Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Informex, the exhibition of custom and batch manufacturers, which was held last month in Anaheim, California, provides an opportunity to review recent activity in the fine-chemicals and contract API market. In examining developments from 2012 and 2013 to date, companies are proceeding with select investments to build capacity and service capabilities. Highlights of some of this activity is outlined below. 

On the expansion side, Lonza reported on the first two build-out phases of its large-scale multpurpose 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. The company’s large-scale antibody drug conjugates project in Visp, Switzerland was finalized on schedule and the plant received FDA approval in the third quarter of 2012. A second expansion phase has started and will be finalized toward the end of the first half of 2014. Five additional high-potency API (HPAPI) laboratories in Visp, with capabilities for cytotoxic substances, are operational and utilized, and new investment in additional cytotoxic API manufacturing capacity in Visp was started up, according to the company. Lonza also increased peptide-manufacturing capabilities at it site in Braine, Belgium. 

Other companies are proceeding with investments and alliances to build HPAPI capabilities. In 2012, Carbogen Amcis and ADC Biotechnology announced a partnership to provide customers with development and manufacturing services for antibody drug conjugates. ADC Bio will provide access to proprietary solid-phase immobilization technologies for conjugation and long-term storage of antibody drug conjugates, and Carbogen Amcis will focus on small- to large-scale GMP supply and on the formulation of antibody drug conjugate. In October 2012, Fujifilm Diosynth Biotechnologies formed a strategic alliance with Piramal for antibody drug conjugate production, whereby the two parties will offer contract development and manufacture of ADCs. Piramal offers antibody drug conjugate production at its site in Grangemouth, Scotland. Fujifilm recently announced an expansion of its cGMP manufacturing facilities at its sites in Research Triangle Park, North Carolina, and Billingham, United Kingdom. Novasep announced in 2012 a $3.9-million (EUR 3 million) investment to expand its highly potent API manufacturing capabilities at its Le Mans, France, facility. The plant expansion is expected to be fully operational by the beginning of 2013. The new Le Mans facility adds to Novasep’s strategy for total synthesis of antibody drug conjugates.

 Other companies are proceeding with investment or recently made investments in 2012. Almac expanded its API manufacturing facility at its European Headquarters in Craigavon, United Kingdom, with a scheduled completion for end of 2012. This upgrade includes installation of two 1000-L reactors and a pressure-filter dryer, which allows production of GMP APIs up to 150-kg batch. Cambridge Major Laboratories (CML) is planning an expansion of its large-scale API manufacturing facility in Germantown, Wisconsin. The expansion comes three years after commissioning the new site. The expansion will include additional reactor capacity as well as isolation equipment. Alongside capacity additions, CML has made additional investments in engineering controls to ensure the sustainability of the business. Cedarburg Hauser Pharmaceuticals expanded the capacity of its Wisconsin-based API manufacturing plant as a result of an increased demand for contract manufacturing of commercial APIs as well as additional upgrades for improving safety and GMP systems. 

Dr. Reddy’s reports expansion in the areas of activated mPEG manufacturing and in the development and manufacture of APIs for use in preclinical through to commercial development at its manufacturing facility in Mirfield, United Kingdom. Also,in addition to its HPAPI capacity expansion, Novasep is investing EUR 30 million ($39 million) to build a chromatography plant for the production of large volumes of commercial APIs. The plant will be built on Novasep’s existing site in Mourenx, France, and is expected to be operational and validated within 18 months. The new plant will contain Varicol continuous chromatography systems with 1200-mm diameter columns operated at up to 70 bars. SAFC, part of Sigma-Aldrich, is expanding its operations in Scotland by investing in the development of a new powder-manufacturing facility on its Irvine site. SAFC’s new facility in Irvine is its second powder manufacturing facility, which will support SAFC’s risk-management program, providing an internal back-up supplier for its customers. The new facility will be used to service customers across Europe.

Almac and DSM Pharmaceutical Products, the custom manufacturing and technology business of Royal DSM, recently reported the successful transfer of enzymes for enzyme screening, process development and scale-up manufacture, as part of an October 2012 agreement in biocatalysis. The agreement grants both parties access to their enzyme platform technologies and services for the manufacturing of APIs. The collaboration also enables Almac to offer its customers a preferred partner for large-scale production. In other news, DSM Pharmaceutical Products  signed a collaboration agreement with Chemtrix in the field of continuous flow chemistry. The collaboration is intended to provide equipment, development, and manufacturing services to the pharmaceutical industry. 

Articles

Contract API manufacturers and fine-chemical producers proceed with select investment in capacity and service additions.

