This year has been one of tremendous activity at the US Food and Drug Administration (FDA) and other government agencies involved with health care, biomedical research and national security. Scientists completed sequencing the human genome, setting the stage for a period of important new medical therapy development. Efforts to protect the nation from biological warfare created pressures to produce new vaccines and medical treatments able to counter biological, chemical and radiological attacks (see sidebar "Combating bioterrorism"). 	

The need to make prescription drugs more affordable for all Americans has shaped a wide range of policy initiatives. Leaders in Congress and the White House tackled the daunting task of crafting a prescription drug benefit for the nation's 40 million plus Medicare beneficiaries. FDA has taken steps to bring new generic drugs to market, while also struggling to stem public access to less expensive but unregulated medicines from abroad. The overarching goal is to make it easier for manufacturers to translate new biomedical discoveries into safe and effective treatments that will be more affordable for consumers. 	

In his first year in office, FDA commissioner Mark McClellan tackled a host of thorny issues head-on. He unveiled a raft of initiatives designed to streamline FDA internal regulatory procedures, encourage innovation in pharmaceutical manufacturing and clarify requirements for testing new therapies (see sidebar "Consolidating drug oversight"). A prime goal has been to reverse the recent slowdown in new drug applications (NDAs) for important new treatments. FDA approved only 17 new molecular entities (NMEs) in 2002, a drop compared with previous years; the numbers are up so far this year, spurring hopes for further gains. 				

In January, the commissioner announced the Improving Innovation in Medical Technology plan, which aims to reduce the costs and delays in drug development by clarifying the regulatory standards and test data required by FDA to approve an NDA in only one review cycle.1 A key element of the scheme is "root cause analysis," designed to help manufacturers develop and submit sufficient test data in initial applications to reduce the need for lengthy and costly multicycle reviews of market applications. The agency is also writing more guidance documents to better define requirements for testing new treatments for diabetes, cancer and obesity - top priority disease areas for all government health agencies. 	

At the same time, FDA officials continued to implement a 2 year campaign to overhaul agency regulations governing good manufacturing practices (GMPs). Launched in August 2002, FDA unveiled several new initiatives in February (2003), followed by further announcements in September.2–4 The GMP update is revising policies governing electronic records and signatures; manufacturing plant inspection programmes; and post-approval manufacturing changes. It aims to encourage manufacturers to adopt new production technologies that can reduce manufacturing costs and better ensure product quality. 	

An overriding theme in McClellan's initiatives is to apply risk management methods to FDA policies and programmes, a concept that he explained further in FDA's Strategic Action Plan, issued in August (2003). Risk management involves targeting FDA's limited resources to best protect public health at the least cost. The agency wants to focus more oversight on higher risk products and processes, while also crafting policies that encourage voluntary compliance. Initiatives that reduce the time, cost and uncertainty of new drug development can improve public health, according to McClellan, by reducing the cost of medical product development and thus helping consumers access effective new treatments. 	

FDA seeks to apply risk management approaches to ensure the safe use of medical products by patients. In April, the agency held a 3 day workshop to examine ways of discovering and managing potential adverse drug events (ADEs). FDA officials, manufacturers and health professionals commented on agency proposals for testing new products more extensively before they reach the market to better identify and study possible safety problems. Participants also discussed how manufacturers could develop pharmacovigilance plans to detect and analyse safety issues that appear after a product reaches the market. FDA wants sponsors to do more to identify risk "signals" and to develop postmarketing risk management programmes for drugs that pose increased safety concerns for patients. 						

Another strategy for reducing potential medication errors is for manufacturers to print barcodes on drug packages, and even individual dosage forms, to ensure that the right patient receives the right dose at the right time. FDA issued a proposed rule in March requiring manufacturers to print barcodes on prescription drug packages.5 The rule compromises in calling only for national drug codes on packages, as opposed to more extensive data indicating lot number and expiration date. 	

FDA said it hoped to publish final rules on preapproval and postapproval drug safety policies, as well as barcoding requirements, by the end of the year. Meanwhile, the agency is linking up with broader health system databases that can help it identify ADEs more rapidly. FDA is also working with the National Library of Medicine to establish an electronic product label system for quickly distributing updated and comprehensive medication information to patients and health care providers. 	

To further facilitate public access to more affordable medicines, FDA is streamlining its generic drug oversight process and promoting the quality and interchangeability of generics to encourage more prescribing. The agency has beefed up resources for its Office of Generic Drugs, has launched a consumer advertising campaign to promote the safety and equivalence of generics, and has backed legislative changes to clarify the rules governing patent listings and challenges. One aim is to reduce the endless litigation between innovator firms and generic competitors regarding patent violations.				

A controversial issue is whether FDA has the authority to approve generic versions of biotech therapies, which appears open to interpretation under current law. In October, FDA issued a lengthy response to several citizens' petitions opposing approval of  "follow-on" versions of brand-name therapies under the "paper NDA" process. A letter from the Center for Drug Evaluation and Research (CDER) claims that FDA may approve certain products based on published studies of the innovator drug as a way of bringing new therapies to market more quickly and without the need to duplicate research. At the same time, FDA fears that too much investment in "copy cat" products could divert industry resources from innovative research. The agency may begin a public process to gain more input from manufacturers, health care providers and consumer groups on how to balance these concerns.	

