It was hot in Philadelphia, and sticky: hard mid-day sun, high haze, and thunder storms possible in the evening. When I got to 13th and Arch Streets, it was over.

Thirteenth Street runs north, across Arch and into the gaping maw of the Philadelphia Convention Center. Inside, BIO 2005 buzzed into its second day. Outside, the streets were thick with police Suburbans, police buses, police paddy wagons, yellow police tape, and the police themselves. 

West on Arch Street, toward 12th, stood a disconsolate little knot of protesters: A girl with sunglasses and a bull-horn. A boy with a camouflage bandana wrapped around his head and another, red, worn bandit-style across his face against the tear-gas that never came. A boy carrying a backpack and a five-foot staff, with which (I fancied) he practiced bo-jitsu moves when he was alone. Another boy with a tuft of red beard and a green bandana hanging down around his neck circled nervously around them. 

They huddled together, talking earnestly, fifty feet down the street. Between us was a thin line of yellow tape... and a much larger, much surlier, line of blue uniforms. 

Every now and then, they would look back toward the line of police.  

More often, the four protesters looked down the street, towards what remained of the Biodemocracy 2005 demonstration. There were only couple of hundred people, a shadow of the 1500 who besieged BIO last year in San Francisco. I could barely make out the ten-foot-tall protest puppets (how did gargantuan toys become a mainstay of left-wing activism?). I never did get to see folks dressed as characters from their own personal nightmare closets: the pharmaceutical monster "with pills for ears and dollar-signs for eyes," the giant tomatoes and sunflowers.  

In a youth misspent as a bouncer in a mob-owned Boston beer-hall, I learned that you could walk into the place from a fresh spring evening and just smell it, behind the stale beer and the fermenting bar fruit: There's going to be trouble tonight. 

I felt the same tension and anger in the blue crowd, and caught a whiff of the same old electric scent. But that Tuesday, the trouble was over.  

"Is it true that an officer was hurt?" I asked a cop on the corner.  

I just looked at him. Maybe my mouth hung open. 

"I wouldn't joke about that," said the cop, short and broad with a bristling mustache. "He had a heart attack and died. Maybe somebody kicked him while he was down. We don't know." 

He accepted the condolences with a short nod. We stood quietly for what seemed like a long time. 

," said the cop, lifting his chin to indicate a stunning woman across the street, "would give you a heart attack." 

Minutes earlier, the protesters had scuffled with police. Paris Williams, a 52-year-old, plain-clothes community affairs officer, had a heart attack, collapsed, and died. 

Amid the unprecedented flood of public relations releases that preceded the BIO meeting was a trickle of jejune statements from the protestors. Here's a sample: 

"We're very concerned about the control of corporations of what we, like most of the people in the world, believe are basic human rights. It is unacceptable to the majority of Americans that healthcare, food, and our national security are being bought and sold to the highest bidder."

The protesters favored reimportation of drugs and opposed animal testing and biowarfare. (Biowarfare? A protest based on a shared prefix?)  

Why, I wondered, can't they just think it 

? How else can we turn our knowledge into benefit? Why is it that they just can't 

And I'm sure the girl with the bull-horn and the boys with the bandanas wondered the same thing about me.  

Articles

Police Lines

Pharmaceutical firms today confront a daunting array of problems—expiring patents, dwindling pipelines, counterfeit drugs, and more. Profits are slowing and share prices plummeting. Is it any wonder that pharmaceutical firms are making billion-dollar cutbacks? 

Information technology (IT) budgets are on the chopping block, yet CEOs are asking IT departments to play a bigger role in drug discovery, clinical trials, and manufacturing automation. It's up to IT to figure out how to do more with less. 

The US Food and Drug Administration regulations make cost-cutting all the more difficult. Although FDA requires companies to comply, it rarely tells them how. Agency guidance documents provide insight into regulatory requirements, but they do not provide a step-by-step quality management framework that IT departments can follow. 

Pharmaceutical IT departments could do better. They must adopt repeatable IT quality practices designed to cope with FDA-regulated environments. The Information Technology Infra-structure Library (ITIL) is a comprehensive set of best practices developed in 1989 by Great Britain's Office of Government Commerce. In essence, ITIL is a series of books that provides detailed guidance on a wide array of IT services. Hundreds of companies use ITIL processes to improve their delivery of everything from change management to systems availability. 