Fine-Chemical Producers Outline Expansion Plans at Informex

In keeping with overall pharmaceutical industry rends, recent growth in the global API market has slowed although the overall market is still increasing at a moderate pace. Led by India and China, Asia Pacific has had the recent highest growth in the API market although North America and the US remain the largest markets, respectively, on a regional and country basis in the global market. Generic APIs are outpacing growth for branded, innovator APIs. On a global supply basis, China remains the largest producer of generic APIs, largely for its domestic market as well as the largest exporter of APIs on global basis, primarily to emerging markets. Italy retains its historical position as the largest supplier of generic APIs to both Western Europe and the US although India’s position as a supplier to developed market is on the rise.

 The global API market (including both the merchant market and the captive market) was valued at $113 billion in 2012, up from $91 billion in 2008, according to a recent report, 

 by the Chemical Pharmaceutical Generic Association (CPA), an organization representing Italian API manufacturers (1). The captive API market is defined as APIs used by pharmaceutical companies for in-house production of finished dosage forms, and the merchant API market is defined as APIs sold by third parties. From 2008–2012, the global API market grew at an average annual rate of 5.6% compared to an annual growth rate of 7.2% from 2004–2008. The slowing market is attributable to factors affecting the pharmaceutical industry as a whole: slowing global economic growth, increased pricing pressure due to cost-containment policies adopted by most countries, increased competition from generic drugs, higher risk of pipeline failures with elevated costs for drug discovery, and increasing competition from low-cost producing countries. 

On a geographic basis, the highest growth rate for APIs between 2008 and 2012 was in Asia-Pacific (excluding Japan), which experienced average annual growth rate of 13.9%, followed by the Middle East with 8.7% average annual growth, and Eastern Europe and the Commonwealth of States (CIS) with 8.2% average annual growth, according to the CPA report (1). The developed markets in Western Europe, North America, and Japan had slower annual growth rate. Western Europe’s API market had the lowest annual average growth rate, 2.5%, followed by Japan at 3.4% and North America at 3.8%. (1). 

On an absolute basis, however, North America is still the largest API market (including both captive and merchant markets) followed by Asia Pacific although Asia Pacific is gaining ground. The North America share of the global API market declined three percentage points between 2008 and 2012 as the share of Asia Pacific increased. North America’s share was 43% in 2012, down from 46% in 2008. Asia Pacific’s share was 28.3% in 2012, up from 24.2% in 2008, according to the CPA report (1). The US remains the largestglobal market on a country basis, accounting for 39.7% of the global API market in 2012. 

These market positions change, however, if looking at the generic API merchant market alone. Led by China, Asia Pacific accounted for 39.6% of the global generic API merchant market in 2012. China is the largest consumer on a country basis of generic APIs in the merchant market, accounting for 23.7% of the global total, surpassing the North American market as a whole (21.9%) and the US (20.4%). Between 2008–2012, China registered the fastest annual average growth rate in the generic API merchant market at 13.2%, followed by India at 11.9%. Collectively, the two countries accounted for 29.7% of the global generic API merchant market, according to the CPA report (1).

During 2008–2012, the global captive API market grew at a slightly higher rate comparative to the global merchant market and is larger on an absolute basis. In 2008, the global captive API market was valued at $55 billion and rose to $69 billion in 2012, representing average annual growth of 5.8%, according to the CPA analysis. The global merchant API market was valued at $36 billion in 2008 and increased to $44 billion in 2012 91). 

. Within the global merchant API market, the generic API market is outpacing the branded, innovator API market. The global generic API merchant market was valued at $17 billion in 2008 and rose to $22.5 billion in 2012, representing average annual growth of 7.3%. In 2012, the global branded, innovator API merchant market was valued at $21.5 billion, slightly less than the generic market. Annual average growth in the global branded, innovator API merchant market between 2008 and 2012 was 3.1%, less than half of growth in the generic API merchant market.

The strength of the generic API merchant market is expected to continue. Overall, the generic API merchant is expected to increase at an average annual rate of 7.7% from $22.5 billion in 2012 to $30.6 billion in 2016. The market in Asia Pacific is projected to increase at 10.8% during the next four years, making it the fastest growing region in the generic API merchant market.  By 2016, China is expected to account for 27.7% of the global generic API merchant market, making it the largest market and surpassing the US, which will be the second largest global market with a 18.2% share. India will remain as the third largest merchant market for generic APIs with a projected 7.2% by 2016, according to the CPA report (1) Ten emerging markets are projected to experience double-digit growth of 10% to 14% in the generic API market. These countries include Brazil, China, Egypt, India, Jordan, Pakistan, South Africa, Thailand, Turkey, and Vietnam (1). 

