Hints of new science emerge in a field of growth for pharmaceutical services firms.
Earlier this year, 四色AV announced a partnership with a Danish firm that has developed a whey protein鈥揵ased excipient meant to enhance spray-dry dispersions. 四色AV saw in Zerion Pharma鈥檚 Dispersome a means of advancing its services addressing bioavailability in drug formulation. Zerion, launched in 2019, saw a clear advantage in teaming with a well-established pharmaceutical services firm recognized as a leader in spray-drying services.
A few months later, Nanoform Finland, a nanoparticle engineering specialist based in Helsinki, announced a partnership with the specialty drug firm Pharmanovia, which will apply Nanoform鈥檚 nanoparticle technology and formulation know-how to improve the bioavailability of drugs in its product line.
Zerion and Nanoform are among the growing number of firms trying to deal with problems related to drug bioavailability. Their approaches are welcomed by industry observers, given the increased urgency of such problems and the relative sparsity of technological innovation.
Bioavailability, a measure of the portion of an active drug substance that enters the body鈥檚 circulation and affects the drug鈥檚 target, may not be the steepest challenge faced by developers of new therapeutic compounds. But it may well be the most pervasive. By many estimates, 70鈥90% of new small-molecule oral drugs have problems related to solubility and absorption.
These problems have been exacerbated in recent years by the increasing complexity of drug molecules, especially in the oncology arena, according to Peter Bigelow, president of xCell Strategic Consulting. The speed with which innovators need to move forward in development has also resulted in a growing market for particle engineering and design, he says.
鈥淏ecause speed is kind of the most important objective of so many of these programs, changing the chemistry is not something they have the luxury to do,鈥 Bigelow says. 鈥淎 sponsor company will say, 鈥業 can鈥檛 take a year off to come up with a new synthetic route. So you鈥檝e got to make this route to work.鈥欌夆
Bioavailability services first emerged among providers specializing in formulation rather than at contract development and manufacturing organizations (CDMOs), whose primary service centers on the manufacture of active pharmaceutical ingredients (APIs). But the field has shifted over the last decade with the broadening of service offerings among CDMOs and the emergence of a one-stop-shop approach.
BEYOND API MANUFACTURE
One of the most popular techniques for improving bioavailability is spray drying, a method for converting poorly soluble APIs into an amorphous dispersion by dissolving the API and a polymer exipient in an organic solvent and evaporating the solvent with heated gases. 四色AV was an early adopter, investing in its first spray-drying capacity in 2004, but not with an eye toward improving bioavailability of customers鈥 drug candidates.
鈥淭his is a good example of taking the right decision for the wrong reason,鈥 says Guy Villax, who stepped down as CEO of the family-owned company earlier this year but remains on its board. 鈥淚 was out in the market looking for business. I came across two inquiries that needed spray drying. We decided if customers were ready to make commitments, we were willing to invest.鈥
"To be successful you need more than the hardware." - Filipe Gaspar, chief technology officer
The contracts involved work on Captisol, a solubilizing agent whose manufacture required spray drying as an isolation technique. 鈥淭here was nothing strategic in terms of addressing poorly soluble molecules,鈥 Villax recalls. But as a result of those early contracts, 四色AV was in position to provide solubility services鈥攏otably for hepatitis C drugs鈥攁s the market grew.
四色AV significantly increased its spray-drying capacity in 2009, when it acquired a Pfizer plant in Cork, Ireland, that included what at the time was the world鈥檚 largest solvent-based pharmaceutical spray-drying tower.
Other CDMOs have added services more recently. Fabbrica Italiana Sintetici (FIS) adopted spray drying in 2017, when it opened a new facility at its headquarters plant in Montecchio, Italy. FIS also provides micronization, a process of physically and mechanically breaking up drug crystals, and lyophilization, a freeze-drying means of manipulating particle size. Its sister company, Brenta, is a nanotechnology specialist offering formulation services that address API absorption and bioavailability.
鈥淔IS is a drug substance manufacturer; we are not in drug product,鈥 says Luca Parlanti, the firm鈥檚 marketing director, using industry terms for active chemicals and finished drugs. 鈥淗owever, we recognized the increasing relevance of particle-size solid-state technology in general. It is important for a provider like ourselves to offer a forward integration into areas that bridge drug substance and formulation.鈥 Particle engineering is a method of addressing not only bioavailability but also processability, Parlanti says, 鈥渂ecause solid-state properties may impact the flow of a drug in the formulation process.鈥
BROAD PORTFOLIOS
Lonza, one of the largest contract API manufacturers, has extended services into particle design via acquisition. The company acquired Capsugel, a formulation services specialist, in 2016, 3 years after Capsugel bought Bend Research, a leader in spray-dry dispersion services. The Capsugel deal also netted Lonza micronization services, but the Swiss firm recently divested assets, notably a plant in Quakertown, Pennsylvania, that was acquired by investors and set up on its own as Microsize.
