, we are pleased to announce the addition of a community of  experts panel to the eNewsletter. The panel consists of leading professionals  involved in the synthesis, manufacture, and sourcing of active pharmaceutical  ingredients and intermediates, and experts in formulation and dosage-form  manufacturing. The community of experts will lend its expertise to the  eNewsletter by providing reviews of technical articles as well  as offering perspectives on topics of relevance to pharmaceutical manufacturers  and their suppliers. 

The panel includes: John A. McCarty, vice-president of  formulation sciences at Azopharma; Michael Cannarsa, PhD and director of  business development of Almac Sciences; Stephen Munk, PhD, president, and CEO of Ash Stevens; Shaukat Ali, PhD and technical services manager at BASF; Mark  Griffiths,head of Cosam Developments; David Rozzell, PhD and vice-president of  biocatalysis technology and applications at Codexis; Pieter de Geus, senior  vice-president of research and development at DSM Pharmaceutical Products;  Steven Grieve, director and team leader of technical development and regulatory  affairs at Pfizer CentreSource; and Ed Roullard, vice-president of SAFC Supply  Solutions.

John McCarty, vice-president of formulation sciences at  Azopharma, has held management positions in research and development at Key  Pharmaceuticals, Schering-Plough, and Pharmavene (acquired by Shire  Pharmaceutical). He is also the founder of Pharmaceutical Productions, an  international consulting firm. He has expertise in developing oral solid dosage  forms, biologicals, parenterals, buccals, topicals, transdermals, liquids and  semisolids, aerosols, controlled-release and novel drug-delivery systems. In addition to dosage-form  development, he has prepared the CMC sections of numerous investigational new  drug applications, new drug applications, and other regulatory applications and  has been a technical representative at meetings with the US Food and Drug Administration. He  is an inventor of 17 US and foreign patents and holds bachelor's degrees in  chemistry and microbiology from Florida  Atlantic University. 

Micheal Cannarsa, PhD and director of Almac Sciences, was  previously general manager of Chiral Quest, a company commercializing  asymmetric chemocatalysis for pharmaceutical manufacture. Before joining Chiral  Quest, he managed the US  custom manufacturing business for Chemi SpA. He has more than 15 years of experience  building business in pharmaceutical fine chemicals. He has held senior business  development positions and led technology acquisition efforts at Synthetech,  Symyx Technologies, and PPG-Sipsy. Dr. Cannarsa received his PhD in organic  chemistry from Cornell University and his bachelor’s degree from Georgetown University. 

Stephen Munk, PhD, president, CEO, and member of the  board of directors of Ash Stevens, is experienced in drug discovery,  development, and manufacturing as both a scientist and manager. Before joining  Ash Stevens in 1997, he worked at the pharmaceutical company Allergan as a drug-discovery scientist and served as the co-team leader of the adregenic  drug-discovery team. Since joining Ash Stevens in 1997, the company has  received nine FDA approvals to manufacture novel drug substances. Those approvals include approvals for bortezomib, clofarabine, and  5-azacitidine during a period in which only a total of 85 new molecular  entities were approved by FDA. In addition to the management of science and API  production, Dr. Munk directed the design and construction of a new,  state-of-the-art  API manufacturing plant  at Ash Stevens.  He earned his PhD in  organic chemistry from the University  of California at Berkley  and was an American Cancer Society postdoctoral fellow at Purdue University  conducting studies in medicinal chemistry and molecular biology. Dr. Munk also serves as an adjunct professor of chemistry at Wayne State University.

Shaukat Ali, PhD and technical services manager at BASF, has more than 17 years of experience that include liposome formulations and drug delivery, transdermal and intraoral film delivery, solid oral dosage coatings  and granulation, lyophilization and injectable formulations, analytical methods  development, and regulatory and CMC experience. Prior to joining BASF in 2004, Dr.  Ali also held technical and management positions with Lavipharm Laboratories,  Penwest Pharmaceuticals, Protarga, and the Liposome Company. Dr. Ali holds a  PhD in chemistry from the City University of New York, a master's degree in  chemistry from Laurentian University, and a bachelor’s of science in chemistry  from Gorakhpur University. He also has completed postdoctoral work at Cornell University and the University of Minnesota.

Mark Griffiths has 24 years of  experience in designing, building, qualifying, and operating pharmaceutical  research, development, and manufacturing facilities. He has designed and built  facilities ranging from research and development laboratories for organics and  biologics to manufacturing facilities for APIs, secondary pharmaceuticals, and  cytotoxic, highly potent materials. He has also audited  many of these types of facilities and was  responsible for a number of successful audits carried out by FDA. Formerly a CEO of successful and highly regarded Swiss-based CMO,  Griffiths also has worked for a  number of engineering design organizations and has held positions with several  fine-chemical and pharmaceutical organizations, including British Petroleum,  SmithKline Beecham Pharmaceuticals, and Sigma-Aldrich. Griffiths is owner of Cosam Developments, a multidiscipline pharmaceutical  consultancy, and is also engaged in the design, development, and operations of  API and secondary manufacturing facilities in India,  China, Saudi Arabia, and Europe.  He holds a master’s degree in engineering from Bristol  University in the United Kingdom. 

David Rozzell, vice-president of biocatalysis technology and  applications at Codexis, was the founder and CEO of BioCatalytics and joined  Codexis in conjunction with the acquisition of BioCatalytics by Codexis in July  2007. He has more than 25 years of experience working in the field of  biocatalysis and enzyme technology. He received his PhD in chemistry from Harvard University  and a bachelor’s of science in chemistry from the University of Virginia. 