. Western Europe ranks second behind Asia Pacific in the supply of generic APIs on a global basis, but its market share declined from 16.7% in 2008 to 14.2% in 2012. Italy remains the largest producer of generic APIs in Western Europe, accounting for 58.3% of the region’s total, followed by Spain at 21%. Italy is also the largest supplier of generic APIs to the US market. Italian API producers accounted for 31.2% of the supply to the US generic API market in 2012, and their growth in supplying the US increased at an annual average growth of 5.2% between 2008 and 2012. India is the second largest supplier of generic APIs to the US market with a 24.4% share, according to the CPA report. India is also increasing its supply to Western Europe, accounting for 19.2% of the supply to the region (1).

 In Asia Pacific, China is the largest generic API producer, with its domestic market representing its strength. Between 2008 and 2012, overall API production in China increased at an average annual rate of 7% from $6.43 billion in 2008 to $8.44 billion in 2012. During this period, sales to China’s domestic increased at an average annual rate of 11% while export growth increased only 5.8%. Sales to emerging markets represented the largest target for China’s API export sales, accounting for 63.1% of production. China’s export sales to developed markets (North America, Western Europe, and Japan) accounted for 36.9% of overall export sales and 24.7% of total API production, according to the CPA report (1). Overall, China ranks as the largest producer of generic APIs in the world and the largest exporter of APIs, followed by India. 

But unlike China, whose domestic market is the largest target for its API production, India relies heavily on export sales. India’s API production was valued at $4.70 billion in 2012, up from $2.27 billion in 2008. India’s supply to the US market has increased at an average annual rate of 44% between 2008 and 2012, increasing from $255 million in 2008 to $1.12 billion in 2012 (1).


 1. Chemical Pharmaceutical Generic Association (CPA), 

 (Milan, March 2013), www.cpa-italy.org/en/indexen.php.

Supply-demand fundamentals show strong growth for generic APIs as gains in innovator APIs lag.

The Weaknesses and Strengths of the Global API Market

	Biopharmaceutical production is an often discussed application for single-use technologies, but single-use technologies also have application for small-scale finished drug-product manufacturing for producing clinical-trial materials. An educational webcast by

Accelerate Sterile and Non-Sterile Clinical Trial Manufacturing with Single-Use Technologies

,” on Wednesday Mar. 6th examines this application.

	Single-use technologies for producing clinical-trial materials may offer several advantages. Pharmaceutical products manufactured with non-dedicated equipment are at risk of being contaminated with traces of the previous product manufactured. This risk is reduced by equipment-cleaning regimes and cleaning verification/validation programs. Single-use disposable systems eliminate the risk of cross-contamination and reduce time and costs while meeting safety requirements for clinical-trial scale batches.

, which will be broadcast live at 11:00 AM EST on Wednesday, Mar. 6, will focus on how single-use technologies improve the economics of manufacturing clinical-trial supplies for both sterile and nonsterile products. Although single-use disposable technologies have been widely adopted for sterile products, they have been used less often for nonsterile products, but can be equally effective and can lead to additional time- saving programs for Phase I clinical-trial materials. The webcast will provide case studies demonstrating the benefits and limitations of single-use disposable systems by focusing on single-use systems for sterile product manufacturing and for tablet and capsule manufacturing.

	Audience members will be able to ask questions during the live webcast on Wednesday Mar. 6th at 11:00 AM EST. Additionally, the webcast will be available for on-demand viewing. Additional information on the webcast and how to register may be found 

Biopharmaceutical production is an often discussed application for single-use technologies, but single-use technologies also have application for small-scale finished drug-product manufacturing for producing clinical-trial materials.

The Next Horizon: Single-Use Technologies for Finished Drug Product Manufacturing

Emerging markets are an important part of the pharmaceutical majors' growth strategy. As these markets become of increasing strategic value,  pharmaceutical companies are ramping up investment in R&D and  manufacturing (API and finished drug product) in these areas. 

Emerging markets are playing an increasingly important role in overall pharmaceutical industry growth. The global market for medicines is expected to rebound from a recent low of 3-4% growth in 2012 to 5-7% growth in 2016, according to a July 2012 analysis by the IMS Institute for Healthcare Informatics. Growth will primarily be from emerging markets as growth in established markets in the United States, Western Europe, and Japan remains weak comparative to historical levels. Overall, annual global spending on medicines will rise from $956 billion in 2011 to $1 trillion by 2013, and to nearly $1.2 trillion in 2016, representing a compound annual growth rate (CAGR) of 3% to 6%. For purposes of the IMS analysis, spending is reported as ex-manufacturer prices and does not reflect off-invoice discounts and rebates and is converted from local currencies to US dollars. Absolute growth in global pharmaceutical spending between 2012-2016 will be between $220 billion and $250 billion, compared with $298 billion in the prior five years. 