Unfortunately, although ITIL is a powerful quality management framework, it was never designed to accommodate FDA's rigorous regulatory regime. There is currently no standard set of evolving best-practices for IT management in the pharmaceutical industry. That is why the industry has had so much trouble coping with 21 

 Part 11 in recent years, and why even today, IT managers dread the thought of consolidating servers in a validated environment, even though most large firms could save millions per year by doing so.  

One need only visit pharmaceutical data centers and count the hundreds of obsolete servers running at 5–10% of capacity to realize that vast sums of money are wasted every year. Why? Because companies have neither developed nor adopted a battle-tested set of best-practices that is designed to accommodate FDA regulations.  

Instead, every pharmaceutical firm has its own approach to managing IT services, validating systems, consolidating servers, and managing clinical trials. Indeed, IT management practices frequently vary widely among departments and business units within the same company. 

ITIL could serve as the foundation of an industry-wide suite of IT best practices, but first it must be substantially modified to accommodate FDA's specific requirements. That task is far too big for any one company. Imagine the difficulty of developing IT management processes for next-generation manufacturing plants employing the latest process analytical technologies, while also developing soup-to-nuts guides for automating drug discovery, clinical trials, outsourcing, and data center management. The effort would require extensive collaboration between a wide array of pharmaceutical IT practitioners, vendors, and consultants for years to come. 

During the past 10 years, my consulting firm has developed a small portfolio of ITIL-based best-practices for pharmaceutical firms—the by-product of numerous consulting engagements—but we have only scratched the surface. We think it is time for IT practitioners, vendors, and consultants in the pharmaceutical and other FDA-regulated disciplines to take a page from ITIL's book and collaborate on industry best practices that will enable every participating company to improve its IT product and service delivery, tackle challenging new opportunities such as IT in drug discovery or process analytical technology manu-facturing automation, while capping or reducing the cost of information technology. 

				We think this effort should have a name appropriate to the pharmaceutical industry and, borrowing from FDA's nomenclature for quality in manufacturing, laboratory and clinical trials management, decided on "Good Systems Practice (GSP)" to balance "Good Manufacturing Practice (GMP)."

We all understand the purpose of GMP on the plant floor and GLP in the laboratory. Why don't we have GSP in our data centers? I propose that we develop a Good Systems Practice that will become an open standard for all FDA-regulated companies to adopt. We should not wait for FDA to regulate how we manage our IT systems. Instead, industry should lead the way to Good Systems Practice. We have already started. Call me if you want to join in.  

 is the CEO of Court Square Data Group, Inc., 1441 Main Street, Suite 223, Springfield, MA 01103 413.746.0054, 

The industry should develop a set of best practices for managing information technology systems and not wait for FDA to take the lead.

Let's Collaborate on IT Best Practices

A task force formed under the auspices of the Pharmaceutical Research and Manufacturers of America (PhRMA) Active Pharmaceutical Ingredient (API) Technical Group recently published an article about four aspects of the US Food and Drug Administration's February 1987 

Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances

 (1, 2). One of these aspects was the "control of critical steps and intermediates," with particular reference to Section 3.2.S.2.4 of the Common Technical Document (CTD) (3). Although this article was published before FDA issued its 2003–2004 draft guidances for drug products and drug substances (4), the authors recognized the potential value of greater clarity and commonality of understanding among PhRMA industry members and health authorities on the subject of critical process parameters (CPPs). 

This article reviews critical quality attributes (CQAs), CPPs, and the associated concepts of critical in-process controls (CIPCs) and critical steps. The intent of this article is twofold: 					

to provide common language at the technical and practical level among industry and health authorities about how CQA and CPP concepts relate to current industry practice in API and drug substance manufacturing;

to illustrate how applying these concepts in a focused way supports drug quality good manufacturing practice (GMP) systems and regulatory dossiers and aligns with on-going science- and risk-based regulatory initiatives.

A common understanding of these concepts—from product development and registration through life cycle management and subsequent quality evaluations of process changes—demonstrates that the industry has extensive technical and practical knowledge about the API process. Thus, presentation of only key portions of this technical knowledge in Section 3.2.S.2.4 of the CTD or in support of internal quality evaluations could logically lead to more streamlined and science-based regulatory dossiers. Consequently, this approach will help increase patient safety and drug efficacy without creating an undue burden of added submission or review activities as a result of excessive or unfocused dossier information requirements. 

