Evaluating Market Opportunities for Solid Dosage Products and Manufacturing


From DCAT Value Chain Insights (VCI)

By Patricia Van Arnum posted 03-08-2015 21:44

  
Solid dosage products are a mainstay of the pharmaceutical market. Despite increased penetration of biologics and small-molecules delivered via parenterally or in other routes, solid dosage products remain an important part of the overall drug market and among new molecular entities. DCAT Value Chain Insights (VCI) examines the opportunity and recent developments on a product and manufacturing basis.

In looking at recent new drug approvals, 46% of the new molecular entities (NMEs) approved by the US Food and Drug Administration’s Center for Drug Evaluation and Research in 2014 were solid dosage products, and 63% of the NMEs approved in 2013 were. Moreover, as pharmaceutical companies aligned their manufacturing networks to product demand, which included rationalization of solid-dosage manufacturing, opportunities have risen in contract manufacturing.DCAT Value Chain Insights (VCI) examines the solid-dosage market.

Solid dosage products in the pharma market
Of the top 20 selling prescription drugs on a global basis in 2013, eight products, or 40%, were solid dosage products. Based on IMS estimates, the top 20 global products accounted for $874.6 billion in sales (based on December 2013 estimates, calculated using US dollars with quarterly exchange rates and including direct and indirect pharmaceutical channels: wholesalers and manufacturers). Of this total, the eight products with solid dosage forms (which also included actives produced in solid dosage forms and other approved dosage forms) accounted for 55% of this total, or $48.04 billion (see Table I). These products were: AstraZeneca’s Nexium (esomeprazole) and Crestor (rosovastatin); Bristol-Myers Squibb’s Abilify (aripiprazole); Eli Lilly’s Cymbalta (duloxetine); Gilead Sciences’ Atripla (efavirenz, emtricitabine, and tenofovir disoproxil fumarate); Merck & Co.’s Januvia (sitagliptin); Novartis’ Gleevec/Glivec (imatinib); and Pfizer’s Lyrica (pregabalin).

In looking at new drug approvals in 2014 and 2013, 46% of the new molecular entities (NMEs) approved by the US Food and Drug Administration’s Center for Drug Evaluation and Research approved in 2014 were solid dosage products, and 63% of the NMEs approved in 2013 were solid dosage products (see Tables II and III at end of article). In 2014, 19 of the 41 NMEs were solid dosage products. Ten were approved as tablets and nine as capsules. In 2013, 17 of the 27 NMEs approved were solid dosage products. Twelve products were approved as tablets and five as capsules (see Tables II and III at end of article).

Table I: Top-Selling Solid Dosage Products* in 2013, Global Prescription Products
Company Proprietary Name (Active Iingredient) Indication FDA-Approved Dosage Forms
AstraZeneca Crestor (rosovastatin) To lower cholesterol Tablet
AstraZeneca Nexium (esomeprazole) Gastroesophageal reflux disease and stomach ulcers Capsule, delayed-release pellets and suspension, delayed release (oral)
Bristol-Myers Squibb Abilify (aripiprazole) Schizophrenia, bipolar disorder, and depression Tablet; tablet (orally disintegrating); solution (oral); and injection (intramuscular)
Eli Lilly and Company Cymbalta (duloxetine hydrochloride) Depression, anxiety, diabetic peripheral neuropathy, fibromyalgia, or chronic muscle or bone pain Capsule, delayed-release pellets
Gilead Sciences Atripla (efavirenz, emtricitabine, and tenofovir disoproxil fumarate) HIV infection Tablet
Merck & Co. Januvia (sitagliptin) Type II diabetes Tablet
Novartis Gleevec/Glivec (imatinib) Certain types of leukemia. Also treats gastrointestinal stromal tumor myelodysplastic syndrome or myeloproliferative disease, aggressive systemic mastocytosis , hypereosinophilic syndrome , and dermatofibrosarcoma protuberans Tablet and capsule
Pfizer Lyrica (pregabalin) Nerve and muscle pain caused by diabetes, shingles, fibromyalgia, or a spinal cord injury. Also treats partial-onset seizures in adults. Capsule and solution (oral)
Source: Top-selling products compiled from IMS Midas (December 2013). Sales were calculated using US dollars with quarterly exchange rates and including direct and indirect pharmaceutical channels: wholesalers and manufacturers.