Growth in annual global spending is forecast to more than double in 2016 to as much as $70 billion, up from a $30-billion pace in 2012, driven by volume increases in what IMS terms the "pharmerging" markets and some uptick in spending in developed nations. The "pharmerging" markets are defined by IMS as countries with greater than $1 billion in absolute spending growth between 2012-2016 and that have gross domestic product per capita of less than $25,000 at purchasing power parity. Using that criteria, China is classified as a Tier-1 country, and Brazil, Russia, and India as Tier-2 countries. Tier 3-countries are Mexico, Turkey, Poland, Venezuela, Argentina, Indonesia, South Africa, Thailand, Romania, Egypt, Ukraine, Pakistan, and Vietnam.  

IMS projects that healthcare systems in pharmerging markets will nearly double their medicine spending over the next several years. Annual spending on medicines in the pharmerging markets will increase from $194 billion in 2011 to between $345 billion and $375 billion by 2016, or $91 in drug spending per capita, according to IMS. The increase will be driven by rising incomes, continued low cost for drugs, and government-sponsored programs designed to increase access to treatments. Generic drugs and other products, including over-the-counter medicines and diagnostics will account for approximately 83% of the increase.  

Among the emerging markets, the BRIC (Brazil, Russia, India, and China) countries represent the largest areas of pharmaceutical industry growth. China's pharmaceutical market was valued at $66.7 billion in 2011 and is expected to reach between $155 billion and $165 billion by 2016, representing a CAGR of 15% to 18% between 2012-2016, according to IMS. Brazil's pharmaceutical market was valued at $29.9 billion in 2011 and is expected to reach between $42 billion and $52 billion by 2016, representing a CAGR of 12% to 15% from 2012-2016. Russia's pharmaceutical market was valued at $15.7 billion in 2011 and is forecast to be between $23 billion and$33 billion by 2016, representing a CAGR of 10% to 13% from 2012-2016. And India's pharmaceutical market was valued at $14.3 billion in 2011 and is expected to reach between $24 billion and $34 billion by 2016, representing a CAGR of 14% to 17%, according to IMS.  

Based on these projections, China will move into second place in the global pharmaceutical market by 2016, surpassed only by the United States, which will continue to hold the number one position on a global basis, according to IMS. Brazil will move into fourth place, India into eighth place, and Russia into ninth. Among developed markets, Japan will drop from the second largest global market to the third by 2016. Germany and France will each drop a notch, from fourth and fifth, respectively, in the global rankings in 2011, to fifth and sixth in 2016 as projected by IMS. Italy will stay in seventh spot in 2016, the same position it occupied in 2011. The developed markets of Spain, Canada, and the United Kingdom, respectively ranked as eighth, ninth, and tenth in 2011, will be eclipsed by Russia and India in the global rankings by 2016, according to IMS projections.  

. The pharmaceutical majors are pursuing direct investment in R&D and manufacturing as well as partnership strategies in emerging markets (1-2). Some recent investment in China by the pharmaceutical majors includes  Hisun-Pfizer Pharmaceuticals, a joint venture formed between Pfizer and the Chinese pharmaceutical company Zhejiang Hisun Pharmaceuticals with the aim to develop, manufacture, and commercialize off-patent pharmaceutical products in China and other  markets. In May 2012, Sanofi inaugurated a new assembling and packaging line for producing its prefilled insulin injection pen Lantus SoloStar at its facility in Beijing. The company announced a second phase $90-million project to install a cartridge aseptic product line at the facility. 

Novartis has been actively building its position in China. In 2007, Novartis opened a start-up facility for a new R&D center in Shanghai, China, and broke ground in 2008 on Phase I of a new facility that was originally to be home to approximately 400 R&D scientists and approximately 400 other pharmaceuticals division personnel. In 2009, it expanded the scope of the site with plans to invest $1 billion during the next five years to increase the size of its operations in Shanghai. Based on a re-evaluation of the site conducted in 2010, the current Phase 1 has been extended by two buildings. The cross-divisional Shanghai campus will house 800 offices and 400 laboratory workplaces 

In 2012, Eli Lilly opened a new diabetes R&D center in Shanghai. The center employs 150 scientists and staff hired primarily from China. Eli Lilly also is constructing a new insulin production, packaging, and warehouse facility in Suzhou, China, which was schedule to open in late 2012. In June 2012, Eli Lilly announced an expansion of its manufacturing capabilities in China through an expanded collaboration with Novast Laboratories, a generic-drug and specialty pharmaceutical company based in Nantong, China. The collaboration will enhance Lilly's efforts to build a portfolio of Lilly branded generic medicines in China, and eventually may be used to provide regional manufacturing support for Lilly's pipeline of products in development. 

