Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

World leaders met in late September 2013 in New York at the United Nations (UN) to examine the progress and future direction of the UN Millennium Development Goals (MDGs), a set of eight goals to improve social and economic conditions of people living in developing countries. Three of the eight MDGs specifically address health-related outcomes in improving children's health, reducing maternal mortality, and addressing diseases endemic to the developing world, such as malaria, tuberculosis (TB), and HIV/AIDs, and a fourth goal encourages partnerships to resolve these challenges as well as help realize the other MDGs. The pharmaceutical industry has been a key stakeholder, particularly through the use of public–private partnerships, to address global health issues and help realize the health-related MDGs. 

At the UN meeting, world leaders agreed to scale up action against extreme poverty, hunger, and disease and called for a 2015 summit to adopt the next set of goals to continue efforts after the target date for the MDGs in 2015 and also noted progress thus far. A joint statement by the World Health Organization (WHO), the United Nations Population Fund (UNFPA), UNAIDS (a joint UN program on HIV/AIDS), UNICEF, and the UN Secretary General’s Special Envoy for Financing the Health MDG, summed up progress thus far. "Over the past 12 and a half years, the world has made remarkable progress against the goals, especially the health-related MDGs. Child and maternal deaths have been almost halved from 1990 levels. Malaria deaths have dropped 50%, driven largely by the distribution of over 400 million mosquito nets in the past several years. Over 6 million people, of the 9 million who need TB treatment, are now on treatment. HIV, once a death sentence with virtually no one on treatment, has undergone a dramatic shift with almost 10 million people on treatment today; and if we can finish the job and put everyone on treatment, we will irreversibly halt the AIDS epidemic. These results are unmistakable proof that success is possible. Now we must come together in one final big push to achieve the health MDGs and lay the strongest of foundations for a post-2015 world." 

 A recent UN report examined the progress of achieving the health-related MDGs. MDG 4 seeks to reduce children mortality, and a recent UN report outlines gains made thus far. Worldwide, the mortality rate for children under five dropped by 47% from 90 deaths per 1000 live births in 1990 to 48 in 2012. Despite this accomplishment, more progress is needed to meet the 2015 target of a two-thirds reduction in under-five mortality, according to the UN report. In 2012, an estimated 6.6 million children—18,000 a day— died from mostly preventable diseases. Increasingly, child deaths are concentrated in the poorest regions—sub-Saharan Africa and Southern Asia accounted for 5.3 million (81%) of the 6.6 million deaths in children under five worldwide. The main killers are pneumonia, preterm birth complications, diarrhea, intrapartum-related complications, and malaria. Newborns account for almost half (44%) of under-five deaths. Also, undernutrition contributes to 45% of all under-five deaths. On the positive side certain countries are making progress. Bangladesh, Ethiopia, Liberia, Malawi, Nepal, Timor-Leste, and the United Republic of Tanzania have lowered under-five mortality rates by two-thirds or more since 1990, according to the UN report. 

MDG 5 is directed to reduce by three-quarters, between 1990 and 2015, the maternal mortality ratio and by 2015, to achieve universal access to reproductive health. Maternal mortality declined by 47% on a global basis over the last two decades and declined by two-thirds in Eastern Asia, Northern Africa, and Southern Asia. The UN report points out that only half of pregnant women in developing regions receive the recommended minimum of four prenatal care visits, and complications during pregnancy or childbirth are one of the leading causes of death for adolescent girls. Most maternal deaths in developing countries are preventable through adequate nutrition, proper health care, including access to family planning, the presence of a skilled birth attendant during delivery and emergency obstetric care. 

In terms of progress, maternal mortality has declined by nearly half since 1990. While progress falls short of achieving MDG 5 by the 2015 deadline, all regions have made important gains, according to the UN report. Globally, the ratio declined from 400 maternal deaths per 100,000 live births in 1990 to 210 in 2010. "Still, meeting the MDG target of reducing maternal mortality by three-quarters will require accelerated efforts and stronger political backing for women and children," according to the UN. Improving maternal health is also key to achieving MDG 4 of reducing child mortality. 

MDG 6 has a target to halt and begin to reverse, by 2015, the spread of HIV/AIDS and to achieve universal access to treatment for HIV/AIDS for all those who need it as well as to halt and begin to reverse by 2015, the incidence of malaria and other major diseases. Worldwide, the number of people newly infected with HIV dropped 33% from 2001 to 2012, but 2.3 million people are newly infected by HIV each year, with 1.6 million of them in sub-Saharan Africa, according to the UN report. The MDG target of halting and beginning to reverse the spread of HIV has been met. In addition a record 9.7 million people living with HIV were accessing treatment in 2012 compared to just over 8.1 million in 2011, an an increase of 1.6 million in one year alone. Global malaria deaths fell by an estimated 26% from 2000 to 2010. More than half of the 1.1 million lives saved were in the 10 countries with the highest malaria burden. The TB mortality rate decreased 41% between 1991 and 2011. Still, TB killed 1.4 million people in 2011, including 430,000 among people who were HIV-positive. Multidrug-resistant TB is a major global challenge. Progress is being made in increasing the percentage of cases being detected, but the rate of people accessing treatment needs to improved. 

