1. Clinical research, specimen procurement services design and conduct clinical trials and field studies, and provide specimens to be used in product evaluation.

2. Laboratory research services provide diverse forms of laboratory support, including analytical testing, specialized product and process development, and materials characterization and evaluation.

3. Legal affairs consultants offer a wide range of support services, including work on intellectual property issues, contracts, regulations, and general business law.

4. Liability insurance firms specialize in advising client companies about their liability insurance needs, including those related to clinical testing of new products.

5. Market research services can provide valuable information throughout the entire product life cycle. Their focus is to identify, quantify, and evaluate emerging product markets, and to track changes in markets as they mature.

6. Marketing, distribution services are provided by specialists with expertise in marketing techniques and distribution logistics, often including just-in-time delivery arrangements.

7. Packaging and labeling consultants can provide help with package design, automation of packaging and labeling processes, and package testing for conformity to manufacturer specifications. Labeling specialists can also help ensure that product labeling meets regulatory requirements, including the language requirements of the European Union's member states.

8. Patenting consultants can write and submit patents, evaluate existing patents to prevent infringement and determine if licensing is necessary, and evaluate product and process designs to determine the status of intellectual properties.

9. Personnel recruitment experts are used to locate, qualify, and hire acceptable candidates.

10. Process development and validation consultants specialize in the design, development, qualification, and validation of manufacturing, packaging, inspection, and testing processes.

11. Product R&D and design consultants specialize in design of products and associated processes, often using advanced software systems such as CAD/CAM. Consulting firms in this area are often certified to the ISO 9001 quality standard.

12. Product testing consultants represent a wide range of testing services for complete or partial testing of raw materials, work-in-process components, final products, or packaging systems.

13. Quality systems certification is performed by organizations certified by accreditors as having the knowledge, skill, and experience to evaluate a company's quality system against the ISO 9000 family of quality standards. Companies pursuing ISO 9000 certification must employ one of these organizations.

14. Regulatory affairs consultants advise companies on their relationships with regulatory agencies, write premarket submissions, manage the product approval process, interpret regulations, and provide answers to specific regulatory questions.

15. Site selection and facility design consultants can identify potential sites for business expansion, locate facilities, negotiate leases, provide direction about building codes and permits, and design and manage the construction of facilities (including specialized facilities such as biocontainment areas or cleanrooms).

16. Software design and programming consultants work from requirements specifications to write programs that operate instruments, control processes, or change existing software to meet an identified need.

IVD manufacturers hire consultants for various reasons. The challenge lies in selecting and making the most effective use of the right consultant.

The need for consulting services is prompted by unplanned, time-sensitive, or crisis situations, when a company may face extreme pressure to find specialized experts quickly. Under such circumstances, a company will often focus on fixing the immediate problem rather than on managing the contracted consultants. After all, the consultants have been hired for their expertise and should know what to do to get the job done.

Unfortunately, applying consulting resources—no matter how skilled or experienced—without proper direction and management rarely gets companies the results they want. To get the highest quality of service, while meeting budget and time constraints, companies need to establish guidelines and consistent processes for managing consultants.

This article discusses a quality framework for managing consulting services that encompasses two interrelated components:

• Project and Performance Management. Managing all consulting assignments—from project definition and planning, through implementation and project completion—to ensure that the company's needs have been met.

• Organizational Learning. Developing a system of tracking and learning from successes and failures to better equip companies to select qualified consultants.

This framework provides broad guidelines for developing a quality plan for managing consulting services, or for enhancing existing quality plans. Such a quality plan should be scaled to meet the company's consulting needs. In addition, it should be part of a larger company-wide quality management system. For example, it can supplement the company's supplier quality plan, which oftentimes does not effectively address the unique aspects of consulting services.

Project Ownership and Accountability

Ownership and accountability are essential to addressing organizational challenges, especially those that call for the use of external consultants. To ensure that the consultants and company are working toward a common goal, companies should assemble a project committee. The committee should include a project owner, project stakeholders, and a project manager.

Project Owner. The project owner is the individual ultimately responsible for the project's success. As such, the project owner should be a senior manager who understands the needs of the organization, has decision-making authority, and can garner the necessary resources (both human and financial) and support to make any necessary changes. The project owner is responsible for the following tasks:

• Leading the assessment of organizational needs and the internal capability to address those needs.

• Determining the feasibility of hiring external consultants to address the organizational challenges.

• Defining the project objectives and expected outcomes.

• Defining the consulting budget and timeframe, as well as the expected quality of results.

• Providing leadership and setting a tone for collaboration among all participants.

Project Stakeholders. Consulting projects often cross many functional areas. To assure project success, it is important to identify and analyze the influence of specific individuals or groups on the project and obtain their “buy-in” from the beginning. Considering the project concerns, expectations, and goals of potential stakeholders can help the company identify key stakeholders. In addition to involving stakeholders at the beginning of a project, a company needs to decide how involved they will be throughout the consulting project.

Project Manager. The project manager is responsible for developing and executing a management framework to carry out the project objectives. The project manager should ensure that external consulting resources are appropriately integrated into the project and that all project participants understand and work toward a common vision. Specific responsibilities of the project manager are discussed in each project phase that follows.

Phase 1: Defining the Consulting Project

Assess Organizational Needs and Internal Capability. The reasons that companies look to outside consultants are unique. They range from simple needs and a specific service (e.g., designing and delivering a specific training course), to more-complex needs that require in-depth diagnosis and analysis (e.g., developing company-wide quality system improvement). Even though two projects may appear similar, the solutions may differ depending on the company's experience with similar issues, its response to crisis and change, the available resources and how it chooses to use these resources, and its overall organization. These factors become especially relevant for more-complex needs.

A well-defined set of guidelines and goals can enhance a company's consulting experience.

Creating an assessment checklist can help companies evaluate essential information and options to decide whether external consulting services are necessary. This assessment should be led by the project owner and should include the project stakeholders and the project manager. All three positions should work to identify project objectives and expected outcomes.

Phase 2: Planning for the Consulting Project

Develop a Statement of Work. Once the organizational needs and internal capability assessment has been conducted and the company has decided to engage the services of external consultants, it is critical to prepare a statement of work (SOW). The SOW should achieve the following goals:

• Give a clear description of the project, its objectives, and anticipated outcomes and deliverables.

• Explain what is expected of the consultants.

• Describe the importance and complexity of the work.

• Guide both the consultant and the company on what they are accountable for and how the project will be managed.

• Ensure that there is no confusion about what is to be achieved so that the project does not go off track.

The project manager should prepare the SOW with information from an overall project plan, which should be reviewed with all project team members. In addition, the SOW should be reviewed with the individual who will be responsible for day-to-day management of the consultant's activities. Although the SOW should be defined before hiring the consultants, it should also be reviewed and revised as needed during the consulting.

Identify and Select Qualified Consultants. Although systems to track both successes and failures with consultants can take time to develop, if done appropriately, they provide a valuable tool for managing consulting services.

A company should begin with a review of its consulting experiences. Conduct a formal evaluation of the consultants' performance with a sampling of project owners, stakeholders, project managers, and team members from diverse projects. Chances are, the same consultants have worked on different company projects. By establishing and maintaining an electronic database of consultants and their performance at different stages in projects, the selection process can be streamlined significantly.

Plan for Knowledge Transfer and Project Sustainability. The following actions should be considered to ensure project and organizational sustainability:

• Be clear about the capability you want transferred from the consulting team to yours.

