
Vetter, a contract manufacturer of aseptic filling of syringes, cartridges, and vials, is moving ahead with expansions in its clinical- and commercial-scale operations. Its expansions are marked by a new clinical-scale facility in the United States, which will complement its commercial-scale capabilities in Germany. 

Vetter is going to open Vetter Development Services USA Inc. at the Illinois Science and  Technology Park in Skoie, Illinois, outside of Chicago by the end of 2009. The 24,000-ft

 facility will provide aseptic filling of clinical-trial materials for Phase I and II. “The facility allows us to be closer to our customers in North America, particularly US companies,” says Oskar Gold, vice-president of key account management and corporate marketing for Vetter. The facility will be Vetter’s first in the US. The company is leasing the facility and is investing in upgrading the facility, which will be fully operational by the end of 2010. Vetter also provides small-scale capabilities at its facilities in Germany. 

The Chicago small-scale facility will complement the company’s commercial-scale manufacturing facilities in Ravensburg, Germany. During the past six years, the company has invested EUR 150 million ($220 million) at its Ravensburg South aseptic filling and packaging facility, with a further EUR 50 million ($74 million) of investment in expanded pharmaceutical production now underway. The Ravensburg South site houses a production facility, a final assembly and packaging plant, and a laboratory for ongoing production-related analysis. Vetter is currently adding a third production line, which is scheduled for completion by mid 2011. The company recently installed six automatic packaging lines at it the secondary packaging plant, which came on line in May 2009. The expansion allowed the company to double its packaging production capacity at the site.

In addition to its Ravensburg South facility, Vetter also operates commercial-scale facilities in Ravensburg City and Langenargen, Germany. The Ravensburg City facility includes production capabilities for single- and dual-chamber syringes and cartridge systems and related facilities for technical support. The Langenargen facility also provides production capabilities for single- and dual-chamber syringes and cartridge systems. Gold points out that each facility operates with its own independent quality systems, and therefore can serve as a second source for supply. “In the risk-mitigation strategies of many pharmaceutical companies, it is important to have more than one facility producing supply. By having multiple facilities, we are able to provide that security of supply,” he says. 

Gold also points out that expanding its clinical-trial materials capabilities is an important focus for the company. “In early-development stages, companies are looking to get material as soon as possible in order to meet developmental timelines,” he says. “But in developing a process for early-stage materials, it is valuable for a company, particularly smaller biopharmaceutical companies, to be able to access the process understanding that will be needed for a commercial product and the related regulatory filings. We can provide that understanding with a view to scale.”  

Reflecting that commitment, earlier this year Vetter launched a quality assurance program for its project managers for purposes of them gaining certification under the International Project Management Association (IPMA), a nonprofit organization that represents 45 national project management associations and more than 55,000 members on an international level. To be eligible, each participant in the certification program must have at least three years of experience in project management, plus two years of practical work leading a project. The candidate is assessed on a wide variety of criteria, including the ability to plan, control, communicate and solve problems. Certification then is awarded to those who demonstrate deep organizational knowledge, as well as leadership qualities. 

“That quality philosophy is at the center of our operations,” concludes Gold.

Articles

Pharma Partner Focus

Vetter moves ahead with a new development facility in the US and expanded capabilities in Germany.

Vetter Expands Clinical-and Commercial-Scale Operations


Biosimilars represent an emerging opportunity for the pharmaceutical industry, but there are challenges and specialized considerations when assessing their potential from both a manufacturing and regulatory perspective. To further understand these issues,  Patricia Van Arnum, senior editor with 

, gained the insight from leading experts: Patricia Seymour, a senior consultant with BioProcessTechnology Consultants; Gillian R. Woollett, MA, D. Phil., and chief scientist, with the law firm Engel & Novitt LLP; Carl Lawton, PhD, and director of the Massachusetts Biomanufacturing Center at the University of Massachusetts in Lowell; and Margit Holzer, PhD, and research and development technology director with Novasep. These experts will be speaking at the 

Biosimilars Manufacturing and Sourcing Dynamics

 conference, organized by the Drug, Chemical, and Associated Technologies Association, on Dec. 2 in Parsippany, New Jersey. 



