"I'm glad I wasn't the forklift driver," exclaims our GMP Agent-in-Place. "Although he wasn't the only one at fault.  You see, we had been having problems with sealing the aluminum caps onto the vials after stoppering, and we thought that a new capper would be just the ticket to improve the situation. So a new capper was ordered 'on approval.' That is, we ordered and received it with the provision that it would be paid for if it worked. 

"But when we tried to put it to use, it didn't fix our problem, and so this new capper was scheduled to be returned to the vendor. It was staged on the dock, ready for pickup. But someone left the dock door open. During routine shuffling of other pallets on the dock, the capper was bumped hard enough to send it out the door, and four feet to the ground. What was a $50,000, unpaid capper to be returned to the vendor now was an unpaid piece of junk. 

"Management then had to get capital authorization approved to pay for a capper that not only wouldn't work for us, but was accidentally busted." 

"Most of us don't give a thought when passing by any of the numerous semi-trucks on the highways. Nor do we consider what they might contain," notes our GMP Agent-in-Place. "We used just such a truck to move product from the manufacturing site to the distribution center that was just one hour away. But one day, our truck became involved in an accident. No one was seriously injured, but inside the trailer the product shifted, damaging some of the glass vials. 

"You don't plan for it, but you always need to have a salvage plan for such occasions. All the vials were inspected for damage to the glass and to the labeling, before they were allowed to be sold." 

"It was the straw that broke the camel's (company's) back," explains our GMP Agent-in-Place. "A pallet of unlabeled, filled glass vials was being moved into storage and needed to be stretch-wrapped first. So the pallet was moved onto the turntable. But the turntable had, over the years, moved from proper installation, which would be flush with the floor, to having the front edge raised about two centimeters above the floor level. The pallet being moved onto the turntable hit that raised edge. Once the pallet hit the edge, many bottles fell to the floor and broke. The product from the broken bottles splashed on other bottles. 

"What a mess! The obviously broken bottles were pulled out. The pallet was moved to a nearby room where the bottles were rinsed off using the hose that contained city water. The unbroken bottles were 100% inspected and released. Unfortunately, we later received adverse event reports from this batch, which was traced to contamination from the water in the hose seeping into unseen cracks in the bottles. 

"Luckily, no deaths were reported, but the adverse events led to an FDA inspection which, when combined with the (not so good) compliance history of our site, in turn led to a consent decree. A review of several companies' consent decree experience in the literature will show that they can cost a billion bucks!"  

 monthly "Agent-in-Place" column distills true-life cautionary tales from the secret files of Control, a senior compliance officer. If you have a story of clueless operators, oblivious management, inopportune lapses of judgment, or Murphy's Law in action, please send it to Control at 

 We won't use any names, but if we do use your tale of disaster, courage, or just plain weirdness, Control will send you a coveted 

Articles

Agent-In-Place

Falling to Pieces

One of the hallmarks of the growth of outsourcing in the pharmaceutical industry has been the evolution of new sourcing models. As outsourcing gains acceptance, pharmaceutical companies and contract service providers experiment with and adopt various approaches to the packaging and delivery of services. The major themes in model evolution include  

moving from bidding individual projects to establishing preferred provider relationships covering multiple projects; 

various approaches to bundling services together 

 outsourcing the delivery of a single capability in support of multiple projects or studies.

Sourcing models pursued in clinical and nonclinical development services have evolved in somewhat opposite directions. For most of the past 10 years, buyers of clinical research services have preferred to buy contract research organization (CRO) services on a full-service basis. That is, they have tended to buy the range of services needed to complete a clinical study—study management, site monitoring, data management, biostatistics, and medical writing—from a single CRO for a fixed price. By contrast, buyers of nonclinical services have tended to buy the necessary services for a particular drug candidate—process development and manufacturing for active pharmaceutical ingredients, dose formulation and development, clinical packaging, and analytical services—from multiple vendors, each specializing in a particular discipline. 

Today, the trends in the two sectors are moving in opposite directions. Major pharmaceutical companies are embracing a functional outsourcing approach for clinical research under which they contract with a single provider to deliver a particular service in support of all their clinical trials. In the nonclinical realm, the trend is toward a full-service model, often referred to as the one-stop shop. 

These opposing trends reflect some very different dynamics in these two sectors of the pharmaceutical services industry. The rise of functional outsourcing in clinical research is being driven primarily by the industry's embrace of clinical information technology (IT). This change brings with it the need for new areas of expertise such as systems integration as well as new opportunities to realize cost savings by offshoring software development and data processing. Creating a single data infrastructure for all clinical trials facilitates using clinical data for applications beyond the study for which it was collected, including strategic planning, marketing, and disease modeling. Contracting with a single, dedicated information technology services provider to build and maintain the clinical data infrastructure offers the promise of best-in-class capabilities and cost savings across all clinical operations. 

The functional outsourcing model in clinical research has been adopted in several major pharmaceutical companies, including 

(Madison, NJ), and based on discussions at April's 

 conference in Orlando, Florida, more companies appear to be adopting it. Furthermore, the model is moving beyond data management into other clinical research areas: Wyeth has struck a deal with 

 (Dallas, TX), a clinical CRO, to provide site monitors for clinical trials, and the company recently contracted with 

(Plantation, FL) to provide logistics for distributing clinical supplies to investigator sites. 

One interesting implication of the trend toward the functional model is that it has opened the door to new competitors in the clinical research sector. IT outsourcing giants 

(Mumbai, India) have become important players in clinical data management, and it is widely speculated that Federal Express and UPS will join DHL in competing with established clinical packagers and couriers. That specter of increased competition from global leaders has traditional CROs very worried. 

Functional outsourcing has been the rule rather than the exception in nonclinical outsourcing. The reason has little to do with the cost and performance advantages being pursued in clinical research, however.  

Instead, the predominance of the functional model in nonclinical development reflects the fact that the component disciplines of nonclinical development have very different and specific technical and operation bases and require expensive specialized capital infrastructure. (Clinical research requires very little capital investment, and its human resource requirements can be met with job-specific training in most cases.) Nonclinical services companies have traditionally been unwilling or unable to make the capital investments and assemble the expertise necessary to offer a full-service nonclinical offering. An early effort to assemble a full-service nonclinical offering, Oread, flamed out more than  five years ago because it couldn't support the cost of maintaining so many capital- and technology-intensive capabilities. 