Consumer efforts to obtain less expensive prescription drugs from Canada and other nations erupted this year into a contentious battle on Capitol Hill and in the media. Despite strong pressure from consumers and health insurers, McClellan insists that reimporting could bring unsafe and untested products into the US. FDA officials testified before Congress about the dangers of escalating drug purchases via Internet pharmacies, many of which operate overseas. Despite such opposition from FDA and the White House, the House approved a bill in July that permits reimporting of low-cost drugs from other countries - with no requirement that FDA first certifies that such activity will not harm consumers.6 Supporters of the measure aim to add it to legislation establishing a Medicare drug benefit. 	

The debate escalated in September when FDA asked the Department of Justice to file suit against a leading pharmacy website, Rx Depot, for arranging drug imports from Canada despite a March warning letter from FDA calling for the firm to cease and desist. FDA claimed that such imports "pose a serious threat to public health" because the agency cannot ensure the safety of these illegally imported medicines from unregulated sources. FDA's warnings appear to be falling on deaf ears as several states and local governments are devising plans to buy medicines from Canada to cut spending on drugs for Medicaid and local pharmacy benefit programmes. 	

The broader problem, according to FDA and manufacturers, is that illegal reimporting opens the door for counterfeit and unsafe products to enter the US market. FDA's counterfeit drug task force issued an interim report on 1 October that describes how counterfeit products slip into the US drug distribution system. To retaliate against the growing trend, the report proposes a mix of:	

stricter licensing standards for wholesalers and distributors

technological innovations that manufacturers can incorporate into actual products or add to packaging to identify bogus as well as legitimate drugs

public education to help health professionals and consumers look for and identify counterfeits more readily.

FDA sponsored a well-attended meeting on 15 October to discuss these proposals and view anticounterfeiting technologies. Not surprisingly, manufacturers urged tighter controls on distributors, including requirements for maintaining detailed pedigree records that track drug origin and distribution; wholesalers, in turn, asked FDA to require manufacturers to include authentication devices and markers in drug products and packages.	

The problem for manufacturers is that the public generally believes that drugs from Canada are just as safe and effective as those made in the US. A recent poll shows that consumers oppose efforts by the government and the US pharmaceutical industry to prevent them from obtaining less expensive foreign medicines, and that a growing number are purchasing them or would like to shop abroad for prescription drugs. 	

Intensified concerns regarding counterfeit drugs and illegal imports are focussing attention on the drug distribution system. One major wholesaler has been investigated for illegally diverting drugs to boost profits. FDA analysis identifies secondary wholesalers and repackagers as a common route of entry for counterfeit products. Florida has adopted a more stringent licensing and oversight policy for drug wholesalers, and other states are looking to follow suit. FDA is talking to Congress about revising a 1988 law that sets rules for tracking and documenting the source and movement of drugs through the distribution system. Manufacturers of products that appear attractive to counterfeiters are tightening up distribution by limiting sales to certain wholesalers or shipping directly to specific pharmacies. New electronic tracking systems may provide better ways to monitor and control the drug supply system.	

One way to deter illegal and dangerous importing, according to McClellan, is to reduce the differences between US and foreign pharma prices. At a September colloquium on generic medicine in Cancun (Mexico), McClellan pointed to international pricing disparities for escalating the battle over whether US consumers may reimport less expensive medicines from Canada.				

And because the US pays higher prices, McClellan commented, other nations do not shoulder a "fair share" of the cost of bringing new medicines to the world. Americans account for approximately half of all pharmaceutical spending worldwide, whereas Germany pays less than 5%, he noted, warning that such price controls abroad may "grind the global development of new drugs to a halt." 	

The commissioner's remedy is to relate drug prices to a nation's income, with rich nations paying more to support R&D so that developing nations can pay less. There's little chance, of course, that political leaders in Europe, Japan and Canada will agree to boost pharmaceutical prices - particularly when they are having trouble coping with escalating health care costs at home. But relating the reimporting problem to wide international differences in pharmaceutical prices gets at the heart of the issue and raises important questions about who will finance future biomedical R&D. 	

1.	J. Wechsler, "Standards for Supplements," Pharm. Technol. Eur. 15(3), 18-20 (2003).				

2.	J. Wechsler, "Overhauling Compliance and GMPs," Pharm. Technol. Eur. 15(4), 19-22 (2003).	

3.	J. Wechsler, "GMP Update: Reducing Obstacles to Innovation," Pharm. Technol. Eur. 15(10), 21-25 (2003).	

4.	J. Wechsler, "FDA Seeks Risk-Based Inspection Programme," Pharm. Technol. Eur. 15(11), 18-21 (2003).	

5.	J. Wechsler, "Drug Safety in the Limelight," Pharm. Technol. Eur. 15(5), 19-22 (2003).	

6.	J. Wechsler, "Counterfeiting, Compliance and Controls," Pharm. Technol. Eur. 15(9), 21-25 (2003).  	

Articles

Features

This year has been one of tremendous activity at the US Food and Drug Administration (FDA) and other government agencies involved with health care, biomedical research and national security. Scientists completed sequencing the human genome, setting the stage for a period of important new medical therapy development. Efforts to protect the nation from biological warfare created pressures to produce new vaccines and medical treatments able to counter biological, chemical and radiological attacks (see sidebar "Combating bioterrorism").

