 and Save the Children have launched a $1- million Healthcare Innovation Award to identify and reward innovations in healthcare which have proven successful in reducing child deaths in developing countries. From June 27 to August 26, 2013, organizations from across the developing world can nominate examples of innovative healthcare approaches they have discovered or implemented. These approaches must have resulted in tangible improvements to under-age-five child survival rates, be sustainable, and have the potential to be scaled-up and replicated. Co-chaired by Sir Andrew Witty, CEO of GSK, and Justin Forsyth, CEO of Save the Children, the judging anel, made up of experts from the fields of public health, science and academia, will award $250,000 to the best healthcare innovation to further progress their work. An additional $750,000 is available for runners-up awards. The award will also provide a platform for winning organizations to showcase their innovations and share information to enable others with an interest in improving healthcare to adapt and replicate successful interventions and create more positive change for children in their own country and beyond. 

 and GDF SUEZ, an energy firm, have signed an agreement to strengthen their collaboration for implementing projects in the field of energy at Sanofi industrial sites. The five-year contract includes mainly renewable energy production and distribution systems. Building on an initial agreement signed in March 2012 for Europe and Turkey, the two groups have expanded their collaboration to include sites in the United States, Canada, Mexico, Brazil, China, and Singapore. All Sanofi’s production lines will be included: chemicals, pharmaceuticals, vaccines, biotechnology, and animal health. The initial three-year term contract is extended to five years.

Articles

CSR and Sustainability Forum

A roundup of developments in global health and sustainability from the bio/pharmaceutical industry, its suppliers, and other public and private organizations.

Pharma News in Global Health and Sustainability

Over the past few years, China and India have been the up-and-coming destinations for international outsourcing of biopharmaceutical manufacturing. Last year, industry research pointed to China and India as the industry's top potential destinations for offshoring over the next five years, which put them ahead of traditional biomanufacturing hubs in the US and Western Europe. China was seen as a favorite likely destination for both US and European respondents to prior studies, with India close behind. 

10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

, however, that initial enthusiasm appears to have diminished (1). Of the more than 25 countries identified as potential destinations for international outsourcing, India fell to the fourth spot among all respondents, with only 14% of respondents indicating there was a likelihood or strong likelihood that they would consider outsourcing production there in the next five years. Surprisingly, that was a more positive result than for China, which was cited by just 10.6% of respondents, putting it in the ninth spot, behind countries such as Austria and Australia. 

This year, the US took the top position for biopharmaceutical outsourcing, with 26.3% of global, non-US respondents, ranking it as the top destination. This ranking likely reflects European companies' plans, as respondents were asked to indicate potential international destinations (see 

). Next on the list were Germany and Singapore, each indicated to be a "likelihood" destination by 15.8% of all respondents. Beyond those top three countries stood a group of countries (India, UK, Austria, and Ireland), each receiving the nod from approximately 14% of respondents. 

Figure 1: Destinations for international outsourcing of biomanufacturing (all respondents). (ALL FIGURES ARE COURTESY OF THE AUTHOR.)			

As noted previously, the US' position atop the rankings this year is reflective of the substantial European presence in this industry. When the respondent sample is narrowed to Western Europeans only, the US is easily the favored destination for outsourcing in the next five years cited by 35.3% of respondents, up slightly from last year's 31.8%. After the US, Europeans are most likely to look in their own backyard, with strong consideration shown for Germany (29.4% of respondents cited in 2013, from 22.7% in 2012) and Belgium (23.5% in 2013, from 22.7% in 2012). 

European responses were evaluated indicating more positive consideration for country destinations as either a "strong likelihood" or "likelihood." The US was again the top response (23.5%), with European countries following: Germany and Ireland (each at 17.7%), followed by Belgium, France, and Sweden.  

This year India was a consideration for outsourcing by just 11.8% of European respondents, down from last year's 22.7%. China's fall has been more precipitous: it was indicated to be a country in consideration by only 5.9% of respondents, down from last year's leading 36.4%.  

US-based respondents are more favorable to Singapore, handing it the top position, with 32.3% of respondents considering it a "potential" destination. After Singapore came Germany (29%), followed by the UK, China, and India.  

This list suggests that US companies appear to be seeking traditional biomanufacturing hubs rather than emerging ones at this time. Compared to last year, respondents in the US demonstrated a heightened potential for outsourcing to some destinations in Western Europe, such as Germany (29% vs. 25%), the UK (26% vs. 22%), Scotland (16% vs. 6%), and Italy (13% vs. 6%). Respondents, however, cooled on China (26% vs. 34%) and India (23% vs. 28%).  

