D ISSOLUTION T ESTING

Dissolution is a test used by drug developers to characterize the dissolution properties of an active drug, the active drug's release and the dissolution from a dosage formulation. Dissolution testing is used to formulate the form of drug dosage desired and to develop quality control specifications for the manufacturing process. In-vitro dissolution testing correlates with in-vivo clinical studies. It measures change on stability, and establishes an in-vitro and in-vivo correlation for some products.

A significant time and effort have been invested in developing automated dissolution testing systems. Large pharmaceutical companies have invested many resources in automation concepts to the point of creating task forces or departments to achieve this objective.

The need for automating these systems comes from an increase in the number of tests performed. This has come about because of the required dissolution testing of older drugs; an increase in the number of stability tests; the need for bioequivalency studies; and increased numbers of tests per production batch. These factors require an increase in capacity. In addition, an increasing number of drugs require dissolution tests that run for several hours. Often these tests have sampling points that require overnight or over-the- weekend processing, which may require hiring additional lab personnel. For the most

part, dissolution testing is important to many different areas – drug research, quality control and methods development. With these various markets, it is less vulnerable to a drug company’s changing development plans. For these reasons, expect the market for automated dissolution testing systems to continue to grow, as seen in Table 4-21.

Table 4-21

World Market for Drug Discovery Dissolution Testing Systems 2008-2012

Revenues (in billions)

2008 2009 2010 2011 2012

$0.13 $0.14 $0.14 $0.15 $0.16

Source: Kalorama Information

Today, with the documentation required for quality control tests and about eight hours in a working day, an average of about four short time tests of 30 minutes each per employee per day may be needed. However, this is only true for short time tests. As soon as the test length increases, the capacity is reduced considerably. An increase in the number of tests performed will require an additional investment in manual equipment or laboratory staff. Important factors to consider are the cost for hiring additional personnel, and the fact that hiring is not always approved, or in some countries the proper personnel cannot be found easily. For these reasons, more laboratories are investing in automated systems.

Automation offers reproducible results. Manual tests with different personnel often create considerable discrepancy in results, resulting in high costs as production batches cannot be released or have to be re-analyzed. Automation of a single test might require a semi-automated system, whereas, automation for a series of tests might require a fully automated system.

Some semi-automated systems are based on a modular concept allowing the customer to customize specific testing needs. Available options include UV on-line, HPLC on-line solutions, as well as off-line, or combinations of both. Options like solvent replacement after sampling and solvent addition for pH-change are also available. Fully integrated automation systems manage all operations simultaneously. With some systems, up to 15 USP 2 tests can be fully automated from the tablet input up to the printout of the report.

Dissolution testing entails measuring the stability of the investigational product, achieving uniformity in production lots and determining the product’s in vivo availability. The test helps a drug developer formulate dosage forms and develop quality control specifications for its manufacturing process. The dissolution test is a relatively new analytical technique that has undergone modifications and improvements in the last 10 years. The importance of the test has increased considerably in that time.

As dissolution testing has evolved, these testing systems have become fully automated. The control of convective diffusion properties through hydrodynamics is emerging as critical. It may be the key factor in obtaining appropriately responsive, relevant and reliable dissolution measurements. Applying to all types of dissolution measurements, this is especially relevant to flow-through techniques, producing a vast improvement in dissolution measurements. The successful development of a discriminating automated dissolution technique is often the critical factor in moving product development forward, releasing manufactured product, avoiding an unnecessary product recall, establishing an in vivo relationship, and even substituting in vitro data in place of in vivo for future product upgrades.

In addition to increasing efficiency and decreasing operational costs, automation of dissolution technology can substantially improve precision, reproducibility and sensitivity to formulation differences. Improving the control of hydrodynamics and convective diffusion, fully automated high-performance multi-sample systems have been developed. They are useful for a wide array of dissolution applications, producing a higher rate of data acquisition, precision and ultimately improved correlation in vivo.

Such companies as Agilent, Shimadzu and Varian have marketed their instruments and software to users through alliances with leading dissolution equipment manufacturers. Some companies sell their own components separately. However, complete solutions are available. Varian's Cary 50 spectrophotometer is part of VanKel's Total Solution system. Agilent's 8453 spectrophotometer and ChemStation software are compatible with Distek's dissolution equipment and Zymark's (a division of Caliper Technologies) MultiDose work station. Shimadzu and Logan Instruments have marketed completely automated HPLC dissolution systems, featuring Shimadzu's LC-10A series HPLC and CLASS VP software.

In the last two decades, dissolution testing has become increasingly automated. However, automation presents some significant challenges as well as opens up new opportunities. FDA and international regulations require the continuous calibration of

instruments and the validation of parameters, such as temperature and agitation rate. Automation has not only increased the number of samples tested but has also increased the level of unmonitored testing, making validation more necessary. New systems appear to be meeting these challenges.

The automation of dissolution testing systems has also made the role of software more crucial. In an effort to further integrate systems, analytical instrument companies have modified their software to enable them to run dissolution testing systems. The pooling method of dissolution testing -- the analysis of samples in batches -- has also simplified the process and increased throughput.

