In case you haven't heard, Jeffrey Kindler, Pfizer's general counsel, is replacing long-time CEO Henry "Hank" McKinnell as the new head of the company. There is a long-range strategy in naming a lawyer to run a drug company and I'll get to that in a moment.  

But first, it's worth noting that McKinnell had a target on his back ever since Pfizer revealed his Trump-worthy retirement package, which amounted to a choice between a lump sum of $83 million or an annual pension of $6.5 million.  

The wailing and gnashing of teeth reverberated from one of end of Wall Street down to the other, with investors piping hot over giving such a generous package to a CEO who presided over a period of time when Pfizer's stock fell 40%. Over that same period the American Stock Exchange Pharmaceutical index was down about 13%. Pfizer shares have traded in a 52-week range of $26.98 to a low of $20.27 since last December—a black mark against not only the management of the company, but on the highly-paid CEO who investors hold responsible for it. 

As one investment wag put it, "It's the equivalent of paying a .220 hitter $10 million a year."  

CEO Image: It Means More Than You Think			

McKinnell also leaves at a time when the cupboard is bare, from a commercial drug point of view. In June 2006, Pfizer's patent on Zoloft expired. The antidepressant drug became a household name across America and it became a cash cow for Pfizer, generating $3.3 billion in 2005 sales. The company is also losing patent protection on two other blockbusters: blood-pressure treatment Norvasc, which had $4.7 billion in 2005 sales, and allergy drug Zyrtec, with $1.3 billion in sales that year. 

While new drugs like Exubera and Sutent could eventually reach the billion dollar mark in sales (analysts think they both will) they may not reach the mega-drug status that Zoloft and Zyrtec did, and that could translate into a big drag on the company's bottom line come 2007 and 2008, when generic drug makers make off into the night with much of Pfizer's customer base. 

Can naming Kindler as CEO change all that? It's hard to say. Wall Street views Kindler, an ex-McDonalds executive (he ran the hamburger titan's Boston Market chain restaurant unit) as a strategic thinker who can tackle the thorny problems of a lackluster drug pipeline and mount legal battles over patent issues surrounding Lipitor and painkiller Celebrex. That's only going to help. 

Kindler's legal background should come in handy on numerous fronts, too. Before going off to the private sector, Kindler made his legal bones at the Federal Communications Commission and then clerked for a judge and for US Supreme Court Justice William J. Brennan, Jr. His first foray into the legal sector came at General Electric, where he was Jack Welch's right-hand legal man. Kindler squashed a price-fixing indictment involving GE and diamond seller De Beers, with the presiding judge tossing out the case a mere six weeks into the trial after Kindler made mincemeat out of the prosecution's witnesses on the stand. GE insiders say it was one of Jack Welch's favorite moments during his highly prominent tenure as CEO at GE. 

That's crisis management at its best—a trait that the Pfizer board must have surely considered before tapping Kindler to the post. After all, crisis management is one of the first "red flags" that shareholders look for in an effective CEO. And pleasing the shareholders is, fairly or unfairly, job Number One for any CEO—from biotech companies to ball bearing makers. 

Kindler gets it. One of his first comments to the press was targeted right at company investors and potential company investors. 

"We will transform virtually every aspect of how we do business, focusing on actions that create and sustain value for our shareholders" Kindler said. He added the company will "pursue a broader portfolio of opportunities, including biologics, oncology medicines, potential new treatments for Alzheimer's disease and even vaccines." 

Part of that plan will be for Kindler to follow through on last month's deal to sell Pfizer's consumer products division to Johnson & Johnson for $17 billion. That should give Pfizer some financial wiggle room as it sorts out its pipeline issues. Deals to sell other operations this year and next should add more cash to Pfizer's financial arsenal—about $34 billion or so. 

While Pfizer will continue to depend on established drugs like Lipitor (analysts estimate $13 billion in sales from the cholesterol drug in 2006), the added cash will buy the company some much needed time and address Wall Street's cry for new drugs to take the place of the expiring old ones. Kindler can help right away by applying his legal smarts to the patent protection process and to the regulatory approval process. In other words, expect to see Kindler lobbying for more lax regulations on C-SPAN during the next several years. 

In broader terms, it's becoming increasingly apparent that Pfizer will be among the first of many pharmaceutical firms to begin bringing in hands-on lawyer types who know patent law, know drug side effect issues inside and out, and know how to work with federal regulators. Gone will be the days of hiring academics, scientists, and marketing gurus as CEOs. 

It's a new reality for drug companies and the board of directors at Pfizer should be given credit for recognizing it first. 

The game is changing in the biosciences market and, as usual, the money changers realize that first. No longer can drug companies afford to prop up loyal company lifers who don't know the difference between patent protection and patent leather shoes.  

That's not to knock McKinnell directly, because patent and regulatory issues aren't his bread and butter. But it had better be for a new generation of CEOs who have to grapple with management issues that transcend simple market share and matrix management strategies. 

Celebrity author and business/finance commentator for CNN and Fox News, 

, 79 Radcliffe Drive, Doylestown, PA 18901, 267.880.3144, fax 267.880.1939, 

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In case you haven't heard, Jeffrey Kindler, Pfizer's general counsel, is replacing long-time CEO Henry "Hank" McKinnell as the new head of the company. There is a long-range strategy in naming a lawyer to run a drug company and I'll get to that in a moment.

StreetTalk: New Sheriff in Town at Pfizer

FDA announced in July that it would develop new guidance to address concerns about potential conflicts of interest among advisory committee members. This action was taken, presumably, to preempt Congress from passing more restrictive rules, particularly those in the Hinchley Bill. Narrowly passed by the House last year, the bill prohibits anyone with a financial stake in the topic under discussion from participating in an FDA advisory committee. While this attempt to prevent bias is admirable, it is also unrealistic.  

In debates like this, it is tempting to be a purist and adopt an all-or-nothing approach. However, that can have unexpected consequences.  

