  annual report on the biotechnology industry—

Biotech 2009–Life Sciences: Navigating the Sea Change

—officially records that after 40-plus years since the industry began, it finally turned a profit in 2008. Yet, this good news has been overshadowed by the financial events that continue to affect the industry. 

Financing and investor confidence in biotech's hopes and dreams helped spawn many of today's world-class biotech powerhouses, such as Amgen and Genentech. The product successes of these companies are a major reason why the industry turned a profit in 2008. But the majority of the industry's biotech companies still remain a work in progress. 

 shows how quickly the financial crisis affected the 357 publicly listed biotechnology companies. Almost 60% have seen their market cap fall to well below $100 million. In addition, over 100 North American public and private biotech/pharmaceutical companies to date have announced a corporate restructuring by slashing staff and putting promising projects on ice.    

As of the end of February 2009, there was no evidence that the restructuring and refocusing strategies of the majority of biotech companies was slowing down. The more mature and blue-chip biotech companies have so far weathered this period quite well because they have plenty of cash, product revenue streams, strong pipelines, and Big Pharma partners. Investors view these large-cap companies as safe havens. However, even these companies are not immune to the macroeconomic environment in which they operate.  

Many of biotech's elite companies took a major hit to their share values in the wake of President Barack Obama's call to expand healthcare coverage and curb costs by providing access to cheaper generic versions of biotechnology drugs, cutting Medicare payments to private insurers, allowing consumers to buy cheaper medicines from overseas, and preventing drug companies from making deals that block generics competition. The budget plan, released on February 26, seeks massive savings to pay for a major healthcare overhaul. 

It was high on President Obama's agenda during his presidential campaign and so it should not have come as a surprise to anyone that the budget plans of his administration put healthcare costs directly in its cross-hairs. However, it appears it did and during the last two trading days of February, investors sold off healthcare shares big time on fears that the proposal would sap industry profits. 

The Burrill Biotech Select Index (Table 1) closed the month of February, down 7% compared to the Dow and NASDAQ, both falling 11.7% and 6.6% respectively. Up until the budget announcement, biotech had been holding firm against the market uncertainties that raged around it. However, the final two days of the month saw the Index fall 8.5%.  Genentech's share value held steady, however, closing up 5% for the month at $85.55 per share even in the face of Roche's hostile takeover offer of $86.50 per share for the outstanding shares it doesn't already own. Biotech's other blue-chip stocks—Amgen (down 11% for the month), Gilead (down 11%), Celgene (down 15%), and Genzyme (down 12%)—took it on the chin, with most of these losses coming at the end of February. 

Biotech got caught up in the general healthcare stock-selling frenzy as a result of this knee-jerk reaction to the budget plans. There is nothing in Obama's healthcare proposals that is surprising or different from what he articulated during the campaign and biotech's fundamentals continue to remain strong. As we saw, investors get quickly spooked over uncertainty. My new book predicts that in the ongoing financial crisis, biotech's elite companies will do just fine—it is the small and medium-sized public biotech companies that will have more difficulty weathering the storm. 

It will be a very painful time for many of them as they are forced to make difficult choices to ensure their survival. Many company obituaries will be written. When the markets do return in 2010, the industry will look very different than it does today. 

The Burrill Mid-Cap Biotech Index dropped 15% in February, sharply illustrating the volatile nature of the share prices of these companies. The share performance of Geron demonstrated just how quickly investor sentiments can change for members of this group. In January, the company's share price jumped 68%, buoyed by the possibility that President Obama might loosen restrictions on federal funding for embryonic stem cell research and the FDA clearing Geron's application to conduct early-stage clinical trials on its stem-cell based therapy, aimed at treating severe spinal-cord injuries. Fast forward one month, and their shares dropped 43% after reporting fourth-quarter revenues were only $544,000, down from $4.7 million in the year-ago quarter. 

Shares of Idenix Pharmaceuticals suffered a similar fate—plummeting 37% in the month—after reporting a wider-than-expected fourth-quarter loss. Shares of Questcor Pharmaceuticals fell 25% in February, after it said the regulatory process for expanded approval of Acthar was taking longer than expected. The drug is currently approved in the US to treat flare-ups of multiple sclerosis. The company wants to expand the drug's use officially to treat infantile spasms, a potentially life-threatening disorder that typically begins in the first year of life. 

GENENTECH'S MARKET CAP SURPASSES THAT OF PFIZER

The collective market cap of the industry closed February at $369 billion, a drop of 7% for the month. Genentech's market cap closed the month at $90 billion (up5%). Genentech now has surpassed Pfizer in terms of market cap, which closed February at $83 billion. Amgen was at $51.2 billion (down 11%) and Gilead Sciences at $40.8 billion (down 12%). According to the Burrill Report, which tracks the progress of the 360 publicly listed biotech companies, there were 187 companies that had a market cap of less than $100 million at the end of February.  

 is chief executive officer at Burrill & Company, San Francisco, CA, 415.591.5400, 

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Big biotechs will do just fine in the ongoing financial crisis, but the smaller companies will have more difficulty weathering the storm.

Biotech Industry Reports a Profit but Many Companies Still Struggle for Survival

A well-designed and implemented deviation management system offers a mechanism for obtaining critical quality data in a timely manner to enable quick response to failures, early warning of potential failures, and redeployment of resources to problematic areas. This article presents the key features of deviation management that can lead to early detection and resolution of problems and uncover gaps and weaknesses at a system's level that can help prevent potential problems in the future.

Each year, the US Food and Drug Administration issues multiple warning letters to establishments citing failures in managing deviations, for example, failure to thoroughly investigate unexplained discrepancies or products that did not meet specifications; failure to determine the scope of a deviation; failure to verify that corrective actions were effective; or failure to recognize, report, investigate, and correct serious discrepancies and deviations later discovered by the FDA during inspections.

  Warning letters arise from inspection observations that are not satisfactorily resolved in a timely manner. In 2004 and 2005, "failure to thoroughly review any unexplained discrepancy" was among the 20 most common inspection observations and "failure to perform a proper investigation" was among the 10 most common observations in 2006 and 2007.

Failure to understand and control process deviations exposes organizations to adverse regulatory action and financial loss, and compromises the organization's brand.    

A well-designed and implemented deviation management (DM) system offers a mechanism for obtaining critical quality data in a timely manner to enable quick response to failures, early warning of potential failures, and redeployment of resources to problematic areas. It is one of the most valuable tools available to management to help maintain a state of control. To be successful, the DM process must work for the organization rather than the organization working for the system. It must be designed to perform at the correct level to meet the organization's needs and to deliver optimal results. This requires incorporating risk-management principles, prioritization, and an understanding of conflicting interests among the consumer, regulatory agencies, and the business.    

