Around the world, news about the revolution in generic biopharmaceuticals is heard almost daily. That is, everywhere except in the United States. While consumers in Europe, Australia, and other countries already do, or will soon, benefit from the savings that generic competition will create for expensive brand-name biopharmaceutical products, here in the United States, consumers continue to wait. 

The science to support the approval of generic versions of biopharmaceutical products in the United States no longer seems to be the key question. Rather, the question appears to be whether Congress and the US Food and Drug Administration (FDA) will have the resolve to open the floodgates on what could amount to billions of dollars in cost savings on these expensive therapies. 

To be sure, there has been much smoke, but little fire. In February of this year, the architects of the US generic pharmaceutical industry implored FDA to take immediate steps to clarify the regulatory requirements for generic versions of insulin and human growth hormone (HGH). Senator Orrin Hatch (R-Utah), and Congressman Henry A. Waxman (D-California), in a letter to Acting FDA Commissioner Andrew C. von Eschenbach, M.D., noted that "the time has come for FDA to issue the guidance documents on the approval requirements for insulin and HGH [human growth hormone]. It is our strong belief that insulin and HGH are two products that could be separated from the development of a larger regulatory framework because they do not raise the same scientific and regulatory issues as biological products." The letter went on to argue that "There simply is no excuse—scientific, legal or otherwise—for FDA to continue to delay the release of these guidance documents." FDA responded in part, that it "has decided that it would be more appropriate to publish guidances that are more broadly applicable to follow-on protein products (FOPPs)."  

When will these guidances be forthcoming? No one knows for sure. Meanwhile, the European Medicines Agency (EMEA) continues to forge ahead. In February and March of 2006, EMEA released final guidelines for generic versions of insulin, somatropin (HGH), granulocyte colony-stimulating factor (GCSF), and erythropoetin. In April 2006, EMEA approved its first generic HGH (Omnitrope), and in May, its second (Valtropin). German consumers are now able to obtain Omnitrope at a discount of 20% when compared with the branded drug. Australian citizens have already had access to a generic HGH since November 2005. In stark contrast, Sandoz's US Omnitrope application still (as of this writing) languishes at FDA despite the US District Court's April 10 ruling, which compels prompt FDA action and roundly criticizes FDA for its failure to act in a timely manner. 

As we have seen in the past with conventional pharmaceuticals, generic competition stimulates innovation. Without generic competition, the US is at risk of losing its position of leadership in biopharmaceuticals, and consumers continue to pay more than necessary because generic competitors have no functional mechanism to develop and receive approval for more affordable versions of these drugs. 

The US can and should be moving forward on a process for approving generic biopharmaceuticals with a sense of urgency driven by the potential for saving billions of dollars for consumers.

is vice president of scientific affairs at 

., 400 Chestnut Ridge Road, Woodcliff Lake, NJ 07677, 

Articles

Columns and Departments

Without generic competition, the US is at risk of losing its position of leadership in biopharmaceuticals.

Final Word: The US is Falling Behind on Generic Biopharmaceuticals

The belief that glycosylation is critical to ensuring the functionality of protein therapeutics—and preventing immunogenicity—drives many manufacturing decisions. But is it time to question this industry tenet? 

At an April conference on vaccine manufacturing sponsored by the Institute of Medicine and the National Academy of Engineering (

), Dave Estell, PhD, did just that. He presented the protein scaffold methods that his company, Genencor, uses to produce industrial enzymes quickly and cheaply. Their typical process takes 8 weeks: 2–4 weeks to create the production host, 3–20 days for fermentation, and 2–10 days for recovery and formulation. And the end product is stable for years at 40°C. These tools and methods, Estell asserted, could be used to produce several million doses of a protein pharmaceutical within weeks of identification—as long as glycosylation doesn't matter. 

And most therapeutic proteins, Estell said, do 

 require glycosylation to ensure their efficacy or important properties.  

If that's true, why isn't the biotech drug industry using industrial biotechnology methods? 

In fact, some are. Every year, more than $13 billion of injectable and oral antibiotics are produced through fungal fermentation. But most of the industry is not. The disconnect, according to Estell, is that the biotech drug industry became fossilized in 1982, when it switched to CHO cells and decided that the high cost of products derived from CHO cells didn't matter, because the doses were small. 

These statements are provocative. But many in the industry will admit that their belief that glycosylation occurs properly in the proteins they manufacture is based more on assumptions than science. In many cases, it's not considered cost-or time-effective to fully characterize protein drug products. The thinking is, "If it weren't working, we'd know it." That is odd. If glycosylation is critical, why aren't we clearer about how well we have controlled it? 

Perhaps the reality is that glycosylation is not as critical as we think. 

The belief that glycosylation is critical to ensuring the functionality of protein therapeutics-and preventing immunogenicity-drives many manufacturing decisions. But is it time to question this industry tenet?

From the Editor in Chief: When Does Glycosylation Matter?

The biopharmaceutical industry is one of the most complex, and disaggregated, when it comes to using Information Technology (IT). If one were to tally up the number of enterprise-level solutions available to manage different parts of the business, it would make a chief financial officer cringe. Although the large enterprise resource planning (ERP) providers (SAP and Oracle) claim to be making the world simpler by integrating more functionality into their systems, best-in-breed advocates within companies have demonstrated that the one-stop-shop model for business management systems is short of being a fully matured concept. 

Simplification is a core concept of Operations Excellence that is contrary to current balkanized IT deployments. Continuous improvement requires a relentless effort to eliminate waste in all forms. The gurus of lean operations would argue that implementation of complex IT systems for business management is wasteful—why not use simple and easy-to-implement visual management tools instead? If statistical process control charting on pieces of paper worked well in the past to determine when a process was reaching an out-of-control state, why do we need distributed control systems and process historians? 

Realistically, the correct balance of IT lies somewhere between today's complex mix of systems and paper-based systems. Finding that balance requires keeping the following key points in mind when developing a software strategy: 					

 An IT system is not going to solve your problem. If you are experiencing challenges meeting your production schedule, it is probably because your processes are operating at a One Sigma level of consistency, not because you don't have a finite scheduling system and electronic batch records. When waste is significantly removed from the system, companies find that the need to automate is suddenly eliminated or reduced. Is there a need for a deviation management system if there is only one discrepancy in every few lots? Implementing a system seems like a solution, but it can often distract an organization from attacking real, and often more challenging, issues

 Developing an IT strategy should begin with an external focus. This process requires taking a critical look at what functionality is truly necessary to support your customer, versus what would be nice to have. The goal of a system is not to remove people from a process, but to provide the customers with what they need. Every screen, every field, every report that does not result in driving better service to the customer is a waste. If the IT solution doesn't reduce the cost to serve the customer successfully, then it should be eliminated. Remember—customers are most frequently internal, not external 

 As long as the current or proposed system meets the most critical requirements of the customer, companies should resist a best-in-breed philosophy. The main problem with the best-in-breed approach to software is the resulting waste that occurs. The overhead expense and configuration redundancy that accompany each new enterprise application add up quickly, and can be somewhat invisible to owners of the system. The biggest risk is that critical resources are focused on the software, and not on their core responsibility of supporting the customer.