• Identify which staff members are to be involved in the project.

• Contract with staff members and their managers for time required and learning outcomes.

• Include both consultants and staff members on the initial project team to ensure a seamless transition after the consultants' assignments end.

• Be sure the consultants create a written record of their work through documentation and regular reports.

Prepare for the Consulting Work. Before a consultant begins work, the appropriate company personnel should be clear about the role and purpose of the work. The consultant should not be seen as a threat to employees' jobs or even as a source of interference.

If the consultant will work on premises, have the work area ready ahead of time. If the project consists of analyzing reports, documents, or problems, the material to be analyzed should be prepared before the consultant arrives or available when the consultant requests it. A company should be prepared to pay fees if the consultant must handle these logistics.

Finally, the consultant should report to the project manager and be teamed up with a project leader or other team member who will be responsible for managing the consultant's day-to-day activities.

Phase 3: Managing the Consulting Project

Change is inevitable in any project. Successful project management requires effective monitoring, control, evaluation, and communication. Mistakes should be identified quickly and corrected. All of these activities are the responsibility of the project manager.

The quality and effectiveness of the consulting project should be evaluated periodically. Managers might consider holding a midterm project review with people involved in or affected by the project, as well as soliciting feedback from stakeholders.

Good monitoring requires good communication. A communication plan should be established for larger, more-complex projects. The project manager should maintain regular communication with the consultant and the entire project team to ensure that all team members understand the expectations as outlined in the project plan and the SOW. Regular team meetings should be held to review progress and any unexpected changes that may affect the project.

The project manager and team must be willing to acknowledge any problems that arise during the project and take steps to overcome them. Although the proper course of action will depend on the situation, the following are key types of corrective action:

• Rearranging the Workload. If a milestone is going to be missed, the preferred option is to rearrange the workload. This may mean completing the work in a different order or finding an alternative way of reaching a milestone.

• Adding More Resources. Another option is to dedicate more resources to the project. However, this will increase the project cost and may not yield the expected level of quality.

• Moving Milestone Dates. Rescheduling current and future milestones may be acceptable if this does not affect the overall timeline.

Phase 4: Completing the Consulting Project

When the project is completed, the company should review and record the consultant's performance. The following questions should be considered:

• How effective was the consultant at meeting the project objectives?

• Did the consultant work within the SOW or venture out side, the scope of the project?

• How well did the consultant keep the project manager or team leader informed of work progress and problems?

• How well did the consultant work with the company's staff?

• What was the quality of the project?

• How effective was the consultant at proposing solutions to challenges encountered during the project?

• Would the company hire the consultant again? If so, for what types of future projects?

Conclusion

A quality plan for managing consulting services should provide companies with a consistent process for deciding whether bringing in a consultant is the best way to address a particular challenge. The company and senior management should be prepared to hire a consultant if the challenge warrants this.

In addition, the company should have a plan to enact the consultant's recommendations into the organization. If the wrong consultant has been hired, or if the consultant is not performing as expected, there should be room for corrective actions to be taken. In the end, the company should be willing and able to learn from its consulting experiences.

1. Bioprocessing services prepare and purify the biochemicals and chemical reagents used in IVDs, many of which are particularly hard to culture and grow in laboratory settings. Suppliers use advanced chemical, physical, and biological processes to recover and purify products from dilute process streams.

2. Converters supply industry with die-cut parts, adhesion of liners to pressure-sensitive products, and multilaminated packaging materials in sheet or roll form.

3. Dispensing and filling (liquid or powder) suppliers provide the essential service of applying reagents to substrates for immunochromatographic assays, and packaging assay-related biochemicals and reagents, often under controlled-environment conditions.

4. Lyophilization may be required since many liquid-state biological products are heat sensitive, react with oxygen, or lose potency over time. Freeze-drying—the removal of water from the product—is one of the safest ways to preserve the immunogenicity of such products as diagnostic controls, sera, plasma, conjugates, and peptides.

5. Machining services manufacture custom components and subassemblies using techniques such as laser cutting and welding, stamping, and coining.

6. Microfabrication refers to the technology of making very small devices using a variety of techniques (photolithography, for example). Using processes very similar to those used for fabricating integrated circuits, it is possible to create ultraminiaturized motors, actuators, pumps, gears, pistons, and other mechanical components. Miniaturization of IVDs is a hot and exciting technology.

7. Packaging and labeling vendors can help firms meet regulatory requirements, minimize materials use, protect sensitive products, and optimize consumer appeal. See also Section 6: Packaging and labeling materials and components.

8. Plastics and rubber-forming services use customer-specified and commodity resins to supply the diagnostic industry with rigid and semirigid tubing and assemblies. Tubing products with exact tolerances are their domain, along with the abilities to provide secondary and finishing processes such as sealing, counting, bundling, bending, bonding, and coating.

9. Product assembly sources provide OEM products and services including private labeling arrangements, system development (R&D), and contract manufacturing.

10. Product testing services are offered to ensure that products and materials meet established quality standards. The scope of testing is diverse, and includes physical, chemical, biological, environmental, and facility-related testing. Physical and chemical tests include materials characterization, solubility, and moisture testing. Biological and microbiological testing involves tests for safety, preservative action, sterility, and viral contaminants. CE marking requires testing that is provided by vendors in this subcategory.

11. R&D, design, and prototyping services can supplement a manufacturer's in-house staff or provide economical design services to start-up companies.

12. Sterilization companies provide contract sterilization via several methods, including ethylene oxide, steam, gamma irradiation, and E-beam irradiation. Some sterilization vendors also provide assembly, packaging, and microbiology and analytical chemistry testing.

13. Surface modification and coating consist of the development and manufacture of product-delivery systems. Customers include those involved in bioseparation media, controlled-release devices, biosensors, and cell-growth supports. Technologies are often handled as proprietary manufacturing arrangements.

14. Welding and sealing are often major parts of product assembly; firms in this category provide services for both metals and plastics.

The trained associates at NERL Diagnostics Corp. (East Providence, RI) carefully inspect each bottle to maintain high quality control standards.

In today's IVD market, as in other segments of the medical product manufacturing industry, change is a constant. A significant large-scale change is the pace at which both large diagnostic companies and numerous smaller start-ups and biotechnology companies are enthusiastically embracing the benefits of contract manufacturing, outsourcing production and other processes to specialty subcontractors.

Many companies prefer to keep production in-house whenever possible. Manufacturing products by means of completely internal processes allows these organizations to retain absolute control over quality and cost. However, that approach becomes problematic when a company realizes either that it could make more money by outsourcing or that difficulties of in-house manufacturing logistics dictate the far more efficient course of outsourcing to a third party.

The decision to outsource a product is a complex one for any company. Myriad reasons underlie the decision, as well as the choice of a company to partner with.

Reasons for Outsourcing

IVD manufacturers' reasons for outsourcing, though many, are readily classified into two general categories—financial and strategic.

Financial Justifications. Large companies often calculate the full production cost of each product manufactured by adding in organizational operating expenses, spreading these costs proportionally over the range of devices produced. These costs reflect the amount of direct labor, space, and ancillary resources (such as management time) applied toward producing a finished kit or component.

If there is a lean infrastructure in place and the company has the luxury of sharing operational costs across a wide range of products, then the overhead expenses assigned to the manufacturing cost of a particular product can be controlled and kept as low as possible. But when that is not possible, and when adding a new product to the company's offerings necessitates an additional new production line, with the labor and other new space and resources dedicated to it, outsourcing becomes an attractive option. This is true particularly if the company is located in a geographic area where the costs of such resources are higher than they are in other regions.