 In meeting the chemistry, manufacturing, and controls (CMC) requirements for a biosimilar product, a company faces additional challenges as compared with a small-molecule generic product. What would you identify as some of these key challenges or issues in biosimilar process development and manufacturing?   



 One of the most significant challenges in developing a biosimilar product is designing the manufacturing process to achieve comparability to the reference product. Unlike small-molecule drugs that can typically be described by a single chemical formula and duplicated relatively easily, a biologic is produced from living organisms and has significantly more complexity and heterogeneity. All development activities starting as early as the generation of the production cell line through definition of the final purification and process conditions must focus on mimicking the host cell line and process conditions of the reference product in order to drive the process toward producing a similar product. It is rare for innovators to provide details about their manufacturing processes publicly, so the challenge for biosimilar companies is to figure out what the process conditions are likely to be and then mimic them. Rigorous analytical testing must accompany process development to select a production cell line and unit operations that are most likely to produce a product that meets comparability goals.

Innovator companies often implement process changes following market launch, either to meet increased product demand, to obtain second-site manufacturing options, or to improve process economics. These changes can involve any part of the process, including such varied activities as the bioreactor control and media optimization for the scale of operations, the purification process, the manufacturing facility, or other manufacturing conditions. During implementation of major process changes into the commercial manufacturing process, the properties of the resultant product need to be monitored to insure that the process changes result in a comparable product. The concept of a ‘well-characterized biologic’ and the comparability guidelines first issued in the mid-1990s laid the foundation for manufacturers to make changes to the manufacturing process of an existing commercial product without it being considered a new product. This allowed companies to implement changes without redoing time consuming and expensive clinical trials if they could demonstrate biochemical comparability through the use of ‘physicochemical studies and quality-related biological studies.’ There is a significant burden of proof for the innovator company; even the innovator isn’t always successful at demonstrating biochemical comparability, and in such cases, either the process change is rejected or additional clinical studies are required prior to a formal decision by the agency.

While innovator companies face significant regulatory and technical challenges in implementing process changes while retaining and demonstrating comparability, the challenge is even greater for a biosimilar company. Unlike the innovator, the biosimilar company does not have access to a large body of useful information about the product and process, such as a detailed process-development history, historical critical-process-parameter evaluation, analytical-development data, and validated analytical methods. The actual gene, protein, and expression vector sequences are often tightly guarded as well and are not always available to the biosimilar developer. In addition, the preclinical information, especially with respect to the safety profile of demonstrated product and process impurities, is not usually publically available.



 Given the challenges in biosimilar development and manufacturing, are there certain types of biologic-based compounds that lend themselves more to biosimilar development than others? How are these issues balanced with the market considerations (i.e., market value of the innovator reference product)? 



 Twenty eight products make up over 87% over the overall biologics pharmaceutical sales value (R. Gal, “Eight Thoughts on Biosimilars,” Bernstein Research, 2008). Of these 28 molecules, the ones most often cited as being attractive biosimilar targets are etanercept, rituximab, bevacizumab, infliximab, and trastuzumab because of their market potential and patent-expiry timing. However, the products that are available as biosimilar targets are generally products that were developed over 15 years ago, even if they were launched more recently than that. As a result, these products are not based on current discovery and development approaches and are not produced using the most advanced biomanufacturing technologies. The biosimilar-development dilemma is whether to focus on matching the innovator’s process or on creating so-called ‘biobetter’ molecules (replacement molecules for current therapeutics that have improved properties), where development can rely on the scientific advances of the past 10 to 20 years to design products that have better characteristics, such as lower immunogenicity, greater efficacy, improved formulations, or other properties leading to less frequent dosing. Molecules with significant changes that lead to these properties would probably not be approved under current or proposed biosimilar regulations, but would be an improvement for the patients and may enable companies to obtain a larger market share of the intended patient population. It is well known that reducing dosing frequency of any injectable medicine is received with great enthusiasm by patients. For example, when Avonex was introduced to the market, it quickly took significant market share from the first interferon-beta product, Betaseron, due to a reduction in dosing frequency from three times a week to two times a week. Such biobetter products could provide stronger competition to both the innovator companies and their direct subsequent biosimilar competition.