Pieter de Geus, senior vice-president of research and  development at DSM Pharmaceutical Products, has held several management  positions in recombinant protein production and engineering at Plant Genetic  Systems, Unilever Research, Gist-Brocades, and DSM. In 1997, he was named site  director of DSM Biologics in Groningen, The Netherlands, where he managed the transition of the company  from a development-services company to a CGMP contract manufacturing company, with its first commercial product approved by FDA in 2004. He was one of the  main initiators for establishing the joint venture between DSM Biologics and  Crucell that focuses of the development of the human cell technology platform,  “PER.C6” for producing biopharmaceutical proteins. In 2006, Dr. de Geus became  senior vice-president of research and development for DSM Pharmaceutical  Products. His responsibilities consist of research and technology advancements in biopharmaceutical manufacturing, API manufacturing, and drug-product formulation development. He received his PhD in biochemistry for the University of Utrecht in the Netherlands. 

Stephen Grieve, director and team leader of technical development  and regulatory affairs at Pfizer CentreSource, joined Pfizer CentreSource from  its predecessor company, The Upjohn Company in 1980 as a quality-control  professional. He subsequently has had positions of increasing responsibility,  reflecting his expanding scope of expertise, encompassing site specific,  regional, national, and international quality control, quality assurance, and  regulatory compliance issues. Most recently, he served as director and team  leader of quality-control and systems. He holds a master's degree in business  administration from Western   Michigan University  and a bachelor of science in chemistry from Indiana University of Pennsylvania. 

Ed Roullard, vice-president of SAFC Supply Solutions, joined  Sigma Aldrich in 2000 and was previously European director of SAFC in Munich, Germany,  where he was responsible for sales, marketing, and operation of the European  region. Prior to his roles with SAFC, Ed served as director of process  improvement at Sigma Aldrich, where he was responsible for driving service,  quality, and cost improvements for the organization. He holds a bachelor of science from Cornell  University and a master of business  administration from Washington University in St. Louis. 

Articles

Ingredients and Materials

Leading professionals join the community of experts panel of Sourcing and Management.

Sourcing and Management Launches Community of Experts Panel

Ricerca Biosciences LLC (Concord, Ohio), a contract drug-development company, is moving forward with a steady expansion program by adding staffing and broadening its biological and pharmaceutical chemical development capabilities.

Ricerca focuses on providing  drug-development services of small molecules from discovery through commercial  manufacture using both biological and chemical capabilities. Its services  include lead optimization, analytical and process chemistry, services for  toxicology and pharmacology, radiosynthesis, manufacturing of active  pharmaceutical ingredients (APIs), and regulatory support. Its API production  facilities in Concord, Ohio, include kilo laboratories operating at  the 50-L scale and plant-production systems with capacities of between 200–2000  L in scale. Ricerca works with large pharmaceutical companies as well as  emerging or start-up companies that often need a broader scope of services to  support their drug development.

In 2007, the company completed a financial  restructuring that includes new equity and term facilities of more than $75 million.  That refinancing is allowing the company to implement a three-year business  plan that includes $25 million of new investment to expand chemistry and  biological laboratories at its 45-acre site in Concord.  


 During the past year, in its chemistry operation, the  company added and qualified isolation and drying suites to allow for more  efficient utilization of pilot-plant equipment. In addition, the company  expanded its nuclear magnetic resonance (NMR) capacity through the acquisition and qualification of a Bruker  400 MHz Avance III NMR (fitted with an autosampler and a low temperature probe  to –100 degrees C with capability to run two- and three-dimensional spectra).

In its biological services (toxicology, bioanalytical, drug metabolism and pharmacokinetics),  the company has made significant investment in a building expansion to augment  its toxicology services, high-end equipment (such as liquid chromatographic–mass spectrometric equipment, API  4000 LC–MS–MS, and flow cytometry) and increased staff numbers by nearly 50%  during 2007 and 2008.


 Ricerca offers integrated resources  to an investigational new drug (IND)  program. Its services support advancing hit  molecules to development candidates for an IND application. These capabilities include  medicinal chemistry services for evaluating, validating and optimizing active  compounds for a discovery program, lead-chemistry optimization, custom-focused  libraries synthesis, synthesis to establish structure activity relationships,  chemistry and synthetic route development, and synthesis of reference  compounds, scaffolds, building blocks, and starting materials. It also provides  drug-ability assessment, metabolite identification, and impurity studies as  well as toxicology and pharmacology services, which include 

 absorption distribution,  metabolism, elimination, and toxicity (ADMET) testing and 

 biological testing, including  animal-efficacy models. To support IND  candidates through clinical development, Ricerca provides process optimization, scale-up, manufacturing under good manufacturing practices (GMPs), and bioanalytical  testing. 


 To support these programs, Ricerca has a strategic alliance  with Latitude Pharmaceuticals (San Diego), a formulation company with expertise and  experience in preclinical formulation development.  “This alliance has increased our ability to  offer formulation capability for drug product to complement our expertise with  drug substance API manufacture,” says Jack Jiang, PhD and vice-president of  drug discovery at Ricerca. 

In addition, Ricerca has a close working relationship with a  Chinese partner, Bicoll (Shanghai), which allows the company to offer low-cost full-time equivalent medicinal  chemists for the synthesis of custom intermediates for early-stage API  synthesis. “Such work is performed in collaboration and under the direction of  our US-based medicinal chemists,” explains Jiang. Ricerca also outsources  late-stage custom intermediates to TCL Research in Ranipet, Tamil Nadu, India, to  enable further cost-savings. 

Overall, Ricerca reports good growth for outsourcing on an  industry level and for the company specifically. “Pharmaceutical outsourcing is  continuing to grow, and demand for service is at an all-time-high,” says R. Ian  Lennox, chairman and CEO. “Market performance in 2008 clearly outstrips 2007,  and we have every expectation that demand will again increase in 2009.”  

APIs

Buoyed by increased demand for pharmaceutical outsourcing services, Ricerca Biosciences proceeds with an expansion plan.

Ricerca Biosciences in Expansion Mode

Major pharmaceutical companies have talked a lot about the need for a new business model, one that is lower cost, more flexible, and more reflective of the risks in drug development. Outsourcing has been cited as a critical strategy element of the new business model, but most outsourcing deals have been too tactical to be thought of as truly innovative. However, deals announced over the summer involving Novartis (Basel, Switzerland) and Eli Lilly (Indianapolis) demonstrate ways in which outsourcing can become a truly strategic element in the new business model. 