Drug Pricing Concerns Shape Policy Decisions

Only a small number of information technology (IT) projects are completed entirely successfully; approximately a third are cancelled and more than half significantly exceed deadlines and budgets (Figure 1). This is often because software suppliers have little or no experience of the validation required for the programs. However, validated software is important because good IT projects can help to reduce costs. 	

Pharmaceutical manufacturing process quality is governed by the requirements of the European Union's (EU's) EU-GMP Guideline, which covers implementing both hardware and software systems in production areas. The area concerning computer systems is described in Annex 11 "Computerized Systems," part of which requires that computer systems are validated from an early stage.	

Figure 1:  The success and failure of IT projects.			

The principle of Annex 11 is that "when a computerized system replaces a manual operation, there should be no resultant decrease in product quality or quality assurance. Consideration should be given to the risk of losing aspects of the previous system, which could result from reducing the involvement of operators." Additionally, it is essential that there is close co-operation between key personnel and those involved in implementing the system.				

Annex 11 details how personnel responsible for computerized systems must be appropriately trained to manage and use such systems. This includes ensuring that relevant expertise is available to advise on aspects of design, validation, installation and operation of computerized systems. 	

According to the annex guidelines, the system requirements can be summarized as follows:	

The system should be in a stable environment, eliminating interference from extraneous factors.

There must be a detailed written description of the system, which needs to be kept up to date.

A computerized system should be thoroughly tested before it is used. If a manual system is replaced, the two should be run in parallel for a time as part of the testing and validation procedure.

Data should only be entered or amended by authorized persons, and suitable methods of 

preventing unauthorized entry must be in place. When critical data are entered manually, there should be an additional check on the accuracy of the record; this may be done by a second operator or by validated electronic means.

It should be possible to obtain clear printed copies of electronically stored data. Data should be regularly backed up and stored at a separate, secure location. 

A procedure should be established to record and analyse system errors, and to enable corrective action to be taken.

Generally, it is the company using the computerized systems that must ensure validation and compliance with Annex 11 requirements. It also has to ensure that its supplier works in accordance to the requirements. 	

Annex 11 devotes only a brief paragraph to the complex subject of validation. It offers little definitive advice to those implementing computerized systems, and leaves much scope for interpretation. However, it does contain an important statement, which frequently causes problems: "Validation should be considered as part of the complete life cycle of a computer system." Often, the responsible personnel are not aware of this and assume that validation is a single process that takes place at the end of the development phase.	

Figure 2:  Each phase must be validated throughout the project life cycle.						

Validation, however, is a continuous process that includes stages such as planning, specifying, programming, testing, commissioning, documenting, operation, monitoring and modifying. Each stage must be validated to comply with Annex 11 requirements. It is essential that if a system is modified, all stages must be validated again (Figure 2). For example, if a user requirement specification (URS) document is not validated at every stage, it cannot be compared with the completed computerized system. More work will be required to bring the URS up to date.	

If each stage is validated, the result is a comprehensive document. The relationship between the effort needed to produce the documentation and the actual system development work is frequently misjudged - the ratio is approximately 8:1 (Figure 3).	

Producing the large amounts of documentation that validation requires is often avoided. Because developers do not primarily associate documentation with functionality, there is no immediate association with system quality. Developers often do not understand the importance of validation documentation until further into the project, by which time it is far more difficult to produce. Inexperienced vendors underestimate the amount of documentation required to validate systems and often just provide general unified modelling language (UML) diagrams and comments. The fact that validation requires extensive documentation must be made clear from the outset, because the quality of a system decreases without this documentation (Figure 4).	

Figure 3:  The relationship between documentation and system development and Figure 4:  Quality decreases without documentation.			

Successful validation is based on a quality assurance (QA) system that encompasses all the departments involved in an IT project. Standard operating procedures (SOPs) must be provided for the work, and only by working to the SOPs will the implemented system achieve the required validation and quality.				

If quality is to be maintained, this principle has to be adhered to. If, for example, a URS is produced according to a particular SOP then all further work on the document must be performed according to the same SOP. It is also important to maintain traceablity during the life cycle of the system. This procedure leads to complete documentation and is a requirement for successful audits.	

Computerized systems are often produced by external providers. 	

To save time and money at a later stage, it is important that the vendor has experience of validation and works according to QA procedures. Although companies should ensure that the vendor is working according to the required guidelines, both sides must be aware of the requirements of computer system development. Only a system developed according to these guidelines will be successfully validated after implementation.	

Many projects fail because of the difficulties addressed earlier in this article. Computerized systems can bring significant cost benefits if they are implemented into processes that, traditionally, have not been automated. For example, during the course of a packaging project, work was produced by a number of people in different areas. The work had to be checked by a second person after all alterations had been made and so the document was sent to proofreaders. Problems arose when a number of copies of the document were circulated, resulting in many copies of the same document being proofed. Because all of the copies were editable, inadvertent changes were being made, resulting in a number of documents with differing content; the whole process, therefore, did not conform to EU-GMP guidelines. It also allowed the possibility of the wrong document being released.				