 For the few biosimilar products that have been approved in Europe, are there certain approaches or insights that the regulators have provided when evaluating the CMC requirements that would be helpful for biosimilar producers? 



 The EU regulatory authority took the approach that a biosimilar product must be shown to be sufficiently similar to a reference product already licensed in the EU so that it can be used for the same indication at the same dose. Additional clinical studies were required to demonstrate that the biosimilar product had the same efficacy in patients as the reference product. These clinical studies must be done in comparison to the reference product; however, the clinical development program can be shorter and less costly than trials for an innovator product, but this will still be a significant cost.

The benefit in a biosimilar-development program is that the risk of failure is reduced because the target and mode of action of the molecule have been well demonstrated through the years of marketed use of the reference product. Further, there is still a clinical and regulatory risk of failure due to small changes in the biosimilar product that might impact clinical efficacy. 

One key issue in biosimilar development is the selection of the reference product and the indication. The current regulations in Europe require that the biosimilar developer compare its product to a reference product that is already approved for the intended indication in the intended territory. In the case where multiple innovator products are already on the market, such as for interferon or growth hormone, the choice of reference product can be critical. Innovator companies also argue that if they perform post-market clinical trials in new indications for a branded product and receive marketing authorization for these indications, they are merely enabling the biosimilar companies to enter the market sooner with competitive products for these new indications. Such concerns may lead to companies forgoing or postponing post-market secondary indication trials, thereby preventing patients’ access to potentially valuable therapies and costing companies significant potential revenue.



 All biologics, whether they are an innovator product representing a totally new molecule and mechanism of action (MOA), a second-generation product (new molecule, shared MOA), or a biosimilar (similar molecule and shared MOA) need their own, entirely independent and complete CMC section. In this sense, a biosimilar is like a generic small-molecule drug where a complete stand-alone CMC section has always been required. However, unlike small-molecule drugs, this CMC section can be expected to be extensive.

If anything, the biosimilar will have more data than the innovator both because the analytical technologies have made so much progress since the innovator product was approved, but most importantly because their sponsor’s dossier will contain extensive comparative data on both its own product (the biosimilar) as well as on the innovator product which it is using as a reference (the previously approved reference product on which the patents have now expired). Indeed, it is likely that the biosimilar sponsor will be analyzing the reference product at a level of detail way beyond that conducted by the innovator sponsor at the point of initial approval, and may well find batch-to-batch variations in the innovator biologic that are previously unknown to anyone, including the FDA. It is to be expected that any parameter that is within the ‘goalposts’ of the innovator’s marketed product can be considered suitable for the biosimilar.

The European regulators, concurrently with reviewing and approving biosimilars in Europe, published with a full public participatory process that included the breadth of the biopharmaceutical industry, a series on guidelines to help inform sponsors as to the anticipated regulatory needs for the development of biosimilar products. As well as specific guidances on ‘classes’ of potential biosimilar products, EMEA [European Medicines Agency] published general guidances on biosimilars. For example, one such general guidance is 

Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues

 (CHMP adopted February 2006). This contains useful advice on CMC issues for potential biosimilar sponsors.



 In considering the proposals for a regulatory pathway for biosimilars in the US and the existing requirements in Europe, what can you identify as the key differences and common agreement in regulatory consideration of biosimilars? 



 Since the enactment of European legislation creating the specific biosimilars pathway in 2003, and the concurrent and ongoing debate in the US, that then increased with the introduction of the first biosimilars legislation here in September 2006, there has been much discussion of the differences between the two jurisdictions. However, the similarities are far greater than the differences when it comes down to the companies making biologics, the patients consuming them, and the regulatory requirements for the approval of biologics in all principal markets. Many of the same innovator products are already marketed in multiple jurisdictions.