Lilly announced three deals with major preclinical and clinical contract research organizations. In its biggest deal, Lilly contracted with Covance (Princeton) for clinical and preclinical research services, valued at a minimum of $1.6 billion over 10 years. As part of the deal, Covance will acquire Lilly's preclinical research campus in Greenfield, Indiana, for $50 million. Covance's services to Lilly will include GLP- and non-GLP toxicology, clinical pharmacology (Phase I), central laboratory, and Phase II–III clinical research. 

The other two deals were for clinical research services. Lilly will outsource all of its clinical monitoring work in the US and Puerto Rico to Quintiles Transnational (Research Triangle Park, NC). The company's data management operations in the US will go to i3 Global (Ann Arbor, MI), a unit of UnitedHealth Group.  

In another big summer deal, Novartis announced a long-term relationship with Lonza (Basel) for development and manufacture of biopharmaceutical candidates in Novartis' pipeline. Under the agreement, Lonza will provide process development, manufacture clinical trial materials, and manufacture commercial launch quantities for all biologics in the Novartis pipeline. In addition, Lonza will provide engineering and other assistance to help Novartis build its own commercial manufacturing infrastructure.  Lonza CEO Stefan Borgas indicated that the relationship could last 10 years or more. 

Of the two deals, the Novartis-Lonza deal is probably the most innovative because of its risk-mitigation aspects. By having Lonza manufacture clinical supplies and commercial-launch quantities, Novartis is avoiding one of the major risks in biopharmaceutical development (i.e., investing in enormously expensive biomanufacturing facilities that could become white elephants if their intended products don't succeed).   

The Lilly deals don't have the same risk-mitigation elements, but there are similarities to the Novartis-Lonza deal in other respects. All four deals make costs more flexible and seek to assure the pharma company partner that it will have access to the contractor's capacity when needed (although the Lonza deal doesn't appear to entail annual "take-or-pay" contract minimums the way the Lilly deals do). Most importantly, in all four deals, the Big Pharma partners are seeking access to the superior technical and/or operational expertise of the contractor partner. 

Lilly's involvement in such broad-ranging outsourcing arrangements is consistent with its stated goal of transforming its business model in the face of looming patent expirations. The company was one of the earliest to set up research operations in China, establishing an innovative model with its ChemExplorer venture in Shanghai. And several years ago, it established a new operating unit, Chorus, to accelerate and lower the cost of drug development using a virtual business model.  

The Novartis-Lonza deal is more surprising because Novartis has considerable experience and manufacturing capacity in its Sandoz generics unit. Headquartered in Holzkirchen, Germany, Sandoz was one of the first companies to launch a biosimilar product in the European market (the human growth hormone "Omnitrope") and has been actively selling contract biomanufacturing capacity for many years.  

A major lesson of these two summer deals is that it takes more than capacity to become a strategic partner of a major pharmaceutical company. These decade-long service relationships require operational and technical excellence, global scale, financial heft, and creative deal-making skills. As more agreements like this are put together (Lonza claims to have five more in negotiation similar to the Novartis deal), industry will need to redefine what constitutes a major player in the services industry.

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

Outsourcing Outlook

Summer deals struck by Novartis and Lilly point to an evolution in contract services.

Big Deals

The European Union’s newly  instituted Registration, Evaluation, Authorization and restriction of Chemicals  (REACH) regulation has a number of requirements that apply to the  pharmaceutical industry. Wading through the regulations and what they mean to  this industry can be confusing as certain substances used in the pharmaceutical  processes are exempt from one or more REACH procedures. 

Under the “No Data-No Market” mantra, REACH requirements state that  companies are required to register any substances imported or manufactured in  quantities of more than 1 metric ton per year with the 

. Substance toxicological data as well as risk assessment of the various  uses is required information at registration. 

Phase-in period spreads  registration costs

The REACH regulation requires registration of the existing 30,000  substances produced or imported within the European Union, which will result in  a huge impact in the chemical industry. To make the first-phase of the  regulation’s implementation easier, the EU has initiated a phase-in period for  existing substances that will extend their registration timeframe over a 10-year  time period to 2018. Substance registration will be prioritized according to  the phase-in timeline (see Figure 1), based on volume and hazardous  characteristics of the materials. 

To benefit from this phase-in period, preregistration of existing  substances before Dec. 1,   2008 is essential, creating a sense of urgency with many companies.

New substances introduced on the EU market after 1981 do not benefit  from this phase-in, so require REACH registration within 18 months.

Authorization and restriction  procedures

As of September 2008, only 16 toxic substances were submitted for authorization. Listed in Annex XIV, scheduled to be published in mid-2009  by ECHA,  they will only be able to be used after authorization by the relevant  authorities and only for usage covered by that authorization for a limited  period of time.

Several list revisions are expected to  occur, with the aim of eventually adding all Substances of Very High Concern  (SVHC) to Annex XIV. (Materials  identified as SVHCs have characteristics such as CMR 1 & 2 [Carcinogenic,  Mutagenic and substances toxic for Reproduction], PBT [Persistent,  Bioaccumulative and Toxic] and vPvB [very Persistent and very Bioaccumulative]).  Roughly any substance at risk for humans and the  environment will be phased out in the European market.

In order to emphasize the goals of the REACH  authorization process, the International Chemical Secretariat (ChemSec), in  collaboration with leading nongovernmental organizations (NGOs) in the EU and  beyond, developed the REACH SIN (Substitute It Now!) list. Published Sept. 17,  2008, this list is designed to be an indicator as to which risk  substances should be replaced.

Although few substitutions will be required in a short term, such as cobalt  chloride, the impact of the current authorization list on the pharmaceutical  industry should be limited. For production, sustainability and cost effective  reasons, pharmaceutical companies should therefore avoid usage of SVHC as early  as possible in their drug-development processes.

