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Pharmaceutical and biopharmaceutical manufacturing and research and development represent an important part of Singapore’s economic base. Several major projects were announced in 2007 as Singapore, along with Ireland and Puerto Rico, compete for investment in the life sciences.

Pharmaceutical manufacturing output

The biomedical sciences (BMS) sector in Singapore is a growing part of the country’s economy and is the target of government initiatives to attract investment. “Today, Singapore’s BMS industry contributes to slightly over 6% of Singapore’s gross domestic product,” says Keat-Chuan Yeoh, executive director of the Biomedical Science Board at the Singapore Economic Development Board (EDB), the government agency charged with business development. “In 2006, the BMS industry did extremely well. The manufacturing output grew strongly to S$23 billion (US $16 billion), an unprecedented 30% increase over 2005. The manufacturing output has grown almost fourfold from the year 2000, when we launched the BMS initiative.”

In breaking down the BMS sector in 2006, of the total S$23 billion (US $16 billion) in manufacturing output, nearly S$21 billion (US$14.6 billion) was for pharmaceuticals and the balance was for medical technology. Manufacturing data for 2007 is scheduled for release in early 2008.

The BMS initiative was launched in 2000 to establish this sector as the fourth part of Singapore’s industry cluster, alongside electronics, chemicals, and engineering, explains Yeoh. “This development was a natural extension of Singapore’s capabilities in chemicals and electronics manufacturing,” he says.

Key projects in 2007

In 2007, several major projects were announced according to the Singapore EDB in pharmaceutical manufacturing and R&D. These included:

• A US$700-million cell-culture facility to be built by Novartis (Basel, Switzerland) that will support clinical and commercial production of new biopharmaceuticals, primarily monoclonal antibodies, scheduled for operation in 2012
• Lonza’s (Basel, Switzerland) breaking ground for its second commercial-scale mammalian cell-culture manufacturing plant in Singapore, representing an investment of US$350-million depending upon uptake.
• Merck & Co.’s (Whitehouse Station, NJ) opening of its regional headquarters in Singapore
• Genentech’s (South San Francisco, CA) decision to set up Singapore’s first microbial-based biopharmaceutical manufacturing facility, representing an investment of approximately US$140 million
• Eli Lilly’s (Indianapolis, IN) US$150-million expansion in drug-discovery for the new Lilly-Singapore Center for Drug Discovery
• GlaxoSmithKline’s (London) investment of S$20 million (US$14 million) in its Center for Research in Cognitive and Neurodegenerative Disorders for the construction of two medicinal chemistry laboratories
• Eisai’s regional clinical coordination and management center in Singapore.

Key projects in 2006

These investments follow several major projects in 2006 as identified by the Singapore EDB. These projects include:

• GlaxoSmithKline’s S$300-million (US$210-million) vaccine manufacturing plant in Singapore, which is scheduled to be operational in 2010
• Merck & Co.’s S$100-million (US$ 70 million) expansion of formulation-manufacturing facilities and supporting infrastructure
• Lonza’s breaking ground for its first large-scale mammalian cell-culture manufacturing plant representing a US$250-million investment
• Novartis’s creation of a new malaria research program in partnership with Wellcome Trust, Medicines for Malaria Venture, and the Singapore EBD
• Abbott Laboratories‘ (Abbott Park, IL) US$280-million nutritional powder manufacturing plant
• Covance’s (Princeton, NJ) opening of an expanded central laboratory to support biopharmaceutical clients in global clinical trials
• SGS’s (Geneva, Switzerland) opening of its new laboratory for quality control testing in analytical chemistry, microbiological testing, method development and validation, and stability testing
• The biopharmaceutical company PT Kalbe Farma’s (Banten, Indonesia) opening offices for research and coordination licensing in Singapore.

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The panel’s activities are managed by a consultant on a fee-for-service basis. The interested excipient manufacturer, through direct discussions with the consultant, provides the consultant with a table of contents and summary of the expected studies needed for the review. The consultant then provides a cost proposal and timeframe based on the expected time of review and the experts’ hourly fees. After the evaluation, the consultant provides the manufacturer with a report. The report can be included in the sponsor’s DMF or given directly to the drug product applicant.