With more than 220 global partnerships addressing a wide range of diseases and focusing on prevention, improvements in health system infrastructures, training, pharmaceutical R&D, and medicine and vaccine donations, the pharmaceutical industry has played  an important role in advancing progress toward the health-related MDGs. A  recent analysis by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) shows that  partnerships and accountability frameworks between civil society, the private sector, and governments can promote more equitable, inclusive, and sustainable development. 

"To maximize the impact of private-sector action on global health goals, we need proactive, cross-sector engagement in framing the next set of development goals," said IFPMA Director General Eduardo Pisani, in an IFPMA press statement. "The original MDGs were conceived without a clear map as to how the private sector could contribute. Pharmaceutical companies came to the fore anyway, recognizing the criticality of their unique contributions. But we know that there is no sector—not government, not civil society, not industry—that can alone drive the system-wide change that is required to address the most intractable health."

In its report, IFPMA highlighted key information on the 220 health partnerships in which the research-based pharmaceutical industry is involved. One of two programs is focused on strengthening health-systems infrastructure. Seven-nine percent focus on training, 38% on awareness raising, prevention, and outreach, and 36% on improving availability of treatments. With respect to specific health targets, 20% of the partnerships focus on HIV/AIDS, 16% on neglected tropical diseases, 16% on women's and children's health, 14% on malaria, and 14% on noncommunicable diseases. On a geographic basis, Tanzania, Kenya, Uganda, India, and South Africa respectively represented the five largest recipient countries, but partnerships are active globally. Sub-Sahara Africa accounts for 146 partnerships, East Asia and Pacific 80 partnerships, and South Asia 76 partnerships. Latin America and the Caribbean account for 71 partnerships, the Middle East and North Africa 39, Europe and Central Asia 38, and North America nine pacts, according to the IFPMA report. 

Articles

The United Nations discusses the progress in achieving the UN Millennium Development Goals and sets a path for post 2015, and the pharmaceutical industry offers its input.

Pharma Industry and WHO Chart Progress on UN Millennium Development Goals

The expectations between a sponsor company and contract service provider define not only the nature of the outsourced relationship but also dictate the quality of the material being supplied or service provided. Quality agreements between contract manufacturers and their pharmaceutical customers are a well-established practice. Recent draft guidance by FDA brings quality agreements into greater focus by applying the science- and risk-based approach inherent in quality risk-management principles and practices. Industry groups and pharmaceutical companies have offered their input of the draft guidance

Contract Manufacturing Arrangements for Drugs: Quality Agreements

, in May 2013 to describe the agency’s current thinking on defining, establishing, and documenting the responsibilities of parties involved in contract cGMP manufacturing of drugs (1). The draft guidance describes how parties involved in contract manufacturing of drugs can use quality agreements to delineate their responsibilities and ensure drug quality, safety, and efficacy. The guidance applies to the commercial manufacturing of APIs (drug substances or their intermediates), finished drug products, combination products, and biological drug products (1). Moreover, the quality agreements described under the draft guidance fit within the larger scheme of pharmaceutical quality systems and provisions of ICH guidelines, including ICH Q7 

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients 

(1–4). In the draft guidance, FDA specifies that the principles of quality management extend to contract manufacturing, and that the agency FDA expects parties engaged in contract manufacturing to implement quality-management practices. The draft guidance is intended to build upon the quality-management principles in ICH guidelines in developing and executing contracted-manufacturing arrangements (1-4). Public comment on the draft guidance ended at the end of July 2013, and the pharmaceutical industry weighed in on the guidance with several major pharmaceutical companies and industry groups offering comments.

  One concern raised by several companies and industry groups was that the draft guidance did not adequately address developmental activities. The Biotechnology Industry Organization (BIO) offered the following comment: “The Draft Guidance applies to commercial manufacturing of product. However, BIO notes that quality agreements are equally important during the development phase. They are a useful tool to provide both thoughtful consideration of reasonable quality expectations based on the item being procured and to provide standards during development and manufacturing. Limiting the guidance to commercial manufacturing may lead contract manufacturers to conclude that such agreements are unnecessary during drug development.” 

BIO suggested that the guidance be further applied to investigational products. “We ask FDA to consider expanding the scope of the guidance to include quality agreements for investigational product during the development phase. Contract manufacturing of drugs may also be subject to good laboratory practices (GLPs) as applicable. While the Draft Guidance is appropriately focused on good manufacturing practices (GMPs), it does not appear to allow for a contract laboratory to perform certain tests in accordance with GLPs. BIO asks that the Guidance recognize that manufacturing of drugs may also be subject to GLPs and therefore, are also included in the scope of the Guidance.” AstraZeneca also concurred that the guidance and related provisions on quality agreements should include GLPs.