The plight of Hutcheson Memorial Forest provides an example. Hutcheson, in central New Jersey, is one of few remaining virgin forests in the Eastern United States. For more than two centuries, the family that owned the land resisted the temptation to harvest its valuable timbers. When they finally gave in, around 1955, a small portion was saved for posterity by an unlikely group—a carpenter's union. Passionate about preserving the woods, the group ceded the land to Rutgers University under a deed that prohibits any land management on the property. 

That sounded like a good, protective policy—at least for 50 years ago, before commercial and residential overdevelopment led to enormous growth in the deer population. Today, deer thrive on the edge of these woods, with no natural enemies to control their numbers. The deer are decimating the undergrowth at Hutcheson, including all the white oak saplings that should create the next generation of canopy. This allows Japanese stilt grass, an invasive species the deer don't eat, to overtake many areas. But because the rules are so strict, Rutgers cannot do anything to control either the deer or the stilt grass, or any other problem that threatens the future of the forest. 

The carpenters, in their quest to save the trees from logging, surely didn't intend to leave the woods vulnerable to other forms of destruction. 

Before finalizing any legislation designed to protect FDA from conflicts of interest, Congress should recall Hutcheson Memorial Forest. Yes, it is necessary to manage industry influence at FDA. But legislators should be sure that the rules are not so restrictive that they interfere with FDA's mission to protect the public. 

The focus of the current debate is FDA committees involved in evaluating new drugs. But new legislation, if not carefully worded, could also affect the agency's other committees, such as CDER's Advisory Committee for Pharmaceutical Science. This committee, and others like it, provide the agency with invaluable advice about manufacturing. FDA doesn't produce drugs and can never have the level of manufacturing expertise that industry does. For this reason, FDA needs these boards. (FDA should probably hire more folks with industry experience, but it's hard to lure experts away from lucrative industry jobs for life in the public sector.) 

Rather than going to extremes, Congress should implement moderate measures, like those in last year's Senate version of the Hinchley law, and in other legislation proposed more recently, such as the Enzi–Kennedy bill. Those measures seek to limit industry influence, not by cutting off FDA's ability to get advice from experts with financial ties to industry, but by revealing the sources of the advice. Such measures can help protect FDA's unbiased role without sacrificing information-gathering, a critical aspect of decision-making.  

Taking a purist stance is always tempting. It can, however, have unintended consequences.

From the Editor in Chief: An All-or-Nothing Approach Could Tie FDA's Hands

The current Good Manufacturing Practices (GMPs) regulations for finished pharmaceuticals and medical devices have been around, in one form or another, for over 25 years. During this time, FDA has provided interpretation and guidance to aid companies in their efforts to comply. Yet, when found to be out of compliance by FDA, some companies experience difficulty making effective corrections in a timely manner. When compliance is finally achieved, it is only after several failures and misdirected expenditures of time and money, often leading to chronic deficiencies even more difficult to remedy. To achieve effective, sustainable corrections to GMP deficiencies, companies need to take a systems-based, organizational approach to compliance.

Recent trends in US Food and Drug Administration (FDA) warning letters attest to the agency's continued priority on GMPs and reflect the challenges companies have in achieving and maintaining GMP compliance. While the number of warning letters the FDA has issued over the past three years has declined, 47 percent of all violations cited in 2005 were GMP deviations. To help prevent occurrence, or reoccurrence, of GMP deviations, regulatory experts including FDA recommend that manufacturers identify and correct the underlying systemic causes of noncompliance, rather than focus on the specific symptoms. This allows manufacturers to redesign quality subsystems to improve both operational efficiency and regulatory compliance. 

A company facing a long list of observations at the end of an FDA inspection may react with great energy and purpose to fix each one. However, when the company focuses on the specific symptoms rather than the underlying causes (i.e., the systems), audit after audit will identify additional examples of system weaknesses. Rapidly this becomes a repetitive, frustrating cycle of failure resulting in chronic GMP noncompliance and ongoing, costly adversity with the FDA.  One pharmaceutical company that received a Warning Letter for GMP deficiencies, for example, found itself subjected to restrictions on product approvals and export certificates for five years despite repeated efforts to address the cited problems. Prohibitions of the original Warning Letter were kept in force because subsequent inspections conducted over the ensuing five years found continuing GMP problems.  

The road to an FDA injunction is usually a long and frustrating one for both FDA and the company. From the company's perspective, it has made good faith attempts to correct the problems cited by FDA. Typically, it has devoted large sums of money and staff resources, hired consultants, developed and executed action plans, etc., yet at each assessment by FDA, new or similar GMP failings are identified. Ironically, company management redoubles its efforts, restarting the same cycle of plans, committees, consultants, milestones, commitments, new beginnings and, predictably, repeated failures.  

FDA, too, becomes frustrated that its best efforts have not elicited effective, voluntary corrective action. It has accepted the proposed corrective action plans and the promises of management and patiently awaited results. When, in spite of these efforts, sustainable compliance is not achieved, FDA may begin to believe management of the company is unwilling or unable to fix its problems.  

Unfortunately, an FDA injunction or the threat of one does not suddenly enable a company to do what it has not been able to do before. Long before FDA considers injunction, a strong admonition from FDA to correct violations either in writing or in a face-to-face meeting frequently doesn't provide insights about how to make corrections. In fact, it can exacerbate the situation by requiring or suggesting many specific activities that do not contribute to resolution of the underlying problems or offer insight to the mechanics of correcting problems.  

BREAKING THE CYCLE WITH A SYSTEMS APPROACH

A systems-based approach is the key to breaking the cycle of GMP failure.  FDA has identified six subsystems (See Figure 1) reflected in the pharmaceutical GMP.  Together these subsystems make up a quality system.  A systems approach leads to effective and sustainable corrections to FDA inspectional findings or a Warning Letter.  The most significant benefit, however, is that it proactively prevents GMP problems.  