Consistency in the regulatory standards applied to all biologics within a given jurisdiction becomes the priority as first and foremost biosimilars are biologics, and not drugs. Europe uses the current regulatory construct of comparability to evaluate its biosimilars—since this standard has been the FDA’s interchangeability standard for biologics since 1996, it can be considered well established and well understood by both regulators and the regulated industry. Indeed PhRMA [Pharmaceutical Research and Manufacturers of America] and the innovator industry helped developed the FDA guidance on comparability with the agency back in 1996—albeit only to enable manufacturing changes to its own innovator products as back then these were the only biologics that were approved. Nonetheless, the EU has shown that comparability principles can be extrapolated to biosimilars to ensure that they are evaluated to the same appropriately high, data-driven and science-based standards. There have been no reports of unusual safety or efficacy problems with those biosimilars now approved and marketed in Europe. Likewise, the use of comparability by innovators making changes to their own products have elicited remarkably few problems, Eprex being an oft-cited exception. And most of the time-comparability studies have not necessitated clinical studies; however, it is anticipated that these will be needed for the first generations of biosimilars, but perhaps not forever.  However, it should be noted that the European statute that enabled biosimilars does not require clinical studies, and nor does the PHS Act in the US, according to which most current biologics are licensed. Ultimately, in the both Europe and US, the discretion lies with the regulators to evaluate that the sponsor has demonstrated quality, safety, and efficacy (Europe), or safety, purity, and potency (US). These standards can pertain to biosimilars and innovator biologics alike. It is only the how and the actual data set that will vary. 
 Joint efforts by FDA and EMEA as well as by the  Japan’s MHLW (Ministry of Health, Labor and Welfare] with industry are ongoing to harmonize the regulatory environment for innovator biologics, and it would make sense that this be extended to biosimilars,  not least because comparability is already established in both jurisdictions as well as Japan (see 

 How do we develop a ‘sameness standard’ for biosimilars that will ensure that these products are safe for patients?



 There have been joint industry-regulator efforts underway for decades to harmonize the regulatory requirements for innovator biologics, and indeed the FDA initiative that became known as the Comparability Guidance in 1996 for manufacturing changes to approved biologics had already become the interchangeability standard used extensively in the more sophisticated markets around the world (i.e., see above). In Europe, it was used to support intra- and inter-manufacturing changes from the beginning. However, in the US and Japan, its use was limited to a sponsor making manufacturing changes to its own products. However, the scientific principles are fully applicable to the comparison of any products from different sources as has been shown by the EU’s use of them as the basis for their own biosimilars pathway and the approval of 13 biosimilars in three product classes (somatropin, epoetin, and filgrastim). It is not an easy standard to achieve. 

A biosimilar approved on the basis of comparability will have been demonstrated to be as much the same as its reference product, as an innovator biologic is before and after a manufacturing change. This is an established and appropriately high standard to apply to the sponsors of all biologics, both for the initial approval of biosimilars and for all manufacturers of biologics, innovator and biosimilars, when they make manufacturing changes. That this is the  current FDA ‘sameness’ standard is best demonstrated by no change being made to the label of the approved biologic before and after the use of comparability to support a manufacturing change;  indeed, neither the physician nor the patient are aware that any change has occurred. This has worked well in the US since 1996, and we have every reason to trust that the FDA will ensure that this continues to be the case when they have the authority to approve biosimilars too.



 Can you outline some recent advancements in analytical characterization and methods development that are particularly useful for biosimilar development? Is additional testing/characterization required for the biosimilar product as opposed to an innovator drug product, and if so, what methods may be employed?



 Biosimilars will have to utilize the same array of analysis tools, including potency assays, that innovator biologics require. Current technology is not sufficiently advanced to characterize quality attributes of all potential biosimilars by physiochemical analysis.  Similarity will have to be demonstrated in terms of quality, efficacy, safety, pharmacokinetic and pharmacodynamic data utilizing preclinical and clinical data.  Immunogenicity that can arise from slight structural changes, process alterations, or contaminating host-cell proteins will need to be evaluated. 

Newer techniques such as capillary electrophoresis/mass spectrometry (CE/MS) and liquid chromatography/mass spectrometry (LC/MS) help to simplify the characterization of biopharmaceuticals.  Several research centers around the world have focused on advancing biopharmaceutical analytical technology.  The Barnett Institute (Northeastern University, Boston, MA) has developed new methods to determine disulfide linkages with LC/MS coupled to ETS (energy-transfer dissociation), local 3-D structures with hydrogen/ deuterium (H/D) exchange mass spectrometry, and analysis of isomeric forms of intact proteins with CE/MS.