This concept also applies to customization. The fastest and most successful ERP implementations are out-of-the box (vanilla systems). An honest assessment of the real needs of the system from the customer perspective can mean the difference between a one-year and a six-year implementation 					

Companies should focus on automating after stabilizing the business. Trying to implement enterprise applications during a growth phase (or with an uncertain future) poses significant risks. Processes are not locked down, strategy is not fully flushed out, and needs of the organization are still evolving. Specifically, in bio-pharma we have witnessed companies that invested millions in systems that became obsolete shortly after being acquired. Often, companies are willing to invest capital and people's time in IT systems during growth periods, but not in stepping back and questioning the effectiveness and efficiency of the underlying processes. This results in IT systems that lock in wasteful ways of conducting business that become difficult and costly to change.

Even with the aforementioned concerns, I'm no Luddite. There is no question that the proper application of IT can be a critical component to driving efficiency and actually reducing waste.  

Highly efficient companies use IT extensively, and with great success. However, the need and resulting form of the IT system were determined through systematic root cause analysis, that determined its use was the only way to drive better and more consistent performance. As companies reach for Six Sigma performance, humans involved in the process become too variable and error prone.  

Additionally, information needs to be viewed, analyzed, and reacted to in real-time. Within biopharma, the most exciting waste reducing technology is process analytical technology. Can you imagine a plant with no quality control laboratories (and no laboratory information management system?) Until then, biopharma should concentrate on solving real problems that cause inefficiencies, making the difficult choices around removing waste, and minimizing the footprint of IT on the organization. 

The complete schedule for future meetings of the Operations Excellence Consortium will be available soon. The next West Coast meeting is scheduled for July 20, hosted by Bayer in Berkeley, CA. Please refer to 

 is a partner at Tefen,Lt.,1065 E. Hillsdale Blvd., Suite 1615, Foster City, CA 94404; tell 650.357.1120 X117 (Office) 415.290.4580 (mobile), fax 650.372.1350, 

The overhead expense that comes along with each new enterprise application adds up quickly, and can be somewhat invisible to owners of the system.

Operations Excellence: Perfecting IT Management System Selection for Biopharmaceutical Organizations

Integrating filtration steps into an aseptic pharmaceutical process has some unusual complications. Various factors, such as particle load, fluctuations in pressure and temperature, and cleaning steps (which may have high temperatures or severe changes in pH), can cause wear to the filter elements. 

Continued performance of the filter elements becomes one of the critical process parameters that must be controlled.

  Using a filter in a process can lead to various damage phenomena such as irreparable blockage of the filter membrane and cracks or changes to the membrane or pore structure. While blockage can be easily detected during the process run, cracks or changes in pore structure cannot be detected that easily.

There is a method for checking these filter element properties throughout the course of the process—the filter integrity test. A typical four-step integrity test procedure (algorithm) is Figure 1.

  We will delve first into the test methods and then we will describe how to ease the burden by automating the entire cycle. Many industry-specific terms are defined in the glossary at the end of this article. 

The four integrity test steps are implemented upstream and downstream of the filtration unit in order to be able to detect any possible changes in filter element properties and thereby supply positive results to confirm the success of the filtration step. The diffusion test and the bubble point test are established, non-destructive test methods. To determine validity, compare the test results to the filter manufacturer's tolerance data. The bases of the tolerance data are validation processes conducted by the manufacturer. These are used to determine tolerances by correlating absolute, destructive test methods (bacteria challenge test) with filter integrity tests. Both test methods rely on a procedure of wetting the filter membrane with a pre-defined medium (typically ultrapure water, but also customer-specific liquids).

To start the automatic filter test, the filtration housing is disconnected from the actual process, or the filter is installed in a separate test housing. In this procedure, the filter element is pressurized at a specific value on the upstream (non-sterile) side. At this test pressure, the diffusion through the filter membrane is determined for values starting at 0.1 mL/min. By contrast, when the bubble point test is carried out, the applied test pressure is raised successively and the diffusion measured in parallel is monitored to determine any disproportionate increase. This increase in diffusion is caused by the wetting medium being pressed out of the pores of the filter membrane, which initially occurs in the largest pores, thereby providing information about the upper limit of the pore size distribution. Typical bubble point values for microfilters range between 3,000 mbar and 4,000 mbar and, in ultrafiltration, can go up as high as 8,000 mbar. These methods also allow reliable detection of cracks or blockage.  

Air filtration also needs a filter integrity test method to guarantee the sterility of critical parameters. Applications for these filter elements include pharmaceutical and biotechnological production systems. Unlike liquid filtration, air filtration elements are based on hydrophobic membranes, which prohibit the test methods previously mentioned (membrane wetting with ultrapure water).  

In this context, an alternate, non-destructive method—the water intrusion test (WIT)

  —is an established test. During the WIT test, or the very similar water flow test (WFT), the penetration of water into the hydrophobic membrane is measured under pressure and evaluated by comparing the results to a limit value. Additionally, this filter type can be tested by a diffusion test after wetting the membrane by liquids with low surface tension such as isopropanol or mixtures of WFI and isopropanol.  

Air filters are sterile barriers that typically are sterilized prior to the test step (Process step 1 in Figure 1), at the same time the production system is sterilized. They can no longer be removed for the test or during the test, but may only be accessed from the non-sterile process direction. Since the sensitive measurands (diffusion, bubble point or water intrusion value) can already be determined within the upstream volume, no contact or inflow to the sterile area is necessary and process-relevant sterile barriers remain intact. 

Figure 1. Process integration of a filter integrity tester			

All of these test methods give  results as either a flowrate (diffusion test, water intrusion test, water flow test) or a pressure value (bubble point test, pressure drop test) which has to be compared to the given limit value of the tested filter element in order to pass the test. These limit values are supplied either by the filter manufacturer as part of the validation documents of the filter element, or are determined during a validation process for customer-specific parameters and correlate to a destructive bacteria challenge test.

  Table 1 shows a typical set. Short test descriptions appear in the glossary. 

Table 1. Typical limit values for different filter types			

The test algorithm described by Figure 1 consists of several steps to be performed by an automated integrity tester (Figure 2). An automated integrity tester therefore needs to be able to handle pressurized air or WFI, in order to pressurize the filter cartridge with the appropriate media. Based on this requirement, hardware such as valves, pressure transducers, and flowmeters are standard components of a today's integrity tester. Typically these parts are controlled by micro-controller-based hardware and run by proprietary firmware (GAMP class 2 or 3).

  Since integrity testers are not only used in a well-defined laboratory environment, but also installed in a rough production process, the integrity tester manufacturer has taken these conditions into consideration. Hardware components should be made of appropriate materials (stainless steels are favored) and have the needed process reliability. Software has to cover the normal operating conditions, and also be able to detect critical changes of process parameters such as temperature or supply media (pressurized air). Often, these requirements are met by an automated functionality test or separate software control loops within the test procedure. 