Figure 1. The diagram below shows the relationship among the six subsystems in pharmaceutical manufacturing-the quality system and the five manufacturing systems. The quality system provides the foundation for manufacturing systems that are linked to and function with it to achieve compliance and consistently produce a quality product.			

FDA first recognized the value of a quality system approach to GMPs in its 1996 publication of the Quality System Regulation for Medical Devices.  FDA realized that a quality system provides the means for assuring consistently high quality of healthcare products.   

USING "CORE TEAMS" TO IMPLEMENT THE SYSTEM APPROACH 

A systems-based approach to establishing a competent quality system can be effectively developed and executed using an interdisciplinary team structure formed around the subsystems of the GMP regulations (for drugs or devices, Figure 2). Each core team, representing a subsystem, is chartered to initially define the existing assigned subsystem and to assess its performance using various quality data. Based on their findings and employing risk-assessment principles, each team designs a new subsystem assuring the controls incorporated are commensurate with the risks posed. This may involve building on what exists, completely redesigning it, or more commonly, doing both. This process frequently identifies opportunities to improve process efficiency in a context that assures a proper balance between efficiency and compliance.  			

Next, the team creates documentation to support the level of controls that have been created. The team identifies metrics to be used in assessing future performance, training needs and necessary linkages between the subsystems. The team also eventually oversees the implementation of the new subsystem.  

Critical to the success of this process is the interdisciplinary make-up of the teams—all stakeholders should be represented, i.e., quality, manufacturing, research and development, engineering, marketing, etc. This enriches the talent pool that will contribute to the creation of the subsystem and prevents the development of subsystems that are not workable throughout the organization. Each team should have an external third-party expert member to provide an objective perspective, provide technical and regulatory advice and aid the team in avoiding cultural "blind spots." A process facilitator can assure team efficiency, achievement of milestones, and resolution of issues.  

Figure 2. Core Team Structure Recommended organizational structure for a core team approach to creating an effective quality system for a pharmaceutical company: 

Overseeing the entire project is the steering committee that may be variously called the leadership or management team. It consists of senior-most managers representing the various functional areas of the company along with a third-party senior management expert for objective regulatory assistance. This team establishes the vision, provides the necessary resources and commitment, assures linkages between the various teams, serves as the change agent for cultural and system issues, and resolves issues that invariably surface during the course of the project. It also reflects senior management's commitment to quality. A project manager is often required to assure the project is completed on budget and on time.  

Documenting a quality system on paper is not enough to assure a company's regulatory or business health. If organizational values are not in sync with quality principles, procedures may get changed but behaviors may not. In this situation, any system corrections that are made will not last. The values reflected in the company's organization and support systems impact behaviors that ultimately influence the manner in which the quality system is executed. The manner in which employees are motivated, rewarded, compensated, and promoted influences their behaviors. Sometimes little attention is given to the behavioral impact these support systems have on a company's quality system implementation. The actions of management, particularly when in conflict with its words, communicate clear messages to the organization. Implementing a systems-based team approach to enhancing the quality system itself can have a positive effect on culture, but a concerted effort must be made by management to assure alignment of values with the quality system. This can be very difficult.  

Using organizational development and management tools, the company must determine which assumptions and beliefs support or hinder successful implementation of a new quality system. Communication must be planned and managed to assure clarity, effective conveyance of key ideas, and consistent support of ongoing development. Support systems—particularly those involving human resources policies, compensation schemes, career planning, recognition and reward systems, hiring and promotion practices, among others—must be evaluated to assure alignment. Providing the necessary attention to organizational culture can speed the process of quality system implementation, as well as assure its ultimate success. 

Establishing a quality system that meets a company's regulatory and business needs is challenging. Companies faced with real or threatened FDA sanctions are usually least prepared to react effectively. Frequently, their efforts of the past have been unsuccessful, leaving little insight into new approaches. However, even a company in this situation can develop a successful approach if it recognizes the value of a systems approach to creating a quality system, understands the value of a robust quality system in achieving regulatory and business objectives, and appreciates the impact and role of organizational culture. With this foundation, a process employing interdisciplinary, systems-focused teams can result in a sustainable, compliant quality system that can withstand regulatory challenge and achieve efficiencies that meet the business needs of the company. 

 is the vice president of pharmaceutical quality systems and validation services for 

Companies faced with real or threatened FDA sanctions are usually least prepared to react effectively.

A Systems-Based Team Approach to GMP Compliance

Operations Excellence, as applied most often in biopharmaceutical organizations, focuses almost entirely on internal manufacturing and quality operations. This is the right place to start; manufacturing effectively is the key to producing quality product on time.  

However, once the quick wins are achieved in the plant, where should organizations look next for continuous improvement opportunities? The next logical place is upstream with the suppliers.  

As a result, the topic at the most recent Operations Excellence Consortium meeting, held July 22 at Bayer Biologicals in Berkeley, CA, was highly relevant to Operations Excellence programs: Supplier Quality Management. 

In highly competitive, commodity industries that have perfected Operations Excellence practices, material costs can compose more than 50% of the overall product costs. Additionally, profit margins can be so small that poor production yields can significantly impact the bottom line. As a result, Operations Excellence programs in those industries have applied Operations Excellence practices aggressively with their suppliers. 

Some examples of supplier management practices at world-class organizations include: 					

Supplier integration: Toyota and other auto manufacturers set aside space within their own facilities for the vendors to produce components for their cars, eliminating transport from the supply chain and providing real-time feedback on quality issues.

Data integration: Demand signals are transmitted electronically in real time to suppliers, providing the most accurate order and forecasting information and reducing inventory backlogs.

Supplier consulting: GE and Hewlett-Packard provide "free" consulting to their key suppliers. This results in lower costs and higher quality incoming materials.