A validated process would require that a uniquely identifiable document is proofed. Because digitally produced documents are frequently still processed manually, the system does not comply with validation guidelines and QA requirements. Many companies still use manual processes because, until recently, appropriate computerized systems have not been available.	

Implementing a computerized system can eliminate the risks of human error inherent in manual systems. The system makes it possible to locate the document to be proofed from a central store. In place of the document, the system provides a non-editable version to the proofreader, which only allows correction notes to be attached, eliminating the possibility of inadvertent changes. The system allows all proofreaders to check the relevant document from one location and add their annotations to this single document. 	

Manual systems are still used for many processes, despite not conforming to the EU guidelines. However, these systems are increasingly being replaced with validated computer systems. The pharmaceutical industry can benefit from the significant time and cost savings to be gained by implementing computerized systems.  	

When implementing computerized systems, it is important that both purchasers and vendors ensure that each stage of the process (from planning through operation to modifying) is properly validated. This article looks at some of the issues that arise when switching from traditional document-based procedures, and at the benefits that computerized systems can bring.

Validating Computerized Systems

Instrument calibration is an essential process in the pharmaceutical industry. The need to comply with good manufacturing practices (GMPs) and other procedures is well documented and globally accepted. The US Food and Drug Administration (FDA) regulations require good and thoroughly applied calibration management; several chapters of 21 CFR Part 11 detail the calibration processes and how pharmaceutical manufacturers should deal with them. 	

In manufacturing processes, calibration management is often implemented by quality assurance (QA) departments as a standalone operation, using standalone software tools. This is probably because calibration is a complex process and tends to be triggered from QA/QC (quality control) requirements. However, calibration can also be considered as an integral part of asset management and maintenance; if handled and managed accordingly, it can bring economic value to the company. This is because	

choosing the right system strategy can reduce information technology (IT) expenses

functional process engineering (or re-engineering) will increase overall efficiency

implementing a risk-based approach to calibration management means calibration efforts can be decreased while still complying with external regulations.

In today's tier one companies, most of the installed software integrates enterprise-wide business processes. For example, enterprise resource planning (ERP) systems deal with a variety of administrative processes such as accounting, financial management, production planning, human resources and fixed financial assets. Maintenance management is not normally part of the scope of the average ERP as it focusses on financial rather than physical asset management. Also, asset maintenance requirements are often not adequately supported by ERP software.	

At the same time, enterprise asset management (EAM) systems cover the technical management of a company's physical assets. Typical business processes implemented in EAMs are asset life cycle management, asset performance, maintenance, inspections, materials management for maintenance repair and operations (MRO) parts, and procurement of parts and services. During the last few years, more and more analytical capability has been added to these systems so they have developed into asset performance management (APM) tools.	

Interestingly, in many global companies, a critical business process such as calibration management is often supported by a standalone software tool, which may not be in accordance with the global IT strategy of the company. The reason for this is the lack of calibration capability in many EAMs, as well as the relative autonomy of QA/QC departments when choosing an application to support their activities. If they are the only benefactors of the application, they will choose the best-of-breed package most suitable for their activities. 	

Nowadays, with the declining profitability of manufacturing, ever increasing competition and other market factors, most companies are having to increase efficiency and find greater cost savings. IT management, personified by the chief information officer (CIO), demands Internet/ Intranet-based applications, enterprise connectivity and total transparency of data. Web-based applications have many advantages compared with workstation applications. Because of their centralized nature, administration is more efficient. One of the main key performance indicators (KPIs) for a CIO is the total cost of ownership (TCO) of installed applications. This cost is calculated from the aggregate costs of owning and maintaining software, not from the cost of acquiring it. The TCO, therefore, includes hardware, software, support, system administration and backup. 				

If the number of installed software applications can be reduced, less expertise is needed. As this expertise is expensive and often external, this is already a significant financial improvement. Additionally, centralizing applications by using a web architecture means that support engineers do not have to work on individual computers. The applications run on web servers and are only accessible to the end-user through the chosen internet browser, thus further reducing TCO.	

The decision the market and the software development community jointly have to make is whether an enterprise calibration management (ECM) system should be developed, or whether the calibration process should be included in the functionality of existing enterprise systems. First, the requirements of such a calibration system have to be defined. 				

Apart from the standard calibration functionality (instrument and instrument loop definition, calibration schedules, algorithms, data entry, and specific report output and graphical analyses) it should be possible to include functions such as stock management of instruments and bill-of-materials, purchasing of instruments, return on asset analyses, and maintenance and operational KPIs. Reports and analyses must include calibration history overviews, reference standard traceability and performance analysis of technicians and specifications. Additionally, there should be a report generator for user-defined reports and a workflow engine to increase day-to-day efficiency.	

The system's architecture should be state-of-the-art and web-based to provide functionality to a variety of users without dramatically increasing TCO, as discussed earlier. All functionality must be available through an intuitive user interface, accessible through the browser.	