After several years of study data showing China and India becoming more heavily favored outsourcing destinations, this year's results are striking and merit some attention. There are some signs that respondents' increased attention to traditional hubs, at the expense of China and India, is likely related to a renewed focus on regulatory issues. This may be drawing  industry attention away from emerging manufacturing clusters, where there may be less confidence in the regulatory expertise.  

As with years past, geographic location continues to be one of the least important factors: only 7% of respondents this year indicated "be local to me" to be a "very important" consideration, squarely in the less than 2-10% range found in the past 4-5 years. 

As geography plays a lesser role, regulatory expertise is becoming a crucial factor in decision-making.  This year, 45.6% of respondents said that it was "very important" that CMOs have regulatory compliance expertise, a significant rise from 38.1% who attached that level of importance last year. This comes amidst separate data suggesting that biomanufacturers are focusing more on regulatory issues to improve operational performance and avoid capacity constraints. It could also be a result of clients outsourcing more core activities than in earlier years, with regulatory compliance more rigid for these activities than for the lower value-added services that have typified outsourcing in the past.  

Finally, although much investment has been made in facilities in China and India for biogenerics production, some companies have been using their existing facilities, looking to leverage well-understood facilities that might otherwise be under utilized, and which are able to quickly and cheaply produce clinical material. Much of this CMO-sourced material has been produced in the US, which may be slanting future expectations for outsourcing. 

Although there has been a noticeable shift in attention away from China and India as outsourcing destinations, there is reason to believe this situation will reverse. Those countries are accounting for an ever-greater share of global biomanufacturing capacity—together, they represent approximately one-sixth of capacity, according to BioPlan's WIKI resource on global biopharmaceutical facilities (2), which pegs China's share of biopharmaceutical manufacturing concentration at 8.6% and India's at 8.1%. Although that's significantly behind North America (35.9%) and Western Europe (26.1%), it's a growing trend that the industry is not ignoring.  

It's important to remember that China is a relatively new player, which continues to suffer from legal and regulatory aspects that hinder commercial-scale contract manufacturing. It may take years for Chinese CMOs to come up to full cGMP standards and to be permitted to operate at commercial scale. These study results may simply be a reflection of the industry thinking that such progress may not come as quickly as expected. Nevertheless, it's short-sighted to believe that this situation will not change. China and India represent a majority of the world's population, and with its growing middle class, biologics production will likely continue to play an important role in their healthcare policy. While some emerging destinations may not find substantial growth in the short term, India and China will need to produce biologics for their huge local populations, and some of this experience will have Western markets taking a close look at their capabilities. 

 is president of BioPlan Associates, tel. 301.921.5979, 

Top 1000 Global Biopharmaceutical Facilities Index, 

Outsourcing

The industry may not be ready for India and China as regulatory issues emerge.

What Happened to Outsourcing in Asia?

Generic-drug incursion and resulting declines in revenues continue to be major issues for the large pharmaceutical companies. An analysis of second-quarter and first-half results in 2013 of some of the leading companies reflect this issue as companies seek to continue to build their pipelines through acquisitions and organic growth. 

 Pfizer reported pharmaceutical/biopharmaceutical revenues of $23.66 billion for the first half of 2013, a 10% drop compared to revenues in the first half of 2012.  A primary contributor to the decline was reduced sales for the company’s anticholesterol drug Lipitor (atorvastatin calcium), which continued to experience sales erosion due to generic-drug competition. Lipitor lost exclusivity in the United States in November 2011 and various other major markets in 2011 and 2012. This loss of exclusivity reduced branded worldwide revenues by $657 million in the second quarter of 2013, in comparison with the second quarter of 2012. The decline in Lipitor’s sales reflected the losses of exclusivity of the drug in developed Europe in the second-quarter 2012 as well as the impact of multisource generic competition in the US beginning in late-May 2012. First-half 2013 sales of Lipitor declined 55% year over year from $2.62 billion in the first half of 2012 to $1.17 billion in the first half of 2013. 

