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Pfizerâ€™s Qbd Approach to Achieving Process Understanding

BioPharm International, May 2010 Issue (PDF)

The massive healthcare reform legislation approved by Congress in March promises to significantly expand the number of Americans with some kind of healthcare coverage and pharmacy benefits, enlarging the market for prescription drugs. Manufacturers will pay fees and discounts adding up to $105 billion over 10 years, according to Avalere Health. But that appears a reasonable tradeoff for policies that support innovation critical for biotech companies.  

The main selling point for the reform package is that it offers healthcare benefits to some 32 million uninsured. Individuals and small companies will be able to purchase coverage through new state-based insurance exchanges. Prescription drug coverage is included on the list of essential benefits required for all insurance plans offered through the exchanges, making reimbursement for orphan drugs and specialty products more likely. Moreover, insurance market reform, which prevents denial of coverage based on pre-existing conditions and curbs copays and annual and lifetime limits, promises to expand pharmacy benefits to patients with serious or chronic health conditions and thus in need of medicines. State Medicaid programs also will expand coverage to 11 million more lower-income adults and children, bolstering drug coverage in the process.  

Multiple changes to Medicare will enhance drug usage by seniors. The legislation authorizes annual wellness visits that will produce immunization and medication recommendations. There's more outreach to low-income beneficiaries to encourage appropriate drug use, and improved complaint and appeals systems to help seniors obtain access to needed therapies. The bill codifies mandatory coverage of drugs in six protected drug classes, while leaving the door open to further modification. 

The biggest change is to close up the controversial Medicare Part D donut hole over 10 years. Currently, Medicare beneficiaries who spend over $2,830 on drugs hit a coverage gap where they have to pay the full cost of medications; after drug outlays exceed $6,440, the government covers 95% of additional "catastrophic" costs. To provide some immediate relief, the government is giving a $250 rebate to beneficiaries who fall in the donut hole this year (2010). Beginning in January 2011, manufacturers will cover 50% of the negotiated rate for brand medicines filled by seniors in the gap. Medicare beneficiaries will pay the discounted price at the pharmacy counter, and manufacturers will reimburse pharmacies for the difference.  

In 2013, Medicare will close the donut hole further by covering a portion of the remaining cost to beneficiaries, starting low but ramping up to pay 25% of donut hole outlays by 2020. Medicare also will increase coverage of generic drugs in the gap, beginning in 2011, until plans pay 75% of the cost in 2020. At that point, policy makers consider the donut hole essentially closed because the remaining 25% patient share will be in line with beneficiary copays on drugs before hitting the coverage gap.  

Although eliminating the donut hole will cost manufacturers up to $32 billion over 10 years, the program removes a major source of confusion and hardship for elderly patients. The change also is expected to boost compliance with prescribed therapy and to reduce the growing number of seniors who halt medications or switch to generics when they hit the gap. The lower cost to beneficiaries, moreover, will move them more quickly to catastrophic coverage.  

In addition to providing donut hole discounts, manufacturers will pay 28 billion over 10 years in new fees, starting at $2.5 billion in 2011. The fees will be apportioned by the Treasury Department based on a company's share of branded prescription drug sales the previous year to Medicare, Medicaid, the Veterans Administration, and Department of Defense healthcare programs. Manufacturers with government sales less than $5 million get a pass, while fees scale up proportionally until sales hit $400 million a year.  

Pharmaceutical companies also will ante up another $38 billion in higher Medicaid rebates. The rebate jumps from 15 to 23.1% of average manufacturer price for brand drugs, and from 11 to 13% for generics, retroactive to the beginning of this year. The rebate also will apply to new formulations of oral solid dosage forms, and it will extend to Medicaid managed care organizations, a change that may encourage community health centers to press for additional discounts.  

Manufacturers are not complaining too loudly about these costs because they gain a pathway for the US Food and Drug Administration to authorize follow-on biologics (FOBs), the crown jewel in the bill for drug and biotech companies. After years of debate on this issue, innovator firms won an unprecedented 12-year data exclusivity period for reference biotech products, with the possibility of a six-month extension for sponsors who conduct pediatric studies. The Biotechnology Industry Organization (BIO) focused its lobbying efforts on this historic provision, which was steered through Congress by Rep. Anna Eshoo (D-CA), despite strong opposition from powerful legislators and the White House.  

The Congressional Budget Office projects that the program will save the government—and cost manufacturers—$7 billion over 10 years. BIO President Jim Greenwood cheered the measure for providing "incentives necessary to attract the massive investment required to speed the discovery and development of the next generation of breakthrough therapies." But Kathleen Jaeger, president of the Generic Pharmaceutical Association, complained that the bill "locks down indefinite brand product monopolies at a deep cost to patients and taxpayers." Timely access to biopharmaceuticals, claims Jaeger, could have produced 10 year savings well over $50 billion.  

All manufacturers, however, stand to benefit from clearer policies on developing and regulating biosimilars and "biobetters." The FDA now has to issue guidance on what analytical assays and clinical studies will be needed to document FOB safety, purity and potency, and what criteria could support product interchangeability, a critical issue for marketing and reimbursement. Sponsors will pay the FDA user fees, there's a process for innovators to challenge patent infringement, and Medicare Part B will pay for biosimilars at average sales price plus 6%—an amount considered high enough to encourage physicians to administer less costly FOBs. 

BIO also championed a relatively minor provision in the legislation that provides tax credits to small biotech companies (less than 250 employees) to cover a portion of R&D expenditures. The bill establishes a two-year program that offers a total of $1 billion in tax credits to cover expenses related to research on certain critical therapies.  

Another plus for the industry is language clarifying that comparative effectiveness research resulting from an expanded national program will not be used to determine coverage or reimbursement decisions by Medicare and other government health programs. The new nonprofit, nongovernment Patient-Centered Outcomes Research Institute will set priorities and support comparative studies with a $150 million annual budget as of 2012. All research will recognize differences in patient populations and will be made public.  

More troubling for manufacturers are new sunshine provisions that require broad, national disclosure of payments and reimbursement from pharmaceutical marketers to physicians. The industry also is concerned about a new Independent Medicare Advisory Board, formed to identify ways to slow the growth in Medicare spending. That could affect Medicare drug coverage, but the board won't be up and running until 2014, providing time for Congress to make it more accountable.  