For the purposes of this article, the terms 

 are used interchangeably, because both are used in various regulatory guidance documents. The terms 

 also are used interchangeably for similar reasons. 

 is generally understood to be a feature or aspect of a process that requires careful control or execution to ensure that the API is of acceptable quality, with the desired end result being a safe and efficacious drug product. Despite this general understanding, the task of assigning some features of a process as critical is inherently subjective, and there are considerable differences of interpretation in the industry and health authorities. 

Therefore, objectives of this article are the following: 					

Provide a common language and understanding to facilitate future discussions of the topics noted above. 

critical quality attributes, critical process parameters, 

 and show their interdependency in the context of chemical and physical characteristics of the drug substances in a particular drug product.

Establish the principle that specifications may contain parameters or attributes other than CQAs and that in-process tests often exist for reasons that are not critical to quality.

Provide a methodology for defining CQAs, CPPs, and CIPC, in a given synthetic process.

Discuss the relationship between process performance and CQAs, CPPs, and CIPCs.

Clarify the identification of CQAs and CPPs in regulatory submissions. 

Provide linkage to on-going industry initiatives in quality risk assessment and the integration of technical knowledge with quality systems.

Identify the regulatory opportunity of reducing supplemental filings for postapproval changes that do not significantly affect API quality.

PhRMA has published its opinion that the focus of process understanding and control must center around CQAs and CPPs. Nevertheless, the term 

 appears in various regulatory guidances. For example, the International Conference on Harmonization (ICH) Q7A 

Good Manufacturing Practices for Active Pharmaceutical Ingredients

 states that industry must validate critical process steps and the quality unit must review and approve batch records for critical process steps (5). Therefore, this article also provides a practical discussion of critical steps.  

With respect to the remaining concepts of CQAs, CPPs, CIPCs, and the importance of characterizing the significant aspects of a particular process, this knowledge provides additional business benefits. Some examples are: 					

Clarifying what constitutes a robust process during process development and the typical industry approaches to generating data that support a robust process (thereby illustrating that current industry practice is consistent with FDA's "quality by design" initiative).

Providing a reference point to methods used by many companies in managing risk, thus laying the foundation for future science- and risk-based decisions. This knowledge also is a key element in the principles outlined in the draft "ICH Q9 Quality Risk Management" document.

Providing a framework for deciding which technical information to include in CTD Section 3.2.S.2.4, "Control of Critical Steps and Intermediates" and which more appropriately remain part of the supportive technical body of knowledge found in a process's history.

Clarifying the relationship between CTD Section 3.2.S.2.4, "Control of Critical Steps and Intermediates" and the selected validation acceptance criteria, and, in particular, identifying why there may be a difference between the two.

A brief history of applicable regulations

The 1987 FDA guidance refers to critical steps and establishes the connections among the critical steps, the testing regimens for intermediates, and the ultimate validation of the process (2). Section 2.E, "Intermediates and In-Process Controls," states: 

"The regulations require that controls ... be employed ... to assure that ... procedures are operating properly and that the intermediate tested is suitable for subsequent processing. The choice [of intermediates, steps, and testing] is the responsibility of the applicant .... As experience is gained with the synthesis, the critical reaction steps and intermediates to be monitored are selected .... The whole operation is part of the process validation of the synthesis." 

Since 1987, the concept of process validation has evolved substantially. It is now standard practice to predefine acceptance criteria for the steps being validated. These validation acceptance criteria typically arise from the need to demonstrate the appropriate control of critical operations within the process. Acceptance criteria typically consist of a requirement for selected critical unit operations to remain within predefined acceptable operating limits during processing and/or in-process or intermediate tests and specification limits that ensure acceptable API quality will be achieved.  

In January 2004, FDA published a draft guidance for industry for drug substances (4) that defined 

 process condition, test requirement, or other relevant parameter or item) that must be controlled within predetermined criteria to ensure that the drug substance meets its specification" (lines 2122–2124) (4).  

				This definition is consistent with the ICH Q7A definition of 

 as "a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification" (5).