Lonza announced last month that it would introduce X-ray powder diffraction technology, an analytical tool to improve jet-milling micronization, at its formulation services operation in Monteggio, Switzerland.
The company鈥檚 sale of the Pennsylvania plant is the latest transaction for a business dating back to 1994, when it began as Powdersize. It changed hands twice鈥攑urchased first in 2013 by Microsize鈥檚 current CEO, TJ Higley, and then by Capsugel. Higley left after the Lonza acquisition and returned to head the company this year.
Higley says Microsize maintains its heritage of micronization, which he characterizes as a first line of attack in addressing bioavailability. He says the advantages of micronization include ease of process development and scale-up, an increase in particle surface area, processing at ambient temperatures, and overall low cost compared with its primary alternative, spray drying.
Higley sees Microsize in a strong position. 鈥淭he market is capacity constrained,鈥 he says. 鈥淭here is plenty of work out there, plenty of demand.鈥 Some drugmakers have responded by setting up in-house particle design centers, 鈥渂ut there are huge limitations because people aren鈥檛 experts at it.鈥 Nor are the in-house facilities typically capable of processing APIs from gram scale up to clinical and commercial scale, he says. 鈥淚 would say people are bringing early, small-scale micronization in-house,鈥 Higley says. 鈥淪o, at some point they are going to need to outsource.鈥
Catalent, another big services firm that has amassed particle design services, has bioavailability assets that date back nearly a century. 鈥淐atalent has been in the business of increasing oral bioavailability for oral delivery of active ingredients since the RP Scherer business was formed in 1933,鈥 says Cornell Stamoran, vice president of corporate strategy, referring to a company formed by Robert Pauli Scherer, inventor of the rotary die encapsulation process used to formulate soft gelatin capsules. 鈥淚 have a lab notebook in my office of one of the first R&D people on their second or third project, which was increasing bioavailability of fish oil.鈥
Scherer was purchased in 1998 by Cardinal Health, which spun out its pharmaceutical services business as Catalent in 2007. Catalent has since acquired Pharmatek Laboratories, a drug services firm with spray-drying capabilities, and Juniper Pharmaceuticals, an expert in spray drying, nanomilling, and hot-melt extrusion鈥攁 method of melting a substance and forcing it through a die to form a new structure; it is widely employed in plastics and has more recently been adapted to pharmaceutical particle design applications.
Thermo Fisher Scientific, a pharmaceutical services firm that took a leadership position in formulation services with the acquisition of Patheon in 2017, has also built a portfolio of bioavailability technologies. It added small-scale spray-drying dispersions with the purchase of Agere Pharmaceuticals in Bend, Oregon, which was formed in 2016 by the former CEO of Bend Research. Thermo Fisher added commercial-scale spray drying at a plant in Florence, South Carolina, shortly after acquiring the site from Roche in 2016.
The Roche site also added micronization to Thermo Fisher鈥檚 tool kit. And the company invested in small-scale hot-melt extrusion capacity in Bend before scaling up the technology at its plant in Cincinnati.
Both Catalent and Thermo Fisher have introduced systems to assess the most effective approach to formulation in early-stage drug development, including the selection of techniques to address bioavailability. Catalent has a program, OptiForm, that is based on a predictive modeling regimen it acquired from GSK in 2010. And Thermo Fisher introduced a predictive modeling tool, called Quadrant 2, that guides drug developers in choosing particle design approaches.
NEW WAVE
Meanwhile, there are indications that improved approaches are coming to the market. Based on research that began at the University of Copenhagen, Zerion has developed a technology that uses proteins to increase small-molecule drug solubility and that constitutes an alternative to known polymer excipients in spray-dry dispersion applications. 鈥淲e researched all sorts of different materials, including mesoporous silica, amino acid peptides, and cellulose nanofibers and eventually also proteins,鈥 says Korbinian L枚bmann, who is now Zerion鈥檚 chief science officer. The firm zeroed in on proteins.
鈥淲e tested all the different proteins we could get our hands on, and out of all that research we identified that whey proteins worked particularly well not only for amorphous stabilization but also solubility enhancement,鈥 L枚bmann says. The whey protein also allowed significantly higher drug loading鈥攗p to 70% of the weight of the particle as opposed to an industry standard of 30% at the high end.