Policymakers may not do that, though, as they are anxious to gain any and all savings for the healthcare system. The new law does little to bend the cost curve on national healthcare spending. Instead, it pays for the program through cuts in Medicare provider fees, which could be rescinded, and by imposing additional taxes on high-income consumers and healthcare companies. Tax hikes, though, do little to curb overall healthcare spending, and may boost outlays even more. 

Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

Broader benefits and biosimilars will offset hefty fees and discounts while preserving R&D incentives.

Healthcare Reform Expands Coverage, Promotes Innovation

There have been several exciting developments in recent weeks related to vaccine manufacturing. Sanofi-Aventis announced a €100 million investment in a new plant in Mexico, where it will manufacture flu vaccines in collaboration with the Mexican firm Birmex. The University of Pittsburgh Medical Center (UPMC), meanwhile, has plans to develop a flexible facility that can respond quickly to manufacture vaccines against bioterrorism. GE Healthcare, Merck & Co, IBM, and Batelle are all partnering on the project, which will be operated by the university's non-profit 21st Century Biodefense organization.  

The developments of the recent H1N1 outbreak, however, remind us that vaccine production is a far cry from the platformed process that monoclonal antibody production has become, and that we still have a long way to go in terms of preparedness for pandemics and bioterrorism. The H1N1 virus was more difficult to grow than expected, leading to delays in production; by the time large quantities were ready, the virus's spread had lessened, easing the public's fears and lowering demand for the vaccine. Meanwhile, many developing countries did not receive as much vaccine as they wanted. The stability of the formulations also posed problems, with several companies forced to recall various lots.   

All of this has made some governments rethink their preparedness strategies. Canada, for example, had opted for single-sourcing from GSK, the only firm with flu vaccine manufacturing facilities in Canada. That approach was based on fears that international borders would close in a pandemic. Borders stayed open during H1N1, however, so after experiencing delays from its only supplier, the government now plans to sign contracts with multiple companies. 

On the positive side, many companies are continuing to pursue solutions. For example, several companies are pursuing universal flu vaccines, and one of them, BiondVax, just received positive results from a Phase 1–2 trial. If successful, this approach would eliminate the need to respond quickly to new flu strains and free up resources to address other pandemic or bioterrorism threats. Meanwhile, equipment and technology suppliers like GE Healthcare and Xcellerex continue to focus on applying single-use technologies to rapid scale-up and commissioning, in partnership with organizations like UPMC, and others, like Novavax, whose virus-like particle technology enabled it to produce H1N1 vaccine in less than four weeks after the strain was identified. 

The initial excitement—and panic—of H1N1 are long gone, and thankfully so. That means now is a good time for manufacturers to assess what the outbreak taught us and use that information to plan for the next one; at least one major manufacturer is doing exactly that right now. For our own analysis of what happened with H1N1 and the outlook for future pandemic response, we recently turned to John Hyde of Hyde Engineering & Consulting. You can watch that interview, recorded live at the Interphex Main Stage, at 

www.biopharminternational.com/Interphex2010

We all know that experience is the best teacher, and I for one am grateful that H1N1 gave us the opportunity to learn without taking an enormous toll in the process. Now, let's take advantage of that lesson. 

From the Editor

We all know that experience is the best teacher. With H1N1, we have a great opportunity to learn important lessons.

Pandemic Response: Progress and Challenges

After an innovator organization decides to take a candidate drug through to clinical trials, it faces key decisions relating to managing the production and supply of material to the clinic. The requirements for progressing a drug through to clinical trials include analytical characterization of the molecule, production of drug substance, manufacture of drug product, analytical method development and validation, and formulation development of drug substance and drug product.  

These requirements also must be managed so timelines for entry into the clinic are not compromised. Finding and managing a supplier network that can meet all of these needs, through all of the phases of the clinical development program, raises the challenge of managing a series of complex operations. It is highly unlikely that a single contract manufacturing organization (CMO) will be able to provide all of the capabilities required to get a drug into clinical trials. Manufacturers who have the expertise and capabilities to produce sufficient quantities of drug substance may have limited capabilities in the secondary manufacture (fill–finish) of drug product. Conversely, companies with the expertise to manufacture the required dosage form for the clinic will not necessarily be able to manufacture the drug substance. Having made its initial decisions about which CMO to use, a company will have to consider potential limitations in any one contractor's capabilities as the pharmaceutical development program progresses. 

In managing its supplier network, an innovator organization may have to shift the balance of certain activities during the course of a development program to make optimum use of the CMOs' strengths. In this article, we discuss the important factors that a company will have to consider to alter the balance of activities between suppliers whose capabilities may be complementary during the development program. Any changes to the formulation or the presentation of the biopharmaceutical product are an important consideration in assessing when, or whether, such a change is necessary. 

Currently, the majority of biopharmaceutical products are parenterals. However, as discussed later in this article, a small but increasing number of products are being developed for nonparenteral use. 

With small (and in many cases, virtual) innovator companies developing parenteral biopharmaceutical products, the strategy adopted tends to be enforced by the need to quickly obtain proof-of-concept data. This shapes the operations of a pharmaceutical development program. The strategies for pharmaceutical development programs can be diverse, influenced by a number of factors. These include: 					

the nature of an organization and available resources. 

The constraints on a small or virtual biotechnology company are very different from those faced by a large pharmaceutical company.

the business model used by the organization.

 Is the intention to partner or sell the drug after successful completion of early-stage clinical trials, or does the organization plan to commercialize the product?

 A major concern is the risk to product stability while clinical trials are ongoing.

 In general, stable liquid formulations are more desirable than lyophilized formulations. Therefore, if a competitor product already on the market is in a liquid form, then lyophilization may not be a viable option.

 A company typically is required to meet milestones and stakeholder expectations.

 Limited funds may be available, especially in the current economic climate.

A summary of the formulation options for taking a parenteral product into early-stage clinical trials, with some of the key advantages and disadvantages of each, is provided in Table 1. When the selected formulation is a liquid, release testing and stability studies typically will reside with either the drug substance manufacturer or the analytical services provider. For early-stage programs, there is little point in incurring the additional costs of transferring analytical methods, or adding to the complexity of a program in which timelines are invariably tight, especially if the drug product manufacturer has the necessary skills to complement the competencies of the drug substance supplier and analytical services provider (models 1 and 2 in Table 2). Inevitably, this model may need to be reconsidered as the development program progresses through clinical trials.  