Active ingredient, indication, and dosage form taken from Drugs@FDA, US Food and Drug Administration, Center for Drug Evaluation and Research.

Among the large pharmaceutical companies, NME approvals in 2014 with solid dosage forms included: AbbVie’s Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets) to treat chronic hepatitis C virus infection; AstraZeneca’s Farxiga (dapaglifozin) for treating Type 2 diabetes, Movantik (naloxegel), a drug to treat opioid-induced constipation in adults with chronic non-cancer pain, and Lynparza (olaparib) for treating advanced ovarian cancer; Boehringer Ingelheim’s Ofev (nintedanib) for treating idiopathic pulmonary fibrosis and Jardiance (empagliflozin) for treating Type 2 diabetes, a drug which is part of Boehringer Ingelheim’s diabetes alliance with Eli Lilly; Gilead Sciences’ Harvoni (ledipasvir and sofosbuvir) for treating chronic hepatitis C virus genotype 1 infection and Zydelig (idelalisib) for treating three types of blood cancer; Merck & Co.’s Belsomra (suvorexant) for treating insomnia and Zontivity (vorapaxar), an antiplatelet; Novarti’s Zykadia (ceritinib), for treating a certain type of metastatic non-small cell lung cancer; Roche, through its acquisition of InterMune earlier in 2014, for Esbriet (pirfenidone) for treating idiopathic pulmonary fibrosis; and Sanofi’s Cerdelga (eliglustat) for the long-term treatment of adult patients with the Type I form of Gaucher disease, a rare genetic disorder.

A drug’s product form is an important consideration in the drug’s marketability and commercialization, a point that was underscored by one of the top-selling drugs in 2014: Gilead Sciences’ Sovaldi (sofosbuvir), the company’s oral drug to treat chronic hepatitis C virus (HCV) infection. Sovaldi, which was approved by the FDA in December 2013 and in the European Union in January 2014, was the first drug that demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon, which is administered by injection. Sovaldi is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate, and that mechanism of action was considered an important advancement as well as the ability to administer the drug orally. Sovaldi was Gilead’s top-selling drug in 2014 and was one of the industry’s top-selling drugs with 2014 sales of $10.28 billion, making it one of the most successful first-year launches for a NME.

Evaluating manufacturing
Over the past several years, the large pharmaceutical companies have been rationalizing production capacity in solid-dosage manufacturing with few new projects in this area although there is some recent investment. Earlier this year, Eisai Co., Ltd.'s Chinese subsidiary, Eisai China Inc. (ECI) announced it will build a new oral solid dose (OSD) production facility (New Plant) at the site of its new Suzhou plant located within the Suzhou Industrial Park in order to relocate and expand its existing OSD production facility (Old Plant) within the same industrial park. ECI has been producing OSD products such as Methycobal (methylcobalamin), Aricept (donepezil), and Pariet (rabeprazole) for the Chinese market at the Old Plant. However, in expectation of increased demand for Eisai products in the growing Chinese pharmaceutical market, the company said a new plant will enable future capacity expansion aimed at strengthening the stable supply chain and improving production efficiency. ECI secured a new lot of land in 2010 within the same industrial park for the New Plant, which is more than five times larger than the Old Plant, and in November 2014, a parenteral facility for the local production of injection products was established at this site as the New Plant.The decision for construction at the New Plant follows the completion of the parenteral facility and involves the establishment of a new OSD production facility and an administration building. Expected to stand three floors aboveground and containing floor space of approximately 20,900 square meters, the new OSD facility will handle the manufacturing and packaging of oral solid dose products for the domestic Chinese market. Construction is scheduled to begin in first half of fiscal 2016 and finish during the second half of fiscal 2017, with operations to commence in the second half of fiscal 2018. Once operations have commenced at the new OSD facility, the Old Plant will be closed down.