Development integration: Key suppliers take an active role in shaping the future product portfolio, combining their specific expertise with that of the customer companies to produce more cutting-edge products.

When compared to those companies, the biopharmaceutical industry is relatively unsophisticated in dealing with suppliers. Some of the reasons for this were covered in the most recent consortium meeting, and include: 					

Lack of trust: Manufacturing products for human consumption demands a focus on patient safety. Most companies in the industry have dealt with suppliers changing processes without notification or supplying out-of-specification product. Because of this lack of trust at the supply base, the industry routinely requires 100% testing inspection of incoming materials, an expensive and time-consuming activity. Additionally, regular auditing of their supplier facilities are mandated by FDA regulations. 

Problem of Scale: Biopharmaceutical companies consume relatively small volumes of raw materials compared to their suppliers' other customers. As a result, working to drive higher quality upstream or asking for better raw material specifications has normally fallen on deaf ears.

Not-Invented-Here Mindset: It is true that the leading biopharmaceutical companies invented the main processes for making drug substance today. However, vendors who support the industry have developed expertise that may be significant to their customers; however, R&D groups may not be open to soliciting vendor advice on future product development. 

These may seem like significant challenges, but companies have found ways to circumvent these issues or minimize their impact: 					

Reducing the number of suppliers to allow better vigilance of their operation and closer management of their supply chain.

More robust auditing that examines not just the supplier, but the supplier's supplier.

In larger firms, a clear process for receiving change notices from suppliers and assuring a proper evaluation and response.

Paying a premium for raw materials with tighter specifications. To guarantee higher quality, companies can work out special deals with vendors to source products with tighter specifications. In some cases, this means that the vendor may be inspecting 100% to achieve that quality, but that cost is likely incurred in a lower cost area, with lower cost resources, than in your own facility. 

Including procurement in development to ensure that inappropriate vendors are not locked in to the bill of materials.

Leveraging supplier knowledge, especially in the area of deviation management and reduction.

Using vendors for noncontrolled materials management, including vendor managed inventory (even in controlled environments) and raw material Kanbans.

Ongoing, robust measurement of supplier performance. This can be used to shift order volume to higher quality suppliers.

Better supplier management doesn't need to wait for the Operations Excellence program to mature in production. Many of the above identified improvements can begin in parallel to production-related improvements.  

However, companies need to face reality: The biopharm industry will not likely reach the production volumes of small molecule producers or companies in other industries for years to come. Until better leverage is achieved, your company will need to put in extra effort and management to minimize supplier risk to quality and delivery. 

The latest East Coast consortium meeting was held August 22 at Human Genome Sciences in Rockville, MD. The meeting was well attended and focused on the challenges of moving a new plant from qualification to commercial development. The session included a tour of the new large scale facility. The next European Consortium is scheduled for September 26 at Avecia in the UK. Go to 

 for information on past and future meetings. 

 is a partner at Tefen, Ltd., 1065 E. Hillsdale Blvd., Suite 421, Foster City, CA, 94404;  Tel 650.357.1120 x117, Fax 650.372.1350, 

Better supplier management can begin in parallel to production-related improvements.

Operations Excellence: Managing Your Suppliers for Maximum Results

Steam traps are part of a steam-in-place system. The current design allots 18 in. of vertical leg for condensate backup. A design with a sensitive bellows has been proven in laboratory tests to need only 6 in. of vertical leg during the 15 min. of 121°C sterilization. Loads of 1 to 27 lb/h are covered by the capability of the new trap, equivalent to required steam for vessels 20 to 40,000 L.   

Biopharmaceutical facilities include hundreds of sanitary steam traps. Steam traps require an 18 in. vertical leg for condensate backup during steam-in-place sterilization (SIP). This adds 18 in. to the elevation of equipment, portable vessels, utility panels, and clean room ceilings. The vertical leg is required by the original equipment manufacturer to guarantee that the condensate backup does not reach the temperature instrument that is monitoring a SIP. 

Steam traps are sized for the high  condensate load during initial heatup of the vessel. However, the condensate load during SIP maintenance is 50 times lower than the heatup load. Jacobs  asked if Spence Engineering Co., the manufacturer of Nicholson Steam Trap, could guarantee their steam traps with 6 in. condensate backup at low loads during SIP maintenance. This article reports on laboratory tests proving a modified bellows in a standard steam trap can hold to the 6 in. maximum.  

THERMOSTATIC TRAP MECHANICAL FUNDAMENTALS

A diagram of a thermostatic sanitary steam trap for vertical installations is shown in Figure 1. The working element in this trap is an alcohol-filled bellows. When this bellows is in contact with steam, the alcohol expands, which forces the plug into the seat and stops the steam flow. When cooler condensate hits the trap, the alcohol condenses, which contracts the bellows, pulls the plug off of the seat, and allows the condensate to be purged from the trap.  			

Several additional features make this a sanitary steam trap. The bellows is located above the plug, which allows a small layer of condensate to remain at the bottom of the trap when the trap is hot. This water layer acts as a seal to prevent small leakages of steam. When the SIP cycle is finished, all condensate drains from the trap as the trap cools. The trap is angled so any condensate left in the trap after the SIP cycle will drain freely. The material is 316L stainless steel to minimize any rouging of the system. The internal surface finish is also less than 20 micro-inch roughness average to prevent any particulate adhesion. 

Figure 1.  Sanitary Thermostatic Steam Trap

The trap operates on the difference in temperature between the steam and the condensate. This difference is referred to as the sub-cool of the steam trap. As condensate backs up above the trap, its temperature drops. A trap with a high sub-cool requires the condensate to back up a greater height to allow it to cool. The piping immediately above a steam trap is uninsulated so the condensate can cool quickly. Steam traps located in a cramped, hot mechanical space where heat cannot be dissipated will not operate properly. This is a bad facility design and should be avoided. 