Initially, the focus of automation systems for dissolution testing was more on the hardware side. Now, regulatory requirements have been published, such as Good Automated Manufacturing Practices (GAMP) guidelines, and the FDA CFR part 11 for software. Validating the systems has become a top priority, especially concerning software. Comprehensive systems have a very high level of complexity. These systems operate with CFR-compliant software with the potential for transferring data to LIMS. Automated dissolution testing systems are not just targeted to large pharmaceutical companies but to mid-sized pharmaceutical companies as well.

LIMS

As in the clinical diagnostic laboratory, a laboratory information management system (LIMS) is used in the drug discovery laboratory to manage the placement, handling, testing and retrieval of samples. LIMS also can direct lab personnel, instrumentation and other laboratory functions, such as invoicing. It impacts plate management and work flow automation in general. Today's trend is to create a seamless organization in which instruments are integrated into the lab network. They receive instructions and worklists from the LIMS and return finished results including raw data back to a central repository where the LIMS can update relevant information.

By means of electronic lab notebooks connected to LIMS, lab personnel perform calculations and review documentation and results using online information from connected instruments, reference databases and other resources. Management can supervise the lab process, react to bottlenecks in work flow and ensure that regulatory requirements are met. External participants, such as physicians and hospitals, can place test or retest requests and follow up on progress. HTS, drug candidate screening, gene

screening, DNA sample handling and genotyping, protein screening, and the like have made LIMS a necessity, even in fundamental laboratories.

Commercially available LIMS have been around since the 1980s. In addition, many laboratories have designed, implemented and maintained their own systems. The heart of any LIMS is the software. Like other laboratory systems, LIMS software is subject to quality control and quality assurance checks. In regulatory environments, this is system validation. The primary purpose of the validation process is to ensure that the software is performing as it was designed to. For example, system acceptance criteria should be established and tested against quantifiable tasks to determine if the desired outcome has been achieved. LIMS features, such as autoreporting, reproducibility, throughput, and accuracy, must be quantifiable and verifiable.

System validation ensures that the entire system has been properly tested, incorporates required controls, and maintains and will continue to maintain the integrity of the data. Laboratories must establish protocols and standards for the validation process and associated documentation. Although vendors of commercial LIMS perform initial internal system validations, the system must be revalidated whenever the end user, vendor or third party modifies the LIMS.

There is no standard way to plan and implement a validation process. Validation activities need to be conducted throughout the entire LIMS life cycle. The validation process starts with the functional requirement development phase when the LIMS is purchased, and it continues through the specification, testing, implementation, operation and retirement of a system.

Despite a slower rate of growth expected in drug discovery lab automation, LIMS will continue to be adopted by drug developers because these systems increasingly meet industry-specific requirements, including the need for companies to comply with various regulatory and manufacturing processes, such as cGMP, NAMAS (National Accreditation of Measuring and Sampling), Environmental Protection Agency (EPA), and of course, FDA regulations.

Many early users of LIMS installed heavily customized systems that proved difficult to upgrade and integrate with other business functions. As merger and acquisition activity occurred, application integration became a necessity to ensure that laboratories made their data accessible throughout the enterprise. After several years, homegrown systems had become almost obsolete. These were replaced by more available, upgradeable and compliant vendor-supplied generic LIMS. These early

systems, while designed to provide basic data management and meet regulatory compliance, required a high degree of customization to meet the specific needs of each particular user group across the enterprise. LIMS were not customarily designed to operate at full functionality, which required pharma users at the research, development or manufacturing phase of drug development to customize the LIMS for a specific laboratory application with its specific work flow and data management requirements.

Advances in technology have transformed LIMS over the years. In-house systems often were simple spreadsheet packages. Vendor systems were modeled on minicomputer platforms and often were multi-user oriented. Most products were then based on a basic Windows platform on top of a DOS operating system. But these systems were slow and not secure. The eventual migration of Windows NT as a corporate standard precipitated the need for NT-based LIMS, which offered a reliable, secure and stable environment for data. Moreover, greater use of the internet affected the way in which scientists managed and accessed data. The eventual growth of supporting technologies enabled LIMS to grow in scope from single-user desktop tools to global, enterprise-wide critical business applications.

The reality for pharmaceutical labs is that generic LIMS typically satisfy only about one-third of their needs. Installations can take from 18 months to three years to complete. System requirements may change during this time, leading to a significant difference in what an LIMS can deliver and what a laboratory truly needs. To close this gap, organizations must configure their LIMS. In addition, companies want LIMS to address the standardization of their global laboratory processes. By unifying documents and rules, LIMS are becoming the corporate standard.

The ineffectiveness of generic LIMS is even more apparent in the pharmaceutical industry when it comes to government regulations — in particular, the International Conference on Harmonization (ICH) guidelines. Once again, organizations are looking to their LIMS to assist with regulatory harmonization by building this functionality into the software.

