CATALENT
COVER STORY
DOSAGE FORMS
Production methods create layered tablets to optimize dosing, therapeutic, and ingredient release profiles.
CUSTOM CHEMICALS GO FURTHER Service firms expand in drug FORMULATION DEVELOPMENT by addressing solubility, other challenges ANN M. THAYER, C&EN HOUSTON
TO WIN AT the drug development game, it’s not enough to show up with a great molecule. Many compounds would stall at the discovery stage without effective ways to get them inside patients. But the days of simple, easy-to-make pills are gone and the endgame now is about shaping uncooperative compounds into well-behaved medicines. More than half of new pharmaceutical compounds moving into development have tricky physical properties that call for some kind of special science and engineering, says Rod Ray, chief executive officer of Bend Research, an Oregon-based drug formulation specialist. Crafted for their therapeutic merits, up to 40% of drug candidates are poorly soluble, overly reactive, not bioavailable, or a confounding combination of such problems. Consequently, pharmaceutical companies that want to advance all of their
clinical candidates have no option but to try to solve physical form and delivery problems. The drug industry has an anemic new-product pipeline, so many big pharma firms are willing to spend money and effort on formulations and dosage forms to turn the compounds they’ve discovered into viable drugs. “Fewer molecules are being brought forward but with more firepower behind them,” Ray says. That willingness to spend is an opportunity for formulation specialists and contract manufacturing organizations (CMOs). In a late-2012 survey conducted by the market research firm Nice Insight, 82% of drug industry respondents said they believe that innovative dosage forms are required to meet the needs of pharma R&D. Capsugel, a drug delivery and capsule specialist that Pfizer sold to private investors in 2011, commissioned the survey. The survey brought other welcome
news for drug formulation service providers from their potential customers. About 58% of drug firms polled said they outsource dosage-form development, and 56% reported that they spend $10 million to $50 million on it annually. Biotech and virtual companies that lack in-house formulation capabilities have long been key formulation customers, suppliers say. More recently, they add, business is on the rise from mid- and large-sized firms that have been cutting back on internal R&D. To meet demand from such firms, manufacturers of drug active ingredients have been moving downstream into formulation and dosage-form creation through investments, acquisitions, and partnerships to add technical capabilities and production capacity. To succeed, these CMOs realize, they must play at the same high level as formulation specialists like Bend, which has been
“Fewer molecules are being brought forward but with more firepower behind them.” WWW.CEN-ONLINE.ORG
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working on drug formulation development for more than 25 years. A decade of that, up to 2008, was exclusively with Pfizer. Playing the game well requires being able to understand drug biology and chemistry, engineer crystal or particle forms, and develop technologies to make problematic compounds workable. Building this expertise and gaining experience with customers will take time, insiders say. To demonstrate value to clients, CMOs “are likely to continue focusing on strategic relationships and promoting more services such as formulation improvements, alternative dose forms, real-time order tracking, and logistics support,” says Jesse Sullivan, an analyst with Frost & Sullivan who covers the outsourcing market. Many established formulation specialists, like Bend, have been at it for a long time. Bend boasts that it has worked with 76 customers on more than 700 compounds in formulation development and manufacturing. Given this broad experience, Ray says, the company has “approaches to handle most everything.” Its lead technologies include spray drying and hot-melt extrusion, both of which yield amorphous solid dispersions with improved solubility (C&EN, May 31, 2010, page 13). The spray method—which mixes a drug compound with a polymer and solvent—allows it to be dried into a powder. The other approach, melting the drug with a polymer, allows for extruding it as a solid. Either dispersion form can then be processed, along with excipients and other formulation aids, into a final dosage or delivery form.