The return of the one-stop-shop model in recent years reflects two major trends in the pharmaceutical industry. The first is the renewed support for early-stage companies developing new drug candidates and their focus on getting to proof-of-concept (positive results at Phase IIA) as quickly as possible. Venture-backed early-stage companies account for over 50% of the new drug candidates in early development (preclinical through Phase IIA), and their development programs are geared toward achieving proof-of-concept as quickly and cheaply as possible. Most of these companies lack the facilities and breadth of scientific and development know-how to manage a program to proof-of-concept, let alone to commercialization. The full-service nonclinical CROs are promising these early-stage companies a quick and cost-effective route to proof-of-concept by providing a turnkey offering with complete nonclinical capabilities and project-management skills to tie it all together. 

The second trend is the interest of private equity investors in the pharmaceutical services market. The nonclinical contract services business is highly fragmented and presents many acquisition opportunities for private equity investors looking to build a large CRO operation by buying up a number of smaller operations. The full-service CRO presents a logical model around which to build an acquisition strategy. 

As the pharmaceutical service industry continues to mature, we will see many variations of the basic full-service and functional models. Early-stage and virtual companies will tend toward the full-service model for both clinical and nonclinical services. That's because they need the regulatory and project-management expertise embedded in the full-service model along with the basic technical disciplines. 

Large pharmaceutical companies are likely to use a hybrid approach, mixing and matching the models as appropriate to meet their objectives of greater flexibility and lower costs. In clinical research, data management, clinical supplies logistics, and central laboratory services will be sourced largely on the functional model, but study management and monitoring services could be provided by full-service CROs with expertise built around specific therapeutic areas. In the nonclinical area, services that are closely linked, (

 formulation and clinical supplies manufacturing, may be sourced on a full-service basis) but we expect functional capabilities to count more heavily in nonclinical sourcing arrangements.

 is president of PharmSource Information Services, Inc., and publisher of Bio/Pharmaceutical Outsourcing Report, tel. 703.383.4903, fax 703.383.4905, 

Outsourcing

Preferred models for clinical and nonclinical services move in opposite directions.

Functional versus Full-Service Outsourcing Models

Since its inception in 1820, the US Pharmacopeia (USP) has developed authoritative, credible, publicly available standards for medicines, dietary supplements, and related products. Then as now, a lack of consistency in how medicines were prescribed, prepared, dispensed, and administered posed a risk to public health. Our mission has always been to promote public health and to benefit health professionals, patients, and consumers by seeking to establish purity and consistency. This is no small task. 

To meet the challenge, USP exercises a vigorous standards-setting process that draws on both public comments and meticulous scientific review. As an independent organization, USP does not have the authority to compel submission of information for standards. Rather, we have worked hard to build relationships with pioneer and generic pharmaceutical manufacturers and experts, many of whom have a strong appreciation for the value of public quality standards. Over time, these (and many other) relationships have allowed the number of monographs in the 

 to grow from the original 1820 tally of 621 to the current total of over 4000. 

The worldwide array of pharmaceutical manufacturers and experts who choose to participate in this effort provide proposed new monographs, General Chapters, and a wealth of data. But that's just part of the story. In addition to industry cooperation, public input and interaction are vital to the development of USP standards. Once materials are received, USP's scientific staff and volunteer experts review the input, conduct laboratory tests, where necessary, and then publish the proposals in 

—USP's bimonthly journal of standards development and compendial review—for public comment. A USP Expert Committee subjects all comments to scientific scrutiny before making the recommendation to publish a standard in the 

). To further ensure transparency, all communications with USP regarding standards become a matter of legal record. 

This public process helps refine and finalize information before its official publication in 

 It is important to note that the volunteer experts are themselves vetted for scientific knowledge and expertise in an open and competitive election process at USP's five-year convention. Expert Committee members serve as unbiased volunteers under strict conflict-of-interest and confidentiality regulations. The combination of fully available public commentary and highly qualified expert oversight ensures both rigor and a broad range of scientific input. For a public standard to be credible, this two-fold approach is key to establishing confidence.  

An explanation is never as clear as an actual example. Consider the progress of General Chapter ‹797› Pharmaceutical Compounding–Sterile Preparations, which is currently headed toward official publication in 

 (at a date still to be determined). The last time ‹797› was revised, USP did so entirely through the efforts of staff working with volunteer experts. The practitioner community was not involved, not by intent but because compounding pharmacists tend not to be subscribers of 

  The Sterile Compounding Expert Committee, responding to growing concern about the quality and consistency of compounded preparations, revised the 1995 General Chapter ‹1206› Sterile Products for Home Use. The revisions were extensive and included the renumbering of the General Chapter to ‹797›. This is significant, of course, because it moved the General Chapter from informational (those numbered over ‹1000›) to enforceable (those numbered under ‹1000›). The impact was even greater given the growing importance of compounding as a means of tailoring a drug dose to an individual patient, or in replacing a discontinued manufactured drug. 

Following publication in 2004, as practitioners realized the effect of the revised, now-enforceable General Chapter ‹797› on their daily work, there was a surge of input that had not initially been solicited— about 2000 comments. This outpouring underscored the importance of public comment as well as expert review, and USP started the current revision cycle as quickly as possible. This time we did it quite differently: We held briefings for 16 stakeholder organizations, plus a stakeholder forum meeting. About 60 compounding professionals and other interested parties attended, and we held Webinars for those who could not be there in person. At these sessions, staff reviewed proposed changes and actively sought stakeholder input. In addition, we provided an online mechanism to view and comment on proposed changes to ‹797›. Through these outreach efforts, we got hundreds of comments that went into the revision process. 

This marked a first-time, singular outreach program for USP. Why did we go to such lengths? In short, the response of the compounding community to the initial lack of inclusion reminded USP-staff and volunteer experts alike that not actively providing channels for public comment is neither in the interest nor the tradition of USP standards setting. The current revision cycle of General Chapter ‹797›, based on extensive interactions among USP staff, volunteer experts, and the compounding community, is fully supportive of USP's core mission of objective science and transparency. Inclusion can sometimes be messy and it can take time—you'll note that ‹797› has yet to be finalized in official publication. But it will be published, as a result of the kind of dialogue between public and experts that has characterized USP standards setting for nearly 200 years. 