This article presents the key features of DM, which if incorporated into working policies and procedures, will not only lead to early detection and resolution of problems but also will uncover gaps and weaknesses at a system's level that will help prevent potential problems. The result will eliminate redundancies in processes for investigating nonconformances; promote comprehensive and permanent solutions; strengthen management's oversight capability; reduce the probability of product recall; and enhance the company's bottom line. 

In this article, the term deviation encompasses events often referred to as nonconformances, errors, discrepancies, failures, or problems and is defined as unexpected or unplanned departures from current good manufacturing practices (cGMPs), regulations, standards, procedures, or specifications that may affect product safety, quality, identity potency, or purity.  

The point of entry into the DM system is the discovery and documentation of a deviation on a standard report form (including automated reporting systems). Other systems can feed into the DM process at this point, e.g., discrepancies and nonconformances discovered during equipment calibration, stability testing, complaints management, production, labeling, validation, and so on. Integrating systems in this way eliminates the need for redundant processes such as investigation and corrective action planning and ensures all deviations, regardless of the system in which they occur, are handled in a consistent manner and generate trending data based on the same parameters.  

A deviation should be documented with a description that is clear and concise and briefly states the who, what, where, and when information. Extraneous information that confuses the investigator and does not add value to the description of the problem should be avoided.  

A good example of a deviation description is: "On Friday Feb 3, 2008, during the manufacturing of drug ABC, in room B-2 the technician failed to take the hourly in-process sample at 4 pm as per SOP 1234."  

Compare the above example with the following deviation description that leaves the reader confused about the event reported: "Cycle count from machine hours 4:20 to 9:36 is not correct. The 24-hour inspection not performed. Cycle count from bin 9 to 11 is not possible." It is difficult to tell from this statement what the actual problem is or why the cycle count is not correct, how this is known, or who discovered the problem and when. 

At the point of discovery, a knowledgeable subject matter expert should evaluate and assess the risk associated with the event. Risk is commonly defined as the combination of the probability of occurrence of harm and the severity of that harm. Deviations range in degree of criticality or potential risk; many are minor and can be corrected on the spot while others present a higher safety risk and require more work. Therefore, deviations must be handled in a manner that is commensurate with the level of risk. Higher risk deviations, that are a risk to the customer, (i.e., health or safety), risk to the business (e.g., loss of product or production), and regulatory risk (e.g., warning letters, recalls) may require immediate or containment actions to stop the deviation from continuing, to contain the damage or to gain control of all potentially affected products.  

The level of investigation should be commensurate with the level of risk. Applying risk-assessment principals helps ensure resources and efforts are used where they are needed most. Instituting a risk-based approach to manage deviation investigations is key to focusing on problems that could result in patient harm. A major biotechnology company recently described how it implemented this type of program.

  Deviations are categorized according to the level of associated risk and investigation techniques are applied proportional to the risk. It is expected that the highest-risk deviations, which are fewer in number, will consume the major part of resources dedicated to DM. The concept of varying the thoroughness of investigation according to the nature of the problem, and the definition of the elements of a thorough failure investigation have been recorded in case law by the United States District Court for the District of New Jersey in United States v. Barr Laboratories, Inc.

Investigations begin with fact-gathering activities designed to collect as much information as possible to enable proper evaluation of the event. The end product of the investigation is an in-depth analysis of the deviation that will lead to determination of the root cause, not merely a restatement of the problem.  

To produce the best results, a team of subject matter experts from the affected department(s) should conduct the investigation according to established procedure(s).  

Information sought includes, but is not limited to:   

the scope of the deviation (i.e., the period over which the deviation occurred, the number of times the deviation occurred, the number (and identity) of products involved)

facts and events surrounding the deviation

interviewing people closest to the problem

inspecting and testing products and materials

reviewing past deviations of the same type

As information is gathered, investigators should resist the temptation to jump to conclusions about what happened and how it happened because this could prevent the discovery of additional information leading to a different or more comprehensive conclusion. There are also pressures to complete the investigation quickly because production and product release may be affected. However, an incomplete investigation affects the ability to analyze risk and the data, which will be used to formulate the preventive action. If done haphazardly, this demonstrates that the process is not in a state of control and the problems will probably recur. 

The importance of performing a good root cause analysis (RCA) cannot be overstated because the actions taken to correct or prevent the deviation from recurring are directly related to and depend on finding the right cause. However, investigators often fail to dig deeply enough to find the cause and apply the wrong corrective action, thereby risking recurrence of the problem. By prematurely ending the search, investigators may incorrectly focus on placing blame on an individual involved or providing unneeded retraining rather than seeking an opportunity to design safety into a process. Other notions that impede successful RCA are:   

believing that when more than one root cause, or potential root cause, is identified, only one may be selected

settling on a best guess of the cause as the quickest way to solve the problem and close the deviation.

Several techniques that support comprehensive root cause analysis include:   

an interactive group-thinking process to identify all possible causes. The exercise can be structured or unstructured. This is a process carried on without criticism or judgment that stimulates thinking and generates many enhanced ideas. 

  a technique which expands the scope of thinking beyond a single type of cause and also allows the focus to be centered on the core of the issue and not the history or personal opinions. This process prompts the problem solvers to consider the five basic components of a process (people, procedures, materials, equipment, and facilities or environment) as possible sources of root causes. 

Failure mode and effects analysis (FMEA):

  a step-by-step approach for identifying all possible failures in a design, a manufacturing or assembly process, or a product or service. Failures are prioritized according to how serious their consequences are, how frequently they occur, and how easily they can be detected. The purpose of the FMEA is to take actions to eliminate or reduce failures, starting with the highest priority ones.

a process that has been determined to uncover the real root cause by asking "why" five times. This expands the depth of thinking beyond the first thought or impression.

The root cause of a deviation can usually be attributed to a defect in the system design (e.g., inadequate procedures, materials, equipment, facilities, or unqualified personnel), system implementation, or individual performance.  

In circumstances where multiple potential root causes have been identified, investigators should narrow the list from possible causes to most probable cause(s). They can use various analytical tools and techniques such as voting on the more probable causes based on objective evidence, rather than gut feeling.  

Generally, industry practice dictates that deviation investigation and root cause determination are completed within 30 days of discovery of the deviation. In fact, in the U.S. v. Barr Laboratories case, the Court declared that “…all failure investigations must be performed promptly, within thirty business days of the problem's occurrence, and recorded in written investigation or failure reports”.

