Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

	Growing demand in emerging regions with simultaneous maturation of western markets has led to a new emphasis on low-cost, low margin products and specialized, low-volume niche drugs for targeted patient populations. To reduce costs and increase flexibility, many large pharmaceutical companies are outsourcing a growing percentage of their business activities. The changing market conditions are also creating opportunities for virtual pharmaceutical companies, which have no manufacturing capabilities of their own. In addition, increasing numbers of new drug candidates are highly potent, requiring specialized production capabilities. Custom manufacturing firms that have established themselves as efficient providers of services across the drug development and commercialization spectrum, and particularly those with specialized capabilities for the production of highly potent APIs, will be in a position to benefit as the trend toward pharmaceutical outsourcing continues.
	
	
	


	Market research firm Visiongain forecasts that the worldwide pharmaceutical custom manufacturing market will earn revenues of $71 billion in 2018 (1). Strong revenue growth is anticipated for market leading custom manufacturing organizations (CMO) between 2014 and 2024, with leaders including DPx Holdings, formed in 2014 from the contract manufacturing businesses of Royal DSM and Patheon; Lonza; and Catalent experiencing the greatest increase in absolute revenue. This growth reverses the trend seen in 2009-2013 of low single-digit revenue growth for the top five developed-market CMOs.
	
	During that same period, leading companies based in developing countries showed strong performance, with revenues increasing at double-digit growth rates, according to Visiongain  Not surprisingly, therefore, while North American and European CMOs have continued to dominate the contract manufacturing market in 2014, going forward, companies based in emerging countries will play a greater role as they experience sustained demand from domestic pharmaceutical companies and, increasingly, foreign drug developers. Specifically, between 2013 and 2024 emerging-market leaders will increase their share of the global CMO market by 15% (1).
	
	


	The increasing demand for CMO services in emerging markets reflects a wider trend in the pharmaceutical industry. The greatest growth in demand for pharmaceuticals is also taking place in emerging markets, but unlike in western countries where high-cost, high-margin sales were the norm, the buying habits are quite different, according to Diane Palmquist, vice-president of product management for GT Nexus, a provider of cloud-based solutions. “People in emerging regions purchase drugs by the dose, not by the bottle, and they are looking for low-cost (and consequently low-margin) products,” she says. “In order to remain successful, pharmaceutical companies have needed to completely transform their old business models,” she adds.
	
	In fact, during the past 10 years, demand for outsourced manufacturing services grew rapidly as pharmaceutical companies sought to take advantage of the benefits of contract manufacturing, such as lower costs, increased flexibility, and external expertise, while increasing their ability to focus resources on core competencies in drug development and marketing, according to Jonathan Weymer, senior pharmaceutical and healthcare industry analyst with Visiongain.
	
	Not surprisingly, in response to the changing market dynamics and in support of the desire to focus on core competencies, many large pharmaceutical companies have been consolidating their manufacturing facilities to reduce their asset bases and associated costs, according to Cristin Grove, director of contract manufacturing at Pfizer CentreSource. “In addition,” she notes, “as many products face loss of patent protection, they are transferred to contract manufacturers in order to allow the remaining captive capacity to be used for pipeline products.”  Pfizer CentreSource also anticipates real growth in the virtual pharmaceutical space, which will have a direct impact on the contract manufacturing sector, because these virtual companies typically have no manufacturing assets and require partners to help commercialize their opportunities.
	
	As a consequence, pharmaceutical companies are outsourcing nearly every aspect of the business, including API manufacturing. Palmquist notes that currently approximately 40% of industry business is outsourced, and she expects that number to increase to 80% over the next several years.
	
	


	CMOs are increasingly seen as strategic partners for pharmaceutical companies, providing a one-stop-shop of services for formulation development and manufacturing throughout the lifecycle of a drug, according to Weymer. “Market-leading CMOs have grown through acquisitions and site expansions and have positioned themselves to offer almost all required services on a global scale,” he says. It is important to note, however, that there is still a role to be played by specialist CMOs, particularly those that offer biological drug manufacturing services. Visiongain also found in its survey of the pharmaceutical industry that CMOs that can ensure supply chain quality control while also providing production flexibility are in greatest demand. “The ability to deliver high-quality, flexible production will drive business to the leading firms in the market in coming years,” Weymer observes.
	
	


	In addition to those CMOs that can offer integrated services from discovery through commercialization and off-patent production, contract manufacturers that have capabilities for the production of highly potent compounds will experience a higher share of the anticipated growth, according to Grove. “We believe there is significant upside in the high-containment space.  The primary driver is that pharmaceutical pipelines are focused on specialized disease areas such as the central nervous system (CNS), oncology, janus kinase (JAK) inhibitors, etc., and the vast majority of these new chemical entities (NCEs) require high containment.”
	
	While Pfizer CentreSource has access to Pfizer Global Supply sites with capabilities for containment of highly potent APIs, other leading CMOs such as Catalent and Lonza have made considerable investments in high-potency API and antibody drug conjugate production facilities in anticipation of long-term growth in demand (at least over the next 10 years), according to Weymer. Even so, with high containment facilities requiring substantial capital investments in excess of $50 million in many cases, this capital constraint will prohibit many pharmaceutical manufacturers and CMOs from adding this type of capacity, according to Grove.
	
	The key to success for highly potent API manufacturing will be for pharmaceutical manufacturers to partner early on in a project--such as Phase II/III--with CMOs that have the capability and capacity to produce highly potent compounds in development and commercial quantities. “With a partnership established in the earlier phases, it is much easier to continue and offer commercial manufacturing as well,” Grove explains. She sees Big Pharma and select (large) pure-play CMOs as the primary providers of this high potent API (and drug substance) capacity moving forward.
	
	Pfizer CentreSource’s current focus is on high containment solid oral dose and biologic drug substance offerings.  “We believe our globally integrated network, specialized manufacturing technologies, and quality/regulatory expertise will allow us to capitalize on the trend toward specialized disease areas,” Grove notes.
	
	

Pharma Leader Series: Leading Pharmaceutical Contract Manufacturing Organizations (CMOs) 2014-2024

 When referring to this article, please cite it as C. Challener, "API Custom Manufacturing Outlook: More Growth in 2015," 

Articles

Changing dynamics of the pharmaceutical industry are driving demand.

API Custom Manufacturing Outlook: More Growth in 2015

	Single-use systems (SUS) have become established in biopharmaceutical drug development. As confidence in the technology has increased, the adoption of disposable equipment for commercial manufacturing has begun to take place. With this shift has come a dependence on suppliers that is related to production capabilities, a situation that did not previously exist. This reliance on suppliers translates to increased risk, and consequently biopharmaceutical manufacturers are focused on managing this risk and ensuring security of supply. Dual sourcing of single-use systems and components was initially proposed as the key solution. After further consideration of the issues surrounding the supply of single-use systems, however, many in the industry believe that dual sourcing presents many challenges that can often be avoided by taking alternative approaches.
	
	


	Today, single-use systems are used throughout the entire process chain from upstream to downstream and from bench scale to production scale. In the past, when drugs were manufactured in stainless steel, the manufacturer was in control of the infrastructure once its facility was in place, sourcing only critical disposable components such as filters and chromatography sorbents. Although disposable systems do provide numerous advantages, such as reduced contamination risks, shorter set-up times, and lower capital costs, biopharmaceutical manufacturers do not have that same level of control over the disposable systems as they did with traditional stainless-steel equipment because the systems and components must be purchased from a supplier, according to John Briggs, director of quality, regulatory, and compliance at ASI-Life Sciences. As a result, adds Mario Philips, vice-president of single-use technologies at Pall Life Sciences, there is a greater dependence on the single-use supplier, which increases the risk for the manufacturer and thus requires greater vendor transparency and supply-chain security.
	