 The Parenteral Drug Association (PDA) further suggested that the scope of the guidance include developmental activity. “Since it is common for virtual companies to use contracted parties in all phases of development, it would be valuable if the guidance could be extended to include manufacture of clinical trial materials.” To this end, PDA suggested a clarification to the language in the draft guidance. “For purposes of this guidance, while the term commercial manufacturing does not include research and development activities or the manufacture of material for clinical trials or treatment Investigational New Drugs (INDs), or for veterinary investigational files (INADs or JINADs), the principles and concepts outline herein could be applied and it would be a best practice to have a quality agreement in place for these drugs prior to start of manufacture of any drug intended for human or animal use.”

The Active Pharmaceutical Ingredient Committee (APIC) of the European Chemical Industry Council (CEFIC) also suggested the inclusion of clinical trial materials with respect to the guidance. “As such trials [clinical trials,], especially Phase III could eventually be used in commercial production plus the level of GMP needs to increase through the different stages of clinical trials, we feel the guidelines should give guidance on the requirements for a quality agreement for such activities.” 

Further refinements of quality agreements 

Other groups and pharmaceutical companies suggested further refinements to the draft guidance. PDA suggested further emphasis on the collaborative relationship between CMOs and owners. “PDA commends FDA on writing this guidance which highlights common gaps which have occurred in the past between CMOs and Owners and clearly points out many elements of current best industry practic. PDA suggests that FDA further emphasize in this guidance, the importance of establishing a collaborative relationship between the parties in addition to clearly assigning and defining the appropriate responsibilities.” 

PDA also made suggestions as to the quality agreement itself. “In some instances the guidance appears to be asking that the Quality Agreement include listings of parts of the CMO’s quality system. We recommend clarifying that the intent is for the Quality Agreement to assign responsibilities to parties by general categories rather than a restatement of individual GMP elements. PDA also recommends against requiring specific procedures to be included in the Quality Agreement since such an approach might inhibit the effective functioning of either party’s quality system with respect to continual improvement.” 

PDA also suggested the guidance include measures relating to audits in a quality agreement. “A initial quality system audit of the Contract Acceptor should precede the signing of a Quality Agreement. During this audit, the Contract Giver is responsible for verifying and accepting (or rejecting) the Contract Acceptor’s quality system and the ability of the Contract Acceptor to meet GMPs. With this approach, the purpose of the Quality Agreement should then be limited to defining the roles and responsibilities for the specific product(s) processes and activities covered by the agreement. The Quality Agreement should also address responsibilities of each party in subsequent audits such as how to schedule, notice, response and corrective actions.” 

 The International Society for Pharmaceutical Engineering (ISPE) recommended that additional key quality elements be included in the scope of the guidance, including a subsection for exception-related events and outcomes and the involvement of the “Owner” in the decision to rework, reprocess, re-inspect product, and product acceptance as these issues are critical aspects as part of the “Owner’s” management oversight of the Contract Facility. ISPE also suggested additional items to be considered for scope inclusion: a subsection for Complaints and Safety Events that includes direction around timeliness, responsibilities and communication; a subsection for field action/recall roles and responsibilities; and a definition section to clearly define specific terms. 

Bristol Myers Squibb (BMS) noted that the quality agreement should also indicate how the parties will communicate information about presenting cross-contamination and maintaining traceability when a contracted facility processes or tests drugs for multiple product owners.  “The product Owner and Contracted Facility might opt to refer to existing documentation or procedures or the presence of such documents verified during the qualification of the facility,” noted BMS. 

Industry comments also focused on definitions used in the draft guidance. For purposes of the draft guidance, the “owner” is defined as the party that introduces the drug into interstate commerce, whether the drug is covered by a marketing application/license or not. The “contracted facilities” are the outside entities performing manufacturing operations for the product owner. Some of the manufacturing operations performed by contracted facilities include: formulation, fill–finish, chemical synthesis, cell-culture manufacturing and fermentation for biological products, analytical testing, other laboratory services, and packaging and labeling. The draft guidance specifies that the owner is responsible for ensuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected contracted facilities. In turn, all contracted facilities must ensure compliance with applicable cGMP for all manufacturing, testing, or other support operations performed to make a drug(s) for the owner (1). 

Merck & Co.  noted that draft guidance covers only pure CMO arrangements, but that pharmaceutical companies are involved in many hybrid forms of contracts, such as in-licensing, comarketing, reciprocal CMO, joint ventures, public-private partnerships, and clinical supply partnerships It noted that the current definition of “owner” in the draft guidance “is ambiguous in contracts that are not pure CMO arrangements. A less ambiguous approach would be to define “Owner” as equal to the Marketing Authorization Holder. In reality, this references the party that is “the lead,” has the principle pharmaceutical liability, and is responsible for all interactions with the Health Authorities. 