The ICH Common Technical Document M4Q Quality, Section 3.2.S.2.4, "Controls of Critical Steps and Intermediates," defines 

 as "tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided" (3). 

A common theme among these regulatory documents is that the process leading to the drug substance itself should be controlled, not just the resulting final drug substance or API. In other words, there should be an adequate evaluation of quality during the process to ensure the acceptable quality of the final drug substance. Another common theme is one of a 

the idea that there is a subset of steps in a chemical process that must be carefully controlled or executed to ensure the API produced is of acceptable quality. 

Introducing a science-and risk-based approach

The foundation of a science-based and risk-based approach can be taken from many recent draft guidance documents. Common to these documents is the use of a science- and risk-based approach for defining and controlling products and processes. The three main components of such an approach are:  					

a well-defined product and a well-characterized process; 

the use of sound risk-based decision principles;

the integration with well-defined quality systems. 

This is consistent with FDA expectations articulated in the 2002 initiative 

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

 and in the process analytical technology (PAT) final guidance 

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

 (6, 7). These documents state the goals are intended to ensure that: 					

"The most up-to-date concepts of risk management and quality systems approaches are incorporated into the manufacture of pharmaceuticals while maintaining product quality."

"Manufacturers are encouraged to use the latest scientific advances in pharmaceutical manufacturing and technology."

"A process is generally considered well understood when (1) all critical sources of variability are identified and explained; (2) variability is managed by the process; and, (3) product quality can be accurately predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions."

In the guidance, FDA further expands on the concept of mitigating and reducing product risk through proper understanding of the process and placement of controls appropriate to the risk. The use of sound risk management principles coupled with scientific understanding can identify and control sources of risk to the product. As the PAT guidance states,  

"The approach is based on science and engineering principles for assessing and mitigating risks related to poor product and process quality. In this regard the desired state of future pharmaceutical manufacturing and regulation may be characterized as follows: 					

Product quality and performance are ensured through the design of effective and efficient manufacturing processes

Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance ....

Risk-based regulatory approaches recognize ... the capability of process control strategies to prevent or mitigate the risk of producing poor quality product."

				ICH also has recognized the importance of process knowledge and identifying and controlling risks associated with the product by forming Expert Working Groups on Quality Risk Management (Q9) and Pharmaceutical Development (Q8).

Irrespective of whether one views the API regulatory landscape from the initial development and registration perspective or from the viewpoint of subsequent quality management and process improvement (life cycle management to more easily implement process improvements is a logical extension of using process knowledge), the science- and risk-based approach can be an appropriate model. To identify the well-defined product and well-characterized processes that this approach requires, one can first focus on the CQAs associated with the product. 

Critical quality attributes as the core concept

The position presented in this article is that the CQA is the core concept linking any proposed science- and risk-based regulatory approach to a basic technical understanding of an API process and related terms such as critical steps, CPPs, and CIPCs. 

 A typical API process consists of several stages or steps, either chemical transformations or purifications that may involve isolated or nonisolated intermediates. Each stage or step comprises numerous unit operations, most of which are typically operated within certain defined ranges according to a batch sheet or a manufacturing order. In-process testing at various points within a stage may be conducted to confirm that a specific point or condition has been achieved before progressing to the next step of the process. In addition, isolated intermediates can be analyzed, and their quality can be determined against specifications. All of the individual steps, their respective unit operations and associated ranges, in-process controls, and specifications make up the API process.  

 Operating ranges for the unit operations in a process, in-process testing regimens, and specifications for reaction intermediates can be defined for several reasons, including:  					

quality: A given range is necessary to ensure that the product of a stage is of appropriate quality to produce acceptable API.

yield: A given range may maximize the yield of a required product.

A stepwise, process risk-assessment approach can facilitate the identification and understanding of critical process parameters, quality attributes, and in-process controls. This approach can lead to more use of science- and risk-based regulatory practices to simplify the regulatory requirements for changes to synthetic processes and to support the underlying quality systems that ensure compliance.