	“Unlike with traditional equipment, where almost everything is physically located at the facility, single-use systems are delivered to the site from a supplier. If the user operates on a just-in-time basis with no inventory, any delay in delivery could put the manufacturing schedule at risk. Consequently, an SUS is a critical part of drug substance manufacturing, and there is a greater need to understand and secure the sourcing of these systems,” says Roman Rodriguez, global market development manager for single-use technologies with EMD Millipore. As such, it is logical to consider qualifying a back-up supplier as part of the SUS risk-management system, and dual sourcing is a response to a need for anticipating unforeseen issues and scenarios.
	
	The implementation of single-use systems in commercial manufacturing has had the additional consequence of shifting the purchasing of these systems from those in development to sourcing professionals. As a result, according to Tony White, a founding director of the BioPhorum Operations Group (BPOG), some biopharmaceutical manufacturers are now starting to consider single-use technologies as a strategic commodity and managing their purchases across their manufacturing network, which often leads to the identification of risks that were not previously perceived. “In addition,” says White, “they are realizing that they have been single-sourcing key components by default--a position they do not find very comfortable.”
	
	Past experience with SUS sourcing problems is also a driver for the increasing focus on multisourcing, according to Terry Hudson, director of process development engineering with Genentech. “At any conference with single-use as a topic, you can find a case study or conversation about a single-use component being changed with either no prior notification or inadequate notification to the end user, and in several cases that has been tied to a negative impact on production,” he explains. In addition, Hudson notes that companies are also learning that occasionally a given process may be more sensitive to a leachable or film type than other processes, and it is beneficial to have an alternative film that can be used with that process.  
	
	There are regulatory drivers as well. Regulatory authorities have had a clear and simple message with respect to single-use products, according to Ross Acucena, product strategy manager-ReadyToProcess with GE Healthcare Life Sciences, which is that their use is analogous to outsourcing crucial elements of GMP operations, such as presterilization. “The role of the supplier is therefore now more critical, and regulators expect drug manufacturers to mitigate any risk with close partnerships and thorough knowledge of their suppliers’ quality systems and supply chains,” he says. Furthermore, the increased focus on suppliers has highlighted the fact that SUS supply chains are both broad and deep because of the integration of many components into the end products. “Single-use customers recognize that it is difficult to fully control the supply chain, which presents a potential risk to their operations and subsequent supply of needed drugs to patients,” Acucena asserts. The industry response has been to increase its focus on mitigating such risk through multisourcing.  
	
	


	The ultimate goal of multisourcing is to have the ability to seamlessly transfer from one single-use product source to another without risk to patient safety, according to Acucena. “There is a strong need to characterize and understand this issue for all parties in the complex supply chains that exist within the industry. Upon investigation, it may materialize that some parties have a robust supply chain where risk is small. The converse is that unacceptably high levels of risk are detected, requiring either dual-source or multisource strategies, or even exiting a specific relationship,” he observes.
	
	In an ideal state, according to Hudson, the multisourced component would be supplied by two different companies with different supply chains to minimize the potential for a single change impacting both components. At a minimum, multisourcing needs to provide assurance that a change or disruption to one source will not also occur at the second source. Thus, risk mitigation can be achieved by using one vendor that has two plants or by using two separate vendors. “The latter option also provides some commercial leverage and tends to be the preferred approach for end users,” Philips says, “but a lack of industry standards for single-use systems makes it more difficult, if not impossible.” Not surprisingly, suppliers prefer the dual site or manufacturing redundancy concept, according to Spencer Parkinson, senior product manager for bioproduction with Thermo Fisher Scientific. “If it is truly assurance of supply that is of interest, then more than one production site addresses this need, while allowing a supplier to provide ‘best-in-class’ products,” he notes.
	
	For Rodriguez, multisourcing is the basic view, and the real issue relates to supply chain understanding, assurance, and control, as well as taking action to reduce inherent risks. “Doing so is not as easy as it seems due to supply chain complexity down to the resin suppliers and the varying approaches that can be taken. It really starts with a close interaction with SUS integrators on a whole supply chain view. An alternative supplier’s products must be assessed with the same science-based qualification process, and if different suppliers adopt slightly different approaches, the end-user must determine what is acceptable,” he says. As an example, Rodriguez points to bioburden levels, which can be tested on every single lot or using a statistical approach. Both methods may be acceptable depending on the end-user’s specifications.
	
	


	There are numerous challenges when considering true dual sourcing, and many relate to the complexity of the single-use supply chain. The SUS business is highly customized, and there are thousands of single-use components, many of which only work with other components made by the same supplier. Of course, not all those components need the same scrutiny depending on their criticality and demand, according to Rodriguez, but due to the huge number of components and suppliers, it is a complex task to track and understand the supply chain to secure and control it. As an integrator, EMD Millipore has prioritized and ranked SUSs based on criteria (i.e., criticality, volume used, lead time, reliability of the suppliers) and customer interaction.
	
	Qualification and validation are, in fact, the critical criteria that must be met to achieve dual sourcing, according to Acucena. “To achieve dual sourcing, one must have documented evidence that a change in input (product contact materials) will not affect the output (product quality, efficacy, safety), and it is ultimately through qualification and validation that such assurance is achieved,” he notes.
	
	ASI-Life Sciences is taking a close look at how to demonstrate functional equivalency of materials obtained from different suppliers. “At this point there is no standard or definition for functional equivalency, but it is necessary to define what constitutes functionally equivalent materials in order to ensure change control,” Briggs observes.

	“The challenge lies in the fact that proprietary plastics/elastomers are used by different suppliers, and thus composition alone cannot be used to determine equivalency, and other characteristics, such as the physical and chemical properties of the single-use product and its performance under process conditions must be evaluated. In addition, the ability to integrate the product into an end-user process and the quality system of the supplier must also be considered,” he comments.
	
	Standardization is frequently raised as another issue for dual sourcing of single-use systems. Philips notes that with limited standards in place, variation in SUS design continues to be significant, and it is much harder to have contingency in supply. Hudson agrees that the main challenge to dual sourcing is the current business model used by most single-use companies, which involves the development of hardware for a SUS that will only work with their single-use components. “This approach for end users is a significant impediment to deploying such systems into a GMP environment. Until companies are willing to standardize enough on their design that they fit more than one single-use assembly, including an assembly from another company, it will be difficult to achieve true dual sourcing,” says Hudson.  

	Parkinson, on the other hand, argues that standardization would lead to a halt in innovation. “Single-use products are not commodities and will not be in the foreseeable future; innovation is critical to improving the technology. While it also leads to the development of different designs and materials by each vendor, improvements would not occur otherwise” he states.
	
	The continued advancement of single-use technology adds to the complexity, however, with new products constantly introduced that require change management. “We are aiming at full process integration by adding supply chain considerations from the lead times associated with single-use items, which requires discussions with the end-user because it is an integral part of technology transfers into manufacturing operations,” Rodriguez says. “Obviously the primary action is to communicate and build a basis of understanding about the supply chain itself and the potential associated risks, which naturally leads to actions to minimize those risks at every level of the supply chain, starting with the single-use integrator. Focusing on the product attributes, quality, and specifications may not be enough, however, as there are other steps involved such as sterilization and transportation (sometimes international) that may impact the product and lead time. Ultimately, therefore, the first challenge is to get a clear understanding of the supply chain, to communicate about it, and then establish an action plan on a case-by-case basis,” he continues.
	