 Understanding a product with the help of analytical characterization is key for the development of biosimilars. This is true for all biosimilars with or without existing monographs since the products are compared to the innovator’s product quality. Advances in analytical method development and its corresponding instruments allow a more rapid and precise determination of the primary, secondary, and tertiary structures of biologics as well as their activity and impurity levels. An example of the primary structure determination is the combination of peptide mapping ultra-performance liquid chromatography–mass spectrometry (UPLC–MS) or sodium dodecyl sulfate polyacrylamide gel electrophoresis/capillary electrophoresis–mass spectrometry SDS PAGE/CE–MS; progress has also been made in nuclear magnetic resonance (NMR) analysis which can help in the understanding of secondary and tertiary structures. Advances in the development and standardization of immunoassays being enzyme-linked immunosorbent assay (ELISA)-based or related (e.g., meso scale or gyros) or using the surface plasmon resonance (SPR)-principle (e.g., Biacore, Sweden) as well as advanced fluorescence activated cell sorter (FACS)-based methods, for example, allow a more precise evaluation of biological structure and activity and can help to gain a greater understanding of the interaction mechanisms between the drug and the receptors. Process-related impurities can be measured more precisely and accurately with low limits of quantification applying the technologies mentioned above for the quantification of: host-cell proteins, endotoxin, residual protein-A or other leachables, as well as residual DNA by ultra-sensitive polymerase chain reaction (PCR) methods.



 In terms of purification strategies, are there particular approaches or best practices to employ when working with a biosimilar product to help enable consistency with the innovator drug product? Can you offer some examples?



 By employing a careful characterization of the innovator drug product(s), a production strategy can be defined. Analysis of a protein structure, including post-translational such as glycosylation pattern, help to establish the DNA code as well as the position of the disulfide bridges and the possible expression systems. Important information about the purification process is also obtained via the method used to access the impurity profile (e.g., the type of host-cell protein, the protein A levels [antibody production], residual-solvent contents, etc.).These are essential elements which will guide the design of the upstream and downstream development.
The overall process performance of  recently developed biosimilar however, can be significantly improved compared to the innovator process. Reasons for this are, for example, the availability of high-expression cell lines or important improvements of available purification technologies (e.g., chromatographic systems, media and processes and tangential flow membranes) that have been developed during the last two decades. Furthermore the application of the FDA’s initiative, PAT (process analytical technologies), during process development and manufacturing, supports process understanding/control and increases therefore process robustness as well as product quality. 


 Given the higher capital costs associated with biologics manufacturing as opposed to small-molecule manufacturing, what type of manufacturing model do you think is necessary to successful compete in the biosimilars market? Do disposables, for example, offer an effective approach in mitigating costs?



 Refined manufacturing technologies are available for the development of biosimilars that were not available 10-15 years ago.  This represents an opportunity to develop a more efficient manufacturing process as well as development of a biosimilar with better quality attributes.  New expression systems (UCOE, Millipore, Billerica, MA) and cell lines can improve productivity and gene stability.  The move away from serum-supplemented media to chemically defined media increases quality uniformity.  The design of cell culture conditions combined with multivariate statistical process control also improves productivity and quality.  These gains in productivity lead the way for the utilization of smaller reactors that will mitigate costs.  Single-use items ranging from mixing tanks, bioreactors, sensors, and purification equipment have the potential to further reduce costs by reducing water usage and labor costs.

Biotech

Leading experts from an upcoming conference on biosimilars by the Drug, Chemical, and Associated Technologies Association share their insights on the manufacturing and regulatory considerations for biosimilars.

Manufacturing and Regulatory Considerations in Biosimilars

 During the mid-decade drug development boom, some of the biggest winners were those contract service providers that are part of the clinical supply chain. Contract development and manufacturing organizations (CDMOs) especially benefited from the dramatic increase in early-stage compounds, which fed a surge in demand for process development, formulation development, and small-scale manufacturing services.  