For Roche, a key project included transforming its manufacturing facility for solid dosage forms in Shanghai from a local to a global supply operation. In early 2011, the facility received FDA and EMA approvals to produce Xeloda (capecitabine) for the US and EU markets. 

Unlike other BRIC countries, such as India and China, which have a domestic manufacturing base, Russia is largely dependent on pharmaceutical imports. Its domestic biomedical industry accounts for only 0.2% of the global market, but the country is committed to change that level through an ambitious program, Pharma 2020. Pharma 2020, a state-initiated plan, seeks to boost output of local medicines from 25% of gross sales in 2010 to 50% by 2020, upgrade domestic pharmaceutical manufacturing operations to GMP standards, and increase the level of innovator pharmaceuticals in the Russian market (3). Several pharmaceutical majors are increasing their presence in Russia with manufacturing and R&D investment (1-2). 

In September 2012, Takeda Pharmaceutical completed construction of a EUR 75 million ($99 million), 24,000-m

  pharmaceutical manufacturing facility in Yaroslavl, Russia. The plant, which is approximately 280 kilometers from Moscow, is one of the first by a major multinational company in Yaroslavl's pharmaceutical cluster. The facility is expected to be fully operational by 2014.  

The Yaroslavl facility will enable Takeda to meet demand in Russia initially for several products: Cardiomagnyl (acetylsalicylic acid and magnesium hydroxide), Actovegin (derived from calf blood), and calcium tablets. The plant will have the initial capacity to manufacture 90 million sterile ampuls and more than two billion tablets per year. Liquid-sterile production includes solution preparation, washing of ampuls, sterilization, filling, inspection, and packaging. Solid production will encompass all stages, from weighing, mixing, and granulation through compression, coating, and packaging. Takeda estimates that it is the seventh largest pharmaceutical company in Russia and expects company annual growth rate of 15% in Russia through 2016.  

In April 2012, Novo Nordisk broke ground on a new $100-million plant in Russia that will formulate and fill insulin into Novo Nordisk's Penfill cartridges and pack the FlexPen prefilled insulin delivery device for the Russian market. Located in Grabtsevo Technopark in the Kaluga region, the plant is expected to start manufacturing in 2014. The company's intention to establish insulin production in Russia was first announced in 2010. At that time, an agreement of cooperation between the government of the Kaluga Region and Novo Nordisk was signed. Sanofi also recently increased insulin capacity at its facility in Orel, Russia. Sanofi obtained the facility following its acquisition of a controlling stake in the pharmaceutical company Bioton Vostok in 2010. 

Novartis is proceeding with a new $140-million manufacturing plant for pharmaceuticals and generic drugs in St. Petersburg, Russia. The plant is expected to produce approximately 1.5 billion units per year (oral solid dosage forms). The greenfield facility is in the Novoorlovskaya Special Economic Zone located to the north of the St. Petersburg city center. Novartis began construction of the facility in 2011. The facility is expected to be completed and approved for commercial production in 2014. 

The facility is part of a five-year, $500-million investment into Russian healthcare infrastructure announced by Novartis in December 2010. This plan addresses three core areas: local manufacturing, R&D collaborations, and public health development in Russia. These activities include collaborations with academia and emerging Russian private businesses in different areas of medical science. The scope of these collaborations may include efforts, such as out-licensing of Novartis compounds to Russian companies with proven scientific capabilities, in-licensing and scouting for promising drug candidates from Russian scientists and universities, and modeling and simulation activities for clinical trials. Novartis is working in all of these areas to identify high potential projects to be jointly developed. Additionally, Novartis also has made a commitment to double its investments in drug development in clinical trials in Russia and expects to enroll approximately 4000 individuals by 2013, said the company in announcing its plans in December 2010. 

In 2011, AstraZeneca announced plans to establish a Predictive Science Center in St. Petersburg, the company's first such center in Russia. The center will focus on developing bioinformatices, data-analysis methods, software, and systems to evaluate safety and efficacy of new drugs. Approximately 30 people will be employed at the center through local collaborations and organizations. Also in 2011, AstraZeneca began construction of a new $150-million manufacturing facility in the Kaluga region in Russia to supply locally produced medicines. The company also has partnerships with several R&D institutes in Russia, including the  Skolkovo Innovation Center and Russia Venture Company, for research and clinical trials. 