For many small and medium-sized organizations, the problem can be more acute. Most smaller companies must cope with a restricted cash flow. The amount of capital required for the production of newly developed IVD devices can be extensive. Capital may be needed not only for additional manufacturing personnel and production space but also to cover such expenses as new manufacturing equipment, good manufacturing practices (GMP) and ISO quality management system consultants (if systems certified to these standards are not already in place), and the advance purchase of raw materials and supplies sufficient to generate a reasonable start-up inventory once marketing and sales have begun. Smaller companies in this situation find outsourcing to be an excellent way to avoid the pitfall of running out of operating capital just as product sales start to increase and additional investment is needed to fuel the momentum.

Strategic Justifications. Many IVD companies manufacture products within a specific discipline of the IVD industry, such as chemistry or hematology. Occasionally, such a company may rush to add a product line that, from a marketing perspective, complements the products it already sells, but that may lie outside the company's field of expertise. Here, business strategy is the motivation for calling on the services of a contract manufacturer.

Consider a chemical reagent manufacturer that intends to add to its product portfolio a new visual rapid test it has developed or has obtained the rights to. The company's present manufacturing equipment, technical support, and production space may not be able to accommodate the addition of such a product. In a case like this, the manufacturer often will decide that the much safer course from a strategic standpoint is to outsource the production rather than build new in-house capability. Also, outsourcing would offer the further strategic advantage, on the marketing side, of a faster time to market.

NERL Diagnostics produces ampules from 1 ml to 10 ml on its two Cozzolis.

Outsourcing is not always a matter of a U.S. manufacturer moving production offshore. For years now, many companies outside of the United States have looked to gain entry into this market. The logistics of setting up a manufacturing plant in the United States are complicated. Various regulatory, marketing, language, and cultural issues can make it a very difficult task. Outsourcing is a viable option for bypassing many of these issues. Overseas companies that want to sell inside the United States will find that outsourcing production to a U.S.-based manufacturer reduces freight costs and provides a more efficient means of distributing products through a market area as large and diverse as that of the United States.

Choosing a Contract Manufacturer

The decision to outsource is momentous, but at least as important is the choice of a contract manufacturing partner. The criteria that companies use in selecting a manufacturing partner are varied but ultimately fall into a few categories—specifically, culture, experience, location, and stability.

Competitiveness matters, too. Most customers of outsource service providers are concerned to have chosen a supplier whose quoted price represents good value. The contractor's purpose, at bottom, is to help the IVD manufacturer meet its financial goals. No supplier who is routinely among the most expensive to do business with will be a manufacturer's first choice if the customer can achieve the same sought-after results through another company at a lower cost.

The Culture of the Contractor

Culture is a broad term that in the context of contract manufacturing refers to the degree of customer orientation exhibited by the service provider.

This quality is revealed through the systems the company uses—its reports, regulatory files, accounts receivable department, and order completion processes, for example—and the attitude of its employees toward their customer, the IVD manufacturer. The culture to be sought is one that makes the customer feel important and cared for when it conducts business with the supplier.

A customer-oriented contract manufacturer will display several distinctive characteristics. It will follow up quickly on questions and inquiries of any nature. If it for some reason cannot, it will keep the customer regularly informed regarding the status of its inquiry until the matter can be closed. This is treatment that can be expected from all departments—customer service, technical support, QA/QC, shipping, production, and sales.

A customer-oriented company also will make a concerted effort to anticipate problems before they occur. Managers not only focus on the task at hand but also anticipate obstacles that could occur should some element of the process break down. For example, they might order supplies with lead times sufficient to avoid back-order delays. Similarly, they would keep QA/QC materials such as testing panels well stocked and would have alternative shipping arrangements ready to use in advance of emergency need.

NERL Diagnostics can manufacture lot sizes up to 23,000 liters.

Some contract manufacturers, happy with the status quo, do not prepare for the possible increases in production volume that may be required by a thriving customer. They may even avoid taking on customers whose prospective sales growth they consider beyond their means. But other suppliers want and pursue customers who are growing so that they can experience growth also. A customer-oriented contract manufacturer that embraces a supportive team attitude toward future growth will attract more referrals of that nature.

Many things can and do go wrong in the manufacturing process. What reveals the character of a contract manufacturing organization is how well it responds when problems arise. A truly customer-oriented company will offer explanations with possible solutions, not excuses. The customer simply wants the problem fixed, and wants to know what steps will be taken to prevent its recurrence. If the contract manufacturer spends energy on placing blame—wherever it may lie—it may be forgetting the main objective: to get the product out, right and on time.

Experience, Stability, and Location

Contract manufacturing experience is a valuable asset for a company being considered as an outsource services provider. That track record as a contractor gives a potential customer the opportunity to talk to referrals and to review an already qualified GMP/ISO manufacturing environment. The experienced supplier knows how to deal with the demands of a customer, such as periodic audits, packaging changes, personnel changes, and so on. A company that has done some contract manufacturing will have put in place a support system to handle all customer needs, including QA/QC, technical support, customer service, and sales support. In addition, the experienced supplier will probably have sufficient space and equipment to perform a variety of functions. This may enable a customer to consolidate several projects in one house.

Experience is an attribute whose value cannot be overestimated in considering a company for contract manufacturing.

In many, if not most, contract manufacturing arrangements, the customer is the larger of the organizations in the relationship. The financial stability and prospective longevity of the contract supplier are key factors in determining the viability of a business partnership. This is so because most contract manufacturing projects have the potential to run 5 to 10 years or longer and to grow in volume over time. A supplier should have good financial statements that are updated periodically, present a strong balance sheet, and show acceptable sales records from year to year. Also, the company should provide evidence of a good payment history and should be involved in no significant outstanding legal proceedings. In the area of stability as well as experience, good references are helpful. The IVD manufacturer should confer with other, or former, clients of the prospective contractor.

The geographical location of a contract manufacturer can be a critical ingredient in the decision to select one supplier over another. A contractor's location should be advantageous either with respect to proximity to the customer or as a distribution point for international sales. There should be no indication that the supplier might have difficulty obtaining additional space should expansion become necessary.

Also, not particularly a geographical concern, the physical plant should be presentable and, in fact, should show well enough to merit the customer's confidence that regulatory agencies will have a positive first impression of it and that products will be manufactured in a proper environment.

Conclusion

An IVD manufacturer that has decided to outsource production has a challenge in finding the best service provider to use. Though candidate companies' experience and referrals can be excellent indicators, making a choice may not be as simple as some would think, particularly for a company new to the outsourcing process. The IVD company in that case ought to outline its own requirements for what would constitute a good contract manufacturing partner.

The factors discussed here are all important considerations for the search, but, like consumers in any marketplace, what manufacturing companies in the IVD industry want ultimately is value for their money.

1. Adhesives, coatings, and solvents companies offer a wide range of such materials for use in product assembly. New adhesives and coatings are constantly being developed to improve product performance. Recent advances in cyanoacrylates and UV or visible-light curing adhesives make them worth consideration.

2. Automation/custom systems suppliers can design and fabricate equipment for converting, assembly, inspection, and packaging of diagnostic products. Such systems are built in strict adherence to FDA quality systems requirements, and can be furnished with state-of-the-art machine control and software for statistical process control.