Current Thoughts on Critical Process Parameters and API Synthesis

If you have traveled to Singapore lately, chances are there have been a number of other pharmaceutical professionals on the plane with you. The island nation has launched an all-out effort to attract bio/pharmaceutical companies and has enjoyed considerable success. Several major pharmaceutical companies, including Merck, Pfizer, Wyeth, Novartis, and Schering-Plough, already have manufacturing operations there, and some contractors are taking a serious look at Singapore for their Asian presence.

As with other popular offshore pharmaceutical hubs Ireland and Puerto Rico, the big draw of Singapore is the tax benefits offered to pharmaceutical companies. Profits on the manufacture and sale of active pharmaceutical ingredients are subject to little or no corporate tax. Those tax benefits, combined with workforce development and education programs, investment participation by the Singapore Economic Development Board (SEDB), political stability, and a legal regime that respects intellectual property, have enabled Singapore to compete with the cost advantages of India and China. 

As yet, few contract services companies have been attracted to Singapore. The local base of pharmaceutical companies is still quite small, and it is difficult to structure a business model that can translate the tax savings into costs that are competitive with those of India and China. Still, the government believes it must build a services base if it is to continue to attract pharmaceutical companies.  

"CROs and service providers are an important part of it," says Beh Swan Gin, director of the Biomedical Sciences Group of the SEDB. "If we want to go out and try to attract leading US and European companies, we need those providers in place here." 

Singapore's central location and excellent transportation links have made it attractive as a base for several CROs. 

) has made Singapore its headquarters for its Asia Pacific operations that include clinical research services, clinical supplies distribution, central lab services, and contract sales and marketing. 

) also has an office and a central laboratory operation in Singapore. 

) has been operating distribution and warehousing services in Singapore for about five years. "There's a lot of local interest [in pharmaceutical research], and local studies are being done," explains Jennifer Worsfold, who oversees the Singapore operation at Fisher's UK site. "We generate work there and draw from the local workforce. It's a good partnership." 

One homegrown player is contract biomanufacturer 

). A-Bio offers cell line and process development and small-scale GMP manufacturing for mammalian cell based biologics using culture technology in its 60,000-ft

 facility. A-Bio signed a clinical supply service agreement with GlaxoSmithKline last fall to develop and produce clinical lots for a vaccine product. 

) is the latest addition to the Singapore CRO scene, with a research operation that opened earlier this year. The company has opened a 15,000-ft

 laboratory and will focus on medicinal chemistry. Ultimately, AMRI expects to invest between $3 and $5 million in its Singapore operation. 

Although Singapore's capabilities in organic synthesis is less well-developed than some other areas, according to AMRI senior vice-president Michael P. Trova, PhD, the government has committed to train and educate scientists in that specialty. The SEDB's Beh says the government also is planning for a new chemical statistics laboratory and initiatives to support the increasing use of molecular imaging in drug discovery.  

One of the constant themes during the past year has been the maturation of the pharmaceutical services industry and the way pharmaceutical companies buy services. Concentration on spending with a few major preferred providers, consolidation in the number of service providers, and increased outsourcing to India and China are all part of that maturation process. 

Supplier consolidation is enabling large, financially sound contractors with broad capabilities to garner a predominant market share. That leaves the small and mid-sized CROs and CMOs to compete for a shrinking piece of the pie. The challenge for those small and midsize service providers will be to come up with strategies and differentiating characteristics that ensure that they can stay in the game. 

CRO/CMO executives won't be up to that challenge until they move beyond the bromides they often use to describe their place in the market. The following are among the worst examples: 

 Acceptable quality has become a minimum threshold for admission to the bidding process and is seldom a distinguishing characteristic. 

 Many CRO/CMO executives have convinced themselves that pharmaceutical companies won't move development activities offshore because the opportunity costs of delay are too great. They tell themselves that compared with the daily sales of a moderately successful drug, the amount spent on their development services is minimal and that pharmaceutical company executives would be foolish to delay a product launch even a day over an issue of cost. 

Unfortunately for them, such arguments don't hold water for their clients. Aside from being pretty abstract, the argument doesn't comport with reality: There are so many factors that will delay a new-product filing that the implications of any single delay are not significant. A new drug approval is more likely to be delayed by a scientific issue, problems in patient recruitment, or internal bureaucratic snarls than it is by the few extra weeks required to source clinical trial materials in India. 