Figure 2. Standard integrity test algorithm 11			

To meet the needs of process integration, most of the available integrity testers have interfaces in order to use additional external hardware. External valves mounted on the filter housing can be handled directly, or controlled by sending commands via a PLC interface. External sensors can be connected in order to perform the measurement directly at the filter housing, because long tubing lengths could interfere with the accuracy of the measurement. 

Because the WIT and WFT test use WFI as penetration media for the filter membranes, additional dedicated equipment has been developed by most of the integrity test manufacturers. A trolley equipped with a stainless steel vessel stores the needed water volume under sterile conditions. A PLC allows automated CIP or even SIP procedures for the vessel, with valves permanently connected. 

Electrical interfaces are specified based on serial protocols, such as RS232 or RS485, or based on the Ethernet/TCP/IP protocol. These interfaces allow a data transfer, or even a remote control of the integrity tester, by a PLC or MES software. 

Data handling involved in integrating an integrity tester into a filtration process can generally be accomplished in one of two ways: electronic data storage in a 21 

 Part 11 environment or hard copy printouts where no data are stored. Hard copy is not covered under 21 

In addition to deciding on the method of data storage, the integrity tester needs to be qualified before it can be used in the production environment. Qualification is typically divided into three steps, namely Installation Qualification (IQ), Operational Qualification (OQ) and a Performance Qualification (PQ). We cover this later. 

When working with electronic data storage, many factors must be considered to properly integrate the integrity tester into the IT process. Not only must the integrity tester fit into the 21 

 Part 11 environment, but also all other equipment (PLCs, computers, SCADA systems) involved in the data transfer must fit. Also, one must consider the method of data transfer. There are many standards in industry for equipment communication. Some of the more common ones found on integrity testers are Ethernet and OPC servers for communication to computers and RS-232 and Profibus DP for communication to PLCs. 

Pay attention to when and how often data are to be transferred from the integrity tester. Integrity testers usually have the ability to transfer data automatically (as it is being created or time based) and manually.  It is important that the data be transferred in a timely fashion to a designated computer where the data can be properly archived and backed up.  While integrity testers may have the memory to store large amounts of data, they are not intended as the sole data storage location for integrity test data (transient data). 			

In principle, two strategies for electronic data handling are common. First a strategy described as the  "stand alone" setup is based on the capability of the state-of-the-art devices to process and store data. The device is only connected from time to time to the process network containing the archive servers or MES systems. This device needs to have the capability to store data (integrity test parameters as well as test results) since GMP-relevant data are being stored. An audit trail, or user access management, is required since all 21

 Part 11 requirements have to be met in the device.  

In the second setup, the devices are permanently connected to the process network. Due to this permanent connection, in most cases all relevant GMP data are not stored on the device, but directly received from or sent to the MES or PLC system ("unique source principle"). The supervising network can handle the start of integrity tests and running the complete test procedure. Since GMP data are not stored on the integrity test device, it is only a part of a 21 

If electronic data files of test results are stored on the integrity tester, the 21 

 Part 11 requirements have to be fulfilled as mentioned above. But because the software capabilities of such a system are much less than that of a common PC, smart solutions have to be found. For instance, electronic data should be stored in separate files. By adding a checksum to each file and naming it with a unique non-reproducible name, it will have the required 21 

 Part 11 features. Then, the computer or data historian (audit trail) can link the data file to the proper filter and product batch records. This is commonly described as traceability and the file content can be checked for integrity based on the specific checksum. The data file includes all test parameters as well as the actual integrity test value with a definitive pass or fail result. Typically, additional information is also included in the integrity test result file such as product, product lot, filter part number, and filter lot or serial number.  

A large majority of existing processes do not have electronic data transfer capability and are organized by a paper-based documentation system. Most integrity testers on the market will have an onboard printer, or a serial port for an external printer. A printout is the only record of the integrity test and it is essential to make a photocopy. Typically, one copy is stored in a safe location while another is incorporated into the batch records for each process run. 

Qualification of an integrity tester is an important part of the process integration. Suppliers of integrity testers support customers with the device, and with qualification protocols that are optimized for an efficient and secure qualification process based on the supplier's know-how. Qualification support is typically available from the supplier and ensures that the qualification can be performed in a professional manner. The documentation used, whether the integrity test results are electronic records or hardcopy printouts, is very similar. Additional protocols are used when data transfer is involved. 

 A qualification generally starts with the IQ. The purpose of the IQ is to provide documented verification that the integrity tester complies with approved design intentions and the manufacturer's recommendations or requirements.  Verification that the proper documentation has been supplied with the unit, a physical inspection of the equipment, and a facility requirements check are common items included in the IQ.  

 The purpose of an OQ is to provide documented verification that the equipment performs as intended.  There are many items verified during an OQ, with some of the more difficult tests confirming that the actual integrity test result is within specification.  Typically, for bubble point, diffusion (forward flow), and water intrusion, the integrity test result will be compared with a measured reference. For example, when testing for diffusion, it is common for the integrity result to be verified using a mass-flow meter. IQ and OQ can be performed by the manufacturer of the integrity tester, or by the end user. Similarly, the IQ and OQ protocols will typically originate from the manufacturer, with the end user using them as is, or modifying them to their validation standards. 

 The last part of a validation is the PQ. The purpose of a PQ is to provide documented verification that the equipment can perform effectively and reproducibly based on approved standard operating procedures (SOPs).  Typically, actual process filters in the production environment are used during this testing. The end user's SOPs, as well as personnel, are used to perform the PQ. The integrity tester manufacturer may be consulted during the PQ, but typically will not perform the protocols. 

The integration of filter integrity testers impacts the filtration process, as well as the IT environment. Available integrity testers offer a wide variety of integration options to perform in a laboratory and also in the process environment. Because the integration concept is based on a standard device, which only has to be configured in an appropriate way, qualifying the device within the customer's validation process can be done by using the integrity tester manufacturer's documentation. This possibility leads to dramatically reduced efforts in the qualification procedure and should therefore result in a preferred choice of standard integrity testers to carry out a filter integrity test step in a filtration process.   

 is head of systems development of the Biotechnology Division, 				

, Weender Landstrasse 94-108, D-37075 Göttingen, Germany, +49 551.308.3984 fax +49 551.308.3289, 				

 is product manager of process filtration integrity testing at 

				, 131 Heartland Blvd., Edgewood NY 11717, 631.254.4249 X8375, fax 631.253.5475, 				

 1.  American Society for Testing and Materials. "Standard test method for determining bacterial retention of membrane filters utilized for liquid filtration." ASTM F-838-83. Philadelphia, PA 1993. 

 2   European Commission. "Guide to good manufacturing practice, Annex 1." Brussels, Belgium 2003. 

 3.  European Medicines Agency. cGMP Note for Guidance on Manufacture of the Finished Dosage Form. London 1996 April Reissue:5-6. 