	Thoroughly understanding the supply chain is, however, an intense endeavor that requires significant resources, according to Acucena. He in particular points to the case where two SUS suppliers purchase equipment from the same precursor company, and thus qualifying the two SUS suppliers does not achieve dual sourcing. He also notes that there are significant costs associated with qualifying dual-source suppliers, and the value of such an investment is an important consideration. “In essence,” says Acucena, “dual-sourcing or multisourcing can be likened to an ‘insurance policy’ that is relatively expensive to buy.”
	
	


	While the initial reaction of many biopharmaceutical manufacturers to concerns over single-use supply chain security was to look at dual-sourcing solutions, the focus has since shifted to the broader issue of security of supply and how best to manage it, according to Acucena. “The need is security of supply,” agrees Kevin Ott, executive director of the Bio-Process Systems Alliance (BPSA). He adds that dual sourcing is one possible solution, but there are others with fewer validation challenges, including redundant supply sources from a single vendor and inventory plans, for example. “The question,” he continues, “also becomes complicated by how far back in the supply chain one needs to go. That depends on volume versus demand, structure of the supply chain, etc.”
	
	For example, Ott notes that suppliers of biocontainers that can assemble containers in two locations and carry sufficient inventory of finished units and film to cover film supply disruptions do not necessarily need to be dual sourced to ensure continuity of supply, just perhaps be “dual located.”
	
	“The justification for dual sourcing should depend on the risk and the level of simplicity, and single sourcing is in many cases appropriate as long as the relationship between the supplier and the end user is a partnership,” asserts White. He notes that many automotive manufacturers only single source strategically important materials because the investment in establishing a reliable supplier is significant and not worth doubling.
	
	One alternative to dual sourcing is, according to Philips, to limit the number of contact materials in single-use systems and aim to create interchangeability for any layer (e.g., films, filters, valves, and tubes) that comes in contact with a drug product. Pall Life Sciences has taken a step forward in this direction by vertically integrating its own production processes one step back in the supply chain. The company uses its own in-house extruded film to make the supply chain more robust and is working to mitigate any potential changes from resin suppliers. “While we can’t prevent change, we are prepared to manage that change, and if we fully understand our supply chain, we have the power to support customers through any change that may occur through our supply strategy, which adds up to an increased ability to offer a greater level of supply-chain security and continuity to users,” remarks Philips.
	
	Business continuity planning and inventory management are additional mechanisms for reducing risk, according to Acucena. He notes that suppliers are now engaged in an increased focus on these aspects, and thus the crucial first step of increasing industry awareness is already taking place. He also notes that the experience with reducing the risk associated with the single-sourcing of critical chromatography media, such as protein A, can be translated to single-use systems. “GE Healthcare sought to satisfy the industry’s need to mitigate this risk through a strong focus on business continuity planning (in accordance with ISO 22301 and achieving conformance to this standard), including qualifying dual sources for critical raw materials and a significant investment in safety stock. These efforts have delivered supply-chain security improvements that should help to eliminate end-user dual sourcing. Similar approaches should be applicable to single-use technology,” he explains.
	
	Both White and Ott also note that focusing on dual sourcing at this stage in the industry’s development may not be appropriate. “Many biopharmaceutical manufacturers are not yet in a good position to dual source, as they are just starting to understand the extent of their complete single-use portfolios across their networks,” White says. Ott adds that it may be premature or counterproductive to imagine risks. “It is better to actually study, evaluate, and understand your own supply chain and the real risks. Once that is done, the need to establish truly independent dual sources and the difficulty that such an approach represents with respect to validation and regulatory filing begins to look like much less of an issue than might be imagined,” he comments.
	
	


	Supply-chain security is a top challenge for both BPSA and BPOG moving forward into 2015. The Parenteral Drug Association (PDA) is also working on concepts to facilitate multisourcing. While these initiatives are important, Philips would prefer to see vendors, users, and regulators working together to bring one set of standards forward, rather than multiple associations working on multiple standards. “The biopharmaceutical industry is still a relatively immature industry, and substantial changes can be expected over the coming decade. Standardization is going to be a key element of true multisourcing, and having one body regulating the industry will make supply chains more transparent and keep user expectations realistic,” he says.
	
	Many of the industry-wide initiatives already underway to provide standardization and guidance on change notification, leachable/extractable testing, and other end-user needs for increased adoption of single-use systems, and particularly for components and systems that already allow some interchangeability such as buffer bags and tubing connectors, will help speed up multisourcing, according to Hudson. On the other hand, where the supplier’s business model is to design a system that only works with its components, education is the key. “Genentech recently presented a proof-of-concept design for a single-use bioreactor that could work with top- and bottom-mounted bags from two different suppliers. The next step is convincing management at suppliers that designs such as this one will lead to higher future sales because they help open the doors to more GMP applications and greater adoption of single-use technology in general,” he states. Genentech is also partnering with several single-use supplier companies to gain greater visibility into their supply chains, to provide recommendations on what it considers “multisourced”, and to communicate what applications of single-use simply will not occur until they can be multisourced.
	
	EMD Millipore, meanwhile, in addition to implementing a business continuity plan and supply risk management and emergency management programs focusing on products, suppliers, and its sites, respectively, has teamed with a third party (Resilinc Corporation) to map its supply chain for key products and suppliers to identify and mitigate risks with suppliers, according to Rodriguez.
	
	In its quest to identify a practical approach for determining the functional equivalency of unassembled components, ASI-Life Sciences submitted platinum-cured silicone tubing with similar specifications, mechanical properties, and performance profiles under typical use conditions obtained from two suppliers to Chemic Laboratories for comparative analysis of their extractable/leachable profiles. “Tubing was selected for this exercise because it is a common component of single-use systems and can be evaluated in a fairly straightforward manner,” Briggs observes. Importantly, no significant differences in the extraction profiles were observed for the two tubing samples. “These results indicated that the materials were comparable within the variability of the analytical techniques used,” Briggs says. He also recognizes that tubing is a universal single-use component, and establishing the functional equivalency of other, more proprietary single-use systems and components will be more challenging. “Our goal is to initiate a dialogue around the practical considerations for achieving dual sourcing of single-use systems.” 


	Vol. 38, Issue 12
	Pages: 24–26, 57
	Citation: When referring to this article, please cite it as C. Challener, "Securing the Single-Use Supply Chain," 

Dual sourcing is one of many possible solutions to securing the supply chain.

Securing the Single-Use Supply Chain

	With respect to FDA approval of new medicines, 2014 has been another strong year for the pharmaceutical industry. The agency’s Center for Drug Evaluation and Research (CDER) approved a total of 34 new medicines (as of the end of October 2014): 22 new molecular entities (NMEs) and 12 biologics license applications (BLAs) (see 

) (1). In 2013, the total number of approvals for the entire year was 27, while in 2012 the number reached 39, which was unusually high compared to the numbers of approvals over the previous 10 years (2). Not only were a high number of new medicines approved in 2014, there were numerous examples of first-ever approvals for the treatment of certain diseases and new classes of drugs that treat diseases via new routes. Treatments were also approved under new designations.