It makes more sense for a CMO to amass specialized formulation-related services than for a drug firm to invest in expensive or untested technology to make a single product, argues Hovione CEO Guy Villax. “A CMO is a more elegant model to invest in specialized technology because we can handle compounds for anyone when they need the technology,” he says. With these
economies of scale, Hovione has seen a 10-fold expansion in spray-drying projects in recent years, including commercial soliddispersion-based and inhalation products. Hovione’s combined active pharmaceutical ingredient (API) manufacturing and particle design business grew about 15% annually over the past five years to reach about $180 million in 2012. This year, it will handle
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BEND, LIKE MANY formulation develop-
ers, has been collaborating with other suppliers to extend its reach. Its own capabilities support customers through Phase III of the drug development process. It has joined with the CMO Hovione for largescale spray drying and with formulation specialist Catalent Pharma Solutions for multiparticulate oral controlled-release drug products. “These relationships are about having a clear commercial pathway for our customers,” Ray says. Bend has already transferred several products to Hovione for scale-up. That Portugal-based company took a big step in the formulation world in 2009 when it acquired a very large-scale pharmaceutical spray dryer, barely used, as part of its purchase of Pfizer’s Cork, Ireland, plant. As of late 2012, Hovione was making five commercial products there and had two more soon to come on-line. WWW.CEN-ONLINE.ORG
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more than 75 compounds in various stages of clinical development. After 2015, Villax expects, formulation development will be the main driver of the company’s growth. In June 2012, Hovione began working with Switzerland’s Solvias, a solid-state chemistry and analytical services firm. The collaboration gives Hovione access to Solvias’ expertise in making pharmaceutical cocrystals as a means of overcoming poor bioavailability and other drug delivery issues. In 2011, Hovione partnered with Bethlehem, Pa.-based Particle Sciences, a drug delivery technology firm. With these partnerships lined up, Hovione launched an expanded particle design solutions business in late 2012. “We recognize that solid dispersions are growing, but they are not the solution for everything, so we are offering a comprehensive portfolio of technologies most likely to solve problems,” Villax says. Along with methods for making amorphous solid dispersions, the business offers commercial-scale crystal design and particle-size control capabilities, supported by formulation development and dosage manufacturing that can assist customers
through Phase II of clinical trials. Similarly, Catalent, which has its headquarters in Somerset, N.J., has increased its focus on advanced drug formulation and final-dosage-form manufacturing. Catalent has been a standalone pharmaceutical services company since 2007 when Cardinal Health sold the FINAL PRODUCT Aesica offers now-$1.7 billion-perZydis, for making freezeyear business to private ingredient manufacturing, dried tablets that disinteformulation development, as well as investors. grate in the mouth within bulk manufacturing and packaging. One area of focus is seconds. its softgel gelatin capIn the modifiedsule technology, which release area, Catalent has originated within R. P. Scherer Corp., a comlicensed technology from Japan’s Sanwa pany Cardinal acquired in 1998. Catalent has Kagaku Kenkyusho for use outside much expanded this offering with a plant-polysacof Asia. With the technology, Catalent can charide-based capsule that can encapsulate make tablets with cores of various shapes, high-melting-point formulations. It also has sizes, and placements. This flexibility of developed a fast-dissolve technology, called design allows for different drug, dosage,
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and release profiles in a single tablet. “We are in the early phases of working on feasibility with two major customers,” says Will Downie, Catalent’s senior vice president for sales and marketing. For preformulation studies, Catalent acquired a solid-state API structure screening and optimization platform from GlaxoSmithKline. In recent years, Catalent has also expanded its analytical labs and production facilities. Just last month, it announced plans to spend $20 million to expand inhalation drug manufacturing at its Research Triangle Park, N.C., site.