Table 1. Formulation options for taking a parenteral biopharmaceutical drug product through early-stage clinical trials			

A formulation that may be adequate for early-stage clinical trials, such as a frozen liquid, is not necessarily suitable for later-stage clinical trials and the marketed product. Also, a change in presentation may be required. In this case, a company will not only need to decide which CMO is best placed to carry out the redevelopment of the formulation, but also the other activities which may need to change as a consequence. Reformulation will require the revalidation of analytical methods to establish their fitness for purpose in the new formulation. A new manufacturing process will need to be developed and validated. A shift toward model 3 (Table 2) may, therefore, represent a better fit between the innovator company's requirements and the CMOs' capabilities.  

Table 2. Models for contracting out a pharmaceutical development program to a contract manufacturing organization (CMO)			

When the selected formulation is a lyophile, it is more likely that the formulation development will be carried out by the drug product manufacturer. Consequently, to support the formulation development activities, an innovator company may have more options and decisions to make about where it would be more practical and advantageous to revalidate analytical methods, as well as carry out the subsequent release and stability testing. Formulation requirements for parenteral products are a pivotal consideration in deciding how to manage the activities performed by CMOs. A proper understanding of their capabilities is important in determining if, or when, to change the balance of activities from one CMO to another to try and achieve as seamless a manufacturing process flow as possible. 

Although currently a relatively small percentage, more biopharmaceuticals are being developed for indications such as wound healing or certain allergies that would require topical or local administration. A growing number of monoclonal antibody (MAb) derived molecules also are being developed. This is a trend that is expected to increase. Although MAbs have many benefits as therapeutic agents, the development of full-sized MAbs is not without significant challenges and disadvantages, from the high cost of goods, to the limited options for delivery to patients. The development of smaller MAb fragments offers the possibility of alternative routes of administration, which, in turn, require the development of suitable formulations.  

Manufacturing a nonparenteral dosage form requires the consideration of other factors that would not arise with the manufacture of parenteral drug products. These factors include the required form of the drug substance (solid or liquid), differences in the approach to formulation development, revalidation of analytical methods, and manufacture. 

For parenteral preparations, the drug substance will be provided in a liquid form, which may need to be reformulated for the drug product. With other more conventional dosage forms, the drug substance may have to be supplied as a solid for use in manufacture. This raises two questions for the innovator organization. 

First, the solid form for the drug substance must be considered. Is it best to supply the drug substance as bulk lyophilized or spray-dried material? Is the drug substance sufficiently stable so that it can be processed into the required solid form? It may be that the importance of selecting the most appropriate solid form of the drug substance for a given program must to be established on a case-by-case basis, taking into account both the ability to formulate and manufacture the drug substance into the solid and the compatibility of the bulk solid form with the formulation and manufacture of the required dosage form. This is an area that is relatively uncharted and could therefore pose unknown challenges.  

The second question is whether the biopharmaceutical drug substance manufacturer has the capabilities to produce the required (intermediate) form of the material in the quantities required for clinical trials supply and beyond.  

These formulations are likely to be more complex than the relatively simple buffer systems typically developed for parenteral products. It is very unlikely that a drug substance manufacturer will have the expertise and the capabilities to formulate a wider range of dosage forms. In this situation, the formulation development and subsequent activities, including re-validation of the analytical methods, would be best placed with a CMO which has the required specialist capabilities. 

Analytical methods for nonparenteral dosage forms will almost certainly need to be redeveloped and revalidated. In all likelihood, the formulation will not be readily compatible with the methods commonly used for protein analysis. There is a strong possibility of matrix components interfering with the analysis. The development of a suitable method of extraction of the drug substance from the matrix also may be required. The innovator organization may be faced with a choice in relation to where the method (re-)development and (re-)validation activities for drug product are now best carried out.  

If the initial method development and validation for drug substance have already been carried out by an analytical contractor laboratory or a drug substance CMO (models 1 and 2 in Table 2, respectively), then the cost and time taken for methods transfer to a drug product CMO (model 3 in Table 2) must be assessed against the potential benefit of bringing together all of the drug product development and manufacturing activities under one roof.  

Currently, it is unlikely that a drug substance CMO also will have the capabilities to manufacture drug product for clinical trials in the potentially wide range of formulations or presentations that may be required for nonparenteral dosage forms. For parenteral products, the final step of drug substance manufacture would involve concentration and exchange into a suitable buffer. Typically, the drug substance solution can then be filled directly into vials, requiring dilution with the formulation buffer beforehand. The additional manufacturing capabilities required for the production of nonparenteral dosage forms are likely to be beyond those that are to be found with drug substance CMOs. 

When embarking on a pharmaceutical development program, an innovator organization will have to make decisions about how key development operations are contracted out. These decisions can be complex because CMOs will have complementary and partially overlapping capabilities, and constraints in terms of scale of manufacture. The initial choice of CMO to provide drug substance and drug product may be sufficient for early-stage clinical trials. Often, for parenteral dosage forms, formulation development, analytical method development, and validation, release, and stability testing are carried out by the drug substance manufacturer, and the fill–finish operations are performed by the CMO. The amount of effort spent trying to optimize the formulation and presentation of the drug product so that it is fit for purpose for early-stage clinical trials must be considered in the broader context of business and resource constraints. This arrangement is common and may work for early-stage development. However, should the pharmaceutical development program progress beyond Phase 1–2 clinical trials, the innovator organization faces a further set of decisions. It is at this stage, when there is confidence in the potential efficacy of the drug, that changes to the formulation and presentation are likely to be made so that they are more suitable for late-phase clinical trials or for a marketed product.  

To ensure regulatory compliance, these changes also will require revalidation of analytical methods. The requirements of increased scale of manufacture must considered. The innovator organization must determine whether its CMO network can meet the requirements for later stage clinical trials and beyond, or if the balance of manufacturing or development activities must be shifted. 

is a biopharmaceutical specialist in pharmaceutical development services at Patheon UK Ltd., Swindon, UK, +44 (0)1793 501273, 

Perspectives on Outsourcing

Formulation strategy is an important consideration when selecting and managing outsourced biopharmaceutical development programs.