 The Consumer Healthcare Product Association, which represents manufacturers of over-the-counter products, also noted issues with the definition of “owner.” “The term owner and its definition do not address the complex license agreements that can arise is today’s pharmaceutical supply chain. Due to the complexities of licensing agreements, there are situations where the ‘ownership” of the application or of the intellectual property rights for the product is different from the contract given, “said CPHA. “For example, a company may license from the application holder the distribution rights and may also take responsibility for the supply of the product. In such as case, the distributor would contract with the contract manufacturer and would enter into a quality agreement. However, such a distributor would own neither the application nor the intellectual property. It is not clear who would be the ‘owner in such an arrangement. If the holder of the application in such an arrangement is a small business that discovered the product, it might not have the expertise or resources to oversee a manufacturer.” 

The Bulk Pharmaceuticals Task Force of the Society of Chemical Manufacturers and Affiliates suggested clarification that the term “contract manufacturing” apply to those activities for a specific customer.  “API manufacturing and its associated activities is composed of custom businesses that are exclusive for specific customers and non-custom businesses that are nonexclusive for a range of customers. A high level of oversight of change control and deviations is appropriate for the former. In the latter case, such a level of oversight and approval is unmanageable....This guidance is appropriate for a custom business but not for a noncustom business.” 

 Pfizer noted the work of ICH in addressing measures in the guidance and to ensure that there is alignment between the draft guidance and specific ICH measures. “The ICH Q7 IWG (Implementation Working Group) is preparing a Q&A that will address much of the same concerns as outlined in this guidance (the first round of questions are loaded with expectations of contract manufacturing quality units, etc.). Suggest holding this guidance as draft to assure alignment and minimize confusion/implementation.” 

Draft Guidance for Industry–Contract Manufacturing–Arrangements for Drugs Quality Agreements 

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 

Pharmaceutical companies and industry organization provide comments to FDA's draft guidance on contract manufacturing and quality agreements.

Pharma Industry Comments on FDA's Draft Guidance for Contract Manufacturing

Quality is crucial to ensure drug safety. A review of FDA’s enforcement reports and related information from September 2013 highlights issues relating to vial-filling, adequacy of quality assurance/quality control (QA/QC) procedures, particulate matter in inhalation powders and injectables, and drug labeling.  


  AstraZeneca and Bristol-Myers Squibb reported in September 2013 that they voluntarily recalled approximately 92,000 vials of their jointly marketed Type 2 diabetes treatment, Bydureon (exenatide extended-release injectable suspension), in several European countries because some vials were not fully filled.

The affected batches were recalled in the United Kingdom, Germany, Romania, the Netherlands, Ireland, Sweden, Finland, and Spain, according to Bristol-Myers Squibb. The Bydureon recall was issued after a review of manufacturing records indicated at least one of the batches may have had a very small number of underfilled vials, according to a Sept. 16, 2013 alert distributed by the UK Medicines and Healthcare products Regulatory Agency (MHRA).

 The affected batch (C164827) was a 4 x 1 single-dose kit (1 vial and 1 syringe) with an expiration date of Aug. 31, 2015. It was first distributed on July 12, 2013. The low fills affect approximately 0.2% of the batch and range between 30% and 75% of the labeled dose. No batches distributed in other markets were affected, and the companies don’t expect any supply issues. There is little evidence that patient safety would be compromised as a result of injecting an underfilled vial, and any health consequences would likely be minimum, according to Bristol-Myers Squibb.

Bydureon is part of the diabetes alliance between AstraZeneca and Bristol-Myers Squibb. Bristol-Myers Squibb acquired Bydureon through its 2012 acquisition of Amylin Pharmaceuticals. AstraZeneca and Bristol-Myers Squibb formed a diabetes alliance in 2007 for certain drugs and later expanded that collaboration following Bristol-Myers Squibb’s acquisition of Amylin to include the diabetes portfolio of Amylin, including Bydureon.
  
  


  FDA issued an import alert under which US officials may detain at the US border drug products manufactured at Ranbaxy Laboratories’ facility in Mohali, India. The firm will remain on the import alert until the company complies with US cGMPs, according to a Sept. 16, 2013 FDA statement. 
  
  FDA also ordered that the Mohali facility be subject to certain terms of the consent decree of permanent injunction entered against Ranbaxy in January 2012. The decree contains provisions to ensure cGMP compliance at certain Ranbaxy facilities, including in Paonta Sahib and Dewas, India, as well as provisions addressing data-integrity issues at those two facilities. Ranbaxy’s Paonta Sahib and Dewas facilities have been on FDA import alert since 2008. FDA exercised its authority under a provision in the consent decree permitting it to order that terms of the decree be extended to a Ranbaxy-owned or operated facility if an inspection determines that the facility is in violation of the Federal Food, Drug, and Cosmetic Act or FDA regulations, including cGMPs.

In September and December 2012, FDA inspections identified cGMP violations at Ranbaxy’s Mohali facility, including failure to adequately investigate manufacturing problems and failure to establish adequate procedures to ensure manufacturing quality.