Similarly, England’s Aesica Pharmaceuticals has created the Aesica Innovation Board to help find academic and small-company technology partners, says Paul Titley, business development director of Aesica’s formulation development business. Aesica was formed in 2004 to buy the unwanted manufacturing plants of big drug companies. Although Aesica started by pursuing both API and formulation assets, formulation is the majority of its business today. When visiting conferences and trade shows, Titley is on the lookout for “anything interesting related to pharma processing, either at the API or dosage-form level.” FOR ALMOST A YEAR, Catalent has had an By keeping his eyes and ears open, he alliance with the chemical giant BASF. The has found success by looking in Aesica’s pact combines BASF’s expertise in developown backyard. Since 2008, the company ing solubilizers and polymeric excipients has worked with Upperton, a spray-drying with Catalent’s formulation approaches, in and formulation firm in Nottingham, Engparticular its hot-melt extrusion capabililand, where Aesica has a facility. “Together ties. Similarly, Bend has set up a collaborawe now have at least three compounds tion with Dow Chemical to develop polyin Phase II development for customers.” mers for improved he says. In 2011, it drug solubility and began collaboratPOPPING PILLS A plurality of use in spray-dried ing with EmulTech, drugs in late-stage development or dispersions. a Dutch firm that awaiting approval are taken orally. Eager to foster develops drug delivmore ideas, last Octoery systems around Transmucosal Transdermal ber Catalent launched microparticulates. 2% 3% Other the Catalent Applied Such combinations Ophthalmic 1% 4% Drug Delivery Instican bring nascent Inhalation tute with the goal of technologies up to a Oral 4% 46% encouraging an exlevel appropriate for Topical change of information clinical use and for 7% between academia attracting pharma and industry. “A lot companies. Although of great work is being an enormous amount Injection 33% done in the academic of invention takes community that often place in universities Number of compounds = 1,319 is fundamental to and small companies, SOURCE: Frost & Sullivan understanding drug most of it occurs in delivery and solving facilities that do not problems,” says Ian Muir, Catalent’s presicomply with the current Good Manufacdent for modified-release technologies. turing Practices (cGMP) required to make Owing to R&D cutbacks within many drug clinical and commercial drugs, Titley excompanies, he adds, “it’s research that just plains. Aesica can provide cGMP-compliant isn’t getting done as often as it used to be.” manufacturing, as well as quality control, The institute is supporting education analytical chemistry, documentation, and and training, student competitions and other regulatory support. internships, and publications and commuAesica recently established a partnernications to promote formulation and drug ship with the Centre for Pharmaceutical delivery science more widely. With conEngineering Science, an arm of England’s nections already to nine U.S. and European University of Bradford that works with academic institutions, the company is now hot-melt extrusion, supercritical fluids, working to bring industry partners into the and nanomilling. “It is an Aladdin’s cave of institute. Initial areas of interest include different technologies,” Titley says. Aesica taste masking, bioavailability enhancement, has gained access to new formulation and the oral delivery of macromolecules development research and in exchange and vaccines, Muir says. has helped train Bradford staff in process WWW.CEN-ONLINE.ORG
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COVER STORY
PRESCRIBED ROUTES
Final Drug Form And Delivery Route Affect Function And Use A drug’s final form has a big list of medical and commercial implications. It can dictate effectiveness, safety, acceptability, handling, stability, and applicability to diseases. Alternative formulations, such as pediatric doses, can reach new patient groups, revive abandoned compounds, and extend patent life. At the same time, regulators, health care providers, and insurers are pressuring the industry to develop new, differentiated products with clear benefits over old ones. But medicines aren’t useful if people won’t take them. A recent analysis by the nonprofit New England
Healthcare Institute found that 50% of U.S. patients don’t take their medicines as prescribed. Improving compliance could save the health care system up to $290 billion annually, NEHI estimates. To make treatments more attractive, developers need to consider how a formulation can affect the number, type, size, and duration of doses, and a therapy’s taste, odor, and side effects. Most small-molecule drugs are taken orally, and most biologics are injected. Although patients prefer pills or capsules, these delivery forms may not be feasible depending on a drug’s properties—such as whether it
can withstand the stomach— and the target disease, Frost & Sullivan market analyst Debbie Toscano points out. For example, oral forms tend to act systemically and may not be appropriate for drugs that work better or cause fewer side effects when targeted to a specific part of the body. Inhalation, topical, and ophthalmic delivery methods can target specific conditions. More efficient drug delivery may reduce toxicity and the amount of active ingredient needed. Improved bioavailability and therapeutic profiles can be achieved in oral drugs through immediate- and controlled-release pill and
capsule formulations that dictate when, where, and how fast a drug is released. Manufacturing methods, such as those that can make multilayer pills, allow for delivering more than one drug at a time. Formulation aids and enhancers are used to alter pharmacokinetics and a drug’s movement through the body. Coatings and capsules can improve drug stability and control dissolution. Producing the final dosage form involves finding the best physical form of a compound, engineering particle sizes or making dispersions, and choosing a delivery route, all in an acceptable size and shape.