Additionally, Pfizer’s second-quarter revenues were negatively impacted by other product losses of exclusivity, government purchasing patterns for Prevnar/Prevenar, a pneumococcal conjugate vaccine, in various markets, and certain other events, primarily within the company’s emerging markets unit. In emerging markets, for the second-quarter of 2014, Pfizer’s revenues grew 4% operationally, primarily due to strong volume growth in China, most notably for Lipitor and Prevenar, which was partially offset by the impact of the transfer of certain product rights to the Pfizer–Hisun joint venture in the first-quarter 2013 and the timing of government purchases of Enbrel (etanercept), a drug to treat psoriasis, psoriatic arthritis, and rheumatoid arthritis, and Prevenar in certain other emerging markets. Pfizer expects operational revenue growth in emerging markets to accelerate in the second half of the year to a high-single-digit percentage, with the full-year 2013 operational revenue growth expected to be a mid-single-digit percentage. 

In key pipeline and other business developments thus far in 2013, Pfizer received breakthrough-therapy designation by FDA for palbociclib, a drug to treat breast cancer. A Phase III study, evaluating the safety and efficacy of inotuzumab ozogamicin in patients with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma who are not candidates for intensive high-dose chemotherapy, was discontinued due to futility. This compound continues to be studied in adult acute lymphoblastic leukemia and other hematological malignancies. 

In other business developments, Pfizer gained $10.5 billion (pretax) for the sale of its 80.2% remaining stake in its animal-health business, Zoetis. In June 24, 2013, Pfizer completed the full disposition of Zoetis, which was achieved through a series of steps, including the formation of Zoetis as a separate company to which Pfizer transferred substantially all of its animal-health assets and liabilities, an initial public offering of a 19.8% interest in Zoetis, and a subsequent exchange offer for the company’s remaining 80.2% interest. Pfizer also entered into a worldwide (except Japan) collaboration agreement with Merck & Co. to develop and commercialize ertugliflozin and ertugliflozin-containing fixed-dose combinations with metformin and Januvia® (sitagliptin) tablets. Ertugliflozin is Pfizer’s investigational medicine for Type 2 diabetes, with Phase III trials expected to begin later in 2013. 

Pfizer also announced plans to move forward to internally separate its commercial operations into three business segments, two of which will include Innovative business lines and a third which will include the Value business line. Each of the three segments will include developed markets and emerging markets. The changes will be implemented in fiscal 2014 in countries that do not require a consultation with works councils or unions and will be implemented in countries that require consultation after the successful conclusion of those processes. 

 Merck reported a 12% decline in pharmaceutical product revenue for the second quarter of 2013. In the second quarter of 2013, the company had pharmaceutical sales of $10.56 billion, which was down from $9.31 billion in the year-ago period. A primary cause was a decline of global sales of Singulair (montelukast sodium) due to generic-drug competition. Worldwide sales of Singulair, a once-a-day oral medicine for the chronic treatment of asthma and the relief of symptoms of allergic rhinitis, declined 80% to $281 million in the second quarter of 2013 from $1.41 billion. The patents for Singulair expired in the US in August 2012 and expired in major European markets in February 2013. The company experienced a significant and rapid reduction in sales in the US and is now also experiencing a substantial decline in Europe. Merck also saw revenue declines due to further loss of market exclusivity for the antimigraine drug Maxalt (rizatriptan benzoate), the antihypertensive drug Cozaar (losartan potassium)/Hyzaar (losartan potassium/hydrochlorothiazide) and the antihistamine Clarinex (desloratadine). These declines were partially offset by growth in the company’s diabetes drugs, Januvia (sitagliptin)/Janumet (sitagliptin/metformin HCI), Gardasil (human papillomavirus quadrivalent (Types 6, 11, 16 and 18) vaccine, recombinant], and the arthritis drug Simponi (golimumab). 

In other key developments for the second quarter, Merck reported preliminary results from an ongoing Phase IB expansion study evaluating the safety and efficacy of MK-3475, Merck’s investigational antibody therapy targeting PD-1, in patients with advanced (inoperable and metastatic) melanoma. Also, FDA approved Liptruzet (ezetimibe and atorvastatin) tablets for the treatment of elevated low-density lipoprotein cholesterol in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. The company also received a Complete Response Letter from FDA regarding the new drug application for suvorexant, Merck’s investigational medicine for the treatment of insomnia. The company is evaluating the requests outlined in the Complete Response Letter and plans to submit definitive data in response to FDA in the first half of 2014. 