The range of temperature in SIP is 259 to 280 °F, corresponding to 20 to 35 psig. The trap has a passive way to determine when the condensate is subcooled. Steam pressure squeezes the bellows, which is counteracted by the vapor pressure of the bellow's fill to compensate for the condensate temperature. Proper design of a steam trap can reduce the sub-cool, making it more sensitive to condensate backup. This sensitivity is controlled by the mechanical properties of the bellows and the bellows fill. 

A thermostatic steam trap can be likened to a control valve with a condensate capacity (Cv) that varies from full-open to full-closed as the stem travels up and down. Manufacturers publish capacity data based on a 10 °F sub-cool, which is a generally accepted benchmark for comparing traps' maximum capacity. Liquid condensate capacity is defined as in equation [1]: 

where q is the flow in gal/min, P1 is the upstream condensate pressure in psia, P2 is the downstream pressure in psia, and G is the specific gravity. Therefore we solve for equation [2].  

where W is the flow rate measured in lb/h, 60 is min/h and 8.337 is cold-water (25 °C) density in lb/gal.  

There is a limit to P2. As the condensate moves through the trap, its pressure is reduced and the hot condensate flashes. When the downstream pressure is approximately 50% of the upstream pressure, the pressure drop becomes critical. At this point the flashing steam reaches sonic velocity, which chokes off any additional flow through the steam trap. In this case the downstream pressure P2 is the vapor pressure of the flashed condensate. 

The test trap discussed in this article is the Nicholson CDS 204 with –B bellows. It has a 5/16 in. orifice (3/4-in. inlet) with a cold water Cv of 1.59. Table 1 indicates the theoretical capacity when passing 80 °C water and the published 10 °F sub-cooled condensate for 20-psig steam. A theoretical capacity at a 2 °F sub-cool is also shown. This calculated capacity is actually larger than the actual capacity because it assumes that the trap is fully open. At a 2 °F sub-cool there is not enough temperature difference to open the trap fully, leaving the trap partially open.  

Table 1.  Theoretical CDS steam trap capacity (wide open Cv = 1.59; steam temperature  =  20 psig).			

SIP systems for vessels and associated piping are highly engineered systems. There are several different arrangements used by the biotech industry to purge air, heat up the vessel, and maintain a steam temperature of 121 °C for a minimum of 15 min.  

Figure 2. Steam trap piping. Arrangement #1 has a three-way valve. Arrangement #2 for smaller systems has no valve.			

Typically, clean steam is introduced to the top of the vessel and exits through feed lines, vent lines, and drain lines. Air, steam, and condensate typically flow through a three-way valve (Arrangement #1, Figure 2) located at the remote end of each pipeline. When the vessel is heated to 95 °C, the air is considered to be sufficiently purged and the three-way valve switches over to the temperature element and steam trap for SIP maintenance. This cycle is shown in Figure 3.  

Figure 3. This is a typical SIP temperature curve with a three-way valve. The steam trap is active only during the SIP maintenance period.			

For smaller vessels, a three-way valve is not required as shown in Arrangement #2 of Figure 2. In this case the Nicholson model CDS can be used to pass Clean-In-Place Return (CIPR). Capacity calculations show that the CDS can pass 3,608 lb/h (Table 1) of 80 °C water, which exceeds the highest condensate load of 2,500 lb/h listed in Table 2. The requirement to use multiple steam traps or a three-way valve on the bottom of a sterilization tank depends on the time required to purge the air and condensate during the air purge cycle. The 3-way valve allows a faster purging of the condensate, but does not allow pressure buildup if steam is vented.  

Placement of the measuring thermocouple is important to system performance. It must be positioned in the most remote part of the SIP system. For accurate measurement and quick response, immerse the thermocouple or the resistance temperature detector (RTD) directly into the line. The primary disadvantage of the direct immersion sensor is that the system must be shut down to perform routine sensor replacement or calibration. However, a thermowell can be used if this is a concern. A thermowell increases the incidence of measurement error and slows down the response time.  

LABORATORY TESTING PROVES 6 IN. LEG SUFFICIENT

Condensate backup tests were conducted for the Nicholson steam trap model CDS –B bellows and for the –A bellows. The –B bellows is a highly sensitive bellows developed to reduce condensate backup for SIP piping systems up to 40 psig. Two different –B bellows were tested for comparison (B1 & B2). The –A bellows is the standard bellows, which can be used at steam pressures up to 100 psig.  

Figure 4. Test arrangement of CDS traps. Steam pressures of 20, 25, 30, and 35 psig were run for five or 10 minutes.			

A diagram and photographs in Figures 4, 5, and 6 illustrate the test arrangement. Low-pressure steam flowed from a boiler, through an air-controlled Spence ED regulator, through a heat exchanger, and through a glass pipe to the CDS sanitary steam trap. Cold water flowed through the tubes of the heat exchanger to create condensate in the steam line. A thermocouple placed vertically 2 in. above the steam trap measured the temperature, which was recorded. (The thermocouple orientation for the test is different for a field installation.)  

Condensate backup tests were conducted from 20 to 35 psig, which represent the practical minimum and maximum values for SIP pressures. Various condensate loads were generated by changing the cooling water load. Condensate backup was measured in inches above the trap's inlet tri-clamp connection. The weight of condensate for these 5-min tests was recorded by the scale shown at the bottom of Figure 5. The trap cycled many times during this 5-min period.  

Figure 6. Close-up view of back-up leg			

Temperatures were recorded throughout the test. The difference between the highest temperature measurement and the lowest temperature measurement for a given cycle was designated as the test sub-cool. The test pressure, condensate load, maximum backup, minimum temperature, maximum temperature and sub-cool are shown in Table 3.  

Table 3.  Test data runs with the CDS trap 			

Loads indicated in Table 3 are the average flow rate over the five-minute test period. Care was taken in the test set-up to ensure that condensate could not settle in low points in the piping. If this occurred, this puddled condensate was periodically pushed to the trap in slugs. The maximum backup reported in Table 3 includes slugs of condensate. Sanitary steam piping is always sloped to be free draining and steam legs are taken from the top of steam headers to prevent condensate buildup in the lines.  