IPEC only tracks the number of completed reviews and plays no role in this process. IPEC does not know any of the specifics of an expert panel project. The evaluation procedure is kept confidential between the panel and sponsor.

FDA’srole

The details of this process were developed in conjunction with FDA staff, who, in a 2006 letter to IPEC, agreed to consider the panel’s conclusions when reviewing “new” excipients within NDAs. Although the agency could not guarantee that they would agree with the panel’s conclusions, they welcomed the additional level of review and acknowledged the value of the process for encouraging new excipient development.

Conclusion

To date, IPEC’s New Excipient Evaluation Procedure panel has received one submission and several others are in the planning stages. The panel represents a potential remedy to the regulatory “logjam” facing new excipient development. The panel’s independent review should provide pharmaceutical manufacturers confidence that specific “new” excipients will be acceptable in their regulatory filings, thus encouraging them to use these excipients in their formulations.

Christopher C. DeMerlis is manager of regulatory affairs at Colorcon and chair of the IPEC–Americas Regulatory Affairs Committee. Jay M. Goldring, PhD, is director of toxicology at Wyeth Consumer Healthcare and chair of the IPEC-Americas Safety Committee. David R. Schoneker is director of global regulatory affairs at Colorcon. and chair of IPEC–Americas. For more information, contact Alan Mercil at IPEC–Americas, 1655 North Fort Myer Drive, Suite 700, Arlington, VA 22209, tel. 703.875. 2127, fax 703.525.5157, info@ipecamericas.org
http://www.ipecamericas.org/index.html.

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Excipients play a crucial role in pharmaceutical formulations, affecting properties such as patient acceptability, rate of release of pharmaceutical actives, and delivery-to-target tissues. Researchers around the world are currently developing new excipients with improvements to these characteristics. In addition, new active pharmaceutical ingredients (APIs) often require new excipients that are compatible with their chemical properties. However, global commercialization of new excipients is currently hindered by the fact that they are only reviewed by regulatory agencies in the context of new drug applications (NDAs). As a result, pharmaceutical manufacturers are reluctant to include them in their formulations because any questions about the excipients could cause delays or rejection of their applications, thus adding additional uncertainty to the process.

To address this situation, the International Pharmaceutical Excipients Council (IPEC) of the Americas has developed a New Excipient Evaluation Procedure. The goal of this process is to provide independent evaluation of the regulatory acceptance of a “new” excipient before a regulatory filing. The process is meant to mirror that of regulatory agencies, ideally providing confidence to pharmaceutical manufacturers that the excipient will be acceptable in their formulations. This process will not provide any type of regulatory approval.

Current regulatory status of new excipients

In the United States, specific requirements for “new” excipients are detailed in the USFood and Drug Adminisration’s Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, published in May 2005. Globally, the International Conference onHarmonization (ICH) has no specific excipient safety evaluation guidelines, but the FDA guidance cites ICH safety testing guidance documents as reference materials for conducting safety tests.

These guidelines, however, address only one aspect of the approval process, leaving a major gap: the precise definition of “newness.” According to ICH, an excipient is considered “new” or novel if it is used for the first time in a human drug product or by a new route of administration. In the US, FDA maintains the Inactive Ingredient Database, which lists excipients used in approved drug products, their route of administration, and their maximum dosage. The database is somewhat difficult to use because of the lack of standardization of chemical names and the time between approval of an excipient and inclusion in the database. In addition, the definition does not distinguish between completely new chemical entities and approved excipients that have been modified, co-processed mixtures of existing excipients, approved excipients proposed for a new route of administration, or excipients approved for food or cosmetics—the latter of which may require less safety testing as a result of extensive human exposure. Finally, few similar specific safety guidelines for excipients exist outside the US.

Supporting information for a new excipient can be provided in a drug application or in an appropriately referenced drug master file (DMF). This information includes full details of chemistry, manufacturing, and controls as well as supporting safety data. The information provided is similar in the level of detail to that provided for a drug substance. The level of information, however, may be less depending on the “newness” of the excipient.