 4. Jornitz MW (editor). Advances in Biochemical Engineering/Biotechnology. Sterile Filtration. Vol. 98, Chap. 6. Springer Verlag. Berlin. 2006. 

 5.  Sterilizing Filtration of Liquids. Parenteral Drug Association Technical report #26 PDA J. Pharm. Sci. Technol. 1998; 52 Suppl 1:1-31. 

 6.  Dosmar M, Wolber P, Bracht K, Tröger H, Waibel P. The water pressure integrity test — A new integrity test for hydrophobic membrane filters.  Journal of Parenteral Science & Technology. 1992 July-Aug 46(4):102-6. 

Air filtration also needs a filter integrity test method to guarantee the sterility of critical parameters.

Filter Integrity Testing in the Pharmaceutical Process Environment

Securing a safe, economical, and reliable supply of a recombinant therapeutic protein for use in clinical trials and commercialization is an important strategic issue that must be addressed early in the development process. Today, bacteria, yeast, and mammalian cell cultures are routinely used for large-scale commercial production of biopharmaceuticals, but these systems are frequently costly and lack flexibility for scaling up production. Typical unit production costs range from US$100–1,000 per gram of purified protein product, depending on the product, volume, and production system. Capital investment is in the order of several hundred million dollars for a large capacity (100,000 L) facility.

The construction and validation of cGMP compliant facilities requires long lead times, typically three to five years, which creates  challenges in matching capacity to demand. As a result, companies must make manufacturing choices and a substantial upfront investment in capacity while their products are still in the test phases. The uncertainty of regulatory approval, and the difficulties in predicting market demand impose a significant business and financial risk. For drug developers, investing large amounts of capital on a drug that is awaiting approval is an expensive and very risky prospect; however, having a drug that is approved without a reliable supply of product can have equally dire consequences. 

Transgenic production holds tremendous promise for dealing with the cost, capacity and scale-up limitations faced by traditional systems. Trans-genics can substantially reduce capital investment and lower production costs through economies of scale and more-flexible scale-up. Such advantages could enable the commercialization of proteins that would otherwise be impractical due to cost or capacity constraints, and provide scope for pricing flexibility that could be passed on to patients and health care systems. These benefits could allow companies to expand into new markets, such as follow-on biologics, where price is a barrier to entry. 

Transgenic technologies have made significant advances in recent years and several companies have moved products into the clinic and validated their technologies through partnerships with well-established pharmaceutical and biotechnology companies.

  Transgenic systems encompass a variety of hosts and tissues from animal, plant, and avian origin. No transgenically derived product has been approved yet. We believe that it is plausible that insulin will be the first. With that in mind, we will discuss our technology based on oilbodies, followed by a description of recombinant protein production systems. We will wrap up with a case study of producing insulin with these technologies.  

Oilbody-oleosin technology offers several advantages for protein production and purification over traditional cell culture and other transgenic systems. Oilbody-oleosin technology is unique, as it is the only recombinant technology that addresses protein recovery and purification (processes that represent as much as 75% of the cost of production) contemporaneously with bulk protein production. The capital investment in an oilseed processing facility is roughly an order of magnitude lower than that of conventional fermentation facilities.  

Beyond economics, oilseeds offer superior inventory management when compared to other transgenic systems. Unlike proteins expressed in milk or leaves, recombinant proteins have been found to be stable in transgenic seeds for several years. Seeds can be stockpiled and safflower, our commercial production crop, can be grown counter-seasonally, allowing maximal flexibility for inventory management. We believe that using safflower will allow us to readily address regulatory issues associated with transgenic crops, because safflower is a small acreage crop that is largely self-pollinating and can easily be geographically segregated from other safflower production and from the main food and feed crops. 

The oilbody-oleosin technology exploits oilseed plants, typically safflower, to produce recombinant proteins abundantly and at low cost. The technology is built on two basic proprietary capabilities. The first is the capability to express recombinant proteins in seed oilbodies. The second is the ability to extract oilbodies inexpensively from seeds. 

Figure 1. Cross-section of a safflower seed stained to show proteins			

The oilbody is a unique seed–oil storage organelle (Figure 1). Oil-bodies possess a highly organized structure consisting of a core of neutral lipid or triacylglycerol surrounded by a half-unit membrane of phospholipids and an outer surface layer composed primarily of a single class of protein known as oleosin. (Figure 2) 

Figure 2. Oilbody structure and a detail showing location of the oleosin at the surface.			

Oleosins are unique proteins with natural surfactant properties derived from alternating amphipathic and lipo-philic domains. The central domain of oleosins is highly lip-ophilic, containing the longest continuous stretch of hydrophobic amino acids yet reported, tightly anchoring the protein within the neutral lipid core of the oilbody. The amphipathic 

-termini interact with the phospholipids membrane forming a network that surrounds the oilbody in an amphipathic shell. The resulting structure is a highly stable, natural microparticle.

Figure 3. Picture A depicts an oleosin protein targeted to a natural oilbody. Picture B depicts the Stratosome Biologics System in which an oleosinârecombinant protein fusion (designated GeneX) is targeted to an oilbody to form a recombinant oilbody carrying the desired protein.			

We have developed two proprietary recombinant protein production systems, the Stratosome Biologics System and the Affinity Capture System. Together, these systems offer the ability to produce a wide array of recombinant proteins. This technology uses genetic engineering to express recombinant proteins in oilbodies in the seed (Figure 3). It works at a large-scale using a continuous flow procedure (Figure 4).

Figure 4. Flowchart of the Stratosome Biologics System			

Using plant genetic engineering techniques, we can target recombinant proteins to the surface of oilbodies through covalent fusions with oleosin. The combination of oilbody engineering with oilbody extraction is the basis of the Stratosome Biologics System. Here are the steps: 					

Genetic engineering is used to introduce a transgene encoding an oleosin–GeneX fusion protein into the plant. As the plant grows and the seed develops, the oleosin–GeneX fusion is expressed to produce a recombinant fusion protein such as insulin or apolipoprotein AI. The recom-binant fusion protein then targets the oilbody to form a recombinant oilbody, as depicted in Figure 3B.

Seed is produced from the genetically engineered plants using conventional farming practices that have been adapted to ensure product integrity and confinement.  

The harvested seed is then processed using the proprietary oilbody extraction process depicted in Figure 4.

Featured Article

Transgenics can substantially reduce capital investment and lower production costs through economies of scale and more flexible scale-up.

Producing Proteins Using Transgenic Oilbody-Oleosin Technology

If there's one thing that avian flu is doing to benefit vaccine development, it is instigating the transition from egg-based, to cell-based,  technologies. Even without avian flu concerns, traditional flu vaccine production is a long and difficult process, requiring that millions of eggs be ordered one or two years ahead of time. The 50-year old process also offers little opportunity for ramp-up in the case of a pandemic or a major compliance failure. To compensate for some of these shortcomings, many vaccine manufacturers are turning to disposable technologies to improve the safety and efficiency of existing processes. 