The subsequent downturn in development activity, prompted by the drop in the availability of capital, has hit CDMOs particularly hard. Double-digit declines have replaced double-digit increases, and many CDMOs are struggling to stay in business. No longer able to float on a rising tide of predevelopment candidates, CDMOs are fighting for market share and survival. 

In an effort to better understand the dynamics of and outlook for the CDMO industry, PharmSource recently completed a major analysis of the clinical supply-chain market. We modeled the spend for clinical trial material (CTM) development and manufacturing, including process development and manufacturing for active pharmaceutical ingredients (APIs), formulation and manufacturing of dosage forms, and associated analytical activities (we excluded clinical packaging). We conducted extensive interviews with buyers and sellers of clinical supply-chain services to understand the key behaviors and trends driving the industry. The analysis goes into considerable depth on analytical chemistry activities. 

The PharmSource analysis estimates annual spend on CTM development and manufacture at about $9.3 billion, divided almost evenly among process and formulation development, analytical development and testing, and manufacture of CTMs. The biggest bucket of spending is in early development (preclinical and Phase 1), thanks to the large number of projects in the pipeline and the high cost of API characterization and process development, especially for large-molecule compounds. 

The most revealing aspect of the PharmSource analysis is the degree to which contract services have already penetrated the clinical supply chain. We estimate that as much as two-thirds of CTM development and manufacturing expenditures are already outsourced, a much larger proportion than we expected. The principal source for contract services' large share is the small and mid-size biotechnology and pharmaceutical companies, which account for 88% of the outsourced spend. Small and mid-size companies tend to be highly dependent on contract services and account for 75% of the candidates in the new drug development pipeline. By contrast, large global companies, which account for one quarter of total development spending, make up just 12% of outsourced spend. 

The PharmSource model highlights the dilemma faced by CDMOs: they benefited greatly as the number of early development candidates grew to more than 6000, a 55% increase from 1999, and are now suffering as the number of compounds slips back. Faced with a shortage of capital, early-stage companies have been forced to halt work on many candidates and expend funds on remaining candidates more cautiously. Our model projects that a 20% drop in the number of early-development candidates would result in a 10–15% drop in outsourced development spending, which is in line with what we are seeing now throughout the marketplace. 

There is good news, however. The PharmSource model also points to some substantial upside opportunities for the CDMO industry. Most importantly, the continuing shift from small-molecule compounds to large molecules will likely be a significant boon to the contract services. We expect that if large molecules grow to 30% of the pipeline from their current 22%, total outsourced development spend will grow by 15%. Of course, where that spending takes place will shift as well. CDMOs specializing in large-molecule API characterization, process development, and manufacture will increase their market share while small-molecule API manufacturers will lose share. 

The CDMO market is going through a significant restructuring as it adjusts to changing realities in the world of finance and the bio/pharmaceutical industry. There will be significant opportunities for contract service providers as we come out of the restructuring process, but there will definitely be winners and losers.  

 is president of PharmSource Information Services, Inc., and publisher of 

Outsourcing

A new analysis highlights growth drivers and challenges for clinical supply-chain services.

Sizing Up the CDMO Market


The 2009 installment of CPhI Worldwide, the large pharmaceutical ingredients and contract services trade show, held in Madrid last month, showed strong attendance as exhibitors reported on new capacity expansions, service offerings, and products. In speaking with exhibitors and attendees, the general consensus was that business conditions have improved since last fall, but have not yet returned to levels post the economic downturn. Companies remain cautious about the return of the emerging pharmaceutical and biotechnology sector in wake of tightening credit and financing, although they said they have seen some improvement. As for Big Pharma, contract manufacturers said they have observed increased receptivity in outsourcing by some players although cost-consciousness remains very much a factor. 




Despite some uncertainty in the market, show attendance was on a par with last year’s event in Frankfurt, with 25,450 attendees in Madrid, only 300 attendees below last year’s show, according to UBM International Media, the organizers of the show. The combined number of exhibitors from all events, CPhI (pharmaceutical ingredients), ISCE (contract services), P-MEC (pharmaceutical machinery and equipment), BioPh (biopharmaceutical ingredients) was 1808, an increase of 100 from last year. First-year exhibitors also increased, with 114 companies making their debut at the show.  