Restriction can apply to all substances, without volume  limits. Restricted substances and restriction details are described in the  current Directive 76/769/EC, which will be replaced by Annex XVII of REACH as  of June 1, 2009.  The new annex reflects the same regulatory requirements as the current directive. 


 To stay on top of these new regulations, pharmaceutical companies need  to rapidly evaluate their readiness to meet REACH requirements. Many are  finding that the safest approach is to assume that all chemicals are subject to  REACH, taking into account the following four special cases.

 Active pharmaceutical  ingredients (APIs) and excipients are subject to REACH but are exempt from  registration, evaluation, and authorization if they are already registered with  the European Medicines Agency (EMEA) as an ingredient of a medicinal product  for human or veterinary use. Only quantities used as a registered API or  excipient will be exempt; however, if the same substance is also produced for  another use, such as food additives, it is still subject to REACH regulation.

 Nonisolated intermediates, that is, intermediates  produced and kept within a reactor vessel to be transformed into a final  molecule or any another intermediate, are not subject to REACH. 

Isolated intermediates have to be registered according to different  rules, although they are not subject to authorization procedures. They are  exempt from the evaluation process as well, provided they remain at the  production site of origin. However, transported isolated intermediates are  subject to REACH registration and evaluation. 

Information in the registration dossier of both categories of isolated  intermediates (i.e., “on site” or “transported”) may be limited to existing  information, provided the manufacturer can prove the intermediates are  manufactured and used under “strictly controlled conditions.” Strictly  controlled conditions comprise rigorous substance containment, procedural, and  control technologies that minimize substance emission and any resulting  exposure.These conditions are usually met in pharmaceutical production sites,  but they must be fully documented and available to the regulatory authorities. 

 All starting materials  and reagents are subject to REACH and are required to go through the  registration process if they are produced or imported in quantities of more  than 1 metric ton per year, per company (i.e., per legal entity). Moreover, compliance  with authorization and restriction requirements is mandatory, even for volumes  lower than 1 metric ton. 

Case 4: PPORD exemption in drug development and clinical  trials.

 For  APIs, excipients, intermediates, starting materials, and reagents used during  drug development and clinical trials, an exemption can be obtained via a product-  and process-oriented research and development (PPORD) notification. ECHA issues  the exemption following the notification, discharging both the supplier and  user from registering substances produced or imported in more than 1 metric ton per  year. This exemption is valid for five years and can be extended for an  additional 5 to 10 years upon proper application. Even with a PPORD  exemption, however, users must document controlled use and apply health and  environmental measures. 

Because common starting materials and reagents used in larger  applications will generally lead to REACH registration by its supplier, PPORD  notification may be of less interest.

Table I summarizes requirements for various  chemicals used by the pharmaceutical industry. 

Table I: REACH    requirements for various chemical types.

If not    registered with EMEA, the regular procedure applies.

Under    strictly controlled conditions, the registration dossier information can be    limited to already available information.

Supplier    and user must apply for the exemption.

REACH is Registration, Evaluation, Authorization and restriction of Chemicals.
 EMEA  is European Medicines Agency.
API is active pharmaceutical ingredient. 
 PPORD is product- and    process-oriented research and development.


 All companies preregistering substances are  required to participate in a Substance Information Exchange Forum (SIEF), an  exchange forum that has been established under the objective of providing more  transparency on substances, like classification, physicochemical, human health,  and environmental properties.

SIEF participation must continue throughout the entire registration  process, and allows for expensive procedure costs to be shared among the  forum members. However, participation also mandates that companies exchange  product data in order to prepare a common registration dossier. The proprietary nature of the pharmaceutical industry makes one ask, “What about  confidentiality?”

A preregistrant can request not to  participate in the SIEF only if there is a relevant rationale such as costs, confidentiality, disagreement  with SIEF leader, etc. Declining SIEF participation means submission of a  separate registration dossier for substances and the elimination of the longer  phase-in period. A full registration dossier must be submitted to REACH within  18 months.   

The pharmaceutical industry is  concerned that potential short-term impacts of REACH regulations could result  in an interruption in the supply of some starting materials or reagents that  have not been preregistered by EU suppliers, or by suppliers outside the EU who  have failed to appoint an “Only Representative.” (Late preregistration can be  granted to phase-in substances that will exceed 1 metric ton per year for the first  time after Nov. 30, 2008).  The registration procedures may also affect the materials provided by many of  their outsourced manufacturing partners.

Investigations into orphan substances-those  that have not been preregistered by any supplier but have a user with more than 1 metric ton per year requirements-are due to be revealed early in 2009. However,  substance withdrawal may also be a consequence due to supplier portfolio  rationalization. The industry’s first interruption of supply occurred in June  2008, and further interruptions are expected to be a continuing challenge to  the industry. The industry should also expect additional substance withdrawals  to occur later this year and in early 2009.

For a pharmaceutical company, understanding  your supply chain, developing strategies for ensuring product availability, and  communication with suppliers is key for avoiding interruptions in chemical  supply as outlined below. 

Knowing your supply  chain is essential considering all the challenges associated with purchased  substances. All your supply-chain participants should be prepared to implement  REACH. No matter the volume you are purchasing, this applies to all critical  starting materials and reagents.

However, obtaining REACH compliance proof  from your supplier could be difficult. As an official  REACH compliance certificate is not available, a  supplier cannot prove REACH readiness until  the entire registration process is complete-between  2010 and 2018 for phase-in substances. Thus, companies must collaborate closely  with their suppliers to ensure the appropriate efforts are being made.

. Dec. 1, 2008 signals the end of  the preregistration period. The next step after preregistration will be for  companies to assess remaining gaps and evaluate risks by documenting which  products have not been preregistered. To ensure continuous supply, many  companies may find the need to partner with alternative raw materials suppliers  that have their products registered, or have the possibility to late  preregister them. Late  preregistration can be granted to phase-in substances that will exceed 1 metric ton  per year for the first time after Nov. 30, 2008.