Managing CMOs with Complementary Capabilities

Attention on healthcare policy is currently focused on how the new legislation passed by Congress will impact the industry. With increasing calls for recalling the new legislation, many in the industry consider the "sit back and wait" approach a prudent plan. Is taking any action before the details of the legislation are determined unnecessary, risky—or not?  

Achieving comprehensive healthcare reform is a leading priority of the President. Healthcare costs are strangling the country. President Obama has outlined eight principles for healthcare reform, seeking to address not only lack of coverage, but also rising healthcare costs and lagging quality.  

What many fail to recognize is that achieving a Congressional consensus is not a prerequisite to instituting far-reaching administrative changes to healthcare. Even if healthcare reform had died in Congress, the department of Health and Human Services (HHS) Secretary Kathleen Sebelius is unlikely to stand by and pilot The Centers for Medicare and Medicaid Service (CMS) into bankruptcy. HHS will continue to take action to achieve fiscal and quality objectives. The outline of where policy is headed is clearly discernable in the grants and pilot programs now being funded.  

The ongoing focus of federal funding has been aligned with the administration's avowed intent to achieve better quality and reduce cost through:  					

aggressively implementing electronic medical records (EMR); 

conducting comparative clinical effectiveness research (CER) to improve outcomes; 

promoting more patient-centered primary healthcare delivery, particularly for disadvantaged populations; and 

understanding the organizational and infrastructure changes needed to support improving quality and reducing costs. 

Health IT programs are focused on ensuring that physicians are meaningful users of EMR —effectively engaging CER and established care paths to improve the quality, safety, and efficiency of healthcare delivery. What many in the industry may not realize is that meaningful use is really a code for making decisions based on CER data that will improve quality and reduce costs.  

Despite the current uncertainty, it's reasonable to expect that the legislation will address the unsustainable trajectory of healthcare expenses in the US. Under scrutiny are ways to link physician payment to high-quality care at lower cost, connect payment bonuses to hospitals that improve patient results, and impose penalties on institutions that don't meet the mark. Fee-for-service payment is being openly challenged as bundled payments paid to medical teams and accountable care organizations are explored. There are likely to be rewards to hospitals for efficiency in their spending. Engaging a dramatic change in the formula for medicare reimbursement that links payment to a value index, up to one-half of a hospital's budget may be linked to efficiency of care.   

With healthcare delivery focused on bundled payments and value, the industry should be very concerned about the economic and clinical value their products bring. Even if the current bill is recalled or modified substantially, it is realistic to expect that CMS will pick up where Congress left off. If they don't, they face almost certain financial collapse. 

Leaders in the healthcare industry must think about the impact of these sweeping changes on their business now, and plan ways to assess risk and strengthen the economic and clinical value of their products in ways that ensure demand and optimal pricing. Are you ready for life in a post–reform world? 

 is the president at Numerof & Associates, Inc., St. Louis, MO, 314.997.1587, 

Final Word

The industry must be prepared for the impact of the sweeping changes expected from the new legislation.

Are You Ready for a Post-Reform World?

The importance of the biosciences industry is unmistakable. Companies in this sector now have revenues of approximately $1.2 trillion per year and growth rates of 6–8% per year. This growth has fostered a need for managers that possess both scientific knowledge and business acumen. Traditional scientific and business programs provide academic backgrounds for the separate disciplines, but lack the sufficient crossover for biosciences managers who need both. To fill this gap, programs augment the graduate curriculum with one or two classes to prepare the manager for an awareness of science, or conversely, the scientist with some rudiments of business. However, this approach falls short in providing the newly minted manager or scientist with the unique background that the biosciences area requires. Biosciences managers must understand the connections between and among all areas associated with the field. Companies representing red (healthcare), white (industrial products), and green (nutrition and agriculture) biotechnology have voiced a desire for such bio-entrepreneurial managers. The North Carolina State University (NCSU) BioSciences Management program was created to fulfill these needs. 

Further complicating management of the biosciences organization is the rapidly changing paradigm of product and service development; this includes the business model used to generate such deliverables. The biosciences industry is complex, ambiguous, fast-evolving, highly entrepreneurial, science-driven, expensive, and ethically charged. Companies require specially trained managers, who are aware of these dynamics to compete and grow their organizations effectively. This has become particularly important of late because the availability of credit and venture capital to biosciences companies has become scarce, making growth all the more challenging. The new leaders and innovators of these industries must be cognizant of, and sometimes fluent in biotechnology; more importantly, they must understand how these technologies affect their particular businesses and operations. They will require the skill sets and behaviors to participate in and become architects of evolving business models such as open collaboration innovation.

The NCSU BioSciences Management Initiative has developed a curriculum that contains elements of traditional business concepts intertwined with scientific concepts. The curriculum contains an initial core of business fundamentals onto which biotechnology and pharmaceutical courses are layered. These involve dynamic areas such as finance, entrepreneurship, alliance forming, intellectual property, innovation management, and marketing, and serve to provide additional background. A principal aspect of the BioSciences MBA is the practicum, a short-term project where students work directly with bio-agricultural, bio-industrial, medical devices, diagnostics, or pharmaceutical firms. The BioSciences MBA culminates in the practicum, which encompasses many aspects of the degree program. The outcome is that students learn the tools needed to pursue management in biosciences and pharmaceutical environments in either science-based functions, such as research and development (R&D), or business functions. In turn, the sponsor receives approaches and solutions to improve performance and positions themselves for enhanced competitive advantage. 

The practicum also is the beginning of interaction with companies. The students begin to understand the needs and wants of the companies and industry and  the companies begin a partnership with the MBA program. This produces a continuous feedback loop of information to program organizers and is used to update and keep the program focused. This essentially is an action-learning module that is specific for companies so that information generated is instantly useful to the company.   

Students select the practicum subjects based on their interest and degree focus area. Because many of the students already have backgrounds in biotechnology, they are encouraged to select projects outside of their area of expertise. During the practicum, the students use the management tools they learned during the first year of the MBA program and apply it to the problem or project of the sponsor institution. Those participating in the practicum have many options ranging from evaluation of supply chain efficiencies, performing data mining, examining company's patent positions, or surveying the competitive landscape to forge strategic partnerships. An extensive array of potential sponsor organizations (approximately 550 companies and organizations) exists in proximity to NCSU within the greater Research Triangle Park area, making these projects readily accessible.