I urge members of the extended pharmaceutical community to participate in this well-established, respected, and effective process. Thorough instructions are available on the USP Web site, at 

, and a diagram illustrating the standards revision process is published in the front matter of every issue of 

 Your participation will help keep the process a model of scientific integrity, thereby helping to ensure good pharmaceutical care for all.  

is the vice-president of the Department of Standards Division at the US Pharmacopeia, 

Guest Editorial

USP exercises a vigorous standards-setting process that draws on both public comments and meticulous scientific review.

Public Comment and Expert Oversight: The Cornerstones of USP Standards Development

Regulatory, consumer, and political organizations continually question the pharmaceutical industry concerning the quality and cost of the medicines that it manufactures. Contract manufacturers experience even further pressure as existing and potential customers weigh the quality and cost of manufacturing their products themselves 

 outsourcing them. This pressure was increased by a recent study, 

Pharmaceutical Manufacturing Research Project–Final Benchmarking Report, 

conducted by Georgetown University and Washington University in St. Louis (1). Although the report contains useful observations for contract manufacturers to consider such as linking electronic deviation-management systems to superior performance metrics, the study also concluded that contract manufacturing correlates with inferior performance metrics.  

Although the report's conclusion raises significant questions about contract manufacturers and their performance, a detailed analysis of the process used and data collected to arrive at this conclusion also raises concerns on the validity of the findings. Such questions arising from the report include:  					

Were they adequately defined and did they meaningfully compare similar processes as they relate to contract manufacturing? 

What was the study's scope and how did it influence and generate these benchmarks for contract manufacturers and their product-owner brethren?

Was this scope adequate to draw such a conclusion? 

The study is useful for accurately identifying the performance metrics most associated with quality and cost:  batches failed, cycle time, yield, and deviations. The study further offers a multitude of variables that may affect these parameters. Unfortunately, when considering how to define these key performance metrics, the study fails to take production volume into account and thus fails to assess each facility's ability to manufacture a batch without deviation or the need for rejection.  

The study also fails to recognize the need to further categorize the data before data pooling, and therefore the data lose any meaningful comparison. As a result, the study's conclusion that contract-manufacturing performance corresponds with inferior performance metrics cannot be supported because of the limitations of the data.  

Despite these limitations, the study does illuminate several strategic operating points for contract manufacturers to consider for optimizing their operations. The sheer number of variables considered in the study serves as a reminder of the importance of having meaningful metrics. The data suggesting that the contract-manufacturing facilities that participated in the study were generally large in size and scope can be an enormous strength for contract manufacturers if they have systems in place to ensure they capitalize on every experience. Also, the study accurately linked the use of electronic deviation-management systems to making corrective and preventive actions. Supported by a strong, metric-driven trending program stemming from an electronic deviation-management system and robust processes that capitalize on experience, contract manufacturers should have little trouble showing superior performance to potential customers. 

 is quality assurance director, sterile operations, DSM Pharmaceutical Products, Inc., tel. 252.707.2327, fax 252.707.7512, 

A detailed analysis by the author may be found in the April issue of 

www.pharmtech.com/pharmtech/static/staticHtml.jsp?id=406098

 1.  J. Macher and J. Nickerson, "Pharmaceutical Manufacturing Research Project–Final Benchmarking Report," McDonough School of Business, Georgetown University, Washington, DC and Olin School of Business, Washington University in St. Louis, St. Louis, MO, Sept. 2006, 

www.olin.wustl.edu/faculty/nickerson/results/

Viewpoint

A recent benchmarking report on pharmaceutical manufacturing raises questions about the performance of contract manufacturers, but further analysis also raises concerns about the process and data used to arrive at this conclusion.

Pharmaceutical Benchmarking: A Contract-Manufacturing Perspective

The US Food and Drug Administration plans to shut down its regional offices and some additional field facilities, a move that reflects an ever-tightening squeeze on agency funding and staff. FDA also seeks to make more efficient use of its limited resources by establishing risk-based approaches for selecting those drug-manufacturing sites most in need of frequent oversight, while reducing inspections for less risky facilities. More highly trained inspectors will be able to assess modern manufacturing systems with greater efficiency, and field staff will collaborate better with reviewers in FDA Centers to understand company quality-control systems better. 

These changes in FDA inspection operations fit the agency's Pharmaceutical Quality in the 21st Century initiative, which encourages broader industry adoption of quality-control and risk-management methods that can better ensure quality drug production and distribution with less direct oversight by the agency. Instead of frequent, in-depth plant inspections, the goal is for FDA to initially verify a manufacturer's process control and quality system and follow up periodically with more efficient audits, commented FDA deputy commissioner Janet Woodcock at a March workshop on pharmaceutical quality initiatives cosponsored by FDA, the American Association of Pharmaceutical Scientists, and the International Society for Pharmaceutical Engineering. Under the "desired state" of pharmaceutical manufacturing, regulators will use risk-based approaches to make regulatory decisions and further streamline the inspection process, she explained. 

The reorganization of FDA's Office of Regulatory Affairs (ORA) has been in the works for several months and now is nearing implementation. Margaret Glavin, FDA associate commissioner for regulatory affairs, described efforts to "dramatically change" ORA in a February message to staff. Gary Dykstra, director of FDA's Southeast regional office, unveiled some of the specifics at an industry conference in March. In addition to eliminating regional offices, ORA plans to streamline the reporting structure of its 20 district offices to create a more efficient operation. ORA also plans to close 7 of its 13 field laboratories, a move that has generated controversy since first announced in December 2006 (see sidebar, "Losing laboratories"). 

This downsizing of ORA reflects cuts in the agency's budget and staff. FDA's field force has dropped from a peak of about 4000 in 2003 to some 3400 today. Glavin emphasizes that the planned reorganization is not designed to accommodate further personnel cuts, but unions representing agency personnel are leery of likely staff relocations and changes in responsibilities and authority. 

A recent ORA report on inspections and enforcement actions in fiscal year 2006 documents the downward trend in domestic and foreign inspections of biologic and drug-manufacturing facilities. ORA inspected 2411 drug facilities in the United States and abroad last year, compared with more than 2600 in the three previous years. Similarly, the agency inspected 1826 facilities producing biologics last year, down from about 2000 in previous years. 