Under the decree, Ranbaxy is prohibited from manufacturing FDA-regulated drugs at the Mohali facility and introducing drugs into interstate commerce, including into the United States, from the Mohali facility until the firm’s methods, facilities, and controls used to manufacture drugs at the Mohali facility are established, operated, and administered in compliance with cGMPs. Ranbaxy is required to hire a third-party expert to conduct an inspection of the Mohali facility and certify to FDA that the facilities, methods, processes, and controls are adequate to ensure continuous compliance with cGMPs. Once the agency is satisfied that Ranbaxy has come into compliance with cGMPs, Ranbaxy will be permitted to resume manufacturing and distribution of FDA-regulated drugs at the Mohali facility. 
  
  

Particulate matter in inhalation powders 


  Boehringer Ingelheim Roxane, based in Columbus, Ohio and a subsidiary of Boehringer Ingelheim, initiated a voluntary nationwide recall in the United States of certain lots of its Spiriva HandiHaler (tiotropium bromide inhalation powder) capsules, 18 mcg per dose (prescription only), according to FDA’s weekly enforcement report of Sept. 25, 2013. Spiriva is used to treat chronic obstructive pulmonary disease. The Class III recall was initiated on Aug. 30, 2013 due to the potential for extrinsic foreign particles in the API used to manufacture Spiriva Handihaler. The product distribution quantity was 15,385,232 capsules, according to the FDA report. The recall applies to several products types: a 10-count blister (NDC 0597-0075-27), 30-count blister (NDC 0597-0075-41), 90-count blister (NDC 0597-0075-47), and 5-count blister physician sample (NDC 0597-0075-75). A Class III recall refers to products that are unlikely to cause any adverse health reaction, but that violate FDA labeling or manufacturing laws. 
  
  


  A federal judge approved a consent decree of permanent injunction against Shamrock Medical Solutions Group, Lewis Center, Ohio, and four of its corporate officers and employees for continued drug manufacturing and labeling violations that resulted in the distribution of mislabeled drugs, according to a Sept. 18, 2013 FDA press statement. Shamrock Medical repackaged and distributed solid and liquid oral nonsterile drug products for human use to hospitals throughout the United States. FDA reported that inspections found several violations at the facility, including failure by the quality control unit to fully follow its own QC procedures and to examine packaged and labeled products to ensure correct labeling. The FDA previously had sent warning letters to Shamrock Medical for violating cGMPs and distributing incorrectly labeled drugs. The September 2013 announcement followed an FDA alert issued in April 2013 advising healthcare providers to remove drugs distributed by Shamrock Medical from supply stock due to the possibility that they were mislabeled. The warning covered many nonsterile medications and dosage forms, including tablets, vials, ophthalmic and otic solutions, and patches. 


  FDA reported on Sept. 13, 2013 that Hospira had initiated on July 12, 2013 a voluntary nationwide recall to the user level for one lot of 0.25% bupivacaine HCl injection, USP (2.5 mg/mL), 30-mL single-dose vial (NDC 0409-1159-02). An expanded recall was issued on Aug. 29, 2013 for one lot of 0.75% bupivacaine HCl injection, USP (7.5 mg/mL), 30-mL single-dose vial(NDC 0409-1165-02). Bupivacaine is indicated for the production of local or regional anesthesia or analgesia. Both recalls were due to confirmed customer reports of particulate floating and/or embedded in the glass vial, according to FDA. The particulate was identified as stainless steel ranging in size from 542 microns to 1700 microns in Lot 18-136-DK (0.25% bupivacaine) and as iron oxide with an average size of 2000 microns in Lot 23-338-DK (0.75% bupivacaine). 

Hospira also initiated a voluntary recall of propofol injectable emulsion, 1%, 200 mg/20 mL (10 mg/mL), packaged in 5 units x 20 mL single-patient infusion vials per carton (prescription only), according to a Sept. 18, 2013 FDA enforcement report. The Class II recall was initiated on Aug. 14, 2013 due to visible particulate embedded in the glass vial being observed and confirmed in a sample bottle during sample inspection. The product distribution quantity was 283,150 vials. 

Recent FDA enforcement activity reveals issues with vial-filling, adequacy of QA/QC procedures, particulate matter in inhalation powders and injectables, and drug labeling.

Tracking Quality in Drug Manufacturing

Fluorine-based compounds play an important role in pharmaceuticals. It is estimated that up to 20% of pharmaceuticals on the market or in clinical development contain a fluorine atom, and 30% of key blockbuster drugs contain fluorine (1). Given the importance of fluorine-based molecules in drug development, chemists must overcome challenges associated with fluorination of small molecules.


  Researchers at the University of California at Berkeley and Stanford University in California reported on their elucidation of engineered polyketide synthase pathways as a means to produce organofluorines (2). The researchers engineered two changes into Escherichia colibacteria that had previously been engineered to make polyketides (2, 3). In their work, the researchers showed that a pathway for producing fluoroacetate can be used as a source of fluorinated building blocks for introducing fluorine into natural-product scaffolds. Specifically, they constructed pathways involving two polyketide synthase systems and showed that fluoroacetate can be used to incorporate fluorine into the polyketide backbone 

. The researchers further showed that fluorine can be inserted site-selectively and introduced into polyketide products 

. The researchers asserted that their work shows the potential of producing complex fluorinated natural products using synthetic biology (2, 3).


