Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

As pharmaceutical and biopharmaceutical companies intensify product development in biologics, they are tasked with meeting the challenges of biologic-based drug development and manufacturing. Unlike traditional small-molecule drugs, stability studies for biopharmaceuticals can be one of the most critical and challenging aspects of large-molecule drug development. The size and complexity of most proteins provide fertile ground for intramolecular changes and multiple routes of degradation, and to assess their effects, each must be correlated to the bioactivity of the drug. 

will examine biopharmaceutical stability studies in more depth by gaining input from leading industry experts, in a live webcast, “

New Strategies for Biopharmaceutical Stability Testing

,” on Thursday May 9th from 2:00 to 3:00 PM EST.

		With the average cost to develop a biopharmaceutical well over $1 billion, and shelf life being an important driver of success, understanding these effects prior to long-term stability profiling is crucial to sound decision-making and efficient development strategy. This 60-minute webcast will provide insight from leading industry experts on the common pitfalls of biopharmaceutical stability testing, regulatory agencies’ expectations for supporting data, and the analytical techniques that can improve information and streamline the development process.

		The panelists for the webcast will be: John Geigert, PhD., RAC, president of BioPharmaceutical Quality Solutions, and past member of the PDA Board of Directors, past co-chair of the PDA Biotech Advisory Board and past expert member of the USP Biotechnology Committee; Carrie L. Anderson, senior scientist from Merck & Co; and John C. Anders, PhD, senior scientific advisor, ABC Laboratories.

		The free webcast is open to audience members, who may pose questions to the panelists in a Q&A session following the presentations by the panelists. Information on how to register for the live event for Thursday May 9th from 2:00 to 3:00 PM EST or for on-demand viewing is available 

Articles

As pharmaceutical and biopharmaceutical companies intensify product development in biologics, they are tasked with meeting the challenges of biologic-based drug development and manufacturing.

Overcoming the Challenges in Biopharmaceutical Stability Testing

The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) and the Biotechnology Industry Organization (BIO) report that  a newly published paper on vaccines provides a set of pragmatic actions to improve global access to and use of high quality, safe and effective vaccines. Published in Vaccine, the peer-reviewed paper, “Delivering the Promise of the Decade of Vaccines: Opportunities and Challenges in the Development of High Quality New Vaccines,” was authored by vaccine experts with support from IFPMA and the BIO (1). 

Launched in 2010, the Decade of Vaccines (DoV) Initiative assembled key global health stakeholders in an effort to reduce vaccine-preventable illnesses by achieving 90% global vaccine coverage by 2020. The paper provides the perspectives of the research- based vaccine industry on how to advance the DoV’s objectives and support vaccine uptake by addressing availability, affordability, adoption, and alliances, as outlined by IFPMA in an Apr. 18, 2013 press release. 

The DoV was introduced at the World Economic Forum in Davos, Switzerland in 2010 with a pledge by the Bill & Melinda Gates Foundation to dedicate $10 billion to the overall goal of researching, developing, and delivering vaccines to developing countries (1). In December 2010, the World Health Organization, the United Nations Children’s Fund (UNICEF), the National Institute of Allergy and Infectious Diseases (NIAID) and the Bill & Melinda Gates Foundation formally launched the DoVthrough a pact to create the Global Vaccine Action Plan (GVAP). Following input from DoV stakeholders, including IFPMA and BIO, a final draft of the GVAP was presented and endorsed at the 65th World Health Assembly in 2012. 

 The consultation received input from governments, policymakers, civil society, healthcare professionals, global development organizations, academics, private sector players, including vaccine manufacturers, and other key stakeholders involved in immunization, health, and human development, The DoV action plan included a key role for these research-based companies to participate by continuing to innovate, develop, produce and supply high quality vaccines. Some specific actions suggested by the action plan for manufacturers are as follows: to participate in open dialogue with countries and the public sector to ensure sustained access to current and future high quality vaccines; advance innovation in R&D and manufacturing; support rapid vaccine adoption as new or improved vaccines become available; develop partnerships that support increasing manufacturing capabilities, supply and innovation work in coordination with other partners on vaccine and immunization advocacy.

According to the authors, accelerating vaccine access and innovation, especially in the developing world, requires a mix of “push and pull” mechanisms. Examples of “push” mechanisms that stimulate R&D are grants and investment tax credits while “pull” mechanisms can include donor guarantees of vaccine purchases and government programs to promote vaccine uptake through increased awareness of vaccines' health benefits.

