Project Description

Strategies for Outsourcing Contract Services for Assays

Commercialization of new diagnostic tests often requires a contract manufacturer that can fill in the gaps in development as well as regulatory assistance

By Taryn Reynolds, Corgenix Inc.

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, hiring and retaining highly trained personnel as well as implementing high-end Quality Management Systems. In addition, FDA, ISO, GMP and other certifications may be required.

Because smaller companies 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 510K approvals, but decide instead to keep 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 opportunities in contract manufacturing 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 proven in an R&D lab but 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. IT to lateral flow), identifying alternative reagents/antibodies and changing the coatings applied to microtiter wells.

In addition, regulatory assistance is also a factor in most contract manufacturing situations. This includes receiving advice and guidance on how to meet the regulatory requirements of the FDA, but also 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.

Some of these 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 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 include ISO certification and a facility that is GMP and FDA-approved. In addition, he prefers to work with contract manufacturers with experience producing similar tests and formats.

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 for devoted to IVD diagnostic test-related activities along with laboratory and a controlled environment production area. Ideally, the contract manufacturer is capable of preparing and producing materials in both a manual and automated production format, to accommodate the size and complexity of the product.

The production area often houses 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 include component and raw material testing and qualification, general reagent formulation and preparation, assay and component production, final product assembly and final product testing.

Leading contract manufacturers can even 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 an advanced security system with access control, video monitoring and even critical condition monitoring for equipment to ensure redundant back-up 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.

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 510K clearance from the FDA and did initial work with a Netherlands based developer of IVD immunoassays.

In 2009 the company engaged with 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 QC processes.

Although the assay was already developed, not all 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 its 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 also responds 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 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

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 the U.S. Food and Drug Administration (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.