  Table 1 lists companies that have projects in the NCSU BioSciences Management program. Organizations that have had or have current NCSU MBA practica are indicated with "yes" in the practica column, and those involved in the industry advisory board (column IAB) are also indicated with a "yes". 

Table 1. The NCSU BioSciences Management Initiative network of biotechnology and pharmaceutical companies in the greater Research Triangle Park area. The table shows which companies have employees as students in the BioSciences MBA program, have been sponsors of practica, and if the organization is a member of the industry advisory board (IAB) of the program. 

The project teams are assembled and are composed of several students with similar interests but diverse professional backgrounds. Professors guide the team in the context of the academic exercise. The teams are introduced to the sponsor organizations and the project objectives in an initial meeting. At this time, the teams becomes familiar with the sponsor organizations, their mission, and interests. Project goals are defined and clarified as a precursor to project execution. Deliverables are defined by interaction with key members from the sponsor organization. Standing meetings are scheduled and arranged so that progress is monitored and directed by interactions with both professors and sponsors.  

Generally, the project is planned and conducted for completion within an academic term. If additional work evolves beyond the term, a consecutive or follow-up practicum is arranged. The practicum is designed to emulate the biosciences environment and to foster teamwork. Given the time constraints of the project, organizational structure and discipline is imposed by the teams themselves. Generally, workloads are divided among team members as appropriate. The completion of intermediate milestones is mapped and progress tracked toward finalization. Facile access to a centralized database and project management tools are necessary, and therefore web-based user groups, MS Project, and Basecamp, are used.  

The practicum culminates with a team presentation of its findings to the sponsors and NCSU professors. Additionally, a key value-added deliverable, summarizing important information and data gathered during the project, is provided to the sponsor.  

CASE STUDY: ALLIANCE FORMING (THE HAMNER PROJECT) 

The traditional business model of pharmaceutical development involves centralized decision-making with top company officials making choices regarding resource allocation. But as companies have grown larger and expanded globally, those executives have become more distant from the research. This leads to poor decisions, miscommunications, non-communications, fewer experimental drug candidates, and missed opportunities. Failure of this model to achieve success does not necessarily stem from a lack of good candidate products, but rather from the inability of the management to overcome the difficulties and challenges encountered in this new environment. As a result, reliance on smaller, more agile biosciences organizations to feed pipelines has become more prevalent, and a new paradigm based on biosciences–pharmaceutical partnering is evolving.

Described here is one such project in which efforts were made to identify a subset of pharmaceutical companies suitable for partnering with a sponsor biosciences organization. The methodology used for screening the industry to identify potential partners is described and major deliverables explained.  

The sponsor organization was The Hamner Institute for Health Sciences (Hamner). This research institution focuses on translational research in biotechnology and pharmaceutical safety. Hamner has been building on its successes in these areas and sought corporate alliances and partnerships to advance its efforts. The NCSU practicum team was assembled to facilitate a networking strategy that included students with experience in the focus area of metabolic disease research, specifically type 2 diabetes, as well as interests in building strategic alliances.

  Additionally, these students possess higher level life sciences degrees and currently work in bioprocessing and manufacturing in large pharmaceutical and startup biosciences companies.  

The goals were to identify what major pharmaceutical companies were doing in the area of type 2 diabetes, and how these programs might gain from Hamner's research. Fundamental research from Hamner could help a company improve its R&D productivity by identifying novel pathways to target and help characterize existing lead molecules for clinical performance. 

A flow-diagram (Figure 1) shows how a two-pronged approach was used to match the Hamner strengths with potential partners. First, the team conducted interviews with Hamner researchers involved in type 2 diabetes to gain an understanding of the ongoing research at Hamner and its core competencies. Next, the team categorized specific research projects to match internal strengths with industry needs. 

Simultaneously, the team surveyed R&D and commercial activities in type 2 diabetes through a market analysis to gauge the commercial landscape and identify pharmaceutical companies with sustained efforts and long-term dedication. The focus of the survey was market size, availability of approved therapies, and corresponding R&D pipelines. Through this survey, it was determined that type 2 diabetes is a global, growing, and potentially lucrative market, currently dominated by five to six key pharmaceutical companies, and many potential partners exist in both industry and academia. 

To evaluate the pool of potential partners, the team then used a systematic approach to score each partner based on the fit of its research pipeline and the strengths of Hamner. To accomplish this, the team created a template for patent searching to build a database for patent and literature information. The team examined patent activities, participation of companies in scientific meetings and publications, and classified R&D efforts as either internally focused or externally focused with a dependence on partnering and collaboration. The data were analyzed and scored for attributes of favorable partnerships in the major diabetes type 2 focus areas. The data are presented in Figure 2. 

The intellectual property search was conducted with uniform search criteria on the Derwent Innovation Index. This database contains patent coverage from 1963 and covers 40 patent-issuing authorities worldwide. The Derwent Innovation Index allows users to perform in-depth analyses on a research area of interest as shown in Figure 3. For example, the Derwent database enabled the search of recent activity by Merck scientists in the area of peroxisome proliferator-activated receptors (PPAR). Patent search results showed that Merck has had a sustained internal development focus on PPAR for the past 10 years. PPAR research also was of interest to the Hamner scientists. A similar approach was taken for scientific journal publications and public domain searching sites such as PubMed and Web of Science. For example, Web of Science provides quick access to the world's leading citation databases and covers over 10,000 of the highest impact journals worldwide, including open access journals and over 110,000 conference proceedings. This practicum also investigated companies' participation in major diabetes scientific meetings. Business activities were gauged from press releases, annual reports, and marketing analyses, and depending on these activities, were categorized as either internally focused, alliance forming, or likely to acquire the technology. Also, science and business leaders were identified from public disclosures and added to the database for eventual contact. 