At the show or through recent announcements, several companies reported capacity expansions, service enhancements, or new products. Some highlights are outlined below.



, a provider of contract small-molecule process research and development (R&D) and custom-manufacturing services, has entered into a strategic partnership with Orochem Technologies to manufacturing an active pharmaceutical ingredient (API) that is in late-stage development of a US-based innovator drug company using simulated moving bed (SMB) chromatography. Orochem manufacturers SMB equipment and stationary chromatography phases for bioanalytical, solid-phase extraction, flash, and preparative applications. 



 (Detroit, MI), a contract drug-development and current good manufacturing practices (CGMP) manufacturer, is planning a $6-million expansion project to upgrade its API manufacturing facility in Riverview, Michigan. The plan’s initial phase includes an isolated new reactor bay, which will house two 100-gallon glass-lined reactors and a 50-gallon hydrogenation vessel. The new reactor bay will provide redundant capacity to a similarly designed existing bay that holds three 100-gallon reactors, while providing additional plant capacity and plant-scale hydrogenation capabilities. The company expects the initial phase to be operational in January 2010.



 (Ludwigshafen, Germany) debuted a new developed solubilizer, Soluplus at CPhI. The excipient forms solid solutions with poorly water-soluble drug substances and was developed specially for pharmaceuticals produced by hot-melt extrusion. 



(CML, Germantown, WI) dedicated a new 125,000-ft.

large-scale API manufacturing facility in Germantown, Wisconsin, in late July. The facility is designed with six GMP suites capable of producing multiton quantities of APIs and advanced intermediates. The installed capacity is 70 m

 with an expansion capability for an additional 120 m

. The new facility follows recent multimillion dollar investments at the company's development facilities in Europe, which includes new R&D and analytical laboratories and additional pilot-plant capacity. Those investments will add more than 40% to CML-Europe's capacity and enable the facility to produce up to hundreds of kilograms and APIs and intermediates



 (Strasbourg, France), a provider of dosage-form solutions, has received authorization from the Agence française de sécurité sanitaire des produits de santé (Afssaps) to produce clinical batches at its product dvelopment center in Strasbourg, France. The company says this allow it to better serve pharmaceutical and biotechnology companies that require small-scale batches of encapsulated compounds for use in clinical trials. The company also has a product development center in Boston. 



 (Lourdes, Portugal) reported that its API plant in Loures, Portugal, successfully passed a preapproval inspection by the US Food and Drug Administration. The inspection covered five abbreviated new drug applications and one new drug application. The Loures plant produces both generic products as well as APIs and bulk formulated products for clinical-trial materials and commercial scale. Early this year, Hovione opened a new API manufacturing site in Cork, Ireland after acquiring the facility from Pfizer (New York). The company also reported in September that its TwinCaps inhaler licensees, Daiichi Sankyo (Tokyo) and Biota Holdings (Victoria, Australia), have both announced successful Phase III trials for CS-8958, a neuraminidase inhibitor for treating influenza. TwinCaps is a dry-powder inhaler. Hovione is planning for large-scale manufacturing of the TwinCaps devices. Daiichi Sanyko is intending to submit its market authorization application for Japan by March 2010. Biota is advancing its clinical development program to support registration in the US and UK.



 (Wayne, NJ) launched a drug-solubility initiative in support of pharmaceutical companies that work with APIs that exhibit poor solubility. The multifaceted initiative will include R&D aimed at advancing the state of solubilization technology, the development and application of a broad portfolio of ingredients for use in solubilization as well as formulation services designed to enhance solubility using different processing approaches to a broad range of actives. ISP says it will expand its facilities and personnel dedicated to solubilization efforts, establish alliances with companies involved in developing technologies for solublization, and outreach to the industry. ISP has a contract-services business that focuses on solid-dispersion technology and offers both spray drying and hot-melt extrusion to develop solid forms.