FDA's budget proposal for 2008 allots much of ORA's budget increase to food oversight, relying on prescription-drug user fees to maintain the current level of drug-manufacturing oversight. Any additional funding for ORA is needed to handle new and expanding assignments. ORA is charged with responding quickly to public-health emergencies such as Hurricane Katrina and the rising number of food contamination crises. The agency also monitors a fast-rising volume of imported food and medical products and is responsible for FDA involvement in detecting and preventing bioterrorism events. ORA's Office of Criminal Investigations is expanding efforts to prosecute Web sites that illegally market counterfeit drugs. And, ORA is working with the Department of Defense to build the Shelf Life Extension Program, a cooperative effort to test drugs in strategic stockpiles to determine if product expiration dates can be extended to reduce unnecessary drug replacement. The program focuses on pharmaceuticals important to the military that are purchased in very large quantities such as antibiotics and antivirals. 

To bolster its resources, FDA has proposed a reinspection user fee that would collect $23 million to cover the cost of revisiting manufacturing facilities cited for violations in initial good manufacturing practice (GMP) inspections. The agency would use $13 million of that new fee revenue to support 100 additional ORA field staffers. 

ORA's streamlining plan is scheduled to take effect on Oct. 1, 2007 unless it is sidetracked by opposition, which is surfacing within the agency as well as among manufacturers. Agency staffers are nervous, and industry fears more difficulty in contacting field officials and getting answers to specific questions. Members of Congress have opposed closing FDA laboratories at a time of increased public concern about food contamination and medical-product safety.  

FDA officials would like to shift the focus from counting the number of plant inspections it conducts to evaluating how well it can ensure medical-product quality and safety. This approach involves adopting more efficient strategies for targeting inspections to high-risk operations likely to have the greatest impact on public health and safety. 

FDA's risk-based approach to regulating GMPs fits ORA's need to do more with less to ensure drug quality. David Horowitz, ORA deputy associate commissioner for compliance policy, noted at the pharmaceutical quality workshop that in addition to a "significant decline in resources for inspections," more complex manufacturing processes require more expertise to evaluate. And, the need to oversee a growing number of foreign drug-manufacturing facilities also stretches ORA resources. 

Moreover, FDA regulatory operations suffer from industry efforts to sidestep the rules, Horowitz said. Industry compliance with GMPs "is bad and getting worse," he remarked, observing that manufacturers are "studying for the test"—correcting specific deficiencies but not investing in systems that can avoid problems and correct root causes. Modern manufacturing and technological developments such as process analytical technology (PAT) provide opportunities for both FDA and industry to establish quality-oriented approaches, Horowitz added, and risk management can better focus and target regulatory and manufacturing activities to "get the most bang for the buck." 

FDA is helping manufacturers adopt innovative approaches for ensuring that drugs meet quality standards, as seen in its 

Quality Systems Approach to Pharmaceutical CGMP Regulations

 guidance published in September 2006. Additional guidances from FDA will clarify approaches for aseptic processing, process validation, investigating out-of-specification test results, and manufacturing standards for Phase I clinical supplies. The anticipated Q10 standard from the International Conference on Harmonization will further describe approaches for harmonizing quality systems on a global basis. FDA also plans to revise its rules governing Part 11 and GMPs. In approaching the long, cumbersome rulemaking process, FDA envisions an "incremental approach" to adjusting specific policies, starting perhaps with those governing potable water and aseptic processing. 

In addition to providing advice to manufacturers, FDA is incorporating quality approaches into internal programs for training field inspectors and for issuing Warning Letters. ORA's transformation initiative, said Horowitz, aims to embed risk-based approaches in all its operations and to better coordinate the perspectives of field and Centers. This strategy, he hopes, will lead to greater harmonization in management approaches internationally and enhanced integration of inspection with review and compliance.  

A key ORA initiative seeks to improve the knowledge and training of pharmaceutical field inspectors so that they better grasp complicated quality-management systems and risk-management approaches they encounter at production sites. The centerpiece is establishing the Pharmaceutical Inspectorate (PI), a group of highly trained individuals with the knowledge needed to evaluate facilities that have adopted the latest scientific and technological innovations for ensuring drug quality. 

ORA and the Center for Drug Evaluation and Research (CDER) are working hard to build a cadre of 50 certified PI members by 2007. PI members would spend 80% of their time conducting drug-quality inspections, compared with about 25% for regular field inspectors. But unlike the agency's centrally located Team Biologics cadre, which inspects biotechnology manufacturing facilities, PI members work at district field offices and can inspect other facilities as needed. 

The PI training and certification process is a joint ORA–CDER undertaking that exposes candidates to risk-management concepts, manufacturing innovations, and the importance of an integrated review and inspection process, explained Doug Ellsworth, director of ORA's New Jersey District Office. A fully trained PI member should be able to identify critical control variables and strategies and whether a manufacturer has established a sound state of control over its production process. PI training includes quality by design (QbD), sophisticated statistical analysis, and advanced concepts in change control, corrective and preventive action plans, and continuous improvement programs. 

The development of the PI program supports FDA's PAT Team, another group of investigators trained in advanced PAT concepts. All PI members now have general training in PAT technology. As these inspectors gain more in-depth PAT knowledge, they most likely will absorb the PAT team, Ellsworth noted. 

FDA also has improved the operations of Team Biologics as part of its GMP modernization effort, with an eye to implementing quality-management systems approaches. This includes establishing standards to better assess team performance and to determine the need for improved training and qualification of team members. FDA is working with the Pharmaceutical Quality Research Institute to evaluate Team Biologics operations and their impact on manufacturers. 

A main approach for using FDA resources more efficiently is to target inspections and oversight to industry operations most in need of FDA scrutiny. CDER has established a risk-based site-selection program for identifying those drug-manufacturing facilities to schedule for GMP inspection each year. This system uses a model for setting inspection priorities according to various risk factors associated with products, processes, and facility characteristics. Of some 1500 drug GMP inspections FDA conducts each year, about 500 are selected based on risk calculations, and 50 are identified as warranting review by the PI cadre. 

Unfortunately, the program's current risk-analysis model does not consider how well a company establishes control strategies based on QbD and risk-management principles. The agency's evaluation system can tap only information in FDA data systems such as type of product (

sterile, biotechnology), mode of operation, and production volume. FDA analysts can factor in past GMP-compliance history, which may reflect a manufacturer's state of control, but not whether an advanced PAT system can manage product variability. 

Despite these limitations, ORA is extending this risk-based model to better target Team Biologics inspections to high-priority situations. The agency also plans to use risk factors to select veterinary-medicine plants for inspection. The long-term goals, says Horowitz, are to develop more outcomes-oriented standards for evaluating risk and to use science and data-driven targeting to determine inspection frequency and intensity, as well as FDA response to the inspectional findings. 