. To minimize the impact of  negative supply issues, the pharmaceutical industry and their suppliers must  use this preregistration period to work in close alignment on REACH  implementation. Good communication against REACH objectives will be a primary  key in achieving these objectives and can be accelerated by proactively  identifying registration/substitution requirements. If these critical steps are  not taken and registration processes are not considered in time, many companies  could face serious supply shortages in the materials key to their development  and commercialization programs, thus, the consequences of not meeting REACH  regulations could be considered extremely unacceptable.


 Understanding the requirements of REACH and  working closely with suppliers is critical for compliance and to ensure the  continuous flow of product through the supply chain. 

Carole Garcia is  market segment manager of pharmaceutical raw materials for SAFC Supply  Solutions, tel.+ 33 474 822853, carole.garcia@sial.com. 

Global Feature

The pharmaceutical industry faces compliance with the REACH regulation, the European Union's regulation on chemicals and their safe use. Fully understanding the requirements, achieving compliance, and developing strategies for working with suppliers are key for avoiding interruption of the supply chain.

REACH's Impact on the Pharmaceutical Industry

As contract manufacturers and pharmaceutical ingredient suppliers gather this week for CPhI Worldwide, the mood is fairly optimistic. Certain key players report healthy gains and expansion plans. 

SAFC ups its investment in high-potency manufacturing 


 SAFC Pharma (St. Louis, MO) is investing $30 million to expand its Madison, Wisconsin, facility, by increasing its capacity to produce commercial-scale high-potency active pharmaceutical ingredients (HPAPIs). The investment includes the purchase of 15 acres of green space in Verona, Wisconsin, near its existing HPAPI production site, where the company will build a new 45,000-ft

 manufacturing facility that will house commercial-scale reactors capable of producing HPAPI batch sizes up to 4000 L. Construction of the new plant is expected to be complete by year-end 2009.
 
 The new facility’s design will adhere to Category IV standards. The site will seek “Safebridge” certification upon its completion. The facility will include development laboratories, a 150-L miniprocessing plant and two large-scale CGMP (current good manufacturing practices) manufacturing suites with reactors up to 4000 L. Specially designed quality-control laboratories, a potent-compound packaging area,  warehouse and office space, and expansion space, will be featured in the building.
 
 Including this expansion, SAFC has invested more than $75 million in developing its HPAPI manufacturing capabilities in recent years. The company  announced a total of $45 million in HPAPI expansions over the past 18 months, including a recently completed $4.5-million extension of its CGMP pilot-plant and kilo-laboratory capacity, and operations have begun at its new biologic-HPAPI conjugation suite in St. Louis. SAFC Pharma has also invested in a major facility in Jerusalem, Israel, for large-scale production of bacterial and fungal fermentation-derived HPAPIs. 

 In other areas, SAFC is  proceeding with a $12-million expansion of its viral-product manufacturing facility in Carlsbad, California. The expansion is scheduled to be operational in the second half of 2009. The new suites will add 8000 ft

 of manufacturing space and enable 100-L batch production in stirred-tank bioreactors and 1000-L batch manufacturing in disposable bioreactors. These investments follow a $10-million expansion of commercial-scale API manufacturing and storage capacity  at its Arklow, Ireland, and Buchs, Switzerland, facilities, respectively, in 2007. 


 To build its contract-manufacturing activities, Dr. Reddy's Laboratories (Hyderabad, India) completed two key acquisitions in 2008: Dow Chemical's (Midland, MI) Dowpharma small-molecules business associated with its Mirfield and Cambridge, United Kingdom, sites, as well as BASF's (Ludwigshafen, Germany) manufacturing facility in Shreveport, Louisiana, and related contract-manufacturing business for finished pharmaceuticals. The acquisition of the Dowpharma small-molecules business includes customer contracts, associated products, process technology, intellectual property,  trademarks and the transfer of the Mirfield and Cambridge facilities. Dr. Reddy's will also have a nonexclusive license to Dow's "Pfenex" expression technology for biocatalysis development. 

 The BASF acquisition includes relevant business, customer contracts, related abbreviated new drug applications, new drug applications, trademarks, and the Shreveport facility and related contract-manufacturing activities. It also includes a tolling and supply agreement. 


 Regis Technologies (Morton Grove, IL), a contract manufacturer of APIs and provider of separation services, is moving forward with several expansions. The company points to strong growth in supplying clinical trial materials and in its separations services. 

Regis expands manufacturing and QC/QA capabilities. 

Regis plans to invest $10 million to expand its manufacturing facility in Morton Grove, Illinois, by 30,000 ft

. The expansion is scheduled to begin in 2009 and will include up to 16 additional reactor bays. The manufacturing expansion is scheduled to be completed by 2011. The company is also currently expanding its quality-control laboratories by 8000 ft

. This expansion will allow the QC department to more than double in size to support the manufacturing expansion and will include a nuclear magnetic resonance (NMR) facility. The QC expansion is scheduled to be complete by the end of 2008. 

. Regis is also expanding its separation services. In early 2007, the company brought its “RegisSEP” supercritical fluid chromatography (SFC) services online. The GMP-approved services provide preparative-scale chiral separations on a gram to multikilogram scale. The SFC services complement the company’s expertise in high-performance liquid chromatography (HPLC) services, which include chiral separations. 

In 2007, Regis Technologies introduced two polysaccharide-coated columns for use in SFC and HPLC analyses for chiral separations. The columns are “RegisCell,” which has a (tris-(3,5-dimethylphenyl) carbamoyl cellulose) selector, and “RegisPack,” which has a (tris-(3,5-dimethylphenyl) carbamoyl amylose) selector. “The amylose and cellulose coatings have a different orientation in space (mirror images),” explains Ted Szczerba, technical director of chromatography with Regis, thereby providing subtle differences in the separation of chiral compounds. 