In July 2012, Pfizer granted exclusive development and marketing rights to the Russian firm SatRx for its dipeptidyl peptidase-4 (DPP-4) inhibitor PF-00734200 for Type 2 diabetes.SatRx, which is part of the ChemRar Hi-Tech Center, received worldwide rights (excluding China) to the drug as a monotherapy or in combination with other diabetes drugs. Pfizer will receive royalties and milestone payments based on commercialization activities. The agreement was developed as partial fulfillment of a memorandum of understanding reached in March 2011, under which Pfizer and ChemRar agreed to explore collaborations focused on research, development, and commercialization of compounds and vaccines to treat cardiometabolic, infectious and oncologic diseases in Russia and other countries. 

In 2010, GlaxoSmithKline formed an alliance with JSC Binnopharm for the local secondary manufacture of several GSK vaccines. Under this alliance, which was announced in November 2010, GSK is supplying bulk vaccine and providing technology and expertise to enable Binnopharm to undertake the secondary manufacture, including filling and packaging of GSK vaccines. Binnopharm will be responsible for gaining approval of their facilities to allow supply of GSK cervical cancer, rotavirus, and pneumococcal vaccines under Binnopharm's trademark for the Russian public market. 

	3.	G. Peach, "Russia Pledges $4 billion for Pharma-2020 Plan," 

As the strategic value of emerging markets increase, pharmaceutical companies increase their R&D and manufacturing investments.

Navigating the Global Manufacturing Supply Chain

As biopharmaceutical/pharmaceutical companies increase their development of biologic-based drugs, companies providing analytical instrumentation and laboratory testing goods and services are, in turn, offering improved tools for biologic characterization, biomanufacturing, and related testing.  

In December 2012, Sartorius Stedim Biotech (SSB) expanded its process analytical technology software capabilities by partnering with Umetrics, a provider of multivariate technology, including software for design of experiments (DoE) and multivariate data analysis (MVA). Under the pact, SSB assumes global marketing and distribution of the Umetrics portfolio for the pharmaceutical and biopharmaceutical industries and will integrate Umetrics software programs as private-label products into its own bioprocess portfolio and market these as stand-alone solutions under a dual branding arrangement. The major areas for these software systems are critical process steps, such as cell-culture processes or specific purification steps. MVA enables process parameters to be added in batch trajectories, and DoE software permits these critical process parameters to be identified and quantified. 

In January 2013, Waters expanded its biopharmaceutical platform solutions with UNIFI, new ACQUITY ultra-performance liquid chromatography (UPLC) CSH130 C18 and XSelect HPLC CSH130 C18 columns for peptide mapping, and three GlycoWorks kits for glycan labeling and sample preparation. These products further progress routine biotherapeutic analysis, particularly for glycoproteins that require analysis of glycan modifications as well as protein- and peptide-level structural analysis. The biopharmaceutical platform solution brings together UPLC/mass spectrometry (MS) characterization technology with the UNIFI Scientific Information System that was first developed for intact protein mass analysis, peptide mapping, and supporting general bioseparations. The expansion supports a mix of quadrupole time-of-flight (Q-TOF) MS and optical-detection instruments within a networked laboratory workgroup. The newly released Glycan application workflow expands the platform's capabilities to support routine assignment and profiling of released glycans using fluorescence detection. The combination of high-performance UPLC HILIC (hydrophilic interaction liquid chromatography) separations, the company's calibration standards and reagents, and access to Ireland's National Institute for Bioprocessing Research and Training (NIBRT)/Waters' GlycoBase 3+ UPLC glycan unit reference database enables glycan assignments, quantification, and profiling. Developed by Prof. Pauline Rudd's research team at NIBRT, the GlycoBase 3+ database is a repository of glycan chromatographic retention data, expressed in glucose calibration units, and which encompasses sets of glycan structures associated with biotherapeutic glycoproteins. 

Also in January 2013, PerkinElmer launched the JANUS BioTx Pro automated workstation for improved process development of proteins. The workstation is designed for high-throughput, small-scale protein purification (of µg to mg proteins) and accommodates multiple chromatography modes (column, tip and batch). It supports commercially available plate and column-based screening tools, such as GE PreDictor plates, PhyNexus PhyTip columns, and Atoll columns. Applications for the workstation include resin-binding studies and conditions screening. 

In May 2012, Shimazdu launched an improved Accurate Glycan Analyzer 2 (AGA2), which provides a glycan database and the company's AXIMA Resonance, a MALDI (matrix-assisted laser desorption/ionization)–QIT (quadrupole ion trap)–TOF (time of flight) mass spectrometer. The AXIMA Resonance is coupled to a database containing glycan structural information generated from actual MS

  spectra to select precursor peaks up to MS

 . The resulting spectra are interpreted to return the most likely glycan structure. The AGA2 was created from biosynthesized glycans and contains well-defined and characterized, biologically relevant, glycans. It also uses common fluorescence-labeling schemes, including 2-aminopyridine, 2-aminobenzoic acid and 2-aminobenzamide, and other types of fluorescence labeling. 

