. Some 48 of the 62 injection molding machines in Stein am Rhein are from Arburg.

Out of a seal market estimated by Global Analysts Inc. as reaching a value of $45.8 billion by 2020, TSS says O-ring seals are the most commonly used type of seals. Aside from industrial seals, TSS now also focuses on medical LSR O-rings, but without referring to drug delivery functions.

Instead, it likes to talk with pride about “tiny” 1.1 mm inner and 1.4mm outer diameter micro O-rings. TSS general manager in Stein am Rhein, Jarno Burkhardt, points out to LSR O-rings advantages of precision molding without any flash, unlike with other elastomers, “which require secondary process steps of cutting, punching or cryogenic deflashing, introducing process variability and manufacturing risks, along with added direct and potentially indirect costs.”

TSS faced challenges in handling such small O-rings, requiring development of a special robot gripper for the lightweight 0.0093 g parts. It also designed a special “Ionicator” ionization device to discharge static electricity from the parts, as they were failing to fall into designated containers, due to static charges and their “feather-like” weight. The rings are molded in 32-cavity tools with separate injection into each cavity. TSS will use 64‑cavity tools “as the next step.”