"These columns provide enantiomeric separations of a wide range of racemate classes, rather than for the separation of a specific group of chiral compounds,” he says. “Therefore, both columns can serve as a starting point for developing a chiral separation method.”  

In evaluating the health of the outsourcing market on an industry level, Scott Mohler, a sales and project manager with Regis Technologies,  sees a similar performance in 2008 as in 2007. “Although more large pharmaceutical companies are outsourcing manufacturing, this appears to be offset by a decrease in outsourcing by smaller companies.” 

Shifting geographic patterns of outsourcing activity represent an important change, a situation attenuated by for example, the high-profile case of contaminated heparin.  “Driven by the cost differential, many large pharmaceutical companies began outsourcing their drug-substance manufacturing over five years ago, mostly to companies in China and India,” says Mohler. “But we have begun to see strong indicators that some outsourcing services have begun to shift from China to the US.” 

On an industry-wide level, several factors are favorably affecting US suppliers. “The weakness of the US dollar is changing the competitive nature of the outsourcing market,” says Mohler. “The cost differential of outsourcing to Asian companies is not as large as it was several years ago,” he says. “In addition, with several quality issues that surfaced this past year, quality has become a major issue. Quality and compliance concerns require increased surveillance and attention to the supply stream to make sure end products have integrity and quality, all of which increase cost and concern. Pharmaceutical companies are looking for partners with a pristine quality and compliance track record and find reassurance in the fact that FDA makes more frequent and more thorough investigations of US manufacturers.” 

He adds that US suppliers also benefit from other logistical issues such as a lack of import delays or rejections when a product is manufactured in the US,  the advantages of working in common time zones, and fewer travel requirements.


Earlier this year, AMRI (Albany, NY) opened its first 

 biology laboratory in Singapore and completed a 10,000-ft

 laboratory expansion for medicinal-chemistry discovery services, more than doubling the capacity of its Science Park III facility. The 

 biology group will test compounds synthesized by AMRI's Singapore-based medicinal-chemistry teams to provide potency data using cell-based or biochemical assays. AMRI anticipates hiring roughly 70 additional chemists and biologists to staff the Singapore facility during the next three years. 

 These moves complement AMRI's recent activity in Asia. In 2007, the company acquired the assets of Ariane Orgachem, in Aurangabad, and Ferico Laboratories, in Navi Mumbai, India, giving the company two API and intermediates facilities in the country. AMRI also acquired additional land for expansion and plans to invest approximately $15 million to increase and upgrade manufacturing capabilities during the next several years. 

 Cambridge Major Laboratories (Germantown, WI) is expanding its large-scale API manufacturing with a new 120,000-ft

 manufacturing facility. The facility is designed for multiple GMP manufacturing suites capable of producing multiton quantities of APIs. The facility will initially feature six manufacturing suites with reactors as large as 2000 gallons. The facility will have complete isolation and containment, several vessels for hydrogenation and cryogenic reactions, and the potential to accommodate additional manufacturing suites to the 4000-gallon scale. Completion is scheduled for August 2009. 

 Carbogen Amcis's (Bubendorf, Switzerland) Indian subsidiary, Carbogen Amcis India, plans to open a high-potency facility in Bavla, India. The facility will be located on the Bavla site of its parent company, Dishman Pharmaceuticals and Chemicals (Ahmedabad, India). The facility's design and operation is modeled after Carbogen Amcis's high-potency operations at its Bubendorf, facilities. The facility is expected to be operational by the first quarter of 2009. 

 Carbogen Amcis is part of Dishman Pharmaceuticals and Chemicals. Dishman acquired Carbogen Amcis in 2006 as part of a broader strategy to increase its global presence by acquiring Western fine-chemicals and pharmaceutical assets. In 2007, Dishman acquired Solvay Pharmaceuticals's (Brussels) fine-chemicals and vitamin businesses for an undisclosed sum. The deal included Solvay's Veenendal, The Netherlands, facilities, as well as the intellectual property rights for fine chemicals, vitamin D, and vitamin D analogues. In 2006, Dishman acquired I03S, a company specializing in ozone chemistry. In 2005, it acquired the UK-based contract research company Synprotec. 

 Earlier this year, Hovione (Loures, Portugal) purchased a 75% stake in China's Hisyn Pharmaceutical. The acquisition includes development laboratories in Shanghai and a 22,000-m

 API plant. Hovione's relationship with Hisyn started with the supply of intermediates, but this facility will now produce  two of Hovione’s largest volume products, according to the company.

News From CPhI

SAFC, Regis Technologies, Carbogen Amcis, Cambridge Major Laboratories, and AMRI are among the companies at CPhI Worldwide in Frankfurt this week that are moving forward with expansions.

Contract Manufacturers and Pharmaceutical Ingredient Suppliers Gather for CPhI

Although their physical and chemical properties seem unusual, ionic liquids are simply molten salts  with melting points below 100 °C, not far from room temperature. With this  technology, a liquid is available that consists entirely of ions making it  different from all other “conventional” liquids. Most people are familiar with  liquids that are neutral such as water or solvents such as ethanol or toluene.  This relatively new class of chemicals with unique properties offers some very  exciting opportunities in synthesis and chemical processing. 


 The physical and chemical properties of ionic liquids can be expected to be very  different from those of typical “neutral” liquids. When ionic liquids were  first studied extensively and articles published in the late 1990s, this small, but important difference, triggered huge interest and excitement in the  academic world. Within a short time of their discovery, ionic liquids received  enormous attention by academic and industrial communities. Mainly chemists  pioneered work with these new materials (1). Their hope was that the ionic  nature of ionic liquids would drastically change speed and selectivity of a  variety of chemical reactions. Extensive work has been carried out in the past  few years, which is probably best summarized in a book (

)  by Wasserscheid and Welton for which a second extended edition has been  published (2).