	Hetlioz (tasimelteon, Vanda Pharmaceuticals), a melatonin receptor agonist, was the first treatment approved by FDA for non-24-hour sleep-wake disorder, a chronic circadian rhythm (body clock) disorder that causes problems with the timing of sleep that occurs almost exclusively in people who suffer complete blindness (3). Vimizim (elosulfase alfa) from BioMarin Pharmaceutical is the first FDA-approved treatment for mucopolysaccharidosis type IVA (Morquio A syndrome), a rare, autosomal recessive lysosomal storage disease caused by a deficiency in 

 -acetylgalactosamine-6-sulfate sulfatase (GALNS). Vimizim is intended to replace the missing GALNS enzyme involved in an important metabolic pathway. Absence of this enzyme leads to problems with bone development, growth, and mobility (4). Myalept (metreleptin for injection), developed by Amylin Pharmaceuticals, which was acquired by AstraZeneca, is an orphan drug and the first treatment approved by FDA  for patients with congenital or acquired generalised lipodystrophy (5). Sylvant (siltuximab, Janssen Biotech) is another drug approved as a first treatment for a rare disease--multicentric Castleman’s disease, a rare disorder that causes an abnormal overgrowth of immune cells in lymph nodes and related tissues in the body. Administered as an injection, Sylvant works by blocking a protein that stimulates abnormal growth of immune cells (6).
	
	


	Several of the drugs approved by FDA also fall into new classes of drugs. Three of the most noteworthy are manufactured by Merck & Co. Zontivity (vorapaxar) tablets reduce the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore the blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs. It is the first protease-activated receptor-1 antagonist and is designed to decrease the tendency of platelets to clump together to form a blood clot (7). Belsomra (suvorexant) for insomnia is the first FDA-approved orexin receptor antagonist, which alters the signaling of orexin in the brain. Orexins are involved in regulating the sleep-wake cycle (8). Keytruda (pembrolizumab) was approved for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs. It is the first approved drug that blocks the programmed death-1 (PD-1) cellular pathway, which restricts the body’s immune system from attacking melanoma cells. Keytruda was also designated a breakthrough therapy and an orphan product and received priority review (9).


	Harvoni (ledipasvir and sofosbuvir) from Gilead Sciences is the first combination treatment (pill) for chronic hepatitis C virus (HCV) genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection. Both drugs in Harvoni interfere with the enzymes needed by HCV to multiply. Harvoni was designated a breakthrough therapy (10).
	
	


	In addition, 2014 saw the first approved antibiotic drugs--Dalvance (dalbavancin, Durata Therapeutics), Sivextro (tedizolid, Cubist Pharmaceuticals), and Orbactiv (oritavancin, The Medicines Company)--designated as qualified infectious disease products (QIDPs) under the Generating Antibiotic Incentives Now title of the FDA Safety and Innovation Act (FDASIA) (11). Vimizin was also the first drug to receive the Rare Pediatric Disease Priority Review Voucher, a provision that aims to encourage the development of new drugs and biologics for the prevention and treatment of rare pediatric diseases (4).
	
	For only the second year, FDA was able to classify new NMEs and BLAs as breakthrough therapies, which are drugs with preliminary clinical evidence demonstrating that they may have substantial improvement on at least one clinically significant endpoint over available therapies. While in 2013 just three approved drugs were designated as breakthrough therapies, to date in 2014, six have already been approved: Zykadia (ceritinib, Novartis), Zydelig (idelalisib, Gilead Sciences), Keytruda, Harvoni, Ofev (nintedanib, Boehringer Ingelheim Pharmaceuticals), and Esbriet (pirfenidone, InterMune). Zykadia was approved for patients with a certain type of late-stage (metastatic) non-small cell lung cancer (12), and Zydelig was approved for patients with relapsed chronic lymphocytic leukemia, elapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma (13). Both Ofev and Esbriet were approved for the treatment of idiopathic pulmonary fibrosis, which is a serious, chronic condition in which the lungs become progressively scarred over time (14). Four additional supplemental submissions also received breakthrough therapy designations (15).
	
	In addition to the breakthrough designation, FDA also has several other designations designed to expedite the review of NMEs and BLAs. These include fast track, orphan product (for rare diseases), and priority review designations. Drugs can receive multiple designations. Up to Oct. 29, 2014, seven approved drugs had fast-track status, nine were designated as orphan products, and 12 underwent priority review (1).


	Looking at companies that received the most approvals, two have come out on top as of Oct. 29, 2014. Boehringer Ingelheim and Merck & Co. each received approvals for two NMEs and one BLA. Boehringer Ingelheim received approvals for Ofev, Jardiance (empagliflozin) for improvement of glycemic control in adults with type 2 diabetes, and Striverdi Respimat (olodaterol), a biologic drug for the treatment of chronic obstructive pulmonary disease (1). Merck’s winners included Zontivity, Belsomra, and Keytruda as described above. AstraZeneca, Eli Lilly, and Gilead Sciences were also successful with two approvals each: Gilead for one BLA and one NME (Harvoni and Zydelig, respectively); Eli Lilly for two BLAs, Cyramza (ramucirumab) for the treatment of stomach cancer and Trulicity (dulaglutide) for the treatment of adults with type 2 diabetes; and AstraZeneca for two NMEs, Farxiga (dapaglifozin) to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes and Movantik (naloxegol) to treat opioid-induced constipation in adults with chronic non-cancer pain (1). Through its acquisition of the diabetes alliance assets of Bristol Myers Squibb, including Amylin Pharmaceuticals, AstraZeneca also acquired Myalept.
	
	


	1. FDA, “New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products of 2014,” 

www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm20025676.htm

, accessed Oct. 29, 2014.
	2. FDA, “Novel New Drugs 2013 Summary,” 

www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM381803.pdf

, accessed Oct. 29,  2014.
	3. FDA, “FDA Approves Hetlioz: first treatment for non-24 hour sleep-wake disorder,” Press Release, Jan. 31, 2014.
	4. FDA, “FDA approves Vimizim to treat rare congenital enzyme disorder,” Press Release, Feb. 14, 2014.
	5. AstraZeneca, “US FDA approves orphan drug Myalept (metrleptin for injection),” Press Release, Feb. 25, 2014.
	6. FDA, “FDA approves Sylvant for rare Castleman’s disease,” Press Release, April 23, 2014.
	7. FDA, “FDA approves Zontivity to reduce the risk of heart attacks and stroke in high-risk patients,” Press Release, May 8, 2014
	8. FDA, “FDA approves new type of sleep drug, Belsomra,” Press Release, Aug. 13, 2014.
	9. FDA, “FDA approves Keytruda for advanced melanoma,” Press Release, Sept. 4, 2014.
	10. FDA, “FDA approves first combination pill to treat hepatitis C,” Press Release, Oct. 10, 2014.
	11. FDA, “FDA approves Orbactiv to treat skin infections,” Press Release, Aug. 5, 2014.
	12. FDA, “FDA approves Zykadia for late-stage lung cancer,” Press Release, April 29, 2014.
	13. FDA, “FDA approves Zydelig for three types of blood cancers,” Press Release, July 23, 2014.
	14. FDA, “FDA approves Esbriet to treat idiopathic pulmonary fibrosis,” Press release, Oct. 15, 2014.
	15. FDA, “CY 2014 Breakthrough Therapy Calendar Year Approvals,” 

www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/UCM380724.pdf

FDA approves treatments for new diseases and drugs that operate by new mechanisms.