 If this is not possible, justification for the delay should be documented in the investigation report along with the date of expected completion. The deviation investigation process is shown in Figure 1. 

DEVELOP AND IMPLEMENT CORRECTIVE AND PREVENTIVE ACTIONS

After the determination of root cause(s), corrective actions can be determined. To narrow the field of possible corrective actions and select the best solution, the following techniques can be used:   

  a method in which the team selects the best of alternatives of the solutions and rates them.

  a method of weighing the pros and cons of change to identify the forces and factors that support or work against the problem.

  a method for sorting multiple ideas into categories.

To be effective, corrective action(s) must address the root cause. In fact, a strong correlation or linkage should be evident throughout the deviation report from one section to the next, i.e., the description should relate to the investigation, which should relate to the cause and that should relate to the corrective action, and so on. In some circumstances, the identified root cause may require several corrective actions. In these cases, the corrective actions may be implemented consecutively, rather than simultaneously, to determine the impact of any single action on the cause. Consideration should be given to the severity and frequency of the occurrence, demands on resources, and priority of the deliverables.  

Features

Follow a risk-based approach to maintain a state of control.

A Risk-Based Approach to Deviation Management

The development of a biodefense vaccine or a related product generally requires a significant investment, often in excess of $50 million.

  These funds are used for discovery, preclinical and clinical testing, development of a manufacturing process, and development and submission of the required regulatory-support documents. The funding process often begins with a grant-funded research project at a not-for-profit organization, such as a university, research center, or similar institution. If that research is successful, the resulting discovery must be transplanted to the commercial world for refinement, testing, regulatory approval, production, and distribution. Two general pathways are possible: Either the not-for-profit organization licenses the new product to an established company, or more commonly, the researchers or their colleagues form a spin-off company and eventually license the now refined and commercialized product to a production firm. This article deals with the sources of funding for that spin-off company. 

Traditional entrepreneurial advice suggests turning to the "four Fs" of bootstrap funding: founders, friends, family, and fools.

  "Founders" refers to the scientists and technicians who are launching the company; "friends" and "family" refer to their personal contacts; and "fools" refers to risk takers hoping for short-term tax advantages and long-term payoffs.  

Because the founders are usually university faculty or professional researchers, they often lack the prerequisites of entrepreneurs, who are willing to "bet the farm" on an idea. Academic founders are not typically motivated by money; they generally choose their careers for the psychological paybacks of involvement in science, a collegial atmosphere, job security, and status, rather than for economic gain. They are risk minimizers or risk averse, in part because of their scientific training and in part because of their choice of a secure career. Finally, and perhaps most importantly, they tend to be realists, aware of the downside of entrepreneurial investment, and familiar with the oft-quoted but poorly documented claim that nine out of 10 new businesses fail. (The reality is that most new businesses are underfunded and poorly planned; moreover, many are spontaneous "street corner" businesses not intended to survive more than a season.) 

Thus, founders tend to be a weak source of funding for a biodefense spin-off company. Similarly, founders are unlikely to recruit friends and family as investors in business ventures they view as highly speculative. Most founders and their friends and family are, not inappropriately, unwilling to risk a downside loss or resulting debt in building a new business. 

The likelihood of recruiting fools is more complex, but equally grim. As used here, fools are not foolish or ignorant, nor are they wild risk takers. Principled entrepreneurs do not recruit the foolish or the ignorant for two reasons: First, doing so is unethical, and second, no one wants a true fool as an advisor, partner, or board member. The word fools in the alliterative saying refers to persons whose motivation is rational but may not be obvious to outsiders. This non-obvious motive may involve a tax advantage: the desire to write off losses from an unprofitable venture against gains from a profitable one. In such a case, an S corporation may be appealing. 

Under the United States tax code, a corporation may be registered as an S corporation (S-corp) or as a C corporation (C-corp). A C-corp is typically a full corporation, with officers, stockholders, and not insignificantly, a degree of liability protection for its investors. (If you buy a share in General Motors—a C-corp—you need not worry that a car owner will sue you if the brakes fail.) 

An S corporation, on the other hand, is designed to help launch new businesses. If profitable, the S-corp pays more tax than a C-corp, and retained earnings, used to fuel business growth, are taxed to S-corp stockholders. However, the losses of an S-corp, which are more likely in the start-up phase, also pass to the stockholders, who can use those losses to offset tax liabilities. Most new companies begin as S corporations, then convert to C corporation status once profitability is achieved. 

S-corp status is unlikely to be appropriate for biodefense spin-offs for two reasons. First, the likelihood of high liability, in case the product develops problems, makes the protection of C-corp status more desirable. Second, S-corp status requires that all stockholders be individuals. Because the typical spin-off has a mandatory contractual license to provide part of its stock to a parent university, it cannot qualify as an S-corp. 

As mentioned above, fools are knowledgeable investors with non-obvious motives, and one of those motives may be a desire to benefit from the tax advantages of an S corporation. Faced with paying taxes on a profitable venture, the fool may wisely opt to obtain shares in a high speculative venture. The foolish choice makes sense because the losses of a speculative S-corp investment may cancel out the taxable profits from another investment; thus, the wise fool will readily pick up high-risk start-up shares rather than pay the Internal Revenue Service. US tax laws, thus, encourage investment and help provide capital to start-up companies. 

However, a biodefense spin-off company typically has a high liability potential and a mandatory contractual licensing agreement that disqualifies it from S-corp status. Therefore, it is unlikely to attract a knowledgeable fool as an investor. The biodefense spin-off must look beyond the four Fs when seeking funding.  

THREE FACTORS THAT OFFSET THE LOSS OF "FOUR F" FUNDING

Fortunately, three factors offset the loss of four F funding for biodefense start-up companies. First, the companies probably benefited from pre-stage grant funding. Second, they are likely to be working on products that are in the public interest. Third, they are typically farther along in the product development process and in the market definition process than are other, more traditional start-ups. These three factors result in substantial advantages for spin-off companies attempting to secure initial and growth funding. 

As a spin-off, a new biodefense company is probably beginning with a patented or developed product initially funded by grants. The organization, therefore, starts without the product development debt that hamstrings many new organizations. Even a new local pizza restaurant must experiment with the right mix of cheese, sauce, crust, and toppings. For a spin-off, that research and development phase has been independently funded before founding. 

Because the product is in the public interest, the biodefense company has a greater likelihood of government and foundation assistance than other companies might have. For example, the US military or the US government may pre-fund future orders or provide grant funding for a company in the biodefense arena.