In addition to internal capacity, external manufacturing is an important part of the manufacturing market for solid dosage products. In 2014, the contract manufacturing market size for solid dosage forms was estimated at $19.6 billion, representing 58% of the total contract manufacturing market value of $33.7 billion, according to a recent industry estimate. Outsourcing opportunities arise in the innovator, generic-drug, and over-the-counter markets. Factors influencing growth include rationalization of pharmaceutical companies’ in-house capacity, technological-driven factors such as high-potency manufacturing and solutions for formulating and manufacturing poorly water-soluble compounds, and overall pharmaceutical industry growth.


Gordon Haines
CEO
Rottendorf Pharmaceuticals
In response, several contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) are expanding. Rottendorf Pharma GmbH, a CDMO specializing in solid dosage formulation, manufacturing, and packaging, headquartered in Ennigerloh, Germany, is one example. The company invested EUR 10 million ($10.8 million) in a new development center in Ennigerloh, Germany, which became operational in 2009, added a new GMP pilot plant for small-scale and submission batches in 2009, and upgraded laboratory facilities in 2014. The company is investing an additional EUR 5 million ($5.4 million) to add granulation and fluid-bed capabilities at its facility in Germany, which are scheduled to be completed in the fourth quarter of 2015. The company also operates a manufacturing and packaging facility in Valenciennes, France, which principally supplies the European generics market. On a technology basis, the company offers specialized services, such as hot-melt extrusion, used to make solid dispersions for poorly water-soluble drugs, and recently added capabilities in hot-melt granulation, a granulation method for improving bioavailability by forming solid dispersions. The company is also evaluating adding additional capabilities in high-potency manufacturing. In 2011, the company established a US subsidiary, Rottendorf Pharmaceuticals, based in Chicago and headed by CEO Gordon Haines.

In terms of overall trends in the industry, Haines points out with the rationalization of solid-dosage capacity on the pharma side and overall industry consolidation, pharmaceutical companies are looking to more strategic partnerships. The company uses a Total Process Ownership (TPO) model to drive that relationship. “TPO relies on open communication and exchange of ideas with our pharma customers to recommend process optimizations to produce a better end product,” says Haines. Overall, the company has seen double-digit growth since 2009. The company was founded in 1928 in Berlin as a family-owned business and since 1971 has belonged to a non-profit foundation. It has approximately 930 employees, with 780 employees at its site in Germany and 150 staff at its facility in France. The company’s annual manufacturing capacity is approximately 7 billion tablets per year, which currently encompasses 5 billion tablets for 200 clients and 600 products.

Other companies are also expanding solid-dosage capabilities and related businesses. Earlier this year, Catalent Pharma Solutions expanded its potent handling and manufacturing capabilities at its facility in Somerset, New Jersey. The company completed the expansion of the facility and engineering controls for its high-potency tableting and OptiMelt Hot Melt Extrusion operations in Somerset to supplement existing potent capabilities in oral solid and its Zydis Fast Dissolve manufacturing. The company is further investing in additional potent containment for large-scale blending, fluid-bed processing, and high-shear granulation,which will come on line throughout the first half of 2015. The Somerset facility is capable of handling SafeBridge Category 3 and 4, with SafeBridge certification expected in July of 2015. The expansion creates a manufacturing Center of Excellence for potent handling across Catalent’s portfolio of oral solid manufacturing solutions, which includes hot-melt extrusion, high-shear and wet granulation processing, solvent-based capability, extrusion/spheronization, fluid-bed processing, Wurster coating, and compression and encapsulation. In 2014, the company also announced an expansion of its highly potent and cytotoxic clinical drug packaging capabilities at its facility in Kansas City, Missouri. Catalent’s Kansas City campus provides a range of fully integrated support services, from formulation development and small and large molecule analytical testing, to clinical and commercial-scale manufacturing and packaging of a variety of oral solid dose forms. Also in 2014, the company acquired Micron Technologies, a provider of particle-size engineering technologies.

