By Steven Richter, Ph.D., President Microtest, Inc.

By any measure, the combination products market – is booming. Navigant Consulting estimated the market at $5.9 billion in 2004 and predicted a 10 percent compound annual growth rate that will have it reach approximately $9.5 billion in 2009.

According to one survey, an estimated 30% of new products under development are “combo products” – involving medical devices embedded with a pharmaceutical or biologics component. But for manufacturers, along with exciting new opportunities, the convergence of drugs and devices also brings a host of challenges. One – underway now in the laboratories of both pharmaceutical and medical device manufacturers – focuses on their struggle to address a host of testing guidelines, practices, and regulations unique to the development and production of combo products.
Defining the Convergence
A pharmaceutical article recognized in the official USP or NF or any supplement are intended to diagnose, cure, or for the mitigation, treatment or prevention of disease in man or other animals and intended to affect structure or any function of the body of man or other animals and intended to be used as a component of any articles specified above but does not include devices. A device means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent of other similar article which is recognized in the USP/NF, intended for use in the diagnosis of disease or other conditions or in the cure , mitigation, treatment, or prevention of disease in man or other animals or intended to affect the structure of any function of the body of man or other animals. A combination product has both the drug component and medical device component.

An example of a combo product is the drug coated stent used for coronary angioplasty (Boston Scientific or Johnson and Johnson). In this case, there are actually two medical device components. One is the balloon delivery system which creates the pressure to push the plaque in coronary arteries out to the edges (intimal lining) in order to increase blood flow. There’s also the stent, or a wire mesh tube, that’s designed to keep that plaque from collapsing back into the artery. Impregnated in that stent is the drug component or pharmaceutical that’s designed to inhibit plaque formation (prevention and treatment).

There have been many devices for drug delivery or implantation and there have always been drugs to treat certain disease states. Interest in combo products is surging among both medical device and pharmaceutical manufacturers as the industry – and the medical community mature. There’s a growing realization among both of the therapeutic benefits of putting a drug into a medical device and providing it as a combination unit – and using the resulting product to deliver drugs directly to certain areas of the body versus the creating havoc with a toxicity and systemic effect. The results of treating specific areas of the disease instead of the entire body can be dramatic.

Most of the pharmaceutical companies, for example, are evaluating the potential of single dose types of devices – the syringe dosing market where a physician can grab a pre-filled unit dose syringe and use it – rather than having to load it themselves. The loading may cause bacteria to enter and contaminate the patient.

The advantages of this combo product are several. They include safety or quality in terms of controlling the dosage – which might otherwise vary if loaded individually by physicians. There’s more peace of mind for the patients who will see that they’re getting a self-contained sterile dose rather than something taken or mixed from a larger supply. There’s an added efficiency for the physician and hospital in terms of labor, dispensing, inventory control, and billing. There’s a corresponding element of economics. With these benefits, the pharmaceutical companies are eagerly opening a new market.
The Dichotomies in Testing
One challenge facing manufacturers – at least in their labs – are the dichotomies that exist when it comes to drug/device combination testing.

As expected, depending on whether the company is a pharmaceutical manufacturer or a medical device manufacturer, their in-house laboratories are equipped, skilled and experienced in their own specialty – either pharmaceutical sciences or medical device sciences – but not both. Previously, there was no such need. Combo products are changing the laboratory requirements

While many pharmaceutical companies have their own laboratories, they don’t have the skilled personnel knowledgeable in medical device testing and succeeding such a device through the FDA maze of regulatory issues. On the medical device side, testing in-house is an issue because device manufacturers generally lack the QSR’s systems to handle a combo product’s pharmaceutical aspects.

The challenges may begin with the classification of the proposed new combo product in terms of regulatory standards – whether it’s a device, a drug or a biologic. Which regulatory agency will be the shareholder of the regulations governing the product? Although certain guidance documents are available, there is no general guidance document containing all the pertinent information. While the FDA’s Office of Combination Products ( is available for information regarding the governing Center, the manufacturer is required to follow both the QSR’s and cGMP for both manufacture and testing schemes.