Finally, the reality of a market made up of civilian or military authorities makes the spin-off an attractive investment for a biomedical corporation; indeed, the appeal is far beyond that available to most new businesses. Many major biomedical companies are actively looking for new developments; others are more passive but are open to discussions. And the model of funding product development by investing in independent spin-offs is well established in the biomedical industry. 

Given these advantages, biodefense spin-off companies have multiple funding options beyond the "four Fs" mentioned above. These options include: government grants, foundation grants, investors, pre-sales funding, loans, and other sources, such as licensing agreements. Spin-off companies can maximize funding success by pursuing a combination of the sources discussed below. 

Although grants can be complex, and attached strings can consume a portion of funds and result in multiple frustrations, grants carry two main advantages: No equity is sacrificed, and no debt is incurred. 

Federal grants are the most publicized source of funding, and they involve the largest pool of money. That pool was estimated at $5 billion in 2004, and since then, it has grown even larger. Most funds are distributed through Project BioShield, which was signed into law in 2004 with the goal of providing new tools to improve medical countermeasures against chemical, biological, radiological, and nuclear attacks. Project BioShield is charged with expediting research and development by the National Institutes of Health (NIH) on medical countermeasures, based on the most promising recent scientific discoveries. Proposals for funding from the US military may be directed through a number of programs; the Defense Advanced Research Projects Agency (DARPA) is probably the best starting point for a biodefense spin-off seeking funding. 

The Department of Homeland Security (DHS) is funding some projects, particularly in biodetection and treatment. Some DHS funds pass to individual states, which may be additional sources of grants (see below). 

The first step in identifying and applying for any federal grant is generally a conversation with the company's local member of the US Senate or US House of Representatives. This representative is likely to have a paid aide responsible for helping companies cope with governmental complexities. Companies outside the US can gain access by partnering with a US company. 

Grants made by an individual US state typically go to companies in that state and provide jobs for the state's residents. Many states have established their own programs to promote the research and development of biodefense products. They also may be distributing federal money, such DHS grants. The best starting point for a company seeking a state grant is usually a congressional representative or senator. 

Some state programs offer tax abatements instead of cash grants. Although abatements are not as desirable as direct funding, they may make it easier to attract investors. Many states use job creation as a major selection criterion for grants, and they may be more open to projects located in economically depressed areas. 

The availability of international government grants seems to change rapidly, and their requirements can range widely. The World Health Organization (WHO) is the focus for the United Nations' programs. The International Red Cross can also be a funding source for applied and delivery projects. 

Many countries have established programs similar to Project BioShield. For example, Great Britain, the Netherlands, Sweden, Germany, Switzerland, and Israel have actively funded biodefense companies in recent years. These national programs generally require that outside companies partner with in-country organizations. 

Foundations can be prime sources of research and development grants for biodefense and other medical applications. The first step for a spin-off seeking such a grant would be a letter to a foundation officer. The spin-off company that applies for multiple government and foundation grants, in cooperation with related universities or international partners, has a high probability of success and generally will carry no debt or loss of equity.  

Research foundations have been established for most major diseases. Biodefense projects with the potential to prevent or treat a specific condition, such as cancer or birth defects, may attract funding from these targeted organizations. 

Other foundations, both large and small, are oriented toward the general public health. Most of these can be easily identified through a web search.  

Corporate foundations have been established to fund promising medical and public health research. These are most commonly biomedical: Johnson and Johnson's Robert Wood Johnson Pharmaceutical Research Institute is an example. Although these foundations are functionally independent of their corporate parents, a spin-off company seeking a corporate foundation grant can enhance its potential for success by matching a project with an area of corporate focus. 

Although abatements are not as desirable as direct funding, they may make it easier to attract investors. To compensate for the high risks of early funding, investors typically seek equity or bond arrangements with high rates of return—often as much as an eight- to 10-fold return in five years. 

Angels are private individuals. They may be successful entrepreneurs themselves, professional athletes, private medical and dental professionals, or other individuals attempting to shelter large, short-term incomes over long-term periods. Angels often invest as groups (known as "angel networks"), and their investments are typically in the range of $50,000 to $1 million. 

Venture capitalists (VCs) are usually corporations that collect investment dollars from wealthy individuals and companies, and that invest in diverse portfolios. Their investments are usually in the range of $50,000 to $5 million. 

Biodefense start-up companies have an abundance of options when seeking funding.

Funding Biodefense Vaccine Development

All the headlines about contaminated syringes and tainted peanuts have put pressure on the US Food and Drug Administration to better detect unsafe medical and food products and to take swift action when problems emerge. In February, President Barack Obama criticized the FDA's ineptness in catching contaminated products and urged a "complete review of FDA operations." The Government Accountability Office (GAO) put the FDA on its federal agency "high-risk" list in January because of its failure to protect public health and ensure the safety of drugs, biologics, and medical devices. The complaints are prompting the White House to provide more resources for the FDA while Congress weighs a number of proposals for expanding foreign inspections and giving the agency more enforcement authority. 

One positive sign is the boost in the FDA's budget to enhance oversight of food and medical product safety. In the long-delayed 2009 federal appropriations bill, the FDA received more than $2 billion from the government, a $325 million increase over 2008. After adding in user fees, the agency will have a record $2.6 billion budget. That includes $413 million for drugs and $184 million for biologics, plus $500 million in user fees. In return, the legislators expect a significant increase in foreign and domestic facility inspections, expansion of laboratory infrastructure, and upgrades in information technology. The Alliance for a Stronger FDA cheered the funding increase and will press to continue the trend as the Obama administration rolls out details of its 2010 funding plan.  

The FDA is slated to receive even more resources to boost inspections under the FDA Globalization Act of 2009 (HR 759), a priority initiative for Rep. John Dingell (D-MI), former chairman of the House Energy & Commerce Committee. Main co-sponsors include Rep. Frank Pallone (D-NJ), head of the E&C Health subcommittee, and E&C Oversight subcommittee chair Rep. Bart Stupak (D-CO), who has been investigating FDA import and inspection failings for several years. Pallone says he plans to hold hearings on the legislation and to move it through the committee simultaneously with health-reform proposals.  

The Globalization Act expands the FDA's authority to inspect foreign plants and block questionable imports, and to crack down on those who fail to comply. Regulatory parity is sought to ensure that lax oversight is not luring manufacturers from the US to Asia. All registered manufacturers and importers—including generic drug makers—will have to pay new user fees to support the broader oversight program, and manufacturers will ensure the integrity of product supply chains through electronic pedigrees.  