FDA Approves Novel Treatments in 2014

	On Oct. 7, 2014 at CPhI Worldwide in Paris, France, UBM Live announced the winners of the 11th annual CPhI Pharma Awards. Winners were recognized for their innovative solutions in formulation, process development, packaging, and partnering. The first three category winners were selected by a panel of judges representing industry and academia, while the latter, which was a new category this year, was determined by voting on the CPhI Pharma Awards website. The winners included MJR PharmJet in the Formulation category, ACIB (Austrian Research Center of Industrial Biotechnology) for Process Development, Locked4Kids for Packaging, and Catalent for Partnering.


	Technologies considered for the innovation in formulation category can be related to drug delivery, excipients, controlled release, stability, or bioavailability. The three finalists included Aptalis Pharmaceutical Technologies for its Diffucaps customized drug-release technology, Powder Systems Ltd. for its advanced microsphere formulation technology, and the winner MJR PharmJet for its counter-ion technology, which enables higher loading of hydrophobic drugs in nanoparticles for more effective delivery.

	Using its Microjet reactor technology, PharmJet generated a self-assembled, equimolar counter-ion complex of the antibiotic ciprofloxacin with sodium dodecyl sulfate (SDS) via formation of electrostatic interactions between the sulfonyl group of SDS and the tertiary amine of ciprofloxacin. The complex, which exhibited higher solubility in organics, was then dissolved with biodegradable poly(lactide-co-glycolide) and precipitated against water, again using its MicroJet reactor technology, to obtain nanoparticles with the desired particle size and much higher drug loading. The nanoparticles can be further formulated into a pulmonary treatment for cystic fibrosis infections due to its higher antibiotic load. The Microjet reactor technology can also be applied to a wide range of drug molecules to increase bioavailability and effectiveness, according to the company.


	Technologies evaluated in the process development category relate to synthesis techniques, crystallization methods, polymorphism control, catalysts, and the use of green chemistry. Finalists for the 2014 award included DSM Sinochem Pharmaceuticals with new statin compounds, Supply Chain Strategies International with new approaches to pharmaceutical manufacturing, and the winner ACIB for its Catalophor system for discovering new enzyme functionalities.

	Unlike typical bioinformatics techniques that generally seek similar amino acid sequences to identify homologous enzymes, the ACIB system identifies enzymes using specific three-dimensional templates of active site geometries and chemical functionalities associated with specific activities (catalophores). The system is comprised of a proprietary search engine and the Protein Data Bank, which contains more than 100,000 proteins. It can also search public databases for new enzyme structures. The search generates a list of possible candidates that contain the desired active site characteristics, avoiding the need to run large numbers of screening experiments. The most promising are then synthesized and tested. This approach is attractive because it creates the opportunity to identify enzymes that operated via previously unknown reaction pathways, thus enabling more environmentally friendly methods for the synthesis of both known and completely new compounds, including chiral molecules.


	New technologies considered in the packaging category must be related to primary packaging, devices and technology, patient compliance, dispensers, materials, or anticounterfeit systems. The finalists for the 2014 award included Haemopharm Healthcare for its Fillchoice room, a compounding pharmacy incorporated in a bag for use in a hospital room, Stiplastics for its granule and tablet dispenser for the distribution of various shapes and sizes of solid forms, and the winner Locked4Kids BV, for its child-resistant carton.

	Locked4Kids, an initiative of Ecobliss, is designed to protect small children from accidental poisoning. The carton contains a tray that holds blister strips. Hooks on the tray insert into openings diagonally positioned on two sides of the carton, resulting in automatic locking of the tray when it is fully loaded into the carton. The hooks, which are placed too far apart for children to reach but easy for adults to manage, must be simultaneously pushed to unlock the tray. The reclosable carton meets the requirements for child-resistant packaging in the United States and Europe and can be mass-produced in multiple sizes using existing manufacturing equipment.


	The new partnering category focuses on partnering methods, novel uses of technology, unexpected outcomes, and unique relationships. The finalists for the first award in 2014 included the licensing of Codexis’s CodeEvolver protein engineering platform technology to GlaxoSmithKline for the development of new enzymes, the new collaborative ID3 innovative business model for the development of customized pharmaceutical building blocks from Solvay Aroma Performance, and the winner, Catalent Pharma Solutions, for its collaboration with Redwood Bioscience on the development and application of SMARTag bioconjugation technology. Catalent brought to the partnership its expertise in biologic development, advanced GPEx expression system, and biomanufacturing capabilities, while Redwood Bioscience contributed its proprietary conjugation platform, advanced cytotoxin-linker chemistry, and ADC development expertise.

	Unlike conventional heterogeneous cysteine and lysine conjugation, the SMARTag site-specific system produces homogeneous antibody drug conjugates (ADCs). An antibody (mAb) containing an inserted formylglycine generating enzyme (FGE) recognition sequence is produced in a cell line that over-expresses FGE, which mediates formylglycine (an aldehyde) formation during sulfatase biosynthesis. The result is the production of an aldehyde-tagged mAb, which is purified using standard processes and then subjected to site-specific conjugation with a proprietary cytotoxin-linker system that reacts selectively with the aldehyde tag. The aldehyde tags can be placed at multiple positions in the antibody in order to maximize ADC performance without affecting its aggregation behavior or other properties, and the linkers are suitable for use with a variety of payloads. Compared to conventional ADCs, a SMARTag-generated ADC has a better toxicity profile, is well tolerated and provides statistically significant survival benefits, and has greater exposure and a longer circulating half-life, according to Catalent, which in early October 2014 acquired the remaining stake in Redwood Bioscience. The company believes that the new bioconjugation technology will lead to the development of bispecific ADCs and ADCs for indications beyond oncology.

On Oct. 7, 2014 at CPhI Worldwide in Paris, France, UBM Live announced the winners of the 11th annual CPhI Pharma Awards.

Novel Technologies Win CPhI Pharma Awards

Medicinal chemistry generally involves the preparation of a lead drug candidate on a milligram scale and uses non-optimized chemistry that will produce the target in the shortest time possible. Often hundreds to thousands of compounds must be synthesized for testing against the target. The chemistry to the specific target is therefore typically not optimized but is phase-appropriate for this stage of development. The process chemistry group then develops safe, robust, and efficient chemistry to enable the preparation of multi-kilogram quantities of the API. This approach is the case for complex heterocyclic APIs. Recent efforts at Genentech and Pfizer and by Phil S. Baran at The Scripps Research Institute have led to improved, practical methods for the synthesis of such complex heterocyclic compounds.


	In one case study from Genentech, the PI3k β-sparing inhibitor Taselisib (GDC-0032) was discovered as a potential treatment for breast cancer (1). The main structural feature of Taselisib is a seven-membered benzoxazepine core that is substituted with a functionalized pyrazole at one end and an 

-isopropyl-3-methyl-1,2,4-triazole heterocycle at the other end.

	The discovery route to prepare the benzoxazepine core of Taselisib required eight chemical steps from commercially available 3-bromophenol, according to Travis Remarchuk, a scientist in the small molecule process chemistry group at Genentech. He notes that while this chemistry was successful for producing the first five kilograms of the benzoxazepine core, it involved the use of hazardous reagents including carbon monoxide gas, 

-dimethylacetamide dimethyl acetal, and 1,2-dibromoethane and, therefore, was not amenable to the large-scale production of hundreds of kilograms. As a result, it was necessary to consider alternative and more practical routes for the preparation of the benzoxazepine core.