In addition to using risk analysis to schedule inspections, FDA also wants to apply risk-based approaches to the plant-inspection process. A firm's ability to establish design space and control strategies may limit an inspection's scope. For firms with strong quality systems, preapproval inspections would be linked closely to the review process and targeted to answer specific questions related to the accuracy of underlying data. Postapproval inspections would focus on whether a firm's quality system can manage production so it stays within an approved design space. Ultimately, FDA and a manufacturer may negotiate a regulatory agreement at the time of approval that describes several acceptable postapproval changes that do not require supplements or inspection. 

Another important component of FDA's more science-based inspection process requires field staff to collaborate more closely with Center product specialists and technical experts in evaluating a firm's risk-management programs, product and process knowledge, process capability, and quality-system robustness, Ellsworth explained. Under an integrated review and inspection approach, says Joe Famulare, deputy director of CDER's Office of Compliance, inspectors would address key areas suggested by Center staff, verify process implementation and state of control, assess product life-cycle improvements, and ensure adequate change control. A PI Quality System Workgroup under FDA's Council on Pharmaceutical Quality is working to define a process for greater interaction of investigators and reviewers. The group is reviewing current operations to make recommendations about policies, procedures, and information-technology systems that will facilitate collaboration between these entities. 

This move toward the increased integration of inspection and review for drugs builds on long-standing procedures in the Center for Biologics Evaluation and Research (CBER). Postapproval GMP inspections of biotechnology manufacturers has been performed by Team Biologics together with CBER product specialists for the past decade, commented Mary Malarkey, director of CBER's Office of Compliance and Biologics Quality. Such integration begins as early as the investigational new drug application stage and is particularly important for dealing with complex and innovative technologies. 

Ironically, while ORA seeks to streamline its oversight responsibilities, other FDA regulatory initiatives require field inspections to play a larger role in ensuring industry compliance with standards. FDA is considering policy changes to permit manufacturers to describe more manufacturing changes in annual reports as one way to reduce the number of postapproval manufacturing changes that require prior approval by reviewers. These change reports would be available to inspectors at the plant to be evaluated as part of an inspection. At the pharmaceutical-quality workshop, attendees agreed that changes in current postapproval policies should not shift burdens from the Centers to the field, a concern likely to surface as FDA continues to seek new approaches for overseeing manufacturing compliance. 

s Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, 

Washington Report

Fewer field offices and inspectors will increase reliance on manufacturers to ensure product and process quality.

FDA Seeks Streamlined, More Effective GMP Inspections

Changes in the biopharmaceutical industry have led to the need for new chromatographic techniques beyond traditional methods such as hydrophobic interaction chromatography, (HIC), ion exchange chromatography, and affinity chromatography. Protein expression titers and feedstock volumes have increased greatly during the past decade, and fermenter volumes of 12,000–15,000 L are not uncommon.  

"Some of the technologies that were developed about 30 years ago are no longer optimal for some of these new challenges," says Sylvio Bengio, scientific communications manager for Pall Life Sciences (East Hills, NY, 

Conventional techniques, including the Protein A affinity, still work well. But the cost of these methods is weighing heavily and has led to increasing interest in alternatives, especially new sorbents for mixed-mode chromatography and specially designed ligands. 

In principle, mixed-mode chromatography is not new. However, researchers now are able to specifically design and finely "tune" the hydrophobic dimension of the mixed-mode mechanism.  

Converting a dilute feedstock to a high-purity protein typically involves three steps: a capture step, an intermediate step, and a polishing step, which may involve ion exchange, but there are situations where this is no longer ideal. One example is when processing large volumes of feedstream. Typically, to obtain sufficient capacity with conventional ion exchangers, the conductivity of the feedstock must be adjusted by dilution, sometimes to as much as five times the original volume. Although this practice is feasible at the laboratory scale involving 5- or 10-L volumes, working with a 10,000-L feedstream is another challenge. "Obviously diluting three or four or five times is totally unacceptable because buffer storage volumes create problems," says Bengio. "Ideally, at the capture step, you would like to have a minimal dilution of the feedstock and still get good capacity and recovery in one step; this is exactly what new mixed-mode platforms will do in most cases." 

Monoclonals currently represent more than 35% of the proteins in clinical trials, and the current platform technology is affinity chromatography on Protein A. Protein A sorbents are very selective for capturing antibodies from complex feedstreams with high purity in just one step. One of the biggest problems with this ligand, however, is its cost. Some antibody processes may require several hundred kilograms of pure mono clonal for different treatments. "There is strong pressure on the industry to cut purification cost," says Bengio. "Chromatography and especially Protein A sorbents are one of the major contributors to purification cost that the industry wants to cut."  

Mixed-mode chromatography also has been used in place of or in combination with HIC processes (

 at the initial HIC step, in which case the methods would be orthogonal). Although conventional HIC is well-known, broadly used, and effective at various stages in purification, it requires the addition of high concentrations of lyotropic salt, typically ammonium sulfate, to the feedstock to promote protein binding to conventional HIC resin. Concentrations can range from 1 to 3 M. At the laboratory or small scale, this is usually not a problem. "But in industry where there are thousands of liters of feedstream, adding massive quantities of salt is a nightmare because salt is expensive and creates hardware problems. Furthermore you have to recycle that salt for environmental protection purposes, and this increases the overall cost" says Bengio.  

Russell Jones, chromatography marketing manager at Pall Life Sciences, notes that a company using conventional HIC sorbents, is likely to use several tons of lyotropic salt per year. "A process column containing hundreds of liters of  conventional HIC sorbent will require the use of significant volumes of buffers containing 1–3 M lyotropic salt, especially over the course of an annual campaign of 30 cycles or more. This will not only have an impact on process cost but also on what you have to do afterward to dispose of the salt in an environmentally friendly way." 

Not only is Protein A expensive, but it leaches and must be removed. Furthermore, the Protein A resin is not stable to 1 M NaOH, which is frequently used for cleaning. (Although GE Healthcare recently introduced "MabSelect SuRe," which is stable in 0.5 M NaOH.) Also, the method requires elution at low pH, which tends to cause aggregation and damage the antibody.  

BioSepra (now Pall Life Sciences) introduced "MEP HyperCel" as the first mixed-mode resin (originally developed to replace  protein A for antibody capturing). The ligand, MEP (4-mercaptoethylpyridine) contains a heterocyclic ring and a thioether linkageknown to have an affinity for antibodies. MEP HyperCel allows antibody binding at neutral pH directly out of the feedstock and, unlike protein A, binds all species and isotypes, including IgM. Elution can be carried out at pH 4 or higher.  