Researchers at the University of North Carolina at Chapel Hill reported on their work involving catalytic enantioselective cyclization and C3-fluorination of polyene (4, 5). The researchers reported that xylyl-phanephos) Pt

 mediates the consecutive diastereoselectivecation-olefin cyclization/fluorination of polyene substrates (5). The researchers reported that isolated yields were typically in the range of 60-69%, and enantioselectivities reached as high as 87%. The researchers noted that the data were consistent with a stereoretentive fluorination of a P

Pt-alkyl cation intermediate (5). The researchers detailed a [Pt]-catalyzed method for first cyclizing polyenes and then selectively fluorinating at the C3 position using XeF

. The addition of TMS-OMe to scrub adventitious HF provided a procedure that gave isolated yields as high as 80% and enantioselectivities up to 87% (4, 5). The researchers proposed a mechanism by which the substrate undergoes a [Pt]-initiated cascade cyclization to generate an intermediate [Pt]-alkyl, which is observed as the catalytic resting state. This compound reacted with XeF

faster than ß-H elimination to give the desired fluorinated product with a stereochemistry that is retentive at the original C3-Pt position (4, 5). 


Tobias Ritter, a professor of chemistry in the Department of Chemistry and Chemical Biology at Harvard University  in Cambridge, Massachusetts, and his team, recently reported on their work involving palladium(III)-catalyzed fluorination of arylboronic acid derivatives. The researchers noted that developing practical carbon−fluorine bond-forming reactions to provide aryl fluorides is challenging. The researchers reported on a palladium-catalyzed fluorination of arylboronic acid derivatives, which allowed for an operationally simple, multigram-scale synthesis of functionalized aryl fluorides (6). The researchers proposed that the reaction mechanism involved a single-electron-transfer pathway involving a palladium (III) intermediate that was isolated and characterized. According to the researchers, the kinetic studies suggested a mechanism distinct from other known arene fluorination reactions without forming organopalladium species and offers an advantage over other metal-catalyzed or -mediated arene fluorination reactions. The researchers noted the reaction does not produce side products from protodemetalation, a common problem in synthesizing aryl fluorides (6), but the reaction had certain drawbacks, such as the inability to fluorinate heterocycles and form constitutional isomers for some electron-poor substrates (6).

Carbon-fluorine bond formation is an active area of research by Ritter and his group. Carbon-fluorine bond formation is a challenging chemical transformation, particularly for functional group-tolerant, late-stage fluorination of arenes (7). The researchers’ approach uses high-valent transition metal fluorides by means of oxidation of aryl transition metal complexes with electrophilic fluorination reagents (7). The group’s long-term goal is to develop new methods for the synthesis of small-molecule tracers for positron emission tomography (PET), an imaging method to study biological processes in vivo. PET with the isotope 18F is currently limited by the absence of general chemistry that can introduce fluorine into molecules at a late stage, and carbon-fluorine bond formation using high-valent transition metal fluorides via oxidation of aryl transition metal complexes with electrophilic fluorination reagents is one approach to resolve that challenge (7-9).

Ritter and his team also developed an approach for silver-catalyzed late-stage fluorination using a cross-coupling reaction that attached fluorine atoms onto aromatic substituents. The reaction used silver oxide to catalyze the fluorination of aryl tin compounds with the electrophilic fluorinating reagent N-chloromethyl-N-fluorotriethylenediammonium hexafluorophosphate. The researchers asserted that the reaction was the first example of silver catalysis for carbon-heteroatom bond formation by cross-coupling chemistry (9, 10). 

Carbon-fluorine bond formation by transition-metal catalysis is difficult. Typically, transition metal-catalyzed fluorination reactions for synthesizing functionalized arenes use palladium as the metal in the catalyst (9, 10). A key benefit of the silver-catalyzed fluorination reaction is the variety of functional groups that can be tolerated and breadth of substrates used. The researchers applied the cross-coupling reaction to fluorinate polypeptides, polyketides, and alkaloids and showed tolerance by various functional groups, including vinyl ethers, dienones, alcohols, allylic alcohols, ethers, esters, and oxetanes (9, 10).


G.K. Surya Prakash, professor of chemistry at the University of Southern California (USC) and director of the USC Loker Hydrocarbon Research Institute, and his team reported on their work in using fluoroform (CF

H) in the direct nucleophilic trifluoromethylation of silicon, boron, sulfur, and carbon centers (11). Fluoroform is a byproduct of the manufacture of polytetrafluoroethylene (Teflon), refrigerants, polyvinylidene fluoride, and other products. Although fluoroform has little practical use, the trifluoromethyl (-CF3) functionality is important for pharmaceuticals (11). The researchers elucidated the conditions needed to convert fluoroform into useful reagents, including the silicon-based Ruppert-Prakash reagent for efficient (-CF3) transfer. Fluoroform with elemental sulfur was also converted to trifluoromethanesulfonic acid, a widely used superacid, according to a Dec. 7, 2012 USC press release. Specifically, the researchers reported on a direct trifluoromethylation protocol using close to stoichiometric amounts of CF

H in common organic solvents, such as tetrahydrofuran, diethyl ether, and toluene. The researchers reported that the approach can be applied to a variety of silicon, boron, and sulfur-based electrophiles as well as carbon-based electrophiles.