The IPEC procedure

Under IPEC’s New Excipient Evaluation Procedure, currently used in the US, excipient manufacturers or users submit a dossier in DMF format containing available safety information for their proposed “new” excipient. The file goes to an expert panel that evaluates the information in the context of the FDA excipient guidance and appropriate ICH guidance documents. The expert panel is made up of highly qualified individuals known throughout academia, industry, and the regulatory community. Upon evaluation, the panel issues a statement of conformance or nonconformance to the sponsor. The evaluation is limited to safety information and chemical characterization information as tied to safety for a specific intended use and exposure level. Global applications of the procedure are currently under consideration.

If the review panel concludes that the requirements of the FDA and ICH guidance documents are not met, it recommends specific steps to bring the dossier information into compliance. The sponsor then has the opportunity to resubmit the dossier with the requested changes. The panel’s report is owned by the sponsor and released at their discretion.

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Figure 2 ALL Figures Courtesy of US Food and Drug Administration

Merck & Co.’s (Whitehouse Station, NJ) sitagliptin is a chiral-β amino-acid derivative (see Figure 2). In collaboration with Solvias AG (Basel, Switzerland), Merck advanced an approach for the asymmetric catalytic hydrogenation of unprotected enamines to synthesize sitagliptin using a ferrocenyl ligand in a rhodium-based catalyst. This approach improved yield and reduced waste from the reaction (7).

Specifically, Merck discovered that hydrogenation of unprotected enamines using rhodium salts of a ferrocenyl-based ligand as the catalyst produces β-amino acid derivatives of high optical purity and yield. Merck applied the method in the final synthetic step. The dehydro precursor to sitagliptin used in the asymmetric hydrogenation is prepared in a one-pot procedure. Following hydrogenation, Merck recovers and recycles over 95% of the rhodium. The reactive amino group of sitagliptin is only revealed in the final step, and therefore there is no need for protecting groups. The new synthesis has only three steps, increasing the overall yield by nearly 50%, and reducing the amount of waste by 80% (7).

Asymmetric hydroformylation is another approach in producing single-enantiomer compounds. Hydroformylation can produce synthetically useful aldehydes in atom economical transformations using readily available alkenes, dihydrogen, and carbon monoxide, but generally, enantioselective hydroformylation has not been well developed. The development of new chiral ligands to produce catalysts with high activity and selectivity, however, is changing this situation (8).

A case in point is work being done at the University of Wisconsin at Madison. Several years ago, Professor Clark Landis and his research group began a collaboration with Dowpharma (Midland, MI) to apply 3,4-diazaphospholane ligands to the problem of enantioselective hydroformylation. These compounds are easily synthesized by the condensation of primary phosphines with azines. With bisphospholane ligands, rapid hydroformylation of substrates such as styrene, allyl cyanide, and vinyl acetate is effected with high enantiomeric excess (89%, 90%, and 97%, respectively), high branch:linear ratios (20:1, 6:1, and 50:1, respectively) at rates similar to commodity scale, nonenantioselective hydroformylation. These results showing excellent selectivity have rekindled interest in the application of similar phosphine and phosphite ligands, many of which were developed for application in enantioselective hydrogenation, to asymmetric hydroformylation, including asymmetric hydroformylation of vinyl arenes.

References

1. P.L. Bonate et al.,”Discovery and Development of Clofarabine: A Nucleoside Analog for Treating Cancer,” Nat. Rev. Drug Discov. 5 (10), 855–863 (2006).

2. W.L. Bauta et al., “A New Process for Antineoplastic Agent Clofarabine,” Org. Process Res. Dev. 8 (6) 889–896 (2004).

3. “Lipoxin Analogs With Improved Performance,” Chem. & Eng. News 85 (46), 45 (2007).

4 P. Guiry et al., “Aromatic Lipoxin A4 and Lipoxin B4 Analogues Display Potent Biological Activities,” J. Med. Chem. 50 (24), 5894–5902 (2007).

5. Q. Chen et al., “Enzymatic Total Synthesis of Enterocin Polyketides,” Nat. Chem. Biol. 3 (9), 557–558 (2007).

6. I.C. Lennon, N.B. Johnson, and P. Moran, “Manufacture of Asymmetric Catalysts” Pharm. Technol. 31 Pharmaceutical Ingredients suppl., s6–s13 (2007).