In February 2013, Thermo Fisher Scientific expanded its high-content analysis portfolio with three new solutions in cell biology: the Thermo Scientific ArrayScan XTI High Content Analysis (HCA) Reader, Thermo Scientific CellInsight NXT High Content Screening (HCS) Platform, and the Thermo Scientific X1 upgrade for current ArrayScan VTI customers. Each of these products features a large-format, sensitive CCD (charged-coupled device) camera, the Thermo Scientific HCS Studio software suite, and greater processing capabilities. The Thermo Scientific X1 CCD camera, used for high-content analysis, offers improved sensitivity, increased resolution, and a large field of view. 

Thermo Fisher Scientific also introduced the Thermo Scientific Dionex GlycanPac AXH-1 HPLC column, which is designed for simultaneous separation of biologically important glycans based on charge, size, and polarity. The column is designed to separate both labeled and native glycans based on the availability of samples. Native glycan separation allows researchers to eliminate the fluorescent labeling step and increase throughput.  

In 2012, Agilent Technologies partnered with Spain's Center for Omic Sciences in mass spectrometry and NMR (nuclear magnetic resonance)-based metabolomics and automation for use in integrated systems biology. The Center for Omic Sciences (COS) was established by the Rovira i Virgili University in collaboration with Spain's Technological Center of Nutrition and Health. COS opened in September 2012 and is equipped with instrumentation from Agilent. The COS is a center of excellence where Agilent will demonstrate integrated biology workflows in genomics, proteomics, transcriptomics, lipidomics, and metabolomics. 

In November 2012, Bruker launched METALJET, a bright microfocus X-ray source for structural biology applications. METALJET is a source option for D8 VENTURET protein crystallography systems and for NANOSTAR Small Angle X-ray Scattering (SAXS) systems. The METALJET source for Bruker structural biology systems was developed in collaboration with Excillum AB and Incoatec GmbH for use in protein crystallography and SAXS applications. 

Instrument manufacturers and testing service providers are offering improved tools to biologic charaterization.

Advancing analytical testing and instrumentation for biopharmaceuticals

When FDA announced in 2002 a new initiative, 

Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century

Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach

, in 2004, it began an effort to enhance product quality and modernize pharmaceutical manufacturing through a science- and risk-based approach under quality-by-design (QbD) principles (1). That effort was further encouraged by the issuance of guidance on process analytical technology (PAT) in 2004 to facilitate new technologies that would enhance process understanding and assist in identifying and controlling critical points in a process (2). These technologies include: appropriate measurement devices, which can be placed at-, in-, or on-line; statistical and information technology tools; and a scientific-systems approach for data analysis to control processes to ensure production of in-process materials and final products of desired quality (1–4). Lyophilization is one specific application of QbD and PAT in parenteral drug manufacturing, and a review of recent literature shows several developments in this field.  

 In applying QbD to the lyophilization process, the first task is to define the parameters that have the potential to affect process performance and product-quality attributes (5). Key points include the freeze-drying process operating parameters, formulation parameters, equipment, and component preparation and devices (5). PAT may be applied through sensors at various stages in freeze-drying, which may include using temperature sensors, pressure-rise analysis, manometric temperature measurements, calorimetry, microscopy, and spectroscopic techniques, such as near-infrared (NIR), Raman, and infrared spectroscopy (6). 

An established approach for PAT in lyophilization is offered by SP Scientific's SMART freeze-dryer technology, which is used to optimize the freeze-drying cycle. The SMART technology was developed by the University of Connecticut and Purdue University through the Center for Pharmaceutical Processing Research and licensed to SP Scientific. The technology relies on the use of manometric temperature measurement, which calculates the product temperature at the sublimation interface without having to place thermocouples or other temperature sensors in product vials (7). The SMART freeze-dryer technology is used on SP Scientific's Lyostar 3 development freezer. The SMART technology uses information, such as the number of vials, fill volume, fill weight, freeze-dryer chamber volume, and critical formulation temperature to optimize a cycle (8). It contributes to several key points in lyophilization: selects an optimum freezing cycle based on whether the formulation is crystalline or amorphous; selects the optimum chamber pressure; determines the target temperature of the product; and adjusts the shelf drying during primary drying to keep the product at a predetermined target temperature (8).  