 Small outsourcing provider companies often get caught up in their own "creation myths" (

, beliefs and values articulated by their founders that somehow make them different from the rest of the industry). Executives in these companies will often tout what makes them special to prospective clients, in the expectation that clients' empathy will increase their desire to do business with them.  

Companies caught up in their own creation myths often fail to realize that their clients have their own strategies and business objectives that have nothing to do with the vendor's self-perception. A creation myth that favors slow growth does not make you more competitive to a client looking for globally capable, financially transparent preferred providers. 

Executives of CROs/CMOs that still hone to these homilies need to assess industry trends more objectively, from a customer's viewpoint, not their own. The next 10 years in the pharmaceutical industry will be very different from the previous 10 years, and changing with the times will require a new way of looking at their companies. 

 is president of PharmSource Information Services, Inc., and publisher of 

Singapore is competing aggressively with India and China for a piece of the Asian sourcing business.

Singapore Fling

Recalls, Resignations, and Manufacturing Suspensions Plague Able Labs

) announced in late May that it would halt all production and recall all available product because of problematic testing procedures discovered during an internal investigation. The company manufactures mostly generic prescription drugs, including drugs containing acetaminophen. 

Chairman and Chief Executive Dhananjay G. Wadekar announced his resignation shortly after the review, as company shares fell nearly 75%. Robert G. Mauro, Able's president and chief operating officer, assumed the role of interim CEO. 

According to a release from Able, the company also intends to withdraw seven of its approved abbreviated new drug applications (ANDAs). The company cited various reasons for the withdrawal, including commercial considerations and the identification of unreliable data included in the filings. 

On May 27, the US Food and Drug Administration (Rockville, MD, 

) followed up on the May 25 recall of Able Laboratory's products with a special warning to consumers. FDA said its action is intended to ensure that the public is fully aware that Able is conducting a nationwide recall of all its manufactured drugs because of serious concerns that they were not produced according to quality assurance standards. 

The company said on May 27 that it had laid off approximately 200 manufacturing and other employees. On June 9, Able announced plans to reduce its workforce even further to conserve assets.  

 In an effort to exert tighter control over the flow of drugs through the supply chain, Purdue Pharma (Stamford, CT, 

) and the drug wholesaler H.D. Smith (Springfield, IL, 

) are implementing a pilot program that uses radio frequency identification (RFID) tags to verify drug authenticity. 

The pilot incorporates a SupplyScape (Cambridge, MA, 

) solution that tracks the distribution of the analgesic product, "Oxycontin," from Purdue's manufacturing facility to the wholesaler. By using RFID electronic barcodes, also known as smart tags, to record the path of the drug in transit, the system is designed to detect whether counterfeit drugs are being introduced into the supply chain. At any point in the supply chain, a tagged drug can be scanned to determine  its origin and authenticity. 

"Pharmaceutical companies are looking to institute standards that safeguard consumers from the growing threat of counterfeit drugs," said Todd Skrinar, partner, Healthcare and Life Sciences, Unisys in a company statement. "The implementation of an electronic pedigree system can help Purdue increase consumer safety." 

This pilot is another phase of Purdue's anticounterfeiting and diversion plan launched in November 2004. The company has already shipped products incorporating RFID tags on individual labels to Wal-Mart and H.D. Smith and expects the new test to help lead to national adoption of pedigree systems for all drugs. The state of Florida has taken a lead in this effort by enacting rules requiring electronic drug pedigrees before July 2006. 

On May 26, the US Food and Drug Administration (New Orleans, LA, 

) sent a warning letter to C&M Oxyfill (Wiggins, MS) concerning violations of current good manufacturing practice (CGMP) regulations at the company's compressed oxygen manufacturing facility. 

The cited CGMP violations included: 					

failure to establish certain laboratory controls;

failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment;

failure to ensure that all production and control records were reviewed and approved by the quality control unit to determine compliance;

The letter warned that the compressed oxygen cylinders manufactured by C&M are misbranded because the product's labels do not have the required statement "Rx Only" prominently placed so it would be likely to be read and understood by an individual during purchase and use. 

New Excipient Guidance Doesn't Fill Regulatory Gap

The US Food and Drug Administration (Rockville, MD, 

) issued a final guidance in June governing the safety evaluation of pharmaceutical excipients. The issuance of the guidance, however, has not created a regulatory pathway for evaluating pharmaceutical excipients independently of drug products. 

The Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients

 outlines the safety tests that should be performed on new excipients. According to Jay Goldring, PhD, a member of the Executive Board and the Regulatory Affairs Committee at the International Pharmaceutical Excipients Council (IPEC Americas, Arlington, VA, 

 the guidance will be useful in some cases, but is really just a first step. "The regulatory framework [governing excipients] is the issue," he says. 

Currently, there is no system for independently evaluating the safety of excipients, which are only evaluated by FDA in the context of a new drug application (NDA). "It's a catch-22," Goldring says. "No drug company wants to use a new excipient until it's been approved, but no drug company wants to submit a new excipient for approval within their drug application because it could jeopardize the approval of their entire application. So there's a regulatory hole here." 

IPEC Americas has submitted a proposal to FDA to narrow that regulatory gap by forming an independent academic board to review safety data about new excipients. According to the proposal, FDA would take the board's conclusion into consideration when evaluating a new drug product that includes the excipient. "It would be a kind of preliminary approval," says Goldring. "FDA still would have final say, but it would allow the excipient manufacturer to go to drug companies and say, 'The panel has approved it, and about 90% of the time FDA takes the recommendations of the panel,' or something like that." Excipient safety still would have to be evaluated in each individual drug product, Goldring says, because excipients can interact differently with various active ingredients. 

Goldring says the board could also help excipient companies determine exactly which safety tests are necessary for a given excipient, particularly when an older excipient has been modified. "For example, if you have an old excipient and just add a hydroxyl group or a new polymer, is there some abbreviated type of testing you could do? That is something that an independent evaluation panel also could determine," says Goldring. 

IPEC hopes to have a formal meeting soon with FDA to discuss its proposal. The guidance lays the groundwork for the discussion, Goldring says, because it establishes the kind of testing needed to ensure excipient safety. "This is a stepwise process," he says. "The first step is done. Now we're moving on to the next step." 

Eli Lilly Scales Back Planned Virginia Insulin Plant

) has halved its planned insulin plant in Prince William County, Virginia, according to a recent 

 report that was confirmed by a Lilly spokesperson. The proposed plant is also two years behind schedule. 

In a meeting with the Board of County Supervisors, the 

 reported, company officials said they now intend to hire only half the approximately 700 workers originally planned and will reduce the planned 600,000-ft

. Construction is now expected to begin this winter, and the plant should be fully operational before 2009. 

The news report cited increasing costs of steel and other building materials as a major reason for the cutback and the delay in the construction start. Industry analysts linked the decision to erosion in Lilly's insulin market share and declining sales of one of the company's insulin products, "Humulin." 

Compounding Pharmacies' Lawsuit Against FDA Will Continue

The US District Court for the Western District of Texas (Midland, TX) has ruled that a lawsuit against the US Food and Drug Administration (Rockville, MD, 

) will proceed, despite a request from FDA to drop the case. 

A coalition of 10 compounding pharmacies sued FDA for engaging in "unlawful" inspections of state-regulated pharmacies. At the center of the lawsuit is a 2003 FDA compliance policy guideline (CPG 7125.40), which prohibits the compounding of drugs from bulk ingredients.  The agency has since inspected several compounding pharmacies to enforce the guidelines. 

The pharmacies petitioned the court to allow them to continue using compounding methods without FDA considering them manufacturers or requiring them to meet the agency's manufacturing guidelines. The coalition alleges that federal law prohibits FDA from inspecting state- regulated pharmacies and that the agency is exercising jurisdiction without the authority to do so. 

Self-Assembly Nanotechnology Improves Microencapsulation

A group of chemical engineers from Rice University (Houston, TX, 

) has developed an environmentally friendly microencapsulation technique that enables researchers to produce microcapsules quickly and easily. 

Though microencapsulation is a promising technique for drug delivery, traditional production methods require multiple steps that could affect the drug molecule. With sacrificial core templating, for example, microcapsules are made by layering a coating onto a template or a core. The core must be dissolved or burned out to form a hollow center, which could damage the drug or its carrier. In addition, techniques using flow methods only produce large capsules and have limited applications. 