	In the second-generation process route, Remarchuk explains that a pre-assembled 

-isopropyl-3-methyl-1,2,4-triazole was prepared via a one-pot, two-step synthesis from isopropylhydrazine. This triazole was then converted to a chloroketone derivative, which was directly reacted in a convergent manner with an aryl amidine to generate the fluoroaryl imidazole ring system. The seven-membered benzoxazepine core compound was then installed via alkylation with ethylene carbonate. “Notably, this reagent is a much safer alternative to 1,2-dibromoethane,” says Remarchuk. Following alkylation of the imidazole, the hydroxyl group underwent S

2 substitution with the aryl fluoride of a second equivalent of the imidazole in the same reaction pot to afford the carboxylic acid precursor to the API. “Using this approach, which involved more efficient methods for assembling both the imidazole ring system and the 1,2,4-triazole component, more than 60 kg of the product was manufactured for the Phase I resupply of the API,” Remarchuk observes.

	A third-generation route was then developed that involved an efficient three-step, one-pot synthesis of the carboxylic acid precursor. In addition, in the final step of the API synthesis, the carboxylic acid group was converted to the primary amide using 1,1-carbonyldiimidazole (CDI) in place of the guanidinium coupling reagent HATU, which is not attractive for use in the last step of the synthesis due to release of several byproducts (tetramethylurea, hydroxybenzotriazole, and hexafluorophosphate anion) that require rigorous analytical testing to mitigate any safety risk for the patients, according to Remarchuk. The CDI coupling reagent is used in several other Genentech small molecule APIs in development.

Pyrazinyl-imidazo and pyrazinyl-pyrazolo pyridines from Pfizer


	Pfizer was interested in compounds containing 5/6 fused ring systems as candidates for oncology treatments. One of the lead compounds, a 3-pyrazinyl-imidazo[1,2-a]pyridine was initially prepared via a palladium-catalyzed reaction of 2,6-dichloropyrazine involving direct arylation at the 3 position of the imidazo ring. This reaction was not amenable to the synthesis of a library of compounds. In addition, few imidazo pyridines are commercially available, and they were synthesized using chloroacetaldehyde, which is a toxic reagent. Therefore, an alternative route to 3-pyrazinyl-imidazo[1,2-a]pyridines for both compound library synthesis and potentially larger-scale preparation was needed.

	Based on the known reaction of a dithiane with 2,6-dichloropyrazine involving nucleophilic tele-substitution, Michael R. Collins, a senior principal scientist at Pfizer, attempted the reaction of 2,3-dichloropyrazines with methyl vinyl ether (metallated), which proceeded as desired to afford the 2,6-disubstituted pyrazine products in good yields (50-60%) (2). A range of 3-pyrazinyl-imidazo[1,2-a]pyridines were then obtained in 31-76% yield by reacting the enol ether intermediates with N-bromosuccinimide in dioxane/water to generate the corresponding hemiacetals, followed by the addition of a 2-amino pyridine without isolation (2). In this reaction, the ring nitrogen of the pyridine displaces the bromide of the bromohydrin. “This reaction is very advantageous because it is done in one pot,” says Collins. The overall yields for both steps were also higher than those obtained for the palladium-catalyzed direct arylation route. “Not only does the reaction proceed fairly rapidly in decent yields, it is possible to prepare a wide variety of imadazo heterocycles, which is important for library synthesis,” Collins observes. He adds that substituents in the 6-position of 2-amino pyridine do not hinder the reaction with the enol ether.  The analogous compound was formed only in trace quantities using the Pd catalyzed procedure.

	Separately, Collins and his colleagues developed an efficient route to 3-pyrazinyl-pyrazolo[1,5-a]pyridines via the [3+2] cycloaddition of enol ethers and 4-substituted 1-aminopyridinim iodides that is, according to Collins, simple to perform, scalable, and proceeds at room temperature. In addition, the reaction proceeds in good yield with 1-aminopyridinium iodides bearing both electron withdrawing and electron donating substituents at the 4-position (3). In this case, to identify the optimum reaction conditions (base and solvent), a high-throughput reaction screen was performed. According to Collins, the best results were obtained using potassium tert-pentylate, sodium hydride, or potassium hexamethyldisilazide in tert-amyl alcohol with a pyrazinyl enol ether.

Sulfur reagents for the alkylation of heterocycles from Scripps and Pfizer


	The Baran group at The Scripps Research Institute, in conjunction with Collins and his colleagues at Pfizer, has also recently developed new reagents for the functionalization of heteroarene compounds. In one example, inexpensive, carboxylic acids are converted to sulfinate salts via an interrupted Barton decarboxylation reaction (4). The generated sulfinate salts are high value reagents and efficient radical precursors. The researchers readily prepared 10 different sulfinate reagents. One of the most interesting, according to Collins, is trifluoromethyl cyclopropyl sulfinate (TFCS-Na), which is effective for the C-H functionalization of various heterocycles. Most importantly, the reaction of the sulfinates is highly tolerant of a wide variety of functional groups, thus allowing for the introduction of substituents in the later stages of a synthesis, according to Collins.

	In a second example, Baran and the Pfizer researchers developed a practical method for the methylation of heteroarenes via C-H functionalization using zinc bis(phenylsulfonyl-methanesulfinate), or PSMS (5). This reagent was designed based on S-adenosylmethionine (SAM), a biologically relevant methylating reagent. In the reaction with PSMS, a (phenylsulfonyl)methylated intermediate is generated that is readily separated from the reaction mixture, and subsequent desulfonylation reveals the methylated (or deuteriomethylated) product. As with the previous sulfinate-based C-H activation reaction, this transformation proceeds under mild conditions in air at room temperature and tolerates numerous functional groups, allowing for functionalization of pharmaceutical intermediates in the later stages of complex synthetic routes, according to Collins.


	1. C.O. Ndubaku et al., J. Med. Chem., 56 (11) 4597-4610 (2013).
	2. M.R. Collins et al., Tet. Lett., 51 (27) 3528-3530 (2010).
	3. M.R. Collins et al., Tet. Lett., 53 (33), 4372-4375 (2012).
	4. P.S. Baran et al., Ang. Chem. Int. Ed., 53 (37) 9851-9855 (2014).
	5. P.S. Baran et al., J. Am. Chem. Soc., 136 (13) 4853-4856 (2014).


	Cynthia A. Challener is a contributing editor at 

New practical approaches to the synthesis of complex heterocycles are reviewed.

Practical Approaches to Large-Scale Heterocyclic Synthesis

CPhI Worldwide 2014, held in early October in Paris, France, presented an optimal opportunity for pharmaceutical manufacturers and their raw material suppliers and service providers to introduce new capabilities. According to UBM Live, host of the show, approximately 35,000 total attendees viewed the offerings of 2250 exhibitors that represented 140 countries. Companies both large and small highlighted a vast range of new products, technologies, services, and facilities designed to meet the needs of the pharmaceutical industry. A few of these new capabilities are described below.


  Rigaku Raman Technologies, a manufacturer of portable Raman analyzers, highlighted its new Progeny handheld device for rapid material identification, including both raw and in-process materials, finished products, and products already on the market (as an anti-fraud measure). What sets Progeny apart from other handheld Raman analyzers, according to marketing director Jennifer Lynch, is the fact that it is the first fully sealed 1064-nm-powered handheld Raman analyzer that enables the analysis of fluorescent compounds, colored materials, and materials stored in colored containers, which hasn’t been possible in the past. “When a company adopts Progeny for their material analysis needs, the quality control laboratory can focus on more value-added work, such as methods development, instead of being bogged down by routine analyses,” Lynch says. 