Disposables eliminate the need for cleaning and cleaning validation. Discarding  a device, without proving that it has been sufficiently cleaned, is one step that both regulatory bodies and manufacturers are happy to eliminate. This is especially true for vaccines, because vaccinating large, healthy populations carries much greater risks than treating relatively small groups of people with conventional drugs. For manufacturers attempting to minimize the risks of vaccine batch contamination, disposables provide an important avenue for enhanced safety. 

The use of disposable technologies is particularly economical for campaign-based vaccine manufacture. Disposables ensure fast set-up, they reduce the need for capital investment in stainless steel equipment, and require little work after use.  

Single-use systems that the supplier pre-sterilizes and bundles together can further simplify set-up. With fewer opportunities for operator error, disposable technologies also improve safety and production economics. Some disposables, such as bags, also save space, because they lie flat and can be stacked before use. Unlike permanent storage tanks, disposable bags are ordered on an as-needed basis to avoid excess unused equipment. 

Figure 1. Disposable technologies can be used in many stages of vaccine production. Solid circles indicate ideal steps where disposable technologies can be applied. Dotted circles indicate where technology is applicable, with hardware support. 			

Although new vaccines are still being developed using traditional egg-based technologies, the race to produce vaccines from cell-based technologies is heating up with a non-egg production method projected to be on the market by 2008, according to Gbola Amusa, a research analyst from  Bernstein Research.

  While there are currently no cell-based vaccines beyond early clinical trial phases in the United States, Solvay Pharmaceuticals has a cell-based flu vaccine approved for use in the Netherlands.   

The use of disposables in egg-based vaccine manufacture can be seen as preparation for the transition to mammalian cell-based development, where single-use systems are becoming more common. While single-use technologies can play a prominent role in egg-based vaccine manufacture in the areas of filtration, storage, and at connection points, their use multiplies in cell-based applications. More specifically, disposable technologies can be used for media preparation, clarification, buffer preparation, capture, and polishing chromatography steps, filling in downstream processes, and for venting and cell harvesting in upstream processes. 			

Disposable bioreactors are an example of the growing role of single-use technologies in upstream processing. Despite the availability of increasingly large disposable bioreactors, the material strength of the cell bag and the ability to supply adequate mixing remain a challenge. Although large volume (over 1,000 L) disposable bioreactors are probably a few years away, current offerings are commonly used in smaller cell culture applications, as well as for growing seed innoculums while the large stainless tanks are being prepared. 

If there is one operation that is ubiquitous throughout biopharmaceutical production, it is the process of making connections. Common connection points occur between two fluid pathways or between stainless steel equipment and media bags. Hundreds of these connections are made every day during full-scale vaccine production, accounting for many hours of labor. Disposable aseptic connection devices that are used to connect two fluid pathways, as well as single-use, steam-in-place connectors that allow fluids to pass from the media bag into the bioreactor and vice versa, can significantly reduce the time and number of steps required to establish these connections. They also reduce bottlenecks in manufacturing environments.  

These devices differ from traditional connection methods, such as "quick connectors" and tubing welders, in that they enable a connection to be made in a non-controlled environment in a matter of seconds. By contrast, quick connectors require assembly under a laminar flow hood, and tubing welders mandate the use of a welding device. It generally takes 15-to-20 minutes to set up a laminar flow hood, plus the time required to make the actual connections. Similarly, connections using tubing welders take approximately 5-to-10 minutes to perform, and like laminar flow hoods, they require validation and record-keeping.  

These newer aseptic connection methods allow connections to be made in seconds, because they do not require the use of a laminar flow environment or tubing welder. Single-use aseptic connectors can be supplied pre-sterilized by gamma irradiation or can be autoclaved up to 130 °C. Disposable steam-in-place connections can be gamma irradiated, steamed up to 130 °C, or autoclaved up to 128 °C.  

The use of disposable sterilizing grade filters also plays an important role in increasing the speed and safety of egg-based flu vaccine manufacture. Because filter capsules are available in a variety of configurations, they can be used to support processes as they are scaled up. Ideally, these differently sized capsules contain identical filter media and hardware materials. This helps ensure that scale-up and scale-down studies yield relevant information and minimum requalification for various batch sizes. These filters form the core of fully-integrated single-use systems that are available pre-sterilized by the supplier. Aside from eliminating cleaning and cleaning validation, the reduced set-up time associated with these systems is critical to the time-sensitive demands of vaccine manufacture. 

The role that disposable technologies play in helping bridge the gap between egg-based methods and conventional cell-based processes will only increase as flu pandemic concerns mount. The fact that disposable technologies are being used for many vaccines that are currently in development reinforces the growth potential of this processing approval. Government and non-governmental agencies are increasing efforts to advance the cause of better vaccine production methods, and many drug companies are following suit by applying greater resources to developing new production methods and optimizing older ones. Despite the challenges facing manufacturers, the life-saving potential and vast market that exists for vaccines will continue to drive innovation in this critical area. 

, Pall France, 3 rue des Gaudines - B.P. 5253, 78175 Saint Germain-en-Laye Cedex-France, tel 33.1.3061.32.20, .fax 33.1.30.51.57.08, 				

 1. Smith A. A bird flu vaccine without eggs? French drug maker Sanofi and others working on a flu vaccine sans oeufs, CNN Money, Oct. 21, 2005; http://

money.cnn.com/2005/10/21/news/fortune500/egg

Disposables can be used for media preparation, clarification, filling in downstream processes . . .

The Case for Disposable Manufacturing Equipment to Accelerate Vaccine Development

Margaret O'K. Glavin became the director of FDA's Office of Regulatory Affairs (ORA) in May 2005 and now faces a serious challenge: finding ways to manage expanding oversight responsibilities in the US and abroad for ORA's regional and district inspection teams despite shrinking resources. Glavin recognizes that ORA cannot inspect all the facilities and operations under its purview and has to determine which ones are most vital to monitor more closely with increased frequency. This determination involves reorganizing the ORA staff, revising policies, and adopting risk-based approaches for "transforming" the field inspection process. 

Since the 1970s, FDA's field force has shrunk from half of the agency's staff to about 35 percent today. And also during this period, ORA's job has grown considerably. Pharmaceutical and biotech manufacturers are adopting more complex production processes and building more plants overseas, Glavin explained in an interview with 

. ORA has to monitor a vast expansion of food imports and has the added responsibility of combating counterfeit drugs and the spread of bovine spongiform encephalopathy (BSE). One new assignment is to develop a compliance program for cellular and tissue products, which involves oversight of some 1,900 registered locations with no additional resources. And national emergencies such as Hurricane Katrina and the specter of avian flu have created new demands for strengthening FDA front line defenses.  