The FDA also would gain the power to recall, destroy, or detain unsafe, adulterated, or misbranded goods. There is added authority to subpoena records and to impose criminal penalties for drug counterfeiting. To improve its inspection program, the FDA is instructed to establish a dedicated cadre of inspectors for foreign food and medical product facilities. And FDA officials are prohibited from closing down field laboratories or district offices without making a case for such changes in a reorganization plan that will be reviewed by GAO and submitted to Congress.  

Of particular interest to biopharmaceutical companies is new language in the bill specifying that FDA policies do not override state laws. This provision reflects Democratic opposition to FDA pre-emption of state liability laws, but may be less important in wake of the recent Supreme Court ruling in the landmark Wyeth versus Levine case. Last month, the Justices rejected Wyeth's claim that FDA approval of a drug's labeling overrides state laws and agreed with the plaintiff that FDA decisions are not the last word in drug regulation. The Globalization Act supports this contention and opens the door for state prosecutors and plaintiffs attorneys to bring actions against companies that violate state laws even though they comply with FDA regulations.  

The revised Dingell bill addresses some concerns raised by the FDA and manufacturers to an earlier proposal. Instead of requiring country-of-origin information on every ingredient in a product, for example, the FDA gains a year to develop rules for providing this information to the public, possibly through web sites. There's noticeable support for risk-based approaches to ensuring product quality and safety, plus flexibility for the FDA to reduce inspections from every two to every four years at plants that produce low-risk therapies and that present a strong record of compliance with good manufacturing practices (GMPs). All registered pharmaceutical manufacturing facilities will have to develop quality risk-management plans that spell out procedures for auditing and qualifying raw ingredients and for monitoring incoming materials.  

The focus on unsafe medical and food products is generating additional legislative proposals in the House and Senate. Rep. Rosa DeLauro (D-CN), chairman of the House Appropriations Committee that oversees the FDA's budget, recently re-introduced a bill to separate food regulation from medical product approvals by creating a separate Food Safety Administration that will provide needed attention to food safety. The FDA Food Safety Modernization Act, sponsored by Senate majority whip Richard Durbin (D-IL), proposes more targeted user fees for domestic and foreign food operators to support increased inspections, while also giving the FDA more power to monitor food quality and to recall noncompliant products.  

The Durbin bill also addresses the need to protect food products from intentional contamination, an issue that reflects concerns about increased overseas production of pharmaceuticals and vaccines. Some members of Congress complain that the massive shift of pharmaceutical production to Asia and other regions not only exposes Americans to low quality and adulterated products, but may leave the US vulnerable to supply chain interruptions during a pandemic outbreak or other emergency.  

Ironically, legislation that increases FDA inspections of foreign drug makers may re-open the door to drug importing. A group of leading senators is sponsoring a bill to allow nationwide re-importation of prescription drugs, claiming the program would save $50 billion over 10 years. All the imports would have to come from FDA-approved manufacturing plants  in Canada, Europe, Australia, New Zealand, and Japan—a policy that assumes more frequent inspections and a viable pedigree system.  

While Congress weighs these proposals, FDA is issuing guidance and launching initiatives that increase overseas inspections and provide greater assurance of drug quality. The FDA's "Beyond Our Borders" program is expanding into South America and India after opening offices in China a year ago and establishing a more formal presence in Brussels, Belgium. At the beginning of this year, the FDA also joined six federal agencies in issuing a government-wide policy to ensure "Good Importer Practices" for preventing and detecting hazards or contamination through a product's lifecycle. A new FDA voluntary secure supply chain pilot program will offer expedited entry to drug manufacturers able to demonstrate control over their supply chain from time of manufacture through entry into the US. The two-year initiative will start with up to five products from 100 manufacturers and aims to identify strategies for preventing import of contaminated or counterfeit drugs. And the FDA is supporting supply chain security by establishing a standardized numerical identifier for drugs and biologics, as required by the FDA Amendments Act of 2007. A guidance document issued in January (2009) advises manufacturers to use a product's national drug code plus a unique eight-digit serial number for identifying drug packages.  

A common thread in FDA and Congressional initiatives is that manufacturers are ultimately responsible for the quality and safety of their products, and that the FDA will never be able to detect every product failure. Increased foreign sourcing of ingredients creates ever more complex supply chains and new challenges in protecting against product contamination, diversion, and counterfeiting. Manufacturers emphasize the need for a universal drug pedigree system that can document product sourcing, and additional legislation may further support harmonization of practices and policies for ensuring product quality through the supply chain. 

Washington editor, Chevy Chase, MD, 301.656.4634, 

The FDA is poised to gain more authority and resources to ensure product quality.

Food and Drug Safety Crises Prompt White House, Congressional Action

The contract manufacturing organization (CMO) landscape has changed dramatically over the past few years. Growth in biotechnology, an increasing emphasis on science-based technology, and the emergence of innovative virtual startups rising from the ashes of corporate mergers have spawned a variety of CMOs that offer competitive pricing and highly specialized services. These new options are wonderful from the buyer's perspective as long as a methodical approach is taken to make CMO selections that fit your company's business model. 

A logical first step in selecting a CMO involves making an assessment of internal capabilities, strengths, and needs that can then be overlaid on anticipated external requirements. A company with marketed products and established infrastructure for manufacturing, testing, packaging, and distribution must identify pockets of supply-chain weakness and then evaluate the financial benefit of outsourcing. If the assessment identifies large-volume under capacity for a product or product line, consideration of a large offshore CMO could represent a cost-effective solution, provided there are no extenuating circumstances associated with product release or distribution. In other cases, the assessment could lead to a decision to outsource processes that require specialized expertise. The CMO choice in that scenario would be made based on an evaluation of the sponsor company's ability to manage the interface with the CMO. 

CMO selection is one of the most critical decisions made by companies with limited internal resources dedicated to production, testing, and control of pharmaceutical products whose definition includes development compounds, clinical trial material, and commercial active pharmaceutical ingredients and products. This article describes a systematic supplier selection approach taken by a company with operations outside the US, but with a commitment to develop, manufacture, and gain approval to market a specialized drug product using a completely outsourced model for manufacture and testing of this product in the US. 

The company wanted a CMO with capability to fill ampoules and vials with a sterile emulsion containing a potent drug substance whose stability is affected by exposure to elevated temperature, but not sufficiently to preclude the requirement to terminally sterilize finished dosage units. Phase 1 lots of this drug product were manufactured and tested by a reputable pharmaceutical company with primary operations in Asia. A specific homogenization technology was used to make the emulsion, which is commonly found in the US food industry, but is not as common in the pharmaceutical industry. The sponsor company did not wish to change homogenization technology because of the potential impact on emulsion properties. 