3. Bioreactors, biochemical processors, tanks, and vessels can be key components of a manufacturer's bioprocessing operations. The companies listed in this subcategory offer a wide range of such equipment in sizes suitable for R&D, pilot production, and scale-up to full production.

4. Component assembly equipment includes ultrasonic sealers and welders, laser welders, UV spot-curing machines, motion control products, and related electronic components. Suppliers in this subcategory may also offer custom products (see subcategory 2).

5. Fluid-handling equipment, dispensers, and fillers are offered by firms specializing in products for bulk fluid transfer, spraying, coating, pattern dispensing, and precise reagent dosing. Included are manual dispensers, automated dispensers, and both volumetric and nonvolumetric systems. In addition, these suppliers can provide a variety of fittings, reservoirs, and tubing types, as well as sophisticated dispensing nozzles for demanding applications. Suppliers in this subcategory may also offer custom products (see subcategory 2).

6. Laminating equipment enables manufacturers of immunoassays to bond antibody-coated membranes and other microporous materials to substrates that can add strength and stability or improve handling characteristics during assembly or use.

7. Lyophilization equipment is critical for manufacturers of liquid-state biochemicals and reagents that are heat-sensitive, react to oxygen, or lose potency over time. Freeze-drying—the removal of water from the product—can increase the stability and reconstitution properties of such products.

8. Materials-coating equipment can include systems using advanced technologies such as plasma polymerization, vapor deposition, and other proprietary surface treatment or modification techniques, as well as traditional coating of web stock with adhesives.

9. Packaging, labeling, and bar coding equipment suppliers offer the materials and systems needed to package a finished IVD product. Marking systems using laser technology have come to offer significant advantages over traditional labels and label applicators, and are key components in today's automated processing systems.

10. Plastics-forming and -sealing equipment includes machines for injection, vacuum/pressure, and blow molding of device enclosures, as well as form-fill-seal systems for packaging end products.

11. Process-control equipment suppliers furnish complete closed-loop control systems for running manufacturing processes. Software for continuous monitoring of process parameters and statistical process control can also be supplied.

12. Product design, prototyping, and testing equipment includes rapid-prototyping technologies such as stereolithography, selective laser sintering, and urethane casting. IVD firms are making use of such technologies to verify product designs more quickly, thereby reducing time to market.

13. Slitters come in a variety of sizes and configurations, from small manual units to large automated systems with high throughput. They are essential equipment for IVD firms that manufacture membrane-based immunoassays such as home-use pregnancy test kits.

14. Sterile processing and cleanroom equipment includes companies that provide contract sterilization of medical products, as well as related equipment and monitoring systems and services. Sterilization methods include ethylene oxide, gamma and E-beam radiation, and steam or autoclaving. Cleanroom equipment includes environmental monitoring and control enclosures, air filters, laminar-flow hoods, and floor coverings and mats. Such equipment is essential to proper manufacturing of many IVD products, or to proper terminal sterilization of instrumentation and related disposables.

15. Surface-modification equipment includes device coatings and treatments such as corona discharge, plasma spray, and other specialized surface-property modifiers. Surface modifications are intended to enhance specific properties of base materials and include treatments for lubricity and wettability, antimicrobial coatings, and biomolecule immobilization.

16. Contract manufacturers often provide consulting services, facilities, and equipment for IVD manufacturing processes. The range of services includes consultation about equipment for product design as well as for product assembly, converting, and packaging.

17. Stock items suppliers offer standard equipment for general use by IVD manufacturers, and may also offer custom-designed systems (see subcategory 2).

The LM 6000 in-line lamination system by BioDot Inc. (Irvine, CA)

As the IVD industry undergoes a shift toward new technologies and new analytes, the relationships among the assay developer, the manufacturing process designer, the equipment supplier, and the manufacturer of the final device are becoming more critical to a product's success than ever before. The IVD industry continues to develop novel solutions for performance- and user-related problems, including the miniaturization and multiplexing of assays, and the use of unique microfluidics, labeling, and reading technologies. Many newer analytical targets, particularly in the point-of-care (POC) diagnostics market, require easy-to-use, quantitative systems, which in turn demand improved reproducibility, stability, sensitivity, and dynamic range.

As demands on the product increase, so do demands on the manufacturing process and its machinery. A natural corollary to the development of novel technologies and applications is the development of custom manufacturing processes and machinery to produce a final product. However, customization brings unique challenges and increased risk. As a result, it is critical that manufacturing process design be performed as early as possible in the product development cycle.

The trend toward outsourcing many product development and manufacturing elements is another natural result of the increased complexity of the assay development process. The development and production of newer-generation POC devices require input from a variety of specialist disciplines. For smaller companies in particular, the range of skills required to complete the design of a complex IVD device can be difficult to access. This can also be true of larger corporations, whose focus may be in other areas.

Risk and Reward

With the outsourcing of numerous specialist disciplines comes both risk and opportunity. For manufacturing process and equipment design, the risk lies in poor communication. It is essential that the disparate disciplines and groups involved in product development understand the manufacturing issues created by their design solutions. Conversely, it is important that they comprehend the manufacturing requirements before their solutions are created and integrated into a product's design. Good internal communication is also critical when setting manufacturing equipment performance specifications, which in turn will be vital to the success of the equipment, the process, and the product.

The AD5000 gantry dispening platform by BioDot Inc.

The willingness to outsource specialty tasks also presents opportunities, to the manufacturer as well as to any consultants that may be hired. One opportunity is the use of experts to identify appropriate manufacturing processes, technologies, and suppliers. Tasks such as building relationships, evaluating technology, and determining the feasibility of a manufacturing approach should be performed by agents skilled in the relevant discipline, whether this be dispensing, drying, cutting, laminating, assembly, or packaging. Including specialist expertise in difficult process design operations is essential to achieving success in the least amount of time and with the least amount of waste. This is especially true for manufacturing processes that involve the interlinking of biological and mechanical systems. To help assess risks and to aid in the design of these types of systems, specialist companies use the skills of cross-disciplinary teams of biologists and engineers, or of personnel with both sets of expertise.

Another opportunity lies in the skills of the specialist suppliers themselves. A manufacturing equipment supplier can make or break time lines, budgets, and, ultimately, products. Getting the most out of the interaction with a capital equipment supplier relies on one critical element: The quality of the relationship. Another often-ignored fact is that many specialist suppliers know a considerable amount about IVD development and manufacturing programs—expertise that can be tapped into by manufacturers.

Cultivating Relationships

Like other business relationships, the interaction between a manufacturer and a specialist equipment supplier must be carefully managed. If a few basic rules are followed, the chance for a project's success will be greatly increased.

Use the Full Capabilities of Your Supplier. Enlist capital equipment partners early in the product design process and use their expertise. This expertise may extend to unanticipated areas, including device design, biological system interfacing, and manufacturing process design, and is quite often extremely practical. Most specialized capital equipment designers and manufacturers likely have seen processes similar to yours. They often understand the potential pitfalls of such systems.

Ask Questions. Listen to a supplier's feedback on a proposed process design, as well as on the equipment that is being designed, which you are ordering. It is important for a manufacturer to remember that it is paying not only for the final delivered machinery, but also for a supplier's expertise and ability to guide the manufacturer through the generation of a process that will ultimately end with a finished product.