Glavin is preparing a 10-year plan to modernize ORA through organizational changes and new approaches that target resources to its most critical activities. This involves utilizing third-party inspection programs, promoting global harmonization, improving information sources, and offering incentives for manufacturers to adopt internal quality assurance programs. The plan's goal is to shift from a periodic, reactive inspection system to more proactive approaches. 

An ORA Transformation Leadership Team composed of staffers within the organization plans to unveil a strategic plan in September 2006 to address these challenges. An immediate task is to correct staff imbalances among regions and districts that have developed in recent years. Changes in ORA's structure "certainly are a possibility," Glavin says, noting that ORA's central region probably is the "least well-staffed," while the Pacific region may be over-populated. The prospect of personnel shifts is already generating concerns among ORA's rank and file. 

One of Glavin's initial moves has been to reorganize her top administrators. Last year, she appointed three deputy associate commissioners to help ensure consistent policies and procedures throughout this far-flung operation. Management of ORA's five regional offices, 20 district offices, and 13 field laboratories now is handled by deputy for field operations, Diana Kolaitis, a long-time and highly respected field leader. 

Steven Niedelman, deputy for regulatory operations and chief operating officer, oversees regulatory policy implementation at the national level. ORA's Office of Enforcement, Office of Criminal Investigations, and Office of Regional Operations report to him. Regional Operations, under Deborah Ralston, coordinates field inspections in the US and overseas with FDA centers and manages Team Biologics, the specially trained cadre of national investigators established in 1997 to conduct routine inspections of biological manufacturers. Ralston also handles FDA interaction with state inspection programs, with US Customs officials, with foreign regulatory authorities, and with emergency preparedness organizations.  

New to ORA is David Horowitz, deputy for compliance policy, who is spearheading efforts to implement risk-based approaches for ORA activities. Horowitz led similar efforts as the former head of the Office of Compliance in the Center for Drug Evaluation and Research (CDER), and now is extending these initiatives to medical devices, veterinary drugs, and other regulated products. CDER compliance officials have set the pace by devising a risk model for selecting sites for GMP inspections based on a range of risk factors: plant size and compliance history; product characteristics (sterile parenterals vs. dentifrices); complexity and contamination potential of manufacturing process; and time lapsed since last inspection. This approach  is also being applied to FDA oversight of manufacturer adverse-event-reporting programs and to drug product sample analysis.  

Most biotech manufacturing operations fall into the high-risk category because they involve sterile injectables and production methods susceptible to contamination. CDER is adopting this model to identify 500 domestic production facilities that fall into the high-risk tier and should be inspected by ORA this year. This group will account for about half of ORA's drug inspections for 2006, with the rest based on the need for a pre-approval inspection, a recall or complaint, or follow-up to a previously unsatisfactory inspection. District inspectors more familiar with specific plant operations have discretion to add or remove certain facilities on the priority list. 

In addition to targeting inspections to high-risk operations, ORA is implementing other strategies to streamline the inspection process. FDA's Good Manufacturing Practices (GMPs) for the 21st Century Initiative, launched to encourage risk-based approaches to compliance and adoption of quality production technologies, has established several new approaches for GMP inspections. One initiative has given Centers more input in issuing warning letters for GMP violations identified during inspections; another seeks to better integrate pre-approval and GMP inspections.  

An important development has been to extend the team inspection approach pioneered by Team Biologics to drugs and other medical products. ORA is establishing a Pharmaceutical Inspectorate of specially trained experts able to audit complex drug products and facilities. However, Team Biologics retains responsibility for inspecting manufacturers producing biotech therapeutics now regulated by CDER, as well as for biologics and blood establishments in the Center for Biologics Evaluation and Research (CBER).  

For pre-approval inspections, CBER compliance staffers continue to take the lead in this area. And now a similar approach has been adopted by CDER for biotech products, explained Brenda Uratani of CDER's Office of Compliance (OC) at a recent conference on biotech regulation sponsored by Pharma Conference. Product specialists from OC's branch overseeing biotech therapeutic facilities and from CDER's Office of Biotechnology Products who review biotech process manufacturing controls now have lead responsibility for conducting pre-approval inspections for biotech therapeutics in CDER. FDA is incorporating this model of more ORA–Center shared responsibility in revising inspection approaches for drugs. Team Biologics and the Pharmaceutical Inspectorate are "the future" of federal GMP inspections, Glavin comments.   

While FDA seeks to streamline the frequency and scope of its field inspection program at home, it is struggling to cope with a rising number of foreign-based inspections. FDA conducts about 1,000 foreign inspections for drugs and biologics each year, but this program, unfortunately, now is only the tip of the iceberg. More than 30 foreign regulatory agencies now want to inspect pharmaceutical manufacturing plants, and the number continues to increase, according to Malcolm Holmes, director of global quality assurance at GlaxoSmithKline. Industry is building large, sophisticated production facilities that may export products to more than 80 different markets, and inspectors from all over the world are showing up to conduct their own audits. This kind of "industrial tourism" does little to enhance public health and safety, Holmes stated, noting that industry now spends some 35,000 person-hours coping with multiple foreign inspectors from Mexico, Argentina, Africa, and Asia.  

International adoption of risk-based inspection models and more sharing of information offer prospects for relief. Although no one is looking for mutual recognition of inspection decisions by foreign agencies, there is growing interest in bilateral agreements for sharing inspection information among regulatory authorities. US membership in the Pharmaceutical Inspection Cooperation Scheme (PIC/S), which is moving forward, could expand acceptance of PIC/S certificates to include that a plant also meets GMP standards. Foreign regulators could save resources by first examining what inspection report information is available from PIC/S, from FDA's inspections database, and from an EU database currently under development. Clarification by the World Health Organization of its recommendations for when plant inspections are needed would be helpful. Manufacturers with sound GMP compliance histories and corporate integrity programs also may gain some regulatory relief if foreign regulatory authorities accept such quality assurance policies as indications of compliance.  

Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634, 

Glavin is preparing a plan to modernize ORA through organizational changes . . .

Regulatory Beat: FDA's Field Force Does More With Less

Big market + Low Competition = $$$$$$. These days you might as well write this formula in Mandarin Chinese because it's the exact recipe for success that more and more biopharm companies are brewing in China. 

Let's take a look at the numbers. China accounts for roughly 20% of the world's population (in comparison, the US accounts for 5%) but it corners only 1.5% of the worldwide pharmaceutical market. 

That won't last long as the life sciences industry in China is growing at a 10% per year clip and has been over the last decade. It's the ninth-largest drug market in the world and by 2008, will step up to the 8th spot. (Wall Street pegs the overall market at $10 billion in 2006.) 

As China's burgeoning middle class settles in for some of the creature comforts enjoyed by its counterparts in Europe and North America; (things like Burger King Whoppers and Buick convertibles); the need for drugs and medicine to satisfy China's booming health care needs is paramount for the country.  

And, needless to say, paramount for companies in the biopharm industry that would love to get there first. 