Andrew Lees, scientific director at Fina Biosolutions LLC (Rockville, MD, 

) explains that elution from MEP HyperCel is conducted by reducing its pH. As the pH decreases, the pyridine ring picks up a positive charge, so the sorbent goes from being hydrophobic to one that has a positive charge (similar to an anion exchanger).  

Decreasing the pH also causes the protein to become more positively charged, so it is repelled. Proteins that are more basic (

 have a net positive charge), including most antibodies, are eluted first and, as the pH decreases, more acidic proteins are eluted. In addition, the column also retains its hydrophobic characteristics. Therefore, the first materials that will elute are those that are more basic and more hydrophilic; materials that tend to elute last are more acidic and more hydrophobic (see Figure 1). Because antibody aggregates tend to be more hydrophobic compared with the monomer, they will be more tightly bound to the sorbent and so will elute at a lower pH than the monomer.  

MEP HyperCel has also been effective in binding recombinant protein from 

Unlike antibodies, which bind by both affinity and hydrophobic interactions, most recombinant proteins will bind only by hydrophobic interactions and require some lyotropic salt (

 ammonium suflate) to effect binding. Because MEP HyperCel is much more hydrophobic than most hydrophobic sorbents used for proteins, lower concentrations of salt can be used.  

 are lipopolysaccharide (LPS), host-cell proteins, and nucleic acid. Those components tend to bind tightly to MEP because they are all hydrophobic and/or negatively charged. LPS is very negatively charged (highly acidic) and very hydrophobic, so it elutes only under very extreme conditions. Thus, as the protein elutes, the LPS stays bound to the column. Nucleic acid is negatively charged, so as the sorbent becomes more positively charged and the protein elutes, the nucleic acid will bind more tightly.  Many host-cell proteins also bind tightly to MEP HyperCel. If used as the polishing step following Protein A capture, mixed-mode chromatography with MEP could be used to remove leached protein A, which is acidic. 

Two recently introduced sorbents, "HEA" and "PPA" (Pall Life Sciences) are hydrophobic resins that have different ligands (a hexyl group and a phenyl group, respectively) and a positive charge until pH 8 or higher. Adsorption to HEA and PPA is performed at a pH above their isoelectric point (pI) and eluted by decreasing the pH below their pI. As the protein becomes positively charged, they are repelled from the positive charges on the HEA and PPA resins. Proteins can bind to HEA and PPA even below their pI by adding lyotropic salts such as ammonium sulfate. Elution of the protein from the sorbent in this case is effected by lowering the salt concentration. "The selectivity of HEA and PPA differs and is not always predictable, but this adds another tool to the chromatographer's kit," says Lees. "The properties of mixed-mode sorbents not only provide unique selectivities but, by combining features of multiple modes, can reduce the total number of column steps needed." 

GE Healthcare Bio-Sciences (Uppsala, Sweden, 

) is designing chromatographic ligand libraries following combinatorial chemistry strategies, which take into account a wide range of parameters and interactions to design ligands for mixed-mode applications.  

The use of specialized sorbents may reduce the number of process steps. (IMAGE COURTESY OF PALL)			

"This approach provides the possibility to tune the performance of your media," says Jean-Luc Maloisel, PhD, staff scientist. "We use it to discover new selectivities and to improve discriminate chromatographic media. GE Healthcare has the traditional media, and we try to introduce new interactions to modulate the performance of these media." The company designs a library of mixed-mode ligands comprising about 50 prototypes to start with. These first, diverse libraries are used in the initial screening step to find a set of interactions that will perform according to a desired specification (

 for protein recovery, protein binding, elution).  

After the identification of promising candidates, a second-generation library is designed by introducing additional interactions, thereby fine-tuning the modification to the media to reach the final target specification. 

"We can screen our libraries of media very rapidly and in different ways using microtiterplate formats. The libraries are not set in stone, and we are always continuously working to diversify them. The libraries we have now may be slightly different tomorrow, so we can design them in different ways," says Maloisel. 

Traditional methods are robust, but may not be the optimal solutions in terms of process economy and time to market. "In some cases you really would like to have a wider range of selectivities and have more customized solutions. And that is where the library of multimodal ligands can be useful. However often, people will not take the time and trouble to screen a lot of media. This is where the microtiterplate format allow for a high-throughput process development and that is where you have a chance to win" says Maloisel. 

GE has launched multimodal cation exchangers as part of its "Capto" platform. One challenge in designing these media was to develop a medium allowing for binding proteins under high-salt conditions without the need to dilute the feedstock. Using computerized programs, the company made a diverse range of cation exchangers and then screened this range with the condition that the prestandard be salt tolerant. The company also developed anion exchange media for monoclonal antibody capture. "It doesn't replace the other chromatographic media, but it can replace traditional chromatography media lacking the prestandard performance." 

UpFront Chromatography (Copenhagen, Denmark, 

) also has developed a library of 200 ligands. The general criteria are that these ligands must be nontoxic, simple to manufacture to high purities, stable to harsh cleaning, and stable when immobilized. The performance of the ligands can be modified using various approaches. 

Process chromatographers continue to work toward systems that are more economical, offer better selectivity, and lead to greater yields. (IMAGE COURTESY OF PALL)			

"It depends on the constituent groups," explains Rob Noel, business development manager at UpFront. "If you take a group of ligands that have a common ionic component such as a carboxyl group, which is negatively charged, then you can change the pI of that carboxyl group depending on its substituents in the ligand." 

 Mixed-mode ligands can use a combination of aromatic, hydrophobic, ionic, and hydrogen bonding groups. Each combination of chemical groups may have a particular target on the protein surface. Most mixed-mode ligands bind to the surface of protein.  

"We try to mimic in some way how a protein–protein interaction would work even though the chemistry is different," says Noel. 

Designing a ligand for a protein depends on the characteristics of the protein, and some general rules can be followed. "For example, if the pI is greater than 7, then because most contaminating proteins are usually acidic, then chances are you can quickly find an absorbent that would work," says Noel. "If it's right in the middle in terms of pI, then you would look to see how concentrated it is in your environment. If it stands out in concentration, such as 10 to 100 times more concentrated than any other protein, which in a recombinant system you would hope it is, then that helps." 