 In reporting its second-quarter 2013 results, Sanofi CEO Christopher A. Viehbacher acknowledged the negative impact resulting from loss of patent expiration and resulting generic-drug incursion. “The second quarter was a difficult quarter. As expected, this was the last quarter with a tough comparison to the prior year due to the residual impact of the patent cliff,” he said in a company press release. “Sales were also affected by our business in Brazil and commercial underperformance in certain business areas. However, sales growth of 7.7% of our growth platforms in the first half of 2013 continues to demonstrate the value of Sanofi’s integrated business model. In addition, we keep on making strong progress in delivering a growing portfolio of high potential R&D assets, as highlighted by the multiple clinical and regulatory milestones reached in the second quarter of 2013. We continue to expect to return to growth in the second half of 2013,” he concluded. 

In the second quarter, Sanofi reported that sales in its pharmaceuticals business were EUR 6.71 billion ($8.92 billion), a decrease of 7.1%, which reflected generic competition, EU austerity measures, and an adjustment of  EUR 122 million ($162 million) related to Brazil. Sales lost due to generic competition on its main legacy products in the US and European Union were EUR 481 million, ($640 million) primarily due to declining sales in the US for  the anticancer drug Eloxatin (oxaliplatin injection), the anticoagulant Lovenox (enoxaparin), and the active ingredient of Plavix  (clopidogrel bisulfate), a drug to inhibit blood clots, and in the EU, for the antihypertensive drug Aprovel (irbesartan). 

Overall, Sanofi’s 2013 first-half sales for its pharmaceuticals business reached EUR 13.5 billion ($18.0 billion), a decrease of 5.7%. First-half sales lost due to generic competition on main legacy products in the U.S. and EU were EUR 1.036 million ($1.378 billion). Sales of Plavix were EUR 493 million ($656 million), down 1.3% in the second quarter impacted by decreased sales of active ingredient for the US (EUR 5 million [$6.6 million] versus EUR 28 million [$37 million] in the second quarter of 2012) as the product lost its exclusivity in the US on May 17, 2012. Sales of Lovenox were EUR 436 million ($580 million) in the second quarter, a decrease of 9.2%, mainly due to generic competition in the US where sales of the branded product declined 43.7% to EUR 48 million ($64 million). Second-quarter sales of Eloxatin were EUR 60 million ($79.8 million), a decrease of 83.7%, reflecting generic competition in the US where the product lost its market exclusivity August 9, 2012,  and sales decline in emerging markets (EUR 31 million [$41 million], down 20.0%). First-half sales of Eloxatin declined 84.2% to EUR 119 million ($158 million). Second-quarter sales of Aprovel/Avapro decreased 27.5% to EUR 238 million ($316 million), reflecting generic competition in Western Europe where sales decreased 45.3% to EUR 94 million ($125 million). 

On a positive note, products from Sanofi’s diabetes franchise sales totaled EUR 1.621 billion in the second quarter, an increase of 16.2%. For the first half of 2013, the company’s diabetes division recorded sales of EUR 3.163 billion, an increase of 17.8% in the first half of 2013. Second-quarter sales of Genzyme reached EUR 525 million ($698 million), an increase of 25.6%, driven by growth of Cerezyme (imiglucerase), a drug to treat Gaucher’s disease, and the enzyme-replacement therapy Fabrazyme (agalsidase beta) and the launch of the multiple-sclerosis drug Aubagio (teriflunomide) in the US. First-half sales of Genzyme totaled EUR 1.018 million ($1.354 million), an increase of 25.5%. 

 AstraZeneca reported a 4% decline in sales to $6.232 billion in the second quarter. Loss of exclusivity on several key brands accounted for approximately $500 million in revenue decline in the quarter. Five growth platforms (emerging markets, Japan, the antiplatelet Brilinta (ticagrelor), its diabetes franchise, and its respiratory franchise) contributed more than $400 million in revenue growth in the second quarter. 

Other key developments thus far for the company in 2013 are the acquisitions of the specialty pharmaceutical company Omthera Pharmaceuticals and the pharmaceutical company Pearl Therapeutics and a recent collaboration with FibroGen to add three late-stage assets to the pipeline. Omthera’s investigational product, Epanova, for the potential treatment of patients with very high triglycerides, is an omega-3 free fatty acid composition that has been shown to bolster levels of eicosapentaenoic acid and docosahexaenoic acid. Pearl Therapeutics specializes in inhaled small molecules to treat respiratory disease. Pearl’s lead product, PT003, is a fixed-dose combination of formoterol fumarate, a long-acting beta-2-agonist and glycopyrrolate, a long-acting muscarinic antagonist. AstraZeneca and FibroGen formed a strategic collaboration to develop and commercialize FG-4592, an oral compound in late stage development for the treatment of anemia associated with chronic kidney disease and end-stage renal disease. Separately, AstraZeneca also filed a new drug application for Forxiga (dapagliflozin) with FDA in July 2013.