After the analyses of patents, publications, and business activities were completed, the overall scoring of potential pharmaceutical company partners, as well as smaller institutions, was ranked. A higher score indicated a favorable strategic fit with a good potential for partnership. The results were presented to Hamner with an accompanying database containing all details, data, and contact information obtained during the exercise. The recommendation by the team was to pursue the top companies that offered the best chance of a successful and fruitful partnership. In summary, the team identified: 1) potential partners; 2) drug development programs that are focused on biochemical pathways where Hamner had specific expertise and knowledge; 3) specific individuals within these key programs who might serve as contact points for Hamner; and 4) where in the development process the expertise of Hamner might add value (e.g., toxicology, clinical development, and postmarket analysis). As a result of the practicum, Hamner used this information to contact potential partners. A future practicum team will use these results to refine further the pool of potential business partners with novel tools such as those discussed in Tech Mining.

We acknowledge the guidance of the following individuals in the preparation of this report: Naina Bhasin, Neil Mason of The Hamner Institutes of Health Sciences, and Mac Rich from NCSU.  

 (above) is an associate research fellow at Pfizer BioTherapeutics and Vaccines Outsourcing, 

 is a principal scientist at Seachaid Pharmaceuticals, Inc., and 

 is the executive director, all at the BioSciences Management Initiative, Jenkins Graduate School of Management, College of Management, North Carolina State University, Raleigh, NC, 919.513.0128, 

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http://www.ncbiotech.org/biotechnology_in_nc/battelle/billiondollarspreadsheet.pdf

3. Hine D, John K. Innovation and entrepreneurship in biotechnology, an international perspective. Concepts, theories, and cases. Cheltenham, UK: Edward Elgar Publishing Limited; 2006. 

4. Françoise S, Philip K. Building global biobrands. In: Taking biotechnology to market. New York: Free Press, Simon and Schuster; 2003. 

5. Alan P, Scott C. Tech mining: exploiting new technologies for competitive advantage. New York: John Wiley and Sons; 2008. 

Features

This practicum combines business elements with scientific concepts.

Building Partnerships Between Academia and Biosciences Companies

Computational fluid dynamics (CFD) has been widely applied as a trouble-shooting and Quality by Design (QbD) tool for bioprocess from downstream, to upstream, to fill–finish. Part 1 of this article series provided an overview of the technology, and the model setup. Here in part 2, we provide a detailed review of the applications of CFD in cell culture and fermentation processes, including flow characterization, mixing, resuspension, scale-up, and cell damage. 

Computational fluid dynamics (CFD) is applied in bioprocesses to collect a wide variety of information from many diverse and complex systems comprising complex bio-fluids and particulate matter. Work has ranged from trouble-shooting to process design and optimization. Processes such as filtration, centrifugation, chromatography, product freezing, thawing, and drying have benefited from CFD analysis in many ways. Here, however, we will focus on how bioreactor operations can benefit from CFD. Reviews of the applications of CFD to other processes shared with pharmaceutical industry, including material transport and storage, blending, granulation, milling, compression, film coating, and spray drying, appear in the literature.

Mechanically agitated or sparged tanks with single or multiple impeller systems are used extensively in the biopharmaceutical industry for various mixing processes, such as fermentation, cell culture, crystallization and emulsification, and resuspension. The empirical approach is still the prevailing practice for process scale-up and scale-down and technology transfer. This article shows how CFD has been used as a Quality by Design tool and for troubleshooting bioreactors.  

Process development engineers frequently face biopharmaceutical performance problems such as cell damage, optimizing hardware configurations including sparger design and impeller choice, and system equivalency for technology transfer. CFD can address the critical operating parameters of mixing time, power consumption, particle size distribution, gas distribution, and the just-suspended agitation speed. 

The flow field in an agitated bioreactor under turbulent flow conditions is quite complex, consisting of several time-dependent flow systems, including discharge flow originating from the impeller, blade wake, trailing vortex systems, impinging jets on the wall, boundary layers on the wall, baffle-bound vortex systems, and large recirculation zones. Primary flow patterns depend on the impeller geometry, impeller clearance, the presence of baffles, liquid height, and blade pitch. Because the tanks and impellers used in bioprocessing come in all sizes and shapes, flow characterization is difficult.  

CFD has been widely used to investigate the flow dynamics in agitated and sparged tanks because it can provide detailed three-dimensional information about velocity and pressure. It can reproduce the key flow pattern—the radial flow generated by a Rushton impeller and the axial flow caused by a pitched-blade impeller. Moreover, it has been used successfully to capture and predict important flow characteristics, such as the large recirculation patterns, the trailing vortex structure in the vicinity of the impeller and  cavity formation, and even three distinctly different stable flow patterns (parallel, merging and diverging) in a tank equipped with dual Rushton impellers.

Recently, numerous studies have verified the existence of the macro-instability (MI), a large-scale low-frequency phenomenon occurring in a baffle-agitated tank.

  The MI, when it appears, scales with the rotational speed of the impeller, 

. Its occurrence is dependent on both the impeller geometry and the location of the impeller relative to the tank walls. MIs can cause practical concerns, such as massive vibrations that lead to significant damage to the tank interior wall, impeller shaft, and impeller, and also may be responsible for some observed phenomena in agitated tanks, such as large dissolved oxygen (DO) fluctuations, which can lead to serious control problems. 

Three frequencies have been discovered, with the lowest being 0.02 

, and various intermediate frequencies in between. These MIs are associated with the mean velocity as determined over a short time interval, rather than with turbulent velocity fluctuations. The MI of the lowest frequency, only under specific conditions and primarily in a region in front of the baffle, is induced by a precessing vortex,

  whereas the MI of the highest frequency may be related to circulation and is present for a wide range of conditions and geometries across a significant part of the vessel volume.

  The existence of intermediate MIs indicates that there is some cross talk between the low- and high-frequency motions for a wide range of frequencies.

, appears between the turbine and the liquid surface, characterizing an organized modification of the flow pattern that creates a transient violent flow activity in the upper part of the vessel.

CFD simulations have identified all three MI frequencies.

  A low-frequency precessional vortex motion in a vessel stirred by a Rushton turbine has MI frequency values nearly identical to the lowest reported frequency.

  Large-eddy simulation (LES) models have revealed unsteady asymmetric flow patterns with intermediate frequency MIs in a pitched-blade turbine (PBT) impeller stirred-tank that is consistent with reported digital particle image velocimetry data.