 “Global health stakeholders share responsibility for achieving the goals of the Decade of Vaccines," says Eduardo Pisani, IFPMA Director General, in the IFPMA release. “This report applies industry learnings and expertise that contributed to several past health successes such as dramatically reduced measles-related deaths and eradication of smallpox. With greater public awareness and access to innovative vaccines, great strides can be made toward preventing other leading communicable and non-communicable diseases.”

The Global Vaccine Action plan maps out a strategy to increase access and R&D for vaccines.

Pharma Industry Participates in Vaccine Initiatives

Despite overall manufacturing rationalization in the pharmaceutical/biopharmaceutical industry, the large pharmaceutical companies continue to invest in biologic-based manufacturing. The author provides an update in recent investment activity among the pharmaceutical majors in biologic-drug substance, vaccine, and parenteral drug manufacturing. 

 Restructuring and manufacturing rationalization have been the order of the day for the large bio/pharmaceutical companies during the past several years. Small-molecule and solid-dosage operations have been the largest target for such cost-cutting, but there are bright spots on the manufacturing investments. Several Big Pharma companies are investing in biologic drug-substance, vaccine, and parenteral drug finished product manufacturing. 

 Bristol-Myers Squibb is investing approximately $250 million to expand its large-scale biologics manufacturing facility in Devens, Massachusetts. The expansion will introduce biologics development and clinical-trial manufacturing capabilities to the site while adding approximately 350 employees to the Devens workforce over time. The Devens site is home to the company’s large-scale bulk biologic manufacturing facility. Construction of the Devens site was completed in 2009. It represented the company’s largest single capital investment ($750 million) and provided Bristol-Myers Squibb with large-scale bulk biologics production capacity. In May 2012, the company received FDA approval to manufacture its arthritis drug Orencia (abatacept) at the Devens facility.

The new $250-million investment will be used to construct two new buildings on the 89-acre Devens campus: one building for process development and one for clinical manufacturing. Together, the two buildings will add approximately 200,000 ft 

 of laboratory and office space to the Devens site, which is now comprised of six major buildings in a 400,000-ft

Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Sanofi, and Roche are among the companies expanding biologic-based manufacturing capacity.

Big Pharma's Investment in Biologics

The global biotechnology industry showed mixed results in 2012, according to a recent analysis by Ernst & Young. On the plus side, companies in the industry’s established biotech centers in the US, Europe, Canada, and Australia experienced revenue growth in 2012. Net income also increased among companies, in part due to cutbacks in R&D, which helped to improve the bottom line.  Also, funding from debt, initial public offerings (IPOs) and venture-capital declined in 2012. In this more difficult funding market, mergers and acquisitions activity increased in 2012. 

 Companies in the industry’s established biotech centers (the US, Europe, Canada, and Australia) achieved revenues of $89.8 billion in 2012, an 8% increase from 2011. Revenues of publicly traded biotech companies in the US were $63.7 billion, an 8% increase but down from the 12% growth rate in 2011and the 10% increase in 2009 and 2008 (on a megadeals-adjusted basis), according to the Ernst & Young analysis. Part of the decline in revenue growth was the result of a few sizeable firms from the list of US biotech companies. Amylin Pharmaceuticals and Gen-Probe were acquired by large non-biotech entities and Jazz Pharmaceuticals relocated to Ireland. More importantly, notes the report, the drop in revenue growth appears to be indicative of other trends, such as an increasingly competitive marketplace and greater scrutiny from payers and providers and a subsequent impact on revenues. Revenues of European public biotechs grew 8% in 2012 to $20.4 billion. 

 On a global basis, R&D spending by public biotech companies grew by 5%, well below the 9% growth rate achieved in 2011, according to the Ernst & Young analysis. Although expenditures remained strong at commercial leaders, precommercial entities substantially reduced R&D spending. In the US, R&D spending increased by 7% in 2012, slightly below the 9% growth rate in 2011. In 2012, commercial leaders increased expenditures by 18%, but other companies cut spending by 5%, reflecting the R&D pressure at many medium-sized and small biotech firms. In 2011, a third of biotech companies had reduced R&D spending. In 2012, that number climbed to 41%. In Europe, R&D expenses decreased by 1% in 2012, an indication that many European firms remain in cost-cutting mode. 