US drug companies are heading in that direction. To get there, they'll have to sidestep Chinese drug companies, which comprise 70% of the life sciences companies in the region, and clear onerous regulatory hurdles initiated by the Chinese government, which historically has treated foreign companies much like a teetotaler treats an open bar. Right now there are about 3,500 biopharm companies operating in China. That number is down from 5,000 in 2004, so the arena is already swallowing up pretenders and  wanna-be's.  

Consider the fact that over 38% of Chinese biopharm companies are state-owned, giving them a distinct advantage over Western competitors. And, many of these companies not only produce the prescription drugs they sell, they also own and operate the pharmacies that sell those drugs. Imagine you were a Bacardi Rum salesman and half the bars you visit used their own rum. How many cases of rum could you sell? Not too many. 

Still, Chinese pharmaceutical companies have no shortage of competitive issues. Compared to Western giants like Merck and Roche, Chinese drug companies are much smaller in size, and are much less innovative in areas like technology and financing. One Wall Street pundit points out that the overall research and development for all Chinese life sciences companies combined doesn't match up to the R&D efforts of any of the top five Western drug companies. 

But a closer look at the numbers reveal a potential gold mine for Western life sciences companies and investors who pour money into them looking for a good return. 

The top 10 Chinese companies in the biopharm sector account for only 20% of the market. But in the US, the top 10 companies account for 50% of the market. That gap between China and the US indicates that there is plenty of room for growth for Western companies in the China market. 

Granted, this is no secret to Western drug makers. Roche touts China as one of its ten-largest global markets and plans to increase over-the-counter drug sales by 50% by 2010. Novartis and Wyeth are also pouring billions into the Chinese market. 

What does the competitive landscape look like for Western biopharm companies hurdling the Great Wall?  

It's not as intimidating as you might think, once you get past the state-sponsored control of  a large part of the biopharm market in China. First, most Chinese pharmaceutical companies are generic drug makers, leaving the brand name prescription drug market to outsiders. American pharmaceutical companies with savvy marketing plans should be able to make inroads in the Chinese drug market by convincing increasingly health-conscious Chinese that they're putting their health in jeopardy by using  second-tier drugs. 

Fair play? Maybe not. But eminently possible in a country that takes so many of its health care cues from the West. Another door opens for US drug makers because the vast majority of life sciences companies in China are marketing traditional Chinese medicine, where quality issues comes into play. With so many American-educated Chinese doctors and medical researchers heading back home to ply their craft in China, chances are many will be taking their US training back home with them—at the expense of Chinese medicine and drugs. These doctorate-carrying expatriates will convince their countrymen and women that Nexium is probably a better bet for stomach problems than bear bile or gum tree extract. 

Another issue that is potentially beneficial to US biopharm companies is the fact that 90% of Chinese in major cities like Shanghai, Beijing, and Guangzhou are covered by state-sponsored health plans. That's a ready made customer base that's at least 80 million strong, leaving plenty of opportunities for US companies to make their case to Chinese consumers, if they can get past the preference (for now) of cheaper generic drugs by thrifty government health care officials. 

One issue that has haunted US drug companies looking to operate in China is the propensity of Chinese biopharm companies to rely on counterfeit drugs. But in July 2005, the US and China agreed on a long-awaited reform on patent protections that should inoculate US companies from Chinese counterfeiters. Now, Chinese companies that engage in patent infringement and counterfeiting could face fines and penalties of anywhere between $400 million and $1 billion. 

Outside of the intellectual property issue, US biopharm companies can't expect too much more help from Chinese authorities, especially in terms of seed money for new life sciences ventures. 

While the Chinese government does spend about $600 million annually on biotech research and development, further sources of local funding are few and far between. In recent years, China has opened a funding pipeline through local venture capital firms but  money is scarce and typical investments rarely reach the $1 million or $2 million that new biopharm ventures can count on in Western countries. Still, labor costs are low in China and the government can contribute in other ways, especially in added funding for infrastructure and other industrial needs that foreign companies need when setting up shop in China. 

US companies who have yet to establish a presence in China run the risk of being left behind. Already, firms from other Western countries like Canada (Dragon Pharmaceuticals) and the United Kingdom (GeneMedix PLC) have established successful manufacturing bases in China. 

Some companies are looking to play catch-up via the acquisition route. That's what US-based Invitrogen Corporation did through its purchase of BioAsia, a Shanghai-based bio-services company.  

Invitrogen, like the handful of US companies that preceded it into China, all see the same profitable landscape. Low-cost levels of entry, a low-cost, yet highly-skilled labor pool, a government bound and determined to establish a haven for life sciences companies, and a vast consumer market of Chinese looking to step forward into the healing light of 21st century healthcare. 

"Add in China's entrepreneurial culture and it all indicates a promising future," notes Matthew Chervenak, president and founder of General Biologic, a Shanghai-based professional services firm. "If China implements appropriate regulatory structures for IP protection and capital markets, which may take a long time, the industry's natural drivers will make China's emergence as a strong player in the field inevitable. Within many products and services sectors, China is poised for dominance."  

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

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

The top 10 Chinese companies in the biopharm sector account for only 20% of the market... leaving plenty of room for growth for Western companies.

StreetTalk: Enter the Dragon: China Biopharm Market is a Land of Opportunity for Investors

The pharmaceutical industry's recent emphasis on continuous improvement, operational excellence, and process analytical technology has motivated us to evaluate the basic tenets of our approach to quality. Historically, the ability to ensure that a drug meets its intended form, fit, and function has been achieved through the application of the quality infrastructure, i.e., standard operating procedures, policies, specifications; qualification or validation, i.e., commissioning, installation qualification (IQ), operational qualification (OQ), performance qualification (PQ), process validation; and testing, i.e., in-process and final release. However, despite these processes, the number of drug recalls continues to rise, escalating from 176 in 1998 to 354 in 2002, according to the US Center for Drug Evaluation and Research.

The use of regulations as a primary means of ensuring product quality began to decline in early 2000, when industry pushed back on FDA's Part 11 compliance requirements for electronic signatures and electronic data exchange, challenging the cost and effort associated with implementation, versus the actual benefit to product quality. Today, however, industry and regulatory agencies are moving toward a more scientific approach to ensuring product quality. 

The International Conference on Harmonization (ICH) Q8 and Q9 guidance documents

 , for example, define a scientific approach to process characterization, advocating a quality by design framework. Risk management is an integral part of this approach. 

Similarly, the US FDA's "GMPs for the Twenty-First Century" initiative focused on quality by design, risk management, continuous process improvement, and quality systems. Rolled out in 2004, this initiative challenged industry's traditional approaches to ensuring product quality by encouraging employees to look beyond traditional inspection methodologies for ensuring product performance. The early process and product characterization emphasized in the quality-by-design and risk-management approaches do not inherently conflict with validation. On the contrary, by deepening the level of scientific understanding of a manufacturing process, the approaches ensure that a process is well understood before it is considered "validated." Methods that involve continuous improvement and real-time control, however, do pose a significant question: Are these quality methods inconsistent with the basic tenets of validation that have served as the backbone of the industry's quality structure for so many years? Once you have "validated" a manufacturing process, how much can you improve it—through real-time control or any sort of continuous improvement step incorporated into Lean, Six Sigma, etc.—without having to file manufacturing supplements with FDA? How much of an impediment are those filing requirements? 