  Frequency analysis of CFD results has revealed an MI with a frequency of 0.186 

 in a PBT tank with a Reynolds number >20,000, also matching experimental results from different scales of tank.

These studies may provide valuable insights for interpreting many previously unexplained hydrodynamic phenomena observed in stirred-tanks, such as the time-dependent settling of solids in dilute suspensions, bi-modal and tri-model velocity histograms in laser-Doppler experiments, and large fluctuations of measured DO and pCO

The published literature on the liquid-phase mixing in a turbulent flow regime presents mathematical models and experimental techniques for determining mixing time, and reveals the effects of the hardware configuration on the mixing performance.

  Mixing is very important for cell culture and fermentation because non-ideal mixing can lead to concentration gradients in nutrients, oxygen, and pH, among others. These gradients are likely to influence cellular behavior, growth, or process yield. Moving oxygen-limiting zones in large fed-batch bioreactors, a result of poor mixing, induce both metabolic and stress responses, which may account for the reduced biomass yield on scale-up and altered physiological properties of cells grown under large-scale conditions.

  CFD has been used to investigate mixing performance in stirred-tanks because it overcomes the limitations of classical reactor flow models, such as compartment and recirculation models.

  One of the applications is to understand local runaways and the quenching of runaway reactions in a tank under imperfect mixing conditions in an effort to develop operating protocols that prevent runaways in stirred reactors.

CFD also can provide a reliable prediction of mixing time.

  After a flow field is set up, an unsteady solution of a tracer transport equation leads to the prediction of the evolution of the tracer concentration inside the tank over time. Figure 1 shows the typical profiles of tracer concentration in a stirred-tank in CFD simulations when a Reynolds Average Navier-Stokes (RANS) model is used. The procedure to obtain the mixing time in CFD simulations is similar to the experimental approach.

  Tracer is added and monitors are turned to trace the concentration of the tracer at randomly chosen locations in the tank. Although it is hard for a RANS-based CFD model to exactly match the transient responses recorded by experimental conductivity probes, the predicted mixing time is in agreement with experiments, especially for single-phase flow. The curve of tracer response predicted by LES was found to be in better agreement with the experimental curve because of the LES's capability of accurately capturing the scalar fluctuations in the tank.

The measured mixing time depends on the location of the added tracer.

  The simulation should be in agreement with experimental values and empirical predictions as long as the addition point is kept away from the wall. In addition, accurately predicting the mean flow-field is key to successfully predicting the mixing time.

  Mixing time as a function of agitation speed is also plotted in Figure 1. The simulations can provide correlations of the mixing time to operating and geometry parameters such as agitation speed (

), as indicated by the solid line in the plot. This information can greatly help the scale-up and scale-down processes if the mixing time is the primary concern.  

The presence of solid particles will dramatically change the flow characteristics in agitated tanks. CFD simulations can provide detailed insight into the behavior of particles and how the liquid flow is altered by the presence of particles.

  The presence of solids in a fluid actually slows down the mixing process, sometimes by more than 10-fold that of a single-phase state.

  LES confirmed that particles heavier than the fluid tend to rise slowly to the top in unbaffled, tall, turbulently stirred-tanks.

CFD simulations have been widely applied to investigate the multi-phase mixing (resuspension) process in an agitated or sparged tank, using either the Euler–Euler approach for dense systems or the Euler–Lagrange approach for dilute-to-moderate dense systems, the former being more popular than the latter because it is less demanding on computation resources. The two-fluid (Euler–Euler) approach can determine the flow pattern and the concentration field in a dense solid–liquid suspension in industrial vessels, when a kinetic theory of granular flow for the solid stress and the solid pressure is adopted, taking into account particle–particle interactions.

  Predictions for solid distribution in an industrial crystallizer show agreement with experiments for several agitation speeds and mean concentrations.  

The two-fluid model, in conjunction with the slide-mesh algorithm, also is used to model the resuspension process in stirred-tanks.

  The model is not only able to predict the formation of the clear liquid layer in the upper part of the tank, but also can provide quantitative agreement with experimental data on suspension height. The model also can predict the critical impeller speed over a wide range of design and operating conditions, e.g., solid loading (0.34–15% wt), different impeller designs (Rushton turbine, pitched blade down- and up-flow turbines),

  solid particle sizes (120–1,000 mm) and for various superficial gas velocities (0–10 mm/s). However, it has been observed that the drag coefficient may sometimes need to be fine-tuned to match the available experimental data.

The performed studies demonstrate that the Euler–Euler approach, when applied to multi-phase flows without consideration for bubble coalescence or break-up, can agree with experiments, particularly when the bubble-flow is dominant.

  When bubble breakup and coalescence are accounted for, and bubble size distribution is important, many researchers have used population balance models to model the spatial evolution of gas bubbles in bioreactors.

  The mechanisms responsible for bubble coalescence and breakage are complex and not yet fully understood. For turbulent flows, most models formulate the kernel functions for the bubble coalescence according to random collision driven by turbulence and wake entrainment and the kernel functions for bubble breakage to turbulent eddies.

Although a uniformly mixed flow-field is optimal, CFD simulations indicate that full homogeneity of the gas–liquid mixture may never be achieved.

  Figure 2 shows the distribution of bubbles in a production-scale cell culture bioreactor, which is strongly dependent on the impeller type, sparger design, agitation rate, and sparging rate. 

Power draw, another important parameter for bioreactor operation, depends primarily on the impeller geometry and fluid dynamics around the impeller blades.

  CFD provides a convenient and reliable tool to calibrate the power number of the impellers and the power consumption for a given bioreactor using the torque on the impeller surface and shaft. For a multiple impeller system, the calculated overall power number is less than the value expected if each of the impellers had the same power number as the single ones because of interference between adjacent impellers.

  Power usage for a sparged tank depends on bubble coalescence, generally lower than the ungassed case.

It has been observed that the biomass yield on the carbon and energy source is decreased by the scale-up of aerobic processes. For example, in an 

-based recombinant protein process, the biomass yield of glucose and the maximum cell density reached in the process dropped by about 20% when scaling up from 3 to 9,000 L.

  In large-scale fed-batch processes, poor mixing may cause a large gradient of the concentration of the limiting substrate. 

 has been shown to have a change of 55-fold in the rates of oxygen and nutrient consumption as it circulates through different micro-environments of varying concentrations of oxygen and nutrient.