There is increasing interest in using Protein A and then using a mixed-mode ligand in the next step. Traditionally, the protein A step is followed by two ion exchangers. "Using a mixed-mode ligand is giving an added advantage and effectively trying to replace those two ion exchangers with one step separation. So your whole process is just two steps," says Noel.  

Recent improvement in mixed mode chromatography involves finding faster ways of identifying the best and most robust conditions. "People are taking one absorbent and looking at a wide range of conditions to get a fuller picture of how the absorbent is working in their system," says Noel. The practice has become popular in the past four years. "It gives the process engineer an understanding of how the absorbent is working in that process and where the no-go areas are, such as for pH, conductivity, or temperature." 

Some process chromatographers point out that mixed-mode ligands have a broad range of applications, and thus tend to be unselective and provide relatively modest increases in purity. For this reason, bioscience firms are developing small chemical ligands for capturing specific target proteins (see Figure 2). 

For example, ProMetic Biosciences, Ltd. (Cambridge, UK, 

) has designed a library comprising tens of thousands of affinity ligands (under its "Mimetic" trade name), which are more specific versions of mixed-mode ligands. Like mixed-mode ligands, these are small, synthetic compounds, but they differ greatly from what are generally understood as mixed-mode ligands because of their precise chemical composition and wide variety of chemical groups used. These affinity compounds are organized such that the orientation and position of chemical groups in a three-dimensional space is fixed. This fixed position enables interaction with specific and complementary groups on the protein, which in turn enables specific capture. The synthetic ligands are designed and developed specifically according to the target protein (

monoclonal antibodies, albumin, glycoproteins, proteases, and plasma proteins). 

"In many cases, we have already identified compounds that are effective in purifying particular proteins," says Steve Burton, CEO, ProMetic Biosciences, Ltd. "For example, we have some very good ligands that we have developed and scaled up for albumin purification. Sometimes we have clients approach us with a new protein that maybe has just been discovered. In this case we may not have anything currently developed for that new target, but within our ligand libraries we can usually find something that will bind specifically and can be used to purify it." 

The affinity ligands are more complex than those used in ion exchange and HIC. Charge interactions, hydrophobic interactions, hydrogen bonding and van der Waals interactions plus specific three-dimensional geometries are incorporated into the media. "These are not generalized interactions," says Burton. With ion exchange, for example, the interaction is not normally on a specific site on the protein; its interaction is with the protein as a whole. "These small, synthetic ligands, however, are actually interacting with a very specific site on the protein. We engineer the ligands so they have complementary charge and hydrophobic groups, depending on the groups that are present in that specific region of the protein." 

As Burton observes, one of the benefits of having small synthetic ligands is they are less expensive to produce than protein-based ligands such as Protein A. In addition, being small entities, they are stable, robust, and can be cleaned effectively with molar sodium hydroxide, for example, so they can be used for hundreds of cycles. 

"Just a few years ago there was a lot of skepticism about whether one could actually use these small compounds in bioprocesses," says Burton. "Now people are realizing that there are some real benefits. They really do work well in many instances, and more time is being devoted to investigating their potential."  

Mixed-mode chromatography sorbents and custom ligands aim to optimize protein purification.

Eluting Possibilities with Mixed-Mode Chromatography

Debate Continues over Follow-On Biologics

The biggest issue in biopharmaceuticals continues to be the ongoing debate over regulation and oversight of follow-on biologics. Regulatory agency representatives, academia, and several professional industry organizations sounded off last month, voicing strong opinions and warnings of potential backlashes to healthcare, the economy, and scientific innovation. 

The congressional Committee on Oversight and Government Reform (

), chaired by Rep. Henry Waxman (D-CA) touched off the debate when it held a hearing to evaluate the cost of biotech drugs as well as strategies for establishing a process for the US Food and Drug Administration's approval of generic versions of these drugs. Janet Woodcock, MD, deputy commissioner for operations and chief medical officer at FDA was among those making a statement at the hearing entitled "Safe and Affordable Biotech Drugs—The Need for a Generic Pathway."  

Woodcock attributed part of the increasing interest in follow-on versions of approved protein products to "advances in manufacturing technology, process control, and characterization" of these products. She acknowledged that the nature of protein products makes comparisons of one protein to another and establishing safety and efficacy "more scientifically challenging" than for small-molecule drugs. Nonetheless, Woodcock also stated that the agency has "considerable experience with reviewing some protein products, including cases where the agency has considered the extent to which existing conclusions about safety and effectiveness of a protein product could be applicable to another protein product based on data and information showing the similarity of the products."    

The Biotechnology Industry Organization (BIO, 

) continues to voice strong opposition to the "Access to Life-Saving Medicine Act" (H.R. 1038), stating that the bill is "deeply flawed" because it "raises numerous patient safety concerns...It would eviscerate incentives to develop life-saving new medicines...[and] lacks data exclusivity for innovative biologics." In its letter to the committee, BIO also states that the potential savings in healthcare costs resulting from the establishment of a pathway for regulatory approval of follow-on biologics is "substantially overestimated."  

Emphasizing a "vast difference" between generic pharmaceuticals and follow-on biologics, Jim Greenwood, BIO president and CEO, stated that "high manufacturing costs, the need for additional safety and efficacy in trials to test these products, and augmented efforts directed at doctors to encourage the use of similar, but not identical, drugs are expected to add to the prices associated with the follow-on product." 

Caroline Loew, senior vice-president of the Pharmaceutical Research and Manufacturers of America (PhRMA, 

) expressed reservations regarding follow-on biologics. Although she maintained that PhRMA would support the establishment of a regulatory pathway for follow-on biologics, the organization worries that the current legislative proposals could put patient safety at risk. PhRMA cites the "significant differences between biologic products from different manufacturers" and the fact that innovator biologics are not identical to follow-on biologics as factors that could affect patients. In addition, PhRMA is concerned that existing legislation allows for a follow-on biologic to be replaced with a similar product, even though the similar product could have a different makeup, at pharmacies, hospitals, and physicians' offices. 

Loew goes on to state that clinical trials are necessary to prove the safety and effectiveness of follow-on biologics.  Current legislative proposals regarding follow-on biologics do not call for clinical trials.  

Meanwhile, Kathleen Jaeger, president and CEO of the Generic Pharmaceutical Association (GPhA, 

) released a statement emphasizing Woodcock's statement that FDA "has the scientific expertise to review" generic biologics and the "same scientific principles that apply to the review of changes made to brand products after approval would also be underpinning the review of biogenerics."  

