We spoke with consultants Lynn Hansen and Bikash Chatterjee in the lead up to Pharmatech Associates’ tutorial at DIA 2018 Global Annual Meeting in Boston, MA, to discuss regulatory approval processes, manufacturing challenges, and the resurgence of the combination drug product in the 21st century.
How are combination products driving technology advancements in the pharmaceutical industry?
The resurgence of the biotech industry is one of the biggest catalysts for the resurgence of combination products. The maturation of prefilled syringe, auto-injector and nebulizer platforms has broadened the potential target patient population for many biologic drugs by eliminating the need to come into a physicians' office or clinic to administer the drug therapy via an IV (intravenous) device.
New and improved diagnostic and development tools, such as Next Generation Sequencing (NGS) and CRISPR/Cas9, give drug developers novel ways to ensure a drug target is the exact cause for the disease state, with great accuracy. The US Food and Drug Administration’s (FDA) establishment of the Office of Combination Products (OCP) has brought a clear regulatory pathway for medical device developers looking to integrate a new drug therapy or novel device delivery solution. Finally, the issuance of 21 CFR Part 4 in 2013 has also provided a framework for medical device developers and drug developers to navigate the integration of the Quality Management Systems requirements (21 CFR 211, 600 and 820).
A simple example of this phenomenon would be the development and evolution of inhalation devices. Prior to the creation of the first metered-dose pressurized inhaler in the 1950s, squeeze bulb nebulizers were used to deliver asthma medication. However, the particles generated by the nebulizers were too large for effective delivery of the drug to the lungs. As a result, the drug was not considered as valuable as a treatment option vs. other drug modalities.
Inhaler and nebulizer technology today has evolved to a point where they can deliver drugs small enough to provide a systemic response, passing directly into the bloodstream and opening up the lung as a viable route of delivery for a much broader suite of drug therapies.
How do small molecule-based combination drug products compare to large molecule-based combination products?
The challenges with developing a biological drug vs. a small molecule drug can be significant. Large molecule drugs are typically biologic proteins and are large and complex, often consisting of heterogeneous mixtures. They are generally made in genetically engineered cells that impose their own variabilities. Small molecule drugs tend to be the product of design, for synthetic pathways with controllable and measurable process characteristics. The complexity of biologic drugs increases the risk of a combination product development program because of the potential avenues for interaction between the device, the drug, and the user.
For example, both small and large molecules have significant added characterization work if the primary container is a device such as a prefilled syringe. If we are to look at the risk associated with Extractables and Leachables testing versus a glass vial: In a glass vial the only source for extractables is a rubber stopper. In a prefilled syringe, you have the plunger, plunger stopper, syringe barrel (if plastic), needle adhesive, needle shield. All of these have the potential to extract compounds, which can impact a large molecule and potentially impact the product’s efficacy and safety.
While the same can be said for small molecule, the potential for a large molecule having chemically active sites is much higher. Now extend this to a needle shield, finger flange, unit dose labeling and final combination product kit packaging and the risk and complexity introduced by a large molecule combination product can be orders of magnitude greater than a corresponding small molecule combination product.
Is industry showing a preference for small or large molecule-based combination products? Why?
The drivers for combination product development are more complicated than industry preference. Large molecule and new cellular and gene therapy product do command a much higher patient price which could incentivize a drug company to embrace the added risk and complexity of a large molecule combination product program.
Another consideration is the emergence of new regulatory pathways that promise swifter review cycles and approvals for breakthrough and orphan drug status programs. One of the most significant developments to impact the overall US drug industry has been the approval of the 21st Century Cures Act which has spawned a whole new movement to bring medical device, drug, and combination products to the market more quickly and at lower cost. These factors are more likely to influence the program pathway pursued.
What do drugmakers need to know before submitting their first combination product for regulatory approval?
The first step for a pharmaceutical manufacturer will be ascertaining whether their product is in fact a combination product. This is performed by filing a Request for Designation (RFD) with the FDA, who will provide a formal response within 60 days. The FDA’s eCTD Technical Conformance Guidance provides a detailed discussion of how to handle the device and drug components of a combination product filing.
Understanding how you will adopt 21CFR Part 4 is essential to make sure you will satisfy the requirements of both quality systems from the beginning, especially the Design Control component and Human Factors Study which is so foreign to most drug developers. Being aware of all the unique additional elements that become part of a combination drug development program is important. Differences such as including the final kit elements as the final drug product – and not just the filled primary container – can avoid adding unnecessary risk to the CCMC component of the filing. It is always shocking to realize your two-year stability study is not valid because it is not in the final tray with the proposed final label.
Making the decision to do a combination product from the outset is essential, and if done properly you will avoid having to repeat major elements of the development program.
What are the main hurdles drugmakers face when first developing or manufacturing a combination drug product?
There are few substantial hurdles for drug manufacturers in developing, marketing, and manufacturing combination drug products. First and foremost, a product will need to be classified as a combination product. Second, manufacturers will need to cope with new and different regulatory pathways.
We have cited that the 21st Century Cures Act passed in 2016 created new initiatives specifically addressing combination products. Having a clear plan for how you will apply 21 CFR Part 4 is essential to not complicating your development and quality programs. It’s important to ask how will you measure quality in the device, drug, and at the system level? How will you release and track each element? Will they be matched and released as a system or will each piece be pre-released and matched separately? Have you done the Error Allocation analysis of the design and release specifications for each element to ensure that when your system comes together you can consistently meet the system CQAs? How will you manage your supply chain when upstream and intermediate contract manufacturers impact your ability to manufacture the final product?
There is tremendous business upside in the decision to develop a combination product, but the complexity associated with pursuing such a strategy must begin at the early development stage if an organization is to avoid costly delays or repeat major development steps.