The supplier selection process began with detailed review of process data from the original clinical trial material manufacturing process. The review revealed specific homogenization parameters and identified two critical features of the process that would be important for technology transfer to the CMO. The first issue was the need to use a rotating autoclave with capability to heat up and cool down quickly to preserve emulsion properties. The second issue related to equipment cleaning, but was not considered a limiting factor in the CMO selection process. 

A checklist of optimum supplier attributes was developed from the data review to be used as a guideline for preliminary supplier screening. The prerequisites included:  

Experience with pharmaceutical emulsion development

Capability to manufacture commercial-scale sterile emulsions

Onsite access to a validated rotating autoclave.

Initial CMO screening was conducted using hardbound and Internet-based directories to identify potential candidates. Benchmarking exercises were completed by contacting development staff employed at companies that market specialized emulsion formulations. Concurrently, the manufacturer of the desired homogenization technology was contacted to determine a potential list of contract manufacturers who purchased the specific technology needed for the sponsor company's product. 

The result of initial screening was a list of 10 CMOs who could potentially handle the sterile emulsion project. A general product information sheet was developed as a tool to facilitate telephone conversations with technical and business development staff at the 10 shortlisted CMOs. Some CMOs were immediately eliminated from the list because their capabilities did not meet the criteria for the project. Other suppliers were eliminated from further consideration because of conflicting requirements associated with a potential business relationship. Ultimately, a short list of five CMOs was developed. 

Confidentiality agreements were executed with each shortlisted CMO. A detailed product specification sheet written in the format of a technical transfer questionnaire was prepared and submitted to each candidate. The CMOs were asked to review the information and respond with details explaining how the project could be managed at their facility and, in particular, explaining any issues that would have to be resolved to make the sterile emulsion properly. For example, buying and validating a new rotating autoclave at the sponsor's expense was not considered a viable option. The result of the in-depth paper evaluation of suppliers was condensed into the matrix shown in Table 1. 

Table 1. The results of the in-depth paper evaluation of suppliers 

A study of the information in Table 1 revealed that none of the five suppliers included on the candidate short list met all of the criteria for this project. Supplier 1 and Supplier 5 were removed from consideration because capital expenditures would have been necessary for the CMO to manufacture the product. Both suppliers requested co-marketing arrangements for the product, which was an unacceptable consideration on the part of the sponsor. The sponsor recognized that a minimum production volume requirement might have to be negotiated as part of the final supply agreement, but was unwilling to consider co-marketing as an option. Supplier 4 was eliminated because the CMO's development capabilities were determined to be inferior to the other suppliers and not robust enough to support an offshore technical transfer of a sterile emulsion. The final decision was to enter the formal evaluation stage with Suppliers 2 and 3. It is notable that virtually none of the suppliers had the capability to handle sterile emulsions and fill ampoules, and therefore, a management decision was made to drop the ampoule from the development plan. 

The final evaluation stage involved detailed financial and regulatory compliance due-diligence. A formal technology transfer questionnaire, comprehensive product specification information, and technical development documentation were provided under protection of the previously executed confidentiality agreement and with additional protection of a two-way letter of intent. At the same time, regulatory compliance audits were scheduled at the sites proposed for manufacturing the sterile emulsion. Supplier 2 met all the criteria for the project but was confronted by a significant logistical problem because their only rotating autoclave was not located at the site that filled sterile emulsions. Shipping the unsterilized emulsion from site-to-site was not an option. Supplier 3 was primarily a large-volume manufacturer of emulsions so their proposal had to identify a cost-effective and timely resolution for filling small-volume parenteral products. Supplier 3 indicated it would consider making large capital improvements as part of the terms of a preferred supplier agreement. 

The financial and regulatory compliance due-diligence audits revealed several important points that affected the final outcome of the outsourcing decision. The financial assessment identified conflicts between the development and manufacturing units of Supplier 2 that had potential to impact negotiation of the supply agreement. Supplier 3, while solvent, was determined to be in jeopardy of being sold by its parent company. It was essential to confirm that a strategy was in place to maintain the ongoing business. 

The compliance audits provided the final information to make the CMO selection decision. Supplier 2 failed the compliance audit. The development group was determined to be underqualified to handle the sterile emulsion product. The proposal offered to handle terminal sterilization was viewed as inadequate. Manufacturing operations were observed to be loosely controlled. Supplier 3 was observed to have the best sterilization technology for an emulsion and had a strong development group. Supplier 3's plan proposed to convert a large-volume parenteral area to small-volume manufacturing was considered as marginal, but staff members at the sponsor company agreed this issue could be jointly resolved. Therefore, Supplier 3 was selected. 

 is vice president of regulatory compliance at Fulcrum Pharma Developments, 919.228.4432,  

"A systematic approach taken by a company involved making an assessment of internal capabilities, strengths, and needs before the selection process."

Criteria for Selecting a CMO: A Case Study

Biopharmaceutical companies generally try to avoid the idea of paying royalties on novel technologies, including novel expression systems, in part because of the inability to predict revenue flow after a product is commercialized. But even when a new expression system could sugnificantly reduce cost, many remain hesitant. Despite this, adopting new technologies continues to be fundamental to improving product quality and cost. 

"High tech industries adopt new technologies so they can produce better, cheaper, and faster. Sticking with what you know may seem safe, but in biomanufacturing this may have more to do with the lack of knowledge about emerging alternatives," says Ronald Rader, author of the BioPlan Associates report, 

Biopharmaceutical Expression Systems: Current and Future Manufacturing Platforms.

Of course, one reason for the limited adoption of expression system technologies in biomanufacturing is the conservative, regulated nature of the industry. Tillman Gerngross, PhD, professor of engineering at Dartmouth College, co-founder and CEO of Adimab Inc. (Lebanon, NH) and co-founder, and ex-CSO at GlycoFi, which was recently sold to Merck & Co. (Whitehouse Station, NJ), says that, "Making things cheaper while increasing regulatory risk has not been a winning formula in this industry; consider transgenic animals and plants." 

Rather, Gerngross believes  adopting technologies that improve product quality in ways that have a direct therapeutic impact is where the greatest value is added. Improved expression systems must do more than simply reduce costs. "Production costs are a small fraction of the final cost of goods—it roughly breaks down into a 1/3 production, 1/3 purification, and 1/3 formulation and QC." Therefore, cost-of-goods for a protein might be as low as 4%, which means reducing production costs will not significantly affect the overall cost structure, and that doesn't leave much room for royalties to the supplier of such technologies. 