Although some of these required functions are available in the average ERP (mainly the materials 	

management and procurement part), it may be more logical to incorporate the calibration management activities into the EAM. In fact, many calibration functional requirements are already covered by maintenance management functions. Examples include instrument life cycle and configuration management, job scheduling (periodical and ad hoc), inspection feedback capability, flexible reporting, 21 CFR Part 11 compliance, and revision control of standard operating procedures (SOPs). 	

Some major EAM vendors offer risk-based inspection (RBI) capability, and this could also be applied to calibration. This would result in additional insights that could be implemented in the calibration process. For example, based on historical calibration results, the likelihood of future deviations can be determined, and changes to the calibration interval can be implemented. These changes must, of course, be subjected to revision control that satisfies GMP, 21 CFR Part 11 and other regulations. Therefore, only tier one EAM vendors, who have the required development budget and focus on asset management to maintain software adhering to these standards, can be assumed to have compliant software. Additionally, EAM applications are more geared towards optimizing cost-effectiveness in day-to-day operations than are standalone calibration systems, which aim to provide best-of-breed calibration functionality. 	

The challenge is to find an EAM system that supports all the asset management advantages as well as the additional calibration requirements. Some pharmaceutical companies have already realized the advantages of combining calibration and preventive maintenance (PM) within one EAM application. They have lowered the TCO by decreasing the number of IT applications required. Also, they are reaping the additional benefits of applying asset life cycle management and APM on their laboratory instruments. For current "wall-to-wall" ERP users, this might mean implementing additional EAM software. Although this may sound risky from an IT perspective, the true EAM vendors have long implemented world-class integration capabilities that make use of business adapters and keep integration and upgrade problems to a minimum.	

In conclusion, there is no need to develop an ECM system. The required functionality can be implemented by choosing the right EAM system. If the system of choice is sufficiently flexible, calibration can be implemented next to preventive maintenance, and all asset management advantages will apply to the instruments as well. The efficiency of the calibration department can be enhanced by streamlining the instrument management with materials management, purchasing and general asset management of the rest of the plant. Also, by eliminating standalone systems, the TCO for the IT department will be improved.  	

The importance of calibrating instruments used in manufacturing processes is well known, particularly for highly regulated industries such as pharmaceutical production. This article discusses software applications used to support calibration management, and the potential economic gain to be had by replacing a standalone software application with a capable enterprise system.

The Hidden Economic of Calibration Management

It has recently been suggested that the adoption rate of Six Sigma has started to slow. The term "Six Sigma" is used to describe processes that operate at the highest quality levels with minimum variation and producing less than four defects per million opportunities. This low rate is achieved through applying statistical techniques and other quality improvement tools in a formalized way.	

The "Sigma" referred to is the standard deviation of a quality characteristic (such as hardness, impurity or friability) against a target value. Figure 1 shows a Three Sigma process that is on target and producing approximately three defects per thousand. The accepted statistic that companies quote to reflect their process performance is Cp, a process capability index, which is defined as 	

for normally distributed data. In Figure 1, Cp equals 1.	

As processes are rarely centred on their target value, a second statistic, Cpk, is used to measure the degree to which the process is off target. For normally distributed data the Cpk statistic is defined as 	

Six Sigma processes achieve a Cp of at least 2 and a Cpk of at least 1.5. This means that the specification range represents 12 times the standard deviation of the process. A Six Sigma process is illustrated in Figure 2. In the pharmaceutical industry the upper and lower specification limits are often defined in the relevant pharmacopoeia and have to allow for lifetime degradation.	

Motorola coined the term Six Sigma more than a decade ago, defining the target capabilities for processes, the standard set of quality tools to use in pursuit of the goal and the way in which they should be applied. Many manufacturing companies use Cp and Cpk as key measures in production, but few pharmaceutical companies apply the Six Sigma methodology during development to fully realize Motorola's vision.	

It is interesting to speculate why Six Sigma has not been whole-heartedly endorsed by the industry, particularly in research and development (R&D). Motorola's goals - to reduce product variation to a bare minimum and achieve specific quality targets - also apply to pharmaceutical companies. The tools and techniques used in Six Sigma are ideally suited to manufacturing, and with its emphasis on strictly meeting targets and specifications, the approach seems particularly relevant to the pharmaceutical industry.	

Figure 1:  Data from a process with a standard deviation of approximately 0.1.  Cp is approximately 1, resulting in 3 defects per thousand opportunities.			

Six Sigma has now spread far and wide, and is used in many service industries as well as in manufacturing. Some large manufacturers, such as General Electric, were quick to adopt the technique, but now service giants such as American Express and Starwood Hotels also have major programmes. So why does the pharma- ceutical industry remain sceptical?	

In the author's opinion, the teaching of applied statistics to science students in higher education is often inadequate, so it is left to employers to give their bench scientists and technicians training in basic statistical skills. And although employees of service companies may be expected to have less experience in using an analytical approach to process improvement, they seem willing to adopt the methods.	

Regulatory agencies have been increasingly pressurizing drug companies to understand their manufacturing processes better. A recent report from the US Food and Drug Administration (FDA) shows that the inability to validate processes is the major reason for withholding GMP approval. A greater emphasis on statistical techniques, such as design of experiments - key to Six Sigma - would improve process characterization.	