Featured Article

Steam traps are part of a steam-in-place system. The current design allots 18 in. of vertical leg for condensate backup. A design with a sensitive bellows has been proven in laboratory tests to need only 6 in. of vertical leg during the 15 min. of 121?C sterilization. Loads of 1 to 27 lb/h are covered by the capability of the new trap, equivalent to required steam for vessels 20 to 40,000 L.

Designing a Shorter Vertical Leg for Sanitary Steam Traps

In the software market for the biopharmaceutical industry these days, it seems that commercial off-the-shelf (COTS) applications are inescapable. Suddenly, everything is COTS. However, rapid proliferation of the term has far exceeded its actual availability. The terminology may have changed, but in most cases, the reality of system deployments has not. If a vendor claims to provide a COTS solution, what should a buyer expect? Better still, what should a buyer demand?  

To understand the current overuse, and in some cases blatant misuse, of the term COTS, a short recap of the laboratory information management system (LIMS) industry is in order. LIMS themselves did not originate in the pharmaceutical industry; they can trace their heritage to environmental laboratories. However, in serving one laboratory environment, vendors quickly realized that there were many similarities between laboratories in different industries, and aggressively marketed their systems to other sectors of business. To make the adoption of their solutions tenable in other industries, LIMS vendors worked to design highly adaptable systems, which was a logical approach. Customers were provided with a basic environment and database, and a set of tools with which to extend the system.  

At the time, most laboratories were completely paper-based, and their information management choices were restricted to two options: build something internally, or build something on top of a commercial LIMS platform. In many cases, the existing LIMS platform provided a good starting point, and could save the laboratory time and money compared with a completely customized solution.  

In many cases, however, limitations imposed by a basic LIMS platform could actually prove to be complex or insurmountable barriers to a successful deployment, and custom solutions were not uncommon. The pharmaceutical industry saw many custom solutions developed due to the intense regulatory scrutiny and complex testing requirements of their day-to-day business.  

Commercial LIMS platforms continued to improve, however, and over the past 5–10 years it has become very uncommon for  pharma companies to develop solutions internally, despite the fact that many significant gaps remain between the commercial, generic LIMS platforms and their specific business needs. 

In the past decade, pharmaceutical companies have increasingly recognized that software development is not their core competency. Executive management encouraged their IT teams to seek commercial solutions to fulfill their needs as much as possible, and actively discouraged internal development.  

LIMS vendors responded to this trend by claiming that their solutions no longer required "customization," but rather could now be "configured." This wordplay was, in many cases, nothing more than marketing. Pharma companies responded, knowing that customizing a LIMS system to suit their needs could represent greater effort than simply building one themselves, and hoping that this new "configurability" would reduce their deployment and maintenance burdens. 

At this point, it is important to provide a clear definition of the difference between configuration and customization: 					

A configuration option should require no programmatic code at all, and be completely tested by the vendor before software release. Ideally, configuration should be done through the user interface, although in some instances, configuration files may be used, provided that appropriate testing has been completed.

 form of programmatic code, including any and all varieties of SQL+Plus and Scripting.

Some systems made progress in offering greater levels of configurability. Unfortunately, however, in many cases vendors' claims of configurability were in fact based on customization. Wrapping a graphic user interface (GUI) window around a script does not change the fact that the script represents a customization. If it was not part of the original system, the component has not been tested, and the validation burden rests completely on the customer. 

The purpose of this discussion is to provide a context in which we can examine the current trend of claiming that systems are COTS. This trend began in the past 1–2 years, as the Food and Drug Administration began using the term in presentations. The term 

 has been used in other industries for many years, particularly in engineering fields. It has been applied to software and hardware components. In our context, it is being applied to software systems, particularly LIMS. LIMS vendors are sometimes painfully aware of the impact of customization on system validation, deployment, and maintenance. The message vendors try to convey is that all that pain is a thing of the past. In some cases, vendors made significant progress; in other cases, the product has barely changed at all, despite marketing claims. 

So, what should a customer be looking for in a COTS solution? 

The first step is to approach the term realistically. No solution will meet 100% of a company's needs out of the box. However, it should not be unreasonable to set a lower target of 75%, and optimistically look for greater than 80% success in meeting your functional requirements. The challenge is to evaluate whether the requirements presented in a demonstration are in fact included in the basic software system. Most LIMS vendors have demonstrated their systems for years, and are prepared to show what their systems are capable of doing. This will frequently include custom functionality that is not delivered as part of the core product, and is not documented or supported. Critical evaluation of the true out-of-the-box capabilities of a system must discriminate between what a system is "capable" of and what it truly delivers.  

In the pharmaceutical industry, there are several areas that have represented challenges for LIMS systems in the past that are excellent indicators of the scope and true capabilities of the basic product: 

Most LIMS systems are sample oriented. In order to accurately connect samples to a product of interest, many fields are typically added to the sample tables in the database to include information like potency, product identification, and formulation type. For a pharmaceutical LIMS system to be truly useful out of the box it should manage drug products and drug substances independently, then simply relate the samples to those products. The same is true of manufacturing batches; these should be independent entities, with their own set of properties, and are related to samples that represent those batches. 

A common test required in biotech and pharmaceutical manufacturing is microbial load testing. This test is used extensively for both in-process and final quality control testing. At first glance, it may seem simple: Collect a sample, inoculate a growth medium in a plate or tube, and observe the number of colonies that form. To really support the testing, however, the software also must record the associated data that validates the test result. 

Suitable software must make it simple for the end user to record that associated data as well as the end result. Questions to ask include: 					

Can the user easily link related data (e.g., media lot, control plate results, diluent lot) in the system to the results without duplicate entry?