7. P. Van Arnum, “Optimizing Strategies for API Synthesis and Formulation Development,” Pharm. Technol. 30 (11), 44–48 (2006).

8 P. Van Arnum, “Advances in Asymmetric Synthesis,” Pharm. Technol. 31 (9), 58–65 (2007).

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Guiry’s research group synthesized novel lipoxin-based molecules. The belief was that an analog could be synthesized with the potency of the lipoxins, but with improved chemical stability. “The challenge is to protect the molecules from the enzymes without altering their biological activity,” he explained.

With this goal, the group identified the region of the molecule essential for its biological function and tailored the nonessential region to make it evade enzymatic degradation. The strategy was that the novel molecules would retain the functions of Lipoxin A4 and Lipoxin B4, while the metabolic reactions that break the molecule down would be blocked, according to the release.

The research team used Sharpless epoxidation, Heck coupling, and diastereoselective reduction to synthesize a new set of lipoxin analogs. The analogs maintained the active carboxyl and hydroxy region of the lipoxins, but contain an aromatic ring in the part responsible for the metabolic activity (3, 4).

Biological testing of the lipoxin analogs was promising. “The Lipoxin A4 analog shows a significant increase of phagocytosis, comparable with the naturally occurring lipoxin, while the lipoxin B4 analog also stimulates phagocytosis,” said Guiry.

Further modification may increase the potency of the analogs by blocking other metabolic pathways. “Work is underway on the synthesis of other analogs and their subsequent biological evaluation. “Several chronic inflammatory conditions may be amenable to therapeutic intervention by stable synthetic lipoxin analogs,” he said.

Bayer Schering Pharma (Berlin, Germany), for example, has a lipoxin molecule in early-stage clinical development to treat inflammatory bowel disease.

Antibiotics

Earlier this year, researchers at the Scripps Institution of Oceanography at the University of California at San Diego and the Skaggs School of Pharmacy and Pharmaceutical Sciences reported success in synthesizing an antibiotic. Natural product sources typically have complex molecular structures that make them difficult to synthesize. The research focused on taking the enzymes that produce these chemicals inside cells and mimicking this process outside of a cell. The research carries the potential to develop new drugs by combining certain natural enzymes to produce new molecules that typically cannot be found in nature.

Qian Cheng and Bradley Moore of Scripps were able to synthesize an antibiotic that is naturally produced by a Hawaiian sea-sediment bacterium, according to a September 2007 press release. Specifically, the researchers reported the multienzyme total synthesis of the Streptomyces maritimus enterocin and Wailupemycin bacteriostatic agents in a single reaction vessel from benzoate and malonate substrates. The researchers believe that their results represent the first in vitro assembly of a complete Type II polyketide synthase enzymatic pathway to synthesize natural products (5).

“This study may signal the start of a new era in how drugs are synthesized,” said Moore, a professor in the Center for Marine Biotechnology and Biomedicine at Scripps. “Assembling all the enzymes together in a single reaction vessel is a different way to make a complex molecule.”

The antibiotic synthesized, enterocin, was assembled in approximately two hours. Such a compound would normally take months if not a year to prepare chemically, according to Moore.

Asymmetric synthesis

Asymmetric chemocatalytic methods, such as asymmetric hydrogenation, is an important tool to synthesize single enantiomer compounds. There are in excess of 3000 ligands known for asymmetric hydrogenation processes, although only a portion are truly available on a kilogram scale within a reasonable time frame (6). Several drugs recently approved by FDA are reported to use asymmetric hydrogenation in their manufacture. These include “Rozerem” (ramelteon) and “Aptivus” (tipranavir), both approved in 2005, “Januvia” (sitagliptin), approved in 2006, and “Tekturna” (aliskiren), approved in 2007 (6).