Another reason why Six Sigma receives little attention could be that supplies of active pharmaceutical ingredients (APIs) are often low, early in development, and batch production costs are high during scale-up, so there may not be sufficient data to measure Cp and Cpk. However, all this may have to change as regulatory authorities apply more pressure on drug companies to understand their processes better before new drug application (NDA).	

The problem may lie in the DMAIC methodology that is most commonly used by companies implementing Six Sigma. The DMAIC acronym comes from the five main steps involved - define, measure, analyse, improve and control. The names given to the steps in the methodology highlight the main goal of each. Within each step there are a number of objectives, activities and deliverables, along with a toolbox of statistical and quality techniques to help achieve the goal. The model is not rigid, giving improvement teams room to adapt it to their own situations.		

Figure 2:  Data from a process with a standard deviation of approximately 0.05. The Cp is approximately 2 and the Cpk approximately 1.5. Despite being off target this process will produce less than 4 defects per million opportunities.			

The DMAIC model begins by identifying a problem - such as poor uniformity or an unwanted polymorph - and then sets about fixing it. Once the problem is resolved controls are put in place to make sure it does not happen again. The approach is useful for well-defined processes that are non-conforming. For example, it could be applied to a plant which has been producing a generic drug for some time but where improvements can still be made. Similarly the approach could be used to improve efficiency and rectify problems in an accounts department where invoice processing is well understood.	

Drug development in the pharmaceutical industry, however, is an evolving process. As a drug moves from early formulation through scale-up and the production of pivotal batches to submission, the processes involved often change - sometimes dramatically. This is equally true for pharmaceutical development, chemical development and analytical development. So managing change and moving towards the ideal process is more important than correcting static processes, and the DMAIC model is less useful.	

"Process," for the purposes of this article, refers to a processing step or small group of steps during which the raw materials are chemically or physically changed. Examples are a blending stage for dry powders, or a chemical stage consisting of a number of operations including crystallization, filtration and drying.	

Figure 3 outlines a valuable approach, which takes a life cycle view of process development and deployment but has at its core the achievement of Six Sigma performance. It is more prescriptive than DMAIC, but at the same time takes advantage of all of the Six Sigma tools and techniques, and is backed by good statistical principles.		

Figure 3:  Using Six Sigma techniques for pharmaceutical development.	

This methodology owes its existence to work done at IBM in the early 1990s, when process engineers were tackling similar manufacturing problems. The approach is to map a course for applying tools and techniques, beginning at formulation and ending in volume production. Despite its origin in the semiconductor industry, the ideas have been used in several pharmaceutical companies.	

As with the DMAIC model, there are clear goals for each of the 12 steps and a set of quality tools available. Process targets are set early on, and by the third step key process measures, targets and measurement capabilities defined. From the fourth step, the process is being modelled and decisions made regarding which process quality characteristics and parameters are most influential. Potential problems in manufacturing are being predicted and addressed from the fifth step, and from step 6 the process is being assessed for control. Initial measurements of Cp and Cpk are being made within confidence limits determined by the volume of data available.	

Control chart design begins once technology transfer is approved. The charts are finalized and implemented with a full statistical process control (SPC) strategy once sufficient data are available. Documentation of all activities is key to the long-term success of this approach, and ensures against warning letters from the regulators.	

Unlike the DMAIC model, this methodology allows for several iterations during the development and scale-up of the process, as indicated in Figure 3. Outputs from each step provide inputs for the next step, allowing data-driven decisions regarding the process to be made. The methodology provides for the most efficient and consistent use of the tools and techniques of Six Sigma whilst ensuring the process under development takes the critical path from discovery through to manufacturing.	

The methodology outlined here can be readily integrated with in-house development procedures to help embed the Six Sigma and design for manufacture culture in the organization. The technique is equally applicable to equipment development and manufacturing as it is to drug development. 	

An increase in statistical awareness within the scientific and management communities may still be needed to get the most from this way of working. A "just-in-time" training programme built around the application of the methodology to real processes can deliver dividends in terms of successful development, training effectiveness and risk management. The latest software packages allow scientists to use statistics in a way they never could 25 years ago, and a few are now providing support for the application of methodologies.	

The potential return for a relatively small investment in training is very high - an important consideration while pressure on companies from external bodies continues to grow.  	

The Six Sigma approach would appear to be ideally suited to pharmaceutical processes, yet the industry has been very slow to adopt it. This article looks at the possible reasons for this, and suggests an alternative methodology that takes advantage of Six Sigma tools and techniques, backed by good statistical principles.

The Decline of Six Sigma

Since the early 1960s, solid dispersion systems have been used to increase the rate of dissolution and bioavailability of poorly water-soluble drugs.1 Solid dispersions of drugs are generally produced by either solvent evaporation or melt methods.2 	

Both procedures require further processing. After production by solvent evaporation, the solvent is removed and the dispersions are hardened then usually pulverized, sieved and mixed. Solid dispersions produced by the melt method are hardened at low temperatures before the pulverizing, sieving and mixing stages.	