Maintain the Relationship while Maintaining Your Options. It's an old cliché, but true nonetheless: Treat a supplier as a partner and friend. For custom, large-capital items, in particular, the design, development, and manufacturing process may last for a while. If this process progresses successfully, and even if it does not, a manufacturer may be spending a lot of time with its suppliers in the years ahead.

Know Your Supplier Well. Be familiar with its technologies, its track record, its employees, and its capabilities. Then find a secondary supplier, if possible. If issues arise during the negotiation, production, or supply of a critical piece of capital equipment, both manufacturer and supplier may wind up in crisis. If a manufacturer is prevented from finding a second supplier due to specialized discipline or equipment, or cost or time considerations, then the IVD company should be prepared to stick with its primary supplier. In such circumstances, a supplier really does become a partner in the enterprise.

Set Specifications Carefully. Great care is necessary when setting the specifications for acceptable performance of a piece of capital equipment. A key element in setting the product specifications for capital equipment, especially in an IVD setting, is defining the difference between equipment performance and final product performance. In biologically linked systems, such as immunoassays, too many other reagent- and process-related factors are typically at play in the process of generating acceptable product performance to set final product performance as a specification for machine performance. Measuring machine function involves engineering measurement, with clearly definable and demonstrable results.

If acceptable final product performance is a specification insisted on by the customer, the equipment supplier must take into account the cost of process development and final product performance verification. Quite often, this cost will be passed on to the customer, and unless that expectation is set early, frustrations and issues can arise. The issue can be dealt with before it arises during planning. Both sides should agree that if process development and verification must be performed to guarantee product performance, in addition to measuring machine performance in terms of machine function, then there will be a cost in time and resources to do that. Setting this expectation will save a lot of time and frustration later in the process, and prevent potentially severe delays to installation and production.

The AD1500 dispensing platform by BioDot Inc.

Choosing suppliers that have an understanding of these potential problems and solutions is key to success. Ideally, it is good to use capital equipment suppliers that have biological science, device, or assay development expertise on board or available. Alternatively, it is advisable to use scientists, consulting or otherwise, who have manufacturing and capital equipment design expertise, to work with in defining the machine specifications and interfacing with the equipment supplier.

Use Specifications and Buy-Off Criteria to Set Expectations. Resist the urge to change specifications during the manufacture of a piece of capital equipment. Set specifications up front and do not change them. Capital equipment is designed to produce a product with a particular specification. If the specification is changed—be it related to component, performance, throughput, or product—the deal and relationship also change. This is no way to treat friends. If the terms of a deal must be altered, do so tactfully and expect repercussions in the form of cost increases, longer time lines, and occasional swearing.

To avoid this type of situation, have buy-off criteria carefully and completely defined before the equipment is ordered and the deal signed. Examine every detail of the proposed buy-off criteria and ensure that they are discussed and agreed to in full by the supplier. Misunderstandings can add severe stress, as well as months of delay and extra costs, to a project.

In many ways, the buy-off criteria for a piece of capital equipment are as important, or perhaps even more important, than the formal product specification. These criteria enable a manufacturer to judge whether the equipment will work as expected. For this reason, they should be used as a tool to set expectations, both with the equipment supplier as well as within the manufacturer's own company.

Be Prepared for Surprises. The process of designing, developing, and producing custom capital equipment is rarely without snags. The effort spent building a strong relationship with the supplier will pay off when responding to unexpected events. In the end, machine design and product development are dynamic processes that tend to overlap. In an ideal situation, both the product and manufacturing process design would evolve together. Many times, however, when the two processes evolve separately, their meeting leads to confusion and cost. Careful management of the expectations of both the capital equipment supplier and the customer is crucial to the success of this relationship and the project.

Conclusion

The outsourcing of key elements of product development or manufacturing is, more and more, becoming a necessary element of project management. Forming strong relationships based on fairness and mutual goals is the key to making any outsourcing relationship work. The capital equipment supply relationship—particularly when it involves custom equipment with its long lead times and high ticket prices—is among the most critical relationships that an IVD manufacturer can form. In the end, if managed carefully, the outsourcing process can be positive not only for the manufacturer and supplier, but ultimately for the product and the consumer as well.

1. Ampules, bottles, jars, vials are primary containers for reagents in both liquid and dry-powder forms. With the increasing market for automated laboratory systems, the need for ready-to-use liquid reagents is also growing.

2. Clamshells, blisters are often the preferred packaging systems for diagnostic kits, enabling manufacturers to package sterile components together in an easy-to-open container.

3. Closures, lidding, caps, stoppers are available in a wide range of materials and configurations, often color coded for ease of recognition. Lidding includes materials, such as spunbonded polyolefin, which are adhesively sealed to molded trays for IVD kits.

4. Desiccants, sterilants are used to protect biochemicals and reagents that can be affected by moisture and to prevent the growth of bacteria in otherwise sterile packaging.

5. Display packaging, cartons, boxes, cases are the essential containers for such over-the-counter products as home-use glucose monitors and pregnancy tests. Such packaging is designed not only to protect products and meet regulatory requirements, but also to be attractive to the consumer market.

6. Films, foils are essential materials for manufacturers that perform their own packaging. Suppliers offer materials in standard or custom sizes and thicknesses, sometimes imprinted according to the manufacturer's specifications.

7. Labels are supplied by companies listed in this year's buyers guide. Offerings range from simple adhesive-backed label stock and preprinted tags to laser-readable bar code labels using chemically resistant substrates and inks.

8. Pouches, bags are generally an inexpensive method of packaging kit components and consumables used by automated laboratory systems. Supplied as raw stock or in imprinted form, these packages come in a wide variety of materials and configurations.

9. Rollstock, including laminated materials used for packaging, is supplied by companies listed in this year's buyers guide.

10. Shipping containers, insulated shippers help to protect fragile instruments and preserve the stability of biochemicals and reagents.

11. Trays are commonly custom molded to meet the needs of IVD kit manufacturers. Like clamshells and blister packs, they enable manufacturers to provide protective and orderly packaging for kit components.

12. Contract manufacturers specializing in IVD packaging can often provide package design and validation services, as well as performing the actual packaging and labeling of finished products.

13. Stock items suppliers are a relative rarity when it comes to IVD packaging, mostly because so much of IVD packaging and labeling is custom designed to meet the needs of individual products. This year's guide lists only the companies that name stock items as a field of specialization.

The Insulated Category A Shipping System by Saf-T-Pak Inc. (Edmonton, Canada).

It should not come as a surprise to those involved in the purchasing of medical device and diagnostics packaging components that a philosophy of packaging does exist. Packaging must efficiently protect, contain, and describe the kits it encloses, whether sent around the globe or to the local drug retailer.

Protecting IVD kits during their distribution requires complex packaging decisions. Each of the components involved in keeping kits safe could easily justify entire textbooks unto itself. As such, the following introduction is meant to provide only a general overview of the important factors involved in IVD packaging decisions.

Before discussing the available components, it is worthwhile to look at the overall design process. The design of protective packages for test kits requires a team of engineers and scientists, as well as a group of marketing, quality, and regulatory representatives.

Where Does Package Design Begin?

During the design phase, IVD manufacturers must consider a number of questions. Although not all of these may require equal attention, each should be addressed to help ensure design quality.

• Will the kits be marketed stateside, overseas, or both? It is important to keep in mind that package design may change from clinical trials to market introduction.

• Have active components been finalized? A manufacturer's development group should have chosen the final dosage format—liquid, lyophilized, tablet, powder, bead, or a combination of these.