 The  key properties that set ionic liquids apart from other liquids include the  following:
 • Existing as molten salts, in many cases even  below room temperature
 • Highly polar 
 • Often immiscible with organic solvents
 • Literally no vapor pressure
 • Nonflammable
 • Large liquidus range (typically > 300 °C grade)
 • Electrically conducting
 • Remarkable dissolution properties (e.g., wood,  cellulose, polyamides)
 • High thermostability.

Commercial  applications of ionic liquids


 The first commercial and  large-scale application of ionic liquids was accomplished and reported by BASF  in 2004 (3–9). The BASF “BASIL” process (i.e., BASIL is Biphasic Acid  Scavenging utilizing Ionic Liquids) was introduced for the synthesis of  alkoxyphenylphosphines, which are important raw materials for photoinitiators. HCl is formed during the synthesis of diethoxyphenylphosphine  (see Figure 1). 

Figure 1: The synthesis of diethoxyphenylphosphine.  Figure courtesy of BASF SE.

Scavenging  with conventional tertiary amines results in a thick, nonstirable slurry that  leads to lower yields and capacities because of insufficient mixing and heat  transfer. The idea of BASF researchers was to use an ionic liquid precursor as  an acid scavenger. This concept turned out to be successful with  1-methylimidazole. After the reaction with HCl, an ionic liquid is formed:  1-methyl-imidazolium chloride (Hmim Cl), which is a liquid at reaction  temperature. Therefore, during the reaction, two clear liquid phases occur (see  Figure 2) that can easily be separated. The upper phase is the pure product (no  solvent is needed anymore); the lower phase is the pure ionic liquid. Hmim Cl  can be switched on and off through simple protonation and deprotonation. This  property is crucial for recycling and purification of the ionic liquids.  

Figure  2: The BASIL process. After the reaction, two clear liquid phases are obtained:  the upper phase is the pure product, and the lower phase is  the ionic liquid 1-methyl-imidazolium  chloride (Hmim Cl). Figure courtesy of BASF SE.

The  advantage of this process setup is even greater as 1-methylimidazole also acts  as a nucleophilic catalyst with completion of the phosphorylation reaction in  less than 1 s (10). Now, having eliminated the formation of solids and  increased the reaction rate, new reactor concepts were possible. Instead of  using a large vessel, the reaction could be carried out in a tiny jet reactor  with the size of a human thumb (see Figure 3). Doing so, the process  productivity could be increased by a factor of 8 x 10

. At  the end of 2004, BASF successfully started a  dedicated BASIL plant using this jet-stream reactor technology.

Figure  3: The BASIL process is run in a small jet reactor that has a capacity of  690,000 kg m

In  addition, the new process offers advantages in eco-efficiency. Recently,  it was shown that the BASIL technology is by far more sustainable than the  process using tertiary amines (11). 


 Further  investigations revealed that BASIL is not restricted to phosphorylation  chemistry but is a general solution to all kinds of acid-scavenging needs  (3–9). Acylations and silylations have been investigated successfully as well  as an elimination reaction. BASIL is also applicable to extractive acid removal  from organic phases such as for the purpose of purification.



Applying ionic liquids in  chemical reactions is not limited to acid scavenging. A strong effect of ionic  liquids can be expected for all reactions with dipolar transition states. Many reactions have been studied, including:
 • Nucleophilic and electrophilic  substitution/addition
 • Acid catalysis, Friedel–Crafts–catalysis
 • Nitration
 • Halogenation
 • Diels–Alder and “ene” eeactions
 • Esterification
 • Michael additions
 • Mannich reactions
 • Oxidation and epoxidation (2).
 

 Nevertheless,  in a number of cases, the advantages of running the reaction in an ionic liquid  compared with a classical solvent were small, not meeting anticipated high  expectations or justifying extra expense. There are examples, however, as in  the BASIL process, where ionic liquids offer valuable advantages. In those  cases, there is a combination of improved speed or selectivity and advantages  in chemical processing. There are four classes of chemical reactions where  advantages are evident:
 • Nucleophilic substitutions
 • Acid and Friedel–Crafts–catalysis
 • High-temperature reactions (e.g., Rearrangement  reactions, Diels–Alder, Heck couplings)
 • Oxidation and epoxidation


 For nucleophilic  substitutions, BASF surprisingly found that chlorination of alcohols can be  achieved with high yields ( > 98% just by using HCl gas if carried out in an  ionic liquid (12). This reaction is typically done with phosgene, SOCl

 in order to achieve sufficient conversion  and selectivity. Ionic liquids are by far the superior solvent for these  reactions because ether byproducts, which typically are the dead-ends of the  reaction in classic solvents, are further cleaved in the ionic environment.  This condition is supported by a publication from researchers at Eli Lilly who  describe the demethylation of the usually very difficult to cleave aromatic  methoxy ethers by using HCl in an ionic liquid (13). 
 

 In the field of acid  catalysis, the advantages of ionic liquids arise from the use of nonvolatile,  liquid, and easy-to-separate catalysts. Moreover, very remarkable  physicochemical properties can be achieved. One example is super acidity. With  the system 1-ethyl-3-methyl-imidazolium (EMIM) Al2Cl7 •  HCl, H

-values on the Hammett acidity scale of approximately –15 can  be achieved, which is comparable to the acidity of liquid HF (14–15). For  comparison, 100% sulfuric acid has a H

 of –12.3, and 100%  trifluoromethansulfonic acid has a H

 The  superacidity is caused by the following equilibrium (see Figure 4) (14-15):

Figure  4: Equilibrium of the 1-ethyl-3-methyl-imidazolium (EMIM) Al

 absorbs the chloride anion of HCl gas so efficiently that a “naked“ superacidic  proton is left over.

 For high-temperature  reactions, the advantage of ionic liquids as solvents is their high  thermostability and nonvolatility. In many ionic liquids, reactions can be carried  out in standard equipment at temperatures above 200 °C without the use of  autoclaves.


A fourth very attractive field for ionic liquids is oxidation  chemistry where suitable stable classical organic solvents are typically hard  to find.
 

