When new assays or diagnostic tests are ready for commercialization, there can be tremendous hurdles to overcome, including significant investment in the infrastructure for automated manufacturing and test equipment and hiring and retaining highly trained personnel, as well as implementing high-end quality management systems. In addition, FDA, ISO, GMP, and other approvals or certifications may be required. This article examines the requirements for manufacturing these complex diagnostics as well as the critical factors to consider when selecting a manufacturer.

Infrastructure Requirements

Because smaller companies often do not have the existing infrastructure, funds, or desire to enter into assay manufacturing, many instead choose to outsource this critical function. Even large pharmaceutical companies sometimes choose to outsource manufacturing of smaller product lines that represent only a small part of the overall gross income.

The simplest of these arrangements involve outsourcing the manufacturing of an existing, established test that is already being manufactured. In many cases, this can occur when a company wants to downsize or shutter manufacturing operations altogether due to cost overruns.

Still others have invested in developing the test and acquiring the required PMA or 510(k) approvals but decide instead to keep their focus on development of the next new test instead of entering the world of manufacturing. In this way, they can remain a lean organization with a limited staff and avoid large capital expenses.

However, the reality is that most diagnostics do not fit neatly into a box. Instead, many assays arrive as “not-ready-for-prime-time” products that may not be fully developed, are still in the concept phase, or are proven in an R&D lab but are not viable for scaled-up production.

When this occurs, contract manufacturers are often called on to provide assay development assistance. This can take many forms, including making changes to format (i.e., from IT to lateral flow), identifying alternative reagents/antibodies, and changing the coatings applied to microtiter wells.

Regulatory, Quality, and More

In addition, regulatory assistance is also a factor in most contract manufacturing situations. This includes not only receiving advice and guidance on how to meet the regulatory requirements of the FDA, but also on how to achieve the required registrations required in other countries such as CE markings, Health Canada, and others. Therefore, finding a qualified contract manufacturer that can also provide development and regulatory assistance is often a critical, even strategic, decision.

Large pharmaceutical companies often choose to outsource manufacturing of smaller product lines.

“Some of the new assays coming out of these labs are great products that are going to change the world, but the scientists that develop them have little understanding or background on the regulatory side, the quality side, or how to manufacture it on a large scale,” says Stephen Hall, CFO of BG Medicine.

In addition to having worked for a contract manufacturer earlier in his career, Hall now works for BG Medicine, a company that licenses the Galectin-3® test. The in vitro diagnostic (IVD) device quantitatively measures galectin-3 in serum or plasma by enzyme linked immunosorbent assay (ELISA) on a microtiter plate platform. The results of the test are used to aid in identifying patients with chronic heart failure that are clinically stable but at a higher risk of hospitalization and mortality.

Hall says that when evaluating a contract manufacturer, he has a list of requirements that includes ISO certification and a facility that is CGMP and FDA certified. In addition, he prefers to work with contract manufacturers with experience producing tests and formats similar to the one he is developing. Ideally, the company would also have all of the necessary instrumentation in house to conduct any steps of the manufacturing process.

To do this, facilities often require space devoted to IVD test-related activities along with a laboratory and a controlled environment production area. Ideally, the contract manufacturer is capable of preparing and producing materials in both a manual and automated formats to accommodate the size and complexity of the product.

The production area should house state-of-the-art technologies, including fully automated filling and packaging lines along with large-lot lyophilization capabilities. Other projects performed in the production area might include component and raw material testing and qualification, general reagent formulation and preparation, assay and component production, final product assembly, and final product testing.

Turnkey contract manufacturers often offer fulfillment and distribution services for completed test kits. This can include warehousing of products in a continuously monitored, controlled, refrigerated storage area; order processing; domestic and international shipping; documentation assistance for shipping to new international destinations; coordination with freight-forwarders to optimize shipping costs; transportation stress testing; and shipping according to specific temperature specifications: blue ice, frozen, or room temperature.