 R&D cutbacks, combined with solid revenue growth resulted in a record high in net income for the biotechnology industry in established markets (US, Europe, Canada, Australia) of $5.2 billion, a $1.4-billion increase from the previous year. Net income of US biotech companies increased 34% from $3.3 billion in 2011 to $4.5 billion in 2012. In part due to R&D cost-cutting, the European biotech industry reached aggregate profitability for the first time in its history in 2012, according to the Ernst & Young analysis. 

The report further showed that the “new normal” funding environment continues. Since the global financial crisis in 2008, biotechnology industry funding totals have been on an upward trend, according to the Ernst & Young analysis. Although most companies faced a challenging funding environment, capital raised increased with every subsequent year, fueled by large debt offerings by the industry’s largest firms. “In 2012, this trend came to an end, as capital raised in North America and Europe fell for the first time since 2008. The decline was due to the same factor that had driven the sharp increases in the first place: debt,” according to the Ernst & Young report. “In every year since 2008, funds raised in public equity offerings and venture capital have remained fairly steady while large swings in the amount of debt raised have driven year-to-year fluctuations in total capital raised. Although a few large companies have benefited from these funds, the amount of capital available for the vast majority of smaller, venture-backed entities has remained frozen at amounts below pre-crisis levels.” This situation, which Ernst & Young calls “the new normal” continued to hold in 2012. In 2012, biotechnology companies in North America and Europe raised $28.2 billion, a drop from the $33.3 billion raised in 2011. This decrease was driven by a reduction in debt funding, which fell by almost a third, from $20.3 billion to $14.1 billion. The IPO market remained weak, with aggregate proceeds of only $805 million, down from $857 million in 2011. “Innovation capital,” defined as the amount of capital raised by companies with less than $500 million in revenues, remained virtually unchanged between 2011 and 2012, increasing only from $15.2 billion to $15.3 billion. 

Venture funding across North America and Europe declined 5% to $5.4 billion in 2012, a much slower decline than was expected given the fundraising challenges encountered by many venture firms in recent years. In 2012, there were 130 venture rounds in the US that had net proceeds equal to or greater than $10 million, with a median amount raised of $21 million, both flat relative to 2011 (when there were 127 rounds and a median value of $22.5 million), according to the Ernst & Young analysis. In both years, these deals represented about 85% of total venture capital invested. Both years were virtually identical in terms of the number of Series A rounds that raised $10 million or more, a measure of new company formation. There were 25 such deals in 2012 and 27 in 2011, with a median deal size of $20 million to $25 million each year. 

 In 2012, the innovation capital raised by companies in North America and Europe held steady at $15.3 billion, practically unchanged from the $15.2 billion raised in 2011. Innovation capital has been consistent over the last four years, averaging $15.2 billion between 2009 and 2012, although lower than the 2004-2007 average of $19.6 billion. “This is significant because, unlike the commercial-stage leaders, companies raising innovation capital require funding to sustain their operations and fund R&D,” notes the Ernst & Young report. 

 On the deal-making side,  the total value of mergers and acquisitions involving European or US biotechs equaled $27.4 billion, an increase of 9% from 2011 (when setting aside the two megamergers in 2011 in excess of $10 billion) and the highest non-megadeal total since 2008. Mergers and acquisitions involving US-based biotech companies increased 5% in 2012 to $23.8 billion (after adjusting for the two megadeals in 2011). In Europe, the value of mergers and acquisitions declined 28% to $2.9 billion, with the number of deals with announced terms falling to 13, the lowest level since at least 2005. 

Financing to biotech companies in North American and Europe declined in 2012 as debt funding decreased and the IPO market remained weak.

The New Normal in Biotech Financing

Solid-form characterization and research are important for improving the understanding of and modification of the physical properties of APIs to ensure therapeutic benefit, optimize product development,and protect intellectual property. Although the primary goal early in drug development is to find a stable form of the drug, the potential patentability of other solid forms offers opportunities in maintaining product exclusivity or for product-life extension. Solid-state chemistry is of growing importance not only for pharmaceutical companies, but also for contract manufacturers and specialists serving the pharmaceutical industry. 