Earlier in 2015, Catalent announced plans to add new coating and blister packaging equipment at its 360,000-square-foot softgel manufacturing facility in Eberbach, Germany. Coating services are expected to be operational in early 2015, with the packaging equipment expected to be on line in the middle of the calendar year. The new coating equipment, designed to coat softgels for controlled, enteric and targeted release, will be capable of processing more than 300 million capsules per year and complements the company's existing softgel coating capability at the company’s 78,000-square-foot facility in Beinheim, France. As part of a $35 million investment begun in 2013, Catalent is expanding the company's Oral Advanced Technologies manufacturing site in Winchester, Kentucky. Also in 2014,, the company announced an investment for a new dedicated laboratory at its Kakegawa, Japan site to provide proof-of-concept support and feasibility studies for its proprietary Zydis Orally Dispersible Tablet (ODT) technology and for an expansion of manufacturing capacity for its OptiGel Micro softgel technology. Catalent also expanded clinical and softgel operations in Brazil and China.

In March 2015, Patheon agreed to acquire Agere Pharmaceuticals, a privately held Bend-Oregon-based CDMO, which specializes in solubiliization technologies and related science to improve the bioavailability of drugs. Agere's Bend facility is expected to serve as a solubility center of excellence and be part of Patheon’s pharmaceutical development services (PDS) operations. In the last year, Patheon expanded its capabilities through several key acquisitions, including the addition of a large-scale facility in Greenville, North Carolina. Patheon's PDS solutions offer advanced scientific and preformulation services for characterizing drug substances, developing and implementing laboratory methodologies, and generating data to enable investigational new drug filings.

Earlier this year, Pharmaceutics International, Inc. (Pii), a CDMO based in Hunt Valley, Maryland, completed the expansion of its manufacturing facility. This expansion, together with the purchase of new 300-L fluid beds for solvent coating, is in preparation for future commercial approvals. In addition, Pii’s UK subsidiary, Pharmaterials, added 11 new manufacturing suites for the European market. Pii provides preformulation testing, formulation development, clinical and commercial GMP manufacturing of solid, parenteral, inhalation, semi-solid and liquid dosage forms, clinical packaging and labeling, clinical trial kit building and distribution, analytical and QP services.

Other companies announced investments in 2014. Cirrus Pharmaceuticals, a Kemwell company, which provides pharmaceutical contract development and manufacturing services, is investing in a flexible cGMP suite in its facility in Research Triangle Park, North Carolina to cGMP manufacturing services for many dosage forms, including oral solids as well as inhalation, liquids, and topicals. The company expects the suite to be ready for service by April 2015. Aptuit added hot-melt extrusion (HME) technology for processing poorly soluble drugs. The addition of the HME technology complemented the company's existing micronization, wet-bead nanomilling, and spray-drying capabilities, as technologies for improving processing of poorly soluble drugs.

In 2014, Aesica validated its new high-capacity manufacturing facility following a $45-million investment at its Queenborough, United Kingdom site. With the completion of this new facility, Aesica expanded the commercial production of a solid dose medication used in treating Type 2 diabetes in adults. The purpose-built facility is capable of producing in excess of 1 billion tablets per annum and was designed with future expansion in mind. It is expected the facility will more than double its current capacity to produce over 2.5 billion tablets per year on expansion. The new facility is equipped with spray granulators, coaters, tablet presses, powder-handling systems, and large-capacity blenders. Also in 2014, Aesica Pharmaceuticals added additional services in its oral solids capability, including a new roller compaction unit for dry granulation production in Zwickau, Germany. The investment complements other recent investments in the region, including a new tablet coater capability and pouch packing line.

In 2014, Metrics Contract Services, a CDMO based in Greenville, North Carolina, expanded its capabilities in spraying drying for use in improving drug bioavailability. Metrics also invested $1.6-million for a new laboratory to support pre-clinical development of early formulation prototypes and related analytical methods. It also added roller compaction equipment for small-scale production at its Greenville site.

