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 (www.fda.gov/oc/combination) 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 srichter@microtestlabs.com or 1-413-786-1680
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