As contract manufacturers and pharmaceutical companies gather later this month for Informex in New Orleans, discussions of approaches for the synthesis of active pharmaceutical ingredients (APIs) and intermediates will invariably ensue. A review of several sources, including contract manufacturers, academicians, and recent literature reveals several interesting approaches in API synthesis. Nucleoside analogs

Nucleoside analogs have provided a rich structural class for the design of novel anticancer and antiviral drugs. “Leustatin” (cladribine) by Ortho Biotech and “Fludara” (fludarabine phosphate), developed by Berlex Oncology and now owned by Bayer Healthcare (Leverkusen, Germany), are two members of that class that were evaluated as potential anticancer agents. “While these were exciting discoveries, there was some initial concern in the discovery community that the glycosidic bond of those agents might prove too labile for ultimate utility in the clinic,” explains Stephen Munk, president and CEO of Ash Stevens (Detroit, MI). Ash Stevens is the contract manufacturer of fludarabine phosphate, the API in Fludara. While both of these agents were subsequently approved as drugs by various regulatory agencies, including the USFood and Drug Administration, that concern led scientists at the Southern Research Institute in Birmingham, Alabama, to consider analogs that would retain activity while affording a chemical structure with a glycosidic bond with enhanced stability, says Munk. Those studies led to the discovery by Secrist and Montgomery of a nucleoside analog now known as clofarabine (1).

Figure 1 ALL Figures Courtesy of US Food and Drug Administration

Clofarabine (see Figure 1) is the API in “Clolar,” an anticancer therapy developed by Ilex Oncology (San Antonio, TX). Ilex was acquired by Genyzme (Cambridge, MA) in December 2004. Clolar was approved by FDA in 2004 as a treatment for children with refractory or relapsed acute lymphoblastic leukemia.

Clofarabine is a second-generation adenosine-related antimetabolite. The original synthesis of clofarabine involved chromatography and was not adequately cost-effective or scalable. The task for improving the synthesis was to develop a new process that would avoid chromatography, produce a drug substance of high purity, and improve the cost-effectiveness of the manufacturing process (2).

Workers at Ilex Oncology (now part of Genyzme) and Ash Stevens developed a very efficient process that proved quite scalable (2). That process involved preparing a suitably protected bromosugar and coupling with chloroadenine in the presence of potassium tert-butoxide to afford protected clofarabine that had excellent anomeric purity following crystallization, explains Munk. Subsequent deprotection and further crystallization afforded clofarabine drug substance with minimal α-anomer as an impurity. “The process proved scaleable and avoided chromatographic purification steps, which can be very costly at plant scale,” says Munk. Ash Stevens successfully commercialized the process.

Lipoxins

Early this year, the Centre for Synthesis and Chemical Biology in Ireland reported progress in synthesizing novel lipoxin-based molecules that may be used as anti-inflammatory agents. The Centre for Synthesis and Chemical Biology is a collaboration in the chemical sciences between University College Dublin (UCD), Trinity College Dublin (TCD), and the Royal College of Surgeons in Ireland (RCSI). The UCD center forms part of the UCD Conway Institute of Biomolecular and Biomedical Research.

Lipoxins were first isolated in the 1980s. These molecules appear at the site of inflammation, leading researchers to believe that they are involved in the process and thus may have potential therapeutic applications. Some of the beneficial action ascribed to aspirin is now believed to be due to the formation of lipoxins. Both Lipoxin A4 and Lipoxin B4 have been detected in a variety of inflammatory conditions.

“Lipoxins have been shown to promote phagocytosis of the neutrophils,” said Pat Guiry, professor of organic chemistry at the UCD School of Chemistry and Chemical Biology, in an April 2007 press release. Reducing the number of neutrophils reduces the inflammation. “However the therapeutic potential of lipoxins is limited by reactions with enzymes in our bodies which break them down.”

Rockville, MD (Jan. 17)—Based on its investigation into the safety of over-the-counter (OTC) cough and cold drug products for children, the US Food and Drug Administration is recommending against such products for all children under two years of age. In a public health advisory, the agency cited the possibility of “serious and potentially life-threatening side effects” associated with these OTCs when administered to children.

During its investigation, FDA reviewed information it had received about serious side effects and the discussion and recommendations made at an October 2007 public advisory committee meeting. In a public statement, the agency said it “supports the actions taken by many pharmaceutical manufacturers to voluntarily withdraw cough and cold medicines that were being sold for use in this age group.” Because it was a voluntary recall, not all products were removed immediately.