Finally, physical security is also a concern. Contract manufacturing facilities must ensure the protection of all fixed assets and production areas with advanced security systems that include access control, video monitoring, and even critical condition monitoring for equipment to ensure redundant backup in the event of a primary system malfunction. Data security with redundant replication is also important to ensure maximum data protection for software and critical data.

Case Study

In May 2007, Hall says BG Medicine entered into a biomarker product license and collaboration agreement with ACS Biomarker B.V. (Netherlands). After licensing the intellectual property, the company decided to pursue 510(k) clearance from the FDA and did initial work with a Netherlands-based developer of IVD immunoassays. In 2009, the company engaged a contract manufacturer to assist in final development and commercialization of the test kit.

“When you don't know if you have the volume to justify producing the test yourself, it just makes sense for a small company to use a contract manufacturer,” says Hall.

According to Hall, the first step in working with the contract manufacturer involved a technology transfer, followed by optimizations and validations to determine compatibility with their manufacturing equipment and quality control (QC) processes.

Although the assay was already developed, not all of the test methods for manufacturing purposes had been developed. The contract manufacturer had to develop the processes and the validations to create the gold standard tests to complete the assay's in-process QC.

In addition, some of the raw materials required validation to ensure availability and real-time stability to scale up for manufacturing. Because the assay was developed in the Netherlands, new sources for critical raw materials in the United States were also required.

Again, stepping beyond its role as a manufacturer only, the company would then also respond to customer service inquiries as needed, along with providing fulfillment and distribution services, including storing inventory, order processing, and shipping to end users.

To manage inventory in a just-in-time fashion, Hall says there needs to be constant communication with the manufacturer to ensure that production remains in line with variations in demand.

“When you are a small company, you have limited resources and so you can't spend a lot of working capital on inventory,” explains Hall. “So, you need to proactively know where you are at with lead times from all the suppliers to ensure there is never an issue.”

Halls say that every Galectin-3 test kit to date has been produced by the contract manufacturer. In addition to selling the kit, BG Medicine also earns pass-through royalties through sublicenses with automated partners that run the tests on their respective platforms.

”[Our contract manufacturer] put together a quality kit for us,” says Hall. “It performs well; it is a consistent product, and there is reproducibility of the results.”

Companion Diagnostics

When outsourcing, be sure that the contract manufacturer has all of the equipment and capabilities in house to avoid having to ship items around.

Today, services organizations with a wide range of capabilities including contract manufacturing are interfacing directly with pharmaceutical companies to develop and get regulatory approval of companion diagnostic tests.

Companion diagnostic tests are co-developed with drugs to aid in selecting or excluding patient groups for treatment with that particular drug on the basis of their biological characteristics. These tests are based on companion biomarkers that help predict the likely response or severe toxicity within a subset of a population.

Companion diagnostics are required as part of the PMA process by FDA in the United States for the “safe and effective use” of a corresponding drug or biological product.

While most were initially focused on oncology, companion diagnostics are now expanding in use for other disease areas, including autoimmune, neurologic, and cardiovascular. A subset of this group, complementary diagnostics, is also growing. Complementary diagnostics are used to aid in the benefit-risk decision without restricting drug access.

Although many of the largest pharmaceutical companies have internal diagnostic capabilities, many still look to partner with an established service organization to complete the PMA requirements related to the test. Smaller companies without the in-house capabilities almost always prefer to outsource this aspect.

Within this area, the requirements go well beyond contract manufacturing and can include product development, regulatory management, clinical trial support, private labeling, warehousing, fulfillment, post-approval commercialization, and life cycle management.


The commercialization of new assays or diagnostic tests can be daunting. It can require investment in automated manufacturing and test equipment, personnel, and quality management systems. Regulatory requirements, quality systems, and many other factors must be considered. For small companies with limited resources or established diagnostics manufacturers that want to remain lean or focus on the next-gen product, outsourcing is a great option but one that must be done strategically.

This article was written by Taryn Reynolds, Vice President, Operations and Technology, Corgenix Inc., Broomfield, CO. For more information, visit here .