Trends In Combination Products

By Fran DeGrazio, Vice President, Scientific Affairs and Technical Services, West Pharmaceutical Services, Inc.

Many individuals use combinations of drugs and delivery systems to deal with a chronic condition or ease an acute condition. People with diabetes may use a human GLP-1 receptor antagonist (a Type 2 diabetes medicine enhancing the secretion of insulin) in a pen injector system to provide a subcutaneous injection, while someone with COPD may use a breath-activated powder inhaler to deliver the bronchodilator albuterol sulfate, which is designed to treat or prevent bronchospasm with medication to relax muscles in airways to prevent wheezing and shortness of breath. As demand grows for more patient-centric drug delivery via self-administration, combination products are on the rise.

Combination products combine drug or biologic products and medical devices to effectively deliver treatments to patients. Recently, the FDA provided greater guidance and focus in this space to encourage and enable the pharmaceutical industry to bring these products to market. Combination products are defined in the Code of Federal Regulations - 21 CFR 3.2(e).

The FDA website lists description and examples of nine types of combination products.  Examples of some of the most common are:

• Drug-eluting stent
• Infusion pump
• Prefilled syringe
• Prefilled syringe in an auto-injector
• Drug-eluting balloon
• Drug-powder inhaler (DPI)
• Metered-dose inhaler (MDI)

While many of these types of products have been available for years, recent FDA and ICH guidances have clarified expectations from both a developmental and commercialization standpoint. These clarifications have led to increased regulatory expectations, resulting in new and increased challenges for manufacturers. To ensure compliance with these regulations and overcome challenges, it is essential to remain familiar with the changing regulations, and to receive additional insights from various sources.

In the public domain, FDA warning letters provide visibility to the areas of focus and expectation from regulatory agencies. Identified areas of weakness include:

• the lack of the establishment (i.e., define, document, and implement) and maintenance of design validation procedures to ensure that devices conform to defined user needs and intended uses. These procedures should include testing of production units under actual, or simulated, use conditions.
• the failure to establish and maintain procedures for the identification, documentation, validation, or where appropriate, verification, review, and approval of design changes before their implementation.
• the failure to establish and maintain the requirements that must be met by suppliers, contractors, and consultants. A firm should evaluate and select potential suppliers, contractors, and consultants on the basis of their ability to meet specified requirements, including quality requirements, and document said evaluation.

Any company producing drug/device combination products should focus on the areas highlighted by the examples above. When we put these examples into everyday language, three major themes arise.

Defining User Requirements

The first theme is the ability to define adequate user requirements, and then prove that the design and user requirements are documented and met through appropriate design verification and design validation testing processes. The ability to understand each unique combination product application, and build toward that end generating the data that supports the decisions being made throughout the development cycle is key to ensuring that documentation of the packaged drug product requirements and the requirements of the delivery system in combination are provided. This must be done while keeping in mind that some of the highest risks occur at the intersection of the drug and its primary package with the delivery system itself.

Change Control Management

Change management is critical during the entire lifecycle. Change control and the ability to document and manage this successfully during the development process and following commercialization is key for any manufacturer. This is covered in the recent ICH Q12 draft guidance entitled Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, due to be finalized this summer, which provides clarity on the management of change by utilizing a deep understanding of product & process. Market surveillance is also needed to provide feedback and establish a continuous improvement mindset within the CP applicant’s facility and those of critical suppliers.

Selecting a Qualified Supplier

The third theme is prioritizing the choice and engagement of qualified suppliers who understand the unique challenges of building the components and constituent parts of a combination product. Quality agreements clarifying requirements and responsibilities should be in place.  It is critical to have improved transparency and collaboration, so the dynamics of the relationship must be different from that of many historic supplier relationships. The critical nature of component and constituent part suppliers to the overall success of a final combination product changes the nature of the relationship, and should be a major consideration in evaluating partners to successfully manage risks.

Combination products bring a great benefit to patients and the pharmaceutical industry in a variety of ways. Managing risks and meeting the regulatory requirements means that manufacturers must build evidence that conveys why choices are made throughout the development process. Captured throughout the supply chain, this evidence is critical to achieving a successful end goal.