• Will a sterile fill be required? As more-specific package components are considered, an answer to this simple question will help determine the primary container and closure materials.

• What type of primary container and closure system will be used? Plastic and glass bottles remain the containers of choice for IVD manufacturers. But manufacturers must also consider the variety of screw caps and liners, stoppers, aluminum seals, syringes, and other specialized components.

• What environmental conditions will the packaging experience? The issues of climate, both surrounding the end-user and encountered during product shipment, are numerous. Protection against light is the responsibility of both the primary and secondary packaging. Similarly, package design must take into consideration the intense heat and arctic cold that may be experienced during shipping and storage. For example, packing kits in dry ice remains the standard for global shipments. The –70°C temperatures endured during the trip require extensive testing to ensure that packaging is not damaged.

• Will hazardous materials be involved? The list of special packaging needs for shipping biohazardous, radioactive, corrosive, and flammable IVD products is extensive. If test kits contain hazardous components, specific labeling and markings must be used.

• What accessories will be required? IVD packaging often includes the plastic accessories required. These can include trays, plates, pipettes, dispensers, and tubes, as well as a multitude of stock and custom components.

• What other special packaging requirements are involved? Additional package needs range from basic desiccant canisters and pouches for protecting consumables from moisture to dunnage and bulk packaging material to prevent damage during shipment.

A Systems Approach

Testing and validation requirements will continue to increase, not decrease, in the future. The overriding concern of every IVD packaging group is to maintain both the safety and quality of the product. To achieve this goal, packaging experts must embrace the concept of integrated systems.

The development of packaging involves suppliers of raw materials, containers, closures, labels, and converters. Secondary package components include cartons, corrugated shipping containers, blister packs and trays, foils, and a multitude of polymer overwraps. In addition, distribution packaging requires pallets, strapping, and stretch wrap, as well as consulting and testing labs.

In a systems approach to packaging, these various components are grouped into a framework of common systems. The systems approach stresses an understanding of the complexities of a package and its individual components, but acknowledges that each of these lends value and quality to the final test. In the end, the packaging is critical to the success of any IVD test.

With IVD packaging, the package and the test it protects are an integrated and often indistinguishable unit. For example, it's not practical to try to distinguish an aerosol product from the container that dispenses it. As such, it is often stated that product development and package development are done together on an interactive basis.

All IVD packages must protect, contain, and identify their tests. Together, these characteristics make up the building blocks with which a package system is developed.

Protection. Quality and protection are intertwined as the foundation of the IVD package. The package must be able to prevent harm to the product from such environmental threats as moisture or oxygen, as well as keep the product from inflicting harm on the environment or user.

Containment. The packaging of an IVD should be convenient to everyone who must handle and use the test. This convenience should extend not only to the final customer, but also to those who manufacture, transport, distribute, store, and ultimately sell the product.

Identification. Package labeling and product inserts are the means through which a manufacturer communicates with a consumer. To adhere to IVD rules and regulations, manufacturers must be willing to make continuous quality improvements to labeling components. For example, if a test contains hazardous materials, specific labeling and markings addressing these materials must be introduced. If products are marketed overseas, label requirements must again be revised.

What Next?

The choice of packaging components that complement the design of a test will greatly influence the final performance of the product.

Due to their seemingly unlimited potential as packaging materials, plastics remain the most widely used IVD component. When screening proposed materials, various characteristics must be weighed against cost and performance. For example, to what extent is sterilization required? If a thermoform is used, will a clear plastic tray help the end-user identify the medical product?

When reviewing plastic components, it is also common that many types of plastics will satisfy the basic package criteria. The relative economics of each material are often, but not always, a deciding factor in the final material selection. Consistent quality, regulatory restrictions, ease of resin processing, environmental disposal concerns, and the use of cost-effective sterilization also become factors.

Developing Component Specifications

A critical step between the development and market launch of a product is the creation of specifications. Product needs and process capabilities define what a purchasing group will specify and order. Specifications that are jointly developed by component supplier and end-user tend to perform better through the life cycle of a diagnostics kit and cause fewer quality issues and less stress.

Because the primary container and closure systems come into direct contact with the product and are subject to quality and regulatory requirements, they tend to be the focus of this process. However, secondary and tertiary (e.g., shelf and distribution) components also play an important role and must not be ignored.

As labels and other printed materials are critical during the life cycle of a test, these must be subjected to printed-commodity qualification and material structural evaluation. The labeling and cartoning of an individual IVD test or a complex kit are essential parts of the overall product design. Proper packaging and labeling ensure that diagnostic testing is efficiently distributed worldwide.

IVD manufacturers must also package their products to guard against vibration damage during truck, railroad, and airline shipment. IVD products can be accelerated and decelerated thousands of times a minute during their shipment to customers. Products encounter both repetitive and random shock sequences.

The Final Step

The 2-8°C PCM System by Saf-T-Pak Inc.

The final link in an IVD purchasing team is incoming quality assurance. The personnel who work in this area inspect and test samples of raw materials purchased from vendors to ensure their quality. Purchased packaging components that become part of a finished IVD kit have a direct effect on the quality of the production of that kit. To prevent the quality of tests from being compromised, components must be defect free.

However, material cannot be kept free of defects through the use of inspection and testing alone. The quality group must also rely on the team of suppliers to provide quality parts. The vendor must employ various techniques, beginning with statistical process control and in-process testing, to ensure that their materials meet high standards. To keep up with changing regulations, suppliers must always strive for quality improvement.

Vendor and supplier certification programs represent one method for recognizing those suppliers who have met all the quality requirements of a customer, often for a minimum of 12 months. A certification program enables manufacturers to forgo routine inspection and testing on incoming lots. Materials purchased from certified suppliers can safely bypass incoming inspections and be placed directly into the raw-material inventory.

Choosing Suppliers

Good suppliers share the same characteristics, no matter what product they produce. A supplier should be a technical and quality leader in its field, and therefore able to contribute technical expertise during the product design stage. In addition, a supplier should be willing to communicate effectively and openly, and be prepared to share its goals, commitments, and risks with a manufacturer in order to promote a long-term relationship. It should be knowledgeable about its own quality history and should be continuously seeking to improve. Finally, a supplier must be financially sound and shouldn't change prices unexpectedly. It must deliver products on time, and should be able to do so with minimal supervision.

Certification. The process by which a supplier meets the certification requirements of an IVD company begins once a product's characteristics have been established. Certificate criteria may include such things as an absence of product-related lot rejections for a specific period or over a specific number of lots.

Quality record. The supplier's quality record must also be thoroughly considered. The quality of a supplier's product has a direct effect on the quality of the final test kit. IVD manufacturers may wish to certify only those suppliers who have had no production- or customer-related negative incidents over a specific period.

Auditing. A packaging supplier should also successfully pass an on-site quality system evaluation audit. The audit is an opportunity for the quality engineering staff to examine and evaluate the following items in a supplier's systems, procedures, and supporting documentation: organizational structure; material identification, storage, and control; handling of design and specification information; inspection procedures; quality assurance and manufacturing procedures; documentation of incoming material, in-process work, and finished goods; customer complaints; calibration of equipment; level of personnel training; equipment maintenance; and housekeeping and pest control.

Documentation. The supplier should fully document its process and quality system. At the quality levels appropriate for certification, all changes must be controlled. This is done to ensure that processes are accurately understood.