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scale-up under cGMP conditions. Aesica also provides cGMP manufacturing services to six other universities. Although Aesica is keen on hot-melt extrusion methods, it doesn’t yet have any commercial-scale capabilities. “We are committed to new technologies, but we probably share the rationale with most CMOs that we will invest at the point a product needs a significant scale of manufacture,” Titley says. Aesica isn’t shy about investing in infrastructure. In the formulation area alone it purchased Abbott Laboratories’ Queenborough, England, site in 2007 and Nottingham-based R5 Pharmaceuticals in 2010, four years after Titley had founded it. Aesica also acquired German and Italian sites from the Belgian firm UCB in 2011. Aesica added capacity in Nottingham in 2011 and is expanding the Queenborough site.
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ern Ireland’s Almac offers pharmaceutical customers a range of services from API synthesis through formulation development, clinical supply, and commercial dosage manufacturing. The formulation landscape is becoming more crowded, acknowledges John McQuaid, Almac’s vice president for technical operations, and many types of firms are jockeying for competitive position. The advantage of small or niche companies may be an ability to offer deep expertise in a specific formulation technology. But the disadvantage is that if a customer wants to try other approaches or outgrows the small firm’s capacity, that customer often must look elsewhere. On the other hand, many large CMOs strive to be one-stop shops with a breadth of technologies and more vertical integration. “Bigger players with a broad service offering can look for strategic or preferred-provider relationships with clients,” McQuaid explains. Although these relationships are desirable, they also raise the bar. “Customers ultimately will want ‘best in class’ in each of the different areas,” he adds. Almac can handle a variety of dosage forms in the early stages of drug development, but it focuses primarily on formulation development and manufacturing of solid oral forms from early development through commercialization, McQuaid says. The company recently spent $10 million to double its dosage-form drug development capacity by adding a noncGMP facility and two additional analyti-
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COVER STORY
cal labs at its Craigavon headquarters. need for more lab-scale batches, he adds. mulation development groups and may Almac’s existing cGMP facility will supReady to go with new facilities and show up with an approach already in mind, port drug product manufacturing from partnerships developed in the past couple he says. Some customers will arrive to talk Phase I through registration and commeryears, CMOs still must get customers about formulation with their API in hand, cialization, whereas the non-cGMP operathrough the door. Understanding when although not always in the best form for tion will handle lab-scale work up to about drugmakers want to begin formulation processing. And then there are those firms 15 kg. To transition processes seamlessly, development is one challenge in attractthat have outsourced API production and the new facility operates under the same ing them. For drug companies focused on know nothing about their compound’s principles and technical physical properties. standards as the existTitley believes in DELIVERY PROBLEMS ing one, but without the getting the customer paperwork, material to “think first about control, and cleaning who is actually going to required for cGMP. use the drug and how, of drug firms’ of drug candidates of potential “We can move faster and then work back compounds are are hygroscopic or drugs are acid and be more flexible from that to how we poorly water soluble. moisture sensitive. sensitive. when not having to are going to physically work under cGMP convert it into a usable SOURCE: Capsugel/Nice Insight September 2012 survey of 500 industry respondents conditions,” McQuaid dosage form.” says. In the new facility, Traditionally, pharAlmac will manufacture maceutical companies prototype formulations, batches for stabilidiscovering and developing therapeutic first try to find the most soluble API form ty studies, and products for any testing that molecules, “it can be a long way off before by screening for a salt, Catalent’s Muir does not involve humans. As customers they think about where they would even says. If that doesn’t work, it’s good to have implement quality-by-design approaches consider doing commercial production of other drug delivery options available to relying on statistically designed experithe dosage form,” Aesica’s Titley says. move compounds forward. “You have to ments, the non-cGMP lab can support the Many big pharma companies have forfind which option is the best scientifically,