  Two possible scenarios may come up—the formation of moving oxygen-limiting zones when the cell density is high enough, caused by the fast use of sugar by cells, and the occurrence of overflow metabolism responded by the many microorganisms being exposed to glucose concentration above a critical level—

  Furthermore, the occurrence of oxygen-limitation may result in anaerobic reactions and concomitant stress responses.

Aeration is an essential requirement for aerobic cell lines. However, DO gradients are likely to occur when the characteristic time for oxygen uptake is shorter than the mixing time. In aerobic fermentation systems, the rate of oxygen transfer to the cells usually is the limiting factor. A key factor that influences oxygen transfer is bubble size distribution, which depend on turbulent characteristics in the reactor.

  The bubble sizes dictate the available interfacial area for gas–liquid mass transfer. The scale-up and design of bioreactors must meet oxygen transfer requirements while maintaining low shear rates and a controlled flow pattern. Therefore, understanding the hydrodynamic environment is critical for fermentation processes.

One of the challenges for fermentation process scale-up is to prevent concentration gradients (from the feed zone to the interior of the tank) resulting in further limitations and unwanted byproduct formation or inhibition of product rate. The following examples indicate that CFD simulations can be applied for the optimization of fed batch processes to avoid oxygen limitations, overflow metabolism, or catabolite regulation.  

Model simulations for large-scale tanks with multiple Rushton and axial flow impellers of different combinations shows that feeding the concentrated sugar solution into the impeller region and axial flow impellers leads to the best equidistribution of substrate.

 is used as a model for an oxygen sensitive culture for the characterization of the effects of inhomogeneities on the intensity of oxygen transfer gas liquid in stirred-tank reactor. CFD predictions for DO concentration and the production rate of butanediol show qualitative agreement with experimental observations.

Gradients of glucose in time and space are found in a 30 m

 grown in minimal medium to a cell density of 20 g/1, which were shown to depend on the feed position. Simulations with an integrated CFD and biokinetic model are performed to investigate the glucose gradients of this model.

  The simulations show a glucose gradient formed according to a change in the point of feeding and caused by a different cell concentration. The glucose concentration is high near the feed inlet and declines further away. The effect of the feed position appears as a generally higher mean concentration for the top feed compared with the bottom.  

It is not rare to observe abnormal performances such as lower cell viabilities, higher death rates, and a drop of titer when cell culture processes are scaled up from laboratory-scale to pilot or product scale. The potentially lethal events in a mechanically agitated and sparged bioreactor have been identified.

  They are bubble formation and detachment at the sparger, bubble interaction with the impeller in the impeller zones, bubbles rising along their path surfacing to the interface, and bubbles bursting at the media–air interface. Sparging gas into a tank generates strong turbulent flow and high shearing force at the sparger.

  Without surfactant additives such as Pluronic F68, 				  cells tend to attach to bubbles and thus experience shearing forces in the thin film surrounding rising bubbles and in the wake behind bubbles.

A complex dynamic takes place in the impeller zones when stable air-filled cavities are formed. Centrifugal force competes with buoyancy force in the impeller zones, of which the coupling interactions determine the bubble residence time, bubble breakup frequency, and bubble size distribution.

  The existence of the medium–air interface has a large effect on cell damage.

  If the air–medium interface at the top of the tank is eliminated, no cell damage is observed at impeller speeds up to 600 rpm for hydridoma cells.

  When a bubble approaches the air–liquid interface and subsequently bursts as a result of film draining, the shear stress in the resultant rimming flow is estimated at up to 200 Pa.

  On average, about 1,000 cells are killed per 2 mm of bubble rupture.

  Computer simulations of bubble rupture processes indicate that the rupture of small air bubbles in pure water generates an energy dissipation rate three to four orders of magnitude higher than that typically created in bioreactors solely because of agitation.

  The energy dissipation rate increases rapidly with a decrease in bubble size.  

CFD can provide information on the parameters most closely linked to cell damage, such as shear stress, power consumption, Kolmogrov eddy length scale distribution, turbulence characteristics including Reynolds stress, kinetic energy, and energy dissipation rate.

  CFD models also can predict process conditions that will cause vortices to occur and also the product vortex strength, compute cell residence time, and provide bubble size distribution, etc. With these kinds of information, one can easily trouble-shoot process performance issues. CFD simulation results show that shear force on the impeller surface, Reynolds stress, and turbulence energy dissipation rate in the impeller zones are unlikely to cause cell damage under typical cell culture process conditions. On the other hand, the interaction between the impeller and bubbles, which leads to bubble breakup in the impeller zones, and bubble bursting at the air–media interface are more likely to be responsible for observed cell damage.

A detailed review has been provided of how computational fluid dynamics (CFD) can be used to analyze bioreactor and fermentater unit operations, including flow characterization, mixing, resuspension, scale-up, and cell damage. CFD technology is a useful approach that provides detailed information that helps process development scientists understand cell culture and fermentation process performance problems encountered during technology transfer. However, some of the studied cases also indicate the inadequacy of the modeling efforts because of the complexity of biological systems and inaccurate physical models. Understanding a process physically and biologically is key to the success of the CFD modeling and simulations with regard to biopharmaceutical processes.   

is the founder and principal consultant of Systems Quality-by-Design, Inc., Newbury Park, CA, 626.716.2016, 

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Computational fluid dynamics can resolve performance problems.

Applying Computational Fluid Dynamics Technology in Bioprocesses-Part 2

A systematic Quality by Design (QbD) strategy was used to develop and characterize a monoclonal antibody production process. A risk assessment approach incorporating design of experiments (DOE), especially multivariate analyses, was used to define and prioritize laboratory-scale experiments and made it possible to focus on high-risk process parameters and study the interactions of those parameters to define the design space. Scale-up/scale-down strategies, such as the effective characterization of a scale-down bioreactor model, ensured the applicability of small-scale studies, and secondary risk assessment approaches were used to ensure that various unit operations were properly integrated in the development of the design space.

Quality by Design (QbD) is a scientific, systematic, risk-based approach applied throughout a product's life cycle to ensure safe, effective products.

How to use risk assessment strategies to integrate operations.

BioPharm International-05-01-2010