According to a December 2007 New England Journal of Medicine article, consumers purchase nearly 95 million packages of OTC cough and cold preparations for children every year (1). These products include various combinations of antihistamines, decongestants, antitussives, and expectorants. “There is no standard for describing these products,” the authors state. “Two products marketed similarly may have different types of ingredients.”

FDA is currently completing its investigation into the safety of cough and cold OTCs for children between 2 and 11 years of age.

1. J.M. Sharfstein, M. North, and J.R. Serwint, “Over the Counter but No Longer under the Radar—Pediatric Cough and Cold Medicines,” N. Engl. J. Med. 357, 2321–2324.

Rockville, MD (Dec. 4)—The US Food and Drug Administration issued a rule that clarifies its requirements for current good manufacturing practices (CGMPs) for aseptic processing, water standards, and verifications standards. Notice of the rule was published in Federal Register.

FDA issued the rule as part of a process for amending certain regulations in an incremental approach to modifying GMPs for finished pharmaceuticals. These changes are designed to modernize or clarify some of the CGMP regulations and harmonize some requirements with those of foreign regulators.

Among other changes, the rule deletes the current requirement for adherence to a specific US Environmental Protection Agency water standard and instead simply requires that the plumbing system contain water that is “safe for human consumption.”

The rule also amends several aseptic-processing regulations to clarify requirements and reflect currently accepted practices. In some cases, the rule harmonizes the regulations with international regulatory standards. The revision to Sec. 211.113(b) applies specifically to the validation of aseptic processes. Other recommendations concern various types of processes and operations in addition to aseptic processes.

Comments are due 75 days after the publication of the rule, and the rule will be effective 135 days after publication. If FDA does not receive any significant comments during the comment period, the agency will publish a notice in Federal Register 105 days after Dec. 4 to confirm the effective date of the rule.

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Washington, DC (Dec. 11)—After a negative year in the news, China has finally agreed to improve the safety of its drug and food exports, according to the US Department of Health and Human Services (HHS).

Li Changjiang, minister of the General Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ) of the People’s Republic of China, and HHS Secretary Mike Leavitt signed two Memoranda of Agreement (MoA) on Dec. 11 in Beijing, just before the third session of the US–China Strategic Economic Dialogue began. The first MoA focuses on food and feed, the second on drugs and medical devices.

“Taken together, these agreements will enhance the safety of scores of household items the American people consume on a daily basis,” said Leavitt.

The agreement has three major components:

1. To promote information-sharing, all Chinese producers will register with Chinese authorities, who will then share the information with US regulators. In this context, China’s State Food and Drug Administration (SFDA) will inform US authorities if a Chinese facility fails inspection or loses certification, and US Food and Drug Administration officials will gain more access to Chinese production facilities.
2. To ensure safety, Chinese regulators will certify that food and feed covered by the agreement meets FDA standards.
3. To ensure compliance, the Chinese companies will adopt quality-assurance methods (e.g., electronic tracking systems for products).

According to Leavitt, the US will import $2 trillion worth of goods from 825,000 importers in 2008. “To keep up with the pace of global commerce, we need a fundamental shift, from trying to catch unsafe products as they come in, to building quality and safety into products before they reach our borders,” he said.

Leavitt submitted an Action Plan on Import Safety to President George W. Bush in November outlining this new approach, which is supported by the MoA. The plan was part of Leavitt’s work as chair of the Import Safety group, initiated last summer by Bush.

Chinese and US representatives began work on the MoA during the second session of the US-China Strategic Economic dialogue last May. The dialogue began this time last year to ensure “that citizens of both countries benefit equitably from our growing economic relationship and that we work together to address economic challenges and opportunities,” according to Bush’s statement on the initiative. The dialogue has been overcast by several reports of contaminated “made in China” products, including pet food, toothpaste, juice, and fish, throughout the world.

The MoA, however, promise to bring “concrete, measurable results” toward alleviating, and fielding off, this problem, said Leavitt.

To read the full US–China agreements, click here:
http://globalhealth.gov/news/agreements/ia121107b.html

http://globalhealth.gov/news/agreements/ia121107a.html

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