Moreover, the devil – in the form of various learning curves as well as physical and process challenges – dwell in the specifics.

Many pharmaceutical companies, for instance, will strain their capabilities when testing combo products like coated devices simply because their facilities are not designed to handle such intrusive products. Pharmaceutical labs specialize in testing fluids in small volumes and in closed containers. Some of the sterilization programs that are unique to a physical device will be very foreign to their scientists. They will also face new validation challenges.

The evolving technology itself is another hurdle. Advancements in combo product technology are happening so quickly that in-house lab personnel – who are already responsible for keeping current with the development, testing, validation, and manufacturing practices and governing regulations in their core manufacturing area –will unlikely be able to assimilate the added burden of managing all the same aspects in regards to combo products.

As manufacturers increase their production – or add new products to their mix – of combo products, their labs will need to manage the increased volume and turnaround pressures that will result. The demand for the availability of equipment and facilities will increase, as will the need for additional skilled lab personnel. At some point, dedicated personnel – with a specific knowledge base in combo devices – will be required. Not only is the testing of combo products is more labor intensive than pharmaceutical testing, it’s more complex. They’ll need to have the expertise not only to do the job right, but to do it the most efficiently.

There’s also the issue of cost. In-house testing is not inexpensive. The dollar cost per person in a testing lab is hundreds of dollars per hour. Given the added training, time, and resources needed for combo product testing, one can see that the incremental costs involved easily climb quite rapidly.

Balancing these challenges is easier said than done, however, for a host of reasons. Thus, despite the growing popularity of combination products, the convergence of the required resources, skill sets, and practices at in-house labs to handle combo products has to date been slow. Instead, the solution for many pharmaceutical and medical device manufacturers has been to outsource the testing and validation needs of combination products.
Outsourcing the Solution
The process of selecting an appropriate outsourcing laboratory testing partner appropriate for combination product work is both critical and complex. Questions should include:     
• Does the partner have the experience and the track record to demonstrate their expertise – not just with drugs or medical devices, but with combination products? Will they not only do it right, but do it smart?     
• What is their capacity, equipment, personnel?     
• Do they have the validated procedures? Best Practices?     
• What is their expertise with regulatory benchmarks and requirements? What comprises their technology platform – cGMP, GLP, QSR, ISO, CMC?     
• Does the lab offer dedicated, onsite project management – rather than relying on outside consultants – to manage the project?     
• Can they perform within the required timeline? Stability?     
• Will they be cost effective?     
• Will the lab – can the lab – assist with managing the process from testing through regulatory approval?     
• How comprehensive is the partner’s own laboratory services to handle what’s needed – without sending it out elsewhere? Additional levels of outsourcing introduce all sorts of possible shipping, loss, damage, control and communications issues.

As an added value-add: Does the lab have manufacturing capabilities? If so, that’s a unique advantage. Another is having “real world” expertise from both sides of the coin as a testing lab and a contract manufacturer would provide an entirely new dimension of knowledge and capabilities to the partnership. Such capabilities also provide an additional manufacturing resource once approval is secured.
Future Considerations
When it comes to testing combination products, laboratories – be they in-house or contract labs – will have to prove themselves in their abilities to manage a regulated drug product and follow CMC controls. While none currently exist, the FDA will issue guidelines specific to combination products and the result will be increased cGMP regulatory action – affecting both laboratory and manufacturing. The future clearly lies with combination products. It will be the major way that the medical community will treat disease in the future. As the market continues to grow, there will be corresponding increases in pressures on laboratories to provide the needed research, development, production, and validation support. And when it comes to testing, the challenge for all of us will be to stay ahead of that curve.

About the Author: Steven Richter, Ph.D. is President, Scientific Director, and founder of Microtest, Inc. where he continues to expand the laboratory, testing facility, and manufacturing facility and is the technical expert in the Sterilization. Dr. Richter has more than 25 years experience at all levels of microbiology and medical devices. He has also worked at the FDA in the Boston District Laboratory Contact Dr. Richter at or 1-413-786-1680