As part of the initiative, ISP is expanding its R&D facilities in Hyderabad, India, to create a Solubility Center of Excellence, which will serve as a focus point for R&D. Activities at the center will center on the use of polymers, disintegrants, and cyclodextrin chemistry and tools to improve drug solubility and bioavailability of oral and parenteral drugs. The company also has R&D and technical support facilities in Colombia, Maryland; Istanbul, Turkey; Sao Paolo, Brazil, Colombus, Ohio; and Wayne, New Jersey. ISP is also  forming an alliance with Coperion (Stuggart, Germany) with the goal of advancing hot-melt extrusion for the pharmaceutical market. Coperion provides equipment and testing and expertise in the physical systems used for extrusion. ISP will bring its expertise in ingredient technology such as polymers and disintegrants. ISP will also hold a series of drug solubility and bioavailability in Europe and the US in first half of 2010, called Solubility Twenty Ten. The day-long programs will be open to pharmaceutical scientists and students and will be held in Cork, Ireland; Duesseldorf, Germany; Basel, Switzerland; and Wayne, New Jersey. 



 (San Antonio, TX) has purchased the assets of Natural Pharmaceuticals, a manufacturer of APIs for oncology drugs. Phyton will acquire intellectual property and patents for the production of taxane-based APIs, a manufacturing facility in Delta, British Colombia, Canada, and an API manufacturing subsidiary in Shanghai, China,  Syntax Biotechnology.  



(Mumbai) announced a further investment in its high-potency substances production facility in Grangemouth, Scotland. The two– year, £1 million ($1.67- million) investment will prepare and validate one of its six production suites for commercial-scale production of antibody drug conjugates. The latest expansion follows a $270,000 investment in 2008 to commission a sixth CGMP suite and a $500,000 investment in 2006, which added clinical-trial-material manufacturing. 

Piramal also reported that Pfizer (New York) has renewed key supply contracts at Piramal’s production facility in Morpeth, United Kingdom. Piramal had acquired the facility from Pfizer in 2006. Under the supply-contract renewal, Morpeth will continue to produce APIs, bulk formulated products, and finished dosages for Pfizer. 

In other news, Piramal’s clinical-trial-services business has been granted a manufacturing license for producing clinical-trial materials by the UK Medicines and Healthcare Products Regulatory Agency. In September, Piramal relocated its UK biocatalysis division to custom-laboratory facilities in Wilton, Teesside, United Kingdom, to allow for further flexibility for expansion. Piramal also commissioned a new formulation and development and clinical-trial-materials supply center in Ahmedabad, India. The center has a footprint of 50,000 ft

. Thirty-four formulators and 48 analytical chemists are based at the center with plans to increase to a total of 180 over two phases. 

Piramal also recently compled a near $40-million merger with Minrad International, which provides the company with additional inhalation anesthetics manufacturing capacity and access to the US market. The company says the move puts it at third in market share in the global inhalation anesthetics sector. The move was complemented by a recent acquisition of the US inhalation anesthetics gas distribution business, RxElite Holdings. 



 (St. Louis, MO) reported that is Pharmorphix solid-state research laboratories in Cambridge, UK, have installed a new single crystal X-ray diffraction system. The company says the installation of the Oxford Diffraction SuperNova system, which is capabler of performing single crystal X-ray analyses on small microcrystallines fragments with dimensions as low as 30 to 50 microns, is the first industrial installation of the instrumentation in the world. 

SAFC also reported that it has completed the $12-million expansion of its Carlsbad, California, viral-product manufacturing facility. The expansion added 8000 ft

 of manufacturing space to the existing 44,000 ft

. The addition enables both 100-L batch production in stirred-tank bioreactors and 1000-L batch manufacturing in disposable bioreactors. The facility is Biosafety Level 2-compliant, thereby alows manipulation of human pathogens.

Also, SAFC’s parent company, Sigma Aldrich (St. Louis, MO) and Sangamo BioSciences (Richmond, CA) expanded their existing license agreement to include the exclusive rights to develop and distribute zinc finger DNA binding protein (ZFP)-modified cell lines for commercial production of protein pharmaceuticals. Additionally, Sigma-Aldrich licensed rights to certain ZFP-engineered transgenic animals for commercial applications.

Global Feature

Exhibitors announce capacity expansions, service enhancements, and new products at CPhI Worldwide in Madrid.

PTSM: Pharmaceutical Technology Sourcing and Management-11-10-2009

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CPhI Exhibitors Announce Expansions