This method involves dissolving the drug and carrier in a common organic solvent, and then removing the solvent by evaporation. Chiou and Riegelman3 used 500 mL of ethanol to dissolve 0.5 g of griseofulvin and 4.5 g of polyethyleneglycol (PEG) 6000. To prepare a piroxicam-PEG 4000 solid dispersion, Fernandez et al.4 dissolved the drug in chloroform and then mixed the solution with a melt of PEG 4000 at 70 Â°C. 	

Many different methods (including spray- and freeze-drying) have been used to remove organic solvents from solid dispersions. Simonelli et al.5 evaporated the ethanolic solvent with a steam bath and removed the residual solvent by applying reduced pressure. Chiou and Riegelman dried an ethanolic solution of griseofulvin and PEG 6000 in an oil bath at 115 Â°C until ethanol bubbles were no longer formed. The viscous mass was then solidified by cooling it in a stream of cold air.	

Removal of organic solvents such as chloroform from large masses of material may be difficult because the solid dispersions are usually amorphous and may be viscous and waxy. Additional problems may be residual solvent, the cost of recovering the solvents and the further processing (such as pulverization and sifting) of the solidified product.	

In 1961, Sekiguchi and Obi6 formed eutectic mixtures of drugs with water-soluble carriers by melting their physical mixtures. This was a significant advance in the development of solid dispersion systems. They prepared solid dispersions of sulfathiazole in carriers such as ascorbic acid, acetamide, nicotinamide, nicotinic acid, succinimide and urea by melting various drug -- carrier mixtures. Eutectic mixtures of the drug with carriers were used to minimize melting temperatures. Various methods were used to harden the melts. Sekiguchi and Obi  used an ice bath with vigorous stirring until the melt solidified. Chiou and Riegelman spread a griseofulvin -- PEG 6000 solid dispersion on a stainless steel plate and blew cold air over it, then stored the material in a desiccator for several days. Timko and Lordi7 applied blocks of dry ice to cool and solidify phenobarbital -- citric acid melt mixtures.		

Semisolids and waxes are usually used as carriers in the melt method. Developing the dosage form of such materials can be difficult because it is hard to pulverize and sift the dispersions. They are usually soft and tacky, with poor flow and mixing properties as well as poor compressibility, and may not be amenable to processing by tablet machines.	

Currently, the melting method is known as 'hot melt technology,' and provides pharmaceutical technologists with new possibilities. This article discusses current melting methods and describes the dropping method, a promising new hot melt technology.	

In 1978, Francois and Jones8 further developed the solid dispersion method by directly filling hard gelatin capsules with semisolid materials as a melt, which solidified at room temperature. Chatham9 reported the possibility of preparing PEG-based solid dispersions by filling drug–PEG melts into hard gelatin capsules. 				

Serajuddin et al.10 demonstrated that PEG itself might not be a suitable carrier for the solid dispersion of poorly water-soluble drugs intended for direct filling into hard gelatin capsules. At room temperature, solid plugs were formed inside the capsules where the dissolution of the drug from PEG-based solid dispersions was incomplete. The water-soluble carrier dissolved more rapidly than the drug, and drug-rich layers were formed over the surfaces of the dissolving plugs, preventing further dissolution of the drug from solid dispersions. 		

Studies report that complete dissolution of the drug from solid dispersions can be achieved using surface- active or self-emulsifying carriers, but only a small number of such carriers are currently available for oral use. The temperature of the melt should not exceed 70 Â°C during filling, which is the maximum acceptable temperature for most hard gelatin capsules. Some of the manufacturing problems mentioned earlier may be encountered in the direct capsule filling method. Despite the difficulties, however, the method is used to produce animal preparations.	

Melt extrusion is a new method for producing solid dispersions. Special equipment is needed to develop the dosage form from solid dispersions, which limits the use of the extrusion method. Forster et al.11 report the use of melt extrusion to prepare glass solutions of poorly water-soluble drugs with hydrophilic excipients. It is claimed that the method is an improvement to existing formulation methods such as spray-drying and co-melting because it uses smaller quantities of drug, reduces particle size and speeds up the formulation process.								

The dropping method, developed by Ulrich et al.12 to facilitate the crystallization of different chemicals, is a new procedure for producing round particles from melted solid dispersions. This technique may overcome some of the difficulties inherent in the other methods.				

Laboratory-scale preparation. A solid dispersion of a melted drug– carrier mixture is pipetted and then dropped onto a plate, where it solidifies into round particles (Figure 1). The size and shape of the particles can be influenced by factors such as the viscosity of the melt and the size of the pipette. Because viscosity is highly temperature-dependent, it is very important to adjust the temperature so that when the melt is dropped onto the plate it solidifies to a spherical shape. 	

Figures 2 and 3 show samples of round particles made by the dropping method. The round particle in Figure 2 is made from melted PEG 4000 alone (Fluka AG, Buchs, Switzerland), which solidifies at room temperature. The use of carriers that solidify at room temperature may aid the dropping process. Figure 3 shows a round particle dropped from a solid dispersion of a melted drug–carrier mixture, and Figure 4 shows a batch of round particles prepared at laboratory scale by the equipment illustrated in Figure 1. The particles, dropped at 58 Â°C onto a stainless steel plate, have a diameter of 2.5 mm (60.13 mm). The temperature of the plate was adjusted to room temperature (20 Â°C 61 Â°C). Stainless steel was chosen because of its optimal surface energy (30.17 mN/m), which results in the formation of round particles.		