In June 2014, Bend Research, a division of Capsugel Dosage Form Solutions, installed a commercial-scale spray dryer in its R&D facility in Bend, Oregon. The new dryer allows for process development and scale-up in a non-GMP environment and complements the existing small- and mid-sized spray dryers already in service at the company. The installation completed the first part of the company's multi-stage, more than $20-million expansion to enhance commercial manufacturing capabilities for spray-dried dispersions at its facilities in Bend. Spray-dried dispersion technology helps increase the bioavailability of compounds with low solubility. The new, high-capacity pharmaceutical spray dryer can be used for scale-up, quality-by-design studies, and the production of appropriate toxicology study supplies. The installation coincides with ongoing construction to expand the cGMP commercial facility, which includes an additional commercial-scale spray dryer for production of late-stage clinical, launch, and commercial spray-dried products. The commercial facility expansion is expected to be completed by mid-2015. Also in 2014, Capsugel launched lipid multiparticulate (LMP) technology based on melt-spray congeal (MSC) processing to combined the benefits of lipid-based formulations (LBF) with the functionality of a multiparticulate dosage form in one offering. MSC processing for LMP production is available at Capsugel’s manufacturing site in Bend and a commercial-scale facility with MSC processing and capsule-filling capability was recently installed at its facility in Greenwood, South Carolina.

In 2014, Almac expanded its UK commercial packaging facility to provide a humidity-controlled blister packaging suite, complete with off-line “just-in-time” blister printing. The company also is investing more than £54 million ($90 million) over the next several years to expand staffing at two operating business units, Pharma Services, which provides contract development and manufacturing services, and Clinical Services, which provides clinical packaging, labeling, logistics, and clinical supply-chain management services.

In 2014, Packaging Coordinators, Inc. (PCI), a provider of packaging solutions, added to its capabilities with the acquisition of Penn Pharmaceutical Services Limited (Penn Pharma), a CDMO headquartered in Tredegar, Wales, Penn Pharma offers drug-development and manufacturing services, including clinical and commercial dosage form manufacturing, as well as clinical packaging, labeling, and global storage, distribution and return drug services.

Table II: Solid Dosage Products Approved as New Molecular Entities
by the US Food and Drug Administration’s Center for Drug Evaluation and Research, 2014
Company Property Name
(Active Ingredient)
Indication FDA-Approved Dosage Forms
AbbVie Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets) Chronic hepatitis C virus genotype 1 infection, including those with cirrhosis Tablet
AstraZeneca Farxiga (dapaglifozin) To improve glycemic control, along with diet and exercise, in adults with Type 2 diabetes Tablet
AstraZeneca Movantik (naloxegol) Opioid-induced constipation in adults with chronic non-cancer pain Tablet
AstraZeneca Lynparza (olaparib) Advanced ovarian cancer Capsule
Boehringer Ingelheim Ofev (nintedanib) Idiopathic pulmonary fibrosis Capsule
Boehringer Ingelheim Jardiance (empagliflozin) To improve gylcemic control in adults with Type 2 diabetes Tablet
Celgene Otezla (apremilast) To treat adults with active psoriatic arthritis Tablet
Cubist Pharmaceuticals Sivextro (tedizolid phosphate) Acute bacterial skin and skin structure infections Tablet
Gilead Sciences Harvoni (ledipasvir and sofosbuvir) Chronic hepatitis C virus genotype 1 infection Tablet
Gilead Sciences Zydelig (idelalisib) To treat three types of blood cancer Tablet
Helsinn Healthcare Akynzeo (netupitant
and palonosetron)
To treat nausea and vomiting in patients undergoing cancer chemotherapy Capsule
Lundbeck/Chelsea Therapeutics Northera (droxidupa) Neurogenic orthostatic hypotension Capsule
Knight Therapeutics Impavido (miltefosine) Leishmaniasis Capsule
Merck & Co. Inc. Belsomra (suvorexant) To treat difficulty in falling and staying asleep (insomnia) Tablet
Merck & Co. Inc. Zontivity (vorapaxar) To reduce the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs Tablet
Novartis Zykadia (ceritinib) A certain type of metastatic non-small cell lung cancer Capsule
Roche/InterMune Esbriet (pirfenidone) Idiopathic pulmonary fibrosis Capsule
Sanofi/Genzyme Cerdelga (eliglustat) Long-term treatment of adult patients with the Type 1 form of Gaucher disease Capsule
Vanda Pharmaceuticals Hetlioz (tasimelteon) To treat non-24-hour sleepwake disorder in blind individuals without light perception Capsule
AstraZeneca completed the acquisition of its diabetes alliance from Bristol-Myers, in February 2014, which include Farxiga (dapagliflozin) and related payments to Bristol-Myers Squibb.