ADOPTION OF NEW EXPRESSION SYSTEM TECHNOLOGIES

Sixth Annual Report and Survey of Biopharmaceutical Manufacturing

, we explored the potential for adoption of new expression systems (Figure 1).

  We were not surprised to find that 55% of respondents at biomanufacturing facilities indicated they would consider an alternative expression system in early R&D. However, we did find that 43% of respondents in process development stages would consider alternative expression systems. This suggests that for new drug products, manufacturing technologies are not written in stone. 

We also found that royalty payments for new expression system technologies were seen as much more acceptable to many biomanufacturers than we had expected. The acceptance of new technologies seems to be dictated by how a new system would improve manufacturing. For example, nearly 46% would pay royalties if the system offered greater yield, and 36% would pay royalties if they were able to commercialize their failed projects.  

The historical reasons that biopharmaceutical organizations are now primarily using the tried-and-true, common protein production expression systems stem from the industry's conservatism. Today, there is a need for increasing titers. Many believe that as long as the large numbers of current manufacturing projects using conventional expression systems continue to improve, the demand for novel systems will stagnate. "It is a conservative industry—nobody ever got fired for using 

, yeast, or CHO," says Gerngross. Many in the industry expect alternative expression systems to make strong headway, but only when they go beyond simply reducing costs, and provide such advantages as improved therapeutic properties.  

Pharmaceutical companies requiring technology improvements may also consider company acquisition. In 2006, for example, Merck acquired GlycoFi for $400 million to access its yeast glycoengineering and optimization technology. GlycoFi's technology is designed to produce therapeutic proteins more effectively in 

 (yeast) instead of Chinese hamster ovaries (CHO) or NS0 cells, offering improved speed and quality.  

Such outright technology acquisitions can be cleaner than technology deals that involve some kind of risk–reward sharing over time, where both the product developer and the innovator company share the risk if product sales do not meet expectations.  

Another concern with licensing and royalties is "royalty stacking." Though more common in drug product licensing, it is one of the risks technology adopters face. Royalty stacking is caused when multiple overlapping patents compel companies to obtain multiple licenses. Pharmaceutical companies are increasingly hesitant to form alliances with biotechnology companies if potential royalty stacking issues exist.  

Information on alternative expression systems and genetic engineering technologies is readily available.

  Most technologies can be licensed at reasonable fees for evaluation purposes, and most are available for commercial license on a nonexclusive basis. Some expression systems may be licensed exclusively. This generally costs more than taking a nonexclusive license, but can provide insurance against your product competing with another similar one. 

Although technology licensing increases costs through licensing fees and royalties based on annual product revenue and sales, it is often the only prudent option for most organizations. Licensing is the only legal and fair method of using technology developed by others, particularly if covered by patents. Most organizations, whether biopharmaceutical companies, CROs, CMOs, universities, or government laboratories, seek to license out any relevant technology that they have invented and patented to get some return on their investment.  

Licensor organizations generally will work with companies to tailor licenses to their needs. This may involve various combinations of upfront and postmarketing fee arrangements. For example, a small company may prefer to pay a lower upfront licensing fee in return for somewhat higher royalty rates on eventually product sales. Those confident that a technology will be used to manufacture one or more products may prefer to pay higher upfront fees with lower back-end royalty rates. For major products, including blockbusters, this approach can save hundreds of millions over the course of a product's commercial life.  

Many technology sources are receptive to providing a limited license for access and use of their technology for in-house evaluation purposes. Some companies and noncommercial organizations with expression systems in development may be eager to collaborate with companies that will actually use their technology for product manufacture. 

With the pharmaceutical industry being very conservative, and with companies and regulators having distinct preferences for proven, known technologies, companies among the first to actually commercially manufacture a product using a newer technology can provide its developer with real-world cost-of-manufacture data and the references needed for wider commercialization of the new technologies. Thus, those among the first to license a new expression system or related genetic engineering technology can often receive better licensing terms, although the risk of failure or problems obviously increases with being among the first adopters.  

Unlike licensing of actual product candidates, most licensing of process technology will be done in the relatively early stages of product development. Because a large number of technologies is available from many sources, there is more competition. This can tend to keep licensing terms down and increase the predictability of licensing terms and royalties associated with manufacturing technologies, compared to licensing of product candidates. Thus, in comparison with licensing of candidate products, licensing of manufacturing technologies tends to be more competitive and predictable in terms of fees and royalties.  

For an industry based on innovation, newer manufacturing technologies can be vital for a company's survival, and thus worth the expense, time, and effort involved. Older technologies have the advantages of predictability and regulatory acceptance. When considering that many of these technologies entail lost opportunities as we move into the future, older technologies may find themselves increasingly limited by their performance.  

 is president and managing partner at BioPlan Associates, Inc., Rockville, MD. He is also the editor of 

Advances in Large-scale Biopharmaceutical Manufacturing and Scale-up Production

's Editorial Advisorial Board. 301.921.5979, 

 1. Rader R. Biopharmaceutical expression systems and genetic engineering technologies. Rockville MD: BioPlan Associates, Inc.;2008. 

 2. Sixth annual report and survey of biopharmaceutical manufacturing, 2008–2009. Rockville MD: BioPlan Associates, Inc.;2009. 

With all of the new expressions systems being developed, companies must decide what improved production and yield are really worth.

Expression System Royalties Battle

Opalescence is a phenomenon that has been observed in several commercially available monoclonal antibodies, both in liquid and reconstituted lyophilized formulations. In this article, we demonstrated that an increase in the ionic strength of a monoclonal antibody formulation (MAb1) led to opalescence and higher viscosity. When the ionic strength was reduced, no opalescence in the MAb1 formulation was observed. The removal of polysorbate-80 (PS-80) from the formulation resulted in an increase in opalescence in NaCl-containing formulations, whereas it had no effect on formulations lacking NaCl. Differential scanning calorimetry with MAb1 formulations containing increasing amounts of NaCl indicated that formulations with higher ionic strength present a lower apparent melting temperature. Opalescent MAb1 formulations placed on stability remained unchanged after four weeks at 4 °C, whereas at 45 °C, an increase in dimers was observed. Using multi-angle light scattering, the MAb1 formulation was found to have a negative second virial coefficient.

There are more than 23 therapeutic monoclonal antibodies that are commercially available for treating a wide variety of diseases.