  SGS Life Science Services, a pharmaceutical analytical and bioanalytical contract solutions provider, has grown rapidly since the business line was established 10 years ago. In 2014 alone, the company is expanding capacity in three regions of the world. Most recently, SGS completed the construction of a new 8000-sq.-ft. GMP/GLP facility in Carson, California, its fifth in North America and the first on the west coast. The location was chosen so the company can provide local support to the significant pharmaceutical and biotechnological community in California, according to Jeff McDonald, COO of SGS North America.
  

SGS is also investing in a new facility in Villeneuve la Garenne, France, which will replace an existing laboratory in Clichy and will include state-of-the art equipment designed to increase the quality control service throughput and support an ever-expanding research and development pipeline of new biopharmaceutical drugs within the country. Services will include analytical chemistry, microbiological analysis, stability studies and method development, as well as amino acid analysis and mycoplasma testing. “We see this investment as an strategically important for meeting the needs of both the small molecule and quality control markets,” notes Paul Beyou, director of life science services, Clichy. SGS is also increasing analytical capabilities at its facility in Poitiers, France, and the company opened a new laboratory in Italy in 2013.


In China, SGS is expanding its Shanghai facility, adding to its cGMP chemistry and microbiology laboratories; constructing a new biotechnology laboratory for cytotoxicity testing, cell-based assays, and endotoxin and ELISA testing; and introducing packaging testing capabilities, including extractables and leachables. “The investment in the Shanghai facility, and the increased and enhanced service offerings that will result, are essential to our continued expansion in China,” states Andy Yi, general manager, SGS Life Science Services, Shanghai.
  

Finally, SGS has also launched a new, searchable web-based database of biopharmaceutical, biosafety, and bioanalysis methods that are available throughout its global network of GMP, good laboratory practice, and good clinical-compliant laboratories. Selection criteria include service type, sample type (e.g., biologic, vaccine, biomarker), and technique. 


  A notable trend in the contract manufacturing industry that was apparent at CPhI Worldwide 2014 is a growing emphasis on integrated services. In addition, several contract manufacturing organizations (CMOs) that are either a business unit of a larger pharmaceutical company and/or a manufacturer of generic APIs and sometimes formulated products see their positions as advantageous compared to CMOs that do not have such capabilities. Two companies in the former category include Pfizer CentreSource and CPS, the custom pharmaceutical services division of Dr. Reddy’s, while examples of the latter type include Hovione and Piramal Pharma Solutions.
  

Reorganization at Pfizer has Pfizer CentreSource (PCS) now reporting through Pfizer Global Supply, the external supply group that manages all the CMOs used by Pfizer. This alignment brings numerous synergies with respect to technology and market knowledge, according to Kenneth F. Ball, senior manager of marketing for PCS. The company is also adding capacity at its Ringaskiddy, Ireland facility, which is the product launch site for all of Pfizer, and thus has extensive experience working with R&D and third parties to introduce new processes and expertise in new product scale-up, process improvement, launch, and commercial manufacture, according to Jeffrey W. Frazier, vice-president of global marketing for fine chemicals at PCS. Additional investments in facilities located in important and stable emerging markets are also under consideration, such as Brazil, Morocco, and Indonesia.
  

For biologics manufacturing, PCS is emphasizing its extensive network of manufacturing facilities and their broad range of capabilities, including mammalian cell expression, microbial fermentation, vaccines, and antibody-drug conjugates (ADCs). The company is also highlighting its high potency production capabilities. It has both development and commercial-scale facilities for the manufacture of high-containment, solid-dosage drugs. “In addition to the depth and breadth of our manufacturing capabilities, because PCS is part of Pfizer, we also have access to the technology and knowhow of a large, successful pharmaceutical company, that we can apply as needed to rapidly design effective solutions for our customers,” says Cristin B. Grove, PCS’s director of contract manufacturing.
  

CPS has made responsiveness to the market a key focus of the company, introducing a new “Power of Now” customer-centric initiative. “We differentiate ourselves in the marketplace by being aware of our customer needs, and today there is great demand for more rapid responses. The ‘Power of Now” reflects that need for immediacy, as well as empowerment of both our customers and employees, partnership, and trust,” says Christian Jones, head of Asia Pacific sales and business development for CPS. The initiative focuses on accelerating project delivery through dedicated response networks with shortened decision-making chains and reduced lead times, according to Jones. To support the initiative, CPS has appointed a new head of R&D and a new North American sales manager and created a new business development position in Asia that Jones has filled. 
  

In addition to its increased responsiveness, Jones notes that CPS offers an integrated portfolio of services from discovery to formulation development through to commercialization and lifecycle extension that is backed by the extensive expertise in generic-drug manufacturing of its parent company. “The experience gained in the competitive generics industry is directly transferred to our CMO services at CPS in the form of efficient and robust process development that includes the use of green chemistry and continuous processing,” Jones notes. Other key technologies for CPS include chiral chemistry, highly potent drug substance and formulated product manufacturing at development and commercial scales, steroid manufacturing, and pegylation.
  

Hovione is a company that offers both customer-manufacturing services (e.g., intermediates, APIs, and finished products) and produces its own generic APIs and formulated products. CEO Guy Villax of Hovione does not see any conflict between the two operations, and in fact, believes that being in the generic-drug business has helped the company’s competitiveness as a CMO. “With generics, it is imperative to be as cost-effective as possible, and to do that requires advanced technologies and science. Those capabilities benefit our custom manufacturing efforts as well,” he says. 
  

Hovione also has the largest installed capacity for commercial GMP spray drying, according to Villax. In 2014, the company is celebrating 10 years of spray drying services. “Through these 10 years, we have accumulated a large amount of knowledge, expertise, and data on spray drying that now enable us to control the physical processes involved in spray drying and predict product behavior on a commercial scale,” comments Villax. 
  

In addition, to reflect the fact that it now has capabilities in both chemistry and biotechnology, Hovione changed its logo. The company will also be expanding its Hovione New Jersey manufacturing site, which has capabilities in cryogenic chemistry, hydrogenation, fluorination, and the production of highly potent APIs.
  Piramal Enterprise is another company that offers contract research and manufacturing services across all phases of the drug lifecycle and the value chain, and has expertise in specialized services such as ADCs and highly potent compounds with a focus on green chemistry. To support its end-to-end manufacturing capabilities including discovery, Phase I-III clinical and commercial production, and off-patent formulation, the company is continuing to invest in its facilities and new technologies that provide value to customers, such as continuous flow chemistry and bio- and chemocatalysis. More than $70 million worth of investments are at various stages of execution, according to Vijay Shah, COO at Piramal Enterprises and pharma business lead. Specifically, the company invested approximately $10 million in a world-class, GMP clinical manufacturing facility in Ahmedabad, India, approximately $15 million in its Morpeth, UK site to triple production capacity for hormonal products, and approximately $5 million at its Grangemouth site to expand commercial ADC capacity. Piramal is also expanding capacity for generic drug production and has plans for the addition of a pilot plant and scale-up facility as it prepares for a tripling of this business over the next five years on a top-line basis.
  

Piramal is also focused on becoming more customer-centric, and has established an internal customer advocacy team that represents the customer throughout all stages of a project. Its PULSE program, launched early in October 2014, is a values-based initiative designed to take the pulse of the customer and create a culture of ‘customer centricity’ across the organization. “It is critical that we maintain our focus on the customer at all times, both internally and externally,” says Shah. 
  