In an era of increased generic-drug competition and growth in emerging markets where intellectual property laws may differ from developed markets, strategies in solid-state chemistry are ever-more important. This issue was brought into prominence with the recent ruling against Novartis by India's Supreme Court in the company's appeal to be granted a patent for the company's anticancer drug, Glivec/Gleevec (imatinib mesylate) in India. Although the ruling, which was issued on Apr. 1, 2013, has broader implications for intellectual property protection and the role of innovator drugs in India's market, it also serves as a useful example on how solid-state chemistry can play a role in building a patent estate. 

At issue in the case was whether Glivec was considered an innovative product and, therefore, afforded protection under Indian patent law. Novartis had argued that the beta-crystal form of imatinib mesylate was novel and that it should be given patent protection under India law. India, which is part of the World Trade Organization, had amended its patent law in 2005 to assert that pharmaceutical companies had to prove enhanced clinical efficacy of their drugs over already patented compounds (1). In its ruling against Novartis, the Indian Supreme Court cited a 1996 patent (US Patent No. 5,521,184), which included several derivatives of 

-phenyl-2-pyrimidine-amine, including imatinib, in a free-base form (2). Novartis asserted that it had first developed the methanesulfonic acid addition salt, imatinib mesylate, and later the beta-crystalline form of the salt, which had improved properties, such as flow, thermodynamic stability, and lower hygroscopicity compared with the alpha-crystal form. The India Supreme Court, however, ruled that the beta-crystalline form of imatinib failed to meet the tests of "invention" and "patentability" under Indian law (1). 

Novartis had filed a Special Leave Petition with the Indian Supreme Court in 2009 challenging the denial of the Glivec beta-crystal form patent on two grounds based on Sections 3(d) and 3(b) of the Indian patent law. In addition to seeking a patent for Glivec, the company filed the case to help clarify these aspects of the patent law. 

"Novartis has never been granted an original patent for Glivec in India," said Ranjit Shahani, vice-chairman and managing director, Novartis India Limited, in an Apr. 1, 2013 company's statement. "We strongly believe that original innovation should be recognized in patents to encourage investment in medical innovation especially for unmet medical needs. We brought this case because we strongly believe patents safeguard innovation and encourage medical progress, particularly for unmet medical needs. This ruling is a setback for patients that will hinder medical progress for diseases without effective treatment options." 

The recent ruling against Novartis followed another court ruling in India against a large pharmaceutical company as it related to a solid form. In September 2012, Roche lost a case in the High Court of Delhi, where it had argued that the Indian drug producer Cipla was infringing on its patents by selling a generic version of the anticancer drug Tarceva (erlotinib). In its ruling, the court sided with Cipla's contention that Tarceva is based on a different polymorph of the active ingredient erlotinib than the one Roche patented in India. Roche had attempted to patent the different polymorph, but the India court had rejected it as too similar to the patented one (3, 4). 

Other cases outside of India are of interest as well. For example, in March 2013, the US Patent and Trademark Office (USPT0) rejected an appeal by Boehringer Ingelheim against its refusal to patent the mesylate salt form of the thrombin inhibitor Pradaxa (dabigatran). In its decision, the USPTO asserted that a salt form of the drug was an obvious choice given that the drug molecule had poor solubility and an ionizable center (5).  

Although intellectual property concerns play a role in the development of pharmaceutical solid forms, the rationale to use a particular solid form (e.g., salt, polymorph, or cocrystal) of an API is dictated by the target product profile and encompasses various factors, such as bioavailability, physical and chemical stability, desired dissolution properties, the impurity profile of the API, drug-substance hygroscopicity, morphology, size distribution, compaction properties, and the ability to formulate the drug (6).   

In the case of polymorphs, for example, screening for and identifying polymorphs when developing and manufacturing APIs is an ongoing challenge for pharmaceutical manufacturers. Polymorphism is the ability of a compound to exist in more than one crystalline structure. Polymorphs or other solid forms are identified using a polymorph study or screen (6). Different solid forms can possess different properties, including solubility, which, in turn, can affect the bioavailability of the drug. 

One of the more well-chronicled examples of polymorphism occurred in ritonavir, the API in Norvir, a protease inhibitor developed by Abbott Laboratories (now AbbVie), The drug was approved in 1996, and in mid-1998, Abbott encountered manufacturing difficulties with the capsule formulation (5). Ritonavir exhibited conformational polymorphism of two unique crystal lattices that had significantly different solubility properties (6, 7). The formation of the polymorph caused Abbott to pull the drug from the market and reformulate. 