Can the results be linked not only to the sample, but also to the manufacturing stage to which they apply?

Are actionable results automatically communicated to the batch manager?

Can one test method be used for in-process, release, and environmental monitoring testing?

Most LIMS vendors targeting the pharmaceutical industry offer some kind of stability testing functionality. However, this functionality sometimes is too rigid to adapt to the reality of stability testing, particularly during research and development. Special considerations include: 									

Can stability studies be altered easily to include additional timepoints or conditions?

Can stability studies easily reference release data as time zero results?

Can inventory material be easily tracked and managed?

Can multiple packages be evaluated simultaneously, in multiple orientations?

As previously mentioned, no system will be able to satisfy 100% of a customer's needs. With that in mind, it is important that the vendor provide capabilities to configure and, if necessary, customize the solution. Questions to ask include: 					

What are the approval lifecycles, including

Are there tools to extend the system without programmatic code?

How can new properties and new entities added?

What is required to design new GUI screens?

Increasingly, pharmaceutical companies have recognized that software development is not their core competency.

The Confusion Around COTS

Several gaps in current regulatory guidelines that govern the analytical method life cycle for the testing of biopharmaceuticals are identified. Strategic guidance on how to monitor and control the life cycle of an analytical test method is provided in this article. Analytical method transfer, analytical method component equivalency, and analytical method comparability protocols are discussed in light of risk-based strategies for validation extensions. The use of an analytical method maintenance program is suggested to control over time the predictable risk to patients and firm.

The successful completion of analytical method transfer (AMT) is a regulatory expectation for the extension of the validation status to other laboratories. The demonstration of equivalent test results and, therefore, an acceptable level of reproducibility when testing at a different location, can limit the potential risk to the patient (hence the regulatory expectation). Acceptable reproducibility also limits the risk of failing test results for the biopharmaceutical firm as established probabilities of passing specifications can be maintained. Similar, postvalidation changes in method components should be monitored and controlled to avoid significant (negative) changes for material or product release probabilities. 

Analytical method validation (AMV) guidelines exist from several recognized sources.

  Detailed validation guidelines for alternative microbiological test methods also exist.

  In addition, a series of practical tips and discussions for AMV and related topics was recently published.

  However, some topics are currently not sufficiently covered in recognized sources. For example, how can we demonstrate method comparability for new methods, extend the validation status onto other laboratories or other test method components, and maintain this validation status over time? What are acceptable levels for differences in method performance and when is a method no longer suitable?  

This two-part series focuses on all postvalidation work that may be required to ensure process and product quality over time. This article discusses practical concepts on how to ensure successful validation extensions. Part II, to be published in the October issue, will include practical tools to ensure a validation continuum (maintenance) for validated methods. The second part will also include case studies for deriving meaningful and risk-based acceptance criteria for validation extensions and validation maintenance and will, furthermore, include a case study on how to reduce analytical variability in validated systems. 

When replacing approved test methods with improved ones, analytical method comparability (AMC) data should be submitted together with the method description and validation results.

  Once a method is approved and in routine use, it should be maintained in an analytical method maintenance (AMM) program that can be administered through the validation master plan (VMP).

  If done well, this will ensure—like all postvalidation activities—consistent (accurate and precise) production process and product quality measurements.

  What exactly are the critical elements of good validations, validation extensions, or suitable validation maintenance? The answer lies mostly in the preset acceptance criteria for method performance and, of course, the actual validation results obtained. For example, if changes in analytical method components cause a change in test results and, therefore, in process or product quality measurements, we should capture when we will have exceeded method suitability limits. In other words, if the analytical method change will cause a predictable shift or spread of results with respect to specification(s), and therefore negatively impact the probability of releasing material, we should monitor this. To monitor and possibly compensate, we must first set reasonable suitability limits, then continuously control the overall method performance. Often, the most difficult part may be to estimate the associated risk of changed results with respect to both patient and firm, and from this, to set reasonable acceptance criteria. Once we truly understand why and when there will be a need for method improvement, we will likely know what should be done to compensate for the difference.  

Each production process has an associated probability for the rate of rejections that can be readily calculated by relating specifications and production process performance. However, instead of having to deal with only two probabilities (pass or reject) that are "visible" and monitored by statistical process control (SPC), we should consider two additional possibilities for all reported results. Therefore, there is a total of four possible cases for releasing product or material, of which three should be avoided as often as practically possible. The four cases for reported test results are illustrated here.  

Measured results are within established specifications.

Measured results are outside established specifications (OOS).

Cases 1A and 2A are routinely monitored by SPC. Cases 1B and 2B originate from other uncertainties such as imperfect test method performance or poor sampling and are not readily visible by SPC. Cases 2A and 2B are obviously not desirable because the firm cannot process nor sell this product or material. Case 1B constitutes a risk primarily to patients, but also means a risk to the firm if adverse product-related reactions or over- or under-dosing would actually occur. Case 2B constitutes a loss solely to the firm and should also be avoided mainly for profit reasons although other problems may also arise from this situation.  

For our validation extension acceptance criteria, we should primarily set acceptable protocol limits from SPC with relation to specifications. We should consider the likelihood and impact for cases 1B and 2B, and avoid as much as possible measurement errors as part of the AMM program. Inaccurate or imprecise measurements will always cause a lower than ideal probability of observing results within specifications. The acceptance criteria for AMV and its continuum requirements must, therefore, ensure the low likelihood for all cases but 1A. 

To meaningfully estimate risk to patients and the firm, we must understand our process data and integrate test measurement aspects into our risk-based validation strategies. Good risk management tools will dictate how much assay performance characteristics can deviate from the ideal. This will then set limits on how much we can tolerate over time for a test method to deviate from ideal (100% accurate and precise). It should also now become apparent why it is so important to maintain our validation status with an AMM program. When this is ignored, we negatively affect all four cases. (

 here means increased risk to patient or firm). Although undetected, negative effects will occur for the "invisible" cases 1B and 2B because measurement errors are not captured by regular SPC. This may also cause the lack of process understanding and control, and may also lead to conflicts with current regulatory expectations (process analytical technology [PAT]) and may impact a firm's profits in the long run.