Patheon, a pharmaceutical services business owned by DPx Holdings, a holding company focused on the CDMO business, is not part of a larger pharmaceutical company, but has been expanding its capabilities through numerous acquisitions to create a true integrated offering. Recent activities have included a merger with DSM Fine Chemicals in March 2014 and most recently the acquisition of Gallus Biopharmaceuticals in August 2014. At CPhI Worldwide 2014, Patheon introduced OneSource, its new integrated development offering for Phase I through Phase II projects. “When assembled correctly and executed with great discipline, an integrated service offering such as OneSource will deliver innovative solutions with regard to critical timing, including contracting, liability coverage, and tax advantages in the design of the supply chain,” states DPx Fine Chemicals president Lukas Utiger. Patheon also has future plans to provide similar simplicity to Phase III through commercial-scale capabilities as well. “We feel strongly that it is important to bring fast and simple solutions to our customers that really address their needs,” Utiger observes.


  Excipients are crucial for effective drug formulation, and excipient manufacturers continue to make advances in technology designed to address the formulation challenges presented by new drug substances. 
  

Dow Pharma & Food Solutions, meanwhile, has expanded its AFFINISOL portfolio of excipients for the solubility enhancement of spray-dried dispersion (SDD) and hot-melt extrusion (HME) formulations. Dow began production of AFFINISOL hydroxypropyl methylcellulose acetate succinate (HPMCAS) products in October 2013 in a new facility located at the Cambrex Karlskoga site. The polymers are the result of a research collaboration between Dow Pharma & Food Solutions and Bend Research that are designed to maintain stable solid dispersions and inhibit API crystallization when formulated as spray-dried dispersions. The original products, however, require the use of plasticizers for processing over a wide temperature range. At CPhI Worldwide 2014, Dow also introduced versatile AFFINISOL HPMC HME with a low glass transition temperature requiring no plasticizers, thus allowing formulation of stable amorphous solid dispersions and controlled-release profiles via extrusion processes. The effectiveness of the new excipient has been demonstrated with the 

 (BCS) Class II API itraconazole and the BSC Class II API griseofulvin, according to Christophe Massip, global marketing director, Dow Pharma & Food Solutions.


Separately, as part of its Dow-Colorcon alliance (the Controlled Release Alliance), Dow announced at CPhI Worldwide 2014 that its next-generation METHOCEL DC2 hydroxypropyl methyl cellulose (HPMC) polymer, an excipient that facilitates roller compaction and direct compression of tablets as alternatives to wet granulation, will be commercially available on a global basis by the end of 2014. Installation of its new manufacturing line in Midland, MI is being finalized, according to Massip. “The designed morphology of METHOCEL DC2 notably improves the flow and processability of powder blends for compression into matrix tablets, which helps the drug product manufacturer produce higher quality tablets using streamlined manufacturing processes,” notes True Rogers, technologies leader for Dow Pharma & Food Solutions.
  

Lubrizol is another company that has, for many years, provided a wide range of polymer-based excipients for use in solid, semisolid, and liquid dosage forms. At CPhI Worldwide 2014, the company highlighted is new Pathway excipient-grade thermoplastic polyurethanes (TPUs) for controlled, sustained drug release in implantable drug delivery and combination products. "As pharmaceutical companies face the challenges of the patent cliff, the development of new routes of administration for existing drug products is an important strategy they can use to help maintain the success of their product franchises. Our new Pathway excipient portfolio is designed to help drug manufacturers achieve their goals of developing these novel, controlled-release drug products," observes Jean Claude Deneuville, global business director for Lubrizol’s LifeSciences business. 
  

The non-biodegradable excipients are ideal for drug delivery over an extended period of time and work with both hydrophobic and hydrophilic APIs. Drug loading can be achieved through blending, or for thermally stable APIs, melt-processing followed by injection molding or extruding. The API and TPU can also be dissolved in a suitable solvent and then cast into shapes such as rods, tubes, films, or a variety of matrix-type designs, according to Deb Langer, vice-president and general manager of Lubrizol Life Sciences. Implantable devices can provide sustained drug delivery for short and longer time periods with, for example, 30-day contraceptive and/or HIV vaginal rings and other subcutaneous implants that last up to 18 months. 
  

“TPUs have a long history of use in medical devices because they are robust and readily customizable. Polyether, polyester, or polycarbonate-based soft segments can be combined with aromatic or aliphatic hard segments to obtain a vast range of release properties while retaining durability chemical resistance, clarity, and abrasion resistance,” says Deneuville. He adds that TPU excipients are being investigated in formulations for hormone regulations and the treatment of mental health, in addition to HIV and pain. They can be used in controlled-release products, as drug reservoirs and matrices, in rate-controlling membranes and drug-eluting medical implants, and other applications. Possible routes of administration include subcutaneous, transdermal, oral, interorganal, intraperitoneal, and intravaginal, among others, according to Langer.


   Vertellus has long been recognized as an expert in pyridine chemistry, offering both standard catalog products and custom manufacturing important pharmaceutical building blocks. At CPhI Worldwide 2014, the company was looking to increase awareness of its full and much broader capability for meeting the needs of the pharmaceutical industry. “The Vertellus Specialty Materials (VSM) business unit comprises a broad basket of complex technologies, manufacturing biomaterials, CPC (cetylpyridinium chloride) biocides, pyridine derivatives, DEET (

-diethyl-meta-toluamide), sulfones, EMA (ethylene maleic anhydride) copolymers, alkenyl succinic anhydrides, reducing agents, and a host of natural and renewable chemistries based on castor and citrates, and we specialize in developing and producing fine chemicals and intermediates for sophisticated chemistry applications,” explains global sales director Mark Lewis. He adds that for the pharmaceutical industry in particular, the company has a broad range of products and synthesis technologies that provide pharmaceutical companies with a unique combination of intermediates and customer manufacturing capabilities.
  

Vertellus was established in 2006 when Rutherford and Reilly merged, and was then acquired by Wind Point Partners in 2007. President and CEO Rich Preziotti was previously vice-president and general manager of Honeywell’s $1.2 billion chemicals business and is focused on improving productivity, reducing costs, and enhancing customer relationships, according to Lewis.


BASF announced at CPhI Worldwide 2014 that Colorcon will be using its Kollicoat IR immediate-release coating polymer in Colorcon’s fully formulated ready-to-use coatings. Kollicoat IR is an ethylene glycol and vinyl alcohol graft copolymer that enables processing at low temperatures and high solids contents while delivering targeted coating results, according to Daniele Piergentili, vice president of global marketing for pharma ingredients at BASF. With the addition of Kollicoat IR to its portfolio, Colorcon will be able to expand its polyvinyl alcohol-based offerings, providing more choice to its customers, according to Cornelis van den Muyzenberg, vice-president of sales and business development at Colorcon.


  IDT Biologica, a manufacturer of human vaccines for infectious diseases, announced at CPhI Worldwide 2014 that it has completed and certified a new large-scale production facility in Dessau, Germany for the filling and lyophilization of biologics and vaccines. The facility includes a sterile liquid filling line for up to 24,0000 vials per hour and has been certified to biosafety levels 1 and 2 for live vaccines. Notably, in addition to capacity for live recombinant and non-recombinant vaccines, the plant includes capacity for the fill-finish of other biologics and small-molecule drugs, including cytotoxics, in separate units. “Completion of this project allows us to accommodate production of an ever more diverse range of biomedical technologies with the precision and efficiency that comes with a highly integrated and automated facility,” says Dr. Ralf Pfirmann, IDT Biologica CEO.

Selected new technologies, products, and facilities from CPhI Worldwide 2014 are reviewed.