The challenge of validation is that it has been viewed as a necessary evil—a regulatory activity that cannot be avoided when manufacturing regulated products. The effort and cost associated with validation continue to escalate as industry and regulatory groups increase their understanding of pharmaceutical processes and identify an increasing number of process variables that must be controlled.  Biotech adds another layer of complexity by introducing the qualified pilot or intermediate-scale model as an integral component of the validation equation.

The prohibitive cost of characterization studies at full scale requires us to establish clear, scientific arguments to show how process development studies relate to full-scale validation lots. The complexity of biotech processes demands an even higher level of scientific argument. As we increase our understanding of biopharmaceutical processing, the value associated with traditional validation diminishes, and industry responds accordingly. 

 The integration of equipment validation and process validation provided incentive to measure the capability of our processes and  analytical methods. However, somewhere along the way, the incentive for validation shifted from a need to measure processes, to a need to satisfy a regulatory requirement as quickly and as cheaply as possible. 

Over time, industry came to believe that validation had to include a broader range of equipment and processes and a greater level of detail, and as a result, validation costs went up. In response, the industry attempted to distribute the responsibility for validation among participants in the quality process. For example, industry suddenly decided that validation had to include commissioning activities and engineering pre-cursor activity to equipment qualification, so they started requiring that contractors and subcontractors test and document various aspects of IQ. The approach of requiring increased involvement from vendors also extended to factory acceptance tests. Such tests—which have ranged from simple vendor testing and certification to constructing simulator panels to mimic the actuation of automated components—have also ranged in their true relevance to the validation process.  

Market drivers completely unrelated to the field of validation often have determined the amount of effort put into validation. For example, when equity markets dried up in the late 1990s, emerging biotech companies shifted their emphasis from scientific investigation to bringing product to market as quickly as possible. The industry looked for cheaper and faster ways to push through the validation process to move programs forward quickly. The result was simpler process validation studies that focused on building three validation lots to demonstrate process predictability, rather than focusing on true process understanding. Likewise, companies began buying more equipment from suppliers who offered "canned" validation protocols that could be purchased and implemented, rather than developing their own protocols to challenge the equipment and thus increase the probability the equipment would meet the needs of the process. The implication of these shifts was that validation was necessary, but not essential to sound process development. 

This short-cut approach to validation resulted in processes that were less stable at the commercial scale. FDA's recent revelations about high-profile, approved products that may be unsafe, such as Vioxx and Serevent, and Congress's pressure on industry to find ways to reduce the cost of drugs to the general public, have impacted both Big Pharma and biotech. In response, the industry has recognized the need for a better way to reduce process and product risk. 

The answer was a shift to a more scientifically driven development approach, often referred to as "Operational Excellence," or "Process Excellence." This approach integrates process, quality, and business requirements to promote the science of development. 

These quality initiatives integrate Six Sigma, Lean Manufacturing, Kepner-Tregoe, Theory of Constraints, Design of Experiments, and Balanced Scorecards to establish process understanding. These methodologies emphasize the need to objectively define, measure, and characterize critical variables that affect a process. While testing and data collection are integral components, verification is the final culmination of the quality assessment—not the basis of quality. 

Looking closely at these approaches, however, reveals that they based in a large part upon an approach that has been integral to our quality systems for over 70 years—Walter Shewhart's cycle of Plan, Do, Check, Act (PDCA).

Walter Shewhart, an enterprising statistician who worked at Bell Laboratories in the US during the 1930s, developed the science of Statistical Process Control. An offshoot was the PDCA Cycle, often referred to as "the Shewhart Cycle." This tool was adopted and promoted from the 1950s on, by W. Edwards Deming, the renowned quality management authority, and as a result the tool also became known as "the Deming Wheel" (Figure 1).

The PDCA Cycle was the first tool broadly adopted as a framework for continuous improvement. PDCA is a four-step quality improvement cycle that promotes continuous  improvement based on the method of design (plan), execution (do), analysis (check), and evaluation (act). Sometimes referred to as plan/do/study/act, the cycle emphasizes the constant attention and reaction to factors that affect quality. 

The chief advantage of the PDCA cycle—flexibility in moving through each phase of the cycle—is also its biggest challenge, because it left the door open for subjectivity. Subjectivity has long been the downfall of our industry. Without a clear vision for success or a defined method for evaluation, the potential exists to rely on unscientific process development and characterization activities, which can lead to incorrect or incomplete conclusions. For example, univariate analysis methods—often called One-Factor-at-a-Time (OFAT) studies

 —have been the backbone of the small-molecule pharma industry, as well as the biopharm industry.  Such studies, however, do not possess the power to fully characterize a process. The result is a false sense of security that the process characteristics are understood. 

An analogy would be that of trying to solve the popular "Rubik's Cube" puzzle. It may be relatively simple to get one side of the cube all one color, thus providing the impression of progress towards your goal. However, the reality is that you are actually further from success than when you started the exercise (Figure 2). Because of these limitations, other industries abandoned the OFAT approach 30 years ago, deeming it ineffective for process characterization and verification.

Figure 2. Cube Plot for Protein Recovery			

The biopharmaceutical industry, too, has come to recognize that the OFAT approach is insufficient. The industry has also realized that to be successful in combining quality, technical, and business requirements in the drug development lifecycle, it must realign not only its scientific approach to process understanding, but also its thinking within the organization. As a result, Operation Excellence initiatives have moved to frameworks such as Six Sigma to provide a roadmap that can meet this need. 

In 1986, Motorola established a framework designed to integrate quality, process, and business requirements into the product development lifecycle. Motorola recognized that variation is the death knell of any process, so the company set out to establish a methodology to identify and eliminate variation. They called this approach Six Sigma

Figure 3. Six Sigma as an organizational development and leadership tool			

 In the late 1990s, CEOs Jack Welch from GE and Larry Bossidy from Allied Signal adapted the Motorola model to a set methodology called the DMAIC roadmap. DMAIC is an acronym for Define, Measure, Analyze, Improve and Control. These are the five phases necessary to measure, characterize, and control a process (Figure 4).

Within each step of the road-map, a defined set of tools is applied. Each phase in the DMAIC process is intended to guide the members of an improvement team through the project in a manner that provides relevant data and in-depth process understanding. The DMAIC project management approach allows businesses to make the best possible decisions with the available data and resources. The five-steps of the DMAIC process are as follows: 

 Clearly define the problem and relate it to the customer's needs (generally, with a cost benefit to the organization identified). 

Measure what is key to the customer and know that the   measurement is good. 

Motorola recognized that vartion is the death knell of any process, so the company established a methodology called Six Sigma

BioPharm International-06-01-2006