Essentially, advances in technology, market trends and strict regulatory requirements have made the industry to look for more purpose-specific LIMS that are not customized but instead are configured to meet their needs. Systems are on the market which offer industry-specific functionality so that companies do not need to go through costly, time-consuming risky customizations. Products are built on open standards that are designed to be quickly and easily implemented. By providing LIMS for specific

applications that are connectible to other technologies, vendors can provide a holistic view across the entire drug development life cycle, while still allowing fast implementation and adoption times for each solution. For drug discovery, a LIMS must be flexible enough to handle changing environments, including the complexities of increasing sample throughput and managing clinical studies.

Drug developers struggle to bring more products to market. To be successful, they must foster collaboration among their researchers to minimize rework and, ensure that they have the information they need to make the right decisions. This is increasingly important as companies expand their operations worldwide. LIMS can help remotely located scientists collaborate and impact research decisions, which results in considerably increased laboratory productivity. Laboratories are generating increasing amounts of data as analytical techniques become more sophisticated, and this means there is greater pressure on them to automate and integrate systems to make use of the additional data. LIMS are key to facilitating automation, data sharing, collaboration and integration across multiple data sources and products, including both hardware and software.

Forward thinking LIMS suppliers must form partnerships with software vendors to ensure that information sharing through LIMS will be enabled on a global scale across multiple locations and disciplines. To meet the needs of pharmaceutical companies, LIMS will need to grow in terms of functionality, breadth of interconnectivity and extent of collaboration. LIMS must be able to plug into a more seamless enterprise that allows users to work more efficiently and at a higher level. Despite the challenges, LIMS suppliers can expect decent growth in drug discovery lab automation, as indicated in Table 4-22.

Table 4-22

World Market for Drug Discovery LIMS 2008-2012

Revenues (in billions)

2008 2009 2010 2011 2012

$0.55 $0.57 $0.59 $0.61 $0.63

S

-R

S

As combinatorial chemistry has increased the size of many companies’ main compound libraries, the complexity of managing these libraries has increased as well. But for the libraries to remain useful to the drug discovery process, they must be accessible. Not only is it essential to manage a repository and to physically locate and handle the compounds, but it is also vital to maintain detailed records of sample use and data from previous assays, while conserving stocks by restricting the use of scarce compounds. The process, results and materials must be managed in an integrated fashion, from combinatorial chemistry, through HTS, to development and lead optimization.

Most companies begin with a manual repository system. After a compound is created and analyzed, it is labeled and stored manually in a central location. Information technology systems can help researchers access compound information and analyze chemicals and biological data. Compound retrieval is simply a matter of going to the storage area, reaching for the compound, and returning with it to the bench. No records are kept of compound usage or stock levels.

But as the compound collection grows, sample retrieval and preparation become increasingly unwieldy. With a larger library, more compounds will be screened against targets, and the number of targets is likely to increase as researchers take advantage of the capabilities of high throughput screening. Automated liquid handling and storage and retrieval systems are usually introduced at this stage together with automated chemical synthesis equipment for library generation and lead optimization. Careful consideration must be paid to their associated information handling systems. Compounds can be lost in a large system -- created and stored but never retrieved. The fear, of course, is that the next big blockbuster drug can be lost in the library.

As combinatorial chemical synthesis and high throughput screening systems advance in speed and complexity, they will necessitate not only more widespread, integrated automation of critical processes, but also, on a broader level, industrialization of the overall drug discovery process. Production-scale compound synthesis and screening operations will involve storage, tracking, and retrieval of perhaps hundreds of millions of compounds. To take the fullest advantage of new technologies, this industrial- scale process will require database management systems that are flexible, accessible, expandable and secure.

In addition to HTS, the storage of compounds also need to be addressed. With a company’s screening capacity exceeding 100,000 compounds a week, resource allocation

to compound storage and speeding the time it takes to retrieve compounds also play a crucial role in aiding the screening of such a large number of compounds. Samples used in biological assays are usually chemically synthesized compounds, plant or animal extracts, and cellular material (RNA and proteins). The storage methods vary by the sample type and the solvent they are solubilized in. Sample retrieval methods need to be automated since the manual location and retrieval of specific samples from millions of samples is time consuming and prone to errors.

The utilization of bar-code labeling and robotic equipment to decrease the time required for sample location and retrieval is the main feature of automated storage- retrieval systems. High end sample storage and retrieval systems can incorporate liquid

handling systems for aliquoting samples inside the cold storage room at -20oC. Among

major vendors specializing in this product line are RTS Lifesciences, Tecan’s REMP and The Automation Partnership.

The importance of storage-retrieval systems in ensuring sample integrity by helping preserve the chemical properties of samples and preventing decomposition will facilitate growth in the overall market for these systems, as seen in Table 4-23.

Table 4-23

World Market for Drug Discovery Storage-Retrieval Systems 2008-2012

Revenues (in billions)

2008 2009 2010 2011 2012

$0.30 $0.31 $0.32 $0.33 $0.34

Source: Kalorama Information

There are a handful of leading competitors in the laboratory automation systems market, including both the clinical segment and the drug discovery segment, as can be seen in Table 4-24.

Table 4-24

Laboratory Automation Market Leaders Percentage of Market Share

Thermo Fischer Scientific 14

Beckman Coulter 7

Caliper Life Sciences 4

Tecan 4

PerkinElmer 3

Molecular Devices 2

Others 66

Corporate Profiles