Ionic  liquids in separation technologies. 


 Ionic liquids offer a  huge potential in separation technology. They have, for example, the  ability to break azeotropes and act as so-called entrainers (16-18). Many  classical azeotropes such as ethanol/water or tetrohydrofuran/water can be  broken by adding ionic liquids to the mixture as shown in Figure 5.

Figure  5: Equilibrium-phase diagram for the system of tetrahydrofuran (THF)/water. The  solid line shows the classic azeotropic mixture. The dots indicate how the  azeotrope has been broken after addition of the ionic liquid. The amount of THF  in the vapor phase is always larger than in the liquid phase. Units are in molfraction of THF. Figure courtesy of BASF SE. 

The advantage of an ionic liquid over a classic entrainer is that ionic liquids  have no vapor pressure. This property means that the entrainer itself does not  need to be distilled. A second separation column is not needed, and energy can  be saved. A benchmark calculation reveals a savings potential of roughly 37% for  energy costs and 22% for investment in equipment. BASF has run an extractive  distillation process in a pilot plant continuously for three months. Although  the ionic liquid faced a severe thermal treatment of about  250 °C in  the recycling step, its performance fully remained without any purge. This underlines the high thermal stability of ionic liquids, and that very high  recycling rates are possible without a decrease in performance.


 Ionic  liquids also exhibit remarkable extraction properties in liquid-liquid  extractions (19). One example is the removal of phenols from reaction mixtures.  The classic way of doing this is an extraction with caustic, acidification, and  re-extraction of the phenol with an organic solvent plus subsequent  distillation. This process is a multistep procedure, which includes generation  of a wastewater stream. If other components are sensitive to high pHs, even  some product decomposition and loss of yield could occur. BASF has found that  acidic ionic liquids such as EMIM HSO

 are very efficient extractants  for phenols. More than 95% of the phenol has been removed from an organic  solvent in one-step extraction and more than 99.8% in a two-step extraction. Other components sensitive under basic conditions are not affected by the  acidic ionic liquid. Also, the recycling procedure for the ionic liquid is  relatively easy. It is a one-step distillation of phenol from the ionic  liquid. The nonvolatile ionic liquid is left at the bottom, whereas the phenol  distills off and can be reused. This is just a one-step workup without  generation of any wastewater stream. 


The examples discussed in this article demonstrate that ionic liquids are no longer just laboratory curiosities, but have shown to bring commercial value in chemical synthesis and separation technology. They are available at large-scale quantities and can be handled successfully on an industrial scale in chemical processes.

1. M.  Freemantle, “Designer Solvents: Ionic Liquids May Boost Clean Technology  Development,” 

,  (Wiley-VCH, 2nd edition Weinheim, Germany,  2007).

3. BASF SE,  “Method for  the Separation of Acids from Chemical Reaction Mixtures by Means of Ionic  Fluids," World Patent WO/2003/062171,  Jul. 31, 2003.

4.  BASF SE, “Method for  the Separation of Acids from Chemical Reaction Mixtures by Means of Ionic  Fluids,” World Patent WO/2003/062251, Jul. 31, 2003. 

5. BASF SE,  “Method for Isolating Acids from Chemical Reaction Mixtures by Using  1-Alkylimidazoles,” World Patent WO2005/061416, Jul. 7, 2005.

6. M.  Maase, “Aus  der Industrie Erstes technisches Verfahren mit ionischen Flüssigkeiten,” 

7. M.  Freemantle, “BASF’s Smart Ionic Liquid,” 

8. K.R. Sed­don, “Ionic liquids: A Taste of the  Future,” 

9. K.R.  Seddon and R.D. Rogers, “Ionic Liquids: Solvents of the Future,” 

10. J.  Chojnowski, M. Cypryk, and W. Fortuniak, “The Extension of the Mechanistic Concept of the Nucleophilic  Catalysis in the Silicon Chemistry to Some Reactions of the P(III) center:  Analogies between Silylation and Phosphorylation,” 

11. M.  Maase, “An  Improved Way of Doing It,” presented at the 1st International  Congress on Ionic Liquids, Salzburg,   Austria, Jun.  20, 2005.  

12. BASF  SE, “Method for Producing Haloalkanes From Alcohols,” World Patent  WO/2005/026089, Mar. 24, 2005.

13. C.R.  Schmid et al., “Demethylation of 4-Methoxyphenylbutyric Acid Using Molten  Pyridinium Hydrochloride on Multikilogram Scale,” 

14. G.P.  Smith et. al. “Broensted Superacidity of Hydrochloric Acid in a Liquid  Chloroaluminate: Aluminum Chloride-1-ethyl-3-methyl-1H-imidazolium Chloride  (55.O m/o AlCl

15. G.P.  Smith et al., “Quantitative Study of the Acidity of Hydrogen Chloride in a  Molten Chloroaluminate System (Aluminum  Chloride/1-ethyl-3-methyl-1H-imidazolium chloride) as a function of HCl  Pressure and Melt composition (51.0–66.4 mol% AlCl

16. BASF  SE, “Ionic  Liquids as Selective Additives for the Separation of Close-Boiling or  Azeotropic Mixtures,” World Patent WO/2002 02/074718,  Sept. 26, 2002. 

17. C. Jork  et al., “Influence  of Ionic Liquids on the Phase Behavior of Aqueous Azeotropic Systems,” 

18. BASF  SE, “Ionic  Liquids as Selective Additives for the Separation of Close-Boiling or  Azeotropic Mixtures,” World Patent WO/2005/016484,  Sept. 26, 2002.

19. BASF  SE, “Method  for Extracting Impurities Using Ionic Liquids,” World Patent WO/2005/019137, Mar. 3, 2005.

Matthias Maase, PhD, is with new business development  for intermediates at BASF in North America. 

Ionic liquids provide an alternative to certain solvents in select reactions used to synthesize intermediates and active pharmaceutical ingredients.

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