"We have made real progress in the second quarter against our strategic priorities despite the anticipated impact on revenue of the loss of exclusivity for some brands,” said AstraZeneca CEO Pascal Soriot,” in a company statement. “We continue to invest in distinctive science, our pipeline projects, products and key markets and our five key growth platforms delivered a double-digit increase in revenue contribution. Despite the fostamatinib disappointment, the late-stage pipeline in our core therapy areas is growing and has been further strengthened with the acquisitions of Omthera Pharmaceuticals and Pearl Therapeutics and the recently announced collaboration with FibroGen. In announcing the Cambridge Biomedical Campus as the location of our new UK strategic center, we also reaffirmed our commitment to invest in research and development productivity." 

Global Feature

Pfizer, Merck, Sanofi, and AstraZeneca are among the companies reporting revenue declines from generic-drug incursion. A look at what the companies are doing to stimulate growth.

Pfizer, Merck, Sanofi, and AstraZeneca Facing the Generic-Drug Squeeze

Led by strong demand for oncology drugs, high-potency manufacturing   continues to be an active area of investment, particularly for antibody drug conjugates (ADCs). ADCs, which consist of a monoclonal antibody (mAb) chemically linked to a small-molecule therapeutic, are a promising modality for certain therapeutic areas. ADCs are attracting the interest of both small and large pharmaceutical companies in their drug-development efforts as well as contract manufacturers specializing in high-potency manufacturing.  

The potential of ADCs was affirmed earlier this year when Roche's Genentech received FDA approval for Kadcyla (ado-trastuzumab emtansine or T-DM1) for treating HER2-positive metastatic breast cancer (mBC). The drug combines trastuzumab (Herceptin), which targets human epidermal growth factor receptor 2 (HER2) receptors with a maytansine derivative DM1, a small-molecule cytotoxin that binds to tubulin to prevent microtubule formation, through a stable thioether linker (4-[

-maleimidomethyl] cyclohexane-1-carboxylate) (1–3). Roche/Genentech has more than 25 ADCs in development, with eight ADCs in Phase I or Phase II studies for different types of cancer. 

Kadcyla is the first FDA-approved ADC for treating HER2-positive mBC, and one of the few commercially approved ADCs. In August 2011, FDA approved Adcetris (brentuximab vedotin), codeveloped by Seattle Genetics and Millennium Pharmaceuticals (now part of Takeda Pharmaceutical). Adcetris consists of three parts: the chimeric IgG1 antibody cAC10, specific for human CD30, the microtubule-disrupting agent monomethyl auristatin E (MMAE), and a protease-cleavable linker that covalently attaches MMAE to cAC10 (1, 2). Before the approval of Adcetris, the only other ADC approved by FDA was Mylotarg (gemtuzumab ozogamicin), approved more than 10 years ago in 2000. The drug, an anti-CD33 mAb conjugated to the cytotoxin calicheamicin, was developed by Wyeth (now part of Pfizer) and granted accelerated approval in 2000 but was voluntarily withdrawn by Pfizer in 2010 because a required Phase III trial failed to demonstrate a survival advantage (1, 3).  

Pfizer suffered another setback in its ADC development program earlier this year, when in May, it discontinued a Phase III study for one of its investigational ADCs, inotuzumab ozogamicin, for treating non-Hodgkin lymphoma. The drug continues to be evaluated as a treatment in adult acute lymphoblastic leukemia. Inotuzumab ozogamicin was originally developed by Celltech (now UCB) before Pfizer acquired all manufacturing and development rights. 

Pfizer, like other pharmaceutical companies, is partnering with smaller biopharmaceutical companies to advance ADCs. In June 2013, Pfizer formed a global strategic collaboration, worth up to $635 million, with CytomX to develop and commercialize multiple CytomX Probody Drug Conjugates (PDCs), propertiary ADCs of CytomX. Pfizer has exclusive rights to pursue development and commercialization of select PDCs. The companies will work together on preclinical research. Pfizer is responsible for development and potential commercialization of any selected PDCs with CytomX eligible to receive upfront, research, and preclinical milestone payments as well as potential tiered royalties.  