In vitro dissolution studies. Solid dispersions of a poorly water-soluble drug were prepared by three different methods to compare their dissolution rates. Dissolution tests were performed using a Pharmatest (Hainburg, Germany) dissolution tester,13 set with a paddle speed of 100 rpm. Artificial enteric juice (900 mL) with a pH of 7.5 (60.1) at 37 Â°C (60.5 Â°C) was used. Samples were withdrawn at 5, 10, 15, 20, 30 and 60 minutes, and were assayed spectrophotometrically at 280 nm (Helios a; Spectronic Unicam, Cambridge, UK) after filtering.	

The results are shown in Figure 5. Samples in Series 1 are solid dispersions made by the dropping method, Series 2 shows those made by direct capsule filling and Series 3 those made by a conventional (pestle and mortar) melting method. The results of the dissolution tests show that the solid dispersions made by the dropping method have better drug-release properties than those produced by the other two methods, particularly during the first 20 min. This shows that using the dropping method not only simplifies the manufacturing process, but also gives a higher dissolution rate.	

Advantages of the dropping method. The dropping method does not use organic solvents and, therefore, has none of the problems associated with solvent evaporation. The method also avoids the pulverization, sifting and compressibility difficulties encountered with the other melt methods. Figure 6 compares the different melting methods for producing solid dispersions.	

Disadvantages of the dropping method. Only thermostable drugs can be used and the physical instability of solid dispersions is a further challenge. 	

Future and industrial scale. Despite many results demonstrating improved bioavailability of poorly water-soluble drugs using solid dispersion systems, manufacturing and scale up has always been difficult. Figure 7 illustrates equipment (Rotoform; Sandvik Process Systems Co, Sandviken, Sweden) that can be used to produce solid dispersions by the dropping method at an industrial level.14	

Although there is still much work to do in this field (better size distribution, uniformity and stability), the dropping method is a promising approach in the formulation of solid dispersions. Simplifying the formulation process for the dropping method may overcome manufacturing difficulties.				

The authors are grateful to Professor Joachim Ulrich (Martin-Luther-University, Halle-Wittenberg, Germany) for providing facilities.				

1.	A.T.M. Serajuddin, "Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs," J. Pharm. Sci. 88, 1058-1066 (1999).				

2.	F. Damian et al., "Physical Stability of Solid Dispersions of the Antiviral Agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30," Int. J. Pharm. 244, 87-98 (2002).	

3.	W.L. Chiou and S. Riegelman, "Preparation and Dissolution Characteristics of Several Fast-Release Solid Dispersions of Griseofulvin," J. Pharm. Sci. 58, 1505-1509 (1969).	

4.	M. Fernandez et al., "Characterization of Solid Dispersions of Piroxicam/poly-(ethylene glycol) 4000," Int. J. Pharm. 84, 197-202 (1992).	

5.	A.P. Simonelli, S.C. Mehta and W.I. Higuchi, "Dissolution Rates of High Energy Poly(vinylpyrrolidone) (PVP)-Sulfathiazole Co-precipitates," J. Pharm. Sci. 58, 538-549 (1969).	

6.	K. Sekiguchi and N. Obi, "Studies on Absorption of Eutectic Mixture. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man," Chem. Pharm. Bull. 9, 866-872 (1961).	

7.	R.J. Timko and N.G. Lordi, "Thermal Characterization of Citric Acid Solid Dispersions with Benzoic Acid and Phenobarbital," J. Pharm. Sci. 68, 601-605 (1979).	

8.	D. Francois and B.E. Jones, "The Hard Capsule with the Soft Center," European Capsule Technology Symposium, Constance (11-13 October 1978) pp 55-61.	

9.	S. M. Chatham, "The Use of Bases in SSM Formulations," S.T.P. Pharm. 3, 575-582 (1987).	

10.	A.T.M. Serajuddin et al., "Effect of Vehicle Amphiphilicity on the Dissolution and Bioavailability of a Poorly Water-Soluble Drug from Solid Dispersions," J. Pharm. Sci. 77, 414-417 (1988).	

11.	A. Foster, T. Rades and J. Hempenstall, "Selection of Suitable Drug and Excipient Candidates to Prepare Glass Solutions by Melt Extrusion for Immediate Release Oral Formulations," Pharm. Technol. Eur. 14(10), 27-37 (2002).	

12.	H.C. BÃ½nd J. Ulrich, "Parameters Influencing the Properties of Drop-Formed Pastilles," in J. Ulrich, Ed., CGOM4 (Shaker Verlag, Aachen, Germany, 1997) pp 123-130.	

13.	European Pharmacopoeia, 4th Edition, EDQM, Council of Europe, Strasbourg, France (2002).	

14.	Sandvik Process Systems, "Rotoform-Verfahren zur Herstellung von Pastillen," Die chemische Produktion 3, 50-52 (1988).  	

The use of solid dispersion technology to increase the bioavailability of poorly water-soluble drugs has always been limited by processing and scale-up difficulties. A new approach may help to overcome some of the problems.

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