Akynzeo is distributed and marketed by Eisai Inc. of Woodcliff Lake, New Jersey, under license from Lugano, Switzerland-based Helsinn Healthcare S.A.

Boehringer Ingelheim and Eli Lilly partnered for Jardiance as part of the companies' diabetes alliance.

Cubist Pharmaceuticals’ Sivextro (tedizolid phosphate) is also approved as a powder for administering via IV (infusion). Merck & Co. acquired Cubist Pharmaceuticals in 2015.

Lundbeck acquired Chelsea Therapeutics in June 2014.

Knight Therapeutics Inc. was formed from the former shareholders of Paladin Labs Inc pursuant to a spin-off transaction made in February 2014; Paladin was acquired by Endo Health Solutions Inc., a specialty pharmaceutical company.

Roche acquired InterMune in 2014.

Source: US Food and Drug Administration’s Center for Drug Evaluation and Research and company information

Table III: Solid Dosage Products Approved as New Molecular Entities
by the US Food and Drug Administration’s Center for Drug Evaluation and Research, 2013
Company Proprietary Name
(Active Ingredient)
Indication FDA-Approved
Dosage Forms
Actelion Pharmaceuticals Opsumit (macitentan) Pulmonary arterial hypertension Tablet
Bayer Healthcare Adempas (riociguat) Two forms of pulmonary hypertension Tablet
Biogen Idec Tecfidera (dimethyl fumarate) Relapsing forms of multiple sclerosis Capsule,
delayed release
Boehringer Ingelheim Gilotrif (afatinib dimaleate) Metastatic non-small cell lung cancer with specific types of epidermal growth factor receptor gene mutation as detected by an FDA-approved test. Tablet
Celgene Pomalyst (pomalidomide) Multiple myeloma Capsule
Gilead Sciences Sovaldi (sofosbuvir) Chronic hepatitis C virus infection Tablet
Janssen Biotech and Pharmacyclics*     Imbruvica (ibrutinib)** Mantle cell lymphoma Capsule
Janssen Pharmaceuticals Invokana (canagliflozin) Used with diet and exercise, to improve glycemic control in adults with Type 2 diabetes Tablet
Janssen Pharmaceuticals Olysio (simeprevir sodium) Chronic hepatitis C virus infection. Capsule
Novartis** Tafinlar (dabrafenib mesylate Advanced melanoma with BRAF V600E mutation as detected by an FDA-approved test Capsule
Novartis** Mekinist (trametinib dimethyl sulfoxide) In combination with tafinlar for advanced melanoma with BRAF V600E mutation as detected by an FDA-approved test Tablet
Pfizer Duavee (bazedoxifene acetate; estrogens, conjugated); new combination Moderate-to-severe hot flashes associated with menopause and to prevent osteoporosis after menopause Tablet
Shionogi Osphena (ospemifene) Moderate to severe dyspareunia Tablet
Sunovion Pharmaceuticals Aptiom (eslicarbazepine acetate) An add-on medication to treat seizures associated with epilepsy Tablet
Takeda Pharmaceuticals Brintellix (vortioxetine hydrobromide) Major depressive disorder Tablet
Takeda Pharmaceuticals Nesina (alogliptin benzoate) To improve blood sugar control in adults with Type 2 diabetes. Tablet
ViiV Healthcare Tivicay (dolutegravir sodium HIV-1 infection Tablet
*Janssen Biotech’s and Pharmacyclics’s Imbruvica (ibrutinib) also was later approved to treat chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia.

In March 2015, AbbVie agreed to acquire Pharmacyclics for $21 billion; the deal is expected to close in mid-2015.

Janssen Biotech and Janssen Pharmaceuticals are part of Johnson & Johnson.

**Novartis acquired GlaxoSmithKline’s oncology portfolio, including Tafinlar and Mekinist in March 2015.

Source: US Food and Drug Administration's Center for Drug Evaluation and Research and company information.
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