In May 2013, Ambrx, a clinical-stage biopharmaceutical company, partnered with Bristol-Myers Squibb for the discovery and development of ADCs using Ambrx's protein medicinal chemistry technology. Ambrx will receive an upfront payment of $15 million, funding for discovery and   research activities, potential development, and regulatory and sales milestones of as much as $97 million per product. BMS will have worldwide rights to develop and commercialize products resulting from the collaboration, and Ambrx is eligible to receive royalties on sales. In April 2013, Ambrx partnered with Astellas in an ADC deal worth up to $300 milllion. Ambrx received an upfront payment of $15 million from Astellas and may receive up to $285 million in potential milestones for an undisclosed number of targets for ADCs in oncology. Ambrx also inked a deal in ADC development with Merck & Co. in 2012. In June 2013, Ambrx partnered with the Chinese pharmaceutical Zhejiang Medicine  (ZMC) to develop and commercialize ARX788, Ambrx's ADC targeting HER2-positive breast cancer. Ambrx and ZMC will continue the development of ARX788, with ZMC bearing the ongoing development cost. ZMC will manufacture the drug on a commercial basis. The CRO WuXi PharmaTech will develop and manufacture the toxin, antibody, and ADC as well as provide preclinical development and clinical trials.  

The "new normal" in biopharmaceutical financing			

Seattle Genetics, which partnered with Takeda for developing Adcetris, is collaborating with Genentech, Pfizer, AbbVie (formerly Abbott), Bayer HealthCare, Progenics, and Genmab for ADCs using Seattle Genetics' proprietary ADC technology. Seattle Genetics' technology uses synthetic cytotoxic agents, such as E (MMAE) and monomethyl auristatin F (MMAF), and stable linker systems. In April 2013, Seattle Genetics reported on a newly developed cytotoxic agent, a pyrrolobenzodiazepine (PBD) dimer. PBDs are a class of highly potent, synthetic DNA-crosslinking agents, and the company presented data on ADCs using the company's site-specific conjugation technology (EC-mAbs) to link PBDs to mAbs targeted to CD33 and CD70. The company also reported on its preclinical candidate, SGN-LIV1A, which uses the same proprietary ADC technology as Adcetris and presented research on a new method for making highly stable linkers, specifically self-stabilizing maleimido-DPR linkers (4).  

In June 2013, Genmab and ADC Therapeutics teamed to develop a new ADC product combining Genmab's HuMax-TAC antibody and ADC Therapeutics' PBD-based cytotoxic and linker technology. In 2012, Spirogen announced a multiyear collaboration and license agreement with Genentech for the discovery and development of ADCs using Spirogen's PBD-based drugs and associated linker technology. Spirogen is primarily responsible for synthesizing and manufacturing drug reagents while Genentech is using Spirogen's drug reagents to generate ADCs and evaluate their potential therapeutic utility. Genentech has the exclusive license to fully develop and commercialize licensed products that contain these ADCs (3). 

Mersana Therapeutics, which is developing ADCs using its Fleximer polymer and customizable linker chemistries, formed a $270-million collaboration with Endo Pharmaceuticals in early 2012. The Fleximer polymer is customized to improve the pharmacokinetics of targeting moieties, such as antibody fragments, and also to optimize the quantity of cytotoxic payload carried per targeted conjugate and the stability of the drug–polymer linkage as well as the targeting moiety–polymer linkage (3). In July 2012, Mersana received $27 million in venture-capital funding, which included investment by Pfizer Venture Investments. Biotecnol and PolyTherics formed a collaboration in 2012 for multispecific tribody drug conjugates to use Biotecnol's tribody technology with PolyTherics' proprietary site-specific linker technologies. Tribody molecules are multispecific antibody products that, from a single molecule, enable the targeting of two or three tumor antigens in the same disease or two or three epitopes on the same tumour target. PolyTherics' ThioBridge linker technology is a conjugation technology for creating more stable, less heterogeneous ADCs through site-specific linkage and rebridging of disulfide bonds (3).  

Contract API manufacturers offering high-potency manufacturing and related services are expanding in response to increased demand for ADCs and other highly potent compounds. In January 2013, Lonza announced plans to invest CHF 14 million ($15 million) to expand ADC manufacturing capacity in Visp, Switzerland. The expansion of the ADC facility will double the company's existing large-scale manufacturing capacity in Visp. The expansion is expected to be completed in the second quarter of 2014.  