For a quality assurance system to be effective, it is essential that the product specifications and testing methods mentioned in this article be understood and agreed upon by supplier and customer. The supplier must be able and willing to furnish timely copies of certificates of analysis, inspection data, and test results.

The certification requirements for approved commodities will eventually result in certified suppliers that are subjected to little or no incoming testing before their packaging components are put into approved stock. It is imperative that the process that produces the commodity be nearly incapable of defect.

Justification. Only after all of these requirements are met should a supplier be certified. Even then, suppliers must still justify each component. There should never be blanket approvals.

In addition to improved product quality, numerous benefits result from a component certification program. The reduction in inventory for both supplier and customer results in cost savings and greater warehouse efficiencies. Certifications create fewer handling costs and free up critical time. They also help IVD manufacturers develop long-term business relationships and an enhanced ability to tackle problems as they arise.

Conclusion

Diagnostics manufacturers should never forget that IVD end-users are also suppliers. All the characteristics that manufacturers look for in a quality packaging component supplier are also valued by patients.

The successful design and development of a package has always required a team approach. While reviewing the following directory, remember the need for continuous quality, for suppliers with a partnership approach, and for a design team that always strives to produce the highest-quality products.

1. Cables, connectors, shielding suppliers offer components that are approved under various U.S. and international standards.

2. Fluid-handling components suppliers specialize in fluidic systems, including low-level pumps to fill pipettors, and the integration of these components.

3. Input devices include the components with which the user interacts, including touch screens, keyboards, and bar code wands and scanners.

4. Motors, motion controls include dc and stepper motors, as well as the control systems for such motors. This is an area of rapid growth for industry suppliers because of the increasing demand for automated clinical laboratory systems.

5. Optics and machine vision systems are used for bar code scanning and recognition of specific shapes (such as tubes). This subcategory includes the electronics and software to control such devices.

6. Output devices include printers, monitors, special communications software, and devices for communication via HL7 or ASTM E1381 and E1394.

7. Power supplies, transformers include power systems that conform to Underwriters Laboratories and international standards for use in a medical environment.

8. Printed circuit boards vendors can fabricate boards for manufacturers and populate the boards with electronic components such as chips and transistors.

9. Sensors, transducers suppliers offer a wide range of sensors for detecting such variables as part position or motion; and liquid presence, pressure, or flow. If it moves, or if you want to enable or disable it, look here.

10. Software for product design includes CAD/CAM and other software tools used to create or prototype a product.

11. Software for instrumentation includes the software building blocks for an IVD system, particularly control and data processing software.

12. Temperature-control components include heaters, temperature sensors (see also subcategory 9), and electronic temperature-control modules that implement proportional integral derivative control loops.

The PSD/4 syringe pump by Hamilton Co. (Reno, NV)

A company approaching the development of an IVD instrument should make sure that supply-chain management is actively undertaken from early in the process. Marketing managers often point out to the engineering staff that time to market is critical to success. Because of that, a sound supply-chain management plan is vital to ensuring that a device can be introduced with no significant loss of time.

Supply-chain management at any company occupies a link between the engineers designing a new system and the vendors of the sourced components. Managers will find that a close working relationship with both vendors and the engineering staff optimizes supply-chain processes and pays great dividends during the transition from development to manufacturing. Organizations are constantly looking to improve margins through lean-flow manufacturing, kanban management, and product synchronization, not to mention the selection of cost-effective components. These techniques often involve maintaining good vendor relationships.

The engineer's perspective is different, and involves a different challenge. The technologies associated with microfluidics, DNA/RNA, microarrays, and the POC device drive critical part selection during the product design stage. Component selection and the system integration associated with that component are the engineer's chief concerns.

System integration involves all engineering disciplines, including the validation and verification effort and the manufacturing process. All too often, designers lose sight of these two project areas. More important, V&V and manufacturing are not even acknowledged in early discussions with vendors during establishment of the supply-chain management plan.

Technology Trends

The IVD market has seen many changes over the years. Twenty years ago, there was little discussion about DNA's use in an IVD. Today that is not the case, and its application is expanding.

Significant development efforts are under way in this area, involving FISH, cytology, various forms of mass spectroscopy, and microarrays. The microarray technology has even captured the eye of FDA, which published a special controls guidance document for instrumentation for clinical multiplex test systems in March 2005. This technology is largely focused on the biotechnology and drug-discovery markets, but there is a strong underlying motivation to bring these technologies to the IVD marketplace as quickly as possible, and as a result FDA has created this guidance document.

Another area of heightened activity in the IVD market, although somewhat underreported, is associated with homeland security and bioterrorism. Significant government funding has occurred in the past years to support this effort. The technologies involved here are now beyond the concept phase and well into demonstrating their viability. Companies working on these technologies use all of the scientific techniques named above, and more, in developing systems hoped to be able to identify biological agents quickly, with great sensitivity and specificity. In the coming year it is expected that some of these systems will begin field evaluation. It has been said what NASA did for the semiconductor industry, biodefense will do for the diagnostics market.

The upshot of these trends is that “smaller, faster, cheaper” and “multiplex testing” are themes that will be prominent in the future. Integration of mechanical, electronic, and software components in creating devices to address the coming technology challenges is crucial. Microarrays will require finer-resolution mechanical systems and optics, as will FISH and cytology. Additional technology is under development to reduce not only the size of IVD systems, but also the complexity and cost, for both system and reagent. All of these technologies militate toward a microfluidics-based technology to reduce cost and system complexity.

The Integration Challenge

Most instrument development projects begin with the establishment of the general system architecture. Here, the engineering staff divides the system into subsystems that address specific areas of functionality. During this process, the system engineer considers what general hardware, software, optics, and electronics can address a particular need. Additional considerations include serviceability once the system reaches production. This architectural process is very fluid and dynamic. When the general structural plan has been settled, the engineers begin to look at alternative hardware solutions and to balance their pros and cons.

Orders of components used in forward-looking diagnostic instrumentation increasingly are placed with vendors who are able to customize their offerings. Customization requires frequent and timely communications between manufacturers and vendors. The challenge for the instrument developer is to select the component that minimizes the integration demand.

There are trade-offs that need to be considered. For example, when implementing a stepper motor driver, a motor controller could either be purchased from a different company and integrated, or be developed internally. Alternatively, a stepper motor with a built-in motor controller could be purchased in order to reduce project risk and accelerate the schedule. However, this would entail costs 15–50% higher. In another case, developers might identify an input/output (I/O) board or PLC that includes features similar to those needed for the instrument and compare this option with designing a custom I/O board to interface with peripheral devices within the instrument. The cost of the former option may be higher because the board has features not required for the application and the margin to the organization supplying the board. The lower-cost latter option will require more development time but provide a more custom and application-specific solution. In considering choices like these, sales projections for the instrument should be measured against the costs of in-house development versus purchasing off the shelf.

As mentioned, microfluidics technology is now central to many diagnostic instruments as the industry matures and miniaturizes. The capability of an instrument to move fluid in nanoliter volumes grows increasingly desirable. Subsequently, focus is directed toward pumps, improved precision and accuracy, and more-sensitive liquid-level-sensing circuitry. The technology for dispensing microliter to nanoliter volumes requires different components than the traditional syringe and stepper motor. The demands on motor controllers and encoders are much greater.

The integration challenge here is the mix of technology—the right hardware and the right electronics with the right software—that will ensure that project requirements are fulfilled in a timely manner for all involved, including the validation and verification team.

