Combination Products: Navigating Two FDA Quality Systems

June 11, 2007
Interest in these products is surging, but unique regulatory issues make them challenging.

Editor’s Note: This is the first in a series of articles that will address the subject of combination drug-devices from various perspectives. A second article will appear in July/August’s issue.

The combination products market is moving forward with a new direction and emphasis regarding product safety and FDA requirements. Navigant Consulting estimated the market at $5.9 billion in 2004 and predicted a 10% compound annual growth rate that will see the market reach approximately $9.5 billion in 2009. FDA received 275 combination product submissions in 2005. According to one survey, an estimated 30% of new products under development are “combo products.”

Along with these exciting new opportunities, the convergence of drugs/biologics and devices also brings a host of regulatory challenges for manufacturers. Both pharmaceutical and medical device manufacturers are struggling to address  a host of testing guidelines, practices and regulations unique to the development and production of combination products. In addition, FDA regulatory centers are laboring with the changes and challenges that these new technologies present.

A device is defined as: an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or 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 or intended to affect the structure of any function of the body of man or other animals.

A combination product has a drug/biologic component and a medical device component. An example of this type of product is the drug-coated stent used for coronary angioplasty (Boston Scientific, Abbott or Johnson & Johnson).

Interest in combination products is surging among both medical device and pharmaceutical manufacturers as both the industry and the medical community mature. There is a growing realization of the therapeutic benefits of putting a drug into a medical device, providing it as a combination unit, and using that unit to deliver medication directly to a certain area of the body. Treating specific areas instead of the entire body can dramatically reduce the toxicity and systemic effects of treatment.

Combination products offer additional advantages. These include safety or quality in terms of dosage control. Patients feel safer as they can see they are getting a self-contained, sterile dose rather than something taken or mixed from a larger supply. There are added efficiencies for the physician and hospital in terms of labor, dispensing, inventory control and billing. Finally, there is an economic advantage.

FDA Responsibility

The FDA’s Office of Combination Products (OCP) determines the primary mode of action (PMOA) for the product. Generally, if the device is for drug delivery, then the Center for Drug Evaluation and Research (CDER) will be the governing center. If the device is used to open vessels, but has a drug coating to impart some secondary preventive action, then it is governed by the Center for Devices and Radiological Health (CDRH). The Center for Biological Evaluation and Research (CBER) is involved with a device component/biologic that is also some sort of drug delivery system, such as implantable encapsulated tissue constructs. All have a responsibility to determine, scientifically, whether the manufacturer has proven beyond a doubt that the product is safe and efficacious.

Mike Treadway from The Tech Group, a division of West Pharmaceuticals, Scottsdale, Ariz., addressed the challenges of combination products in a recent report. Treadway noted that one of the biggest hurdles is making sure that all the quality systems are in place and compliant with regulatory requirements. The Tech Group is manufacturing the insulin multi-dose inhaler, Exubera, for Pfizer.

The dichotomy between drug GMPs (21 CFR 210/211), Biologics Product Standards (21 CFR 610) and medical device QSRs (21 CFR 820) is immutable. A combination product manufacturer must have a robust pharmaceutical GMP system in place that addresses some QSR issues. However, the main regulatory foundation must be the drug GMPs. These regulations cover batch records, QC drug-release criteria and biologics.

Manufacturers also may be required to comply with foreign compendia methodology when harmonization has not been successful. The EU requires a certification by a qualified person prior to clinical trial material (CTM) studies in the European Community.

Medical device regulations are concerned with design review and ISO documentation that may not be part of a drug’s GMP program. ISO certification may be required for shipment into the EU. The documentation short list includes: Design Review, Quality Systems Requirements, ISO 13485 Requirements and ISO 9000 Requirements.

Drug regulations are shifting focus from product to process, according to the Process Analytical Technologies (PAT) approach taken by CDER/CBER. The PAT approach is to test drug/biologics products online in real time, and effectively determine the acceptability of the lot prior to release testing. Thus a process that is inherently out of specification is stopped.

The value in drug manufacturing depends in part on the ability to validate a process and demonstrate its robustness and reproducibility over time. The PAT initiatives emphasizing Quality by Design (QbD) and Design of Experiments (DoE) strategies are associated with FDA requirements. These technologies will be the driving forces for validating critical process controls used in the manufacture of drug/biologic products.

The combo product manufacturer’s largest challenge will be during the scale-up process, because additional quality control (QC) measures are required to determine the process scale-up parameter shift. During scale-up, combination products should be under additional QC pressures along with a robust release testing program. New technologies will require operations that are proven within acceptable ranges based on process scale-up and manufacturing limitation regarding device technology and delivery.

Risk analysis tools and failure mode and effect analysis (FMEA) methods are required during scale-up and validation. These tools help establish critical risk factors that could create safety and quality issues during manufacturing. They can be an integral part of a PAT program whereby the decision to reject or salvage a valuable raw material can be made in real time.

Combination biologic products create new dichotomies in terms of scale-up and marriage downstream during manufacturing. Scale-down processes are needed to determine if critical attributes are measured during the DoE phases of a robust quality attribute program.

Cell-based therapeutics create unusual challenges for combination product manufacturers and FDA. Characterization of biological source material is a critical requirement for safety considerations. This is due to the inherent variability in the source material.

Sterilization of combination products can be problematic, due to drug/biologic and sterilant incompatibilities. Radiation and ethylene oxide sterilization cycles may degrade drug/biologic characterization and potency. Impurities may actually increase due to these harsh process parameters. Aseptic processing, for instance, coating drug products, can be used as an alternative to final product sterilization through radiation or ethylene oxide gas. A dry-heat sterilization process can be an option for most small-molecule combination products.

Future Considerations

When it comes to developing robust analytic systems for combination products, the device manufacturer’s knowledge base will be challenged in its ability 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 that affects both laboratory and manufacturing.

We expect this guideline will incorporate both PAT and DoE requirements for small- and large-molecule process design and scale-up. The medical device component and molecular interactions regarding delivery or disease integration will be more important as biologics enter.


1. Code of Federal Regulations, Food and Drug Administration Title 21 sections 610, 820, 210 & 211.

2. “Bioprocessing: Regulatory Shifts from Product to Process,” Feb. 15, 2007, Genetic Engineering News.

3. Stuart Portnoy and Steven Koepke, “Regulatory Strategy: Pre-clinical Testing of Combination Products,” MDDI, May 2005.

About the Author

Steven Richter, Ph.D., is president and chief scientific officer of Microtest Laboratories, Inc. He founded Microtest in 1984 after a career at the FDA.

About the Author

Steven Richter | Ph.D.