  Researchers at the RIKEN Advanced Science Institute in Wako, Japan reported on their work on the copper-catalyzed trifluoromethylation of allylsilanes (12). Trifluoromethylation of allylsilane derivatives was achieved using CuI and Togni’s reagents under mild conditions. Specifically, the researchers developed a synthesis technique that selectively and efficiently combined fluorine and amino acids into the same organic molecule, according to a Sept. 28, 2012 RIKEN Advanced Science Institute press release. The starting materials were alpha-keto esters that contained a carbonyl group and an ester group. The first reaction involved the substitution of a hydrogen atom, on the carbon atom adjacent to the carbonyl group, for a fluorine atom, resulting in two enantiomers for which a palladium-based catalyst was used to preferentially produce one of the enantiomers, thereby making the reaction enantioselective. The carbonyl group of the fluorinated alpha-keto ester was then transformed to a hydroxyl group with two possible stereoisomers, for which one stereoisomer could be preferentially produced by using different reagents. The technique not only introduced fluorine, but two stereogenic centers to the molecule. Forming two stereogenic centers created the possibility of four different stereoisomers, which were subsequently isolated in separate reaction sequences. The researchers’ future interests involve widening the fluorination reaction to other starting materials, according to the release. 

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  12.	M. Sodeoka et al., 

Fluorinated molecules play an important role as pharmaceutical compounds. Recent advances seek to overcome the challenges of selective and late-stage insertion of fluorine into small molecules.

Overcoming Challenges in Fluorine-Based Chemistry

The wage gap between advanced economies and emerging economies, such as China, India and the Philippines is expected to decline significantly by 2030, according to a recent analysis by PricewaterhouseCoopers (PwC). 

India and the Philippines remain at the lower end of wage projection in relative terms, but average wages in India could more than quadruple over the period in real dollar terms and more than triple in the Philippines, according to a Sept. 26th PwC press release. Real wages in the United Kingdom and the United States are projected to rise by only one-third over the same period, remaining at similar levels to each other. 

PwC projects that the wage gap could close significantly by 2030. For example, India’s current average monthly wage is approximately 25 times smaller than that of the UK. By 2030, that wage gap will still exist, but will be only 7.5 times smaller. Average wages in US are currently 7.5 times greater than in Mexico, but the gap could close to a factor of less than four times by 2030. Over the same time period, the average monthly Chinese wage could rise to around half that of Spain, according to PwC. 

In looking further at projected average monthly wage levels relative to the US, PwC further outlines the narrowing gap. For example, monthly wage rates in China in 2011 represented 15% of monthly wage levels in the US, but by 2020, China's average montly wage levels rises to 29%o of that of US wages and to 45% by 2030. Monthly wage rates in India in 2011 represented 4% of monthly wage levels in the US, but by 2020, India's average monthly wage levels rises to 8%o of that of US wages and to 13% by 2030. 

“While any such projections are subject to significant uncertainties, the direction of change is clear. The large wage advantages enjoyed today by many emerging economies will shrink as their productivity levels catch up with those in advanced economies and their real exchange rates rise as a consequence," said John Hawksworth, chief economist at PwC. "Places like Turkey, Poland, China and Mexico will therefore become more valuable as consumer markets while low-cost production could shift to other locations such as the Philippines. India could also gain from this shift, but only if it improves its infrastructure and female education levels and cuts red tape.” 

PwC suggests that this narrowing wage gap have several important strategic implications. First, companies may re-shore their manufacturing or service operations, as some US companies have already started to do, or move them to cheaper locations. Moreover, as current large cost advantages decline, companies may move to locations that are initially more expensive but that closer to home, thereby gaining more control over supply chains to respond to customers’ changing needs. In addition, middle-income economies, such as Turkey, Poland, and China may begin offshoring to relatively cheaper economies, such as Vietnam, India and the Philippines, according to the PwC report. Lastly, current Western offshorers (to India and China, for instance) will reorient their operations to sell their goods and services to increasingly affluent local populations. 

"It's inevitable that the manufacturing and services industries in countries will transform as the cost base evolves, and also that there will be winners and losers," said Michael Rendell, PwC partner and Global Human Resource Services leader, in the release. "Governments, regulators and business communities need to be ready for that shift." 

A recent analysis by PricewaterhouseCoopers projects that the wage gap between advanced economics and emerging economies, such as China and India, will shrink significantly by 2030.