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commercially, and from a regulatory point of view,” he adds. With compounds that need help, finding a formulation up front can be critical to making the drug behave its best in clinical trials. “Everybody wants to try to compress the development and regulatory path, and so choosing an approach early and then progressing it all the way through is the most efficient,” Muir says. Changing midstream and having to repeat studies is to be avoided, he adds. Bend’s Ray agrees that it’s important to get things right from the start. Luckily, he says, it can usually be done. “We can usually formulate for first-in-human studies with a formulation that is pretty close to what the commercial one is going to be,” he says. “And we have figured out how to do it fast and cheap enough so that it is not really an extra investment.” Bend has “bulk sparing” methods, such as spray drying at the milligram scale, that allow it to develop a formulation when the amount of API is limited. Although specialists argue for early action on drug formulation, not all drug developers are concerned. Only about half of respondents in the Nice Insight survey said it would be valuable or extremely valuable to use the same delivery form throughout clinical development and commercialization. Hoping to conserve funds and time, some drug developers want to hold off on formulation until after Phase I or II proof-of-concept studies. According to a 2012 industry survey by Catalent and the market research firm PharmSource, about 40% of companies make the decision on formulation route and form after Phase I. Instead, for early clinical work, drug developers may look for a PRODUCTION PUSH
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COVER STORY
first-generation, or “fit for purpose,” formulation, Almac’s McQuaid says. If done with enough rigor behind it, this initial form can be a good starting point for the final product. To get in the clinic even faster and cheaper, some companies use extremely simple delivery approaches. One that has grown in popularity in recent years involves putting
small quantities of API without excipients into a capsule, such as with automated Xcelodose systems sold by Capsugel. This “drug in capsule” route works well when only limited amounts of API are available, McQuaid explains. It also has advantages for potent drugs for which the volumes are small and the production system can help contain the API. However,
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he points out, it’s not a good strategy for poorly soluble compounds that need some type of formulation development. “There isn’t a one-size-fits-all approach; you have to look at the properties of the drug substance” to avoid going down the wrong path, McQuaid says. “We spend a lot of time with our clients up front trying to understand the attributes of their drug substance and what the appropriate formulation strategy is for them.” THE AMOUNT of guidance needed differs,
however. “Large pharma has a pretty deep understanding of what is available and often has experience with a number of different technologies, either in-house or externally,” Muir says. But the same is not true
THINKING AHEAD Most drug firms say they consider the dosage form in early development. Early development Preclinical 24%
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Other 6% Phase II 34% Drug industry respondents = 500 SOURCE: Capsugel/Nice Insights September 2012 industry survey
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for many specialty or virtual companies, Catalent found from its industry survey. As a result, suppliers are trying to educate potential customers about the pros and cons of different formulation options to address drug delivery problems, he suggests. The learning curve notwithstanding, drug formulation providers expect their businesses to grow, driven by the pharmaceutical industry’s need for problem solving and some recent marketplace successes. A dozen or more approved products—from the likes of Pfizer, Novartis, Abbott, Vertex Pharmaceuticals, and others—have been successfully formulated and are being manufactured at large scale using once-exotic techniques such as spray drying and hotmelt extrusion. Getting these points on the board gives confidence to both specialists and CMOs now entering the formulation field that they are on the right track. ◾