In 2012, Carbogen Amcis and ADC Biotechnology (ADC Bio) partnered for ADC development and manufacturing services. ADC Bio is providing proprietary solid-phase immobilization technologies for conjugation and long-term storage of ADCs, and Carbogen Amcis is providing small- to large-scale GMP supply and the formulation of ADCs. ADC Bio also recently expanded its facility in St. Asaph, United Kingdom in northern Wales with the addition of a new technical service laboratory. Commissioned in April 2013, the additional facility at St. Asaph provides ADC screening, process development, and scale-up capabilites. 

In October 2012, Fujifilm Diosynth Biotechnologies formed a strategic alliance with Piramal for ADC production, whereby the two parties will offer contract development and manufacture of ADCs. Piramal offers ADC production at its site in Grangemouth, Scotland. Fujifilm recently announced an expansion of its cGMP manufacturing facilities at its sites in Research Triangle Park, North Carolina, and Billingham, UK. Novasep announced in 2012 a EUR 3 million ($3.9-million) investment to expand its highly potent API manufacturing capabilities at its Le Mans, France facility, which is part of the company's strategy to be positioned in the ADCs.  

Earlier this year, Catalent Pharma Solutions acquired an exclusive license to market Redwood Bioscience's proprietary SMARTag protein-chemical engineering technology used in site-specific protein modification and linker chemistry for ADCs. Catalent will have the exclusive right to sublicense the SMARTagtechnology and will work with Redwood to comarket the technology and support sublicense programs. As part of the collaboration, Catalent will also take a minority equity stake in Redwood, which may increase over time up to a potential acquisition. 

Companies also are expanding on the finished product side. In February 2013, Baxter International's BioPharma Solutions business began an approximately 1750-m

  capacity expansion at the company's fill–finish cytotoxic contract manufacturing facility in Halle (Westfalen), Germany. This expansion follows previous expansions in Halle in 2007 and 2011. In April 2013, Goodwin Technology and Coldstream Laboratories agreed to develop and manufacture high-potency, highly cytotoxic materials, such as small molecules, protein toxins, cytotoxic ADCs, and other bioconjugates. GBI will use Coldstream's cGMP platform of services, including analytical testing, formulation, liquid or lyophilized fill–finish, storage and shipment of manufactured highly-potent bioconjugates. 

In May 2013, Penn Pharma successfully completed the first batch of coated tablets at its new contained manufacturing facility in South Wales, UK. The facility is designed for the clinical and commercial manufacture of tablets and capsules. In November 2011, Metrics began offering neat API capsule-filling at its potent and cytotoxic facility in Greenville, North Carolina. The company secured a Capsugel Xcelodose system, a powder microdoser and automated encapsulator that places API directly into capsules with a high level of accuracy. Metrics also installed a custom-built isolation system for the equipment. The company offers dedicated and segregated potent and cytotoxic cGMP manufacturing for Phase I–III projects. It opened a new potent and cytotoxic drug-development facility in 2009 as part of an expansion of the company's Greenville facility. 

Other companies are positioned in both API and finished product manufacturing for highly potent compounds. For example, CordenParma has facilities in Plankstadt (Germany), Latina (Italy), and Boulder (Colorado) for manufacturing highly potent APIs and drug products. Aesica, based in Newcastle-Upon-Tyne, UK, opened a new high-potency manufacturing facility in Queenborough for formulated products in late 2011. The company later upgraded its UK-based API manufacturing facilities in Cramlington and Queenborough to manufacture high-potency APIs.   

 485 Route One South,  Bldg F, First Floor,  Iselin, NJ 08830 tel. 732.346.3072,  

 2. FDA, "Label for Adcetris, BLA 125338," FDA Approved Drug Products: Drugs@FDA, accessed June 5, 2013. 

 4. Seattle Genetics, "Seattle Genetics and Collaborators Highlight Multiple Antibody-Drug Conjugate (ADC) Programs and Technology Advances at AACR," Press Release, Apr. 9, 2013. 

APIs

Contract service providers expand capabilities in API and finished product manufacturing to meet demand for high-potency drugs

PTSM: Pharmaceutical Technology Sourcing and Management-08-07-2013

Pharma News in Global Health and Sustainability

What Happened to Outsourcing in Asia?

Pfizer, Merck, Sanofi, and AstraZeneca Facing the Generic-Drug Squeeze

Gauging Investment in High-Potency Manufacturing