Emerging-Market Wage Gap Projected to Narrow

With China’s pharmaceutical market expected to reach $161 billion by 2016, according to estimates by IMS Health, the major pharmaceutical companies and contract service providers are investing in China to build their development and manufacturing capabilities. 

Several large pharmaceutical companies are investing in China. In September 2013, Boehringer Ingelheim inaugurated the expansion of its manufacturing plant and the building of its chemicals R&D laboratory Center of Competence in the Zhangjiang High-Tech Park in Shanghai. The EUR 70-million ($95-million) investment makes the Zhangjiang plant one of Boehringer Ingelheim’s most important sites in the Asia Pacific region, according to the company.  The number of employees will rise to 350, and the production capacity is expected to triple by 2018. The future vision is to make the Shanghai plant a competitive regional supply site in Boehringer Ingelheim’s global operations network. The project consists of a packaging center with space for packaging lines, new quality-control laboratories, and an automated warehouse and logistics. The main technologies are solid forms (tablets) and liquids (syrups) with a future output of more than 150 million packages in 2016 and up to 220 million in 2018. In addition, the company has built a new facility for the Center of Competence, which has been relocated from Waigaojiao to this new site. This chemicals R&D laboratory, which started operation in 2010, specializes in optimizing processes and analytical testing of APIs and chemical intermediates procured from Boehringer Ingelheim’s strategic partners in China. 

Earlier this year, Merck & Co. opened a new $120-million, 75,000-m

pharmaceutical manufacturing facility in Hangzhou, China. The facility has capacity of up to 16 high-speed lines to package pharmaceutical tablets and sterile products. Annual packaging capacity is more than 300 million packages. The facility builds on other recent investment by Merck in China. In 2011, the company established its Asia R&D headquarters in Beijing and committed to invest more than $1.5 billion in R&D in China during the next several years. 

Novartis is moving ahead with an expansion of its research facilities in China. In 2009, Novartis announced it was investing $1 billion to increase its R&D operations in Shanghai. Based on a re-evaluation of the site conducted in 2010, the company expanded its Phase 1 plan to include two buildings to house 800 offices and 400 laboratory work places. As of Dec. 31, 2012, structural work was finished, and the first above-ground buildings began to be built.  

In Shanghai, Roche is investing CHF 260 million ($278 million) for ongoing expansion of its pharmaceutical facilities, including new laboratory, warehouse, office, and training facilities, to be completed in 2014. In 2012, Sanofi opened a new facility for assembly and packaging of SoloSTAR, the company's prefilled injection system for Lantus (insulin glargine). In 2012, Pfizer formed a joint venture with China's  Zhejiang Hisun Pharmaceuticals for developing, manufacturing, and commercializing off-patent pharmaceutical products in China and global markets. Also, Amgen announced in September 2013 that it had entered into a memorandum of understanding (MOU) with ShanghaiTech University to form a strategic partnership for the advancement of biopharmaceutical discovery and translational research in China. This agreement includes plans for Amgen to open a China R&D center at ShanghaiTech University. Under the terms of the MOU, Amgen will colocate its China R&D center with ShanghaiTech University's two life-science institutes: the Shanghai Institute for Advanced Immunochemical Studies (SIAIS) and the iHuman Institute. Amgen expects its China R&D center will be fully operational in 2014.

Reflecting the increased presence of pharmaceutical companies in China, CMOs are expanding in China on both the API and finished product side. Earlier this year, Catalent formed two joint ventures in China, one for its softgel technologies business and one for its clinical-supply-solutions business. In softgels, Catalent acquired, a majority share in the Haining-based and privately held Zhejiang Jiang Yuan Tang Biotechnology, which produces nutritional softgel products for the Chinese and Asia Pacific markets. In a separate move, Catalent, and ShangPharma Corp., formed a new joint venture, which includes a new 31,000-ft

 facility in Shanghai. The facility, currently under construction, will offer capabilities in clinical-trial supplies, including comparator sourcing, primary and secondary packaging and labeling, storage, and distribution. The facility is scheduled to open later this year. 

 production plant in Nantong, China. The company broke ground for the new facility in July 2013. The plant will begin commercial production in mid-2014 and employ a workforce of about 300 by 2015. In 2012, Lonza proceeded with the first of two build-out phases of its large-scale multipurpose cGMP API plant in Nansha, China, following FDA approval of several customer projects in late 2011. Also, a new cGMP kilo-laboratory in Nansha and an additional small-scale manufacturing train were successfully brought on line. 

West Pharmaceutical Services, a provider of solutions for injectable-drug administration, started up its compression-molding plant in the Shanghai Zhangjiang High-Tech Industrial Development Zone Qingpu Park in China. The new plant is adjacent to West’s injection-molding facility that was dedicated in September 2009. The 11,900-m

 compression-molding plant manufactures components used for packaging injectable drug and primarily supplies customers in China and the Asia Pacific region. Construction began in June 2011. 

Contract service providers position in China as biopharmaceutical and pharmaceutical companies align their strategies in emerging markets for growth.