  Of these products, several have an opalescent appearance either as liquids or following reconstitution of a lyophilized formulation.

 is defined as exhibiting a play of colors like that of the opal, or having a milky iridescence.

Factors influencing the opalescence of an IgG1 monoclonal antibody formulation include the concentration of the antibody as well as formulation components such as buffers, ionic strength, excipients, and pH. It was demonstrated that an increase in the concentration of the antibody and a decrease in temperature (5 °C) of an IgG1 formulation resulted in opalescence.

It is well known that ionic strength can affect the behavior of proteins in solution. In most cases, at low and high salt concentrations either salting-in or salting-out occurs, respectively.

  Salting-in is observed when electrostatic interactions between the salt ions and charged residues of the protein are favorable.

  Salting-out occurs when the salt ions are excluded from the protein, which is mainly caused by unfavorable interactions between the salts and hydrophobic regions of the protein.

  There are examples, however, in which proteins are soluble at high salt concentrations.

The ionic strength can also mediate protein–protein interactions. One example is with the protein b-lactoglobulin, which is predominantly monomeric at pH 3 in the absence of salt, but is dimeric in the presence of salt.

  Additionally, the type of salt may also affect the stability of the protein. Bovine serum albumin is stabilized against thermal unfolding with NaSCN and NaClO

, both kosmotropic salts, yet destabilized by chaotropic salts at high ionic strength.

  In other examples, aggregation was decreased in the presence of NaCl for both recombinant factor VIII SQ and recombinant keratinocyte growth factor, whereas aggregation increased in the presence of NaCl with recombinant human granulocyte colony stimulating factor.

In the following article, we sought to determine whether ionic strength and excipients mediated the opalescence of an IgG1 formulation (MAb1). It was demonstrated that MAb1 formulations become opalescent as the ionic strength of the formulation is increased. Conversely, MAb1 formulations without salt lack opalescence. The second virial coefficient of MAb1 was negative. Stability studies indicated that opalescent MAb1 formulations have increased amount of irreversible dimers at elevated temperatures. 

MAb1 is a fully human IgG1 monoclonal antibody. MAb1 was purified from Chinese hamster ovary (CHO) cells by Bioprocess Research and Development, Merck Research Laboratories (Whitehouse Station, NJ). The MAb1 formulation contains 24 mg/mL IgG1 in a formulation containing a buffer, NaCl, and polysorbate-80 (PS-80), pH 6. Polysorbate-80 was from Croda Incorporated (Mill Hall, PA). NaCl, KCl, MgCl

, hexamethylenetetramine, and hydrazine sulfate were from Sigma (St. Louis, MO). The filter used was a 0.22 μm Millex GV from Millipore (Billerica, MA). 

Opalescence of the samples was assessed according to the 

 5.0 (2.2.1). Opalescence reference suspensions were made using hexamethylenetetramine and hydrazine sulfate. Samples were evaluated at a volume of 11 mL in 20 mL glass vials by comparing them to the reference suspensions in diffused daylight against a black background.  

The opalescence of MAb1 was measured by subtracting the optical density (OD) at 350 nm from the OD at 550 nm using an HP spectrophotometer as previously described.

Size Exclusion High Performance Liquid Chromatography

Size exclusion high performance liquid chromatography (SEC–HPLC) was performed using a TSKgel 3000SW

 column from Tosoh Corporation (Tokyo, Japan) with a mobile phase consisting of 25 mM phosphate, 0.3 M NaCl, pH 7.0. The flow rate was 0.5 mL/min. The temperature of the column was maintained at 25 °C. The samples were detected at 230 nm. 

The particle sizes of samples tested were measured by dynamic light scattering (DLS) using a Zetasizer Nano System from Malvern Instruments (Malvern, UK). A total of 10 measurements for each sample were taken and the results were reported as the Zave, the average hydrodynamic size.  

Viscosities were measured using a LVDV-III Ultra Programmable Rheometer by Brookfield Engineering (Middleboro, MA). Sample volumes of 0.5 mL were tested for each measurement.  

Determination of the Osmotic Second Virial Coefficient Values

The osmotic second virial coefficient was obtained using a Dawn Heleos multi-angle light scattering (MALS) instrument from Wyatt Technology Corporation (Santa Barbara, CA). The formulations containing buffer and 150 mM NaCl (no PS-80) were diluted and injected into the instrument as follows: 1:2.5 (8.20 mg/mL), 1:5 (4.10 mg/mL), 1:10 (2.05 mg/mL), and 1:20 (1.03 mg/mL). The Rayleigh equation was used by the computer software to generate data on the Zimm plot. The software also calculated the molecular weight and particle size of the sample. 

The Rayleigh equation is described as follows (Malvern Instruments):

θ is the the Rayleigh ratio—the ratio of scattered light to incident light of the sample (cm

 is the angular dependence of the sample scattering intensity, and 

 is the optical constant, which is calculated using Equation 1.1: 

 is the the differential refractive index increment (cm

For particles that are smaller than the incident light (laser) used to measure the particle size, Equation 1 can be reduced to the linear form shown in the following:

MAb1 in a liquid formulation consisting of 24 mg/mL of IgG1 in a buffer, 150 mM NaCl, and PS-80, pH 6.0 in glass vials was inspected visually at 25 °C and was determined to be opalescent (Figure 1). The MAb1 formulation was equivalent to a Reference III standard [18–30 nephelometric turbidity units (NTU)] according to the 

 (5.0, 2.2.1, Clarity and degree of opalescence of liquids). Following filtration of MAb1 through a 0.22-μm sterilizing filter, the opalescence remained unchanged, indicating it was not caused by insoluble aggregates (data not shown).  

The particle size of MAb1 was evaluated beginning at a concentration of 20 mg/mL of IgG1 in a buffer, 150 mM NaCl, and PS-80, pH 6.0 in glass vials and was diluted in the same formulation to approximately 1 mg/mL (Figure 2). It was determined that MAb1 had a larger apparent hydrodynamic radius at higher concentrations, and that it decreased as the formulation was diluted.  

Can increase in ionic strength result in higher viscosity?

BioPharm International-04-01-2009

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Funding Biodefense Vaccine Development

Food and Drug Safety Crises Prompt White House, Congressional Action

Criteria for Selecting a CMO: A Case Study

Expression System Royalties Battle

Opalescence of an IgG1 Monoclonal Antibody Formulation is Mediated by Ionic Strength and Excipients

Process Validation Guidance—Redux

Adapting to Opportunity

Disposables Cost Contributions: A Sensitivity Analysis