Validated analytical methods can be transferred from one laboratory to another without the need for revalidation at the receiving laboratory.

  A typical AMT is accomplished by testing at the sending and receiving laboratories in a round-robin format. Testing is performed on three different product lots over three days, using two operators and two instruments in each laboratory.

  Reproducibility of test results, within and between laboratories, is demonstrated in Table 1 by evaluating intermediate precision (different operators, instruments, days and product lots at each site) using an analysis of variance (ANOVA) and by comparing the differences in mean results for each lot between both sites.

  For each AMT, preset acceptance criteria for intermediate precision and for the absolute differences between sites are derived and justified from the validation at the sending laboratory.

Table 1.  Analytical method transfer (AMT) execution matrix.			

The AMT reports should include descriptive statistics (means, standard deviations and coefficients of variance), comparative statistics (ANOVA 

-values) for inter-laboratory results, and the differences-of-mean values for both (or each) laboratories. Each report documents evidence that the transferred test method is suitable (qualified) for testing at the receiving laboratory. 

-value is less than 0.05, secondary acceptance criteria should be established for the comparison-of-means and variability of the results to demonstrate the overall lab-to-lab reproducibility of test results. It is advisable to include a numerical fall-back limit (or percentage) because the likelihood of observing statistical differences may increase with the precision of the test method. In addition, some differences (bias) between instruments, operator performances and days are expected.

  We should tailor our acceptance criteria for overall (intermediate) precision and for the maximum tolerated difference between mean laboratory results (accuracy or matching) to minimize the likelihood of obtaining OOS results (2A and 2B) or 1B results.

  The setting and justification of all acceptance criteria must strike a balance and is a critical part of each protocol. A detailed AMT case study was presented elsewhere.

As we need to demonstrate equality or improvement whenever approved methods are replaced, which and how are method performance characteristics compared? Table 2 provides guidance on which validation characteristics to use for comparability protocols for each assay type per ICH Q2A/B. All qualitative tests should contain a comparison of hit-to-miss ratios (for "specificity") between the approved method and the new method. If a qualitative limit test is exchanged, the detection limit (DL) of the new method should be compared and should be equal or lower for the new method. For all quantitative methods, the method performance characteristics accuracy and precision (intermediate precision) should be compared.

Table 2.  General guidance for using appropriate statistics to assess method comparability from validation characteristics per ICH Q2A/B.			

It is of great regulatory concern whether results may change overall by drifting (change in "accuracy" or "matching") or by an increase in data spreading ("intermediate precision"). An increase in data spreading or lack of precision will mostly increase the likelihood of observing cases 1B or 2B and should be avoided. A drift in results or "lack of matching" may require a change in the specifications. This drift in release results can occur in two directions, lower or higher results. Both directions are not acceptable outcomes for the demonstration of accuracy, and testing for equivalence between methods is therefore correct.

  The goal of comparisons of other characteristics (e.g., DL) is different such that two outcomes (equal or better) are acceptable. For example, for the comparison of DLs, the two outcomes of having either an equal or lower DL would both be acceptable.

  A third comparison category is the demonstration of noninferiority and is usually the easiest to pass for comparability. However, we should keep in mind that the use of any of the comparability categories (noninferiority, equivalence, superiority) using ICH E9 and Committee for Proprietary Medicinal Products (CPMP) guidance documents should be properly chosen and justified.

  In other words, noninferiority testing may be justified for the comparison of some primary characteristic such as DL if other secondary criteria (e.g., increased number of tests or test samples) can compensate for the small level of inferiority of the primary comparison characteristic.

Quantitative limits (QLs) could also be compared. However, both QLs would have to be estimated by the same principle (e.g., estimated by regression analysis). A low QL is desirable as it will let us quantitatively report and monitor low-value results by SPC. There are several ways to compare QLs. For example, we could compare the regression coefficients of both linear assay response curves to estimate both QLs and would also get a general idea how accuracy and precision characteristics compare over the assay range. Table 2 constitutes a general guidance. Particular examples for noninferiority, equivalence, and superiority testing to demonstrate method comparability were provided and discussed elsewhere.

No matter which comparability category we may use for a statistical comparison (with 

 = 0.05), a protocol should provide the design of experiments to be done and the pre-specified value for the allowable difference in results. The prespecified maximum allowable difference is illustrated in CPMP's Points to Consider On The Choice Of Non-Inferiority Margin.

  The allowable difference should be set similar to AMV or AMT. The difference should be set and justified by relating specifications to SPC data and considering the likelihood of observing any of the four cases (1A, 1B, 2A, and 2B).

 is the manager of QC Technical Services and Compendial Liaison at 

, Berkeley, CA 94701, tel. 510.705.4191, 

 1. Guideline for Industry Text on Validation of Analytical Procedures, ICH Q2A, 60, 1995. 

 2. Guidance for Industry Q2B Validation of Analytical Procedures: Methodology, ICH Q2B, 62, 1996. 

 3. The Fitness for Purpose of Analytical Method, Eurachem, Teddington, UK (1998). 

 4.  Traceability in Chemical Measurement, Eurachem/CITAC, Teddington, UK (2003). 

www.eurachem.ul.pt/guides/EC_Trace_2003.pdf

 5. Guidance for Industry, Bioanalytical Method Validation (2001). 

 6. Draft Guidance for Industry, Analytical Procedures and Methods Validation (2000). 

 7. Technical Report 33, Evaluation, Validation and Implementation of New Microbiological Testing Methods (PDA, Bethesda, MD, USA). 

Good risk management tools dictate how much assay performance characteristics can deviate from ideal.

BioPharm International-09-01-2006

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