SP Scientific has partnered with the industrial-gas company Praxair for another PAT-based tool for lyophilization, Praxair's ControLyo Nucleation on Demand Technology, used to control the nucleation of the product solution in the freeze dryer. The companies first partnered in 2010, which gave SP the exclusive, global rights to commercialize the technology on development lyophilzers. In 2012, the companies expanded their collaboration to allow SP Scientific to equip its clinical, pilot, and production dryers with theControLyo Technology and to transfer the technology to allow SP to retrofit existing pilot and production units. 

IQ Mobil Solutions, based in Holzkirchen, Germany, offers wireless and battery-free temperature sensors (Temperature Remote Interrogation System, TEMPRIS) as a PAT tool for lyophilization. In a recent study, the TEMPRIS system was assessed for measurement accuracy, capability of accurate endpoint detection, and effect of positioning by using product runs with sucrose, mannitol and trehalose (9). Data were compared to measurements with 36-gauge thermocouples and to noninvasive temperature measurement from manometric temperature measurements. The results showed that the TEMPRIS temperature profiles agreed with thermocouple data when sensors were placed center bottom in a vial. In addition, TEMPRIS sensors revealed reliable temperature profiles and endpoint indications relative to thermocouple data when vials in the edge position were monitored (9). 

Researchers at Ghent University in Belgium used Raman and NIR spectroscopy as PAT tools in a freeze-drying process (10). For the study, Raman and NIR probes were built in the freeze-dryer chamber to allow simultaneous process monitoring of a 5% (w/v) mannitol solution. Raman and NIR spectra were continuously collected during freeze-drying and analyzed using principal component analysis and multivariate curve resolution (10). Raman spectroscopy provided data about the mannitol solid state, the endpoint of freezing, and several physical and chemical conditions (e.g., onset of ice nucleation and onset of mannitol crystallisation). NIR spectroscopy monitored key points in drying, the endpoint of ice sublimation, and the release of hydrate water during storage (10). A later study further examined the use of in-line spectroscopic process analyzers (Raman, NIR, and plasma emission spectroscopy) (11).   

 Another recent study examined the use of tunable diode laser absorption spectroscopy (TDLAS) for monitoring secondary drying in laboratory-scale freeze-drying with the purpose of targeting intermediate moisture contents in the product (12). An earlier study examined TDLAS to determine the average product temperature in primary drying (13). 

Researchers recently implemented and evaluated an optical-fiber system as a process-monitoring tool during lyophilization. The study recorded temperature profiles of mannitol, sucrose, and trehalose using various prototypes of optical fiber sensors (OFSs) (14). The data were compared to data obtained with conventional thermocouples or Pirani/capacitance manometry with respect to the endpoint of primary drying. The researchers reported that the data obtained with the OFS in contact with product were in good agreement with data obtained by thermocouples or Pirani/capacitance manometry. The OFSs showed higher sensitivity, faster response, and better resolution compared to thermocouples (14). Another study examined the use of a soft sensor for in-line monitoring of the primary drying step of a freeze-drying process in vials (15). 

Pharmaceutical CGMPs for the 21st Century—Risk-Based Approach: Final Report

Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance

Progress Report on Process Analytical Technology

www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswer-sonCurrentGoodManufacturingPrac-ticescGMPforDrugs/ucm072006.htm

 5. F. Jameel and W.J. Kessler, "Real-time Monitoring and Controlling of Lyophillization Process Parameters Through Process Analytical Technology Tools," in 

PAT Applied in Biopharmaceutical Process Development and Manufacturing: An Enabling Tool for Quality by Design, 

C. Undey et al., Eds. (CRC Press, Taylor & France, Boca Raton, FL, 2012), pp. 241-243.   

 6. R.B. Shah et al., "Scientific and Regulatory Overview of Process Analytical Technology in BioProcesses," in 

PAT Applied in Biopharmaceutical Process Development and Manufacturing: An Enabling Tool for Quality by Design,

 C. Undey et al., Eds. (CRC Press, Taylor & France, Boca Raton, FL 2012), p. 5.  

 7. D. Sesholtz and L. Mather, "'Smart Freeze Drying," 

www.biopharma.co.uk/wp-content/uploads/2010/07/Smart_Freezedrying_article_2007

 8. . Shon, "Optimization of Primary Freeze-Drying Cycle Times," 

www.iptonline.com/pdf_viewarticle.asp?cat=7&article=887

 DOI 10.1016/j.ejpb.2012.10.009, 15 Nov. 2012.  

 15. S. Bosca, A.A. Barresi and D. Fissore, 

 DOI 10.3109/10837450.2012.757786, Jan. 22,  2013.  

Applying quality-by-design and process analytical technology facilitates process understanding and control of various operations in lyophilization.