Incorporating Other Technologies

A fully functional system including transport mechanisms for samples and cuvettes, temperature regulation for assay reactions, reagent cooling, and, depending on the technology involved, even thermal control to 80°–95°C. Many other subsystems besides microfluidics require some form of active temperature control. Improvements in flex circuitry and thick-film technology have provided advances in this area in recent years—advances that address both price points and the design of the heaters, coolers, and temperature-monitoring technology employed in applications like thermal cyclers for DNA and RNA.

The Quadrus Mini imager (left) by Microscan Systems Inc. (Renton, WA) offers true autofocus capabilities. The MS-4 imager (right) by Microscan Systems was designed specifically for embedded bar code and 2D symbol applications.

Industry miniaturization efforts have been accompanied by a need for greater motion control precision in applications like microarrays and FISH. Thus, encoders with nanometer resolution are now part of many systems, especially those that require imaging in pixels as small as 0.1–50 µm. The introduction of such encoders has increased processing demands and information management overhead, which require more processing power at the controller level. Whenever there is significant motion control involving an encoder with nanometer precision, the best solution may be, from the standpoint of cost and development schedule, to purchase a dedicated controller as one of the system components.

Not to be overlooked are larger subsystems that integrate components into subassemblies. Examples of these are fluidic pipettors, microtiter plate stackers, and electro-optical imaging subassemblies. Again, the balance between cost and schedule should be considered. While these larger subassembly components are costly to purchase, the alternative, an in-house development effort, also requires a substantive investment. It may be less expensive to purchase the component and integrate it than to design, refine, validate, document, and produce a large subassembly internally. The deciding factor will probably be the anticipated instrument production volume.

System Control. The evaluation of controllers should be performed with care to ensure that the processing power and interface options necessary to support the project are all present. Without proper planning, such evaluation may not be sufficient, which could lead to significant delays in the project schedule if problems should arise. It is once again important to take a system view to ensure that all disciplines are supported, including testing and manufacturing. Today's embedded micro markets provide for full-featured processors with built in digital I/O, A/D, D/A, and memory, all for < $10 in large quantities. Suppliers provide the development tools at no or low cost to accelerate development. When implementing the design, test points can very easily be included on a circuit board if the need is considered in the design phase. The time involved in adding them later and returning the board through the fabrication process during the manufacturing stage can hold up the schedule by weeks. Such test points also facilitate the software development effort when used in conjunction with the rich feature set that the development tools provide.

A similar line of thinking should apply in dealing with component vendors. A vendor is not going to rework its production line to accommodate a manufacturer without foresight. Ensuring at an early project stage that the electrical components have the necessary test points can save a lot of time, preserve good relations with the vendor, and result in a successful product launch on schedule.

The Right Integration Mix. The cost of development, the cost of production, and time to market are considerations always in tension and in balance. Similarly, design and development is an iterative process, involving periodic reference to time to market, system production cost, a possibly shifting sales forecast, the dedication of effort to system integration, and the availability of mechanical, electronic, and software components that suit the system architecture.

With every component selection, the entire IVD system and its development project should be taken into account. A component that may be the best choice from an electromechanical standpoint could cost months in software development. It is of little value to select a processor that has a 6-month lead time. Every instrument development effort is different, but each involves a mix of electronic, mechanical, and software elements. The challenge is to find the mix best suited to the system design that will demand the least complicated and laborious integration effort during the design phase, prototype verification, and transfer of the design to manufacturing.

While the architecture of the system may make writing custom software seem highly desirable, customization may necessitate substantial validation and verification. Off-the-shelf software also requires validation and verification when it is integrated into a product, but the likelihood of bugs should be significantly lower as long as the product is fully developed and reputable. Not to be overlooked, consideration should also be given to the regulatory submission process. Systems that include software require more validation and backup data for PMA or 510(k) submissions. IVD manufacturers should ensure the regulatory pathway is not a significant gating item due to design decisions that should be taken.

As the design effort iterates, the selection of components will change. A component that had been eliminated as a candidate may come back into favor. Here is an area where regular communication with knowledgeable vendors can enhance the development effort.

NMP miniature air and gas diaphragm pumps by KNF Neuberger Inc. (Trenton, NJ) have 316 stainless or aluminum heads to provide threaded ports.

User Interface. From the operator's perspective, the IVD system is often a product developed on top of a Microsoft Windows–based platform. In addition to the typical Microsoft tools for development such as Visual Studio, numerous libraries exist to support all aspects of the development process. These include cross-platform development tools, medical connectivity tools for HL7, libraries for specific I/O boards, and dynamic link libraries for bar code readers. In recent years, there has been increased utilization of Linux in IVD systems. There are a growing number of libraries and development environments that support this platform. While the platforms should meet the product requirements, it may provide a very cost-effective solution.

Bar code readers today are generally of the 1-D or 2-D type. The 2-D reader is gaining in popularity because it can store significantly more information. Unfortunately, information cannot be written back to a bar code. Alternatives involve radio-frequency identification (RFID), which allows writing back to the disposable identifier. The volume of information that can be stored ranges from bytes to kilobytes, significantly more than a bar code holds. Such a feature provides great flexibility, but with a price penalty—one that may be worth paying, depending on the application.

Bar code readers and RFID readers have a similar look and feel. The read range of RFID technology is typically a bit longer. RFID readers are often significantly less expensive as well. Such technology is not the best solution for all applications, but may answer a specific need.

Working with Vendors

Time to market can be vital to a project's success. Certainly, delays in delivery of any component do not help. The component selection process calls for attention to more than just the technical features and capabilities of a subsystem; it is also important to ascertain vendors' logistical capabilities to supply prototype and production components when and in the quantities needed. Paying visits to key vendors to get a first-hand view of their operations is well worth the up-front cost. Ultimately, the regulatory process requires some form of vendor qualification. But knowing the vendors' capabilities during development may save significant time and cost down the road. Also important is knowing the vendor's track record of on-time delivery. That history may not need to be exemplary to ensure that the vendor-customer relationship is successful. Knowledge and communication and the best component are the cornerstones of a good relationship; a spotty delivery schedule may be something for which the IVD manufacturer can plan accordingly. Asking the vendor for on-time delivery history, out-of-box failures, shipment linearity, and other similar metrics is a key indicator of the commitment that a supplier is making to ensure customer satisfaction. They demonstrate a vendor's desire to track key indicators of customer satisfaction and not simply revenue generated.

Keeping current with technology is a major challenge for every company. Many organizations focus on a core technology and outsource that which they see as not central to their business. For example, a company whose core technology is microarrays, FISH, or biochips may find instrument design to be beyond its core competency. To fully comprehend the disciplines of instrument design, development, QSR compliance, lean-flow manufacturing, microfluidics manufacturing, flex-circuit assembly, ESD compliance, CE marking, and industrial design—let alone maintaining a balance among their demands and requirements—can be too much for many companies to expect of themselves. Since managing all these resources is at times overwhelming, outsourcing enterprises that perform these services as their primary business can be a great help to an IVD manufacturer. (See the introduction to Section 8, “Contract Manufacturing,” for a discussion of these organizations.)

Both contract engineering firms and IVD manufacturers with their own engineering resources should find this year's IVD Technology buyers guide of great assistance in selecting components for their systems. Both supply chain managers and engineers can identify and distinguish key vendors in relevant technology areas. The guide is intended to save them time in their search for essential IVD system components, and to make it easier for them to locate the right vendors.