Polymorph stability is evaluated experimentally by monitoring the phase transition of the different polymorphs in different crystallization media and at different temperatures by using 

 monitoring probes and analytical solid-state methods (6). These data are used to manufacture the desired polymorph and to control it through the various manufacturing steps. Polymorphs can undergo phase transitions when exposed to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray drying and compaction. Exposure to environmental conditions, such as humidity and temperature, also can induce polymorph transition. The extent of transition depends on the relative stability of the polymorphs, kinetic barriers to phase transition, and applied stress (6). Moreover, the physical stability of polymorphs may be monotropic or enantiotropic, where the relative thermodynamic stability between the two forms can be inverted with temperature (6). Additional considerations are made when the physical form of the drug-substance may be modified in the formulation process, such as in hot-melt, lyophilization, solubilization or suspension in a semisolid matrix. Drug substance–excipient interactions also are considered when stabilizing particular physical and other process parameters that may affect the performance or quality of the product.  

 1. Indian Supreme Court, Civil Appeal No. 2728 

Novartis AG vs. Union of India and Others 

 2. J. Zimmerman, "Pyrimidine Derivatives and Processes for the Preparation Thereof (US Patent No,521,184), 28, May, 1996.  

 3. R. Ahmed, "India Revokes Roche Patent," 

 5. S. Houlton, "India Rejects Novartis Patent Appeal," 

 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, 

The rejection by India's Supreme Court on Novartis' Glivec/Gleevec (imatinib mesylate) and other recent case law raise important issues on patent strategies for solid forms.

Intellectual Property Battles in Solid-State Chemistry

Although the actual synthesis of an API is crucial, it is not the exclusive consideration in API development. In addition to producing an API with high purity, yield and stereoselectivity, an API must be able to remain stable during storage and distribution and have the desired drug mechanism once administered to a patient. Solid-state chemistry is an important part of drug development, and public research is advancing the field.  

Researchers at the Institute of Chemical and Engineering Sciences (ICES) at Singapore's Agency for Science, Technology, and Research (A*STAR) recently reported on a novel method for producing cocrystals. The researchers discovered that adding water droplets can help form cocrystals of caffeine. Caffeine is unstable to humidity and cocrystal formation is possible with biocompatible compounds such as 4-hydroxybenzoic acid (4HBA). Previous research showed that computer models could predict cocrystals of caffeine and 4HBA in the ratio of 1:1, which would be the form with the most stable structure. To date, researchers had only been able to produce 2:1 and 1:2 co-crystals, according to information from A*STAR (1). 

The ICES researchers successfully formed 1:1 cocrystals of caffeine and 4HBA in the form of a monohydrate. By grinding together a 1:1 mixture of the two components with two drops of water, a crystal structure was formed in which each pair of crystallization partners is partly held together by a water molecule. The key to the water's ability to produce the 1:1 cocrystal is its capacity to both donate and accept hydrogen bonds, the intermolecular force that holds cocrystals components together. In the case of the caffeine-4HBA cocrystal hydrate, unused hydrogen-bond acceptors and donors are satisfied by forming hydrogen bonds with the water molecule. Without water, the number of hydrogen-bond donors and acceptors is unbalanced, resulting in the preferential formation of the 2:1 and 1:2 crystals instead, according to the A-STAR information. The researchers have also applied the process to other APIs. They generated a 1:1 cocrystal hydrate of 4HBA with piracetam, a cognitive-enhancing drug. The results suggest that forming hydrates offers an alternative way to generate cocrystals with particular ratios of constituents, expanding the options for forming pharmaceutical materials. 

The Synthesis & Solid State Pharmaceutical Center (SSPC) at the University of Limerick in Ireland was recently one of seven research centers that received part of an EUR 300 million ($391 million) investment through the Science Foundation Ireland's (SFI) Research Centers Program. SFI is the national research foundation in Ireland, and the funding represents funding from both SFI and private funding from industry. SSPC is a collaboration between 17 companies and academic institutions. These groups have expertise in process modelling and design, scale-up, computational fluid dynamics, in situ solution and solid-phase monitoring, crystallography and powder characterisation. The center's goal is to rationally design solid-state pharmaceutical materials in the required physical and chemical forms for advanced formulation and drug-delivery systems. 

Solid-state chemistry is an important part of drug development, and public research is advancing the field.