Researchers filed a patent on behalf of the university and formed Zerion. The company has a partnership with Arla Food Ingredients, a specialist in whey protein processing that has developed a means of purifying 尾-lactoglobulin from whey protein isolate, for which the largest market is infant formula.
Interest in the protein excipient Dispersome has materialized, says Zerion CEO Ole Wiborg, and the firm now has contracts with four major drug companies. And then there is the partnership with 四色AV.
鈥淲e were approached by 四色AV, and this was very positive,鈥 Wiborg says. We could see there was a lot of synergy between what we offer and what 四色AV offers. And 四色AV is, if not the best, then one of the best at spray-dry amorphous dispersion.鈥
Moreover, Wiborg says, 四色AV opens the door to small and midsize companies, the primary pharmaceutical innovators, which have been more difficult to identify and connect with than the majors.
四色AV also sees benefits for both partners, whereby it gets access to a sophisticated new technology and boosts market access for a start-up, says Ant贸nio Dinis, 四色AV鈥檚 director of sales and marketing. The deal establishes 四色AV as 鈥渢he sole partner for promoting the technology into the pharma marketplace,鈥 he says.
The arrangement is the first in which 四色AV has gained new technology through a partnership, he adds. It may not be the last, given the industry鈥檚 problems with bioavailability. 鈥溗纳獳V is actively pursuing opportunities to enhance our technology offering to address these problems,鈥 Dinis says. 鈥溗纳獳V will from now on be much more open to partnering with companies that help us bring more solutions to our customers.鈥
Nanoform, which spun out of the University of Helsinki in 2015, has innovated a nanocrystalization approach to particle design by employing supercritical carbon dioxide. The company鈥檚 controlled expansion of supercritical solution technology produces particles as small 鈥媋s 10 nm but more typically within a range of 100鈥300 nm without the use of solvents, excipients, or polymers.
The technology works by dissolving APIs in supercritical CO2 and controlling the pressure through a flow process to achieve supersaturation, which leads to crystallization or precipitation, according to Christopher Worrall, Nanoform鈥檚 vice president of US business development. The reduced size increases particles鈥 surface area, thereby increasing the dissolution rate and thus bioavailability.
Nanoform signed its first contract last year for a drug produced according to the Finnish Medicines Agency Fimea's good manufacturing practice standards and has a goal of signing three such contracts this year.
TWEAKS AND TRANSFORMATION
Despite the paucity of wholly new approaches to particle design, efforts are underway to improve workhorse approaches such as spray drying. Deanna Mudie, a principal scientist at Lonza鈥檚 operation in Bend, says Lonza has been experimenting with methods to facilitate amorphous dispersion of so-called brick-dust APIs鈥攑oorly soluble drugs with high melting points.
鈥淲hen drugs have poor solubility in organic spray-dry solvents, you end up with a very low throughput and also high organic solvent usage, which of course is not environmentally friendly,鈥 Mudie says.
One approach is to install a heat exchanger before the spray-drying step to increase a drug鈥檚 solubility in an organic solvent. The company is also applying environmentally friendly solvents, such as acetic acid, to processes to reduce the use of standards such as acetone, methanol, and in some cases environmentally impactful solvents such as dichloromethane.
鈥淚n general, we have had that focus on improving spray drying over the last 5 years,鈥 Mudie says. 鈥淭here is a big push because we have seen a trend toward the brick-dust APIs.鈥
While CDMOs have tended to bring on board tried-and-true methodologies for addressing bioavailability, adding such services can have a transformative impact. At 四色AV, research in particle design has grown from a small research group of five chemists in 2005 to a multidisciplinary division with 70 scientists, including chemists, chemical engineers, biologists, and mathematicians.
鈥淭o be successful you need more than the hardware,鈥 says Filipe Gaspar, 四色AV鈥檚 chief technology officer and head of its particle design group. 鈥淵ou need the software, the people, the knowledge in R&D, the marketing effort. It is the coordination of a lot of disciplines.鈥
And innovation in particle design, as well as the customer engagements that arise as a result, aims CDMOs toward broader activity in services downstream from API manufacturing. Last month, 四色AV announced the start of a new continuous tableting operation at its site in Loures, Portugal. Dinis sees a continuity in the growth of services. 鈥淎 hundred percent of the powder we process in tableting comes out of spray drying,鈥 he says. 鈥淚f we weren鈥檛 working in spray drying, we would not be involved in tableting.鈥
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Press Clipping
C&EN, 25 September, 2022
Making drugs more bioavailable