"[The] hearing also proved that the claim by PhRMA and BIO that the legislation will restrict FDA's ability to require testing is simply false," said Jaeger, claiming the organizations are "playing the scare-tactics card." 

) plans to close its manufacturing site in Waterford, Ireland. 

The company attributes the closure to increasing pressure from generics. Sanofi came to the decision after evaluating its plant network and concluding that other sites had excess capacity and could take over the manufacturing currently performed at the Waterford site with minimal extra investment. 

The Waterford plant currently manufactures mature and over-the-counter products, including "Essentiale" for liver protection and "Flagyl" for microbial infections. Manufacture of these two products will be taken over by Sanofi plants in France and Germany. 

The site is expected to close by the end of the year, with the loss of about 200 jobs. 

FDA Inspections and Warning Letters Continue to Decline

The number of US Food and Drug Administration (

) inspections of biologic and drug-manufacturing facilities declined to 4237 in fiscal 2006, according to a report by the Office of Regulatory Affairs. This total has decreased since 2002, when the agency reported 4570 inspections. 

The report states that the Center for Drug Evaluation and Research (CDER) conducted 2411 domestic and foreign inspections in 2006, compared with 2682 in 2005. The number of CDER inspections is at its lowest point since 2002, when the center reported 2585 inspections. 

The Center for Biologics Evaluation and Research (CBER) also conducted fewer inspections in 2006. The center reported 1826 domestic and foreign inspections in 2006, a decline from the 1931 inspections during 2005. CBER's inspections have decreased since 2003, when the center's annual total was 2205. 

In contrast, both CDER and CBER issued more Class I recalls in 2006 than in 2005. 

A recall is an action taken by a firm either to remove a product from the market or to conduct a field correction. A Class I recall is a situation in which there is a reasonable probability that the use of or exposure to a product will cause serious adverse health consequences or death, according to FDA. 

CDER's total of 45 Class I recalls in 2006 is the greatest number of the past five years and an increase from the 18 such recalls in 2005. CBER issued 13 Class I recalls in 2006, compared with a single such recall in 2005. In 2006, CBER issued more Class I recalls than in 2005 and 2004, but fewer than its recent peak of 24 in 2003. 

The report also shows that the number of Warning Letters issued by the two centers has declined during the past 10 years. In 2006, CDER issued 66 Warning Letters, and CBER issued 22 Warning Letters. 

The US Food and Drug Administration (FDA, 

) submitted to Congress its final proposals for reauthorizing the fourth Prescription Drug User Fee Act (PDUFA IV), which will follow the expiration of the current user fee on September 30, 2007. The law provides user-fee funds paid by brand drug and biotechnology companies that help support the review of new drugs. 

According to an FDA release, annual user fees under PDUFA IV would increase to $392.8 million, an $87.4 million increase over PDUFA III. 

The funds would support "key goals," including enhancing premarket review and creating a modern postmarket drug safety system that follows products across their full life cycle. 

"Our proposed recommendations for PDUFA IV aim to strengthen our drug safety system and upgrade resources to enhance FDA's information technology capability," said Commissioner of Food and Drugs Andrew C. von Eschenbach, MD. 

DHS Releases Interim Final Rule on Chemical Site Security

The US Department of Homeland Security (DHS, 

) released an interim final rule that imposes federal security regulations on high-risk chemical facilities. The new rule gives the department authority to seek compliance through the imposition of civil penalties of as much as $25,000 per day and the ability to shut down noncompliant facilities. 

Under the rule, DHS will require owners of chemical facilities that house certain quantities of specified chemicals to complete a preliminary screening assessment that determines the level of risk associated with the facility. If a chemical facility preliminarily qualifies as high-risk, its owners will be required to prepare and submit a security vulnerability assessment (SVA) and site-security plan. Submissions will be validated through audits and site inspections. The department will provide technical assistance to facility owners and operators as needed. Security standards will be required to achieve specific outcomes such as securing the perimeter and critical targets, controlling access, deterring theft of potentially dangerous chemicals, and preventing internal sabotage. 

Facilities contacted by the department will have 120 days from the publication of the regulation in the Federal Register to provide information for the risk-assessment process. Other requirements will follow that time period. Additional facilities will follow a similar timeframe after future Federal Register publications. 

Some states have existing laws for regulating chemical facilities. Only state laws and requirements that conflict or interfere with these regulations or the purpose of the regulations will be preempted. DHS says the department currently has no reason to conclude that any existing state laws are applied in a way that would impede the federal rule. 

DHS says the final regulation will be published in the Federal Register and also may be found at 

www.dhs.gov/xlibrary/assets/IP_ChemicalFacilitySecurity.pdf

The Synthetic Organic Chemical Manufacturers Association (SOCMA, Washington, DC, 

), the US-based trade association representing custom and batch manufacturers, including contract manufacturers of active pharmaceutical ingredients and intermediates, outlined its concerns about the new rule. 

"SOCMA wants to commend DHS for their hard work in promulgating these regulations," said Joe Acker, the group's president, in a prepared statement. "We support the phased-in approach to the rules, but would like to have seen more time given for companies to perform their SVA, especially small companies with limited resources. The shortened timeframe will make it extremely difficult for companies to evaluate the new rules and then perform the appropriate tasks in the prescribed timeframe required by the rule." 

SOCMA pointed out issues relating to the type of facilities able to conduct alternative SVAs. "DHS's decision to limit alternative SVAs to only Tier 4 facilities is disappointing," said Acker. "Facilities that have taken the proper action over the last five years, which include all of SOCMA's member facilities, will need to unnecessarily reconduct risk assessments, even though nothing has changed in their overall risk profiles." 

Sanofi to Close Irish Plant, FDA Inspections and Warning Letters Continue to Decline, FDA Submits Final Proposals for PDUFA IV, and more.

Pharmaceutical Technology-05-02-2007

Falling to Pieces

Functional versus Full-Service Outsourcing Models

Public Comment and Expert Oversight: The Cornerstones of USP Standards Development

Pharmaceutical Benchmarking: A Contract-Manufacturing Perspective

FDA Seeks Streamlined, More Effective GMP Inspections

Eluting Possibilities with Mixed-Mode Chromatography

May 2007

Review of Current Issues in Pharmaceutical Excipients

Advancing the Peptide Pipeline

Dissolution Testing and Metrological Measurement of Quality for Solid Oral Dosage Forms