The pharmaceutical and biotech industries have not only made significant progress in coming to terms with the nuances of FDA’s risk-based approach to cGMPs and the International Committee on Harmonization (ICH) Q8 product development guidance, but have made great strides in identifying a path forward within the product development and quality infrastructure.
Over the last 10 years, however, a new market segment has made conforming to these guidelines more challenging than ever: drug delivery systems developed for new and innovative therapies. Drug delivery or combination products range from the relatively simple, such as pre-filled syringes or injector pens, to highly complex systems, such as self-regulating insulin pumps and drug-eluting cardiac stents.
Establishing success metrics for drug delivery applications requires leveraging the best in device technology while ensuring maximal therapeutic performance.
It’s not easy. When Johnson & Johnson launched the first drug-eluting stent, industry and FDA were hard-pressed to find a model that balanced business and public-safety requirements. Still, the allure of these products is undeniable. Low-cost delivery systems as vehicles for novel or enhanced therapeutic efficacy provide the perfect “razor/razor blade” model of which venture capitalists dream and the pharmaceutical industry rarely glimpses.
Can the pharmaceutical industry as a whole benefit from the lessons learned in this market segment? From a purely regulatory perspective, developing a drug delivery system has the potential to be a minefield. Depending on the product, there is likely to be combined oversight from CDRH and CDER or CBER, potentially bringing together three specialized perspectives regarding development philosophies. With so much “help”, the potential for misstep may appear to be great, but there are several advantages that arise from needing to combine these seemingly disparate quality systems, and meaningful guidance is available.
FDA’s Quality System Regulations (QSRs) establish clear requirements for understanding a device’s key performance drivers early in its development lifecycle. Then, as the product progresses through clinical application, the design controls around these systems serve to identify key considerations in moving the product toward commercialization. The development of a medical device routinely integrates a product hazard analysis at the outset of the design phase, followed by a series of Failure Modes and Effects Analyses, as the design, automation, software and performance are refined. The Product Quality Assurance system demands a clear audit trail through the development process as the device history file is created. A design for manufacturing and reliability components is routinely performed prior to commercialization.
These components mirror the requirements advocated as a Quality by Design (QbD) approach within ICH Q8 and integrate the risk management component prescribed within ICH Q9 and Q10. Historically, the challenge faced by drug delivery companies has been finding a common lexicon that could speak to the requirements of both 21 CFR 820 and 210/211. The terms “specification error allocation analysis” and “gauge R&R analysis” were unheard of in the pharmaceutical development lifecycle. Today, this is changing. The gap between a device Validation and Verification exercise and a pharmaceutical Commissioning and Qualification exercise is narrowing. Risk management tools have become an expected component of any process scale-up and/or troubleshooting exercise. Further, integrating operational excellence approaches means asking the same questions during the development and scale-up phases of the drug lifecycle.
The trend to outsource formulation development — along with clinical trials management — to emerging markets will eventually level the playing field as companies gain an understanding of FDA’s and EMEA’s quality expectations. Our ability to navigate the transition between the current product development paradigm and QbD will dictate our capacity to respond to the imperatives of shorter time-to-market for development programs and lower cost therapies.
The drug delivery sector has always dared to integrate two quality and compliance philosophies that demand significantly different levels of rigor, and the shift to QbD has better aligned the two philosophies from the outset. This convergence brings with it the potential for more rapid and effective drug delivery programs, better aligned with the agencies’ expectations. More importantly for the industry as a whole, we have a proven framework that is ready to go, if we only choose to see it.