The Rice technique involves self-assembly, which means that hollow spheres form spontaneously when certain polymer and salt components are combined. "If you know how to mix things, you can make microcapsules," says Michael S. Wong, assistant professor of Chemical Engineering at Rice. "That's the novelty of what we've been able to do. It's easy and has a lot of potential applications." 

Researchers mix together three common off-the-shelf ingredients: a water-soluble, cationic polymer such as polylisine or polyallylamine, citric acid, and silica nanoparticles. The mixing process occurs in water at room temperature, under normal pressure, and at mild, near-neutral pHs. Upon mixing, 1-4-μm particles form in less than a minute. According to Wong, the structures hold up under their own weight and will not puncture or collapse like deflated balloons. In addition, the research team believes the technique will be suitable for large-scale production. 

Because the process occurs in water, any chemical or drug that's suspended in the water gets trapped inside the hollow sphere when it forms. To encapsulate a drug particle, for example, the team adds the "cargo" to the solution and then mixes in the other components. A hollow sphere naturally forms around the droplet of water that contains one drug molecule. Says Wong, "It's green chemistry. You don't have to waste solvents, and it happens very easily, quickly, and nondestructively."

One application of interest could be timed and controlled drug release in the body. The research team is currently exploring how to use factors such as pH level or temperature to prompt the microcapsules to open and release drug. The team has already experimented with magnetic microcapsules (using iron oxide nanoparticles rather than silica) that enable physicians to control exactly where the drug will be released using magnets. 

The group also is exploring how various molecules affect the self-assembly chemistry and how to make the spheres monodispersive. "We're now trying to make the chemistry such that the spheres will all be the same size. And we're on the right track," says Wong.  

Able Laboratories, Inc. (Cranbury, NJ, www.ablelabs.com) announced in late May that it would halt all production and recall all available product because of problematic testing procedures discovered during an internal investigation. The company manufactures mostly generic prescription drugs, including drugs containing acetaminophen.

July 2005

Remote Visual Inspection Tools Helps Validate Vessel Cleaning

The "CA-Zoom Pan–Tilt–Zoom 6.0" digital video inspection system from Everest VIT (Flanders, NJ, 

) has been expanded to include clean-in-place (CIP) inspection tools for pharmaceutical tanks, vessels, and piping systems.

Users spray a 0.02% riboflavin (vitamin B

)–water rinse on the inner surface of a vessel through the tank's CIP spray ball system. When the CA-Zoom's ultraviolet light source is placed inside the tank after the cleaning process, "the riboflavin solution glows to display areas where the surfaces were not cleaned properly," Jim Disser, sales manager at Everest VIT explains. According to Disser, the technology helps companies validate their cleaning processes. 

The system includes a joystick-controlled, high-power zoom camera that tilts and pans to achieve wide-angle or zoom views. The company's "iView" software–hardware platform enables users to capture, store, view, and compare still and video images on- or off-site. Camera head sizes for both tanks and small nozzles are included. 

Fluid-Bed System Automates Tilting and Dropping

Applied Chemical Technology (ACT, Florence, AL, 

) has introduced its "PG-100" fluid bed, featuring a swinging bowl that can be programmed to automatically tilt and drop material.

Rather than having to move the bowl by pulling out a cart, the fluidizing chamber revolves around a column so that "it can dump material completely by itself, swing back to the right position, and then close itself back up so it can begin the fluidizing process again," says Tim Holt, ACT's laboratory manager. The system can be activated by either a touch-screen panel or a remote computer for applications in which operators cannot be in direct contact with the substance (

, for highly potent materials). The bowl's tilt range extends to 180Âº. 

In addition, the PG-100 system is designed to granulate, coat, and dry particulates in the same bowl. Traditional models require users to use various bowls depending on whether one dries or coats material from the top or bottom spray apparatuses. "We've engineered it so that users have unlimited nozzle positioning with one bowl," says Holt. 

Water Purification System Combines Four Components in One 

Pharmaceutical Technology-07-02-2005

Police Lines

Let's Collaborate on IT Best Practices

Current Thoughts on Critical Process Parameters and API Synthesis

Singapore Fling

July 2005

In the Spotlight: Pharmaceutical Science & Technology Innovations

FDA, Congress Push for Safer Drugs

Bioseparations Look Ahead to the Past

US Pharmacopeia's International Activities